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Archive for the ‘Hypopituitarism’ Category

Correction of In-Patient Severe Hypernatremia in an 81-Year-Old Female With Hypopituitarism – Cureus

Correction of In-Patient Severe Hypernatremia in an 81-Year-Old Female With Hypopituitarism  Cureus

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Correction of In-Patient Severe Hypernatremia in an 81-Year-Old Female With Hypopituitarism - Cureus

Hypopituitarism: Symptoms, causes, and treatment – Medical News Today

Hypopituitarism: Symptoms, causes, and treatment  Medical News Today

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Hypopituitarism: Symptoms, causes, and treatment - Medical News Today

Hypopituitarism – Hormonal and Metabolic Disorders – Merck Manuals …

Blood tests to measure hormone levels

An evaluation usually begins by measuring blood levels of the hormones that the pituitary gland produces (typically, thyroid-stimulating hormone, prolactin, luteinizing hormone, and follicle-stimulating hormone) and at the same time measuring levels of the hormone produced by the target organs (typically, thyroid hormone, testosterone in men, and estrogen in women).

For example, a person with hypothyroidism due to failure of the pituitary gland has low levels of thyroid hormone and low or inappropriately normal levels of thyroid-stimulating hormone, which is produced by the pituitary gland. In contrast, a person with hypothyroidism due to failure of the thyroid gland itself has low levels of thyroid hormone and high levels of thyroid-stimulating hormone.

Growth hormone production by the pituitary is difficult to evaluate because no single blood level accurately reflects it. The body usually produces growth hormone in several bursts a night, and the hormone is quickly used. Thus, the blood level at any given moment does not indicate whether production is normal over the course of a day. Instead, doctors measure the levels of insulin-like growth factor 1 (IGF-1) in the blood. Production of IGF-1 is controlled by growth hormone, and the level of IGF-1 tends to change slowly in proportion to the overall amount of growth hormone produced by the pituitary. In infants and young children, doctors may instead measure levels of a similar substance, IGF-binding protein type 3. Measurement of IGF-1 is not sufficient to make the diagnosis of growth hormone deficiency in adults, because people with normal levels may still have growth hormone deficiency. In many cases, a stimulation test to try to make the pituitary secrete growth hormone is used.

Because the levels of luteinizing hormone and follicle-stimulating hormone fluctuate with the menstrual cycle, their measurement in women may be difficult to interpret. However, in postmenopausal women who are not taking estrogen, luteinizing hormone and follicle-stimulating hormone levels normally are high. When they are found to be low, this can be an indication of pituitary damage or insufficiency of other hormones.

Production of ACTH is usually assessed by measuring the levels of its target hormone (cortisol) in response to stimuli, such as an injection of synthetic ACTH (ACTH stimulation test) or a low level of sugar in the blood after an insulin injection (insulin tolerance test). If the level of cortisol does not change and the level of ACTH in the blood is normal or low, a deficiency of ACTH production is confirmed.

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Hypopituitarism - Hormonal and Metabolic Disorders - Merck Manuals ...

Diagnosis and Treatment of Hypopituitarism – PMC – National Center for …

Abstract

Hypopituitarism is a chronic endocrine illness that caused by varied etiologies. Clinical manifestations of hypopituitarism are variable, often insidious in onset and dependent on the degree and severity of hormone deficiency. However, it is associated with increased mortality and morbidity. Therefore, early diagnosis and prompt treatment is necessary. Hypopituitarism can be easily diagnosed by measuring basal pituitary and target hormone levels except growth hormone (GH) and adrenocorticotropic hormone (ACTH) deficiency. Dynamic stimulation tests are indicated in equivocal basal hormone levels and GH/ACTH deficiency. Knowledge of the use and limitations of these stimulation tests is mandatory for proper interpretation. It is necessary for physicians to inform their patients that they may require lifetime treatment. Hormone replacement therapy should be individualized according to the specific needs of each patient, taking into account possible interactions. Long-term endocrinological follow-up of hypopituitary patients is important to monitor hormonal replacement regimes and avoid under- or overtreatment.

Keywords: Hypopituitarism, Adrenocorticotropic hormone deficiency, Thyrotropin deficiency, Gonadotropin deficiency, Growth hormone deficiency, Anti-diuretic hormone deficiency

Hypopituitarism is defined as the total or partial loss of anterior and posterior pituitary gland function that is caused by pituitary or hypothalamic disorders [1]. The incidence rate (12 to 42 new patients per million per year) and the prevalence rate (300 to 455 patients per million) seems to underestimate the actual incidence of this disorder given that as many as 30% to 70% of patients with brain injury exhibit symptoms of diminished hormone secretion from their pituitary gland [2]. Additionally, factors such as the cause of hypopituitarism, age of onset, and the speed and degree of loss of hormone secretion may affect the clinical manifestations of hypopituitarism. For example, although a partial hormone deficiency that progresses slowly may go undetected for years, the sudden and complete loss of hormone secretion results in an emergency situation that requires immediate medical attention [2]. The treatment of hypopituitarism typically involves a replacement of the deficient hormone but care must be taken because several studies have reported an increased incidence of cardiovascular disorders and number of deaths among these patients [3]. Additionally, a significant proportion of patients who have been treated for a hormone deficiency suffer from more or less vague discomforts and a reduced quality of life [4]. The present review will describe the general aspects of hypopituitarism focusing on the limitations of the stimulation test and hormone replacement treatment.

A variety of diseases may cause hypopituitarism and, accordingly, this disorder can be divided into two types depending on its cause [1]. Primary hypopituitarism is caused by disorders of the pituitary gland itself and may be due to the loss, damage, or dysfunction of pituitary hormone-secreting cells. On the other hand, secondary hypopituitarism is the result of diseases of the hypothalamus or pituitary stalk interrupting the nerve or vascular connections to the pituitary gland, thereby reducing the secretion of the pituitary hormones (). Reductions in hormone secretion in the posterior pituitary gland may largely be due to failures in hormone synthesis or secretion from the hypothalamus while decreased hormone secretion in the anterior pituitary gland may be due to deficiencies in the activity of one or more of the neurohormones secreted from the hypothalamus [1].

Causes of Hypopituitarism

The most common causes of primary hypopituitarism are pituitary adenoma and complications from surgery or radiation therapy for the treatment of pituitary adenoma [5]. In these situations, the diameter of the pituitary adenoma is 1 cm or larger and, the onset of hypopituitarism is usually slow unless the patient suffers from a pituitary apoplexy whose symptoms occur within several hours or a few days [5]. Several putative mechanisms of hormone deficiency include the application of direct pressure onto or damage to the normal tissues surrounding the tumor, mechanical compression of the portal veins by the pituitary stalk, raised intrasellar pressure, and focal necrosis due to the prolonged portal vein interruption [5]. Furthermore, inflammatory hypophysitis (including various types of autoimmune hypophysitis), which has an unknown etiology and presents with symptoms that are difficult to differentiate from those associated with a tumor, is another possible cause of hypopituitarism [5]. Although this cause is rare, it is known to exhibit clinical features such as the isolated or combined lack of adrenocorticotropic hormone (ACTH), thyroid stimulating hormone (TSH), gonadotropin, and/or growth hormone (GH) [5].

Radiation exposure for the treatment of malignant conditions in the head and neck area may also cause hypopituitarism [6]. Additionally, a variety of hormone deficiencies may occur when treating a pituitary tumor with radiotherapy and the onset of these conditions depends on the total amount of radiation, whether fractioning was done, and the time elapsed after radiation [5]. The frequency of the manifestation of a hormone deficiency is greater than 50% at 10 years after the radiation exposure. Most patients, like patients with pituitary adenomas, present with a typical course starting with GH deficiency, gonadotropin deficiency, ACTH deficiency, progressing to TSH deficiency (or TSH deficiency followed by ACTH deficiency) [7]. Additionally, although further study is warranted, it is generally accepted that the incidence of hypopituitarism is lower following gamma knife radiosurgery than after conventional radiotherapy techniques [5].

The occurrence of hypopituitarism following surgery to remove a pituitary tumor varies from 10% to 25% and may have to do with the size of the tumor, the degree of invasion, the quantity of remaining normal tissues, and the degree of technical competency of the neurosurgeon [5]. In rare cases, hypopituitarism has been observed when a cytomegalovirus infection occurs in patients with the AIDS virus [8]. Sheehan's syndrome, which is hypopituitarism caused by the postpartum hemorrhage of the pituitary gland, frequently occurred in the past but it is rarely seen today [5]. Tuberculosis meningitis and hemorrhagic fever with renal syndrome, which were occasionally observed in the past but are virtually nonexistent today [1]. In still rarer cases, solitary or complicated pituitary hormone deficiency syndromes may occur due to genetic causes and typically affect children () [5].

Genetic Causes of Hypopituitarism

Damage to the pituitary stalk often occurs after the head and/or neck injury accompanying a fracture of the bones surrounding the sella turcica [5]. Additionally, tumors near the sella turcica may press against the stalk and damage it. The stalk is often accidentally severed during surgery on a sellar or parasellar mass [1]. Central nervous system disorders involving the hypothalamus, such as craniopharyngioma and germ cell tumor, may also cause hypopituitarism by impeding the secretion of releasing hormone from hypothalamus [1]. Depending on the anatomical location of the lesion, patients may manifest symptoms consistent with a single hormone deficiency, panhypopituitarism, or a posterior pituitary failure (diabetes insipidus) [1]. Recently, the prevalence of idiopathic hypopituitarism has increased but it is thought that these cases are likely due to a severed stalk resulting from traumatic brain injury (TBI) or hypothalamic damage [1]. Similarly, the incidence of hypopituitarism after a TBI seems to be more frequent than previously thought as the prevalence rate ranges from 30% to 70% based on the patients' charateristics and the types of diagnostic tests [2]. The most common problem associated with hypopituitarism is a GH deficiency. Following TBI, the early diagnosis of a hormone deficiency has an important impact on their degree of recovery from TBI [2]. Additionally, it has been demonstrated that hormone replacement therapy improves rehabilitation outcome and the quality of life of a patient [9]. Whereas approximately half of the patients who exhibit hypopituitarism within 6 months of a TBI recover normal pituitary function within 1 year, some patients with normal hormone levels after a TBI develop new hormone deficiency after 12 months [2]. Early posttraumatic panhypopituitarism generally persists [2]. Thus, it is recommended to re-evaluate anterior pituitary function and quality of life after approximately 6 to 12 months of an injury [2]. However, it is controversial regarding the most appropriate early evaluation time after this type of injury.

It is also important to closely monitor patients after a subarachnoid hemorrhage because the symptoms of a pituitary hormone deficiency may become evident [2]. Generally, the loss of pituitary function due to secondary hypopituitarism (dysfunction in the hypothalamus or pituitary stalk) is less serious than primary hypopituitarism but diabetes insipidus is more frequent in secondary hypopituitarism [1].

Health problems such as metabolism disorders, systemic diseases, and stress can all be related to selective pituitary hormone deficiencies. The influence of stress seems to manifest via inflammatory cytokines such as interleukin 1 (IL-1) and IL-6, which have severely suppressive effects on thyroid releasing hormone (TRH) and gonadotropin releasing hormone (GnRH) levels while at the same time stimulating the secretion of corticotropin releasing hormone (CRH). This is one possible explanation for euthyroid sick syndrome or hypothalamic amenorrhea because when the original stress is eliminated, these suppressive effects are also ameliorated. In contrast, inflammatory or invasive diseases that destroy the hypothalamus may explain the infrequent recovery of neuroendocrine function in patients suffering from these disorders even after the underlying disease is treated [1].

In rare cases, genetic conditions such as Kallmann syndrome or neurohypophyseal diabetes insipidus may contribute to reduced pituitary function. Kallmann syndrome manifests from a wide array of genetic mutations, including the KAL1 gene [10]. In these patients, there is a loss of GnRH neurons in the hypothalamus which leads to GnRH deficiencies and hypogonadotropic hypogonadism (the lack of secondary sex characteristics) in conjunction with olfactory loss (anosmia or hyposmia) that is due to olfactory bulb loss or hypoplasia [10]. There is also a condition known as neurohypophyseal (familial) diabetes insipidus that is triggered by mutations of the neurophysin II part of the vasopressin-neurophysin precursor genes [11]. Due to these mutations, the precursor genes do not divide into vasopressin and neurophysin II which, in turn, causes an excessive accumulation of the precursor substance within the cells that leads to the eventual death of the hypothalamic neurons (apoptosis) in which these genes are expressed. Depending on the genetic disorders or degree of the mutation, the symptoms manifest immediately after the birth or during childhood [11].

The underlying pathology, speed of onset and the severity of hypopituitarism have a significant impact on the clinical features [5]. In particular, if hypopituitarism is caused by a space-occupying lesion (tumor), then mass effects such as headache, visual impairment, and rarely, personality changes and hypothalamic syndrome may appear [5]. The clinical expression of severe panhypopituitarism, which typically occurs immediately after hypopituitary patients discontinue hormone replacement or following the pituitary apoplexy or hypophysectomy, may be evident within several hours (diabetes insipidus) or a few days (adrenal insufficiency) [4]. However, most patients exhibit a slow and progressive loss of pituitary function with a relatively mild and vague or nonspecific clinical symptoms. In fact, in many cases, these patients are not diagnosed with hypopituitarism for a prolonged time [3].

GH-secreting cells (somatotrophs) are particularly vulnerable to pressure, which is why GH deficiency occurs first and most frequently among all pituitary hormones, followed by deficiencies of gonadotropin (luteinizing hormone [LH] and follicle stimulating hormone [FSH]), TSH and ACTH (or ACTH and TSH), and prolactin [12]. The most common hormones that show selective deficiencies are GH and gonadotropins. Children tend to suffer from GH deficiency while adults often complain of symptoms from gonadotropin deficiency [3]. The clinical symptoms stemming from a lack of ACTH, TSH, and/or gonadotropins vary somewhat but are similar to those associated with target gland hormone deficiency; the major symptoms are listed in [4].

Clinical Symptoms and Signs of Hypopituitarism

If ACTH deficiency is partial, then the patient may experience a relatively normal and event-free life, but patients with severe ACTH deficiency suffer from a variety of vague and nonspecific complaints [13]. ACTH deficiency (secondary adrenal insufficiency) is different from a primary adrenal insufficiency (Addison's disease) in that the true onset of an Addisonian crisis (adrenal crisis) is very rare because aldosterone secretion is partially independent of the pituitary gland [13]. Although it is possible that aldosterone secretion may be diminished in the case of hypopituitarism due to ACTH deficiency, the residual secretion of aldosterone, which is controlled by the renin/angiotensin system, is sufficient for the maintenance of normal plasma volume and blood pressure except acute stress [13]. No hyperpigmentation has been observed in other cases of ACTH deficiencies [13]. Because ACTH stimulates the secretion of adrenal androgen, the lack of adrenal androgen due to ACTH deficiency may contribute to the loss of sexual desire in females and it may become the primary cause for the loss of pubic and axillary hair [13]. In contrast, the loss of adrenal androgen is not as important for males due to the abundant testosterone that is secreted from the testicles [13].

TSH deficiency produces symptoms that are similar to those associated with primary hypothyroidism except that its clinical symptoms are not as severe [14]. Although the underlying mechanism has yet to be ascertained, the cases of family with isolated TSH deficiency have been reported [15].

In both males and females, complete FSH/LH deficiency is tantamount to the loss of the target organs function (gonads) but the clinical expression varies depending on whether it occurs prior to or after puberty [6]. Partial FSH/LH deficiency due to hypothalamic lesions may often be associated with the loss of sexual desire, oligomenorrhea, and anovulation, In most cases, both LH and FSH are diminished at the same time, but cases in which just one of these hormones is deficient have been reported [6].

GH deficiency results in growth disorders; the degree of decreased GH secretion and the extent of the growth delay may be severe when they are associated with organic illnesses of the pituitary gland [16]. On the other hand, when there is no organic illness (idiopathic GH deficiency), the deficiency in GH secretion and the accompanying growth delay vary widely such that the height of the affected children may be the same as shorter unaffected children of the same age [16]. In the case of idiopathic severe GH deficiency, they presented fasting hypoglycemia, and it is of the utmost importance to perform a detailed assessment of the family history and to conduct complementary hormone measurements. On the other hand, a GH deficiency in adults is difficult to clinically diagnose because it is usually nonspecific. The typical symptoms include fatigue, general weakness, reduced vitality and physical strength, and diminished mental agility. Additionally, moderate obesity with evident visceral deposition may occur and hyperlipidemia, reduced levels of high density lipoprotein cholesterol, osteopenia, and reduced myocardial contractility are typically observed [16]. The increase in cardiovascular risks may be related to an increased frequency of metabolic syndrome and a higher incidence of death among these patients [16].

Prolactin deficiency cause only one clinical symptom, which is the inability to produce milk after childbirth [6]. A lack of prolactin is more closely associated with difficulty synthesizing milk than with producing milk and is not clinically important in countries where artificial lactation is readily available [6]. However, because prolactin is regulated by dopamine, which acts as a neuroendocrine inhibitor in the hypothalamus, hyperprolactinemia accompanied by other pituitary hormone deficiencies is more frequent and problematic and may result in hypogonadism [6].

Of the two posterior pituitary hormones, oxytocin and vasopressin (anti-diuretic hormone [ADH] or arginine vasopressin [ADH]), only vasopressin deficiency leads to the clinical presentation. The major symptoms include polydipsia, polyuria, and nocturia. The onset of the disorder may be acute or chronic depending on the underlying diseases [6]. Because patients with partial diabetes insipidus may not show severe symptoms, this disorder may not be immediately diagnosed. Moreover, the symptoms associated with diabetes insipidus may improve when accompanied by an anterior pituitary hormone deficiency, in particular ACTH deficiency or severe TSH deficiency. This may be because there is an enhanced secretion of ADH due to a cortisol deficiency or because ADH functionality of the renal tubule is strengthened [6]. Accordingly, the symptoms of diabetes insipidus reappear after cortisol or thyroxine replacement.

The diagnosis of hypopituitarism is made by measuring basal hormone levels in the morning fasting status or performing stimulation tests if necessary. Six anterior pituitary hormones (GH, prolactin, LH, FSH, TSH, and ACTH) as well as target hormones can be measured via sensitive and reliable immunoassay techniques. Other pituitary hormones except GH and ACTH deficiency can be diagnosed with basal hormone measurement. Hence, combined pituitary function tests (i.e., the cocktail test) is rarely used [17].

Measurement of basal hormone levels is sufficient for the differentiation of hypopituitarism from primary target organ hormone deficiency. For example, the lack of an increase in pituitary hormone levels in conjunction with reduced target organ hormone levels is typically observed in case of a hypothalamic or pituitary gland disease [4]. Conversely there is an increase in pituitary hormone levels when there is target organ hormone deficiency. Thus, the differentiation of a target organ deficiency from a hypothalamic or pituitary gland disease is relatively simple but a stimulation test may also be necessary to determine the origin of the disease, albeit rarely. The expected values and responses of the pituitary gland and target organ hormones under basal and stimulated states are provided in . In several cases, it is necessary to distinguish between a pituitary disease (primary hypopituitarism) and a hypothalamic disease (secondary hypopituitarism), but this is not easily accomplished. In these situations, it is helpful to diagnose hypothalamic diseases based on the expression of clinical manifestations, such as diabetes insipidus or hypopituitarism accompanying hyperprolactinemia, neuro-ophthalmological symptom, such as visual impairments, neuropsychiatric symptoms [5]. For purposes of differentiation, a stimulation test using hypothalamus releasing hormones can be performed. However, sellar magnetic resonance imaging (MRI) can distinguish pituitary diseases from hypothalamic diseases, and treatment is not different. Thus, differentiation pituitary diseases from hypothalamic diseases may not be necessary.

Diagnostic Evaluation of Hypopituitarism

Pituitary ACTH deficiency is difficult to diagnose using basal ACTH or cortisol measurements. Because cortisol levels are normally at their peak in the morning due to diurnal rhythm, it is advisable to measure these concentrations at approximately 8:00 AM to 9:00 AM [4]. If the cortisol level is very low (<3 to 4 g/dL) or very high (>15 to 16 g/dL) then a stimulation test is not needed. Because this value is not absolute, a stimulation test is only necessary when a definite diagnosis is required and, in this case, ACTH deficiency can be diagnosed by measuring ACTH and/or cortisol levels via the administration of metyrapone, ACTH, or CRH, or with an insulin-induced hypoglycemia test (insulin tolerance test) [4]. The insulin tolerance test has long been considered to be the gold standard test for this diagnosis but it may cause severe hypoglycemia [4]. However, it can be safely administered under the close supervision of a physician to effectively determine the level of GH secretion as well as the presence of an ACTH deficiency. In a clinical context, the rapid ACTH stimulation test, which measures cortisol levels after the administration of ACTH, is preferred if the risk of hypoglycemia is evident in a patient (normal level, >18 to 20 g/dL) [4]. An insulin tolerance test is conducted when it is necessary to determine GH levels.

It is widely accepted that maximum serum cortisol levels can be observed after the administration of doses of ACTH much lower than the usual dose of 250 g that is given in the rapid ACTH test [18]. This implies that the sensitivity of the test can be improved by reducing the amount of ACTH that is administered. Indeed, several studies have reported that the low-dose 1 g ACTH stimulation test is more sensitive than the usual 250 g ACTH dose that is generally used in the rapid ACTH test for diagnosing adrenal gland hypofunction (central or secondary adrenal insufficiency) due to ACTH deficiency [18]. However, the low-dose ACTH stimulation test has not yet replaced the standard 250 g stimulation test in clinical contexts because other studies have reported that the low-dose diagnostic test is not as precise as the conventional high-dose test and that there are technical problems associated with diluting a 250 g solution into a 1 g solution [19]. A recent study conducted by the present author indicated that the low-dose 1 g ACTH stimulation test is not superior to the standard high-dose 250 g test [20]; as a result, this author continues to utilize the conventional high-dose ACTH stimulation test. Furthermore, the findings of this study demonstrated that the normal range of the cortisol response during the ACTH stimulation test exceeded 18 g/dL for patients with hypopituitarism and 20 g/dL for all others. This is likely because other pituitary hormone deficiencies typically accompany ACTH deficiencies, which would make the cortisol response of these patients lower than that of healthy individuals [20].

It is possible to diagnose a TSH deficiency using only a thyroid function test. Despite the presence of reduced free thyroid hormones, TSH concentrations that are at or below the normal range (with often a slight increase in its concentration) imply that there is a problem in the pituitary gland or the hypothalamus [4]. TSH deficiency can be easily distinguished from primary hypothyroidism in cases where the TSH level increases inordinately [5]. Although the TRH stimulation test is not administered clinically [21], it is possible to easily distinguish pituitary lesions from hypothalamic lesions because hypothalamic diseases result in an increased but delayed TSH response [21].

In many cases, it is possible to diagnose gonadotropin deficiency using a basal hormone test and an evaluation of clinical symptoms. This is particularly true for postmenopausal females because it is always possible to diagnose this population based on the lack of an increase in gonadotropin concentrations [2,4]. For males, this diagnosis can be made based on normal or reduced serum LH and FSH concentrations despite reduced serum testosterone levels [4]. For females, it is possible to make this diagnose based on reduced levels of estradiol and normal or reduced levels of LH and FSH in conjunction with oligomenorrhea or amenorrhea. Moreover, it is also necessary to distinguish gonadotropin deficiencies that are due to hyperprolactinemia, which frequently occurs in male and female hypopituitary patients [4], and to determine whether reduced serum testosterone levels in males are due to decreased levels of sex-hormone binding globulin. In a clinical context, the GnRH stimulation test is often performed to diagnose gonadotropin deficiency and may be helpful for identifying problems in the pituitary gland and hypothalamus [10]. However, it takes several days of stimulation for the gonadotrophs that were not stimulated by GnRH due to a hypothalamic disease to detect the gonadotropin secretion response. This makes it difficult to determine the primary cause of a gonadotropin deficiency with only a single GnRH injection.

When diagnosing GH deficiency in adult patients, the basal GH concentration is not considered to be valuable but measures of insulin-like growth factor 1 (IGF-1) may be of some use, although they are not sufficient themselves [4]. Thus, a stimulation test is necessary for a definitive diagnosis. Additionally, the use of previous test results and other data is warranted, including past medical records detailing GH deficiencies, organic pituitary gland diseases, and other pituitary hormone deficiencies during childhood (during which it is sufficient to use a single stimulation test) [4,5]. Although controversy remains regarding which GH stimulation test is the most appropriate for the purpose, the most widely used and reliable measure is the insulin tolerance test in which GH levels lower than 3 g/L are considered to indicate a severe deficiency, GH levels between 3.0 and 4.9 g/L indicate a partial deficiency, and GH levels higher than 5.0 g/L are considered normal [4]. For patients in whom hypoglycemia is contraindicated, it is possible to administer a variety of stimulation tests and, in this case, the diagnostic criteria of GH deficiency according to the type of stimulation tests and standard GH assay [4].

The diagnosis of posterior pituitary hormone deficiency can be easily made through a review of clinical symptoms/signs and a water deprivation test [5]. Additionally, the recently available plasma ADH concentration measurement technique can distinguish central diabetes insipidus from nephrogenic diabetes insipidus although it cannot differentiate central diabetes insipidus from compulsive water drinking or psychogenic polydipsia [5]. Given the limited availability of reliable laboratories that are capable of testing blood ADH levels and the longer time that it takes to perform and analyze these levels compared to the performance of the water deprivation test, the blood ADH test is conducted only when absolutely necessary [5].

It is advisable to re-evaluate pituitary gland functionality 2 to 3 months after an operation because, although most hypopituitarism symptoms are irreversible, a patient may recover some of level of function [4]. When a pituitary hormone deficiency occurs following a TBI, it is also necessary to re-evaluate function after some time has elapsed. In addition, of the patients with prolactinoma that are treated with a dopamine agonist, two-thirds recover pituitary gland function [22], which indicates that sporadic re-evaluations of pituitary gland function can prevent unnecessary replacement therapy. Similarly, children who exhibit an idiopathic single GH deficiency or severe GH deficiencies due to radiotherapy require re-evaluation of their GH function when they reach maturity [4].

The pre- and postoperative incidence rates of hypopituitarism are similar because some hormone function can be recovered following the removal of a pituitary tumor [5] whereas deficiencies in other pituitary hormones may develop after surgery. Except in cases such as transient diabetes insipidus after surgery or hypopituitarism after TBI, most hypopituitarism symptoms are irreversible [4]. This is why it is necessary for physicians to inform their patients that they may require lifetime treatment unless there are special circumstances, such as the discontinuation of estrogen replacement after menopause [3]. Accordingly, the primary goals of treatment should be centered around the recuperation of the physiological health of the patient in terms of growth, reproduction, metabolism, and body composition [2,4,5].

Although replacement with hypothalamic or pituitary hormones are physiologic (at least theoretically), we administrate target organ hormone due to the high cost and inconvenience of repeated injections. Exception is GH or ADH replacement and the recovery of reproductive abilities [3]. In clinical situations, prolactin and oxytocin deficiency are generally not treated [4]. Although the basic principles underlying the replacement of deficient hormones remain very clear and simple, it is not possible to replace hormones to physiological levels using current treatment technologies and there are limitations to monitor the treatment response [3,4]. There is no doubt that hypopituitarism is associated with an increased incidence of cardiovascular death but the mechanisms linking these disorders remain unclear [3]. However, possible contributing factors include GH deficiencies that are left untreated, replacement of other target hormones in non-physiological ways, and the specific underlying disease. For example, if hypopituitarism develops in a patient with acromegaly, Cushing's disease, or craniopharyngioma then the underlying disease may increase the mortality [3]. Similarly, the method of tumor treatment will matter because surgery, pharmacotherapy, or i.e., radiotherapy may increase the incidence of death [3]. Given that there is a variety of causes underlying hypopituitarism as well as varying degrees of hormone deficiencies and types of deficient hormones, it is important to individualize hormone replacement therapy to the specific needs of a particular patient.

ACTH deficiency can be treated with either hydrocortisone or prednisolone, which is a synthetic corticosteroid drug [3]. In patients with hypopituitarism whose aldosterone levels are approximately normal, there is no need to replace mineralocorticoids [3]. However, in most cases of hypopituitarism, ACTH deficiency is only partial which makes it difficult to determine whether the patient needs lifetime therapy or treatment only under conditions of stress [3]. If blood cortisol levels exceed 10 g/dL during a stimulation test in conjunction with the absence of specific deficiency symptoms, then there is likely to be a partial deficiency and, thus, it would be advisable for the physician to either monitor the patient but not administer medicine or to observe the progress of the patient after administration of 10 mg of hydrocortisone or 2.5 mg of prednisolone [3]. If there is little difference in clinical response before and after the administration, the treatment can be discontinued. If clinical improvement is seen in patients after the administration, it must be decided whether the treatment can proceed using the same dose or if it should be slightly increased to 12.5 to 15.0 mg of hydrocortisone or to 3.75 mg of prednisolone. The choice of hydrocortisone or prednisolone is at the physician's preference but the use of hydrocortisone, which is more physiologic glucocorticoid, is recommended because prednisolone has been associated with more side effects following long-term use despite the longer and stronger efficacy [3].

The dose of the drug may be steadily increased but it is advisable that administration of hydrocortisone be performed only once or twice a day with daily dose of 10 to 15 mg. Although the most commonly used treatment regimens include two times per day, some doctors advocate the use of three administration. It may also be possible to treat patients with a partial deficiency using 5 to 10 mg of hydrocortisone once a day [3]. When using prednisolone, it is desirable to take 2.5 to 3.75 mg once a day on an empty stomach [3]; the present author prefers to use once a day prednisolone with administration of 2.5 and 3.75 mg on alternate days. In terms of the appropriate dosage, there are no biochemical markers to aid in the determination of proper glucocorticoid levels and, as a result, it is recommended that the minimum dose needed to improve patients' symptoms [3]. When using hydrocortisone, the measurement of cortisol concentrations in the blood or urine does not aid in determining proper dosage. The recommended doses for hydrocortisone (20 mg a day) and prednisolone (5 mg) are clearly excessive for the average Korean patient. Although there is a new slow-acting formulation of hydrocortisone and a special hydrocortisone drug has been designed to take into account the diurnal differences that parallel normal cortisol secretion [3]. It is too early to tell if these drugs are appropriate for clinical purposes.

