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Hair loss – Symptoms and causes – Mayo Clinic

Overview

Hair loss (alopecia) can affect just your scalp or your entire body, and it can be temporary or permanent. It can be the result of heredity, hormonal changes, medical conditions or a normal part of aging. Anyone can lose hair on their head, but it's more common in men.

Baldness typically refers to excessive hair loss from your scalp. Hereditary hair loss with age is the most common cause of baldness. Some people prefer to let their hair loss run its course untreated and unhidden. Others may cover it up with hairstyles, makeup, hats or scarves. And still others choose one of the treatments available to prevent further hair loss or restore growth.

Before pursuing hair loss treatment, talk with your doctor about the cause of your hair loss and treatment options.

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Male-pattern baldness typically appears first at the hairline or top of the head. It can progress to partial or complete baldness.

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Female-pattern baldness typically starts with scalp hairs becoming progressively less dense. Many women first experience hair thinning and hair loss where they part their hair and on the top-central portion of the head.

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In the type of patchy hair loss known as alopecia areata, hair loss occurs suddenly and usually starts with one or more circular bald patches that may overlap.

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Hair loss can occur if you wear pigtails, braids or cornrows, or use tight hair rollers. This is called traction alopecia.

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Early treatment of a receding hairline (frontal fibrosing alopecia) might help avoid significant permanent baldness. The cause of this condition is unknown, but it primarily affects older women.

Hair loss can appear in many different ways, depending on what's causing it. It can come on suddenly or gradually and affect just your scalp or your whole body.

Signs and symptoms of hair loss may include:

See your doctor if you are distressed by persistent hair loss in you or your child and want to pursue treatment. For women who are experiencing a receding hairline (frontal fibrosing alopecia), talk with your doctor about early treatment to avoid significant permanent baldness.

Also talk to your doctor if you notice sudden or patchy hair loss or more than usual hair loss when combing or washing your or your child's hair. Sudden hair loss can signal an underlying medical condition that requires treatment.

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People typically lose 50 to 100 hairs a day. This usually isn't noticeable because new hair is growing in at the same time. Hair loss occurs when new hair doesn't replace the hair that has fallen out.

Hair loss is typically related to one or more of the following factors:

A number of factors can increase your risk of hair loss, including:

Most baldness is caused by genetics (male-pattern baldness and female-pattern baldness). This type of hair loss is not preventable.

These tips may help you avoid preventable types of hair loss:

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Hair loss - Symptoms and causes - Mayo Clinic

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Cell Size and Scale – University of Utah

Some cells are visible to the unaided eye

The smallest objects that the unaided human eye can see are about 0.1 mm long. That means that under the right conditions, you might be able to see an amoeba proteus, a human egg, and a paramecium without using magnification. A magnifying glass can help you to see them more clearly, but they will still look tiny.

Smaller cells are easily visible under a light microscope. It's even possible to make out structures within the cell, such as the nucleus, mitochondria and chloroplasts. Light microscopes use a system of lenses to magnify an image. The power of a light microscope is limited by the wavelength of visible light, which is about 500 nm. The most powerful light microscopes can resolve bacteria but not viruses.

To see anything smaller than 500 nm, you will need an electron microscope. Electron microscopes shoot a high-voltage beam of electrons onto or through an object, which deflects and absorbs some of the electrons. Resolution is still limited by the wavelength of the electron beam, but this wavelength is much smaller than that of visible light. The most powerful electron microscopes can resolve molecules and even individual atoms.

The label on the nucleotide is not quite accurate. Adenine refers to a portion of the molecule, thenitrogenous base. It would be more accurate to label the nucleotide deoxyadenosine monophosphate, as itincludes the sugar deoxyribose and a phosphate group in addition to the nitrogenous base. However, the morefamiliar "adenine" label makes it easier for people to recognize it as one of the building blocks of DNA.

No, this isn't a mistake. First, there's less DNA in a sperm cell than there is in a non-reproductive cellsuch as a skin cell. Second, the DNA in a sperm cell is super-condensed and compacted into a highly dense form. Third, the head of a sperm cell is almost all nucleus. Most of the cytoplasm has been squeezed out in order to make the sperm an efficient torpedo-like swimming machine.

The X chromosome is shown here in a condensed state, as it would appear in a cell that's going through mitosis. It has also been duplicated, so there are actually two identical copies stuck together at their middles. A human sperm cell contains just one copy each of 23 chromosomes.

A chromosome is made up of genetic material (one long piece of DNA) wrapped around structural support proteins (histones). Histones organize the DNA and keep it from getting tangled, much like thread wrapped around a spool. But they also add a lot of bulk. In a sperm cell, a specialized set of tiny support proteins (protamines) pack the DNA down to about one-sixth the volume of a mitotic chromosome.

The size of the carbon atom is based on its van der Waals radius.

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Cell Size and Scale - University of Utah

Recommendation and review posted by Bethany Smith

Arizona cryonics facility preserves bodies to revive later

SCOTTSDALE, Ariz., Oct 12 (Reuters) - Time and death are "on pause" for some people in Scottsdale, Arizona.

Inside tanks filled with liquid nitrogen are the bodies and heads of 199 humans who opted to be cryopreserved in hopes of being revived in the future when science has advanced beyond what it is capable of today. Many of the "patients," as Alcor Life Extension Foundation calls them, were terminally ill with cancer, ALS or other diseases with no present-day cure.

Matheryn Naovaratpong, a Thai girl with brain cancer, is the youngest person to be cryopreserved, at the age of 2 in 2015.

"Both her parents were doctors and she had multiple brain surgeries and nothing worked, unfortunately. So they contacted us," said Max More, chief executive of Alcor, a nonprofit which claims to be the world leader in cryonics.

Bitcoin pioneer Hal Finney, another Alcor patient, had his body cryopreserved after death from ALS in 2014.

The cryopreservation process begins after a person is declared legally dead. Blood and other fluids are removed from the patient's body and replaced with chemicals designed to prevent the formation of damaging ice crystals. Vitrified at extremely cold temperatures, Alcor patients are then placed in tanks at the Arizona facility "for as long as it takes for technology to catch up," More said.

The minimum cost is $200,000 for a body and $80,000 for the brain alone. Most of Alcor's almost 1,400 living "members" pay by making the company the beneficiary of life insurance policies equal to the cost, More said.

More's wife Natasha Vita-More likens the process to taking a trip to the future.

"The disease or injury cured or fixed, and the person has a new body cloned or a whole body prosthetic or their body reanimated and (can) meet up with their friends again," she said.

Many medical professionals disagree, said Arthur Caplan, who heads the medical ethics division at New York University's Grossman School of Medicine.

"This notion of freezing ourselves into the future is pretty science fiction and it's naive," he said. "The only group... getting excited about the possibility are people who specialize in studying the distant future or people who have a stake in wanting you to pay the money to do it."

Reporting by Liliana Salgado; Editing by Richard Chang

Our Standards: The Thomson Reuters Trust Principles.

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Arizona cryonics facility preserves bodies to revive later

Recommendation and review posted by Bethany Smith

Ted Williams – Wikipedia

American baseball player (19182002)

Baseball player

Williams in 1949

As manager

Theodore Samuel Williams (August 30, 1918 July 5, 2002) was an American professional baseball player and manager. He played his entire 19-year Major League Baseball (MLB) career, primarily as a left fielder, for the Boston Red Sox from 1939 to 1960; his career was interrupted by military service during World War II and the Korean War. Nicknamed "Teddy Ballgame", "the Kid", "the Splendid Splinter", and "The Thumper", Williams is regarded as one of the greatest hitters in baseball history and to date is the last player to hit over .400 in a season.

Williams was a nineteen-time All-Star,[1] a two-time recipient of the American League (AL) Most Valuable Player Award, a six-time AL batting champion, and a two-time Triple Crown winner. He finished his playing career with a .344 batting average, 521 home runs, and a .482 on-base percentage, the highest of all time. His career batting average is the highest of any MLB player whose career was played primarily in the live-ball era, and ranks tied for 7th all-time (with Billy Hamilton).

Born and raised in San Diego, Williams played baseball throughout his youth. After joining the Red Sox in 1939, he immediately emerged as one of the sport's best hitters. In 1941, Williams posted a .406 batting average; he is the last MLB player to bat over .400 in a season. He followed this up by winning his first Triple Crown in 1942. Williams was required to interrupt his baseball career in 1943 to serve three years in the United States Navy and Marine Corps during World War II. Upon returning to MLB in 1946, Williams won his first AL MVP Award and played in his only World Series. In 1947, he won his second Triple Crown. Williams was returned to active military duty for portions of the 1952 and 1953 seasons to serve as a Marine combat aviator in the Korean War. In 1957 and 1958 at the ages of 39 and 40, respectively, he was the AL batting champion for the fifth and sixth time.

