Endocrine Diseases in Pregnancy | GLOWM

Posted: February 18, 2019 at 2:45 pm


Pregnancy is a unique clinical scenario in which several endocrine disorders may be more frequent and/or have specific considerations for diagnosis and treatment. In this review, anterior pituitary insufficiency, adrenal, parathyroid, and thyroid disorders of pregnancy are discussed.

Anterior pituitary insufficiency is an uncommon disease. The etiology includes destruction of the anterior pituitary gland by tumors, infarction (postpartum necrosis or Sheehan's syndrome), idiopathic disease (Simmonds' disease), surgery, and radiotherapy to the pituitary gland. There have also been reports of pituitary necrosis in patients with elevated intracerebral pressure.1 Disease of the hypothalamus affecting the secretion of releasing hormones may produce a similar clinical picture; some cases of Sheehan's syndrome and idiopathic hypopituitarism are due to hypothalamic diseases.2 Finally, congenital hypopituitarism is a rare diagnosis among newborn infants.3

Sheehans syndrome

The most common cause of panhypopituitarism in women of childbearing age is postpartum necrosis, or Sheehan's syndrome.4 The pathogenesis is not clear, although Sheehan in his original description did associate it with severe postpartum hemorrhage.5 Although the classic clinical etiology of Sheehan's syndrome in about 90% of patients is severe bleeding of the anterior pituitary during delivery or immediately postpartum, no catastrophic event can be detected in more than 10% of patients.

Lack of lactation after delivery, amenorrhea, loss of pubic and axillary hair or failure of pubic hair to grow back, anorexia and nausea, lethargy and weakness, and weight loss are typical presenting signs and symptoms. On physical examination, the findings depend on the severity and duration of the disease. Commonly, the skin has a waxy character with fine wrinkles about the eyes and mouth. There is some periorbital edema, and a decrease in pigmentation is often seen. Axillary and pubic hair becomes increasingly sparse. Atrophy of the breast tissue may be present. Even in those patients losing weight, cachexia is not a feature of the disease. Hypotension may be present, and normocytic anemia is common. However, this full constellation of symptoms does not occur in every patient, and it is not unusual for the full-blown picture to take 1020 years to develop. Occasionally, the diagnosis is made when the patient develops acute adrenal insufficiency secondary to a stressful situation (e.g. infection, trauma, surgery).

It was recognized by Sheehan that not all patients with pituitary apoplexy develop panhypopituitarism, and partial pituitary insufficiency is not uncommon. In one retrospective case series of 44 patients in France, only 88% had hypopituitarism, with adrenocorticotropic hormone (ACTH) deficiency most common (70%).6 A few patients with partial hypopituitarism may present with the classic syndrome of acute panhypopituitarism with deficiency of all pituitary hormones. However, after treatment with corticosteroids alone, there is a spontaneous normalization in the menstrual cycle, with a return of thyroid test results to normal limits.

Successful pregnancies following a diagnosis of Sheehan's syndrome have been reported.7, 8, 9 In a few patients, the diagnosis of partial hypopituitarism may occur upon the presentation of a pregnancy. Although several patients conceive after treatment with gonadotropin, others conceive spontaneously, an indication of partial pituitary failure. Placental function is not altered in patients with pituitary insufficiency.

Pituitary adenoma

During normal pregnancy, the pituitary enlarges by approximately one-third of its size.10 Pituitary insufficiency in women of childbearing age may result in the setting of a pituitary tumor, usually in association with increased production of prolactin. The most common symptom is secondary amenorrhea with galactorrhea, although cases of primary amenorrhea have been reported. When there is local expansion of the tumor, patients may have neurologic symptoms, such as headache or bilateral temporal hemianopia. In such cases, other pituitary hormones may become affected with growth hormone, ACTH, and thyrotropin-stimulating hormone (TSH) deficiencies.

The diagnosis is confirmed by the use of appropriate tests to investigate each of the pituitary hormones. Baseline or random determination of serum pituitary hormone concentrations is of no value in the diagnosis of the disease; dynamic tests to evaluate pituitary reserve must be used. The most practical tests are presented in Table 1. However, their use in pregnancy is limited because of the blunted response of many of these tests.

Table 1. Tests of anterior pituitary hormone reserve



Normal Response

Response in Pregnancy


L-Dopa, 500 mg, GH levels at 0, 1, 2 hour

by 10 ng/dl


Insulin hypoglycemia 0.1 U regular IV/kg, then draw GH at 0, 20, 60, 90 min

by 10 ng/dl



Insulin hypoglycemia (see above), then draw cortisol at 0, 20, 60, 90 min

by 10 g/dl


Metyrapone 750 mg every 4 hour 6

Urinary 17-KGS



Free thyroxine index


Serum TSH



Can no longer be tested, given the inavailability of TRH


Assess by regularity/presence of menses

When anterior pituitary insufficiency develops in pregnancy, the clinical manifestations may be local signs, such as headaches and visual disturbances, which are the consequence of an acute enlargement of, or bleeding into, the pituitary gland.11 The initial manifestations also could be related to endocrine deficiency, mainly hypoglycemia, nausea, vomiting, and hypotension secondary to ACTH deficiency.