Under stressful conditions, a patient must be treated with the same methods as those used to treat patients with primary adrenal insufficiency; i.e., increase the dose by 2- to 3-fold for mild stress and administer an intravenous (IV) injection of hydrocortisone (150 to 200 mg) a day for severe stress. Moreover, it is necessary to increase glucocorticoid doses by 1.5- to 2-fold when used in tandem with liver enzyme inducers such as phenytoin, barbiturate, rifampin, and carbamazepine, and to reduce the glucocorticoid dose when liver enzyme inhibitors such as ketoconazole, itoconazole, cyclosporine, and tacrolimus are being used [3]. If the liver or renal function of a patient is not at an ideal level, the dose should not be adjusted [3].

For pregnant women, it is advisable to prescribe hydrocortisone rather than prednisolone because the latter can pass through the placental barrier [4]. During the first trimester of pregnancy, there is no need to increase the dose of glucocorticoid but an increase of approximately 50% (2.5 to 10.0 mg) is needed during the third trimester due to increased levels of corticosteroid binding globulin [4]. At the time of delivery, a large amount of hydrocortisone needs to be injected intravenously [4]. In contrast to pregnant females, females that are receiving estrogen therapy do not require an adjustment in glucocorticoid doses [4]. Although several studies have indicated that replacement with dehydroepiandrosterone (DHEA), which is the adrenal androgen that is typically deficient in women, improves sexual desire [23], it is not yet recognized as a standard replacement treatment. In these situations, the patient must be trained regarding the onset of acute adrenal insufficiency (adrenal crisis), which requires an increase in dose, and must always carry a hydrocortisone injection as well as a card indicating his/her status as an adrenal insufficient patient. Additionally, the patient should learn how to self-inject hydrocortisone.

TSH deficiency is treated with L-thyroxine (T4) [4]. Because the biological activities of currently available drugs are quite similar to T4, there is no need to change doses when shifting from one drug to another [4]. It is advisable to initiate drug treatment with 25 to 50 g per day and then steadily increase the dose to 75 to 125 g per day (0.6 g/kgbody weight/day) and to administer the drug on an empty stomach [4]. Since the TSH concentration has dropped below normal levels, it is more appropriate to evaluate the treatment response using clinical symptoms and measures of plasma free T4 concentrations [3,4]. These levels should be measured prior to administration and then maintained within the mid-range of normal concentrations.

Triiodothyronine should not be used to treat hypopituitarism except under special circumstances. In patients with clear indications of adrenal insufficiency, glucocorticoids should be administered prior to or in conjunction with T4 to prevent adrenal crisis [3]. When used in combination with liver enzyme inducers such as phenytoin, barbiturate, rifampin, and carbamazepine, the dose of T4 should be increased by 30% to 50%, especially when treating females in early pregnancy and patients receiving estrogen [3,4]. On the other hand, the T4 dose should be reduced by approximately 20% when it is given to patients receiving testosterone or to those who are elderly [3,4]. Additionally, although there is no need to adjust the dose when a patient exhibits reduced liver or renal function, it must be increased in the case of nephrotic syndrome [3,4].

For patients with hypogonadotropic hypogonadism, it is important to consider both gonad steroid replacement treatment and fertility. Androgen replacement for men can be accomplished using testosterone; for example, the treatment preferred by the present author includes intramuscular injections of testosterone enanthate or cypionate (200 mg per injection) every 3 to 4 weeks and oral pills of testosterone undecanoate (80 to 120 mg twice a day) with or immediately after a meal. Korean patients require smaller doses of testosterone than Western patients but have few problems taking the medication orally. In addition to shots and tablets, a transdermal gel can be applied to the skin of the patient, a patch can be applied on the patient's testicles or other sites, and pellets can be implanted in a muscle once every 6 months [3,4]. Although these drugs are expensive, the biological activity of testosterone is excellent. Recently, a novel testosterone undecanoate injection that is administered intramuscularly once every 3 months was introduced and shown to effectively maintain appropriate concentrations of testosterone in the blood [4]. However, the drug chosen for treatment depends on the patient based on factors such as efficacy, side effects, convenience, and cost.

The primary goal of gonadotropin treatment in males is to completely recover characteristics such as beard growth, physical strength, sexual desire, and sexual functionality. For patients who have yet to undergo puberty, the initial dose must be small and then it can be gradually increased depending upon the clinical response and presence of side effects until a maximum dose is reached. In addition to the clinical response, measures of serum testosterone concentrations are helpful for determining the appropriate dose when intramuscular delivery methods are used and it is advisable to maintain blood testosterone concentrations at 400 to 700 g/dL in the middle of an injection procedure [2]. For elderly patients or patients with obstructive sleep apnea syndrome, it is desirable to adjust the testosterone dose downward. Side effects of testosterone were erythrocytosis, acne, prostate hyperplasia, prostate cancer, and/or reduced spermatogenesis [4]. In the initial stages of testosterone treatment, it is important to perform hematocrit and reduce the dose if the result is over 50% and discontinue treatment if the result is over 55%. For patients over 40 years of age, a prostate cancer test is also necessary and a digital rectal exam and blood prostate-specific antigen (PSA) test should be conducted 3 to 6 months after treatment and once per year thereafter. If the results of the PSA test are over 3 ng/mL immediately after treatment, show an increase of 1.4 ng/mL at 1 year after treatment, or exhibit a PSA growth rate of more than 0.4 ng/mL per year for more than 2 years and there are unusual findings from the digital rectal exam or prostate ultrasonic test, the patient must visit a urologist [24].

When a male patient wishes to father a child, various infertility treatments can be used depending on the type of disease. In the case of hypothalamic hypogonadotropic hypogonadism, sporadic GnRH treatment using an infusion pump (2 g via subcutaneous injection every 2 hours) will restore masculinity and improve sperm count. However, this technique is used only infrequently due to the inconvenience of continuously carrying a bulky infusion pump. Similar to the case of hypopituitary hypogonadotropic hypogonadism, treatment with gonadotropin is used in this situation [2]. Like gonadotropin, human chorionic gonadotropin (hCG) and human menopausal gonadotropin (hMG; which is a drug extracted from the urine of menopausal women, generic name: menotropin) are available commercially as are recombinant LH (rLH) and FSH (rFSH) [2]. Gonadotropin typically needs to be injected intramuscularly 2 to 3 times per week, although subcutaneous injection is also available, and its use requires regular sperm analysis to determine the efficacy of the treatment [2]. Approximately 60% of males whose sperm counts have recovered to normal levels exhibit a restoration of their reproductive abilities [2]. If a patient suffers from hypogonadotropic hypogonadism prior to puberty, his testicles will be smaller than normal and the possibility of maintaining full reproductive abilities is very low, even following treatment [2]. Thus, prepubescent patients are advised to undergo gonadotropin treatment even though it is considerably more expensive and inconvenient than other methods.

For females with hypopituitarism, the administration of ethinyl estradiol (2 to 4 mg a day), which is a conjugated estrogen (0.625 to 1.25 mg a day) combined with progesterone, or the use of oral contraceptives can fully restore regular menstruation prior to menopause [2]. However, if the patient did not fully physically develop during puberty, then it is necessary to increase the estrogen dose during the initial stages of treatment and administer daily administration without drug holiday. For females with an intact uterus, administration of medroxyprogesterone (10 mg), which is a type of progesterone, 12 to 14 days per month in conjunction with estrogen treatment is recommended [2]. Transdermal estrogen patches may also be used as a complementary measure and, although it is an expensive regimen, it is efficacious for maintaining biological activity. Treatment must be continued at least until menopause to prevent osteoporosis and to maintain the antiatherosclerotic lipoprotein effects and, after menopause, the dose of estrogen should be progressively reduced until treatment is discontinued. Moreover, the patient should take annual mammography and breast ultrasound and gynecologic exam if unexpected vaginal bleeding or the patient wants to get pregnant [2].

Similar to males, the restoration of reproductive ability may be accomplished via the administration of hCG and hMG (or rLH and rFSH) as these hormone therapies are known to improve the possibilities of ovulation and conception. Due to recent advancements in dosage determination and supervising techniques, the incidence rates of ovarian hyperstimulation and multiple pregnancies have substantially declined, although these risks are still present. With respect to the possibility of these risks, the pulsatile injection of GnRH rather than gonadotropin treatment is considered to be much safer in hypothalamic hypogonadism. Additionally, the GnRH-based treatment is more effective and has fewer side effects but, in real clinical situations, the gonadotropin treatment is preferred due to the inconvenience of carrying the injection pump and other disadvantages [2].

For patients with hyperprolactinemia, which in most cases represents only a slight increase unless it is prolactinoma, the administration of a small amount of a dopamine agonist (bromocriptine or cabergoline) will return prolactin levels to normal [4]. If prolactinoma is present, then treatment with an adequate dose of a dopamine agonist is conducted for an extended period so that the prolactin levels can be reduced to within a normal range. If gonadotropin deficiency continues despite treatment, then the appropriate (male/female) hormone replacement treatment can be initiated.

In the past, GH replacement treatment is generally only utilized in children with growth disorder due to GH deficiency. However, the recent development of recombinant human GH has made it possible to use GH to treat adults with hypopituitarism or reduced GH secretion (e.g., due to obesity, old age, burn injury, and catabolic disease) [5]. This treatment technique was used in Europe earlier than in the United States and showed positive results including the post-treatment normalization of body composition (reduced body fat and increased muscle mass), improvements in muscular strength and physical vitality, increased bone density, reduced cardiovascular risks (particularly improved dyslipidemia), enhanced cardiac function, and improved mental health [5]. The recommended initial dose of GH is 0.5 units a day but the dose steadily increases after a few weeks. According to the experience of the present author, the maintenance dosage for Korean patients is 1 to 2 units per day with smaller amounts for older people. The best way to gauge the dosage over an extended period of time is to determine the optimal amount (lowest dose) at which the body composition of the patient can be maintained at a normal level. During short treatment periods, it is advisable to maintain IGF-1 levels within the mid-ranges according to the gender and age of the patient [5].

Males respond to GH treatment better than females, which implies that females will require a greater number of doses than males. This is likely because the efficacy of GH in the liver is interfered with by orally-administered estrogen which, in turn, inhibits the production of IGF-1. In contrast, testosterone tends to enhance IGF-1 levels [4]. The administration of GH also seems to influence the metabolism rates of hydrocortisone and T4 such that the doses of these drugs need to be adjusted upward [2]. If cortisone, which is not used in Korea, is utilized instead of hydrocortisone, then problems may occur but there will not be a need to adjust the dose of hydrocortisone, at least in the experience of the present author. GH treatment is never recommended for patients with malignant tumors, increased intracranial pressure, or proliferative diabetic retinopathy or for pregnant females [5]. A majority of the short-term side effects associated with GH treatment stem from overdoses or retained fluids due to normal GH mechanisms while side effects such as arthralgia, dilated cardiomyopathy, and diabetes mellitus have been reported with the long-term use of GH [5]. However, most of these side effects disappear once the dose is reduced. The effects of GH emerge after a few months of treatment and patients with more severe deficiencies exhibit the most improvement. In terms of body composition, a full recovery of muscular strength and physical ability may take several years [4].

After 20 years of using GH treatment for hypopituitarism patients, there is still no evidence demonstrating that this regimen may increase the incidence of cancer or cause the recurrence of a tumor [5]. Nonetheless, patients undergoing GH treatment warrant careful observation to identify the development of additional risk factors. Additionally, future studies are required to determine whether GH treatment may reverse the high mortality (or shortening of life expectancy) due to cardiovascular events. Because GH requires daily subcutaneous injections and its efficacy is not evident over extended periods of time, patients tend to discontinue treatment or receive the treatment only infrequently. Recently, a once-a-week self-administered subcutaneous injection of GH was developed and is currently undergoing clinical study. Once this treatment modality is made available in Korea, it is expected that the compliance rate for GH treatment will improve substantially.

Diabetes insipidus that results from ADH deficiency can be easily treated with a novel synthetic analogue of vasopressin known as desmopressin (1-desamino-8-D-arginine vasopressin [DDAVP]) which specifically interacts with ADH V2 receptors in the kidney [3]. DDAVP can be administered orally at doses of 0.1 to 0.2 mg 2 to 3 times a day, nasally at doses of 10 g/0.1 mL 2 to 3 times per day, or intravenously at 1 to 2 g twice a day. Beginning with oral doses at 0.05 mg one a day (before bedtime) or 0.05 mg twice a day, it is possible to gradually increase the dose or adjust the intervals between doses depending on the amount of urine. As a result, it is necessary to perform regular tests to assess electrolyte levels, particularly serum sodium levels. This drug is considered to be safe even during pregnancy but the dose should be increased during the second trimester based on the amount of urine and the degree of thirst [3]. When it is not feasible to orally administer DDAVP, for example, following surgery, it is necessary to utilize IV techniques when there is a rapid increase in urine volume by closely monitoring the amount of urine and serum sodium levels in the urine [3]. In the postoperative period, it is better to administer the drug when necessary rather than regular administration. It is advisable to regularly resume oral drug if the patient can take the drug orally. If there is an abrupt decrease in the amount of urine in conditions such as dehydration due to diarrhea, vomiting, or severe perspiration, DDAVP can be administered as needed. Drugs such as glucocorticoids, T4, alcohol, lithium, and demeclocycline decrease DDAVP efficacy. On the other hand, drugs like chlorpropamide, carbamazepine, and nonsteroidal anti-inflammatory medications can enhance DDAVP actions. In this case, the patient may suffer from either hypernatremia or hyponatremia and, thus, close supervision is warranted. If diabetes insipidus is accompanied by hypopituitarism, particularly in conjunction with an adrenal insufficiency or severe T4 deficiency, symptoms such as polyuria, polydipsia, and nocturia improve due to increased ADH secretion and action. As a result, this may lead medical staff to believe that the patient's symptoms are improving but once the patient complements his/her deficient hormone levels, the symptoms associated with diabetes insipidus will return. However, diabetes insipidus may improve over time especially if it is due to only a partial deficiency. Currently, it is better to discontinue drug administration intermittently and resume the treatment regimen only if urine volume increases [3].

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Diagnosis and Treatment of Hypopituitarism - PMC - National Center for ...

Hypopituitarism – StatPearls – NCBI Bookshelf

Continuing Education Activity

Hypopituitarism is defined as a deficiency of one or more of the hormones produced by the pituitary gland. Hypopituitarism is associated with increased mortality due to increased cardiovascular and respiratory diseases, and early diagnosis is essential to prevent further morbidity due to the subtle presentation. This activity reviews the pathophysiology of hypopituitarism and highlights the role of the interprofessional team in its management.

Objectives:

Review the causes of hypopituitarism.

Describe the presentation of a patient with hypopituitarism.

Summarize the treatment options for hypopituitarism.

Explain modalities to improve the care coordination among interprofessional team members to improve outcomes for hypopituitarism patients.

The pituitary gland is responsible for producing and secreting various hormones that play a vital role in regulating endocrine function within the body. The pituitary gland consists of an anterior and a posterior lobe. Hormones produced by the anterior lobe of the pituitary gland include growth hormone (GH), thyroid-stimulating hormone (TSH), luteinizinghormone (LH), follicular-stimulating hormone (FSH), adrenocorticotropin hormone (ACTH), and prolactin (PRL). Hormones stored and released from the posterior pituitary are antidiuretic hormone (ADH)/vasopressin and oxytocin. ADH and oxytocin are produced by neurosecretory cells in the hypothalamus. Trophic hormones produced by the hypothalamus stimulate or inhibit the production of different anterior pituitary hormones, affecting target organs.

Hypopituitarism is defined as a deficiency of one or more of the hormones produced by the pituitary gland. Hypopituitarism is associated with increased mortality due to increased cardiovascular and respiratory diseases, and early diagnosis is important to prevent further morbidity due to the subtle presentation.[1][2][3]

The causes of hypopituitarism can be attributed to either a pathology of the hypothalamus affecting the production of trophic hormones that act on the pituitary or direct pathology of the pituitary gland itself. The most common cause of hypopituitarism (61%) is pituitary tumors. Pituitary tumors may cause the increased production of one hormone with resultant deficiency of the other pituitary hormones as in acromegaly (excess GH with hypopituitarism from the macroadenoma). Most pituitary tumors are benign and may be secretory or non-secretory. Secondary metastases originating from, for example, breast, colon, and prostate cancers do occur less commonly. Hypothalamic and para-pituitary tumors such as suprasellar meningiomas, gliomas, and craniopharyngiomas may also be associated with hypopituitarism. Other causes of hypopituitarism include injury to the pituitary gland following traumatic brain injury or iatrogenic injury during surgery or cranial irradiation.[4]

Inflammatory conditions of the pituitary may also be responsible for the occurrence of hypopituitarism. The infectious agentspotentially related to pituitary insufficiency include Mycobacterium tuberculosisand non-mycobacterial agents such as histoplasmosis, syphilis, viruses, and protozoa. Lymphocytic hypophysitis usually presents in the post-partum period as a mass lesion on magnetic resonance imaging (MRI) due to infiltration of the pituitary with lymphocytes and plasma cells and is responsive to steroid therapy.

Infiltrative diseases such as hemochromatosis, sarcoidosis, and histiocytosis may be associated with the development of hypopituitarism.

Pituitary apoplexy is a medical emergency andoccurs due to acute ischemic infarction or hemorrhage of the pituitary gland. Pituitary apoplexy may occur in the presence of a pituitary adenoma but may also occur in the normal pituitary gland. Sheehan syndrome refers to infarction of the hyperplastic pituitary gland during pregnancy after severe blood loss (post-partum hemorrhage). Because of the rich and complex vascular supply, pituitary adenomas have an increased risk of bleeding compared to other brain tumors.[5]

The congenital absence of the pituitary gland is related to midline craniofacial defects. Genetic mutations in transcription factors such as HESX1, PROP1, and Pit-1 can lead to congenital hypopituitarism. Empty Sella syndrome is a rare disorder that is characterized by enlargement or malformation of the sella turcica resulting in a herniation of the arachnoid membrane into the pituitary fossa, dislodging the pituitary to the floor of the fossa. It is associated with a small or absent pituitary gland. Empty Sella syndrome may be idiopathic or occur secondary to a treated pituitary tumor, head trauma, or a condition known as idiopathic intracranial hypertension (pseudotumor cerebri). Kallmann syndrome is a rare genetic condition associated with an inability to smell (hyposmia/anosmia) and hypogonadotropic hypogonadism (decreased FSH, decreased LH, and reduced testosterone/estradiol levels) due to a mutation in the Kal1 gene that is the commonest genetic abnormality in males.

There is limited data available regarding the incidence and prevalence of hypopituitarism, and it is placed in the category of rare disorders by the National Institute of Health (NIH). One study from Northwestern Spain conducted by Regal et al. reported a prevalence of 45.5 cases per 100,000 population.[6][7]

It appears that 75% of the pituitary needs to be damaged to result in hypopituitarism. Clinical features of hypopituitarism may be subtle and ill-defined or severe with the acute presentation. Conditions such as Sheehan syndrome/pituitary apoplexy, pituitary infection, hypophysitis, and traumatic brain injury present with acute findings.[8][9][10]

Presenting signs and symptoms may be linked to those of a deficiency of the pituitary hormone, mass effects in the presence of pituitary tumors,and/or features of the causative disease.

Patients with hormonal deficiencies present with the following:

ACTH deficiency - Adrenal insufficiency

TSH deficiency - Hypothyroidism

Gonadotropin deficiency - Hypogonadism

GH deficiency - Difficult to thrive and short stature in children. Adults are usually asymptomatic; however, they may feel fatigued and weak.

ADH deficiency - Diabetes Insipidus presenting with polydipsia and polyuria

Mass effects include visual field defects, with the most common being bitemporal hemianopsia. Visual field defects may also occur unilaterally. Patients may present with headaches secondary to the mass lesions.

Physical examination may not reveal any significant findings as the presentation is usually subtle. Variable features may be present owing to the involvement of different target hormones, such as:

Hypothyroidism - small and soft thyroid gland, dry and coarse skin, thinning of hair and alopecia, delayed tendon reflexes, cold skin with loss of sweating, and non-pitting type edema.

Adrenal insufficiency - fatigue and postural hypotension

Hypogonadism - small and atrophied testes in men; loss of axillary and pubic hair in women

Neurological and ophthalmic involvement - loss of visual acuity, extraocular paresis, and bitemporal hemianopsia

Diabetes Insipidus - hypernatremia, polyuria, and diluted urine

The presence of a secretory pituitary tumor may result in features of hormone excess for the particular hormone produced by the tumor, while other pituitary hormones may be deficient.[11][12][13][14]

Investigations

Laboratory Investigations: Initial testing involves baseline levels of pituitary hormones andhormones produced by target glands. Due to the variation of hormone levels related to the time of day, season, and pulsatile secretion of certain pituitary hormones, baseline levels may not be helpful. In this instance, dynamic function testingcan confirm biochemical deficiency or excess of a particular pituitary hormone. In dynamic function testing, for the investigation of a hormone deficiency, a stimulatory agent that would normally increase secretion of the hormone is given to the patient, and blood levels are measured before and after the administration of the agent.After administering this stimulant, measurements are taken at defined intervals to determine if there has been an adequate response to stimulation.[15]

Insulin Tolerance Test:This is the best provocative test that is used to assess the presence of the deficiency of both GH and ACTH. Following an overnight fast, baseline samples are obtained for cortisol, GH, and glucose. An insulin dose of 0.1 U/kgor 0.05 U/kg is administered intravenously (IV). Further samples for analysis of the hormones measured in the baseline samples are then taken at several other points in timefollowing administration. It should not be performed in those with cardiac disease or epilepsy. The plasma glucose should fall to 40 mg/dl within 30 to 45 minutes or by 50% of baseline. The test is terminated by giving IV dextrose and assessing the patient's status for at least another 90 minutes. A normal/adequate response is indicated by cortisol of more than 20 ug/dL and GH of more than5 ng/mLto 10 ng/mL.

ACTH Stimulation Test: This is used to assess the pituitary-adrenal axis when the insulin tolerance test is dangerous fora patient's health due to the high risk of hypoglycemia. It can be done with ACTH administration, either250 mcg (that is the most commonly used)or 1 mcg, given IV or IM. Cortisol levels are measured before the medication administration and then 30, 60, and 90 minutes after. Cortisol levels over 18 mcg/dL indicate normal response.[16]

Modern Combined Test:The patient is given growth hormone-releasing hormone (GHRH), cortisol releasing hormone (CRH), gonadotropin-releasing hormone (GnRH), and thyroid releasing hormone (TRH) as the provocative stimuli and GH, TSH, ACTH, cortisol, LH, and FSH are measured at baseline andat specified time intervals after that. Doses of each stimulating hormone are as follows:

GHRH (1.0 ug/kg)

CRH (1.0 ug/Kg)

GnRH (100 ug)

TRH (200 ug).

However, this testing is rarely required.

Radiological Investigations:Imaging studies of the pituitary using magnetic resonance imaging (MRI) with gadolinium enhancement are used to visualize the pituitary, particularly to detect the presence of a mass lesion. Visual field defects needto be assessed if a pituitary mass is the cause of hypopituitarism.

Management is dependent on the cause of hypopituitarism. Initial treatment should aim to address the underlying cause of hypopituitarism. Mass lesions should be removed surgically, and other medical conditions treated accordingly.Many patients may require hormone replacement therapy.[17]

ACTH Deficit

Corticosteroid replacement should be initiated before the replacement of the thyroid hormone to avoid precipitating an adrenal crisis. Hydrocortisone at a dose of 10 mg to 20 mg in the morning and 5 mg to 10 mg in the afternoon are usually recommended. Some endocrinologists still recommend hydrocortisone to be given three times a day on symptomatic patients to imitate the physiologic hormonal secretion. The lastdose of the day (second or third)should not be administered at night as it can cause insomnia. Sometimes patients do well with only once a day dose, which can be trialed on an individual basis.[18] Prednisone may also be used once daily. Increased dosages of corticosteroids are needed during periods of stress, surgery, and pregnancy.

TSH Deficit

Thyroid hormone (L-thyroxine) replacement is required, particularly for the elderly and those with cardiac disease. It is important to start with a low dose of 25 ug/daily and then up-titrate as required according to biochemical findings and clinical signs or symptoms. Peripheral hormone levels (T4 free or total) need to be measured as the TSH is not a reliable marker anymore.

FSH/LH Deficit

In men: testosterone can be delivered by gel, patch, oral, or intramuscular (IM) injections with careful monitoring of prostate-specific antigen (PSA) and hemoglobin levels.[19]

In women: estrogen/progesterone hormone replacement therapy via oral, intramuscular, or transdermal routes can be given.

If fertility is desired in men, then one starts with human chorionic gonadotropin(HCG) to augment testosterone levels and improve semen quality. If this is not successful after one year, considerhuman menopausal gonadotropin (HMG)/recombinant FSH concomitant therapy to further enhance fertility. Specialty fertility clinics are dedicated to further evaluate and manage those patients.[20]

Growth Hormone Deficit

Unlike in children with short stature due to GH deficiency, the role of GH replacement in the treatment of adult GH deficiency has not been well established. In children, synthetic growth hormone replacement is used for this purpose, such as somatotrophin. Replacement therapy is titrated against IGF1 levels. The goal of treatment is to ensure that adult height is obtained. Further evaluation is made post-puberty to determine whether GH replacement should continue into adulthood.

ADH Deficit

Replacement of ADH with intranasal or oral desmopressin (synthetic vasopressin) helps stabilize water balance and polyuria. Sodium levels need to be kept within normal range; urinespecific gravityandosmolality can be measured to warranty appropriate replacement of ADH.

A diagnosis of hypopituitarism may be missed or delayed in complex situations where apparently normal pituitary hormone levels are misinterpreted in the context of suboptimal target organ hormone levels. However, adrenal insufficiency shouldreceive treatment based on clinical suspicion without waiting for the biochemical evidence.

Following are some differential diagnoses that may be considered while making a diagnosis of hypopituitarism:

Primary hypothyroidism

Kallman syndrome

Pituitary macroadenomas

Hyponatremia

Polyglandular autoimmune syndrome type-1

Polyglandular autoimmune syndrome type-2

Patients who are stable on hormone replacement usually have a good prognosis. Mortality increases in patients with acute decompensation who are in a critical state.Morbidity is variable and depends on the type of hormone deficiency. The systemic effects of hypopituitarism are also variable depending on the extent of pituitary involvement.Some clinical states that result from the acute decline in pituitary production may lead to increased mortality risk, such as deficiency of ACTH leading to adrenal crisis or TSH deficiency causing myxedema coma and death.[22]

Otherhormonal deficienciesthat may accompany hypopituitarism can lead to secondary diseases. For example, human growth hormone (HGH) deficiencycorrelates with obesity, increased cholesterol, and metabolic syndrome. Another example isestradiol deficiency, potentially leading to osteoporosis.[23]

Patient education should mainly focus on the need for lifelong hormone replacement therapy, increased glucocorticoid dose during times of stress, and rapid medical access as appropriate. Regular monitoring to preventinadequate or excessivereplacement is crucial.

Patients with hypopituitarism should carry some form of identification of their medical problems with them. This can be in the form of a bracelet to be worn on the wrist or a necklace.

For emergency purposes, patients may also need to carry a vial of hydrocortisone 100 mg and a syringe at home and while traveling.

The diagnosis and management of hypopituitarism are made with an interprofessional team that consists of a neurosurgeon, endocrinologist, pathologist, radiologist, primary care provider, nurse practitioner, and ophthalmologist. Nurses and pharmacists can also play key roles as part of the interprofessional healthcare team. Management is dependent on the cause of hypopituitarism. Initial treatmentshould address the underlying cause of hypopituitarism. Mass lesions may be removed surgically, and other medical conditions treated accordingly.Many patients may require hormone replacement therapy. The outcome in most patients with hypopituitarism is good, but those who have a neurological deficit may continue to have partial deficits even after treatment.[1][24][25][Level5]

Original post:
Hypopituitarism - StatPearls - NCBI Bookshelf

Panhypopituitarism: What It Is, Symptoms & Treatment – Cleveland Clinic

OverviewWhat is panhypopituitarism?

Panhypopituitarism is a rare condition in which theres a lack (deficiency) of all of the hormones your pituitary gland makes. It can affect infants, children and adults.

Hormones are chemicals that coordinate different functions in your body by carrying messages through your blood to your organs, muscles and other tissues. These signals tell your body what to do and when to do it.

Your pituitary gland is a pea-sized gland located at the base of your brain below your hypothalamus (the part of your brain that controls your autonomic nervous system). Its a part of your endocrine system.

The pituitary hormones are in charge of several important functions in your body, such as metabolism, growth and reproduction.

Normally, your body carefully controls hormone levels. If the levels of any of these hormones are unbalanced, it causes symptoms and health issues. Panhypopituitarism causes several symptoms since all of your pituitary hormone levels are lower than what they should be.

Panhypopituitarism is a type of hypopituitarism.

If you have a deficiency (lack) of one or multiple hormones your pituitary gland makes, you have hypopituitarism.

Panhypopituitarism happens when theres a deficiency in all of the hormones your pituitary makes. The prefix pan- means all.

Your pituitary gland makes and releases the following hormones:

Your pituitary gland stores and releases the following hormones, but your hypothalamus produces them:

Panhypopituitarism can affect anyone at any age.

Panhypopituitarism is rare. There are approximately four cases of panhypopituitarism per 100,000 people across the globe per year.

Yes, panhypopituitarism can be life-threatening, especially if you have a significant deficiency of adrenocorticotropic hormone (ACTH or corticotropin).

Adrenal crisis (acute cortisol insufficiency) is a life-threatening complication of panhypopituitarism. The cause is a lack of ACTH, which is a hormone that controls your cortisol levels. Its treatable but requires immediate medical treatment.

Signs and symptoms of adrenal crisis include:

If you or your child are experiencing these symptoms, call 911 or get to the nearest hospital as soon as possible.

The signs and symptoms of panhypopituitarism vary widely based on how much of each of the pituitary hormones is lacking and whether the condition develops rapidly or slowly.

Symptoms of panhypopituitarism that children and adults can have include:

Additional symptoms of panhypopituitarism that are specific to infants, children and/or adolescents include:

These symptoms may resemble other conditions or medical issues. Its important to always consult your healthcare provider if youre experiencing new or prolonged symptoms to get a proper diagnosis.

Many conditions and situations can cause panhypopituitarism. In some cases, healthcare providers cant determine the cause. This is called idiopathic panhypopituitarism.

In general, the cause of panhypopituitarism is some type of damage to your hypothalamus and/or pituitary gland that causes either or both of them to not function properly.

Understanding the possible causes of panhypopituitarism involves understanding how your hypothalamus and pituitary gland work together.

Together, your pituitary gland and hypothalamus form a hypothalamus-pituitary complex that serves as your brains central command center to control vital bodily functions.