Williams retired from playing in 1960. He was inducted into the Baseball Hall of Fame in 1966, in his first year of eligibility.[2] Williams managed the Washington Senators/Texas Rangers franchise from 1969 to 1972. An avid sport fisherman, he hosted a television program about fishing, and was inducted into the IGFA Fishing Hall of Fame.[3] Williams's involvement in the Jimmy Fund helped raise millions in dollars for cancer care and research. In 1991, President George H. W. Bush presented Williams with the Presidential Medal of Freedom, the highest civilian award bestowed by the United States government. He was selected for the Major League Baseball All-Time Team in 1997 and the Major League Baseball All-Century Team in 1999.

Williams was born in San Diego on August 30, 1918,[4] and named Theodore Samuel Williams after former president Theodore Roosevelt as well as his father, Samuel Stuart Williams.[5] He later amended his birth certificate, removing his middle name,[5] which he claimed originated from a maternal uncle (whose actual name was Daniel Venzor), who had been killed in World War I.[6] His father was a soldier, sheriff, and photographer from Ardsley, New York,[7] while his mother, May Venzor, a Spanish-Mexican-American from El Paso, Texas, was an evangelist and lifelong soldier in the Salvation Army.[5] Williams resented his mother's long hours working in the Salvation Army,[8] and Williams and his brother cringed when she took them to the Army's street-corner revivals.[9]

Williams's paternal ancestors were a mix of Welsh, English, and Irish. The maternal, Spanish-Mexican side of Williams's family was quite diverse, having Spanish (Basque), Russian, and American Indian roots.[10] Of his Mexican ancestry he said that "If I had my mother's name, there is no doubt I would have run into problems in those days, [considering] the prejudices people had in Southern California."[11]

Williams lived in San Diego's North Park neighborhood (4121 Utah Street).[12] At the age of eight, he was taught how to throw a baseball by his uncle, Saul Venzor. Saul was one of his mother's four brothers, as well as a former semi-professional baseball player who had pitched against Babe Ruth, Lou Gehrig, and Joe Gordon in an exhibition game.[13][14] As a child, Williams's heroes were Pepper Martin of the St. Louis Cardinals and Bill Terry of the New York Giants.[15] Williams graduated from Herbert Hoover High School in San Diego, where he played baseball as a pitcher and was the star of the team.[16] During this time, he also played American Legion Baseball, later being named the 1960 American Legion Baseball Graduate of the Year.[17]

Though he had offers from the St. Louis Cardinals and the New York Yankees while he was still in high school,[18] his mother thought he was too young to leave home, so he signed up with the local minor league club, the San Diego Padres.[19]

Throughout his career, Williams stated his goal was to have people point to him and remark, "There goes Ted Williams, the greatest hitter who ever lived."[20]

Williams played back-up behind Vince DiMaggio and Ivey Shiver on the (then) Pacific Coast League's San Diego Padres. While in the Pacific Coast League in 1936, Williams met future teammates and friends Dom DiMaggio and Bobby Doerr, who were on the Pacific Coast League's San Francisco Seals.[21] When Shiver announced he was quitting to become a high school football coach in Savannah, Georgia, the job, by default, was open for Williams.[22] Williams posted a .271 batting average on 107 at bats in 42 games for the Padres in 1936.[22] Unknown to Williams, he had caught the eye of the Boston Red Sox's general manager, Eddie Collins, while Collins was scouting Bobby Doerr and the shortstop George Myatt in August 1936.[22][23] Collins later explained, "It wasn't hard to find Ted Williams. He stood out like a brown cow in a field of white cows."[22] In the 1937 season, after graduating from Hoover High in the winter, Williams finally broke into the line-up on June 22, when he hit an inside-the-park home run to help the Padres win 32. The Padres ended up winning the PCL title, while Williams ended up hitting .291 with 23 home runs.[22] Meanwhile, Collins kept in touch with Padres general manager Bill Lane, calling him two times throughout the season. In December 1937, during the winter meetings, the deal was made between Lane and Collins, sending Williams to the Boston Red Sox and giving Lane $35,000 and two major leaguers, Dom D'Allessandro and Al Niemiec, and two other minor leaguers.[24][25]

In 1938, the 19-year-old Williams was 10 days late to spring training camp in Sarasota, Florida, because of a flood in California that blocked the railroads. Williams had to borrow $200 from a bank to make the trip from San Diego to Sarasota.[26] Also during spring training Williams was nicknamed "the Kid" by Red Sox equipment manager Johnny Orlando, who after Williams arrived to Sarasota for the first time, said, "'The Kid' has arrived". Orlando still called Williams "the Kid" 20 years later,[26] and the nickname stuck with Williams the rest of his life.[27] Williams remained in major league spring training for about a week.[26] Williams was then sent to the Double-A-league Minneapolis Millers.[28] While in the Millers training camp for the springtime, Williams met Rogers Hornsby, who had hit over .400 three times, including a .424 average in 1924.[29] Hornsby, who was a coach for the Millers that spring,[29] gave Williams useful advice, including how to "get a good pitch to hit".[28] Talking with the game's greats would become a pattern for Williams, who also talked with Hugh Duffy, who hit .438 in 1894, Bill Terry who hit .401 in 1930, and Ty Cobb with whom he would argue that a batter should hit up on the ball, opposed to Cobb's view that a batter should hit down on the ball.[30]

While in Minnesota, Williams quickly became the team's star.[31] He collected his first hit in the Millers' first game of the season, as well as his first and second home runs during his third game. Both were inside-the-park home runs, with the second traveling an estimated 500 feet (150m) on the fly to a 512-foot (156m) center field fence.[31] Williams later had a 22 game hitting streak that lasted from Memorial Day through mid-June.[31] While the Millers ended up sixth place in an eight-team race,[31] Williams ended up hitting .366 with 46 home runs and 142 RBIs. He received the American Association's Triple Crown and finished second in the voting for Most Valuable Player.[32]

Williams came to spring training three days late in 1939, thanks to Williams driving from California to Florida, as well as respiratory problems, the latter of which would plague Williams for the rest of his career.[33] In the winter, the Red Sox traded right fielder Ben Chapman to the Cleveland Indians to make room for Williams on the roster, even though Chapman had hit .340 in the previous season.[34][35] This led Boston Globe sports journalist Gerry Moore to quip, "Not since Joe DiMaggio broke in with the Yankees by "five for five" in St. Petersburg in 1936 has any baseball rookie received the nationwide publicity that has been accorded this spring to Theodore Francis [sic] Williams".[33] Williams inherited Chapman's number 9 on his uniform as opposed to Williams's number 5 in the previous spring training. He made his major league debut against the New York Yankees on April 20,[36] going 1-for-4 against Yankee pitcher Red Ruffing. This was the only game which featured both Williams and Lou Gehrig playing against one another.[37] In his first series at Fenway Park, Williams hit a double, a home run, and a triple, the first two against Cotton Pippen, who gave Williams his first strikeout as a professional while Williams had been in San Diego.[38] By July, Williams was hitting just .280, but leading the league in RBIs.[38] Johnny Orlando, now Williams's friend, then gave Williams a quick pep talk, telling Williams that he should hit .335 with 35 home runs and he would drive in 150 runs. Williams said he would buy Orlando a Cadillac if this all came true.[39] Williams ended up hitting .327 with 31 home runs and 145 RBIs,[36] leading the league in the latter category, the first rookie to lead the league in RBIs[40] and finishing fourth in MVP voting.[41] He also led the AL in walks, with 107, a rookie record. Even though there was not a Rookie of the Year award yet in 1939, Babe Ruth declared Williams to be the Rookie of the Year, which Williams later said was "good enough for me".[42]

Williams's pay doubled in 1940, going from $5,000 to $10,000.[43] With the addition of a new bullpen in right field of Fenway Park, which reduced the distance from home plate from 400 feet to 380 feet, the bullpen was nicknamed "Williamsburg", because the new addition was "obviously designed for Williams".[44] Williams was then switched from right field to left field, as there would be less sun in his eyes, and it would give Dom DiMaggio a chance to play. Finally, Williams was flip-flopped in the order with the great slugger Jimmie Foxx, with the idea that Williams would get more pitches to hit.[44] Pitchers, though, were not afraid to walk him to get to the 33-year-old Foxx, and after that the 34-year-old Joe Cronin, the player-manager.[45] Williams also made his first of 16 All-Star Game appearances[46] in 1940, going 0-for-2.[47] Although Williams hit .344, his power and runs batted in were down from the previous season, with 23 home runs and 113 RBIs.[36] Williams also caused a controversy in mid-August when he called his salary "peanuts", along with saying he hated the city of Boston and reporters, leading reporters to lash back at him, saying that he should be traded.[48] Williams said that the "only real fun" he had in 1940 was being able to pitch once on August 24, when he pitched the last two innings in a 121 loss to the Detroit Tigers, allowing one earned run on three hits, while striking out one batter, Rudy York.[49][50]