Isolated ACTH deficiency is rare and has been infrequently described.12, 13 Acute enlargement of the pituitary gland is characterized by severe, deep, midline headaches (lasting for 23 days) and visual field disturbances. Severe hypoglycemia with convulsions and coma, unresponsive to large doses of glucose, but rapidly reversible after the administration of hydrocortisone, can be seen.

Partial or total hypopituitarism developing in patients with diabetes mellitus has been reported.14 In a review of 31 cases (19 women), the episode was associated with pregnancy in 11 (during the postpartum period in seven and during the antepartum period in four, with three maternal deaths).15 The mean age of the patients in this case series was 27 years, and the mean duration of their diabetes mellitus was 6 years, which makes vascular complication an unlikely cause of pituitary insufficiency. Furthermore, no specific vascular changes were found in the examined pituitary glands. Characteristically, the patients developed severe headaches that lasted for a few days with or without visual field disturbances, and a decrease in insulin requirement was observed. There was a high proportion of women with fetal loss. Although the mechanism supporting the increased risk of hypopituitarism among individuals with diabetes mellitus remains unclear, an association between pituitary antibodies and type 1 diabetes mellitus has been described.16

Lymphocytic hypophysitis

Lymphocytic hypophysitis can be another cause of pituitary dysfunction,17 and in pregnant women, usually presents close to delivery or in the immediate postpartum period.18 Sheehan described lymphocytic infiltration of the pituitary gland in some women with postpartum pituitary insufficiency,19 and it is possible that many of the cases mentioned above were due to lymphocytic hypophysitis.

The clinical presentation may be characterized by headaches and visual disturbances related to pressure from the expanding lesion mimicking a pituitary tumor;20, 21 spontaneous regression of the lesion was seen in several cases.22 diabetes insipidus and galactorrhea. Report of a case and review of the literature) The differential diagnosis between pituitary tumor and hypophysitis can be made only by histologic examination.18 Conversely, the patient may present with signs and symptoms of hypopituitarism, such as protracted hypoglycemia responding to glucocorticoid therapy and hypotension. It can also present in the postpartum period as pituitary insufficiency, similar to Sheehan's syndrome without the history of profound bleeding.22, 23, 24, 25

Involvement of other endocrine glands has been recognized, consistent with the concept of an autoimmune disease,26 in addition to antibodies against pituitary cells.27 It is possible that these cases are typical of the autoimmune polyendocrine deficiency syndrome that may be exacerbated during pregnancy or in the immediate postpartum period.


Patients with partial or total hypopituitarism who become pregnant spontaneously or after treatment with gonadotropins may carry a normal pregnancy with no increase in the dose of corticosteroid replacement therapy. The usual amount of hydrocortisone in patients with pituitary insufficiency is 2030 mg/day (two-thirds of the total amount in the morning and one-third in the evening). In some instances, the amount of hydrocortisone can be decreased by one-third of the total dose because the effect of hydrocortisone is potentiated during pregnancy by estrogen.28 However, this potentiation does not occur when synthetic corticosteroids (i.e. prednisone, dexamethasone) are used. The equivalent amounts of prednisone and dexamethasone, respectively, are 5.07.5 mg daily and 0.50.75 mg daily. Because these patients have ACTH deficiency, aldosterone secretion is normal and there is no need for mineralocorticoid replacement therapy. If thyroid deficiency is present, the amount of levothyroxine needed for replacement is usually 0.10.2 g daily.

Successful pregnancy in cases of isolated growth hormone deficiency has been reported.29, 30 In these patients, lactation was unimpaired and placental function studies and intrauterine growth were normal.

The most common pituitary tumor diagnosed in women of childbearing age is a prolactinoma.31 It can be accompanied by amenorrhea, oligohypomenorrhea, and anovulation, and with or without galactorrhea. Hyperprolactinemia decreases gonadotropin-releasing hormone (GnRH) secretion, accounting for the infertility observed in these patients. Pituitary tumors are divided, according to size, into microadenomas (less than 10 mm in diameter) and macroadenomas (greater than 10 mm in diameter); the latter are further classified according to suprasellar extension and invasion of adjacent structures. Serum prolactin concentrations correlate fairly well with the size of the tumor. Hyperprolactinemia in the absence of a pituitary adenoma (idiopathic hyperprolactinemia) is a common finding.