Your hypothalamus is the part of your brain thats in charge of some of your bodys basic operations. It sends messages to your autonomic nervous system. Your hypothalamus also tells your pituitary gland to produce and release hormones that affect other areas of your body.

Your pituitary gland connects to your hypothalamus through a stalk of blood vessels and nerves (the pituitary stalk). Through that stalk, your hypothalamus communicates with your pituitary gland.

Your hypothalamus makes the following hormones to communicate with and stimulate your pituitary gland:

Since your pituitary gland and hypothalamus work together so closely, if one of them becomes damaged, it can affect the hormonal function of the other. This can result in panhypopituitarism.

Conditions or situations that can damage your pituitary gland and cause panhypopituitarism include:

Conditions or situations that can damage your hypothalamus and cause panhypopituitarism include:

If youre experiencing symptoms of panhypopituitarism, your healthcare provider will ask detailed questions about your symptoms and medical history and perform a physical exam.

Theyll then order tests to confirm a panhypopituitarism diagnosis and/or to rule out other conditions that could be causing your symptoms.

Healthcare providers typically order multiple tests to diagnose panhypopituitarism, including imaging and hormone levels tests.

Since panhypopituitarism results from damage to your hypothalamus or pituitary gland, your provider may order the following imaging tests to help determine the cause of panhypopituitarism:

If you have symptoms of panhypopituitarism, your provider will need to measure the levels of all the hormones your pituitary gland releases to check how deficient each one is and to help rule out other conditions.

While some pituitary hormones normally maintain a fairly stable level in your bloodstream, other pituitary hormone levels normally vary widely throughout the day. Because of this, some hormone tests are simple blood tests and others are specialized stimulation tests.

Hormone level tests include:

The treatment for panhypopituitarism greatly depends on how deficient each pituitary hormone is and the cause of the condition. Because of this, treatment is very individualized. Your healthcare team will determine what the best treatment plan is for you. Common treatment options for panhypopituitarism include:

In some cases, panhypopituitarism is reversible by treatment of the underlying cause, such as surgically removing a pituitary adenoma that was compressing the pituitary gland without causing damage. But in most cases, the hormone deficiencies from panhypopituitarism require lifelong treatment.

In most cases, you cant prevent panhypopituitarism. But there are ways to catch it in its early phase if youre at risk for developing it.

If youve experienced any of the following situations, youre at greater risk for developing panhypopituitarism:

Your healthcare provider will likely recommend regular testing to check the function and health of your pituitary gland and/or hypothalamus if youre at a greater risk for developing panhypopituitarism.

The prognosis (outlook) for panhypopituitarism depends on several factors, including:

Panhypopituitarism is associated with significant decreases in quality of life and life expectancy.

People with panhypopituitarism often develop obesity, decreased lean body mass and an increased risk of cardiovascular disease. People with panhypopituitarism may also have an increased risk of osteoporosis and bone fractures.

Careful, thorough treatment with hormone replacements and aggressive monitoring and treatment for cardiovascular disease risk factors may improve outcomes.

If you have symptoms of panhypopituitarism or received a diagnosis of the condition, youll likely need to see an endocrinologist a healthcare provider who specializes in treating hormone-related conditions.

Youll need to see your endocrinologist regularly throughout your life to ensure that your hormone replacement therapy is working well and to prevent excessive hormone replacement.

A note from Cleveland Clinic

A new diagnosis can be scary, but dont be afraid to ask your healthcare provider questions about panhypopituitarism. Most cases of panhypopituitarism require lifelong treatment and monitoring of your hormones, so its important to see your provider regularly. Be sure to contact your provider if you have new or concerning symptoms. Theyre available to help.

See the article here:
Panhypopituitarism: What It Is, Symptoms & Treatment - Cleveland Clinic

Hormonal Replacement in Hypopituitarism in Adults: An Endocrine Society …

Objective:

To formulate clinical practice guidelines for hormonal replacement in hypopituitarism in adults.

Participants:

The participants include an Endocrine Society-appointed Task Force of six experts, a methodologist, and a medical writer. The American Association for Clinical Chemistry, the Pituitary Society, and the European Society of Endocrinology co-sponsored this guideline.

Evidence:

The Task Force developed this evidence-based guideline using the Grading of Recommendations, Assessment, Development, and Evaluation system to describe the strength of recommendations and the quality of evidence. The Task Force commissioned two systematic reviews and used the best available evidence from other published systematic reviews and individual studies.

Consensus Process:

One group meeting, several conference calls, and e-mail communications enabled consensus. Committees and members of the Endocrine Society, the American Association for Clinical Chemistry, the Pituitary Society, and the European Society of Endocrinology reviewed and commented on preliminary drafts of these guidelines.

Conclusions:

Using an evidence-based approach, this guideline addresses important clinical issues regarding the evaluation and management of hypopituitarism in adults, including appropriate biochemical assessments, specific therapeutic decisions to decrease the risk of co-morbidities due to hormonal over-replacement or under-replacement, and managing hypopituitarism during pregnancy, pituitary surgery, and other types of surgeries.

1.1 We suggest measuring serum cortisol levels at 89 am as the first-line test for diagnosing central adrenal insufficiency (AI). (2|)

1.2 We recommend against using a random cortisol level to diagnose AI. (1|)

1.3 We suggest that a cortisol level <3 g/dL is indicative of AI and a cortisol level >15 g/dL likely excludes an AI diagnosis. (2|)

1.4 We suggest performing a corticotropin stimulation test when morning cortisol values are between 3 and 15 g/dL to diagnose AI. Peak cortisol levels <18.1 g/dL (500 nmol/L) at 30 or 60 minutes indicate AI. (2|)

1.5 We suggest that clinicians perform biochemical testing for the hypothalamic-pituitary-adrenal (HPA) axis at least 1824 hours after the last hydrocortisone (HC) dose or longer for synthetic glucocorticoids (GCs). (2|)

1.6 We recommend measuring serum free T4 (fT4) and TSH to evaluate central hypothyroidism (CH). An fT4 level below the laboratory reference range in conjunction with a low, normal, or mildly elevated TSH in the setting of pituitary disease usually confirms a CH diagnosis. (1|)

1.7 In patients with pituitary disease and low-normal fT4 levels suspected to have mild CH, we suggest starting levothyroxine (L-T4) if suggestive symptoms are present or following fT4 levels over time and starting treatment if the fT4 level decreases by 20% or more. (2|)

1.8 We suggest against using dynamic TSH-secretion testing to diagnose CH. (2|)

1.9 In patients with suspected GH deficiency (GHD), we recommend GH stimulation testing. Single GH measurements are not helpful. (1|)

1.10 We recommend using appropriately controlled body mass index (BMI) cutoffs to assess peak GH values. (1|)

1.11 We suggest against biochemical testing for GHD in patients with clear-cut features of GHD and three other documented pituitary hormone deficits. (2|)

1.12 In males with suspected hypogonadism, we recommend measuring serum T, FSH, and LH to diagnose central hypogonadism. (1|)

1.13 We recommend that clinicians perform hormonal testing for central hypogonadism in males in the absence of acute/subacute illness and before 10 am (after overnight fast) combined with serum prolactin (PRL). (1|)

1.14 In the presence of oligomenorrhea or amenorrhea, we recommend measuring serum estradiol (E2), FSH, and LH. Clinicians should exclude other causes of menstrual irregularities related to impaired ovulation (hyperprolactinemia, hyperandrogenism, and thyroid disease), particularly if no other pituitary hormone deficits are present. In cases of amenorrhea, clinicians should also exclude pregnancy. (1|)

1.15 We suggest against dynamic testing with GnRH, which offers no useful diagnostic information. (2|)

1.16 We recommend that in postmenopausal women, the absence of high serum FSH and LH is sufficient for a diagnosis of gonadotrope dysfunction (provided the patient is not on hormonal replacement therapy [HRT]). (1|)

1.17 We recommend simultaneously measuring serum and urine osmolarity in patients with polyuria (more than 50 mL/kg of body weight/24 hours, 3.5 L/d in a 70-kg person). In the presence of high serum osmolarity (>295 mOsmol/L), urine osmolarity should reach approximately 600 mOsmol/L (urine osmolality/plasma osmolality ratio should be 2), whereas urine dipstick should be negative for glucose. (1|)

2.1 We recommend using HC, usually 1520 mg total daily dose in single or divided doses. Patients using divided doses should take the highest dose in the morning at awakening and the second in the afternoon (two-dose regime) or the second and third at lunch and late afternoon, respectively (three-dose regime). (1|)

2.2 We suggest using longer-acting GCs in selected cases (eg, nonavailability, poor compliance, convenience). (2|)

2.3 We recommend that clinicians teach all patients with AI regarding stress-dose and emergency GC administration and instruct them to obtain an emergency card/bracelet/necklace regarding AI and an emergency kit containing injectable high-dose GC (1|)

2.4 We recommend against using fludrocortisone in patients with secondary AI. (1|)

2.5 We recommend that clinicians treat patients with suspected adrenal crisis (AC) due to secondary AI with an immediate parenteral injection of 50100 mg HC. (1|)

2.6 We recommend L-T4 in doses sufficient to achieve serum fT4 levels in the mid to upper half of the reference range. Appropriate L-T4 doses in CH average 1.6 g/kg/d, with dose adjustments based on clinical context, age, and fT4 levels. (1|)

2.7 We suggest against treating CH with levotriiodothyronine (L-T3), thyroid extracts, or other formulations of thyroid hormones. (2|)

2.8 We recommend against using serum TSH levels to adjust thyroid replacement dosing in patients with CH. (1|)

2.9 We suggest T replacement for adult males with central hypogonadism and no contraindications in order to prevent anemia related to T deficiency; reduce fat mass; and improve bone mineral density (BMD), libido, sexual function, energy levels, sense of well-being, and muscle mass and strength. (2|)

2.10 We recommend gonadal hormone treatment in premenopausal women with central hypogonadism, provided there are no contraindications. (1|)

2.11 We recommend offering GH replacement to those patients with proven GHD and no contraindications. We recommend a starting dose of 0.20.4 mg/d for patients younger than 60 years and 0.10.2 mg/d for patients older than 60 years. (1|)

2.12 We recommend titrating GH doses and maintaining IGF-1 levels below the upper limit of normal and reducing the dose if side effects manifest. (1|)

2.13 We suggest against administering GH to elderly adults with age-adjusted low IGF-1 levels and no history of pituitary or hypothalamic disease. (2|)

2.14 We recommend against using GH to enhance athletic performance because this practice is illegal in the United States, has poor scientific or ethical justification, and does not have substantiated efficacy. (Ungraded Good Practice Statement)

2.15 When administering desmopressin (DDAVP) in diabetes insipidus (DI), we suggest individualized therapeutic schedules. Although clinicians should offer therapy to all patients, some patients with partial DI may not be bothered by polyuria and may prefer no treatment. To reduce the risk of hyponatremia, we recommend that clinicians educate all patients receiving DDAVP about the risk of overdosing. Periodically (at least weekly), patients should experience a phase of polyuria during which the effect of the medication has obviously worn off. (Ungraded Good Practice Statement)

2.16 In postpituitary surgery DI, we suggest that clinicians should make at least one attempt to discontinue DDAVP during the weeks/months after surgery to determine whether posterior pituitary function has recovered. (Ungraded Good Practice Statement)

2.17 In cases of adipsic DI, we suggest careful DDAVP and fluid intake titration that includes frequent weighing and serum sodium level monitoring. (Ungraded Good Practice Statement)

2.18 We suggest that all patients with DI wear an emergency bracelet or necklace to inform clinicians of the patients health problem if incapacitated. (Ungraded Good Practice Statement)

2.19 We suggest testing HPA axis functionality before and after starting GH replacement in patients who are not receiving GC replacement and who have demonstrated apparently normal pituitary-adrenal function. (2|)

2.20 We suggest evaluating patients with CH for AI before starting L-T4 therapy. If this is not feasible, clinicians should prescribe empiric GC therapy in patients with CH who are starting L-T4 therapy until there is a definitive evaluation for AI. (2|)

2.21 We suggest that when clinicians assess adrenal reserve or the adequacy of HC replacement, they take into consideration that total serum cortisol level can be elevated due to the effects of estrogen on corticosteroid-binding globulin (CBG). (2|)

2.22 We recommend that clinicians monitor euthyroid patients with GHD who begin GH therapy for the risk of developing CH, and if fT4 levels decrease below the reference range, these patients should begin L-T4 therapy. CH patients with GHD who are already receiving L-T4 may require increased L-T4 doses when they begin GH therapy to maintain fT4 levels within target ranges. (1|)

2.23 We suggest clinicians treat CH before performing GH stimulation testing because CH may impair the accurate diagnosis of GHD. (2|)

2.24 In patients with CH requiring changes in estrogen therapy, we recommend monitoring fT4 levels and adjusting L-T4 doses to maintain fT4 levels within target ranges. (1|)

2.25 We suggest that women on oral estrogen replacement receive higher GH doses compared with eugonadal females or males. (2|)

2.26 Because AI may mask the presence of partial DI, we suggest monitoring for the development of DI after starting GC replacement. Conversely, patients with improved DI without an AI diagnosis should undergo AI testing. (2|)

2.27 Clinicians should individually assess GC replacement and avoid over-replacement to reduce the risk of osteoporosis. We suggest low-dose HC replacement because this approach might be associated with increased bone formation and a positive bone-remodeling balance. (2|)

2.28 In men with hypopituitarism over-replaced with GC and at risk for fractures, we suggest vertebral fracture assessment (baseline plain spinal x-rays or dual-energy x-ray absorptiometry) to identify patients with unsuspected vertebral fractures. (2|)

2.29 We suggest clinicians monitor L-T4 replacement, as recommended in previous sections, and avoid over-replacement to reduce the risk of fractures. (2|)

2.30 In patients with central AI, we recommend using the lowest tolerable dose of HC replacement to potentially decrease the risks of metabolic and cardiovascular disease. (1|)

2.31 To avoid the possible long-term cardiovascular risks of insufficient or excess thyroid hormone treatment, clinicians should adjust L-T4 doses to avoid low or elevated fT4 levels in CH. (Ungraded Good Practice Statement)

3.1 We recommend GC replacement until full HPA axis recovery after surgically resecting ACTH-secreting tumors. (1|)

3.2 After curative surgery for Cushings disease, we recommend retesting thyroid and GH axes before starting replacement treatment. (1|)

3.3 We recommend reassessing all pituitary axes in patients with macroprolactinoma and central hypogonadism who have had successful dopamine agonist treatments. (1|)

3.4 We suggest low-dose GH replacement in patients with cured acromegaly and documented GHD in the absence of known contraindications. (2|)

3.5 We recommend using stress doses of steroids in AI before surgery and tapered doses after surgery before repeating testing. (1|)

3.6 In patients with normal preoperative adrenal function, we suggest an individualized clinical approach for postoperative GC administration until the HPA axis can be evaluated. (2|)

3.7 With preoperative CH, we recommend using L-T4 therapy before nonemergency surgery and throughout the perioperative period. (1|)

3.8 With intact preoperative thyroid function, we recommend measuring fT4 levels 68 weeks postoperatively to assess for CH. (1|)

3.9 We suggest that initial therapy for DI utilizes short-acting sc aqueous antidiuretic hormone (ADH), allowing for safer use in the vast majority of cases in whom DI resolves spontaneously. (2|)

3.10 We do not suggest prescheduled DDAVP dosages in the first week postsurgery because of the risk of hyponatremia after transient DI resolves and the risk of syndrome of inappropriate ADH secretion that may occur 710 days after surgery. (2|)

3.11 We suggest oral or intranasal DDAVP after discharge, with clear instructions that patients should only use the medication if significant polyuria occurs. (2|)

3.12 We suggest retesting all pituitary axes starting at 6 weeks after pituitary surgery and then periodically to monitor the development or resolution of pituitary deficiencies. (2|)

3.13 On the day of surgery, we recommend adjusting GC doses according to the severity of illness and magnitude of the stressor. (1|)

3.14 In cases of minor to moderate surgical stress, we suggest 2575 mg HC per 24 hours (usually for 12 days). (2|)

3.15 In cases of major surgical stress, we suggest a 100-mg HC per iv injection followed by a continuous iv infusion of 200 mg HC per 24 hours (alternatively 50 mg every 6 hours iv or im). (2|)

3.16 We suggest using HC as the preferred GC in pregnancy and increasing the dose based on the individual clinical course; higher doses may be required, in particular during the third trimester. (Ungraded Good Practice Statement)

3.17 We suggest that pregnant patients with central AI be closely monitored for clinical symptoms and signs of GC over- and under-replacement (eg, normal weight gain, fatigue, postural hypotension or hypertension, hyperglycemia). (Ungraded Good Practice Statement)

3.18 We recommend against using dexamethasone in pregnancy because it is not inactivated in the placenta. (1|)

3.19 We recommend HC stress dosing during the active phase of labor, similar to that used in major surgical stress. (1|)

3.20 We recommend that clinicians monitor fT4 or total T4 levels every 46 weeks for women with CH who become pregnant, and that these women may require increased L-T4 doses to maintain levels within target ranges for pregnancy. (1|)

3.21 In pregnant women with pre-existing DI, we suggest continuing DDAVP during pregnancy and adjusting doses if required. (2|)

3.22 We suggest discontinuing GH replacement during pregnancy because there is no clear evidence yet for efficacy or safety, and the placenta produces GH. (2|)

3.23 We recommend testing for acute pituitary insufficiency in all patients with pituitary apoplexy. (1|)

3.24 Because acute AI is a major cause of mortality, we recommend GC therapy until a laboratory diagnosis is established and the patient maintains normal pituitary function. (1|)

3.25 We recommend that clinicians monitor pituitary axes in pituitary apoplexy patients treated with either surgical decompression or conservative management because hypopituitarism may develop over time. (1|)

3.26 We suggest clinicians educate AI patients that are taking nondexamethasone GCs and who start enzyme-inducing antiepileptic drugs (AEDs) about the early signs and symptoms of AI. (2|)

3.27 In patients with AI on dexamethasone, we suggest increasing dexamethasone replacement doses if enzyme-induced AEDs are coadministered. (2|)

3.28 In CH patients receiving L-T4, we recommend checking fT4 at least 6 weeks after starting an AED and increasing L-T4 doses if fT4 levels decrease below the target range. (1|)

3.29 In women who have started estrogen replacement, we suggest evaluating AED levels and adjusting AED doses as required. (2|)

3.30 We suggest monitoring DDAVP doses and making further adjustments as needed in patients who are started on AEDs. (2|)

The Clinical Guidelines Subcommittee (CGS) of the Endocrine Society deemed hormonal replacement in hypopituitarism a priority area in need of practice guidelines and appointed a Task Force to formulate evidence-based recommendations. The Task Force followed the approach recommended by the Grading of Recommendations, Assessment, Development, and Evaluation group, an international group with expertise in the development and implementation of evidence-based guidelines (1). A detailed description of the grading scheme has been published elsewhere (2). The Task Force used the best available research evidence to develop the recommendations. The Task Force also used consistent language and graphical descriptions of both the strength of a recommendation and the quality of evidence. In terms of the strength of the recommendation, strong recommendations use the phrase we recommend and the number 1, and weak recommendations use the phrase we suggest and the number 2. Cross-filled circles indicate the quality of the evidence, such that denotes very low quality evidence; , low quality; , moderate quality; and , high quality. The Task Force has confidence that persons who receive care according to the strong recommendations will derive, on average, more good than harm. Weak recommendations require more careful consideration of the persons circumstances, values, and preferences to determine the best course of action. Linked to each recommendation is a description of the evidence and the values that the Task Force considered in making the recommendation. In some instances there are remarks, a section in which the Task Force offers technical suggestions for testing conditions, dosing, and monitoring. These technical comments reflect the best available evidence applied to a typical person being treated. Often this evidence comes from the unsystematic observations of the Task Force and its values and preferences; therefore, one should consider these remarks as suggestions.

In this guideline, the Task Force made several statements to emphasize the importance of shared decision making, general preventive care measures, and basic principles of hormonal replacement in hypopituitarism. The Task Force labeled these as Ungraded Good Practice Statement. Direct evidence for these statements was either unavailable or not systematically appraised; therefore, the Task Force considers these statements out of the scope of this guideline. The intention of these statements is to draw attention to and remind providers of these principles; one should not consider these statements as graded recommendations (3).

The Endocrine Society maintains a rigorous conflict-of-interest review process for developing clinical practice guidelines. All Task Force members must declare any potential conflicts of interest by completing a conflict-of-interest form. The CGS reviews all conflicts of interest before the Societys Council approves the members to participate on the Task Force and periodically during the development of the guideline. All those participating in the guidelines development must also disclose any conflicts of interest in the matter under study, and a majority of these participants must be without any conflicts of interest. The CGS and the Task Force have reviewed all disclosures for this guideline and resolved or managed all identified conflicts of interest.

Conflicts of interest are defined as remuneration in any amount from commercial interest(s) in the form of grants; research support; consulting fees; salary; ownership interest (eg, stocks, stock options [excluding diversified mutual funds]); honoraria or other payments for participation in speakers bureaus, advisory boards, or boards of directors; or other financial benefits. Completed forms are available through the Endocrine Society office.

Funding for this guideline was derived solely from the Endocrine Society; the Task Force received no funding or remuneration from commercial or other entities.

The guideline Task Force commissioned two systematic reviews to assist with summarizing the evidence base for this guideline.

The first review addressed the question of whether adults with panhypopituitarism of any cause have increased all-cause mortality. The review identified 12 studies reporting on 26 017 patients. Studies were observational, with incomplete adjustment for confounders. Meta-analysis suggested increased mortality in patients with panhypopituitarism (RR, 1.55; 95% confidence interval [CI], 1.142.11). Factors associated with increased mortality were female gender, younger age at diagnosis, an underlying diagnosis of a craniopharyngioma or aggressive tumor, the presence of DI, and prior treatment with surgery or radiotherapy. The most common causes of death were malignancies, cardiovascular disease, and cerebrovascular disease.

The second review attempted to answer the question of whether GH replacement is associated with a risk of pituitary tumor recurrence, secondary malignancy, or stroke. The review included seven studies reporting on 22 654 patients. Meta-analysis did not show an association between GH replacement and pituitary tumor recurrence (RR, 0.87; 95% CI, 0.561.33) or the risk of secondary malignancies (RR, 1.24; 95% CI, 0.652.33). There were no data on the outcome of stroke.

Each review addressed a question of association and both demonstrated that the evidence (overall) warrants low certainty in the provided estimates.

Hypopituitarism results from complete or partial deficiency in pituitary hormones and includes AI, hypothyroidism, hypogonadism, GHD, and (more rarely) DI. Not all disorders that affect anterior pituitary function may cause DI, and DI can occur without anterior pituitary dysfunction. Hypopituitarism is the consequence of diseases that either reduce or destroy secretory function or interfere with the hypothalamic secretion of pituitary-releasing hormones.

The prevalence (probably underestimated) is approximately 45 cases per 100 000, with an incidence of about four cases per 100 000 per year (4). Considering evidence from the commissioned systematic review and other evidence extracted mostly from contemporary studies on the management of hypopituitarism due to heterogeneous etiologies, it seems that mortality associated with hypopituitarism is indeed high (510). Recently published evidence indicates that pituitary hormonal deficits managed with the currently used replacement protocols (including nonsupraphysiological doses of HC and appropriate thyroid and gonadal hormone replacement) might not adversely affect mortality (11).

Hypopituitary patients exhibit increased incapacitation and sick days, lower health status, and higher cost of care (12, 13). Those with GHD are less often working full time, more often on sick leave/disability, and often live alone or with parents (14). Despite receiving long-term GH replacement, the working capacity of hypopituitary patients remains lower than the general population (14).

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Hormonal Replacement in Hypopituitarism in Adults: An Endocrine Society ...

31 days of horror movies: Orphan: First Kill is a reminder to have fun with movies – 1428 Elm

Orphan: First Kill, directed by William Brent Bell (The Boy, Brahms: The Boy II), was released in 2022 and is a prequel to the 2009 flick, Orphan. Like its predecessor, First Kill follows the exploits of the murderous Leena (Isabelle Fuhrman), a 31-year-old woman with a hormonal disorder called hypopituitarism that gives her the appearance of a 10-year-old child. Leena uses this to her advantage, scheming her way into different families who have a first date with their Maker once the gloves (or in this case, the teeth) come off and Leena reveals her true intentions. While the story is loosely based on a case in real life, the campy set-up suggests a film that doesnt take itself too seriously and audiences shouldnt either. Note: I will be discussing spoilers from Orphan and Orphan: Kill, so consider this your official spoiler warning.

Isabelle Fuhrman as Esther in Orphan: First Kill from Paramount Players, eOne, and Dark Castle Entertainment. Photo Credit: Steve Ackerman/Paramount Pictures

Orphan: First Kill has the benefit of leaning into all the campy elements in the first film, which had to play them off as slightly more serious and presented Leena as a straightforward villain. I think the first film is well-made, definitely thrilling, and pretty shocking with some of the material it presents, and not just with Leenas twist. However, First Kill is where the fun begins and it centers the attention directly on Leena rather than the family shes infiltrating.

First Kill opens with Lena staging her escape from the Saarne Institute by seducing one of the guards and killing the institutes art therapist Anna. Because audiences are already familiar with the twist, First Kill wastes no time in presenting Leena as a homicidal, but calculated maniac. Leena researches missing American children with whom she bears a resemblance, choosing to pass herself off as Esther.

Within no time and hardly any investigation later, Esther is the in the states with her family the Albrights: mother Tricia (Julia Stiles), father Allen (Rossif Sutherland), and their son Gunnar (Matthew Finlan). Julia Stiles steals the spotlight as the matriarch of the Albright clan, and while Vera Farmigas character in Orphan was beaten down and broken by tragedy, Stiles Tricia is the opposite: calculated, cruel, manipulative, and straight-up evil.

You see, the twist of First Kill is that Julia was responsible for killing her own daughter Esther and staging her kidnapping to protect the reputation of her equally as awful son Gunnar. Leenas arrival as Esther presents Julia with an unexpected opportunity, to save her marriage with her unaware husband and position her family back to the top of the social ladder. Julia wastes no time in letting Leena know shes on to her, suddenly forcing the audience to take Leenas side as she faces off against someone whos just as manipulative and cruel.

First Kill takes the psychological elements present in Orphan and turns them on their head for a ridiculous slasher film that allows itself to have fun with its premise. Sure the film might have some plot holes and other elements worth critiquing, but at the end of the day, its an entertaining outing with Esther, who I would love to see in more films. A certain suspension of disbelief is required when tuning in to films like Orphan: First Kill.

Sometimes its okay to have fun with a movie and relax the expectation that each new film will break the mold or be the next huge thing. To be honest, I was grinning the entire movie because its just what I like in a horror flick, unapologetic fun, and off-the-rails insanity.

Orphan: First Kill is currently streaming on Paramount+.

Do you think Orphan: First Kill deserves a spot on your October watch list? Tell us why or why not in the comments section.

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31 days of horror movies: Orphan: First Kill is a reminder to have fun with movies - 1428 Elm

New to Streaming: Ken Jacobs, The Legend of Molly Johnson, Spin Me Round, The Princess & More – The Film Stage

Each week we highlight the noteworthy titles that have recently hit streaming platforms in the United States. Check out this weeks selections below and past round-upshere.

Costa Brava, Lebanon (Mounia Akl)

What can you do when your homelands falling apart? The easy answer is stay or leave, but both options carry too much complexity to simply choose and be done. For starters, not everyone has that choicewhether due to finances, family, or myriad other reasons. And those who are able must dig deep within themselves to rationalize why. Do you leave because of greater opportunity? Do you stay because you want to be part of the solution? Or do you find yourself in a sort of purgatoryone foot planted on each side, only to discover your fear of losing out on the benefits of one for the potential of the other has you locked in stasis? Thats where Walid (Saleh Bakri) currently exists. Jared M. (full review)

Where to Stream: Kino Now

The Ken Jacobs Collection

Filmatique is exclusively streaming work by Ken Jacobs, one of the most wildly creative and influential artists in cinema history. The 20-title curation spans Jacobss nearly 70-year career: early films using New York City as a poetic landscape (Orchard Street) and as a setting for Smiths carnivalesque performances (Little Stabs at Happiness and Blonde Cobra); experiments with found footage (Tom, Tom, the Pipers Son); and an embracing digital tools to create stroboscopic effects that turn silent shorts and Victorian stereoscopic photographs into mind-expanding 3D investigations (Capitalism: Child Labor).

Where to Stream: Filmatique

The Legend of Molly Johnson (Leah Purcell)

A favorite of Leah Purcells as a child, Henry Lawsons short story The Drovers Wife was always at the front of her mind when growing into adulthood as an artist. It only makes sense, then, that she would take that 1892 tale and reimagine it as an Australian western that would bring her own ancestral history as a fair-skinned Aboriginal woman to light. First she had to give the titular wife a name: Molly Johnson. Next it was fleshing out a dramatic narrative beyond that of a devoted mother staying up all night to protect her children from a hidden snake while reminiscing about all the other times for which she did the same (fire and flood) with her husband consistently away. A legend was born. Jared M. (full review)

Where to Stream: VOD

Media Man (Danny Lyon)

Over the next two weeks Le Cinma Club will stream, for free, Media Man. Filmed by Danny Lyon over the course of five years with his wife Nancy Weiss,it barrels across cities and countrysides, quilting together a warm study of Americas many faces. This patchwork portrait of overlooked people and their passions encapsulates Lyons ability to immortalize fleeting histories through momentous encounters.