In the second week of spring training in 1941, Williams broke a bone in his right ankle, limiting him to pinch hitting for the first two weeks of the season.[51] Bobby Doerr later claimed that the injury would be the foundation of Williams's season, as it forced him to put less pressure on his right foot for the rest of the season.[52] Against the Chicago White Sox on May 7, in extra innings, Williams told the Red Sox pitcher, Charlie Wagner, to hold the White Sox, since he was going to hit a home run. In the 11th inning, Williams's prediction came true, as he hit a big blast to help the Red Sox win. The home run is still considered to be the longest home run ever hit in the old Comiskey Park, some saying that it went 600 feet (180m).[53] Williams's average slowly climbed in the first half of May, and on May 15, he started a 22-game hitting streak. From May 17 to June 1, Williams batted .536, with his season average going above .400 on May 25 and then continuing up to .430.[54] By the All-Star break, Williams was hitting .406 with 62 RBIs and 16 home runs.[55]

In the 1941 All-Star Game, Williams batted fourth behind Joe DiMaggio, who was in the midst of his record-breaking hitting streak, having hit safely in 48 consecutive games.[56] In the fourth inning Williams doubled to drive in a run.[57] With the National League (NL) leading 52 in the eighth inning, Williams struck out in the middle of an American League (AL) rally.[56] In the ninth inning the AL still trailed 53; Ken Keltner and Joe Gordon singled, and Cecil Travis walked to load the bases.[57] DiMaggio grounded to the infield and Billy Herman, attempting to complete a double play, threw wide of first base, allowing Keltner to score.[57] With the score 54 and runners on first and third, Williams homered with his eyes closed to secure a 75 AL win.[57][58] Williams later said that that game-winning home run "remains to this day the most thrilling hit of my life".[59]

In late August, Williams was hitting .402.[59] Williams said that "just about everybody was rooting for me" to hit .400 in the season, including Yankee fans, who gave pitcher Lefty Gomez a "hell of a boo" after walking Williams with the bases loaded after Williams had gotten three straight hits one game in September.[60] In mid-September, Williams was hitting .413, but dropped a point a game from then on.[59] Before the final two games on September 28, a doubleheader against the Philadelphia Athletics, he was batting .39955, which would have been officially rounded up to .400.[59] Red Sox manager Joe Cronin offered him the chance to sit out the final day, but he declined. "If I'm going to be a .400 hitter", he said at the time, "I want more than my toenails on the line."[61] Williams went 6-for-8 on the day, finishing the season at .406.[62] (Sacrifice flies were counted as at-bats in 1941; under today's rules, Williams would have hit between .411 and .419, based on contemporaneous game accounts.[61]) Philadelphia fans ran out on the field to surround Williams after the game, forcing him to protect his hat from being stolen; he was helped into the clubhouse by his teammates.[63] Along with his .406 average, Williams also hit 37 home runs and batted in 120 runs, missing the triple crown by five RBI.[36][61]

Williams's 1941 season is often considered to be the best offensive season of all time, though the MVP award would go to DiMaggio. The .406 batting averagehis first of six batting championshipsis still the highest single-season average in Red Sox history and the highest batting average in the major leagues since 1924, and the last time any major league player has hit over .400 for a season after averaging at least 3.1 plate appearances per game. ("If I had known hitting .400 was going to be such a big deal", he quipped in 1991, "I would have done it again."[61]) Williams's on-base percentage of .553 and slugging percentage of .735 that season are both also the highest single-season averages in Red Sox history. The .553 OBP stood as a major league record until it was broken by Barry Bonds in 2002 and his .735 slugging percentage was the highest mark in the major leagues between 1932 and 1994. His OPS of 1.287 that year, a Red Sox record, was the highest in the major leagues between 1923 and 2001. Despite playing in only 143 games that year, Williams led the league with 135 runs scored and 37 home runs, and he finished third with 335 total bases, the most home runs, runs scored, and total bases by a Red Sox player since Jimmie Foxx's in 1938.[64] Williams placed second in MVP voting; DiMaggio won, 291 votes to 254,[65] on the strength of his record-breaking 56-game hitting streak and league-leading 125 RBI.[62]

In January 1942, just over 2 years after World War II began,[66][67] Williams was drafted into the military, being put into Class 1-A. A friend of Williams suggested that Williams see the advisor of the governor's Selective Service Appeal Agent, since Williams was the sole support of his mother, arguing that Williams should not have been placed in Class 1-A, and said Williams should be reclassified to Class 3-A.[66] Williams was reclassified to 3-A ten days later.[68] Afterwards, the public reaction was extremely negative,[69] even though the baseball book Season of '42 states only four All-Stars and one first-line pitcher entered military service during the 1942 season. (Many more MLB players would enter service during the 1943 season.)[70]

Quaker Oats stopped sponsoring Williams, and Williams, who previously had eaten Quaker products "all the time", never "[ate] one since" the company stopped sponsoring him.[68]

Despite the trouble with the draft board, Williams had a new salary of $30,000 in 1942.[68] In the season, Williams won the Triple Crown,[62] with a .356 batting average, 36 home runs, and 137 RBIs.[36] On May 21, Williams also hit his 100th career home run.[71] He was the third Red Sox player to hit 100 home runs with the team, following his teammates Jimmie Foxx and Joe Cronin.[citation needed] Despite winning the Triple Crown, Williams came in second in the MVP voting, losing to Joe Gordon of the Yankees. Williams felt that he should have gotten a "little more consideration" because of winning the Triple Crown, and he thought that "the reason I didn't get more consideration was because of the trouble I had with the draft [boards]".[62]

Williams joined the Navy Reserve on May 22, 1942, went on active duty in 1943, and was commissioned a second lieutenant in the United States Marine Corps as a Naval Aviator on May 2, 1944. Williams also played on the baseball team in Chapel Hill, North Carolina, along with his Red Sox teammate Johnny Pesky in pre-flight training, after eight weeks in Amherst, Massachusetts, and the Civilian Pilot Training Course.[72] While on the baseball team, Williams was sent back to Fenway Park on July 12, 1943, to play on an All-Star team managed by Babe Ruth. The newspapers reported that Babe Ruth said when finally meeting Williams, "Hiya, kid. You remind me a lot of myself. I love to hit. You're one of the most natural ballplayers I've ever seen. And if my record is broken, I hope you're the one to do it".[73] Williams later said he was "flabbergasted" by the incident, as "after all, it was Babe Ruth".[73] In the game, Williams hit a 425-foot home run to help give the American League All-Stars a 98 win.[74]

On September 2, 1945, when the war ended, Lt. Williams was in Pearl Harbor, Hawaii awaiting orders as a replacement pilot. While in Pearl Harbor, Williams played baseball in the Navy League. Also in that eight-team league were Joe DiMaggio, Joe Gordon, and Stan Musial. The Service World Series with the Army versus the Navy attracted crowds of 40,000 for each game. The players said it was even better than the actual World Series being played between the Detroit Tigers and Chicago Cubs that year.[75]

Williams was discharged by the Marine Corps on January 28, 1946, in time to begin preparations for the upcoming pro baseball season.[76][77] He joined the Red Sox again in 1946, signing a $37,500 contract.[78] On July 14, after Williams hit three home runs and eight RBIs in the first game of a doubleheader, Lou Boudreau, inspired by Williams's consistent pull hitting to right field, created what would later be known as the Boudreau shift (also Williams shift) against Williams, having only one player on the left side of second base (the left fielder). Ignoring the shift, Williams walked twice, doubled, and grounded out to the shortstop, who was positioned in between first and second base.[79][80] Also during 1946, the All-Star Game was held in Fenway Park. In the game, Williams homered in the fourth inning against Kirby Higbe, singled in a run in the fifth inning, singled in the seventh inning, and hit a three-run home run against Rip Sewell's "eephus pitch" in the eighth inning[81] to help the American League win 120.[82]

For the 1946 season, Williams hit .342 with 38 home runs and 123 RBIs,[36] helping the Red Sox win the pennant on September 13. During the season, Williams hit the only inside-the-park home run in his Major League career in a September 10 win at Cleveland,[83][84] and in June hit what is considered the longest home run in Fenway Park history, at 502 feet (153m) and subsequently marked with a lone red seat in the Fenway bleachers.[85] Williams ran away as the winner in the MVP voting.[86] During an exhibition game in Fenway Park against an All-Star team during early October, Williams was hit on the elbow by a curveball by the Washington Senators' pitcher Mickey Haefner. Williams was immediately taken out of the game, and X-rays of his arm showed no damage, but his arm was "swelled up like a boiled egg", according to Williams.[87] Williams could not swing a bat again until four days later, one day before the World Series, when he reported the arm as "sore".[87] During the series, Williams batted .200, going 5-for-25 with no home runs and just one RBI. The Red Sox lost in seven games,[88] with Williams going 0-for-4 in the last game.[89] Fifty years later when asked what one thing he would have done different in his life, Williams replied, "I'd have done better in the '46 World Series. God, I would".[87] The 1946 World Series was the only World Series Williams ever appeared in.[90]

Williams signed a $70,000 contract in 1947.[91] Williams was also almost traded for Joe DiMaggio in 1947. In late April, Red Sox owner Tom Yawkey and Yankees owner Dan Topping agreed to swap the players, but a day later canceled the deal when Yawkey requested that Yogi Berra come with DiMaggio.[92] In May, Williams was hitting .337.[93] Williams won the Triple Crown in 1947, but lost the MVP award to Joe DiMaggio, 202 points to 201 points. One writer left Williams off his ballot. Williams thought it was Mel Webb, whom Williams called a "grouchy old guy",[94] although it now appears it was not Webb.[95]

Through 2011, Williams was one of seven major league players to have had at least four 30-home run and 100-RBI seasons in their first five years, along with Chuck Klein, Joe DiMaggio, Ralph Kiner, Mark Teixeira, Albert Pujols, and Ryan Braun.[96]

In 1948, under their new manager, Joe McCarthy,[97] Williams hit a league-leading .369 with 25 home runs and 127 RBIs,[36] and was third in MVP voting.[98] On April 29, Williams hit his 200th career home run. He became just the second player to hit 200 home runs in a Red Sox uniform, joining his former teammate Jimmie Foxx.[64] On October 2, against the Yankees, Williams hit his 222nd career home run, tying Foxx for the Red Sox all-time record.[99] In the Red Sox' final two games of the regular schedule, they beat the Yankees (to force a one-game playoff against the Cleveland Indians) and Williams got on base eight times out of ten plate appearances.[97] In the playoff, Williams went 1-for-4,[100] with the Red Sox losing 83.