Serum prolactin levels in women with prepregnancy hyperprolactinemia, with a few exceptions, remained unchanged during pregnancy. It was shown that prolactin levels did not change significantly in most women with baseline prolactin levels of over 60 pg/dL.32 However, in those patients with prolactin levels of less than 60 pg/dL, the mean level doubled at the end of pregnancy and returned to pretreatment levels at the end of lactation. Therefore, serum prolactin determination during pregnancy is not a predictor of tumor growth and is of no value in monitoring tumor growth.

The incidence of complications during pregnancy in patients with pituitary tumors varies according to tumor size. Due to the stimulatory effect of estrogen on lactotrophs, the size of the tumor increases in 2.7% of microprolactinomas and 22.9% of macroprolactinomas during pregnancy.31 In one study of 56 pregnant women with microprolactinomas, one developed headaches and five showed mild tumor growth.33 In studies of pregnant women with macroprolactinomas, the proportion of women developing neurologic symptoms and visual disturbances is significantly decreased upon treatment.31

Complications can occur at any stage of pregnancy. In patients with microadenomas, visual field examinations are indicated only if there are signs and symptoms of tumor enlargement, in which case an MRI is also indicated. If there is any objective evidence of tumor enlargement, bromocriptine is resumed and continued throughout pregnancy at up to 20 mg/day. If after a few days there is no improvement, dexamethasone 4 mg every 6 hours can be added. Surgery is indicated in those complicated cases not responding to the above therapies, but the recurrence rate is high among those with invasive prolactinomas even after surgery.34

Breastfeeding is not contraindicated in mothers with a diagnosis of prolactinoma. There is no difference in the remission rates of women with prolactinomas managed with dopamine-receptor agonists who breastfeed following delivery versus those who do not.35 It is advisable in patients with microadenomas to measure prolactin levels a few months after delivery and to reinstate bromocriptine therapy in the presence of persistent hyperprolactinemia. A pituitary MRI should be repeated in cases of macroprolactinoma soon after delivery because of the potential for tumor size increase.


Once the diagnosis of prolactinoma is made, several types of therapy are available. The choice of therapy depends on tumor size, radiologic classification, local symptoms, and the patient's age and desire for pregnancy or current pregnancy.36

Medical therapy with dopamine-receptor agonists has been very effective in producing ovulation among hyperprolactinemic women37 and restores ovulation in approximately 90% of cases.31 Bromocriptine has historically been the preferred option, and no significant adverse effects have been observed in over 6000 pregnancies managed with bromocriptine.38 Most patients respond to doses of 2.55 mg/day, although occasionally a dose of 7.5 mg/day or more is needed. Bromocriptine is effective not only in normalizing prolactin levels but also in reducing the size of the tumor.31 It is advisable to use mechanical contraception during the first few months of bromocriptine therapy until the rhythm of the menstrual period is established. In those patients who have side effects such as nausea and vomiting, the oral bromocriptine tablet can be administered vaginally.39

Cabergoline is another dopamine-receptor agonist which can be considered.40 Although only 800 pregnancies have been reported with its use, there similarly does not appear to be any increased risks of preterm delivery or congenital malformations associated with this medication.38 In one 10-year observational study of 143 women, carbergoline therapy during pregnancy resulted in the ability of nearly 98% of the women to breastfeed following delivery.41 Once conception takes place, the dopamine-receptor agonist should be discontinued and the patient followed closely. For women in whom the macroprolactinoma is likely to increase, or in whom pressure symptoms occur, therapy during pregnancy should be continued.42

Radiation therapy as the initial and only therapy is seldom indicated, as medical therapy is usually very effective. The duration required for radiation therapy to normalize serum prolactin levels is lengthy and may produce hypopituitarism as a last sequela. Radiation therapy is indicated in those with prolactinomas refractory to conventional therapy.43

Surgical treatment, mainly transsphenoidal adenectomy, has been effective in restoring ovulation in patients with small tumors.32 The cure rate (i.e. sustained normalization of serum prolactin concentrations) is about approximately 70% at both 5 and 10 years of follow up; the associated proportion of successful pregnancy was similar.44 The best results are obtained in patients with microadenomas with low initial serum prolactin levels and lack of abnormal postoperative residual tissue.45

A recommended treatment approach in patients who wish to conceive is summarized in Table 2. It is suggested that treatment with bromocriptine be continued for at least 12 months before conception because it seems to reduce the risk of tumor enlargement during pregnancy.46