Where to Stream: Le Cinma Club

On the Count of Three (Jerrod Carmichael)

Considering the raw, uncomfortable truths found in Jerrod Carmichaels comedy, the logline of his directorial debut shouldnt come as a surprise: two friends make a pact to end their lives and experience one final day together before plans to carry through with the dual deeds. Though not scripted by Carmichael himself,The Carmichael Showwriter-producer Ari Katcher and hisRamyco-writer Ryan Welch have crafted a character-focused story with layers of necessary darkness and pathos while still injecting humor that mostly feels like a natural fit considering the subject matter. As to be expected,Taste of Cherrythis is not, but with its layers of despair and dark comedy mixed with genuine friendship, Carmichael owes a bit toMikey and Nickyin this ride-or-die, last-day-in-a-life outing. Even if the last act doesnt succeed as intended,On the Count of Threethreads the difficult task of finding the humor in hopelessness while not exploiting the genuine pain of severe depression. Jordan R. (full review)

Where to Stream: Hulu

Orphan: First Kill (William Brent Bell)

Screenwriters Alex Mace and David Leslie Johnson-McGoldrick gave their character Leena Klammer, aka Esther Albright, a complete back story at the end of Jaume Collet-SerrasOrphan. A victim of a rare hormone disorder known as hypopituitarism, causing proportional dwarfism, had made it so this 33-year-old woman looked as though she were only nine. The condition obviously prevented her from being seen as a mature adult; thus she used it to her manipulative advantage. What began as thieving, however, eventually escalated to murder once her desire to sleep with her adopted fathers reinforced that finding love, while unquestionably difficult, proved impossible when her targets initially believed themselves to be herdad. At least seven people were left dead in her wake alongside their homes charred remains. Jared M. (full review)

Where to Stream: VOD

The Princess (Ed Perkins)

By design, Ed PerkinsThe Princesskeeps a healthy, mediated distance from its subject, the late Princess of Wales. After all, the news is the first draft of history, and the film restricts its view to what we knew at the time. In doing so Perkins orchestrates a film that demystifies the lore and media obsession with Princess Diana, in essence pointing its gaze inwardtowards the media covering the adoring fans in the moment. They sometimes turn against the media, defending the Peoples Princess in shouting matches on talk shows and sometimes in the streets, yet the economic incentives for rabid paparazzi persist. John F. (full review)

Where to Stream: HBO Max

Shadow (Zhang Yimou)

With its gorgeously choreographed sword duels, sabers slicing through paddles of blood and rain, watercolor bi-chromatic palettes and sumptuous costumes, Zhang YimousShadow(Ying) is a film of visual charms. To enter into the Fifth Generation maestros latest period piece is to be invited to marvel at a 116-minute long dance a stunning return to form from a director whod previously ventured into semi-autobiographical terrain with the 2014 movingComing Home, and later veered into the bombastic Chinese-cum-Matt Damon blockbuster epic letdownThe Great Wall(2016).Shadowbrings heart and spectacle together, and the result is a bombastic martial artswuxiareplete with duels of breath-taking beauty that will please longtime Zhang acolytes and newbies alike. Leonardo G. (full review)

Where to Stream: MUBI (free for 30 days)

Spin Me Round (Jeff Baena)

There are a number of reasons to recommendSpin Me Round, a winning comedy about the manager of an Olive Garden-style restaurant who gets chosen to attend a training program in Italy. The film features a shockingly stacked supporting cast of comedy titans: Aubrey Plaza, Tim Heidecker, Molly Shannon, Fred Armisen, Lil Rel Howery,The Offices Zach Woods,Lookings Lauren Weedman, andHigh Maintenances Ben Sinclair. The latest from director Jeff Baena, whose strange and wildly diverse filmography includesLife After BethandThe Little Hours,Spin Me Roundstood out as one of the better comedies in a strong SXSW lineup earlier this yeareven its Harlequin romance novel-apingposteris a gem. Chris S. (full review)

Where to Stream: VOD

Vengeance (B.J. Novak)

Despite its generic title, B.J. Novaks feature-directing debutVengeanceis a smart, subversive fish-out-of-water comedy about a stereotypical coastal elite that gets intellectually catfished into traveling to a remote Texas town complete with a rodeo and Whataburger, seemingly the defacto town meeting place. Novak plays Ben Manalowitz, a Brooklyn-based writer for theNew Yorkerand Bumble power user who dreams of branching out into podcasting, though he just hasnt had his big break. After trading witty quips with famed ladies man John Mayer at a rooftop party about the first-world problem of having too many beautiful women in your phone to keep track of, he meets Eloise (Issa Rae), a producer at a podcast network modeled on NPR. John F. (full review)

Where to Stream: VOD

Also New to Streaming

Hulu

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Nonalcoholic Fatty Liver Disease and Hypothyroidism: What You Need to Know – Cureus

Non-alcoholic fatty liver disease (NAFLD) is a form of chronic liver disease increasingly arising among children and adults. It ranges from simple steatosis and non-alcoholic steatohepatitis (NASH) to advanced fibrosis and cirrhosis with chronic liver failure. Non-alcoholic fatty liver disease is a condition marked by the deposition of lipids in the liver cells in patients who consume very little or no alcohol. The histological picture is similar to alcohol-induced liver injury, yet it occurs in people who do not drink or consume very little. Liver enzymes such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), and other markers of liver injury are increased in NAFLD. However, those levels are normal in a large percentage of patients with NAFLD [1,2].

According to a meta-analysis that included more than eight and a half million people from 22 countries, the worldwide prevalence of fatty liver is 24%, whereas, in the United States, the prevalence of NAFLD is also24% [3]. Compared to a worldwide population, patients with NAFLD and non-alcoholic steatohepatitis have an increased death rate due to liver-related diseases. These patients are strongly associated with extrahepatic diseases such as endocrinopathies like diabetes mellitus, metabolic syndrome, thyroid dysfunction, insulin resistance, cardiovascular diseases, and chronic kidney diseases [3].

Subclinical hypothyroidism is characterized by increased plasma thyroid-stimulating hormone (TSH) and plasma thyroid hormone levels within the reference range and without obvious clinical symptoms. Overt hypothyroidism has obvious clinical symptoms and low free Thyroxine (fT4) [4]. Thyroid hormones are crucial in multiple physiological processes like homeostasis, mineral, lipid, carbohydrates, and protein metabolisms. Lipid metabolism has been reported, such as increased metabolic rate, weight loss, lipolysis, and lowering serum cholesterol levels. The physiological process of thyroid hormones (TH) affects almost every organ, and the liver is one of the most critical targets of TH [5]. Low thyroid hormone function may cause hypercholesterolemia which plays a fundamental role in the pathophysiology of hypothyroidism-induced NAFLD [6].

In recent years, more attention has been brought to hypothyroidism-induced NAFLD. The pathogenesis of non-alcoholic fatty liver disease and thyroid hormones may have close correlations, as research in the last ten years showed that disruptions of cellular TH signaling, trigger chronic hepatic disease, including non-alcoholic fatty liver disease, alcoholic fatty liver disease, and hepatocellular carcinoma. This disruption results in decreased hepatic lipid utilization and secondary lipid accumulation [3,5,7].

The present review will discuss associations between hypothyroidism and NAFLD and the importance of thyroxine (T4), triiodothyronine (T3), and thyroid-stimulating hormone (TSH) in its pathophysiology. The association between NAFLD and hypothyroidism is still controversial. At present, there are multiple studies showing an association. Therefore, it is necessary to conduct more studies in order to answer this question [8,9].

Since discovering alcohol-related liver disease in 1845, fatty liver disease (FLD) has been primarily linked to excessive alcohol consumption. Non-alcoholic fatty liver disease was first described in 1981, and it includes a wide variety of hepatic conditions that include simple steatosis to steatohepatitis, advanced fibrosis, and cirrhosis. Non-alcoholic steatohepatitis and NAFLD have a similar presentation on histology, but in the case of NAFLD, there is different pathophysiology [10].

The prevalence of NAFLD among the population drastically increased in the last twenty years. NAFLD manifests itself in various ways in people worldwide, affecting both the female and male sex. The global prevalence of NAFLD is 25 percent, which is approximately as high as one billion and growing. One of the most common causes of chronic liver disease in the United States is NAFLD. It affects 80 to 100 million people, and approximately 25% of the cases progress to NASH. NAFLD includes a wide range of histopathological conditions such as non-alcoholic fatty liver (NAFL), non-alcoholic steatohepatitis (NASH), fibrosis, NASH cirrhosis, and NASH-related hepatocellular carcinoma (HCC). NAFLD is a diagnosis of exclusion. The number of NASH patients with cirrhosis is rising, resulting in an increase in liver transplantation for end-stage cirrhosis [11-13].

NAFLD is characterized by the accumulation of more than five percent of hepatic fat in the absence of any secondary causes. NAFLD can manifest in different ways, ranging from a simple accumulation of fat that is a metabolic condition with no symptoms and no inflammation of the liver (non-alcoholic fatty liver) to symptomatic non-alcoholic steatohepatitis with inflammation of the liver. It has the capacity to progress into severe fibrosis, end-stage liver disease, and HCC depending on NAFLD subtypes. While 10 to 20% of NAFLD patients develop NASH, only zero to four percent develop cirrhosis within 10 to 20 years. The rising prevalence of NAFLD with advanced fibrosis is concerning because individuals with advanced fibrosis tend to have an increased death rate of liver-related and non-liver-related diseases than the general population [11,14-17].

NAFLD is divided into four stages: 1. Simple steatosis (NAFL) - accumulation of fat in the liver without inflammation or damage to the liver cells; 2. NASH - accumulation of fat in the liver with the presence of inflammation and liver celldamage - hepatitis; 3. Fibrosis - scarring of the liver tissue (excess of fibrous tissue) in the inflamed liver. Fibrosis is categorized into stages - mild, moderate, and advanced, or into four stages (0-4) based on the progression of scaring; 4. Liver cirrhosis - permanently damage to the liver with nodules of damaged liver cells surrounded by scar tissue; 5. Progression to HCC [18].

To diagnose NAFLD, we must exclude other causes such as alcohol abuse (which is defined as consumption of >20 g/day for women or >30 g/day for men), drug abuse, Hepatitis C and Hepatitis B, Wilson's disease, hemochromatosis, celiac disease, and autoimmune liver disease, because NAFLD is a diagnosis of exclusion [19,20].

Insulin resistance and obesity are the two most important risk factors for NAFLD. However, NAFLD is associated with other extrahepatic manifestations such as obstructive sleep apnea, hypertension, gut microbiota alterations, dyslipidemia, sedentary lifestyle, overconsumption of carbohydrates (leading to de novo lipogenesis), and genetic predisposition. The prevalence of NAFLD in obese patients is 51%, patients with dyslipidemia are 69%, Type 2 diabetes 22,5%, and patients with hypertension are 39,3%, respectively. Nonetheless, there are other endocrine diseases that are associated with NAFLD: hypopituitarism, hypogonadism, polycystic ovarian syndrome, and hypothyroidism [11,14,19].

Thyroxine (T4 or 3,3,5,5-tetraiodo-l-thyronine) and triiodothyronine (T3 or 3,5,3-triiodo-l-thyronine) are thyroid hormones. The thyroid gland produces predominantly T4, but deiodination of T4 in peripheral tissues creates the majority of systemic T3, which is the most potent thyroid hormone. The hypothalamic-pituitary axis controls the secretion of TH from the thyroid gland. Thyrotropin-releasing hormone (TRH) is a hormone released by the hypothalamus that acts on the pituitary gland by binding to G protein-coupled TRH receptors on the thyrotrope, causing an increase in intracellularcyclic adenosine monophosphate (cAMP) and the production of thyrotropin. TSH stimulates the generation and release of TH by binding to a G protein-coupled TSH receptor on the thyroid follicular cell [21,22].

The thyroid gland regulates many biological activities in the liver, adipose tissue, central nervous, cardiovascular, and musculoskeletal systems by producing and releasing thyroid hormones such as thyroxine and triiodothyronine into the blood. One of the main physiological functions of TH is to maintain basal energy expenditure by glucose and lipid metabolism modulation. Thyroid hormones increase the production of fatty acids, modulate the sensitivity of the insulin in the hepatic tissue, and decrease hepatic gluconeogenesis, in addition to increasing lipid export and oxidation. The TH receptor (TR) regulates lipid metabolism (synthesis, mobilization, and degradation) as well as the metabolism of glucose by regulating the expression of several other nuclear receptors.HMG-CoA reductase (3-hydroxy-3methylglutarylcoenzyme A), which initiates cholesterol biosynthesis, can be stimulated by thyroid hormones. Also, triiodothyronine (T3) has the ability to bind to certain thyroid hormone-responsive elements and activate the LDL receptor gene, thereby upregulating LDL receptors. Also, thyroid hormones regulate HDL metabolism. Thyroid hormones increase the expression of the regulatory sterol element-binding protein-2, which regulates cholesterol metabolism (SREBP-2). T3 also stimulates lipoprotein lipase, which catabolizes triglyceride (TG)-rich lipoproteins, resulting in a reduction in TG levels [15,22-25].

Both T3 and T4 act via TRs, when thyroid hormones binding to the genes of thyroid receptors, which then help facilitate the transport of free fatty acids in the cells of the hepatic tissue, with the help of protein transporters like liver fatty acid-binding proteins (L-FABPs), fatty acid transporter proteins (FATPs), and fatty acid translocases (FAT). THs can increase intrahepatic lipolysis through lipophagy in hepatocytes via THR-, resulting in decreased TG clearance and increased TG hepatic uptake [10,26]. This type of lipophagy is linked to triiodothyronine physiology. T3 plays a significant role in fatty acid transport to mitochondria and mitochondrial metabolism by altering the range of hepatic lipid-related metabolites T3. T3 stimulates lipophagy in cultured hepatic cell lines, which leads to hepatic autophagy and ketogenesis. These results suggest that T3 regulates hepatic autophagy, which is an important step in the management of NAFLD [27].

We know that hypothyroidism is linked to hypometabolism. It is characterized by increasing weight, decreasing resting energy expenditure, and decreasing gluconeogenesis and lipolysis. Obesity, impaired lipid metabolism, and insulin resistance can be caused by THs dysfunction, which are symptoms of metabolic syndrome that are also present in NAFLD [28]. Overt hypothyroidism and subclinical hypothyroidism are both related to NAFLD [8].

In subclinical hypothyroidism, there are several factors that contribute to the progression of NAFLD, such as the physiology of TSH on the hepatocytes cell membrane, impairing hepatic triglyceride metabolism (promoting hepatic lipogenesis) through the upregulation of SREBP-1c activity provoked by stimulation of TSH receptors. Also, in the case of low thyroid hormone, diminished glucose-sensing receptors of the beta cells of the pancreas. In this manner, it reduces insulin secretion and decreases lipolysis in the adipose tissue, increasing the traffic of FFA to the hepatic tissue [19,22,29].

Patients with hypothyroidism often have atherogenic dyslipidemia. It has been established that the pathophysiology of hypothyroidism-induced hyperlipidemia is due to a reduction in cholesterol excretion and a marked rise in apoB lipoproteins as a result of insufficient catabolism and turnover brought on by a reduction in the number of low-density lipoprotein (LDL) receptors on the surface of the hepatic cells. In this manner, elevated total and LDL cholesterol levels are common in hypothyroid patients. Also, decreased clearance level of triglycerides from plasma and the buildup of intermediate density lipoproteins were noted in hypothyroidism. Hypothyroidism-induced NAFLD may develop because of the rising LDL and accumulation of triglycerides in the hepatic tissue [22,27]. Accumulation of the lipids causes oxidative stress and inflammatory response in the liver [8].Another factor that may be involved in the thyroid-liver complex is leptin. Leptin is elevated in hypothyroid patients and is also elevated in NAFLD patients. Leptin can promote hepatic insulin resistance and play a role in hepatic fibrogenesis [7].

In the meta-analysis from 2018 that involved 26 studies and 61,548 participants, 11 studies with a total of 47,217 patients with NAFLD/NASH had significantly higher thyroid-stimulating hormones than healthy controls, this difference remains significant. With the progression of NAFLD, the level of TSH increased as well. The research found that hypothyroidism raised the probability of non-alcoholic fatty liver disease or non-alcoholic steatohepatitis. These results were disputed in subsequent evaluations based on the degree of hypothyroidism. The risk of non-alcoholic steatohepatitis was substantially correlated with subclinical hypothyroidism but not with the risk of NAFLD. On the other hand, the risk of non-alcoholic fatty liver disease is substantially correlated with overt hypothyroidism in adults but not with the risk of NASH. These results might be inconsistent due to the small number of included studies. This meta-analysis also discovered that the relationship between NAFLD and free T3 (FT3) and free T4 (FT4) may vary by the number of people that live in the area and that non-alcoholic fatty liver disease is perhaps unrelated to FT3 or FT4. These results might be evidence that TSH, rather than thyroid hormones, plays a key role in the onset and progression of NAFLD [8].

In another meta-analysis from 2021 that involved 17 articles and 14,514 participants included, elevated TSH levels maybe be a risk factor that is independently associated with NAFLD. FT4 was significantly associated with NAFLD when FT3 was not associated [30].

There is no drug therapy for hypothyroidism-induced NAFLD that is currently approved. Steatosis can be reduced through structured lifestyle changes such as weight loss, dietary changes such as reduced drinking of alcohol, decreasing intake of food and drinks that have a high level of fructose, and increased daily activities and workouts [16,29].

In a case report of a patient with NASH who was diagnosed with Graves' disease (GD), the liver enzyme levels improved after the onset of GD and subsequent hyperthyroidism. They worsened after starting treatment and returning to a euthyroid state [31].

A small-molecule liver-directed thyroid hormone receptor agonist (Resmetirom) with high liver uptake is administered orally and is under development (currently in Phase 3 of trial) for the treatment of NAFLD/NASH and familial hypercholesterolemia [4,32].

Continued here:
Nonalcoholic Fatty Liver Disease and Hypothyroidism: What You Need to Know - Cureus

Global Metabolic Partnering Report 2022: Deal Trends, Players and Financials Analysis of 1100+ Deals Signed Since 2015 – ResearchAndMarkets.com -…

DUBLIN--(BUSINESS WIRE)--The "Global Metabolic Partnering 2015-2022: Deal trends, players and financials" report has been added to ResearchAndMarkets.com's offering.

Global Metabolic Partnering 2015 to 2022 provides the full collection of 1100+ Metabolic disease deals signed between the world's pharmaceutical and biotechnology companies since 2015.

Most of the deals included within the report occur when a licensee obtains a right or an option right to license a licensor's product or technology. More often these days these deals tend to be multi-component including both a collaborative R&D and a commercialization of outcomes element.

The report takes readers through the comprehensive Metabolic disease deal trends, key players and top deal values allowing the understanding of how, why and under what terms companies are currently entering Metabolic deals.

The report presents financial deal terms values for Metabolic deals, where available listing by overall headline values, upfront payments, milestones and royalties enabling readers to analyse and benchmark the value of current deals.

The initial chapters of this report provide an orientation of Metabolic dealmaking trends.

Chapter 1 provides an introduction to the report.

Chapter 2 provides an overview of the trends in Metabolic dealmaking since 2015 covering trends by year, deal type, stage of development, technology type and therapeutic indication.

Chapter 3 includes an analysis of financial deal terms covering headline value, upfront payment, milestone payments and royalty rates.

Chapter 4 provides a review of the leading Metabolic deals since 2015. Deals are listed by headline value. The chapter includes the top 25 most active Metabolic dealmakers, together with a full listing of deals to which they are a party. Where the deal has an agreement contract published at the SEC a link provides online access to the contract.

Chapter 5 provides comprehensive access to Metabolic deals since 2015 where a deal contract is available, providing the user with direct access to contracts as filed with the SEC regulatory authorities. Each deal title links via Weblink to an online version of the deal record contract document, providing easy access to each contract document on demand.

Chapter 6 provides a comprehensive directory of all Metabolic partnering deals by specific Metabolic target announced since 2015. The chapter is organized by specific Metabolic therapeutic target. Each deal title links via Weblink to an online version of the deal record and where available, the contract document, providing easy access to each contract document on demand.

In addition, a comprehensive appendix is provided with each report of all Metabolic partnering deals signed and announced since 2015. The appendices are organized by company A-Z, stage of development at signing, deal type (collaborative R&D, co-promotion, licensing etc) and technology type. Each deal title links via Weblink to an online version of the deal record and where available, the contract document, providing easy access to each contract document on demand.

The report includes deals for the following indications: Acromegaly, Addison's disease, Cirrhosis, Cushing's syndrome, Diabetes, Type 1, Type 2, Insipidus, Fatty liver, Gallstones, Goitre, Growth hormone disorders, Gynaecomastia, Inborn errors of metabolism, Phenylketonuria, Hyperaldosteronism, Hypercalcaemia, Hyperthyroidism, Hypocalcaemia, Hypogonadism, Hypopituitarism, Hypothyroidism, Liver disease, Nonalcoholic steatohepatitis (NASH), Lysosomal storage disorders, Nutrition and vitamins, Rickets, Pheochromocytoma, Primary bilary cirrhosis, Prolactinemia, Short stature, Syndrome of Inappropriate Antidiuretic Hormone (SIADH), Thyroid disease, plus other metabolic indications.

Report scope

Global Metabolic Partnering 2015 to 2022 includes:

In Global Metabolic Partnering 2015 to 2022, available deals and contracts are listed by:

Analyzing actual contract agreements allows assessment of the following:

Key Topics Covered:

Executive Summary

Chapter 1 - Introduction

Chapter 2 - Trends in Metabolic dealmaking

2.1. Introduction

2.2. Metabolic partnering over the years

2.3. Metabolic partnering by deal type

2.4. Metabolic partnering by industry sector

2.5. Metabolic partnering by stage of development

2.6. Metabolic partnering by technology type

2.7. Metabolic partnering by therapeutic indication

Chapter 3 - Financial deal terms for Metabolic partnering

3.1. Introduction

3.2. Disclosed financials terms for Metabolic partnering

3.3. Metabolic partnering headline values

3.4. Metabolic deal upfront payments

3.5. Metabolic deal milestone payments

3.6. Metabolic royalty rates

Chapter 4 - Leading Metabolic deals and dealmakers

4.1. Introduction

4.2. Most active in Metabolic partnering

4.3. List of most active dealmakers in Metabolic

4.4. Top Metabolic deals by value

Chapter 5 - Metabolic contract document directory

5.1. Introduction

5.2. Metabolic partnering deals where contract document available

Chapter 6 - Metabolic dealmaking by therapeutic target

6.1. Introduction

6.2. Deals by Metabolic therapeutic target

Appendices

Appendix 1 - Directory of Metabolic deals by company A-Z since 2015

Appendix 2 - Directory of Metabolic deals by deal type since 2015

Appendix 3 - Directory of Metabolic deals by stage of development since 2015

Appendix 4 - Directory of Metabolic deals by technology type since 2015

For more information about this report visit https://www.researchandmarkets.com/r/7b8gbu

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Global Metabolic Partnering Report 2022: Deal Trends, Players and Financials Analysis of 1100+ Deals Signed Since 2015 - ResearchAndMarkets.com -...

A Case of Undiagnosed Functional Gonadotroph Adenoma Leading to Ovarian Hyperstimulation Syndrome – Cureus

A functional gonadotroph adenoma is a very rare endocrinopathy, and only a few cases have been reported in the literature. We present a case of a woman in her early 50s with a past medical history of recurrent ovarian cysts who developed bilateral hemianopsia and was referred to the endocrinology clinic after a magnetic resonance imaging (MRI) identified a pituitary mass. Anterior pituitary hormone workup confirmed hypersecretion of follicle-stimulating hormone (FSH), which suggested ovarian hyperstimulation syndrome (OHSS) as the etiology of recurrent ovarian cysts. The patient underwent transsphenoidal resection of the pituitary tumor with improvement in visual symptoms. Our case illustrates that functional gonadotroph adenoma can be a potential cause of OHSS apart from the setting of assisted reproductive technology and hence warranting a meticulous endocrine evaluation to rule out this rare disease.

Functional gonadotroph adenomas (FGAs) are pituitary masses that secrete either follicle-stimulating hormone (FSH) or luteinizing hormone (LH) [1]. These are extremely rare endocrinopathies with only a few cases in the literature as the majority of immunohistochemically confirmed gonadotroph adenomas are nonfunctional [2]. While pituitary masses, in general, can cause symptoms of mass effect such as headaches and visual disturbances, FGAs can present with various ambiguous findings, such as menstrual disturbances, and gonadal stimulation, making them difficult to diagnose [2]. They are best managed with surgical excision, although options are available for medical management, they have no effect on tumor burden [2]. Ovarian hyperstimulation syndrome (OHSS) is most commonly an iatrogenic complication of assisted reproductive techniques. While its pathophysiology is largely unknown, the process is thought to be an amplified response to gonadotropin stimulation [3]. This article describes the case of an FSH-secreting pituitary adenoma presenting as OHSSin a premenopausal woman.

A woman in her early 50s with a past medical history of recurrent ovarian cysts and hypothyroidism was referred to the endocrinology clinic for evaluation of a possible functioning pituitary macroadenoma found on an MRI of the brain. Six months prior to the presentation, the patient began experiencing bitemporal hemianopia. She also reported having right-sided frontotemporal headaches for the past several years but denied nipple discharge or trouble with conception and had a child. MRI brain done prior to presentation showed a 3.5 x 3.8 x 4.3 cm sellar and suprasellar mass consistent with a pituitary macroadenoma causing prechiasmatic optic nerve compression.Her medical history was significant for menorrhagia secondary to recurrent ovarian cysts for which she underwent totalhysterectomy with bilateral oophorectomy 11 years prior to presentation. She also had hypothyroidism managed with a stable dose of levothyroxine 50 g daily.On presentation to the endocrinology clinic, her vital signs were stable. Neurological examination confirmed bilateral temporal hemianopia, consistent with her history.

Anterior pituitary hormone evaluation on presentation revealed elevated FSH and low LH(Table 1). The remaining labs were unremarkable.Based on the elevated FSH and history of recurrent ovarian cysts, it was determined that the mass identified on MRI was likely a true FSH secretory adenoma. Given the tumor size, mass effect, and lack of effective medical management, the patient was referred for surgery.A repeat MRI of the brain was obtained for surgical planning which confirmed the presence of a 4.1 x 3.6 x 3.9 cm mass extending into the sphenoid sinuses and pterygoid recess(Figures 1A, 1B). The patient underwent surgical debulking of the tumor by transsphenoidal resection two months following presentation, and histopathological examination confirmed FSH immunoreactive adenoma. Postoperatively, she was treated with hydrocortisone 30 mg daily, divided into a 20 mg and 10 mg dose, which was gradually tapered to discontinuation. A repeat pituitary panel following resection revealed a lowFSH (2.55 mIU/mL) and LH level (0.75mIU/mL), indicating resolution of the FSH hypersecretion(Table 1).The patient had an uncomplicated hospital course and was discharged home three days aftersurgery. On follow-up two weeks after discharge, she reported a subjective improvement of 30% in her vision. At the three-month follow-up, she did not have further improvement in her visual symptoms and MRI confirmed gross total resection of the tumor with postsurgical changes(Figures 2A, 2B).Unfortunately, the patient was lost to follow-up afterward.

The incidence of pituitary adenomas is between 3.9 and 7.4 cases per 100,000 per year, and these tumors most commonly arise from gonadotroph cells, which account for 15%-40% [1,4]. These adenomas are generally nonfunctioning clinically but can cause headaches, visual disturbances, and hypopituitarism due to the mass effect [2]. In contrast, clinically functioning pituitary adenomas are extremely rare, accounting for less than 1% of all pituitary adenomas [1]. Functional gonadotroph adenomas (FGAs) can present in various ways depending on the patient, although many patients are asymptomatic [5]. Women often present with menstrual irregularities, and younger children may experience precocious puberty [2]. The excess secretion of FSH by a gonadotropin-secreting pituitary adenoma has also been associated with gonadal stimulation and OHSS in women of childbearing age [2].

OHSS itself is most often an iatrogenic complication of assisted reproductive techniques and results in enlarged ovaries with multiseptated cysts significantly larger than those found in polycystic ovary syndrome [2,3]. The pathogenesis is thought to be related to the ovarian response to FSH stimuli [3]. Conversely, patients who experience spontaneous OHSS should undergo further evaluation for an FGA [6].

In this case, the patients visual difficulties necessitated imaging, which identified the pituitary mass before any labs were obtained. However, in the absence of symptoms of mass effect, an elevated ratio of FSH to LH should raise suspicion for OHSS secondary to a pituitary adenoma, as FSH hypersecretion ultimately limits LH secretion via negative feedback [2]. In addition to elevated estradiol, most cases have a mild elevation of the prolactin level, likely due to pituitary stalk compression [2]. Our patient is unique as the diagnosis was likely missed in early reproductive age. She had the clinical characteristic including elevated FSHand low LH with a history of recurrent ovarian cysts further in addition to the adenoma seen on MRI. All of this indicates that the adenoma was not only functional but also symptomatic. It is also important to mention the difference between polycystic ovarian syndrome and OHSS as causes of ovarian cysts and we described the major clinic differences inTable 2as it could sometimes lead to misdiagnosis of the patients [7,8].

FGAs are generally treated with transsphenoidal resection of the tumor, which normalizes hormone levels, leads to regression of ovarian cysts, restores regular menses, and improves fertility [2]. For scenarios where surgical resection is difficult or contraindicated, medical therapy involves dopamine agonists, such as cabergoline [2]. These agents can reduce levels of FSH and estradiol and reduce the ovarian sizebut do not address the issue of tumor burden and mass effect [2]. Radiotherapy or radiosurgery may be also considered for residual tumors [1].

Clinicians should have a high degree of suspicion for FSH-secreting pituitary adenoma while evaluating patients with multiple ovarian cysts who do not meet the criteria for PCOS especially if these patients are not undergoing any treatment with assisted reproductive technology. Early evaluation and diagnosis of the functional FSH-secreting pituitary adenomacould lead to the preservation offertility and prevent patients from undergoing repeated surgeries for ovarian cyst removals and/or hysterectomy.

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A Case of Undiagnosed Functional Gonadotroph Adenoma Leading to Ovarian Hyperstimulation Syndrome - Cureus

Hypopituitarism: Symptoms, Treatment & Diagnosis

OverviewWhat is hypopituitarism?

Hypopituitarism is a rare condition in which theres a lack (deficiency) of one, multiple or all of the hormones made by your pituitary gland. Hormones are chemicals that coordinate different functions in your body by carrying messages through your blood to your organs, muscles and other tissues. These signals tell your body what to do and when to do it.

The pituitary hormones are in charge of important functions in your body, such as metabolism, growth and development and reproduction. Your pituitary gland is a pea-sized gland located at the base of your brain below your hypothalamus (the part of your brain that controls your autonomic nervous system). Its a part of your endocrine system.

Your pituitary gland is connected to your hypothalamus through a stalk of blood vessels and nerves. This is called the pituitary stalk. Through the stalk, your hypothalamus communicates with your pituitary gland and tells it to release certain hormones. Your hypothalamus is the part of your brain that controls functions like blood pressure, heart rate, body temperature and digestion.

Hypopituitarism can occur from disorders of or damage to your pituitary gland or hypothalamus.

Your pituitary gland makes the following hormones:

There are three different kinds of hypopituitarism based on the number of hormones that are lacking (deficient):

There are three kinds of hypopituitarism based on the cause of it and how your pituitary gland and its hormones are affected:

Hypopituitarism can affect anyone at any age, though its a rare condition.

Hypopituitarism is a rare condition. There are approximately 10 to 40 new cases per one million people a year.