In 1949, Williams received a new salary of $100,000 ($1,139,000 in current dollar terms).[101] He hit .343 (losing the AL batting title by just .0002 to the Tigers' George Kell, thus missing the Triple Crown that year), hitting 43 home runs, his career high, and driving in 159 runs, tied for highest in the league, and at one point, he got on base in 84 straight games, an MLB record that still stands today, helping him win the MVP trophy.[36][102] On April 28, Williams hit his 223rd career home run, breaking the record for most home runs in a Red Sox uniform, passing Jimmie Foxx.[103] Williams is still the Red Sox career home run leader.[64] However, despite being ahead of the Yankees by one game just beforea 2-game series against them (last regular-season games for both teams),[97] the Red Sox lost both of those games.[104] The Yankees won the first of what would be five straight World Series titles in 1949.[105] For the rest of Williams's career, the Yankees won nine pennants and six World Series titles, while the Red Sox never finished better than third place.[105]

In 1950, Williams was playing in his eighth All-Star Game. In the first inning, Williams caught a line drive by Ralph Kiner, slamming into the Comiskey Park scoreboard and breaking his left arm.[46] Williams played the rest of the game, and he even singled in a run to give the American League the lead in the fifth inning, but by that time Williams's arm was a "balloon" and he was in great pain, so he left the game.[106] Both of the doctors who X-rayed Williams held little hope for a full recovery. The doctors operated on Williams for two hours.[107] When Williams took his cast off, he could only extend the arm to within four inches of his right arm.[108] Williams only played 89 games in 1950.[36] After the baseball season, Williams's elbow hurt so much he considered retirement, since he thought he would never be able to hit again. Tom Yawkey, the Red Sox owner, then sent Jack Fadden to Williams's Florida home to talk to Williams. Williams later thanked Fadden for saving his career.[109]

In 1951, Williams "struggled" to hit .318, with his elbow still hurting.[110] Williams also played in 148 games, 60 more than Williams had played the previous season, 30 home runs, two more than he had hit in 1950, and 126 RBIs, twenty-nine more than 1950.[36][110] Despite his lower-than-usual production at bat, Williams made the All-Star team.[47] On May 15, 1951, Williams became the 11th player in major league history to hit 300 career home runs. On May 21, Williams passed Chuck Klein for 10th place, on May 25 Williams passed Hornsby for ninth place, and on July 5 Williams passed Al Simmons for eighth place all-time in career home runs.[111] After the season, manager Steve O'Neill was fired, with Lou Boudreau replacing him. Boudreau's first announcement as manager was that all Red Sox players were "expendable", including Williams.[110]

Williams's name was called from a list of inactive reserves to serve on active duty in the Korean War on January 9, 1952. Williams, who was livid at his recalling, had a physical scheduled for April 2.[112] Williams passed his physical and in May, after only playing in six major league games, began refresher flight training and qualification prior to service in Korea. Right before he left for Korea, the Red Sox had a "Ted Williams Day" in Fenway Park. Friends of Williams gave him a Cadillac, and the Red Sox gave Williams a memory book that was signed by 400,000 fans. The governor of Massachusetts and mayor of Boston were there, along with a Korean War veteran named Frederick Wolf who used a wheelchair for mobility.[113] At the end of the ceremony, everyone in the park held hands and sang "Auld Lang Syne" to Williams, a moment which he later said "moved me quite a bit."[114] Private Wolf (an injured Korean veteran from Brooklyn) presented gifts from wounded veterans to Ted Williams. Ted choked and was only able to say,"... ok kid...".[115] The Red Sox went on to win the game 53, thanks to a two-run home run by Williams in the seventh inning.[114]

In August 1953, Williams practiced with the Red Sox for ten days before playing in his first game, garnering a large ovation from the crowd and hitting a home run in the eighth inning.[116] In the season, Williams ended up hitting .407 with 13 home runs and 34 RBIs in 37 games and 110 at bats (not nearly enough plate appearances to qualify for that season's batting title).[36] On September 6, Williams hit his 332nd career home run, passing Hank Greenberg for seventh all-time.[117]

On the first day of spring training in 1954, Williams broke his collarbone running after a line drive.[116] Williams was out for six weeks, and in April he wrote an article with Joe Reichler of the Saturday Evening Post saying that he intended to retire at the end of the season.[118] Williams returned to the Red Sox lineup on May 7, and he hit .345 with 386 at bats in 117 games, although Bobby vila, who had hit .341, won the batting championship. This was because it was required then that a batter needed 400 at bats, despite Lou Boudreau's attempt to bat Williams second in the lineup to get more at-bats. Williams led the league in base on balls with 136 which kept him from qualifying under the rules at the time. By today's standards (plate appearances) he would have been the champion. The rule was changed shortly thereafter to keep this from happening again.[36][119] On August 25, Williams passed Johnny Mize for sixth place, and on September 3, Williams passed Joe DiMaggio for fifth all-time in career home runs with his 362nd career home run. He finished the season with 366 career home runs.[120] On September 26, Williams "retired" after the Red Sox's final game of the season.[121]

During the off-season of 1954, Williams was offered the chance to be manager of the Red Sox. Williams declined, and he suggested that Pinky Higgins, who had previously played on the 1946 Red Sox team as the third baseman, become the manager of the team. Higgins later was hired as the Red Sox manager in 1955.[122] Williams sat out the first month of the 1955 season due to a divorce settlement with his wife, Doris. When Williams returned, he signed a $98,000 contract on May 13. Williams batted .356 in 320 at bats on the season, lacking enough at bats to win the batting title over Al Kaline, who batted .340.[123] Williams hit 28 home runs and drove in 83 runs[36] while being named the "Comeback Player of the Year."[124]

On July 17, 1956, Williams became the fifth player to hit 400 home runs, following Mel Ott in 1941, Jimmie Foxx in 1938, Lou Gehrig in 1936, and Babe Ruth in 1927.[125][126] Three weeks later at home against the Yankees on August7, after Williams was booed for dropping a fly ball from Mickey Mantle, he spat at one of the fans who was taunting him on the top of the dugout;[127] Williams was fined $5,000 for the incident.[128][129] The following night against Baltimore, Williams was greeted by a large ovation, and received an even larger one when he hit a home run in the sixth inning to break a 22 tie. In The Boston Globe, the publishers ran a "What Globe Readers Say About Ted" section made out of letters about Williams, which were either the sportswriters or the "loud mouths" in the stands. Williams explained years later, "From '56 on, I realized that people were for me. The writers had written that the fans should show me they didn't want me, and I got the biggest ovation yet".[130] Williams lost the batting title to Mickey Mantle in 1956, batting .345 to Mantle's .353, with Mantle on his way to winning the Triple Crown.[131]

In 1957, Williams batted .388 to lead the majors, then signed a contract in February 1958 for a record high $125,000 (or $135,000).[132][133] At age forty that season, he again led the American League with a .328 batting average.[134]

When Pumpsie Green became the first black player on the Red Soxthe last major league team to integratein 1959, Williams openly welcomed Green.[135]

Williams ended his career with a home run in his last at-bat on September 28, 1960. He refused to salute the fans as he returned the dugout after he crossed home plate or after he was replaced in left field by Carroll Hardy. An essay written by John Updike the following month for The New Yorker, "Hub Fans Bid Kid Adieu", chronicles this event.[136]

Williams is one of only 29 players in baseball history to date to have appeared in Major League games in four decades.[137]

Williams was an obsessive student of hitting. He famously used a lighter bat than most sluggers, because it generated a faster swing.[138] In 1970, he wrote a book on the subject, The Science of Hitting (revised 1986), which is still read by many baseball players.[138] The book describes his theory of swinging only at pitches that came into ideal areas of his strike zone, a strategy Williams credited with his success as a hitter. Pitchers apparently feared Williams; his bases-on-balls-to-plate-appearances ratio (.2065) is still the highest of any player in the Hall of Fame.