Table 2. Management of women with pre-conception hyperprolactinemia

Visual field monthly

*Therapy for 1 year before conception

Acromegaly is a chronic disease caused by hypersecretion of growth hormone by the adenohypophysis of the pituitary gland. It is almost always associated with a benign pituitary tumor and is characterized by slow and progressive enlargement of the acral parts. Facial changes are typical, but they usually develop so gradually that neither the family nor the patient recognizes the changes. As in other endocrine disorders, comparison of the patient's photographs taken over many years may be the only clue to the progression of the disease. Symptoms may be due to local expansion of the tumor (i.e. headaches and visual field disturbances), or they may be due to the somatic effects of chronic excess growth hormone, such as hyperhidrosis, weight gain, arthralgias, and acroparesthesia (carpal tunnel syndrome). Most women with acromegaly have been reported to suffer from oligohypomenorrhea or amenorrhea. In addition to the bony deformities, organomegaly (particularly enlargement of the heart, thyroid, and liver) is not uncommon on physical examination. The skin appears coarse and leathery. Galactorrhea with hyperprolactinemia is a common finding.


The diagnosis is confirmed by an elevation in plasma insulin-like growth factor 1 (IGF-1) levels and a lack of suppression of growth hormone following the administration of a glucose load.47 However, IGF-1 levels may not be reliable during pregnancy, as they can be physiologically increased48 or decreased during pregnancy.49

Thus, suspected cases of acromegaly among pregnant women should be confirmed with a growth hormone suppression test, which requires determination of plasma growth hormone levels before and 1 and 2 hours after the administration of a solution of 100 g glucose orally. A normal response is characterized by growth hormone levels lower than 1 g/L after glucose administration. Patients with acromegaly typically have elevated baseline IGF-1 levels and respond to the glucose load with no growth hormone suppression of growth hormone concentration or even occasionally with a paradoxical increase.

In patients with acromegaly, there are increased risks of several associated cormorbidities, including hypertension, diabetes mellitus, cardiovascular disease, osteoarthritis, and sleep apnea, which should be evaluated for upon the confirmed diagnosis of acromegaly.47


Treatment is mandatory in patients with the disease because the long-term prognosis is poor; untreated individuals have an almost 3-fold increased mortality rate.48 Conventional pituitary irradiation, transsphenoidal hypophysectomy,50 and drug therapy with octreotide (or other somatostatin receptor analogues) or the growth receptor antagonist, pegvisomant51 are used most often and can improve disease survival.52

Acromegaly during pregnancy

There are limited data of successful pregnancies in women with acromegaly. In 1954, Abelove and colleagues reported two normal pregnancies in an acromegalic woman and reviewed 33 reported cases from the world literature.53 Since that time, several other cases have been published, including a recent report of ten pregnancies among eight acromegalic women in Brazil, in which plasma IGF-1 levels were not significantly changed during gestation.54 In most instances, the infants have been reported as being normal. However, in a case described by Fisch et al.,55 the infant was born with acromegalic features. In this infant, growth was above average during the neonatal period, but a normal growth pattern subsequently returned, although no serum laboratory measurements were obtained. The lack of acromegalic features in most cases is in accordance with the report by King and colleagues demonstrating no placental transfer of growth hormone from mother to fetus.56

Historically, bromocriptine has been used as a successful treatment to induce pregnancy in patients with acromegaly.57, 58 In each of these cases, pregnancy occurred in spite of persistent elevated serum growth hormone levels.

The current guidelines for management of acromegalic women during pregnancy have been summarized in the 2014 Endocrine Society guidelines for acromegaly.47 In general, discontinuation of long-acting medical therapy (somatostatin receptor analogues or pegvisomant) is recommended approximately 2 months prior to attempting to conceive; therapy can be replaced with short-acting octreotide instead during the pre-conception period. During gestation, medical therapy should only be administered only for tumor and headache control, and plasma growth hormone and IGF-1 levels should not be monitored.

Diabetes insipidus is an uncommon disease characterized by polyuria and polydipsia due to a deficiency of antidiuretic hormone (central or neurogenic diabetes insipidus) or the peripheral resistance to the antidiuretic hormone at the renal tubules (nephrogenic diabetes insipidus). Central diabetes insipidus may be a result of a lesion at the level of the hypothalamus or pituitary gland. It may arise following hypophysectomy, invasion of the neurohypophysis by tumors, malignant metastasis (i.e. breast cancer), trauma, granulomas, or infection. In 50% of cases, however, it is considered idiopathic, with some causes probably on an autoimmune basis. Nephrogenic diabetes insipidus is a hereditary disorder affecting males; therefore, symptomatic women carriers are extremely rare. Several cases of transient nephrogenic diabetes insipidus during pregnancy and/or postpartum have been reported. A third type of diabetes insipidus, called psychogenic, which is rarely reported in pregnancy,59 is differentiated from the other two in most cases by the results of the water deprivation test.


Endocrine Diseases in Pregnancy | GLOWM

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