The symptoms of hypopituitarism depend on which pituitary hormone(s) are affected and deficient (lacking). The following factors also affect what kind of symptoms youll experience:

Symptoms of growth hormone deficiency in newborns include:

Symptoms of growth hormone deficiency in children include:

Symptoms of growth hormone deficiency in adults include:

Symptoms of thyroid-stimulating hormone deficiency in newborns include:

Symptoms of thyroid-stimulating hormone deficiency in children and adults are similar to symptoms of hypothyroidism, an underactive thyroid. This is because TSH stimulates your thyroid to produce its own hormones.

Symptoms of hypothyroidism include:

FSH and LH are called gonadotropins and affect your reproductive system.

Symptoms of FSH deficiency and/or LH deficiency in newborns assigned male at birth include:

Symptoms of FSH deficiency and/or LH deficiency in children include:

Symptoms of FSH deficiency and/or LH deficiency in adults assigned male at birth include:

Symptoms of FSH deficiency and/or LH deficiency in adult assigned female at birth can include:

Symptoms of ACTH deficiency in newborns include:

Symptoms of ACTH deficiency in children and adults include:

The main symptom of prolactin deficiency is a lack of breast milk production after giving birth.

Symptoms of oxytocin deficiency include:

Symptoms of ADH deficiency in newborns include:

Symptoms of ADH deficiency in children include:

Symptoms of ADH deficiency in adults can include:

Many conditions and situations can cause hypopituitarism. In some cases, healthcare providers cant determine the cause. This is called idiopathic hypopituitarism. In general, these three main factors can cause hypopituitarism:

Examples of conditions that can cause pressure on your pituitary gland or hypothalamus include:

Examples of situations that can cause pituitary or hypothalamus damage include:

Examples of rare conditions that can cause hypopituitarism include:

Your healthcare provider may order any of the following tests to diagnose hypopituitarism:

Treatment for hypopituitarism depends on which pituitary hormone(s) are deficient and the cause of the hypopituitarism. For that reason, treatment is very individualized. Your healthcare team will determine what the best treatment plan is for you. Common treatment options for hypopituitarism include:

Currently, theres no known cure for hypopituitarism, but it is treatable.

The following conditions or situations are considered risk factors for hypopituitarism:

Unfortunately, there are no known ways to prevent hypopituitarism.

The prognosis for hypopituitarism varies and depends on the following four factors:

In most cases, people with hypopituitarism require close, lifelong monitoring of their hormones and symptoms. While many people with hypopituitarism lead healthy lives, long-term pituitary damage is associated with an increased risk of mortality (death) compared to people without hypopituitarism of the same age.

Although it is not as common, a sudden and severe onset of hypopituitarism can result in a medical emergency and death if its not treated. Be sure to call your healthcare provider or go to the nearest emergency room if you are experiencing symptoms.

In most cases, hypopituitarism requires close, lifelong monitoring of the hormones affected. Be sure to see your healthcare provider regularly to make sure your treatment plan is working. If youre experiencing new or concerning symptoms, contact your healthcare provider as soon as possible.

If youve been diagnosed with hypopituitarism, you may want to ask your healthcare provider the following questions:

A note from Cleveland Clinic:

A new diagnosis can be scary, but dont be afraid to ask your healthcare provider questions about your hypopituitarism. Most cases of hypopituitarism require lifelong treatment and monitoring of your hormones, so it is important to see your provider regularly. Be sure to contact your provider if you have new or concerning symptoms. Theyre there to help.

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Hypopituitarism: Symptoms, Treatment & Diagnosis

Polyendocrine gland injury induced by an immunosuppressant | DMSO – Dove Medical Press

Introduction

In recent years, break through progress has been made in immunotherapy of malignant tumors, and it has become a new treatment method for refractory or recurrent tumors. Immune checkpoint inhibitors (ICIs) can target programmed death-1 (PD-1), Cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed death ligand-1 (PD-L1) to reactivate the killing function of effector T cells in tumor cells, thus exerting an antitumor effect.1 Currently, ICIs are divided into three main types: PD-1 inhibitors, PD-L1 inhibitors and CTLA-4 inhibitors. Due to their unique mechanism of action, their adverse reactions are different from those of traditional chemoradiotherapy and targeted therapy, and immune dysfunction is the most common therefore, adverse reactions to ICIs are called immune-related adverse events (irAEs).2 Endocrine adverse reactions are one of the most common adverse reactions and mainly involve the pituitary gland, thyroid gland, pancreas, adrenal gland and other endocrine glands, resulting in corresponding endocrine dysfunction. The mechanism of irAEs is not clear, but it has been determined that it is related to the excessive immune response caused by ICIs. This article reports a case of irAEs related to type 1 diabetes mellitus (T1DM) and diabetic ketoacidosis (DKA) after the occurrence of hypophysitis during immunotherapy and includes a review of the related literature to analyze the clinical characteristics of the disease and provide a basis for the diagnosis and treatment of endocrine system irAEs caused by such drugs.

1.The patient was a 45-year-old man with a body mass index of 25.51 kg/m2. In January 2018, a chest CT examination was performed due to cough and sputum, and it showed a mass in the right lower lung. An additional chest enhanced CT scan and bronchoscopy biopsy led to a diagnosis of right middle and lower lobe adenocarcinoma. In view of the rapid growth of the lesion and the difficulty of surgery, no surgical treatment was performed. The patient received pemetrexed, gemcitabine and platinum chemotherapy successively, routine blood tests were performed, and liver and kidney function and blood glucose were monitored regularly during chemotherapy; no abnormalities were found. Later, due to obvious adverse reactions to chemotherapy drugs, the patient was enrolled in the Phase II clinical trial to evaluate the efficacy, safety and drug resistance of KN046 in subjects with advanced non-small-cell lung cancer in July 2019 using KN046 (recombinant humanized PD-L1/CTLA-4 bispecific single-domain antibody Fc fusion protein injection), the clinical trial identifier number:KN046-201. The patient received KN046 223.5 mg intravenous drip treatment successively from July 2019 to July 2021 every 14 days as a cycle. After 11 months of starting treatment (June 2020), the patient went to the doctor due to fatigue, and hypopituitarism was found. At that time, the levels of cortisol and adrenocorticotropic hormone and thyroid hormone levels were lower than normal. An MRI of the pituitary gland was normal. After that, prednisone tablets (7.5 mg) and levothyroxine tablets (75 g) were taken daily as replacement therapy, and the symptoms improved.

2. On July 26, 2021, the patient developed nausea, vomiting and poor appetite without obvious causes and did not improve after receiving fluid reinfusion and gastric protection at the local hospital for acute gastroenteritis. On August 2, 2021, the patient was admitted to our hospital due to a fasting blood glucose (FBG) result of 360 mg/dl and HbA1c of 9.25%. The patient had no history of diabetes or hypertension. The patient regularly underwent routine biochemical review during immunotherapy, and his FBG was 7290 mg/dl. The last routine biochemical review suggested that the FBG was 100.8 mg/dl on July 20, 2021. On admission, the body temperature was 36.6 C, heart rate was 120 beats/min, breathing was 21 breaths/min, blood pressure was 136/105 mmHg, and blood oxygen saturation (SpO2) was 99%. At that time, he was conscious, poor in spirit, short of breath, and had dry skin.

3. Auxiliary examination: The blood glucose level of the fingertip was 291.6 mg/dl, and the blood ketone level of the fingertip was 6.4 mmol/L upon admission. The results of arterial blood gas analysis were as follows: pH: 7.14, partial pressure of carbon dioxide (PaCO2): 21 mmHg, partial pressure of oxygen (PaO2): 102 mmHg, bicarbonate: 7.1 mmol/L, residual alkali: 21.9 mmol/L; routine urinalysis: 3+ of ketone and + of glucose; HbA1c was 9.25% (normal range 4.06.5%) in the outpatient department. These data indicated the onset of diabetic ketoacidosis. Further examination results showed that there were no obvious abnormalities in the contrast-enhanced MRI scan of the pituitary gland (Figure 1) and the high-resolution CT of the pancreas, and the other laboratory examinations are shown in Table 1.

Table 1 Laboratory Results for the Patient

Figure 1 Sagittal and coronal slices of the pituitary MRI (A) Precontrast T1-weighted coronal slices MRI image. (B) Postcontrast T1-weighted coronal slices MR image. (C) Precontrast T1-weighted sagitta slices MRI image. (D) Postcontrast T1-weighted sagitta slices MR image. (E) Precontrast T2-weighted coronal slices MRI image. (F) Postcontrast T2-weighted sagitta slices MR image.

4. Diagnosis and treatment: The patient had no history of diabetes, and his FBG was within normal range according to regular tests; however, his HbA1c was high, so postprandial blood glucose could not be ruled out during KN046 immunotherapy. Insulin and C-peptide levels could hardly be detected after admission, suggesting that islet cell function had been lost. The patient was diagnosed with hypopituitarism for more than a year. Considering that immunotherapy involved the pituitary and caused hypophysis, HbA1c and postprandial blood glucose levels had not been monitored in the past. Therefore, based on the patients medical history and auxiliary examination, and referring to the domestic expert consensus (expert consensus on immune-related adverse reactions of the endocrine system caused by immune checkpoint inhibitors (2020)) for the recommended diagnostic criteria and disease classification of endocrine irAEs caused by ICIs, the following diagnoses were considered: 1. Immune checkpoint inhibitor-associated diabetes mellitus complicated by ketoacidosis, CTCAE grade 3; 2. Hypopituitarism hypofunction pituitary gland inflammation disease immune-checkpoint inhibitors correlation, CTCAE grade 2.3 The patient received intravenous fluid and insulin therapy in addition to oral rehydration and potassium. Intravenous insulin therapy was then followed by multiple injections of insulin aspart. For patients to stop taking prednisone and prior to administration of levothyroxine sodium replacement therapy, the hospital laboratory tests suggest that ACTH and cortisol levels are low, furthermore, Thyroxine was reduced, and thyroid stimulating hormone (TSH) was at the lower limit. To avoid pituitary induced crisis, the patients was temporarily placed on a 100 mg hydrocortisone intravenous drip. Nausea and vomiting ceased, and appetite improved markedly. After that, the prednisone tablets were substituted with low-dose therapy, and a physiological dose of levothyroxine sodium was supplemented. The patient has been treated with multiple daily subcutaneous insulin injections since August 5, 2021, and blood glucose gradually decreased and stabilized.

The main cause of irAEs induced by ICIs is excessive activation of T lymphocytes, while endocrine-related irAEs mainly include hypophysitis, thyroiditis, diabetes, and adrenal cortical hypofunction, and so on. Among them, hypophysitis and thyroiditis are the most common, while diabetes is relatively rare. Previous studies have focused on the incidence of a single endocrine irAEs; however, people with one autoimmune disease are at higher risk of developing a second autoimmune disease.4,5

A meta-analysis of ICI treatment found that 85 of 6472 patients had hypophysitis,6 but the clinical symptoms of hypophysitis were mostly atypical.7,8 The most common symptoms were headache and fatigue, and multiple hormone deficiencies were also common,9,10 including TSH, ACTH, follicle stimulating hormone and luteinizing hormone. Early pituitary MRI examination was helpful for differential diagnosis.11 There is currently no consensus on the pathogenesis of ICI-associated hypophysitis, and studies have found that the presence of antipituitary gland autoantibodies and human leukocyte antigens (HLAs) in the serum of patients may increase the susceptibility of ICIs-induced hypophysitis.12 The occurrence time of hypophysitis was related to ICI type,10 among which the incidence of PD-L1/PD-1 plus CTLA-4 inhibitor was the highest (6.4%), followed by CTLA-4 inhibitor (3.2%), PD-1 inhibitor (0.4%) and PD-L1 inhibitor (less than 0.1%).7,13 Some studies have shown that the incidence of hypophysitis induced by CTLA-4 inhibitor therapy is much higher in men than in women.6,9 The higher incidence in males may be explained by the positive effect of androgens on the expression of CTLA-4.12 Therefore, it is suggested that male patients treated with ICIs need to pay attention to the occurrence of hypophysitis, especially in those treated with CTLA-4 inhibitor or combination therapy, and the onset time is mostly within the first half-year after treatment.3 In this case, the patient was male, and hypopituitarism was found due to fatigue after KN046 immunotherapy, which was consistent with the sex characteristics of hypophysitis-related cases reported in the past, but the onset time was later than in most related cases. This patient was admitted to the hospital due to ICI involving pancreatic injury and causing DKA, and the patients previous hypopituitarism was considered to be due to hypophysitis caused by ICI treatment. After admission, pituitary-related target gland hormone levels were tested, and the levels of TT3, TT4, cortex alcohol and ACTH were still low, which may be related to the patients decision to stop taking levothyroxine tablets and prednisone tablets after the onset of this disease. At the same time, a pituitary MRI showed no abnormalities, which may be related to the patients longer onset and long-term hormone replacement therapy.

Diabetes is a relatively rare adverse reaction to ICIs, mainly seen in PD-1 inhibitor treatment, with a few cases occurring in PD-L1 inhibitor treatment and only a few cases reported in CTLA-4 inhibitor treatment.14 PD-L1 is widely expressed not only in lymphoid tissues, but also in target organs including pancreatic b cells. Blocking the interaction of PD-1 and PD-L1 might stimulate T cell proliferation and activation then leading to the destruction of b cells, providing a possible mechanism for anti-PD-1 induced T1DM.15 A meta-analysis of 7551 patients from 38 randomized clinical trials showed that ICI induced diabetes in 0.2% (13 cases).6 The combination of anti-CTLA-4 with anti-PD-1 or PD-L1 increased the frequency of irAEs by 60% compared with ICI monotherapy.16 Among these cases, the median time of onset was 20 weeks, with most cases associated with monotherapy against PD-1/PD-L1 occurring after 10 weeks.14 Similarly, a small number of patients developed T1DM later. Stamatouli et al described a case of T1DM at 228 weeks (54 months) after initial treatment.14 The onset time of T1DM in this case was 25 months after receiving KN046 immunotherapy, and the onset was sudden and reached the diagnostic criteria of ICI-related diabetes recommended by Chinese experts.3 This reminds clinicians to regularly monitor the indicators related to islet function during immunotherapy, and they still need to pay more attention even after a long period of treatment.

ICI-related diabetes has a more acute onset and rapid progression, and the symptoms may be present in a short time, with high blood glucose or DKA symptoms. During immune therapy, patients have no obvious thirst or polyuria, such as with nonspecific symptoms of diabetes, and periodically tested fasting glucose levels are within normal range. Therefore, in patients with clinical symptoms that are not obvious or with no specific symptoms, dynamic monitoring of other indicators is also required. According to European and American guidelines,2,1720 regular monitoring of blood glucose levels is recommended to detect type 1 or type 2 diabetes; however, even routine monitoring of blood glucose levels may not detect or predict its occurrence. After the onset of ICI-related diabetes, insulin and C-peptide often rapidly decreased to less than one-third of the normal value and may not return to normal for a long time. Therefore, we believe that dynamic monitoring of C-peptide levels is an effective means to predict ICI-related diabetes. In this case, the C-peptide level was too low to be detected after onset. This suggests that islet cell function was severely impaired after KN046 therapy, and some cases have reported that partial recovery of islet function can be achieved in individual patients due to the release of glycotoxicity or the onset of the honeymoon phase.21,22 Diabetes autoantibody positivity is not necessarily related to the occurrence of ICI-related diabetes but may be related to the occurrence time of diabetes. The onset time of ICI-associated T1DM with antibody positivity was shorter, and DKA occurred more frequently than in patients with insulin autoantibody negativity.14 The patients diabetes autoantibodies were negative, and the onset time was long, which was consistent with the onset characteristics of most cases at present.

In contrast to previous related cases, hypopituitarism was found in this patient for 14 months before the occurrence of DKA, suggesting that patients after ICI treatment may have multiple endocrine gland injuries. And such events have also been reported. For example, Giulia Lanzolla reported a case of hyperglycemia after 2 cycles of the PD-L1 inhibitor atezolizumab and DKA, primary adrenal hypofunction, and hypophysitis with pituitary insufficiency after 4 cycles of treatment.23 Malik Asif Humayun also reported a case of T1DM secondary to hypophysitis during treatment with nivolumab, a PD-1 inhibitor, in combination with ipilimumab, a CTLA-4 inhibitor.24 Laura Boswell reported a case of hypophysitis in the course of immunotherapy with ipilimumab, a CTLA-4 inhibitor, and then explosive T1DM after the cessation of combined immunotherapy.25 Therefore, patients undergoing immunotherapy need to pay close attention to changes in endocrine and glandular functions during treatment, and even after the treatment ends.26 We should not let our guard down, and especially in the course of combined immunotherapy, we should pay close attention to the function of other glands after the injury of one endocrine gland. More importantly, the new drug KN046 used in this patient was a PD-L1/CTLA-4 bispecific antibody independently developed by Jiangsu Corning & Jerrys Co. LTD. Its innovative design includes the fusion of CTLA-4 and PD-L1 single-domain antibodies with different mechanisms, which can simultaneously recognize PD-L1 and CTLA-4 and effectively enhance the killing of tumor cells.27 It is different from the combined immunotherapy used in previous cases, which may have caused injury to multiple endocrine glands in this patient, and the onset of the disease is late because of its unique therapeutic mechanism. In this case, a patient with polyendocrinopathy damage occurred during immunotherapy with KN046, and a trial on KN046 proposed a smart reagent that binds a nanoprobe and a double-blocking immunotherapy antibody, which improves the anti-tumor efficacy while having a high safety profile, which may reduce the incidence of irAEs.27 At present, we have not inquired about the endocrine-related irAEs caused by KN046 immunotherapy.

Due to lack of thyroid hormone function in this example patient, we were unable to determine whether the hypothyroidism is due to autoimmune thyroiditis or pituitary gland inflammation. However, the thyroid hormone function test results show that the TPOAb and TGAb levels were higher, and TRAb was negative, which may have been caused by autoimmune thyroiditis. It is also impossible to rule out whether thyroid dysfunction is caused by ICI-related thyroid damage. To determine the etiology, thyroid puncture can be performed to determine the pathological type. The causes of ICI-related thyroid dysfunction are related to the patients underlying thyroid disease, TSH levels, autoantibody titers, fluorodeoxyglucose uptake, and tumor immune microenvironment status.3

Unfortunately, the vast majority of patients described in these articles received no baseline assessment of endocrine gland function; thus, we cannot know how many had a silent metabolic/endocrine disorder before ICI therapy, and how many developed these conditions at a later date. Therefore, the strong need to have clear indications to assess patients before ICI therapy, along with a well-defined follow-up, plainly emerges.28

ICIs are widely used and can significantly prolong the survival period of tumor patients. However, we need to pay attention to various adverse reactions while focusing on their therapeutic effect. Among them, endocrine-related irAEs have unknown pathogenesis and complex clinical manifestations, which may endanger life in severe cases. In the course of ICI combination therapy, especially with immunosuppressive drugs such as KN046 that block both PD-L1 and CTLA-4 targets at the same time, patients may suffer damage to multiple endocrine glands, and it is necessary to pay close attention to the patients endocrine system irAEs for a long time, even after treatment.

Written informed consent for publication of their details was obtained from the patient. Based on the hospital there is no need for ethical clearance for the case report.

The authors declare that they have no competing interests in this work.

1. Dougan M, Pietropaolo M. Time to dissect the autoimmune etiology of cancer antibody immunotherapy. J Clin Invest. 2020;130(1):5161. doi:10.1172/JCI131194

2. Haanen J, Carbonnel F, Robert C, et al. Management of toxicities from immunotherapy: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017;28:iv119iv142. doi:10.1093/annonc/mdx225

3. Immune-endocrinology Group, Chinese society of Endocrinology, Chinese Medical Association. Chinese expert consensus on immune checkpoint inhibitors-induced endocrine immune-related adverse events (2020). Chin J Endocrinol Metab. 2021;37(01):116.

4. De Block C, De Leeuw I, Decochez K, et al. The presence of thyrogastric antibodies in first degree relatives of type 1 diabetic patients is associated with age and proband antibody status. J Clin Endocrinol Metab. 2001;86(9):43584363. doi:10.1210/jcem.86.9.7833

5. De Block C, De Leeuw I, Vertommen J, et al. Beta-cell, thyroid, gastric, adrenal and coeliac autoimmunity and HLA-DQ types in type 1 diabetes. Clin Exp Immunol. 2001;126(2):236241. doi:10.1046/j.1365-2249.2001.01668.x

6. Barroso-Sousa R, Barry W, Garrido-Castro A, et al. Incidence of endocrine dysfunction following the use of different immune checkpoint inhibitor regimens: a systematic review and meta-analysis. JAMA Oncol. 2018;4(2):173182. doi:10.1001/jamaoncol.2017.3064

7. Faje A, Sullivan R, Lawrence D, et al. Ipilimumab-induced hypophysitis: a detailed longitudinal analysis in a large cohort of patients with metastatic melanoma. J Clin Endocrinol Metab. 2014;99(11):40784085. doi:10.1210/jc.2014-2306

8. Albarel F, Gaudy C, Castinetti F, et al. Long-term follow-up of ipilimumab-induced hypophysitis, a common adverse event of the anti-CTLA-4 antibody in melanoma. Eur J Endocrinol. 2015;172(2):195204. doi:10.1530/EJE-14-0845

9. Scott E, Long G, Guminski A, Clifton-Bligh R, Menzies A, Tsang V. The spectrum, incidence, kinetics and management of endocrinopathies with immune checkpoint inhibitors for metastatic melanoma. Eur J Endocrinol. 2018;178(2):173180. doi:10.1530/EJE-17-0810

10. Chang L, Barroso-Sousa R, Tolaney S, Hodi F, Kaiser U, Min L. Endocrine toxicity of cancer immunotherapy targeting immune checkpoints. Endocr Rev. 2019;40(1):1765. doi:10.1210/er.2018-00006

11. Joshi M, Whitelaw B, Palomar M, Wu Y, Carroll P. Immune checkpoint inhibitor-related hypophysitis and endocrine dysfunction: clinical review. Clin Endocrinol (Oxf). 2016;85(3):331339. doi:10.1111/cen.13063

12. Frasca F, Piticchio T, Le Moli R, et al. Recent insights into the pathogenesis of autoimmune hypophysitis. Expert Rev Clin Immunol. 2021;17(11):11751185. doi:10.1080/1744666X.2021.1974297

13. Sznol M, Postow M, Davies M, et al. Endocrine-related adverse events associated with immune checkpoint blockade and expert insights on their management. Cancer Treat Rev. 2017;58:7076. doi:10.1016/j.ctrv.2017.06.002

14. Stamatouli A, Quandt Z, Perdigoto A, et al. Collateral damage: insulin-dependent diabetes induced with checkpoint inhibitors. Diabetes. 2018;67(8):14711480. doi:10.2337/dbi18-0002

15. Yadav D, Sarvetnick N. Costimulation and pancreatic autoimmunity: the PD-1/PD-L conundrum. Rev Diabet Stud. 2006;3(1):610. doi:10.1900/RDS.2006.3.6

16. Wolchok J, Chiarion-Sileni V, Gonzalez R, et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2017;377(14):13451356. doi:10.1056/NEJMoa1709684

17. Higham C, Olsson-Brown A, Carroll P, et al. Society for endocrinology endocrine emergency guidance: acute management of the endocrine complications of checkpoint inhibitor therapy. Endocr Connect. 2018;7(7):G1G7. doi:10.1530/EC-18-0068

18. Thompson J, Schneider B, Brahmer J, et al. NCCN guidelines insights: management of immunotherapy-related toxicities, Version 1.2020. J Natl Compr Cancer Netw. 2020;18(3):230241. doi:10.6004/jnccn.2020.0012

19. Brahmer J, Lacchetti C, Schneider B, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American society of clinical oncology clinical practice guideline. J Clin Oncol. 2018;36(17):17141768. doi:10.1200/JCO.2017.77.6385

20. Puzanov I, Diab A, Abdallah K, et al. Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group. J Immunother Cancer. 2017;5(1):95. doi:10.1186/s40425-017-0300-z

21. Kumagai R, Muramatsu A, Nakajima R, et al. Acute-onset type 1 diabetes mellitus caused by nivolumab in a patient with advanced pulmonary adenocarcinoma. J Diabetes Investig. 2017;8(6):798799. doi:10.1111/jdi.12627

22. Matsumura K, Nagasawa K, Oshima Y, et al. Aggravation of diabetes, and incompletely deficient insulin secretion in a case with type 1 diabetes-resistant human leukocyte antigen DRB1*15:02 treated with nivolumab. J Diabetes Investig. 2018;9(2):438441. doi:10.1111/jdi.12679

23. Lanzolla G, Coppelli A, Cosottini M, Del Prato S, Marcocci C, Lupi I. Immune checkpoint blockade anti-PD-L1 as a trigger for autoimmune polyendocrine syndrome. J Endocr Soc. 2019;3(2):496503. doi:10.1210/js.2018-00366

24. Kikuchi F, Saheki T, Imachi H, et al. Nivolumab-induced hypophysitis followed by acute-onset type 1 diabetes with renal cell carcinoma: a case report. J Med Case Rep. 2021;15(1):214. doi:10.1186/s13256-020-02656-7

25. Humayun M, Poole R. A case of multiple immune toxicities from Ipilimumab and pembrolizumab treatment. Hormones. 2016;15(2):303306. doi:10.14310/horm.2002.1656

26. Boswell L, Casals G, Blanco J, et al. Onset of fulminant type 1 diabetes mellitus following hypophysitis after discontinuation of combined immunotherapy. A case report. J Diabetes Investig. 2021;12(12):22632266. doi:10.1111/jdi.13604

27. Jiang C, Zhang L, Xu X, et al. Engineering a smart agent for enhanced immunotherapy effect by simultaneously blocking PD-L1 and CTLA-4. Adv Sci. 2021;8(20):e2102500. doi:10.1002/advs.202102500

28. Ruggeri R, Campenn A, Giuffrida G, et al. Endocrine and metabolic adverse effects of immune checkpoint inhibitors: an overview (what endocrinologists should know). J Endocrinol Invest. 2019;42(7):745756. doi:10.1007/s40618-018-0984-z

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The CHMP's recommendation was based on results from the pivotal KEYNOTE-522 trial, which was the first Phase 3 study with an immunotherapy to show positive event-free survival (EFS) results in high-risk early-stage TNBC. As previously reported, after a median follow-up of 39 months, the KEYTRUDA regimen (neoadjuvant KEYTRUDA plus chemotherapy followed by adjuvant KEYTRUDA monotherapy) reduced the risk of events or death by 37% (HR=0.63 [95% CI, 0.48-0.82]; p

Triple-negative breast cancer is an aggressive type of breast cancer, which has the highest risk of recurrence within the first five years after diagnosis and is associated with worse outcomes compared to other forms of breast cancer.

"This positive CHMP opinion reinforces our efforts to advance the treatment of breast cancer in Europe and expand the use of KEYTRUDA in TNBC to potentially help even more patients with this aggressive disease who are in need of new treatment options," said Dr. Gursel Aktan, vice president, global clinical development, Merck Research Laboratories. "We look forward to the European Commission's decision and are excited about the prospect of bringing the first immunotherapy regimen for high-risk, early-stage TNBC to appropriate patients in Europe."

The CHMP's recommendation will now be reviewed by the European Commission for marketing authorization in the European Union, and a final decision is expected in the second quarter of 2022. If approved, this will be the second indication for KEYTRUDA in TNBC in Europe. In October 2021, KEYTRUDA plus chemotherapy was approved for the first-line treatment of certain patients with locally recurrent unresectable or metastatic TNBC.

Merck is rapidly advancing a broad portfolio in gynecologic and breast cancers with an extensive clinical development program for KEYTRUDA and several other investigational and approved medicines across these areas.

About Triple-Negative Breast Cancer (TNBC)

Approximately 10-15% of patients with breast cancer are diagnosed with TNBC. While some breast cancers may test positive for estrogen receptors, progesterone receptors or overexpression of human epidermal growth factor receptor 2 (HER2), TNBC tests negative for all three. Triple-negative breast cancer tends to be more common in people who are younger than 40 years of age, who are Black or who have a BRCA 1 mutation.

About Merck's Early-Stage Cancer Clinical Program

Finding cancer at an earlier stage may give patients a greater chance of long-term survival. Many cancers are considered most treatable and potentially curable in their earliest stage of disease. Building on the strong understanding of the role of KEYTRUDA in later-stage cancers, Merck is studying KEYTRUDA in earlier disease states, with approximately 20 ongoing registrational studies across multiple types of cancer.

About KEYTRUDA (pembrolizumab) Injection, 100 mg

KEYTRUDA is an anti-programmed death receptor-1 (PD-1) therapy that works by increasing the ability of the body's immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

Merck has the industry's largest immuno-oncology clinical research program. There are currently more than 1,700 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient's likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.

Selected KEYTRUDA (pembrolizumab) Indications in the U.S.

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma.

KEYTRUDA is indicated for the adjuvant treatment of adult and pediatric (12 years and older) patients with stage IIB, IIC, or III melanoma following complete resection.

Non-Small Cell Lung Cancer

KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA, in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, is indicated for the first-line treatment of patients with metastatic squamous NSCLC.

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with NSCLC expressing PD-L1 [tumor proportion score (TPS) 1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and is:

KEYTRUDA, as a single agent, is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS 1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.

Head and Neck Squamous Cell Cancer

KEYTRUDA, in combination with platinum and fluorouracil (FU), is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC).

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [Combined Positive Score (CPS) 1] as determined by an FDA-approved test.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy.

Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL).

KEYTRUDA is indicated for the treatment of pediatric patients with refractory cHL, or cHL that has relapsed after 2 or more lines of therapy.

Primary Mediastinal Large B-Cell Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy.

KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy.

Urothelial Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC):

Non-muscle Invasive Bladder Cancer

KEYTRUDA is indicated for the treatment of patients with Bacillus Calmette-Guerin-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.

Microsatellite Instability-High or Mismatch Repair Deficient Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options.

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established.

Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC).

Gastric Cancer

KEYTRUDA, in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma.

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Esophageal Cancer

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic esophageal or gastroesophageal junction (GEJ) (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma that is not amenable to surgical resection or definitive chemoradiation either:

Cervical Cancer

KEYTRUDA, in combination with chemotherapy, with or without bevacizumab, is indicated for the treatment of patients with persistent, recurrent, or metastatic cervical cancer whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test.

Hepatocellular Carcinoma

KEYTRUDA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Merkel Cell Carcinoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Renal Cell Carcinoma

KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of adult patients with advanced renal cell carcinoma (RCC).

KEYTRUDA is indicated for the adjuvant treatment of patients with RCC at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions.

Endometrial Carcinoma

KEYTRUDA, as a single agent, is indicated for the treatment of patients with advanced endometrial carcinoma that is MSI-H or dMMR, as determined by an FDA-approved test, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation.