Williams nearly always took the first pitch.[139]

He helped pass his expertise of playing left-field in front of the Green Monster to his successor on the Red Sox, Carl Yastrzemski.[140]

Williams was on uncomfortable terms with the Boston newspapers for nearly twenty years, as he felt they liked to discuss his personal life as much as his baseball performance. He maintained a career-long feud with Sport due to a 1948 feature article in which the reporter included a quote from Williams's mother. Insecure about his upbringing, and stubborn because of immense confidence in his own talent, Williams made up his mind that the "knights of the keyboard", as he derisively labeled the press, were against him. After having hit for the league's Triple Crown in 1947, Williams narrowly lost the MVP award in a vote where one Midwestern newspaper writer left Williams entirely off his ten-player ballot.

During his career, some sportswriters also criticized aspects of Williams's baseball performance, including what they viewed as his lackadaisical fielding and lack of clutch hitting. Williams pushed back, saying: "They're always saying that I don't hit in the clutches. Well, there are a lot [of games] when I do."[141] He also asserted that it made no sense crashing into an outfield wall to try to make a difficult catch because of the risk of injury or being out of position to make the play after missing the ball.[142]

Williams treated most of the press accordingly, as he described in his 1969 memoir My Turn at Bat. Williams also had an uneasy relationship with the Boston fans, though he could be very cordial one-to-one. He felt at times a good deal of gratitude for their passion and their knowledge of the game. On the other hand, Williams was temperamental, high-strung, and at times tactless. In his biography, Ronald Reis relates how Williams committed two fielding miscues in a doubleheader in 1950 and was roundly booed by Boston fans. He bowed three times to various sections of Fenway Park and made an obscene gesture. When he came to bat he spat in the direction of fans near the dugout. The incident caused an avalanche of negative media reaction, and inspired sportswriter Austen Lake's famous comment that when Williams's name was announced the sound was like "autumn wind moaning through an apple orchard."

Another incident occurred in 1958 in a game against the Washington Senators. Williams struck out, and as he stepped from the batter's box swung his bat violently in anger. The bat slipped from his hands, was launched into the stands and struck a 60-year-old woman who turned out to be the housekeeper of the Red Sox general manager Joe Cronin. While the incident was an accident and Williams apologized to the woman personally, to all appearances it seemed at the time that Williams had hurled the bat in a fit of temper.

Williams gave generously to those in need. He was especially linked with the Jimmy Fund of the DanaFarber Cancer Institute, which provides support for children's cancer research and treatment. Williams used his celebrity to virtually launch the fund, which raised more than $750million between 1948 and 2010. Throughout his career, Williams made countless bedside visits to children being treated for cancer, which Williams insisted go unreported. Often parents of sick children would learn at check-out time that "Mr. Williams has taken care of your bill".[143] The Fund recently stated that "Williams would travel everywhere and anywhere, no strings or paychecks attached, to support the cause... His name is synonymous with our battle against all forms of cancer."[143]

Williams demanded loyalty from those around him. He could not forgive the fickle nature of the fansbooing a player for booting a ground ball, and then turning around and roaring approval of the same player for hitting a home run. Despite the cheers and adulation of most of his fans, the occasional boos directed at him in Fenway Park led Williams to stop tipping his cap in acknowledgment after a home run.

Williams maintained this policy up to and including his swan song in 1960. After hitting a home run at Fenway Park, which would be his last career at-bat, Williams characteristically refused either to tip his cap as he circled the bases or to respond to prolonged cheers of "We want Ted!" from the crowd by making an appearance from the dugout. The Boston manager Pinky Higgins sent Williams to his fielding position in left field to start the ninth inning, but then immediately recalled him for his back-up Carroll Hardy, thus allowing Williams to receive one last ovation as he jogged onto then off the field, and he did so without reacting to the crowd. Williams's aloof attitude led the writer John Updike to observe wryly that "Gods do not answer letters."[136]

Williams's final home run did not take place during the final game of the 1960 season, but rather in the Red Sox's last home game that year. The Red Sox played three more games, but they were on the road in New York City and Williams did not appear in any of them, as it became clear that Williams's final home at-bat would be the last one of his career.

In 1991, on Ted Williams Day at Fenway Park, Williams pulled a Red Sox cap from out of his jacket and tipped it to the crowd. This was the first time that he had done so since his earliest days as a player.

A Red Smith profile from 1956 describes one Boston writer trying to convince Ted Williams that first cheering and then booing a ballplayer was no different from a moviegoer applauding a "western" movie actor one day and saying the next "He stinks! Whatever gave me the idea he could act?" Williams rejected this; when he liked a western actor like Hoot Gibson, he liked him in every picture, and would not think of booing him.

Williams once had a friendship with Ty Cobb, with whom he often had discussions about baseball. He often touted Rogers Hornsby as being the greatest right-handed hitter of all time. This assertion actually led to a split in the relationship between Ty Cobb and Ted Williams. Once during one of their yearly debate sessions on the greatest hitters of all time, Williams asserted that Hornsby was one of the greatest of all time. Cobb apparently had strong feelings about Hornsby and he threw a fit, expelling Williams from his hotel room. Their friendship effectively terminated after this altercation.[144] This story was later refuted by Ted Williams himself.[145]

Williams served as a Naval Aviator during World War II and the Korean War. Unlike many other major league players, he did not spend all of his war-time playing on service teams.[146] Williams had been classified 3-A by Selective Service prior to the war, a dependency deferment because he was his mother's sole means of financial support. When his classification was changed to 1-A following the American entry into World War II, Williams appealed to his local draft board. The draft board ruled that his draft status should not have been changed. He made a public statement that once he had built up his mother's trust fund, he intended to enlist. Even so, criticism in the media, including withdrawal of an endorsement contract by Quaker Oats, resulted in his enlistment in the U.S. Naval Reserve on May 22, 1942.

Williams did not opt for an easy assignment playing baseball for the Navy, but rather joined the V-5 program to become a Naval aviator. Williams was first sent to the Navy's Preliminary Ground School at Amherst College for six months of academic instruction in various subjects including math and navigation, where he achieved a 3.85 grade point average.

Williams was talented as a pilot, and so enjoyed it that he had to be ordered by the Navy to leave training to personally accept his American League 1942 Major League Baseball Triple Crown.[146] Williams's Red Sox teammate, Johnny Pesky, who went into the same aviation training program, said this about Williams: "He mastered intricate problems in fifteen minutes which took the average cadet an hour, and half of the other cadets there were college grads." Pesky again described Williams's acumen in the advance training, for which Pesky personally did not qualify: "I heard Ted literally tore the sleeve target to shreds with his angle dives. He'd shoot from wingovers, zooms, and barrel rolls, and after a few passes the sleeve was ribbons. At any rate, I know he broke the all-time record for hits." Ted went to Jacksonville for a course in aerial gunnery, the combat pilot's payoff test, and broke all the records in reflexes, coordination, and visual-reaction time. "From what I heard. Ted could make a plane and its six 'pianos' (machine guns) play like a symphony orchestra", Pesky says. "From what they said, his reflexes, coordination, and visual reaction made him a built-in part of the machine."[147]

Williams completed pre-flight training in Athens, Georgia, his primary training at NAS Bunker Hill, Indiana, and his advanced flight training at NAS Pensacola. He received his gold Naval Aviator wings and his commission as a second lieutenant in the U.S. Marine Corps on May 2, 1944.

Williams served as a flight instructor at NAS Pensacola teaching young pilots to fly the complicated F4U Corsair fighter plane. Williams was in Pearl Harbor awaiting orders to join the Fleet in the Western Pacific when the War in the Pacific ended. He finished the war in Hawaii, and then he was released from active duty on January 12, 1946, but he did remain in the Marine Corps Reserve.[77]

On May 1, 1952, 14 months after his promotion to captain in the Marine Corps Reserve, Williams was recalled to active duty for service in the Korean War.[148] He had not flown any aircraft for eight years but he turned down all offers to sit out the war in comfort as a member of a service baseball team. Nevertheless, Williams was resentful of being called up, which he admitted years later, particularly regarding the Navy's policy of calling up Inactive Reservists rather than members of the Active Reserve.

Williams reported for duty on May 2, 1952. After eight weeks of refresher flight training and qualification in the F9F Panther jet fighter with VMF-223 at the Marine Corps Air Station Cherry Point, North Carolina, Williams was assigned to VMF-311, Marine Aircraft Group 33 (MAG-33), based at the K-3 airfield in Pohang, South Korea.[77]

On February 16, 1953, Williams, flying as the wingman for John Glenn (later an astronaut, then U.S. Senator), was part of a 35-plane raid against a tank and infantry training school just south of Pyongyang, North Korea. As the aircraft from VMF-115 and VMF-311 dove on the target, Williams's plane was hit by anti-aircraft fire, a piece of flak knocked out his hydraulics and electrical systems, causing Williams to have to "limp" his plane back to K-3 air base where he made a belly landing. For his actions of this day, he was awarded the Air Medal.[149]

Williams flew 39 combat missions in Korea, earning the Air Medal with two Gold Stars representing second and third awards, before being withdrawn from flight status in June 1953 after a hospitalization for pneumonia. This resulted in the discovery of an inner ear infection that disqualified him from flight status.[150] John Glenn described Williams as one of the best pilots he knew,[146] while his wife Annie described him as the most profane man she ever met.[151] In the last half of his missions, Williams was flying as Glenn's wingman.[152]

Williams likely would have exceeded 600 career home runs if he had not served in the military, and might even have approached Babe Ruth's then record of 714. He might have set the record for career RBIs as well, exceeding Hank Aaron's total.[146] While the absences in the Marine Corps took almost five years out of his baseball career, he never publicly complained about the time devoted to service in the Marine Corps. His biographer, Leigh Montville, argued that Williams was not happy about being pressed into service in South Korea, but he did what he thought was his patriotic duty.

Following his return to the United States in August 1953, he resigned his Reserve commission to resume his baseball career.[148]

After retirement from play, Williams helped Boston's new left fielder, Carl Yastrzemski, in hitting, and was a regular visitor to the Red Sox' spring training camps from 1961 to 1966, where he worked as a special batting instructor. He served as executive assistant to Tom Yawkey (196165), then was named a team vice president (196568) upon his election to the Hall of Fame. He resumed his spring training instruction role with the club in 1978.

Beginning in 1961, he would spend summers at the Ted Williams Baseball Camp in Lakeville, Massachusetts, which he had established in 1958 with his friend Al Cassidy and two other business partners. For eight summers and parts of others after that, he would give hitting clinics and talk baseball at the camp.[5] It was not uncommon to find Williams fishing in the pond at the camp. The area now is owned by the town and a few of the buildings still stand. In the main lodge one can still see memorabilia from Williams's playing days.

Williams served as manager of the Washington Senators, from 19691971, then continued with the team when they became the Texas Rangers after the 1971 season. Williams's best season as a manager was 1969 when he led the expansion Senators to an 8676 record in the team's only winning season in Washington. He was chosen "Manager of the Year" after that season. Like many great players, Williams became impatient with ordinary athletes' abilities and attitudes, particularly those of pitchers, whom he admitted he never respected. Fellow manager Alvin Dark thought Williams "was a smart, fearless manager" who helped his hitters perform better. Williams's issue with Washington/Texas, according to Dark, was when the ownership traded away his third baseman and shortstop, making it difficult for the club to be as competitive.[153]

On the subject of pitchers, in Ted's autobiography written with John Underwood, Ted opines regarding Bob Lemon (a sinker-ball specialist) pitching for the Cleveland Indians around 1951: "I have to rate Lemon as one of the very best pitchers I ever faced. His ball was always moving, hard, sinking, fast-breaking. You could never really uhmmmph with Lemon."

Williams was much more successful in fishing. An avid and expert fly fisherman and deep-sea fisherman, he spent many summers after baseball fishing the Miramichi River, in Miramichi, New Brunswick. Williams was named to the International Game Fish Association Hall of Fame in 2000. Williams, Jim Brown, Cumberland Posey, and Cal Hubbard are the only athletes to be inducted into the Halls of Fame of more than one professional sport. Williams was also known as an accomplished hunter; he was fond of pigeon-shooting for sport in Fenway Park during his career, on one occasion drawing the ire of the Massachusetts Society for the Prevention of Cruelty to Animals.[154]

Williams reached an extensive deal with Sears, lending his name and talent toward marketing, developing, and endorsing a line of in-house sports equipmentsuch as the "Ted Williams" edition Gamefisher aluminum boat and 7.5hp "Ted Williams" edition motor, as well as fishing, hunting, and baseball equipment. Williams continued his involvement in the Jimmy Fund, later losing a brother to leukemia, and spending much of his spare time, effort, and money in support of the cancer organization.

In his later years Williams became a fixture at autograph shows and card shows after his son (by his third wife), John Henry Williams, took control of his career, becoming his de facto manager. The younger Williams provided structure to his father's business affairs, exposed forgeries that were flooding the memorabilia market, and rationed his father's public appearances and memorabilia signings to maximize their earnings.

One of Ted Williams's final, and most memorable, public appearances was at the 1999 All-Star Game in Boston. Able to walk only a short distance, Williams was brought to the pitcher's mound in a golf cart. He proudly waved his cap to the crowda gesture he had never done as a player. Fans responded with a standing ovation that lasted several minutes. At the pitcher's mound he was surrounded by players from both teams, including fellow Red Sox player Nomar Garciaparra, and was assisted by Tony Gwynn in throwing out the first pitch of that year's All-Star Game. Later in the year, he was among the members of the Major League Baseball All-Century Team introduced to the crowd at Turner Field in Atlanta prior to Game Two of the World Series.

On May 4, 1944, Williams married Doris Soule, the daughter of his hunting guide. Their daughter, Barbara Joyce ("Bobbi Jo"), was born on January 28, 1948, while Williams was fishing in Florida.[155] They divorced in 1954. Williams married the socialite model Lee Howard on September 10, 1961, and they were divorced in 1967.

Williams married Dolores Wettach, a former Miss Vermont and Vogue model, in 1968. Their son John-Henry was born on August 27, 1968, followed by daughter Claudia, on October 8, 1971. They were divorced in 1972.[156]

Williams lived with Louise Kaufman for twenty years until her death in 1993. In his book, Cramer called her the love of Williams's life.[157] After his death, her sons filed suit to recover her furniture from Williams's condominium as well as a half-interest in the condominium they claimed he gave her.[158]

Williams had a strong respect for General Douglas MacArthur, referring to him as his "idol".[159] For Williams's 40th birthday, MacArthur sent him an oil painting of himself with the inscription "To Ted Williamsnot only America's greatest baseball player, but a great American who served his country. Your friend, Douglas MacArthur. General U.S. Army."[160]

Politically, Williams was a Republican,[161] and was described by one biographer as, "to the right of Attila the Hun" except when it came to Civil Rights.[162] Another writer similarly noted that while in the 1960s he had a liberal attitude on civil rights, he was pretty far right on other cultural issues of the time, calling him ultraconservative in the tradition of Barry Goldwater and John Wayne.[161]

Williams campaigned for Richard Nixon in the 1960 United States Presidential Election, and after Nixon lost to John F. Kennedy, refused several invitations from President Kennedy to gather together in Cape Cod. He supported Nixon again in 1968, and as manager of the Senators, kept a picture of him on his desk, meeting with the President several times while managing the team. In 1972 he called Nixon, the greatest president of my lifetime.[161] In the following years, Williams endorsed several other candidates in Republican Party presidential primaries, including George H. W. Bush in 1988 (whom he also campaigned for in New Hampshire),[163] Bob Dole in 1996, and George W. Bush in 2000.[164]

According to friends, Williams was an atheist[165] and this influenced his decision to be cryogenically frozen. His daughter Claudia stated "It was like a religion, something we could have faith in... no different from holding the belief that you might be reunited with your loved ones in heaven".[166]

Williams's brother Danny and his son John-Henry both died of leukemia.[167]

In his last years, Williams suffered from cardiomyopathy. He had a pacemaker implanted in November 2000 and he underwent open-heart surgery in January 2001. After suffering a series of strokes and congestive heart failure, he died of cardiac arrest at the age of 83 on July 5, 2002, at Citrus Memorial Hospital, Inverness, Florida, near his home in Citrus Hills, Florida.[168]

Though his will stated his desire to be cremated and his ashes scattered in the Florida Keys, Williams's son John-Henry and younger daughter Claudia chose to have his remains frozen cryonically.

Ted's elder daughter, Bobby-Jo Ferrell, brought a suit to have her father's wishes recognized. John-Henry's lawyer then produced an informal "family pact" signed by Ted, Claudia, and John-Henry, in which they agreed "to be put into biostasis after we die" to "be able to be together in the future, even if it is only a chance."[169] Bobby-Jo and her attorney, Spike Fitzpatrick (former attorney of Ted Williams), contended that the family pact, which was scribbled on an ink-stained napkin, was forged by John-Henry and/or Claudia.[170] Fitzpatrick and Ferrell believed that the signature was not obtained legally.[171] Laboratory analysis proved that the signature was genuine.[171] John-Henry said that his father was a believer in science and was willing to try cryonics if it held the possibility of reuniting the family.[172]

Though the family pact upset some friends, family and fans, a public plea for financial support of the lawsuit by Ferrell produced little result.[172] Citing financial difficulties, Ferrell dropped her lawsuit on the condition that a $645,000 trust fund left by Williams would immediately pay the sum out equally to the three children.[172] Inquiries to cryonics organizations increased after the publicity from the case.[170]

In Ted Williams: The Biography of an American Hero, author Leigh Montville claims that the family cryonics pact was a practice Ted Williams autograph on a plain piece of paper, around which the agreement had later been hand written. The pact document was signed "Ted Williams", the same as his autographs, whereas he would always sign his legal documents "Theodore Williams", according to Montville. However, Claudia testified to the authenticity of the document in an affidavit.[173]

Williams body was subsequently decapitated for the neuropreservation option from Alcor.[174] Following John-Henry's unexpected illness and death from acute myeloid leukemia on March 6, 2004, John-Henry's body was also transported to Alcor, in fulfillment of the family agreement.[175]

In 1954, Williams was inducted by the San Diego Hall of Champions into the Breitbard Hall of Fame honoring San Diego's finest athletes both on and off the playing surface.[176]

Williams was inducted into the Baseball Hall of Fame on July 25, 1966.[177] In his induction speech, Williams included a statement calling for the recognition of the great Negro leagues players: "I've been a very lucky guy to have worn a baseball uniform, and I hope some day the names of Satchel Paige and Josh Gibson in some way can be added as a symbol of the great Negro players who are not here only because they weren't given a chance."[178] Williams was referring to two of the most famous names in the Negro leagues, who were not given the opportunity to play in the Major Leagues before Jackie Robinson broke the color barrier in 1947. Gibson died early in 1947 and thus never played in the majors; and Paige's brief major league stint came long past his prime as a player. This powerful and unprecedented statement from the Hall of Fame podium was "a first crack in the door that ultimately would open and include Paige and Gibson and other Negro league stars in the shrine."[178] Paige was the first inducted in 1971. Gibson and others followed, starting in 1972 and continued on and off into the 21st century.