Tumor Mutational Burden-High Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [10 mutations/megabase] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with TMB-H central nervous system cancers have not been established.

Cutaneous Squamous Cell Carcinoma

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) or locally advanced cSCC that is not curable by surgery or radiation.

Triple-Negative Breast Cancer

KEYTRUDA is indicated for the treatment of patients with high-risk early-stage triple-negative breast cancer (TNBC) in combination with chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery.

KEYTRUDA, in combination with chemotherapy, is indicated for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS 10) as determined by an FDA-approved test.

Selected Important Safety Information for KEYTRUDA

Severe and Fatal Immune-Mediated Adverse Reactions

KEYTRUDA is a monoclonal antibody that belongs to a class of drugs that bind to either the PD-1 or the PD-L1, blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, can affect more than one body system simultaneously, and can occur at any time after starting treatment or after discontinuation of treatment. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions.

Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Early identification and management are essential to ensure safe use of antiPD-1/PD-L1 treatments. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. For patients with TNBC treated with KEYTRUDA in the neoadjuvant setting, monitor blood cortisol at baseline, prior to surgery, and as clinically indicated. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue KEYTRUDA depending on severity of the immune-mediated adverse reaction. In general, if KEYTRUDA requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose adverse reactions are not controlled with corticosteroid therapy.

Immune-Mediated Pneumonitis

KEYTRUDA can cause immune-mediated pneumonitis. The incidence is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA, including fatal (0.1%), Grade 4 (0.3%), Grade 3 (0.9%), and Grade 2 (1.3%) reactions. Systemic corticosteroids were required in 67% (63/94) of patients. Pneumonitis led to permanent discontinuation of KEYTRUDA in 1.3% (36) and withholding in 0.9% (26) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Pneumonitis resolved in 59% of the 94 patients.

Pneumonitis occurred in 8% (31/389) of adult patients with cHL receiving KEYTRUDA as a single agent, including Grades 3-4 in 2.3% of patients. Patients received high-dose corticosteroids for a median duration of 10 days (range: 2 days to 53 months). Pneumonitis rates were similar in patients with and without prior thoracic radiation. Pneumonitis led to discontinuation of KEYTRUDA in 5.4% (21) of patients. Of the patients who developed pneumonitis, 42% interrupted KEYTRUDA, 68% discontinued KEYTRUDA, and 77% had resolution.

Immune-Mediated Colitis

KEYTRUDA can cause immune-mediated colitis, which may present with diarrhea. Cytomegalovirus infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 4 (

Hepatotoxicity and Immune-Mediated Hepatitis

KEYTRUDA as a Single Agent

KEYTRUDA can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 4 (

KEYTRUDA With Axitinib

KEYTRUDA in combination with axitinib can cause hepatic toxicity. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider monitoring more frequently as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt KEYTRUDA and axitinib, and consider administering corticosteroids as needed. With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased alanine aminotransferase (ALT) (20%) and increased aspartate aminotransferase (AST) (13%) were seen at a higher frequency compared to KEYTRUDA alone. Fifty-nine percent of the patients with increased ALT received systemic corticosteroids. In patients with ALT 3 times upper limit of normal (ULN) (Grades 2-4, n=116), ALT resolved to Grades 0-1 in 94%. Among the 92 patients who were rechallenged with either KEYTRUDA (n=3) or axitinib (n=34) administered as a single agent or with both (n=55), recurrence of ALT 3 times ULN was observed in 1 patient receiving KEYTRUDA, 16 patients receiving axitinib, and 24 patients receiving both. All patients with a recurrence of ALT 3 ULN subsequently recovered from the event.

Immune-Mediated Endocrinopathies

Adrenal Insufficiency

KEYTRUDA can cause primary or secondary adrenal insufficiency. For Grade 2 or higher, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold KEYTRUDA depending on severity. Adrenal insufficiency occurred in 0.8% (22/2799) of patients receiving KEYTRUDA, including Grade 4 (

Hypophysitis

KEYTRUDA can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Hypophysitis occurred in 0.6% (17/2799) of patients receiving KEYTRUDA, including Grade 4 (

Thyroid Disorders

KEYTRUDA can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Thyroiditis occurred in 0.6% (16/2799) of patients receiving KEYTRUDA, including Grade 2 (0.3%). None discontinued, but KEYTRUDA was withheld in

Hyperthyroidism occurred in 3.4% (96/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (0.8%). It led to permanent discontinuation of KEYTRUDA in

Type 1 Diabetes Mellitus (DM), Which Can Present With Diabetic Ketoacidosis

Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold KEYTRUDA depending on severity. Type 1 DM occurred in 0.2% (6/2799) of patients receiving KEYTRUDA. It led to permanent discontinuation in

Immune-Mediated Nephritis With Renal Dysfunction

KEYTRUDA can cause immune-mediated nephritis. Immune-mediated nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 4 (

Immune-Mediated Dermatologic Adverse Reactions

KEYTRUDA can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms, and toxic epidermal necrolysis, has occurred with antiPD-1/PD-L1 treatments. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes. Withhold or permanently discontinue KEYTRUDA depending on severity. Immune-mediated dermatologic adverse reactions occurred in 1.4% (38/2799) of patients receiving KEYTRUDA, including Grade 3 (1%) and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 40% (15/38) of patients. These reactions led to permanent discontinuation in 0.1% (2) and withholding of KEYTRUDA in 0.6% (16) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 6% had recurrence. The reactions resolved in 79% of the 38 patients.

Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse reactions occurred at an incidence of Cardiac/Vascular: Myocarditis, pericarditis, vasculitis; Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barr syndrome, nerve paresis, autoimmune neuropathy; Ocular: Uveitis, iritis and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss; Gastrointestinal: Pancreatitis, to include increases in serum amylase and lipase levels, gastritis, duodenitis; Musculoskeletal and Connective Tissue: Myositis/polymyositis, rhabdomyolysis (and associated sequelae, including renal failure), arthritis (1.5%), polymyalgia rheumatica; Endocrine: Hypoparathyroidism; Hematologic/Immune: Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection.

Infusion-Related Reactions

KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% of 2799 patients receiving KEYTRUDA. Monitor for signs and symptoms of infusion-related reactions. Interrupt or slow the rate of infusion for Grade 1 or Grade 2 reactions. For Grade 3 or Grade 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Fatal and other serious complications can occur in patients who receive allogeneic HSCT before or after antiPD-1/PD-L1 treatments. Transplant-related complications include hyperacute graft-versus-host disease (GVHD), acute and chronic GVHD, hepatic veno-occlusive disease after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between antiPD-1/PD-L1 treatment and allogeneic HSCT. Follow patients closely for evidence of these complications and intervene promptly. Consider the benefit vs risks of using antiPD-1/PD-L1 treatments prior to or after an allogeneic HSCT.

Increased Mortality in Patients With Multiple Myeloma

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Pfizer and Biohaven's VYDURA Granted First Ever Marketing Authorization by European Commission for Both Acute Treatment of Migraine and Prophylaxis of...

COVID-19 and hypopituitarism – DocWire News

This article was originally published here

Rev Endocr Metab Disord. 2021 Aug 13. doi: 10.1007/s11154-021-09672-y. Online ahead of print.

ABSTRACT

Besides the pulmonary manifestations caused by severe acute respiratory syndrome (SARS) coronavirus 2 (SARS-CoV-2), an emerging endocrine phenotype, which can heavily impact on the severity of the syndrome, has been recently associated with coronavirus disease 2019 (COVID-19). Patients with pituitary diseases or the pituitary gland itself may also be involved in COVID-19 clinical presentation and/or severity, causing pituitary apoplexy.Moreover, hypopituitarism is frequently burdened by several metabolic complications, including arterial hypertension, hyperglycemia, obesity and vertebral fractures, which have all been associated with poor outcomes and increased mortality in patients infected by SARS-CoV-2.This review will discuss hypopituitarism as a condition that might have a bidirectional relationship with COVID-19 due to the frequent presence of metabolic comorbidities, to the direct or indirect pituitary damage or being per se a potential risk factor for COVID-19. Finally, we will address the current recommendations for the clinical management of vaccines in patients with hypopituitarism and adrenal insufficiency.

PMID:34387832 | DOI:10.1007/s11154-021-09672-y

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COVID-19 and hypopituitarism - DocWire News

Orphan: First Kill Has a Surprise Twist That Could Rival the Original’s Shocking Ending – MovieWeb

Orphan: First Kill star Julia Stiles has teased another big twist in the upcoming horror prequel, one which may even rival the first movie's shocking finale. Many had wondered how, what with Orphan: First Kill taking place before the first movie and after audiences have been made aware of Esther's surprising identity, the prequel would bring the shocks and scares, but according to Stiles they have found a way.

Released in 2009, the first Orphan centers on a couple who, after the death of their unborn child, adopt a mysterious nine-year-old girl, Esther. As she demonstrates increasingly bizarre behaviour, it is revealed during the movie's climax that Esther is in fact an adult woman with hypopituitarism, a rare hormonal disorder that stunted her physical growth and caused proportional dwarfism.

While it remains unknown how exactly Orphan: First Kill will pull out a twist to rival the first movie, Stiles goes on to assure fans that the prequel will continue to opt for psychological scares rather than blood and gore.

Orphan: First Kill will once again follow Isabelle Fuhrman as Esther, who is now living under the name Leena Klammer. The horror begins when she orchestrates a brilliant escape from an Estonian psychiatric facility and travels to America by impersonating the missing daughter of a wealthy family. But Leena's new life as 'Esther' comes with an unexpected wrinkle and pits her against a mother who will protect her family at any cost.

Fuhrman, who is now 24 years old, will once again play the role of the adult killer who disguises herself as a child, with director William Brent Bell recently providing some insight into how the movie plans to resurrect Esther all these years later. "For me it's like, we know the secret of the first film, so the fun of bringing Isabelle Fuhrman back into the role - which was a whole process to get approved - that is a challenge in and of itself," the filmmaker said. "And likewise, not doing modern CGI... I mean, we use digital, we use CGI to help us... but not to create her at all. It's all old school techniques: forced perspective, camera angles, where we put the light."

Orphan: First Kill does not yet have a release date. This comes to us from Collider.

Topics: Orphan 2

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Orphan: First Kill Has a Surprise Twist That Could Rival the Original's Shocking Ending - MovieWeb

Merck (MRK) Granted Positive EU CHMP Opinion for KEYTRUDA (pembrolizumab) in Combination with Chemotherapy – StreetInsider.com

News and research before you hear about it on CNBC and others. Claim your 1-week free trial to StreetInsider Premium here.

Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion recommending approval of KEYTRUDA, Mercks anti-PD-1 therapy, in combination with platinum- and fluoropyrimidine-based chemotherapy for the first-line treatment of patients with locally advanced unresectable or metastatic carcinoma of the esophagus or human epidermal growth factor receptor 2 (HER2)-negative gastroesophageal junction (GEJ) adenocarcinoma in adults whose tumors express PD-L1 (Combined Positive Score [CPS] 10). The CHMPs recommendation will now be reviewed by the European Commission for marketing authorization in the European Union, and a final decision is expected in the second quarter of 2021.

Patients with metastatic esophageal cancer currently face five-year survival rates of just 5%, said Dr. Scot Ebbinghaus, vice president, clinical research, Merck Research Laboratories. There is a critical need for new treatment options in the first-line setting that can potentially extend their lives. Todays positive opinion for KEYTRUDA is an important step forward for patients in Europe with certain types of gastrointestinal cancers.

The positive CHMP opinion is based on results from the pivotal Phase 3 KEYNOTE-590 trial, in which KEYTRUDA plus 5-fluorouracil (5-FU) and cisplatin demonstrated significant improvements in overall survival and progression-free survival compared with 5-FU and cisplatin alone in patients regardless of histology or PD-L1 expression status. KEYTRUDA plus 5-FU and cisplatin reduced the risk of death by 27% (HR=0.73 [95% CI, 0.62-0.86]; p

Merck is studying KEYTRUDA across multiple settings and stages of gastrointestinal cancer including esophageal, gastric, hepatobiliary, pancreatic, colorectal and anal cancers through its broad clinical program.

About Esophageal Cancer

Esophageal cancer begins in the inner layer (mucosa) of the esophagus and grows outward. Esophageal cancer is the eighth most commonly diagnosed cancer and the sixth leading cause of death from cancer worldwide. Globally, it is estimated there were more than 604,000 new cases of esophageal cancer diagnosed and approximately 544,000 deaths resulting from the disease in 2020. In Europe, it is estimated there were more than 52,000 new cases of esophageal cancer diagnosed and approximately 45,000 deaths resulting from the disease in 2020.

About KEYTRUDA (pembrolizumab) Injection, 100 mg

KEYTRUDA is an anti-PD-1 therapy that works by increasing the ability of the bodys immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

Merck has the industrys largest immuno-oncology clinical research program. There are currently more than 1,400 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient's likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.

Selected KEYTRUDA (pembrolizumab) Indications in the U.S.

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma.

KEYTRUDA is indicated for the adjuvant treatment of patients with melanoma with involvement of lymph node(s) following complete resection.

Non-Small Cell Lung Cancer

KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA, in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, is indicated for the first-line treatment of patients with metastatic squamous NSCLC.

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with NSCLC expressing PD-L1 [tumor proportion score (TPS) 1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and is stage III where patients are not candidates for surgical resection or definitive chemoradiation, or metastatic.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS 1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.

Head and Neck Squamous Cell Cancer

KEYTRUDA, in combination with platinum and fluorouracil (FU), is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC).

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [combined positive score (CPS) 1] as determined by an FDA-approved test.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy.

Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL).

KEYTRUDA is indicated for the treatment of pediatric patients with refractory cHL, or cHL that has relapsed after 2 or more lines of therapy.

Primary Mediastinal Large B-Cell Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy. KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy.

Urothelial Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 (CPS 10), as determined by an FDA-approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

KEYTRUDA is indicated for the treatment of patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.

Microsatellite Instability-High or Mismatch Repair Deficient Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR)

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established.

Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer

KEYTRUDA is indicated for the first-line treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC).

Gastric Carcinoma

KEYTRUDA, in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test, with disease progression on or after 2 or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Esophageal Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic esophageal or gastroesophageal junction (GEJ) (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma that is not amenable to surgical resection or definitive chemoradiation either:

Cervical Carcinoma

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Hepatocellular Carcinoma

KEYTRUDA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Merkel Cell Carcinoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Renal Cell Carcinoma

KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of patients with advanced renal cell carcinoma (RCC).

Tumor Mutational Burden-High

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [10 mutations/megabase] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with TMB-H central nervous system cancers have not been established.

Cutaneous Squamous Cell Carcinoma

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) that is not curable by surgery or radiation.

Triple-Negative Breast Cancer

KEYTRUDA, in combination with chemotherapy, is indicated for the treatment of patients with locally recurrent unresectable or metastatic triple-negative breast cancer (TNBC) whose tumors express PD-L1 (CPS 10) as determined by an FDA-approved test. This indication is approved under accelerated approval based on progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Selected Important Safety Information for KEYTRUDA

Severe and Fatal Immune-Mediated Adverse Reactions

KEYTRUDA is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death receptor-1 (PD-1) or the programmed death ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, can affect more than one body system simultaneously, and can occur at any time after starting treatment or after discontinuation of treatment. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions.

Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Early identification and management are essential to ensure safe use of antiPD-1/PD-L1 treatments. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue KEYTRUDA depending on severity of the immune-mediated adverse reaction. In general, if KEYTRUDA requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose adverse reactions are not controlled with corticosteroid therapy.

Immune-Mediated Pneumonitis

KEYTRUDA can cause immune-mediated pneumonitis. The incidence is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA, including fatal (0.1%), Grade 4 (0.3%), Grade 3 (0.9%), and Grade 2 (1.3%) reactions. Systemic corticosteroids were required in 67% (63/94) of patients. Pneumonitis led to permanent discontinuation of KEYTRUDA in 1.3% (36) and withholding in 0.9% (26) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Pneumonitis resolved in 59% of the 94 patients.

Pneumonitis occurred in 8% (31/389) of adult patients with cHL receiving KEYTRUDA as a single agent, including Grades 3-4 in 2.3% of patients. Patients received high-dose corticosteroids for a median duration of 10 days (range: 2 days to 53 months). Pneumonitis rates were similar in patients with and without prior thoracic radiation. Pneumonitis led to discontinuation of KEYTRUDA in 5.4% (21) of patients. Of the patients who developed pneumonitis, 42% of these patients interrupted KEYTRUDA, 68% discontinued KEYTRUDA, and 77% had resolution.

Immune-Mediated Colitis

KEYTRUDA can cause immune-mediated colitis, which may present with diarrhea. Cytomegalovirus infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 4 (

Hepatotoxicity and Immune-Mediated Hepatitis

KEYTRUDA as a Single Agent

KEYTRUDA can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 4 (

KEYTRUDA with Axitinib

KEYTRUDA in combination with axitinib can cause hepatic toxicity. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider monitoring more frequently as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt KEYTRUDA and axitinib, and consider administering corticosteroids as needed. With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased alanine aminotransferase (ALT) (20%) and increased aspartate aminotransferase (AST) (13%) were seen, which was at a higher frequency compared to KEYTRUDA alone. Fifty-nine percent of the patients with increased ALT received systemic corticosteroids. In patients with ALT 3 times upper limit of normal (ULN) (Grades 2-4, n=116), ALT resolved to Grades 0-1 in 94%. Among the 92 patients who were rechallenged with either KEYTRUDA (n=3) or axitinib (n=34) administered as a single agent or with both (n=55), recurrence of ALT 3 times ULN was observed in 1 patient receiving KEYTRUDA, 16 patients receiving axitinib, and 24 patients receiving both. All patients with a recurrence of ALT 3 ULN subsequently recovered from the event.

Immune-Mediated Endocrinopathies

Adrenal Insufficiency

KEYTRUDA can cause primary or secondary adrenal insufficiency. For Grade 2 or higher, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold KEYTRUDA depending on severity. Adrenal insufficiency occurred in 0.8% (22/2799) of patients receiving KEYTRUDA, including Grade 4 (

Hypophysitis

KEYTRUDA can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Hypophysitis occurred in 0.6% (17/2799) of patients receiving KEYTRUDA, including Grade 4 (

Thyroid Disorders

KEYTRUDA can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Thyroiditis occurred in 0.6% (16/2799) of patients receiving KEYTRUDA, including Grade 2 (0.3%). None discontinued, but KEYTRUDA was withheld in

Hyperthyroidism occurred in 3.4% (96/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (0.8%). It led to permanent discontinuation of KEYTRUDA in

Type 1 Diabetes Mellitus (DM), Which Can Present With Diabetic Ketoacidosis

Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold KEYTRUDA depending on severity. Type 1 DM occurred in 0.2% (6/2799) of patients receiving KEYTRUDA. It led to permanent discontinuation in

Immune-Mediated Nephritis With Renal Dysfunction

KEYTRUDA can cause immune-mediated nephritis. Immune-mediated nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 4 (

Immune-Mediated Dermatologic Adverse Reactions

KEYTRUDA can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms, and toxic epidermal necrolysis, has occurred with antiPD-1/PD-L1 treatments. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes. Withhold or permanently discontinue KEYTRUDA depending on severity. Immune-mediated dermatologic adverse reactions occurred in 1.4% (38/2799) of patients receiving KEYTRUDA, including Grade 3 (1%) and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 40% (15/38) of patients. These reactions led to permanent discontinuation in 0.1% (2) and withholding of KEYTRUDA in 0.6% (16) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 6% had recurrence. The reactions resolved in 79% of the 38 patients.

Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse reactions occurred at an incidence of Cardiac/Vascular: Myocarditis, pericarditis, vasculitis; Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barr syndrome, nerve paresis, autoimmune neuropathy; Ocular: Uveitis, iritis and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss; Gastrointestinal: Pancreatitis, to include increases in serum amylase and lipase levels, gastritis, duodenitis; Musculoskeletal and Connective Tissue: Myositis/polymyositis rhabdomyolysis (and associated sequelae, including renal failure), arthritis (1.5%), polymyalgia rheumatica; Endocrine: Hypoparathyroidism; Hematologic/Immune: Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection.

Infusion-Related Reactions

KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% of 2799 patients receiving KEYTRUDA. Monitor for signs and symptoms of infusion-related reactions. Interrupt or slow the rate of infusion for Grade 1 or Grade 2 reactions. For Grade 3 or Grade 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Fatal and other serious complications can occur in patients who receive allogeneic HSCT before or after antiPD-1/PD-L1 treatment. Transplant-related complications include hyperacute graft-versus-host disease (GVHD), acute and chronic GVHD, hepatic veno-occlusive disease after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between antiPD-1/PD-L1 treatment and allogeneic HSCT. Follow patients closely for evidence of these complications and intervene promptly. Consider the benefit vs risks of using antiPD-1/PD-L1 treatments prior to or after an allogeneic HSCT.

Increased Mortality in Patients With Multiple Myeloma

In trials in patients with multiple myeloma, the addition of KEYTRUDA to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of these patients with an antiPD-1/PD-L1 treatment in this combination is not recommended outside of controlled trials.

Embryofetal Toxicity

Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. Advise women of this potential risk. In females of reproductive potential, verify pregnancy status prior to initiating KEYTRUDA and advise them to use effective contraception during treatment and for 4 months after the last dose.

Adverse Reactions

In KEYNOTE-006, KEYTRUDA was discontinued due to adverse reactions in 9% of 555 patients with advanced melanoma; adverse reactions leading to permanent discontinuation in more than one patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%). The most common adverse reactions (20%) with KEYTRUDA were fatigue (28%), diarrhea (26%), rash (24%), and nausea (21%).

In KEYNOTE-054, KEYTRUDA was permanently discontinued due to adverse reactions in 14% of 509 patients; the most common (1%) were pneumonitis (1.4%), colitis (1.2%), and diarrhea (1%). Serious adverse reactions occurred in 25% of patients receiving KEYTRUDA. The most common adverse reaction (20%) with KEYTRUDA was diarrhea (28%).

In KEYNOTE-189, when KEYTRUDA was administered with pemetrexed and platinum chemotherapy in metastatic nonsquamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 20% of 405 patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonitis (3%) and acute kidney injury (2%). The most common adverse reactions (20%) with KEYTRUDA were nausea (56%), fatigue (56%), constipation (35%), diarrhea (31%), decreased appetite (28%), rash (25%), vomiting (24%), cough (21%), dyspnea (21%), and pyrexia (20%).

In KEYNOTE-407, when KEYTRUDA was administered with carboplatin and either paclitaxel or paclitaxel protein-bound in metastatic squamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 15% of 101 patients. The most frequent serious adverse reactions reported in at least 2% of patients were febrile neutropenia, pneumonia, and urinary tract infection. Adverse reactions observed in KEYNOTE-407 were similar to those observed in KEYNOTE-189 with the exception that increased incidences of alopecia (47% vs 36%) and peripheral neuropathy (31% vs 25%) were observed in the KEYTRUDA and chemotherapy arm compared to the placebo and chemotherapy arm in KEYNOTE-407.

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Merck (MRK) Granted Positive EU CHMP Opinion for KEYTRUDA (pembrolizumab) in Combination with Chemotherapy - StreetInsider.com

Six-and-a-Half-Year Outcomes for Opdivo (nivolumab) in Combination with Yervoy (ipilimumab) Continue to Demonstrate Durable Long-Term Survival…

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Data evaluating Opdivo plus Yervoy represent the longest reported median overall survival from a Phase 3 advanced melanoma trial

49% of patients treated with Opdivo plus Yervoy were alive at 6.5 years and 77% of these patients remained treatment-free

Data to be featured in an oral presentation during the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting

PRINCETON, N.J.--(BUSINESS WIRE)--Bristol Myers Squibb (NYSE: BMY) today announced new six-and-a-half-year data from CheckMate -067, a randomized, double-blind, Phase 3 clinical trial, demonstrating durable improvement in survival with first-line Opdivo (nivolumab) plus Yervoy (ipilimumab) therapy and Opdivo monotherapy, versus Yervoy alone, in patients with advanced melanoma. With a minimum follow-up of 6.5 years, median overall survival (OS) was 72.1 months with Opdivo plus Yervoy (95% CI: 38.2-NR), the longest reported median OS in a Phase 3 advanced melanoma trial, 36.9 months with Opdivo (95% CI: 28.2-58.7) and 19.9 months with the Yervoy group (95% CI: 16.8-24.6). In addition, the Opdivo plus Yervoy combination demonstrated a 6.5-year progression-free survival (PFS) rate of 34% (median of 11.5 months) while PFS rates were 29% (median of 6.9 months) and 7% (median of 2.9 months) for Opdivo alone and Yervoy alone, respectively. Of the 49% of patients alive and in follow-up, 77% of patients who received the combination (112/145), 69% of Opdivo-treated patients (84/122) and 43% (27/63) of Yervoy-treated patients have been off treatment and never received subsequent systemic therapy.

Durable, sustained clinical benefit was also observed with Opdivo plus Yervoy or Opdivo alone across relevant subgroups, including in patients with BRAF mutation, wild-type tumors, and baseline liver metastases. Among patients with BRAF-mutant tumors, the rate of OS at 6.5 years was 57% in patients who received Opdivo plus Yervoy, 43% for Opdivo alone, and 25% for Yervoy alone. In patients with BRAF wild-type tumors, the rate of OS was 46% in patients who received Opdivo plus Yervoy, 42% for Opdivo alone and 22% for Yervoy alone. The rate of OS among patients with liver metastases was 38% for those who received Opdivo plus Yervoy, 31% for Opdivo alone, and 22% for Yervoy alone. Median duration of response (DoR) was not reached for those who received Opdivo plus Yervoy nor Opdivo, while the DoR for Yervoy-treated patients was 19.2 months.

The sustained overall survival and progression-free survival benefit shown with nivolumab-based treatment, particularly the nivolumab plus ipilimumab combination, has changed the way we look at long-term efficacy outcomes for patients with advanced melanoma, said Jedd D. Wolchok, M.D., Ph.D., FASCO, Chief, Immuno-Oncology Service, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center. These new results from the CheckMate -067 trial, with nearly half of patients treated with the nivolumab and ipilimumab combination surviving to six-and-a-half years, confirm the durable, sustained benefit of the combination in patients with advanced melanoma.

The safety profile for Opdivo plus Yervoy was consistent with prior findings, with no new safety signals observed and no additional treatment-related deaths occurring since the five-year analysis. Grade 3/4 treatment-related adverse events were reported in 59% of patients in the combination group, 24% of patients in the Opdivo group, and 28% of patients in the Yervoy group.

These results build upon our decade-long legacy in treating melanoma, which began when the average life expectancy following a diagnosis of metastatic melanoma was roughly six months and less than 10% of patients survived beyond five years, said Gina Fusaro, development lead, melanoma, Bristol Myers Squibb. With some of the longest follow-up with immunotherapies to date, Opdivo and Yervoy have consistently demonstrated durable, long-term survival benefits for patients diagnosed with advanced melanoma.

Bristol Myers Squibb thanks the patients and investigators involved in the CheckMate -067 clinical trial. The 6.5-year CheckMate -067 data (Abstract #9506) will be presented in an oral abstract session on Sunday, June 6, 2021 from 8:00 a.m. to 11:00 a.m. EDT at the American Society of Clinical Oncology (ASCO) Annual Meeting 2021 from June 4-8.

Dr. Wolchok has provided consulting services to Bristol Myers Squibb.

About CheckMate -067

CheckMate -067 is a Phase 3, double-blind, randomized trial that evaluated the combination of Opdivo plus Yervoy or Opdivo monotherapy versus Yervoy monotherapy in 945 patients with previously untreated advanced melanoma. Patients in the combination group (n=314) received Opdivo 1 mg/kg plus Yervoy 3 mg/kg every three weeks (Q3W) for four doses followed by Opdivo 3 mg/kg every two weeks (Q2W). Patients in the Opdivo monotherapy group (n=316) received Opdivo 3 mg/kg Q2W plus placebo. Patients in the Yervoy monotherapy group (n=315) received Yervoy 3 mg/kg Q3W for four doses plus placebo. Patients were treated until progression or unacceptable toxic effects. Overall survival (OS) and progression-free survival (PFS) were dual endpoints of the trial. Secondary endpoints included objective response rates (ORR), descriptive efficacy assessments and safety.

About Melanoma

Melanoma is a form of skin cancer characterized by the uncontrolled growth of pigment-producing cells (melanocytes) located in the skin. Metastatic melanoma is the deadliest form of the disease and occurs when cancer spreads beyond the surface of the skin to other organs. The incidence of melanoma has been increasing steadily for the last 30 years. In the United States, 106,110 new diagnoses of melanoma and about 7,180 related deaths are estimated for 2021. Globally, the World Health Organization estimates that by 2035, melanoma incidence will reach 424,102, with 94,308 related deaths. Melanoma is mostly curable when treated in its very early stages; however, survival rates decrease if regional lymph nodes are involved.

Bristol Myers Squibb: Creating a Better Future for People with Cancer

Bristol Myers Squibb is inspired by a single vision transforming patients lives through science. The goal of the companys cancer research is to deliver medicines that offer each patient a better, healthier life and to make cure a possibility. Building on a legacy across a broad range of cancers that have changed survival expectations for many, Bristol Myers Squibb researchers are exploring new frontiers in personalized medicine, and through innovative digital platforms, are turning data into insights that sharpen their focus. Deep scientific expertise, cutting-edge capabilities and discovery platforms enable the company to look at cancer from every angle. Cancer can have a relentless grasp on many parts of a patients life, and Bristol Myers Squibb is committed to taking actions to address all aspects of care, from diagnosis to survivorship. Because as a leader in cancer care, Bristol Myers Squibb is working to empower all people with cancer to have a better future.

About Opdivo

Opdivo is a programmed death-1 (PD-1) immune checkpoint inhibitor that is designed to uniquely harness the bodys own immune system to help restore anti-tumor immune response. By harnessing the bodys own immune system to fight cancer, Opdivo has become an important treatment option across multiple cancers.

Opdivos leading global development program is based on Bristol Myers Squibbs scientific expertise in the field of Immuno-Oncology and includes a broad range of clinical trials across all phases, including Phase 3, in a variety of tumor types. To date, the Opdivo clinical development program has treated more than 35,000 patients. The Opdivo trials have contributed to gaining a deeper understanding of the potential role of biomarkers in patient care, particularly regarding how patients may benefit from Opdivo across the continuum of PD-L1 expression.