On November 18, 1991, President George H. W. Bush presented Williams with the Presidential Medal of Freedom, the highest civilian award in the US.[179]

The Ted Williams Tunnel in Boston, Massachusetts, carrying 1.6 miles (2.6km) of the final 2.3 miles (3.7km) of Interstate 90 under Boston Harbor, opened in December 1995, and Ted Williams Parkway (California State Route 56) in San Diego County, California, opened in 1992, were named in his honor while he was still alive. In 2016, the major league San Diego Padres inducted Williams into their hall of fame for his contributions to baseball in San Diego.[180]

The Tampa Bay Rays home field, Tropicana Field, installed the Ted Williams Museum (formerly in Hernando, Florida, 19942006) behind the left field fence. From the Tampa Bay Rays website: "The Ted Williams Museum and Hitters Hall of Fame brings a special element to the Tropicana Field. Fans can view an array of different artifacts and pictures of the 'Greatest hitter that ever lived.' These memorable displays range from Ted Williams's days in the military through his professional playing career. This museum is dedicated to some of the greatest players to ever 'lace 'em up,' including Willie Mays, Joe DiMaggio, Mickey Mantle, Roger Maris."

In 2013, the Bob Feller Act of Valor Award honored Williams as one of 37 Baseball Hall of Fame members for his service in the United States Marine Corps during World War II.[181]

At the time of his retirement, Williams ranked third all-time in home runs (behind Babe Ruth and Jimmie Foxx), seventh in RBIs (after Ruth, Cap Anson, Lou Gehrig, Ty Cobb, Foxx, and Mel Ott), and seventh in batting average (behind Cobb, Rogers Hornsby, Shoeless Joe Jackson, Lefty O'Doul, Ed Delahanty and Tris Speaker). His career batting average of .3444 is the highest of any player who played his entire career in the live-ball era following 1920.

Most modern statistical analyses[which?] place Williams, along with Ruth and Barry Bonds, among the three most potent hitters to have played the game. Williams's baseball season of 1941 is often considered favorably with the greatest seasons of Ruth and Bonds in terms of various offensive statistical measures such as slugging, on-base and "offensive winning percentage." As a further indication, of the ten best seasons for OPS, short for On-Base Plus Slugging Percentage, a popular modern measure of offensive productivity, four each were achieved by Ruth and Bonds, and two by Williams.

In 1999, Williams was ranked as number eight on The Sporting News' list of the 100 Greatest Baseball Players, where he was the highest-ranking left fielder.[182]

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These symptoms can interfere with everyday life and happiness, so it's important tofind the underlying cause and work out what can be done to resolve it.

The "male menopause" (sometimes called the andropause) is an unhelpful term sometimes used in the media.

This label ismisleading because it suggests the symptoms are the result of a suddendrop in testosterone in middle age, similar to what occurs in the female menopause. This is not true.

Although testosterone levels fall as men age, the decline is steady at about 1% a year from around the age of 30 to 40,and this is unlikely to cause any problems in itself.

A testosterone deficiency that develops later in life, also known as late-onset hypogonadism, can sometimesbe responsible for these symptoms, but in many cases the symptoms are nothing to do withhormones.

Lifestyle factors or psychological problems can also be responsible for many of these symptoms.

For example,erectile dysfunction,low sex driveandmood swingsmay bethe result of:

There are alsophysical causes of erectile dysfunction, such as smoking or heart problems, which may happen alongside any psychological cause.

Psychological problems are typically brought on by workor relationship issues,money problems or worrying about ageing parents.

A "midlife crisis" can also be responsible. Thiscan happen when men think they have reached life's halfway stage.

Anxieties over what they have accomplished so far, either in their job or personal life, can lead to a period of depression.

Other possible causes of the "male menopause" include:

In some cases, where lifestyle or psychological problems do not seem to be responsible, the symptoms of the "male menopause" may bethe result ofhypogonadism, wherethe testes produce few or no hormones.

Hypogonadism issometimes present from birth,which can cause symptoms like delayed puberty and small testes.

Hypogonadism can also occasionallydevelop later in life, particularly in men who are obese or have type 2 diabetes.

This is known aslate-onset hypogonadism and can cause the "male menopause" symptoms.

But this is an uncommon and specific medical condition that's not a normal part of ageing.

A diagnosis oflate-onset hypogonadism can usually be made based on your symptoms and the results of blood testsused tomeasure your testosterone levels.

If you're experiencing any of these symptoms, see your GP. They'll ask about your work and personal life to see if your symptoms may be caused by a mental health issue, such as stress or anxiety.

If stress or anxiety are affecting you, you may benefit from medication or a talking therapy, such as cognitive behavioural therapy (CBT).

Exercise and relaxation can also help.

Read about:

Your GP may also order ablood test to measure your testosterone levels.

If the results suggest you have a testosterone deficiency, you may be referred to an endocrinologist, a specialist in hormone problems.

If the specialist confirms this diagnosis,youmay be offered testosterone replacementto correct the hormone deficiency, which should relieve your symptoms.

This treatment may be given as an injection or a gel.

Page last reviewed: 13 October 2022Next review due: 13 October 2025

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The 'male menopause' - NHS

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Stem cell therapy side effects & risks: infections, tumors & more

What are the possible stem cell therapy side effects of going to an unproven clinic? This is a common question I get asked. Most often it is asked by patients who reach out.

Check out the YouTube video below on our stem cell channel. If you like such videos please subscribe to our channel.

Many clinics have said over the years to potential customers that the worst that can happen is that the stem cells wont work.

We know this isnt true and its irresponsible.

Anything that has the potential to help a medical condition also poses some risks of harm. For this reason, its important to discuss potential stem cell therapy side effects. In this case I am focusing on the risks primarily associated with unproven stem cell clinics. Not for established methods like bone marrow transplantation.

Recent publications in journals including one by my colleague Gerhard Bauer and a special report by The Pew Charitable Trust have helped clarify risks. Gerhards paper presents the types of side effects that appear more common after people go to stem cell clinics. After closely following this area for a decade I was familiar with many of the examples of problems. However, some were new to me.

One of the highest profiles examples of bad outcomes was the case where three people lost their vision due to stem cells injected by a clinic.See image below of one set of damaged eyes. More on that case at the end of the post.

Why do stem cells pose risks?

Stem cells are uniquely powerful cells.

By definition they can both make more of themselves and turn into at least one other kind of specialized cells. This latter process is called differentiation. That former ability to make more of themselves is called self-renewal.

The most powerful stem cells are totipotent stem cells that can literally make any kind of differentiated cell. The fertilized human egg is the best example of a cell having totipotency. Next in the power line are pluripotent stem cells including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). Adult stem cells are multipotent. The best type of stem cell depends on the condition that is trying to be treated. The best type may not be the most powerful.

In any case, the power of stem cells is a main reason they also pose risks. These cells are not always easy to control and misdirected power can do harm.

Let me explain and start with the side effect that seems scariest to most.

If someone injects a patient with stem cells, its possible that the self-renewal power of stem cells just wont get shut off. In that scenario the stem cells could drive formation of a tumor or even cancer. Note that tumors are not always malignant whereas cancer is always malignant.

Why wouldnt a transplanted stem cell always eventually hit the brakes on self-renewal? It could be that the stem cell has one or more mutations. For any stem cells grown in a lab, within the population of millions of cells in a dish, there are going to be at least a few with mutations that crop up. Thats just the way it goes with growing cells in a lab.

Even stem cells not grown in the lab have the same spectrum of mutations as the person they were isolated from. It may seem weird to think about, but we all have some mutations.

When someone like a clinic person tells us that theres a risk to you thats a one in a million chance it doesnt sound that bad. However, with cells being injected into a person in theory all it takes is one cell out of a million cells in a syringe with a couple really bad mutations to potentially cause disaster. Research suggests it takes more than one cell with cancer-causing potential to make a tumor in experiments in the lab, but in actual people we just dont know. Many cancers may arise from one stem cell gone awry. If a clinic injects 50 or 100 million cells, a one-in-a-million rate of dangerous cells means that 50-100 such cells end up in the patient.