In July 2014, Opdivo was the first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world. Opdivo is currently approved in more than 65 countries, including the United States, the European Union, Japan and China. In October 2015, the Companys Opdivo and Yervoy combination regimen was the first Immuno-Oncology combination to receive regulatory approval for the treatment of metastatic melanoma and is currently approved in more than 50 countries, including the United States and the European Union.

INDICATIONS

OPDIVO (nivolumab), as a single agent, is indicated for the treatment of patients with unresectable or metastatic melanoma.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the treatment of patients with unresectable or metastatic melanoma.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the first-line treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors express PD-L1 (1%) as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab) and 2 cycles of platinum-doublet chemotherapy, is indicated for the first-line treatment of adult patients with metastatic or recurrent non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.

OPDIVO (nivolumab) is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving OPDIVO.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the first-line treatment of adult patients with unresectable malignant pleural mesothelioma (MPM).

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the first-line treatment of patients with intermediate or poor risk advanced renal cell carcinoma (RCC).

OPDIVO (nivolumab), in combination with cabozantinib, is indicated for the first-line treatment of patients with advanced renal cell carcinoma (RCC).

OPDIVO (nivolumab) is indicated for the treatment of patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy.

OPDIVO (nivolumab) is indicated for the treatment of adult patients with classical Hodgkin lymphoma (cHL) that has relapsed or progressed after autologous hematopoietic stem cell transplantation (HSCT) and brentuximab vedotin or after 3 or more lines of systemic therapy that includes autologous HSCT. This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO (nivolumab) is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) with disease progression on or after platinum-based therapy.

OPDIVO (nivolumab) is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO (nivolumab), as a single agent, is indicated for the treatment of adult and pediatric patients 12 years and older with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the treatment of adults and pediatric patients 12 years and older with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO (nivolumab) is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

OPDIVO (nivolumab) is indicated for the adjuvant treatment of patients with melanoma with involvement of lymph nodes or metastatic disease who have undergone complete resection.

OPDIVO (nivolumab) is indicated for the treatment of patients with unresectable advanced, recurrent or metastatic esophageal squamous cell carcinoma (ESCC) after prior fluoropyrimidine- and platinum-based chemotherapy.

OPDIVO (nivolumab), in combination with fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the treatment of patients with advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma.

IMPORTANT SAFETY INFORMATION

Severe and Fatal Immune-Mediated Adverse Reactions

Immune-mediated adverse reactions listed herein may not include all possible severe and fatal immune-mediated adverse reactions.

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. While immune-mediated adverse reactions usually manifest during treatment, they can also occur after discontinuation of OPDIVO or YERVOY. Early identification and management are essential to ensure safe use of OPDIVO and YERVOY. Monitor for signs and symptoms that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate clinical chemistries including liver enzymes, creatinine, adrenocorticotropic hormone (ACTH) level, and thyroid function at baseline and periodically during treatment with OPDIVO and before each dose of YERVOY. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue OPDIVO and YERVOY depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information). In general, if OPDIVO or YERVOY interruption or discontinuation is required, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy. Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids (e.g., endocrinopathies and dermatologic reactions) are discussed below.

Immune-Mediated Pneumonitis

OPDIVO and YERVOY can cause immune-mediated pneumonitis. The incidence of pneumonitis is higher in patients who have received prior thoracic radiation. In patients receiving OPDIVO monotherapy, immune-mediated pneumonitis occurred in 3.1% (61/1994) of patients, including Grade 4 (

In Checkmate 205 and 039, pneumonitis, including interstitial lung disease, occurred in 6.0% (16/266) of patients receiving OPDIVO. Immune-mediated pneumonitis occurred in 4.9% (13/266) of patients receiving OPDIVO, including Grade 3 (n=1) and Grade 2 (n=12).

Immune-Mediated Colitis

OPDIVO and YERVOY can cause immune-mediated colitis, which may be fatal. A common symptom included in the definition of colitis was diarrhea. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. In patients receiving OPDIVO monotherapy, immune-mediated colitis occurred in 2.9% (58/1994) of patients, including Grade 3 (1.7%) and Grade 2 (1%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, immune-mediated colitis occurred in 25% (115/456) of patients, including Grade 4 (0.4%), Grade 3 (14%) and Grade 2 (8%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, immune-mediated colitis occurred in 9% (60/666) of patients, including Grade 3 (4.4%) and Grade 2 (3.7%).

In a separate Phase 3 trial of YERVOY 3 mg/kg monotherapy, immune-mediated colitis occurred in 12% (62/511) of patients, including Grade 3-5 (7%) and Grade 2 (5%).

Immune-Mediated Hepatitis and Hepatotoxicity

OPDIVO and YERVOY can cause immune-mediated hepatitis. In patients receiving OPDIVO monotherapy, immune-mediated hepatitis occurred in 1.8% (35/1994) of patients, including Grade 4 (0.2%), Grade 3 (1.3%), and Grade 2 (0.4%). In patients receiving OPDIVO monotherapy in Checkmate 040, immune-mediated hepatitis requiring systemic corticosteroids occurred in 5% (8/154) of patients. In patients receiving OPDIVO 1 mg/ kg with YERVOY 3 mg/kg every 3 weeks, immune-mediated hepatitis occurred in 15% (70/456) of patients, including Grade 4 (2.4%), Grade 3 (11%), and Grade 2 (1.8%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, immune-mediated hepatitis occurred in 7% (48/666) of patients, including Grade 4 (1.2%), Grade 3 (4.9%), and Grade 2 (0.4%).

In a separate Phase 3 trial of YERVOY 3 mg/kg monotherapy, immune-mediated hepatitis occurred in 4.1% (21/511) of patients, including Grade 3-5 (1.6%) and Grade 2 (2.5%).

OPDIVO in combination with cabozantinib can cause hepatic toxicity with higher frequencies of Grade 3 and 4 ALT and AST elevations compared to OPDIVO alone. Consider more frequent monitoring of liver enzymes as compared to when the drugs are administered as single agents. In patients receiving OPDIVO and cabozantinib, Grades 3 and 4 increased ALT or AST were seen in 11% of patients.

Immune-Mediated Endocrinopathies

OPDIVO and YERVOY can cause primary or secondary adrenal insufficiency, immune-mediated hypophysitis, immune-mediated thyroid disorders, and Type 1 diabetes mellitus, which can present with diabetic ketoacidosis. Withhold OPDIVO and YERVOY depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information). For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism; initiate hormone replacement as clinically indicated. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism; initiate hormone replacement or medical management as clinically indicated. Monitor patients for hyperglycemia or other signs and symptoms of diabetes; initiate treatment with insulin as clinically indicated.

In patients receiving OPDIVO monotherapy, adrenal insufficiency occurred in 1% (20/1994), including Grade 3 (0.4%) and Grade 2 (0.6%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, adrenal insufficiency occurred in 8% (35/456), including Grade 4 (0.2%), Grade 3 (2.4%), and Grade 2 (4.2%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, adrenal insufficiency occurred in 7% (48/666) of patients, including Grade 4 (0.3%), Grade 3 (2.5%), and Grade 2 (4.1%). In patients receiving OPDIVO and cabozantinib, adrenal insufficiency occurred in 4.7% (15/320) of patients, including Grade 3 (2.2%) and Grade 2 (1.9%).

In patients receiving OPDIVO monotherapy, hypophysitis occurred in 0.6% (12/1994) of patients, including Grade 3 (0.2%) and Grade 2 (0.3%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, hypophysitis occurred in 9% (42/456), including Grade 3 (2.4%) and Grade 2 (6%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, hypophysitis occurred in 4.4% (29/666) of patients, including Grade 4 (0.3%), Grade 3 (2.4%), and Grade 2 (0.9%).

In patients receiving OPDIVO monotherapy, thyroiditis occurred in 0.6% (12/1994) of patients, including Grade 2 (0.2%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, thyroiditis occurred in 2.7% (22/666) of patients, including Grade 3 (4.5%) and Grade 2 (2.2%).

In patients receiving OPDIVO monotherapy, hyperthyroidism occurred in 2.7% (54/1994) of patients, including Grade 3 (

In patients receiving OPDIVO monotherapy, hypothyroidism occurred in 8% (163/1994) of patients, including Grade 3 (0.2%) and Grade 2 (4.8%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, hypothyroidism occurred in 20% (91/456) of patients, including Grade 3 (0.4%) and Grade 2 (11%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, hypothyroidism occurred in 18% (122/666) of patients, including Grade 3 (0.6%) and Grade 2 (11%).

In patients receiving OPDIVO monotherapy, diabetes occurred in 0.9% (17/1994) of patients, including Grade 3 (0.4%) and Grade 2 (0.3%), and 2 cases of diabetic ketoacidosis. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, diabetes occurred in 2.7% (15/666) of patients, including Grade 4 (0.6%), Grade 3 (0.3%), and Grade 2 (0.9%).

In a separate Phase 3 trial of YERVOY 3 mg/kg monotherapy, Grade 2-5 immune-mediated endocrinopathies occurred in 4% (21/511) of patients. Severe to life-threatening (Grade 3-4) endocrinopathies occurred in 9 (1.8%) patients. All 9 patients had hypopituitarism, and some had additional concomitant endocrinopathies such as adrenal insufficiency, hypogonadism, and hypothyroidism. Six of the 9 patients were hospitalized for severe endocrinopathies. Moderate (Grade 2) endocrinopathy occurred in 12 patients (2.3%), including hypothyroidism, adrenal insufficiency, hypopituitarism, hyperthyroidism and Cushings syndrome.

Immune-Mediated Nephritis with Renal Dysfunction

OPDIVO and YERVOY can cause immune-mediated nephritis. In patients receiving OPDIVO monotherapy, immune-mediated nephritis and renal dysfunction occurred in 1.2% (23/1994) of patients, including Grade 4 (

Immune-Mediated Dermatologic Adverse Reactions

OPDIVO can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug rash with eosinophilia and systemic symptoms (DRESS) has occurred with PD-1/PD-L1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes.

YERVOY can cause immune-mediated rash or dermatitis, including bullous and exfoliative dermatitis, SJS, TEN, and DRESS. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-bullous/ exfoliative rashes.

Withhold or permanently discontinue OPDIVO and YERVOY depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information).

In patients receiving OPDIVO monotherapy, immune-mediated rash occurred in 9% (171/1994) of patients, including Grade 3 (1.1%) and Grade 2 (2.2%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, immune-mediated rash occurred in 28% (127/456) of patients, including Grade 3 (4.8%) and Grade 2 (10%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, immune-mediated rash occurred in 16% (108/666) of patients, including Grade 3 (3.5%) and Grade 2 (4.2%).

In a separate Phase 3 trial of YERVOY 3 mg/kg monotherapy, immune-mediated rash occurred in 15% (76/511) of patients, including Grade 3-5 (2.5%) and Grade 2 (12%).

Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse reactions occurred at an incidence of

In addition to the immune-mediated adverse reactions listed above, across clinical trials of YERVOY monotherapy or in combination with OPDIVO, the following clinically significant immune-mediated adverse reactions, some with fatal outcome, occurred in

Some ocular IMAR cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Haradalike syndrome, which has been observed in patients receiving OPDIVO and YERVOY, as this may require treatment with systemic corticosteroids to reduce the risk of permanent vision loss.

Infusion-Related Reactions

OPDIVO and YERVOY can cause severe infusion-related reactions. Discontinue OPDIVO and YERVOY in patients with severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions. Interrupt or slow the rate of infusion in patients with mild (Grade 1) or moderate (Grade 2) infusion-related reactions. In patients receiving OPDIVO monotherapy as a 60-minute infusion, infusion-related reactions occurred in 6.4% (127/1994) of patients. In a separate trial in which patients received OPDIVO monotherapy as a 60-minute infusion or a 30-minute infusion, infusion-related reactions occurred in 2.2% (8/368) and 2.7% (10/369) of patients, respectively. Additionally, 0.5% (2/368) and 1.4% (5/369) of patients, respectively, experienced adverse reactions within 48 hours of infusion that led to dose delay, permanent discontinuation or withholding of OPDIVO. In melanoma patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, infusion-related reactions occurred in 2.5% (10/407) of patients. In HCC patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, infusion-related reactions occurred in 8% (4/49) of patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, infusion-related reactions occurred in 5.1% (28/547) of patients. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, infusion-related reactions occurred in 4.2% (5/119) of patients. In MPM patients receiving OPDIVO 3 mg/kg every 2 weeks with YERVOY 1 mg/kg every 6 weeks, infusion-related reactions occurred in 12% (37/300) of patients.

In separate Phase 3 trials of YERVOY 3 mg/kg and 10 mg/kg monotherapy, infusion-related reactions occurred in 2.9% (28/982) of patients.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation

Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with OPDIVO or YERVOY. Transplant-related complications include hyperacute graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between OPDIVO or YERVOY and allogeneic HSCT.

Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with OPDIVO and YERVOY prior to or after an allogeneic HSCT.

Embryo-Fetal Toxicity

Based on its mechanism of action and findings from animal studies, OPDIVO and YERVOY can cause fetal harm when administered to a pregnant woman. The effects of YERVOY are likely to be greater during the second and third trimesters of pregnancy. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO and YERVOY and for at least 5 months after the last dose.

Increased Mortality in Patients with Multiple Myeloma when OPDIVO is Added to a Thalidomide Analogue and Dexamethasone

In randomized clinical trials in patients with multiple myeloma, the addition of OPDIVO to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of patients with multiple myeloma with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials.

Lactation

There are no data on the presence of OPDIVO or YERVOY in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment and for 5 months after the last dose.

Serious Adverse Reactions

In Checkmate 037, serious adverse reactions occurred in 41% of patients receiving OPDIVO (n=268). Grade 3 and 4 adverse reactions occurred in 42% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse drug reactions reported in 2% to 2%) serious adverse reactions were pneumonia, diarrhea, febrile neutropenia, anemia, acute kidney injury, musculoskeletal pain, dyspnea, pneumonitis, and respiratory failure. Fatal adverse reactions occurred in 7 (2%) patients, and included hepatic toxicity, acute renal failure, sepsis, pneumonitis, diarrhea with hypokalemia, and massive hemoptysis in the setting of thrombocytopenia. In Checkmate 017 and 057, serious adverse reactions occurred in 46% of patients receiving OPDIVO (n=418). The most frequent serious adverse reactions reported in 2% of patients receiving OPDIVO were pneumonia, pulmonary embolism, dyspnea, pyrexia, pleural effusion, pneumonitis, and respiratory failure. In Checkmate 057, fatal adverse reactions occurred; these included events of infection (7 patients, including one case of Pneumocystis jirovecii pneumonia), pulmonary embolism (4 patients), and limbic encephalitis (1 patient). In Checkmate 743, serious adverse reactions occurred in 54% of patients receiving OPDIVO plus YERVOY. The most frequent serious adverse reactions reported in 2% of patients were pneumonia, pyrexia, diarrhea, pneumonitis, pleural effusion, dyspnea, acute kidney injury, infusion-related reaction, musculoskeletal pain, and pulmonary embolism. Fatal adverse reactions occurred in 4 (1.3%) patients and included pneumonitis, acute heart failure, sepsis, and encephalitis. In Checkmate 214, serious adverse reactions occurred in 59% of patients receiving OPDIVO plus YERVOY (n=547). The most frequent serious adverse reactions reported in 2% of patients were diarrhea, pyrexia, pneumonia, pneumonitis, hypophysitis, acute kidney injury, dyspnea, adrenal insufficiency, and colitis. In Checkmate 9ER, serious adverse reactions occurred in 48% of patients receiving OPDIVO and cabozantinib (n=320). The most frequent serious adverse reactions reported in 2% of patients were diarrhea, pneumonia, pneumonitis, pulmonary embolism, urinary tract infection, and hyponatremia. Fatal intestinal perforations occurred in 3 (0.9%) patients. In Checkmate 025, serious adverse reactions occurred in 47% of patients receiving OPDIVO (n=406). The most frequent serious adverse reactions reported in 2% of patients were acute kidney injury, pleural effusion, pneumonia, diarrhea, and hypercalcemia. In Checkmate 205 and 039, adverse reactions leading to discontinuation occurred in 7% and dose delays due to adverse reactions occurred in 34% of patients (n=266). Serious adverse reactions occurred in 26% of patients. The most frequent serious adverse reactions reported in 1% of patients were pneumonia, infusion-related reaction, pyrexia, colitis or diarrhea, pleural effusion, pneumonitis, and rash. Eleven patients died from causes other than disease progression: 3 from adverse reactions within 30 days of the last OPDIVO dose, 2 from infection 8 to 9 months after completing OPDIVO, and 6 from complications of allogeneic HSCT. In Checkmate 141, serious adverse reactions occurred in 49% of patients receiving OPDIVO (n=236). The most frequent serious adverse reactions reported in 2% of patients receiving OPDIVO were pneumonia, dyspnea, respiratory failure, respiratory tract infection, and sepsis. In Checkmate 275, serious adverse reactions occurred in 54% of patients receiving OPDIVO (n=270). The most frequent serious adverse reactions reported in 2% of patients receiving OPDIVO were urinary tract infection, sepsis, diarrhea, small intestine obstruction, and general physical health deterioration. In Checkmate 142 in MSI-H/dMMR mCRC patients receiving OPDIVO with YERVOY (n=119), serious adverse reactions occurred in 47% of patients. The most frequent serious adverse reactions reported in 2% of patients were colitis/diarrhea, hepatic events, abdominal pain, acute kidney injury, pyrexia, and dehydration. In Checkmate 040, serious adverse reactions occurred in 49% of patients receiving OPDIVO (n=154). The most frequent serious adverse reactions reported in 2% of patients were pyrexia, ascites, back pain, general physical health deterioration, abdominal pain, pneumonia, and anemia. In Checkmate 040, serious adverse reactions occurred in 59% of patients receiving OPDIVO with YERVOY (n=49). Serious adverse reactions reported in 4% of patients were pyrexia, diarrhea, anemia, increased AST, adrenal insufficiency, ascites, esophageal varices hemorrhage, hyponatremia, increased blood bilirubin, and pneumonitis. In Checkmate 238, serious adverse reactions occurred in 18% of patients receiving OPDIVO (n=452). Grade 3 or 4 adverse reactions occurred in 25% of OPDIVO-treated patients (n=452). The most frequent Grade 3 and 4 adverse reactions reported in 2% of OPDIVO-treated patients were diarrhea and increased lipase and amylase. In Attraction-3, serious adverse reactions occurred in 38% of patients receiving OPDIVO (n=209). Serious adverse reactions reported in 2% of patients who received OPDIVO were pneumonia, esophageal fistula, interstitial lung disease, and pyrexia. The following fatal adverse reactions occurred in patients who received OPDIVO: interstitial lung disease or pneumonitis (1.4%), pneumonia (1.0%), septic shock (0.5%), esophageal fistula (0.5%), gastrointestinal hemorrhage (0.5%), pulmonary embolism (0.5%), and sudden death (0.5%). In Checkmate 649, serious adverse reactions occurred in 52% of patients treated with OPDIVO in combination with chemotherapy (n=782). The most frequent serious adverse reactions reported in 2% of patients treated with OPDIVO in combination with chemotherapy were vomiting (3.7%), pneumonia (3.6%), anemia (3.6%), pyrexia (2.8%), diarrhea (2.7%), febrile neutropenia (2.6%), and pneumonitis (2.4%). Fatal adverse reactions occurred in 16 (2.0%) patients who were treated with OPDIVO in combination with chemotherapy; these included pneumonitis (4 patients), febrile neutropenia (2 patients), stroke (2 patients), gastrointestinal toxicity, intestinal mucositis, septic shock, pneumonia, infection, gastrointestinal bleeding, mesenteric vessel thrombosis, and disseminated intravascular coagulation.

Common Adverse Reactions

In Checkmate 037, the most common adverse reaction (20%) reported with OPDIVO (n=268) was rash (21%). In Checkmate 066, the most common adverse reactions (20%) reported with OPDIVO (n=206) vs dacarbazine (n=205) were fatigue (49% vs 39%), musculoskeletal pain (32% vs 25%), rash (28% vs 12%), and pruritus (23% vs 12%). In Checkmate 067, the most common (20%) adverse reactions in the OPDIVO plus YERVOY arm (n=313) were fatigue (62%), diarrhea (54%), rash (53%), nausea (44%), pyrexia (40%), pruritus (39%), musculoskeletal pain (32%), vomiting (31%), decreased appetite (29%), cough (27%), headache (26%), dyspnea (24%), upper respiratory tract infection (23%), arthralgia (21%), and increased transaminases (25%). In Checkmate 067, the most common (20%) adverse reactions in the OPDIVO arm (n=313) were fatigue (59%), rash (40%), musculoskeletal pain (42%), diarrhea (36%), nausea (30%), cough (28%), pruritus (27%), upper respiratory tract infection (22%), decreased appetite (22%), headache (22%), constipation (21%), arthralgia (21%), and vomiting (20%). In Checkmate 227, the most common (20%) adverse reactions were fatigue (44%), rash (34%), decreased appetite (31%), musculoskeletal pain (27%), diarrhea/colitis (26%), dyspnea (26%), cough (23%), hepatitis (21%), nausea (21%), and pruritus (21%). In Checkmate 9LA, the most common (>20%) adverse reactions were fatigue (49%), musculoskeletal pain (39%), nausea (32%), diarrhea (31%), rash (30%), decreased appetite (28%), constipation (21%), and pruritus (21%). In Checkmate 017 and 057, the most common adverse reactions (20%) in patients receiving OPDIVO (n=418) were fatigue, musculoskeletal pain, cough, dyspnea, and decreased appetite. In Checkmate 743, the most common adverse reactions (20%) in patients receiving OPDIVO plus YERVOY were fatigue (43%), musculoskeletal pain (38%), rash (34%), diarrhea (32%), dyspnea (27%), nausea (24%), decreased appetite (24%), cough (23%), and pruritus (21%). In Checkmate 214, the most common adverse reactions (20%) reported in patients treated with OPDIVO plus YERVOY (n=547) were fatigue (58%), rash (39%), diarrhea (38%), musculoskeletal pain (37%), pruritus (33%), nausea (30%), cough (28%), pyrexia (25%), arthralgia (23%), decreased appetite (21%), dyspnea (20%), and vomiting (20%). In Checkmate 9ER, the most common adverse reactions (20%) in patients receiving OPDIVO and cabozantinib (n=320) were diarrhea (64%), fatigue (51%), hepatotoxicity (44%), palmar-plantar erythrodysaesthesia syndrome (40%), stomatitis (37%), rash (36%), hypertension (36%), hypothyroidism (34%), musculoskeletal pain (33%), decreased appetite (28%), nausea (27%), dysgeusia (24%), abdominal pain (22%), cough (20%) and upper respiratory tract infection (20%). In Checkmate 025, the most common adverse reactions (20%) reported in patients receiving OPDIVO (n=406) vs everolimus (n=397) were fatigue (56% vs 57%), cough (34% vs 38%), nausea (28% vs 29%), rash (28% vs 36%), dyspnea (27% vs 31%), diarrhea (25% vs 32%), constipation (23% vs 18%), decreased appetite (23% vs 30%), back pain (21% vs 16%), and arthralgia (20% vs 14%). In Checkmate 205 and 039, the most common adverse reactions (20%) reported in patients receiving OPDIVO (n=266) were upper respiratory tract infection (44%), fatigue (39%), cough (36%), diarrhea (33%), pyrexia (29%), musculoskeletal pain (26%), rash (24%), nausea (20%) and pruritus (20%). In Checkmate 141, the most common adverse reactions (10%) in patients receiving OPDIVO (n=236) were cough (14%) and dyspnea (14%) at a higher incidence than investigators choice. In Checkmate 275, the most common adverse reactions (20%) reported in patients receiving OPDIVO (n=270) were fatigue (46%), musculoskeletal pain (30%), nausea (22%), and decreased appetite (22%). In Checkmate 142 in MSI-H/dMMR mCRC patients receiving OPDIVO as a single agent (n=74), the most common adverse reactions (20%) were fatigue (54%), diarrhea (43%), abdominal pain (34%), nausea (34%), vomiting (28%), musculoskeletal pain (28%), cough (26%), pyrexia (24%), rash (23%), constipation (20%), and upper respiratory tract infection (20%). In Checkmate 142 in MSI-H/dMMR mCRC patients receiving OPDIVO with YERVOY (n=119), the most common adverse reactions (20%) were fatigue (49%), diarrhea (45%), pyrexia (36%), musculoskeletal pain (36%), abdominal pain (30%), pruritus (28%), nausea (26%), rash (25%), decreased appetite (20%), and vomiting (20%). In Checkmate 040, the most common adverse reactions (20%) in patients receiving OPDIVO (n=154) were fatigue (38%), musculoskeletal pain (36%), abdominal pain (34%), pruritus (27%), diarrhea (27%), rash (26%), cough (23%), and decreased appetite (22%). In Checkmate 040, the most common adverse reactions (20%) in patients receiving OPDIVO with YERVOY (n=49), were rash (53%), pruritus (53%), musculoskeletal pain (41%), diarrhea (39%), cough (37%), decreased appetite (35%), fatigue (27%), pyrexia (27%), abdominal pain (22%), headache (22%), nausea (20%), dizziness (20%), hypothyroidism (20%), and weight decreased (20%). In Checkmate 238, the most common adverse reactions (20%) reported in OPDIVO-treated patients (n=452) vs ipilimumab-treated patients (n=453) were fatigue (57% vs 55%), diarrhea (37% vs 55%), rash (35% vs 47%), musculoskeletal pain (32% vs 27%), pruritus (28% vs 37%), headache (23% vs 31%), nausea (23% vs 28%), upper respiratory infection (22% vs 15%), and abdominal pain (21% vs 23%). The most common immune-mediated adverse reactions were rash (16%), diarrhea/colitis (6%), and hepatitis (3%). In Attraction-3, the most common adverse reactions (20%) in OPDIVO-treated patients (n=209) were rash (22%) and decreased appetite (21%). In Checkmate 649, the most common adverse reactions (20%) in patients treated with OPDIVO in combination with chemotherapy (n=782) were peripheral neuropathy (53%), nausea (48%), fatigue (44%), diarrhea (39%), vomiting (31%), decreased appetite (29%), abdominal pain (27%), constipation (25%), and musculoskeletal pain (20%).

In a separate Phase 3 trial of YERVOY 3 mg/kg, the most common adverse reactions (5%) in patients who received YERVOY at 3 mg/kg were fatigue (41%), diarrhea (32%), pruritus (31%), rash (29%), and colitis (8%).

Please see US Full Prescribing Information for OPDIVO and YERVOY.

Clinical Trials and Patient Populations

Checkmate 037previously treated metastatic melanoma; Checkmate 066previously untreated metastatic melanoma; Checkmate 067previously untreated metastatic melanoma, as a single agent or in combination with YERVOY; Checkmate 227previously untreated metastatic non-small cell lung cancer, in combination with YERVOY; Checkmate 9LApreviously untreated recurrent or metastatic non-small cell lung cancer in combination with YERVOY and 2 cycles of platinum-doublet chemotherapy by histology; Checkmate 017second-line treatment of metastatic squamous non-small cell lung cancer; Checkmate 057second-line treatment of metastatic non-squamous non-small cell lung cancer; Checkmate 743previously untreated unresectable malignant pleural mesothelioma, in combination with YERVOY; Checkmate 214previously untreated renal cell carcinoma, in combination with YERVOY; Checkmate 9ERpreviously untreated renal cell carcinoma, in combination with cabozantinib; Checkmate 025previously treated renal cell carcinoma; Checkmate 205/039classical Hodgkin lymphoma; Checkmate 141recurrent or metastatic squamous cell carcinoma of the head and neck; Checkmate 275urothelial carcinoma; Checkmate 142MSI-H or dMMR metastatic colorectal cancer, as a single agent or in combination with YERVOY; Checkmate 040hepatocellular carcinoma, as a single agent or in combination with YERVOY; Checkmate 238adjuvant treatment of melanoma; Attraction-3esophageal squamous cell carcinoma; Checkmate 649previously untreated advanced or metastatic gastric or gastroesophageal junction or esophageal adenocarcinoma.

About the Bristol Myers Squibb and Ono Pharmaceutical Collaboration

In 2011, through a collaboration agreement with Ono Pharmaceutical Co., Bristol Myers Squibb expanded its territorial rights to develop and commercialize Opdivo globally, except in Japan, South Korea and Taiwan, where Ono had retained all rights to the compound at the time. On July 23, 2014, Ono and Bristol Myers Squibb further expanded the companies strategic collaboration agreement to jointly develop and commercialize multiple immunotherapies as single agents and combination regimens for patients with cancer in Japan, South Korea and Taiwan.

About Bristol Myers Squibb

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Six-and-a-Half-Year Outcomes for Opdivo (nivolumab) in Combination with Yervoy (ipilimumab) Continue to Demonstrate Durable Long-Term Survival...

Merck Receives Positive EU CHMP Opinion for KEYTRUDA in Combination With Chemotherapy as First-Line Treatment for Certain Patients With Esophageal…

Opinion Supports Use of KEYTRUDA in Combination With Platinum- and Fluoropyrimidine-Based Chemotherapy in Patients Whose Tumors Express PD-L1 (CPS 10)

Recommendation Based on Significant Survival Benefit Demonstrated With KEYTRUDA Plus Chemotherapy Versus Chemotherapy in Phase 3 KEYNOTE-590 Trial

Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion recommending approval of KEYTRUDA, Mercks anti-PD-1 therapy, in combination with platinum- and fluoropyrimidine-based chemotherapy for the first-line treatment of patients with locally advanced unresectable or metastatic carcinoma of the esophagus or human epidermal growth factor receptor 2 (HER2)-negative gastroesophageal junction (GEJ) adenocarcinoma in adults whose tumors express PD-L1 (Combined Positive Score [CPS] 10). The CHMPs recommendation will now be reviewed by the European Commission for marketing authorization in the European Union, and a final decision is expected in the second quarter of 2021.

Patients with metastatic esophageal cancer currently face five-year survival rates of just 5%, said Dr. Scot Ebbinghaus, vice president, clinical research, Merck Research Laboratories. There is a critical need for new treatment options in the first-line setting that can potentially extend their lives. Todays positive opinion for KEYTRUDA is an important step forward for patients in Europe with certain types of gastrointestinal cancers.

The positive CHMP opinion is based on results from the pivotal Phase 3 KEYNOTE-590 trial, in which KEYTRUDA plus 5-fluorouracil (5-FU) and cisplatin demonstrated significant improvements in overall survival and progression-free survival compared with 5-FU and cisplatin alone in patients regardless of histology or PD-L1 expression status. KEYTRUDA plus 5-FU and cisplatin reduced the risk of death by 27% (HR=0.73 [95% CI, 0.62-0.86]; p

Merck is studying KEYTRUDA across multiple settings and stages of gastrointestinal cancer including esophageal, gastric, hepatobiliary, pancreatic, colorectal and anal cancers through its broad clinical program.

About Esophageal Cancer

Esophageal cancer begins in the inner layer (mucosa) of the esophagus and grows outward. Esophageal cancer is the eighth most commonly diagnosed cancer and the sixth leading cause of death from cancer worldwide. Globally, it is estimated there were more than 604,000 new cases of esophageal cancer diagnosed and approximately 544,000 deaths resulting from the disease in 2020. In Europe, it is estimated there were more than 52,000 new cases of esophageal cancer diagnosed and approximately 45,000 deaths resulting from the disease in 2020.

About KEYTRUDA (pembrolizumab) Injection, 100 mg

KEYTRUDA is an anti-PD-1 therapy that works by increasing the ability of the bodys immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

Merck has the industrys largest immuno-oncology clinical research program. There are currently more than 1,400 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patients likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.

Selected KEYTRUDA (pembrolizumab) Indications in the U.S.

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma.

KEYTRUDA is indicated for the adjuvant treatment of patients with melanoma with involvement of lymph node(s) following complete resection.

Non-Small Cell Lung Cancer

KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA, in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, is indicated for the first-line treatment of patients with metastatic squamous NSCLC.

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with NSCLC expressing PD-L1 [tumor proportion score (TPS) 1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and is stage III where patients are not candidates for surgical resection or definitive chemoradiation, or metastatic.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS 1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.

Head and Neck Squamous Cell Cancer

KEYTRUDA, in combination with platinum and fluorouracil (FU), is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC).

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [combined positive score (CPS) 1] as determined by an FDA-approved test.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy.

Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL).

KEYTRUDA is indicated for the treatment of pediatric patients with refractory cHL, or cHL that has relapsed after 2 or more lines of therapy.

Primary Mediastinal Large B-Cell Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy. KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy.

Urothelial Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 (CPS 10), as determined by an FDA-approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

KEYTRUDA is indicated for the treatment of patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.

Microsatellite Instability-High or Mismatch Repair Deficient Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR)

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established.

Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer

KEYTRUDA is indicated for the first-line treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC).

Gastric Carcinoma

KEYTRUDA, in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test, with disease progression on or after 2 or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Esophageal Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic esophageal or gastroesophageal junction (GEJ) (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma that is not amenable to surgical resection or definitive chemoradiation either:

Cervical Carcinoma

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Hepatocellular Carcinoma

KEYTRUDA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Merkel Cell Carcinoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Renal Cell Carcinoma

KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of patients with advanced renal cell carcinoma (RCC).

Tumor Mutational Burden-High

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [10 mutations/megabase] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with TMB-H central nervous system cancers have not been established.

Cutaneous Squamous Cell Carcinoma

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) that is not curable by surgery or radiation.

Triple-Negative Breast Cancer

KEYTRUDA, in combination with chemotherapy, is indicated for the treatment of patients with locally recurrent unresectable or metastatic triple-negative breast cancer (TNBC) whose tumors express PD-L1 (CPS 10) as determined by an FDA-approved test. This indication is approved under accelerated approval based on progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Selected Important Safety Information for KEYTRUDA

Severe and Fatal Immune-Mediated Adverse Reactions

KEYTRUDA is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death receptor-1 (PD-1) or the programmed death ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, can affect more than one body system simultaneously, and can occur at any time after starting treatment or after discontinuation of treatment. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions.

Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Early identification and management are essential to ensure safe use of antiPD-1/PD-L1 treatments. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue KEYTRUDA depending on severity of the immune-mediated adverse reaction. In general, if KEYTRUDA requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose adverse reactions are not controlled with corticosteroid therapy.

Immune-Mediated Pneumonitis

KEYTRUDA can cause immune-mediated pneumonitis. The incidence is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA, including fatal (0.1%), Grade 4 (0.3%), Grade 3 (0.9%), and Grade 2 (1.3%) reactions. Systemic corticosteroids were required in 67% (63/94) of patients. Pneumonitis led to permanent discontinuation of KEYTRUDA in 1.3% (36) and withholding in 0.9% (26) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Pneumonitis resolved in 59% of the 94 patients.

Pneumonitis occurred in 8% (31/389) of adult patients with cHL receiving KEYTRUDA as a single agent, including Grades 3-4 in 2.3% of patients. Patients received high-dose corticosteroids for a median duration of 10 days (range: 2 days to 53 months). Pneumonitis rates were similar in patients with and without prior thoracic radiation. Pneumonitis led to discontinuation of KEYTRUDA in 5.4% (21) of patients. Of the patients who developed pneumonitis, 42% of these patients interrupted KEYTRUDA, 68% discontinued KEYTRUDA, and 77% had resolution.

Immune-Mediated Colitis

KEYTRUDA can cause immune-mediated colitis, which may present with diarrhea. Cytomegalovirus infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 4 (

Hepatotoxicity and Immune-Mediated Hepatitis

KEYTRUDA as a Single Agent

KEYTRUDA can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 4 (

KEYTRUDA with Axitinib

KEYTRUDA in combination with axitinib can cause hepatic toxicity. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider monitoring more frequently as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt KEYTRUDA and axitinib, and consider administering corticosteroids as needed. With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased alanine aminotransferase (ALT) (20%) and increased aspartate aminotransferase (AST) (13%) were seen, which was at a higher frequency compared to KEYTRUDA alone. Fifty-nine percent of the patients with increased ALT received systemic corticosteroids. In patients with ALT 3 times upper limit of normal (ULN) (Grades 2-4, n=116), ALT resolved to Grades 0-1 in 94%. Among the 92 patients who were rechallenged with either KEYTRUDA (n=3) or axitinib (n=34) administered as a single agent or with both (n=55), recurrence of ALT 3 times ULN was observed in 1 patient receiving KEYTRUDA, 16 patients receiving axitinib, and 24 patients receiving both. All patients with a recurrence of ALT 3 ULN subsequently recovered from the event.

Immune-Mediated Endocrinopathies

Adrenal Insufficiency

KEYTRUDA can cause primary or secondary adrenal insufficiency. For Grade 2 or higher, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold KEYTRUDA depending on severity. Adrenal insufficiency occurred in 0.8% (22/2799) of patients receiving KEYTRUDA, including Grade 4 (

Hypophysitis

KEYTRUDA can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Hypophysitis occurred in 0.6% (17/2799) of patients receiving KEYTRUDA, including Grade 4 (

Thyroid Disorders

KEYTRUDA can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Thyroiditis occurred in 0.6% (16/2799) of patients receiving KEYTRUDA, including Grade 2 (0.3%). None discontinued, but KEYTRUDA was withheld in

Hyperthyroidism occurred in 3.4% (96/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (0.8%). It led to permanent discontinuation of KEYTRUDA in

Type 1 Diabetes Mellitus (DM), Which Can Present With Diabetic Ketoacidosis

Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold KEYTRUDA depending on severity. Type 1 DM occurred in 0.2% (6/2799) of patients receiving KEYTRUDA. It led to permanent discontinuation in

Immune-Mediated Nephritis With Renal Dysfunction

KEYTRUDA can cause immune-mediated nephritis. Immune-mediated nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 4 (

Immune-Mediated Dermatologic Adverse Reactions

KEYTRUDA can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms, and toxic epidermal necrolysis, has occurred with antiPD-1/PD-L1 treatments. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes. Withhold or permanently discontinue KEYTRUDA depending on severity. Immune-mediated dermatologic adverse reactions occurred in 1.4% (38/2799) of patients receiving KEYTRUDA, including Grade 3 (1%) and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 40% (15/38) of patients. These reactions led to permanent discontinuation in 0.1% (2) and withholding of KEYTRUDA in 0.6% (16) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 6% had recurrence. The reactions resolved in 79% of the 38 patients.

Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse reactions occurred at an incidence of Cardiac/Vascular: Myocarditis, pericarditis, vasculitis; Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barr syndrome, nerve paresis, autoimmune neuropathy; Ocular: Uveitis, iritis and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss; Gastrointestinal: Pancreatitis, to include increases in serum amylase and lipase levels, gastritis, duodenitis; Musculoskeletal and Connective Tissue: Myositis/polymyositis rhabdomyolysis (and associated sequelae, including renal failure), arthritis (1.5%), polymyalgia rheumatica; Endocrine: Hypoparathyroidism; Hematologic/Immune: Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection.

Infusion-Related Reactions

KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% of 2799 patients receiving KEYTRUDA. Monitor for signs and symptoms of infusion-related reactions. Interrupt or slow the rate of infusion for Grade 1 or Grade 2 reactions. For Grade 3 or Grade 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Fatal and other serious complications can occur in patients who receive allogeneic HSCT before or after antiPD-1/PD-L1 treatment. Transplant-related complications include hyperacute graft-versus-host disease (GVHD), acute and chronic GVHD, hepatic veno-occlusive disease after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between antiPD-1/PD-L1 treatment and allogeneic HSCT. Follow patients closely for evidence of these complications and intervene promptly. Consider the benefit vs risks of using antiPD-1/PD-L1 treatments prior to or after an allogeneic HSCT.

Increased Mortality in Patients With Multiple Myeloma

In trials in patients with multiple myeloma, the addition of KEYTRUDA to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of these patients with an antiPD-1/PD-L1 treatment in this combination is not recommended outside of controlled trials.

Embryofetal Toxicity

Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. Advise women of this potential risk. In females of reproductive potential, verify pregnancy status prior to initiating KEYTRUDA and advise them to use effective contraception during treatment and for 4 months after the last dose.

Adverse Reactions

In KEYNOTE-006, KEYTRUDA was discontinued due to adverse reactions in 9% of 555 patients with advanced melanoma; adverse reactions leading to permanent discontinuation in more than one patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%). The most common adverse reactions (20%) with KEYTRUDA were fatigue (28%), diarrhea (26%), rash (24%), and nausea (21%).

In KEYNOTE-054, KEYTRUDA was permanently discontinued due to adverse reactions in 14% of 509 patients; the most common (1%) were pneumonitis (1.4%), colitis (1.2%), and diarrhea (1%). Serious adverse reactions occurred in 25% of patients receiving KEYTRUDA. The most common adverse reaction (20%) with KEYTRUDA was diarrhea (28%).

In KEYNOTE-189, when KEYTRUDA was administered with pemetrexed and platinum chemotherapy in metastatic nonsquamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 20% of 405 patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonitis (3%) and acute kidney injury (2%). The most common adverse reactions (20%) with KEYTRUDA were nausea (56%), fatigue (56%), constipation (35%), diarrhea (31%), decreased appetite (28%), rash (25%), vomiting (24%), cough (21%), dyspnea (21%), and pyrexia (20%).

Originally posted here:
Merck Receives Positive EU CHMP Opinion for KEYTRUDA in Combination With Chemotherapy as First-Line Treatment for Certain Patients With Esophageal...

Sheehan’s syndrome – Symptoms and causes – Mayo Clinic

Overview Pituitary gland and hypothalamus Open pop-up dialog box

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The pituitary gland and the hypothalamus are situated within the brain. Together, they control many of the body's hormone production processes.

Sheehan's syndrome is a condition that affects women who lose a life-threatening amount of blood in childbirth or who have severe low blood pressure during or after childbirth, which can deprive the body of oxygen. This lack of oxygen that causes damage to the pituitary gland is known as Sheehan's syndrome.

Sheehan's syndrome causes the pituitary gland to not produce enough pituitary hormones (hypopituitarism). Also called postpartum hypopituitarism, Sheehan's syndrome is rare in industrialized nations, largely because care during pregnancy and childbirth is better than in developing countries.

Treatment of Sheehan's syndrome involves lifelong hormone replacement therapy.

Signs and symptoms of Sheehan's syndrome typically appear slowly, after a period of months or years. But sometimes problems appear right away, such as the inability to breast-feed.

Signs and symptoms of Sheehan's syndrome occur because of having too little of the hormones the pituitary gland produces. Signs and symptoms include:

For many women, Sheehan's syndrome symptoms are often thought to be caused by other things. Fatigue, for instance, is commonly experienced by new mothers. You might not realize you have Sheehan's syndrome until you need treatment for thyroid or adrenal insufficiency.

It's also possible to remain relatively symptom-free if you have Sheehan's syndrome, depending on the extent of damage to the pituitary gland. Some women live for years without knowing that their pituitary gland isn't working properly. Then an extreme physical stressor, such as severe infection or surgery, triggers an adrenal crisis, a serious condition in which your adrenal glands produce too little of the hormone cortisol.

Sheehan's syndrome is caused by severe blood loss or extremely low blood pressure during or after childbirth. These factors can be particularly damaging to the pituitary gland, which enlarges during pregnancy, destroying hormone-producing tissue so that the gland can't function normally.

Pituitary hormones regulate the rest of your endocrine system, signaling other glands to increase or decrease production of the hormones that control metabolism, fertility, blood pressure, breast milk production and many other vital processes. A lack of any of these hormones can cause problems throughout the body.

Hormones from the front of your pituitary gland include:

Adrenocorticotropic hormone (ACTH). This hormone stimulates your adrenal glands to produce cortisol and other hormones. Cortisol helps your body deal with stress and influences many body functions, including blood pressure, heart function and your immune system.

A low level of adrenal hormones caused by damage to the pituitary gland is called secondary adrenal insufficiency.

Any condition that increases the chance of severe blood loss (hemorrhage) or low blood pressure during childbirth, such as being pregnant with multiples or having a problem with the placenta, can increase the risk of Sheehan's syndrome.

Hemorrhage is a rare childbirth complication, however, and Sheehan's syndrome is even more uncommon. Both risks are greatly reduced with proper care and monitoring during labor and delivery.

Because pituitary hormones control many aspects of your metabolism, Sheehan's syndrome can cause many problems, including:

The most serious complication is adrenal crisis, a sudden, life-threatening state that can lead to extremely low blood pressure, shock, coma and death.

Adrenal crisis usually occurs when your body is under marked stress such as during surgery or a serious illness and your adrenal glands produce too little of a powerful stress hormone (cortisol).

Because of the potentially serious consequences of adrenal insufficiency, your doctor is likely to recommend that you wear a medical alert bracelet.

Nov. 26, 2019

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Sheehan's syndrome - Symptoms and causes - Mayo Clinic

atrophy | Definition, Types, & Effects | Britannica

Atrophy, decrease in size of a body part, cell, organ, or other tissue. The term implies that the atrophied part was of a size normal for the individual, considering age and circumstance, prior to the diminution. In atrophy of an organ or body part, there may be a reduction in the number or in the size of the component cells, or in both.

One example of atrophy is the progressive loss of bone that occurs in osteoporosis (normal bone shown on left; osteoporotic bone shown on right).

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Certain cells and organs normally undergo atrophy at certain ages or under certain physiologic circumstances. In the human embryo, for example, a number of structures are transient and at birth have already undergone atrophy. The adrenal glands become smaller shortly after birth because an inner layer of the cortex has shrunk. The thymus and other lymphoid tissues atrophy at adolescence. The pineal gland tends to atrophy about the time of puberty; usually calcium deposits, or concretions, form in the atrophic tissue. The widespread atrophy of many tissues that accompanies advanced age, although universal, is influenced by changes of nutrition and blood supply that occur during active mature life.

The normal cyclic changes of female reproductive organs are accompanied by physiologic atrophy of portions of these organs. During the menstrual cycle, the corpus luteum of the ovary atrophies if pregnancy has not occurred. The muscles of the uterus, which enlarge during pregnancy, rapidly atrophy after the delivery of the child, and after completion of lactation the milk-producing acinar structures of the breast diminish in size. After menopause the ovaries, uterus, and breasts normally undergo a degree of atrophic change.

Atrophy in general is related to changes in nutrition and metabolic activity of cells and tissues. A widespread or generalized atrophy of body tissues occurs under conditions of starvation, whether because food is unavailable or because it cannot be taken and absorbed because of the presence of disease. The unavailability of certain essential protein components and vitamins disturbs the metabolic processes and leads to atrophy of cells and tissues. Under conditions of protein starvation, the body protein is broken down into constituent amino acids, which serve to provide energy and help maintain the structure and cells of the most essential organs. The brain, heart, adrenal glands, thyroid gland, pituitary gland, gonads, and kidneys show less atrophy, relatively, than the body as a whole, whereas the fatty stores of the body, liver, spleen, and lymphoid tissues diminish relatively more than the body as a whole. The brain, heart, and kidneys, organs with abundant blood supply, appear to be the least subject to the wasting effects of starvation.

Associated with the widespread atrophy due to lack of protein is the atrophy of certain tissues that is caused by deficiencies of specific vitamins. Atrophic changes of the skin increase because of the lack of vitamin A, and atrophy of muscle increases because of the unavailability of vitamin E.

After a growth period of human metabolism, there sets in a gradual decline: slow structural changes other than those due to preventable diseases or accidents occur. Aging eventually is characterized by marked atrophy of many tissues and organs, with both a decline in the number of cells and an alteration in their constitution. This is reflected eventually in the changed, diminished, or lost function characteristic of old age and eventuates in death. The changes in senescence are affected by both inherited constitution and environmental influences, including disease and accident.

Atrophic changes of aging affect almost all tissues and organs, but some changes are more obvious and important. Arteriosclerosisthe thickening and hardening of arterial wallsdecreases the vascular supply and usually accentuates aging processes.

Atrophy in old age is especially noticeable in the skin, characteristically flat, glossy or satiny, and wrinkled. The atrophy is caused by aging changes in the fibres of the true skin, or dermis, and in the cells and sweat glands of the outer skin. Wasting of muscle accompanied by some loss of muscular strength and agility is common in the aged. In a somewhat irregular pattern, there is shrinkage of many individual muscle fibres as well as a decrease in their number. Other changes have been observed within the muscle cells.

Increase of the pigment lipofuscin is also characteristic in the muscle fibres of the heart in the aged in a condition known as brown atrophy of the heart. Wasting of the heart muscle in old age may be accompanied by increase of fibrous and fatty tissue in the walls of the right side of the heart and by increased replacement of elastic tissue with fibrous tissue in the lining and walls of coronary arteries within the heart muscle. Abnormal deposits of the protein substance amyloid also occur with greater frequency in the atrophic heart muscle in old age.

Atrophy of the liver in the aged is also accompanied by increased lipochrome pigment in the atrophied cells.

The bones become progressively lighter and more porous with aging, a process known as osteoporosis. The reduction of bone tissue is most marked in cancellous bonethe open-textured tissue in the ends of the long bonesand in the inner parts of the cortex of these bones. In addition to changes in and loss of osteocytes, or bone cells, there is decreasing mineralization, or calcium deposit, with enhanced fragility of the bones.

Atrophy of the brain in old age is shown by narrowing of the ridges, or gyri, on the surface of the brain and by increased fluid in the space beneath the arachnoid membrane, the middle layer of the brain covering. There is shrinkage of individual neurons, with an increase in their lipochrome pigment content, as well as a decrease in their number. Sometimes the nerve fibrils have degenerated, and deposits called senile plaques may be found between the neurons, particularly in the frontal cortex and hippocampus (a ridge in the wall of an extension, or horn, of the lateral ventricle, or cavity, of the brain). Similar atrophic changes are seen in the brain in Alzheimer disease, a condition of unknown cause most likely to occur in older patients. The mental deterioration (senile dementia) of the aged is the clinical manifestation of these changes. Senile atrophy may be increased and complicated by the presence of arteriosclerosis.

Positron emission tomography (PET) scans showing a healthy brain (left) and a brain affected by Alzheimer disease (right). Reductions in the size of certain structures of the brain were found to be predictive for mild cognitive impairment and progression to dementia.

Simmonds disease is a chronic deficiency of function of the pituitary gland, a form of hypopituitarism, that leads to atrophy of many of the viscera, including the heart, liver, spleen, kidneys, thyroid, adrenals, and gonads. The disease results in emaciation and death if left untreated.

A destructive or atrophic lesion affecting the pituitary gland with loss of hormones leads to atrophy of the thyroid gland, adrenal glands, and gonads and in turn brings atrophic changes to their target organs and the viscera. The decrease in size of the endocrine glands may be extreme.

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atrophy | Definition, Types, & Effects | Britannica

Hormone Replacement in Hypopituitarism Guideline Resources …

Full Guideline: Hormonal Replacement in Hypopituitarism in AdultsJCEM | October 2016Maria Fleseriu (Chair), Ibrahim A. Hashim, Niki Karavitaki, Shlomo Melmed, M. Hassan Murad, Roberto Salvatori, and Mary H. Samuels

The 2016 guideline addresses:

The guideline addresses special circumstances that may affect the treatment of patients with hypopituitarism, including pregnancy care, post-surgical care following pituitary or other operations, treatment in combination with anti-epilepsy medication, and care following pituitary apoplexya serious condition that occurs when there is bleeding into the gland or blood flow to it is blocked.

Recommendations from the guideline include:

+ 1.0 Diagnosis of hypopituitarism

Central adrenal insufficiency

Central hypothyroidism

GH deficiency

Central hypogonadism in males

Central hypogonadism in females

Central diabetes insipidus

+ 2.0 Treatment

Hormonal replacement in panhypopituitarism

Glucocorticoid replacement

Adrenal crisis

Thyroid hormone replacement

Testosterone replacement

Estrogen replacement in premenopausal women

GH replacement therapy

Diabetes insipidus

Interactions between replacement hormones

Glucocorticoids and GH

Glucocorticoids and thyroid hormone

Glucocorticoids and estrogen

GH and thyroid hormones

Estrogen and thyroid hormones

GH and estrogen

Glucocorticoids and diabetes insipidus

Risk of hormonal over-replacement in hypopituitarism

Bone disease

Cardiovascular risks in patients with hypopituitarism on replacement therapy

Glucocorticoid over-replacement

Thyroid replacement

+ 3.0 Special circumstances

Cushings disease

Prolactinomas

GH replacement in cured acromegaly after surgery and/or radiation

Perioperative management of hypopituitarism

Pituitary surgery

Non-pituitary surgery

Management of hypopituitarism in pregnancy

Glucocorticoids

Thyroid

Desmopressin

Growth hormone

Management of hypopituitarism in pituitary apoplexy

Treatment of hypopituitarism in patients receiving antiepileptic medications

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Hormone Replacement in Hypopituitarism Guideline Resources ...

World Alopecia Market Segmentation & Impact Analysis, by Gender, Application and Region – Featuring Profiles of Key Players Cipla Inc, Johnson AG,…

DUBLIN, Dec. 29, 2020 /PRNewswire/ -- The "Alopecia Market Share, Growth & Analysis, By Disease, By Application, By Sales Distribution, By Gender And Segment Forecasts, 2016-2026" report has been added to ResearchAndMarkets.com's offering.

The growing prevalence of diseases that trigger alopecia, such as hyperthyroidism, hypopituitarism, lupus, acute stress disorder, and diabetes, are stimulating market growth.

Market Size - USD 9.08 billion in 2019, Market Growth - CAGR of 5.1%, Market Trends - Growing focus on aesthetic appearance and rise in disposable incomes.

The Global Alopecia Market size is expected to reach 13.65 Billion from USD 9.08 Billion in 2019, delivering a CAGR of 5.1% through 2027. The market growth is driven by the growing prevalence of chronic disorders, such as celiac disease, hypothyroidism, hyperthyroidism, Hodgkin's disease, acute stress disorder, hypopituitarism, Hashimoto's disease, lupus, diabetes, Addison's disease, and others, which trigger alopecia in patients.

Changing lifestyle habits, such as overconsumption of alcohol and tobacco and growing stress levels, are resulting in an increased number of alopecia cases globally. Increasing focus on physical appearance and rising disposable incomes are favoring industry growth.

The increasing prevalence of oral treatments, licensed topical treatments, such as minoxidil, finasteride, and surgical procedures, such as hair transplantation or replacement, is expected to boost alopecia market growth over the forecast period.

Further key findings from the report suggest

The growing prevalence of alopecia areata on account of the rising incidences of autoimmune diseases among the populace, including diabetes, Down's syndrome, hyperthyroidism, and others, is driving alopecia market growth.

Growing focus on the aesthetic appeal and physical appearance among individuals is the key factor contributing significantly to the alopecia market revenue share.

The growing popularity of laser treatments as a common non-invasive approach for alopecia is likely to boost the growth of the androgenetic segment.

On the basis of disease type, the alopecia areata segment accounted for around 39.30% of the alopecia market share in 2019.

Based on application, the dermatology clinics segment contributed a revenue share close to USD 4.69 billion in 2019 and is estimated to gain major traction over the analysis period. The growth can be attributed to effective and suitable medication or therapy prescribed by dermatologists for positive results.

In the regional landscape, the Asia Pacific region is estimated to exhibit the fastest growth rate of 5.4% through 2027 on account of a vast population suffering from alopecia along with growing awareness among patients regarding the available therapeutic options in the region.

The rise in economic development, coupled with increasing per capita healthcare spending in emerging countries such as China, Singapore, and India, is anticipated to offer major opportunities for the alopecia market.

North America region accounted for around 22.30% of the alopecia market share in 2019 and is forecast to grow significantly through 2027 on account of the increasing consumer disposable incomes, rise in the introduction of new drugs, and the complementary initiatives taken by relevant organizations like NAAF and AHLA in the region.

Prominent players in the global alopecia market are Cipla Inc., Transitions Hair Pty Ltd., Johnson and Johnson AG, Sun Pharmaceutical Industries Ltd., Cirrus Hair Centers, Merck & Co., Inc., Lexington International LLC, Follica, Inc., Capillus, and Vita-Cos-Med Klett-Loch GmbH, among others.

Key report features:

Story continues

A robust analysis and estimation of the Alopecia Market with four levels of quality check - in-house database, expert interviews, governmental regulation, and a forecast specifically done through time series analysis

A holistic competitive landscape of the all the major players in the Alopecia market. The report covers their market shares, strategic initiatives, new product launches, R&D expenditure, M&As, Joint ventures, expansionary plans, product wise metric space analysis and key developments

Go-to-market strategies specifically formulated in line with location analysis which takes into the factors such as government regulations, supplier mapping, supply chain obstacles, and feedback from local vendors

Most deep dive segmental bifurcation available currently in the market. Our stellar methodology helps us understand the overall gamut of the supply chain and will help you explain the current market dynamics

Special focus given on vendor landscape, supplier portfolio, customer mapping, production capacity, and yearly capacity utilization

Key Topics Covered:

Chapter 1. Market Synopsis

Chapter 2. Executive Summary

Chapter 3. Indicative Metrics

Chapter 4. Alopecia Market Segmentation & Impact Analysis

Chapter 5. Alopecia Market By Disease Insights & Trends

Chapter 6. Alopecia Market By Sales distribution Insights & Trends

Chapter 7. Alopecia Market By Gender Insights & Trends

Chapter 8. Alopecia Market By Application Insights & Trends

Chapter 9. Alopecia Market Regional Outlook

Chapter 10. Competitive Landscape

Chapter 11. Company Profiles

Cipla Inc.

Johnson AG

Transitions Hair Pty Ltd.

Sun Pharmaceutical Industries Ltd.

Merck & Co. Inc.

Cirrus Hair Centers

Lexington International LLC

Vita-Cos-Med Klett-Loch GmbH

Follica Inc.

Capillus.

For more information about this report visit https://www.researchandmarkets.com/r/17nnqu

About ResearchAndMarkets.comResearchAndMarkets.com is the world's leading source for international market research reports and market data. We provide you with the latest data on international and regional markets, key industries, the top companies, new products and the latest trends.

Research and Markets also offers Custom Research services providing focused, comprehensive and tailored research.

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View original content:http://www.prnewswire.com/news-releases/world-alopecia-market-segmentation--impact-analysis-by-gender-application-and-region---featuring-profiles-of-key-players-cipla-inc-johnson-ag-transitions-hair-pty-ltd-and-more-301199082.html

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World Alopecia Market Segmentation & Impact Analysis, by Gender, Application and Region - Featuring Profiles of Key Players Cipla Inc, Johnson AG,...

Global Alopecia Market is Forecast to Deliver a CAGR of 5.1% Between 2019 and 2027 – GlobeNewswire

Dublin, Dec. 09, 2020 (GLOBE NEWSWIRE) -- The "Alopecia Market Share, Growth & Analysis, By Disease, By Application, By Sales Distribution, By Gender And Segment Forecasts, 2016-2026" report has been added to ResearchAndMarkets.com's offering.

The growing prevalence of diseases that trigger alopecia, such as hyperthyroidism, hypopituitarism, lupus, acute stress disorder, and diabetes, are stimulating market growth.

Market Size - USD 9.08 billion in 2019, Market Growth - CAGR of 5.1%, Market Trends - Growing focus on aesthetic appearance and rise in disposable incomes.

The Global Alopecia Market size is expected to reach 13.65 Billion from USD 9.08 Billion in 2019, delivering a CAGR of 5.1% through 2027. The market growth is driven by the growing prevalence of chronic disorders, such as celiac disease, hypothyroidism, hyperthyroidism, Hodgkin's disease, acute stress disorder, hypopituitarism, Hashimoto's disease, lupus, diabetes, Addison's disease, and others, which trigger alopecia in patients.

Changing lifestyle habits, such as overconsumption of alcohol and tobacco and growing stress levels, are resulting in an increased number of alopecia cases globally. Increasing focus on physical appearance and rising disposable incomes are favoring industry growth.

The increasing prevalence of oral treatments, licensed topical treatments, such as minoxidil, finasteride, and surgical procedures, such as hair transplantation or replacement, is expected to boost alopecia market growth over the forecast period.

Further key findings from the report suggest

Key report features:

Key Topics Covered:

Chapter 1. Market Synopsis

Chapter 2. Executive Summary

Chapter 3. Indicative Metrics

Chapter 4. Alopecia Market Segmentation & Impact Analysis

Chapter 5. Alopecia Market By Disease Insights & Trends

Chapter 6. Alopecia Market By Sales distribution Insights & Trends

Chapter 7. Alopecia Market By Gender Insights & Trends

Chapter 8. Alopecia Market By Application Insights & Trends

Chapter 9. Alopecia Market Regional Outlook

Chapter 10. Competitive Landscape

Chapter 11. Company Profiles

For more information about this report visit https://www.researchandmarkets.com/r/jrlv6p

About ResearchAndMarkets.comResearchAndMarkets.com is the world's leading source for international market research reports and market data. We provide you with the latest data on international and regional markets, key industries, the top companies, new products and the latest trends.

Research and Markets also offers Custom Research services providing focused, comprehensive and tailored research.

See more here:
Global Alopecia Market is Forecast to Deliver a CAGR of 5.1% Between 2019 and 2027 - GlobeNewswire

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