The odds are far lower for cells never grown in a lab to cause a tumor, but its still possible. Oddly, its possible that receiving someone elses stem cells (we call this allogeneic) might pose a lower cancer risk because your immune system is going to see those cells as foreign from the start.

But some stem cells, especially those with mutations, might be able to somewhat fly under the radar of the immune system to some extent even if they are from another person. This could allow them to grow into a tumor. The Pew report does a nice job of summarizing risks and there are several reports of tumors.

The possibility of infections after stem cell injections is another risk that is often discussed. Infections from injections of stem cells or other materials like PRP are probably the most common type of side effect. Bacteria can either sometimes already be in the product that is injected or can be introduced by poor injection or preparation methods by the one doing the procedure.

The distributor Liveyon had a product contaminated with bacteria that sickened at least a dozen people who were hospitalized. Some of them ended up in the ICU. A few may even have permanent issues.

Clinics using excellent procedures and products should have a low risk of infection more similar to getting any kind of invasive procedure even unrelated to stem cells.

Many preparations of stem cells sold at stem cell clinics these days are made from fat tissue or birth-related materials. I put stem cells in quotes because most fat and birth-related preparations only contain a small population of true stem cells.

In the case of adipose biologics, they mostly consist of a mixture of a dozen or so other kinds of cells found in fat.

The injections of fat cells are most often made IV right into the bloodstream. Fat cells just live in fat so they arent supposed to be floating around in your blood. As a result, after IV injection, many fat cells are thought to get killed right away.

Others end up landing in the lungs, where many are also probably meeting their doom. However, during this process of wiping out the fat cells it is possible that clots can start forming. Maybe the fat cells form small clots in the blood before they even get into the lungs. Either way, if the clots grow and are big enough, patients can get pulmonary emboli.

The same kind of risk may apply to IV injections or nebulizer inhalations of other kinds of stem cells.

There are other possible risks to stem cell injections too.

I wrote a post about possible graft versus host disease in stem cell recipients. This would only happen in people receiving someone elses stem cells. Its not clear if GvHD is something that happens to patients after going to clinics.

Beyond outright tumor formation it is also possible that stem cells will turn into an undesired or even dangerous tissue type. The example that comes to mind is the practice mentioned earlier of some clinics injecting fat cells into peoples eyeballs. What seems to have happened in some cases is that the mesenchymal cells (MSCs) that were injected turned into scar tissue, which caused retinal detachment. Unfortunately, what are called MSCs by some clinics can mostly consist of close relatives of fibroblasts or in some cases may even largely consist of fibroblasts. Fibroblasts are good at making scar tissue under some circumstances and that can create pull on surrounding tissues including the retina if inside the body.

Specific kinds of stem cells or routes of administration may pose unique risks as well. For instance, intranasal administration of stem cells is getting popular with unproven clinics and could lead to stem cells ending up in the brain.

Other products in the regenerative sphere that are not stem cells may be risky as well for various reasons. For instance, an exosome product harmed quite a few people in Nebraska.Some problems may relate to product contamination.

There have also been cases of unusual immune reactions to stem cell injections.

Finally, stem cells also pose unknown risks because of their power. We just dont have long-term follow up data to have a clear sense of risks.

Related Posts

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Stem cell therapy side effects & risks: infections, tumors & more

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Stem cell therapy for diabetes – PMC – PubMed Central (PMC)

Stem cell therapy holds immense promise for the treatment of patients with diabetes mellitus. Research on the ability of human embryonic stem cells to differentiate into islet cells has defined the developmental stages and transcription factors involved in this process. However, the clinical applications of human embryonic stem cells are limited by ethical concerns, as well as the potential for teratoma formation. As a consequence, alternative forms of stem cell therapies, such as induced pluripotent stem cells, umbilical cord stem cells and bone marrow-derived mesenchymal stem cells, have become an area of intense study. Recent advances in stem cell therapy may turn this into a realistic treatment for diabetes in the near future.

Keywords: Embryonic stem cell, induced pluripotent stem cell, mesenchymal stem cell, diabetes

This lecture is based on a recent review.[1]

The increasing burden of diabetes worldwide is well-known, and the effects on health care costs and in human suffering, morbidity, and mortality will be primarily felt in the developing nations including India, China, and countries in Africa. New drugs are being developed at a rapid pace, and the last few years have seen several new classes of compounds for the treatment of diabetes e.g. glucagon-like peptide (GLP-1) mimetics, dipeptidyl-peptidase-4 (DPP-4) inhibitors, sodium glucose transporter-2 (SGLT2) inhibitors. New surgical treatments have also become increasingly available and advocated as effective therapies for diabetes. Gastric restriction surgery, gastric bypass surgery, simultaneous pancreas-kidney transplantation, pancreatic and islet transplantation have all been introduced in recent years. To avoid the trauma of a major operation, there have been many studies on the transplantation of isolated islets removed from a cadaveric pancreas. There was encouragement from the Edmonton protocol described by Shapiro and colleagues in the New England Journal in 2000. The islets were injected into the portal vein and patients, especially those suffering from dangerous, hypoglycemic unawareness, were treated before they had developed severe complications of diabetes, especially renal complications. While the early results were promising, with some 70% of the patients requiring no insulin injections after two years, at five years, most of these patients had deteriorated and required insulin supplements, despite some having received more than one transplant of islets. In the more recent series of patients, the Edmonton group has reported better long-term results with the use of the monoclonal anti-lymphocyte antibody, Campath 1H given as an induction agent, 45% of patients being insulin-independent at five years, and 75% had detectable C-peptide.

However, cadavaric pancreata and islets compete for the same source and are limited in number, and so, neither treatment could readily be offered to the vast majority of diabetic patients. Some have attempted to use an alternative source, for example, encapsulated islets from neonatal or adult pigs. This is still very experimental and will be a far away alternative with many technical and possibly ethical obstacles to overcome.

More recently, with the successes in the development of pluripotent adult stem cells (from Yamanaka, awarded the 2012 Nobel prize for medicine for developing induced pluripotent stem cells iPSCs), new approaches to seek a methods that may be more accessible and available have been attempted. Much hope was derived initially from embryonic stem cell (ESC) research, since these cells can be persuaded to multiply and develop into any tissue, but the process was expensive, and the problem of teratoma formation from these stem cells proved extremely difficult to overcome. Many of the important factors related to fetal development are not understood and cannot be reproduced. However, some progress has been made, and (occasionally) cells been persuaded to secrete insulin, but so far, there have been very minimal therapeutic application.

Scientists are now aware that to persuade a cell to produce insulin is only one step in what may be a long and difficult journey. Islets cells are highly specialized to have not only a basal release of insulin but also to respond rapidly to changes in blood glucose concentration. With insulin, the process and regulation of switching off secretion is as important as the switching on secretion.

A variety of approaches has been made with different starting points. The stem cell reproduces itself and can then also divide asymmetrically and form another cell type: This is known as differentiation. Although initially they were thought to be available only from embryos, non-embryonic stem cells can now be obtained without too much difficulty from neonatal tissue, umbilical cord, and also from a variety of adult tissues including bone marrow, skin, and fat. These stem cells can be expanded and made to differentiate, but their repertoire is restricted compared with embryonic stem cells: oligo- or pluri- as opposed to toti-potent embryonic stem cells. Even more, recently, there has been much interest in the process of direct cell trans-differentiation, in which a committed and fully differentiated cell, for example a liver cell, is changed directly to another cell type, for example an islet beta-cell, without induction of de-differentiation back to a stem cell stage.

Yamanaka, in 2006, was able to produce pluripotent stem cells from mouse neonatal and adult fibroblast cultures by adding a cocktail of four defined factors.[2] This led to a series of other studies developing the process, which was shown to be repeatable with human tissue as well as laboratory mice. The use of iPS cells avoided the ethical constraints of using human embryos, but there have been other problems and obstacles still. There have been emerging reports of iPS cells becoming antigenic to an autologous or isologous host, and the cells can accumulate DNA abnormalities and even retain epigenetic memory of the cell type of origin and thus have a tendency to revert back. Like embryonic stem cells, iPS cells can form teratoma, especially if differentiation is not complete.

Despite this, there has been very little success in directing differentiation of iPSCs to form islet beta-cells in sufficient quantity that will secrete and stop secretion in response to changes in blood glucose levels.

Another approach that has been tried is to combine gene therapy with stem cells. Some progress has been made in trying to express the desired insulin gene in more primitive undifferentiated cells by coaxing stem cells with differentiation factors in vitro and then by direct gene transfection using plasmids or a viral vector. We, and others, have used a human insulin gene construct and introduced ex vivo or in vivo into cells by direct electroporation (in ex vivo cells obviously) or by viral vectors. The adenovirus, adeno-associated virus, and various retro viruses have been most studied, especially the Lentivirus. However, any type of genetic engineering raises fears not only of infection from the virus but also of the unmasking of onco-genes, leading to malignancy, and there are strict regulations how to proceed to avoid these risks.

We have been interested in umbilical cord stem cells and in mesenchymal stem cells as targets for combined stem cell and gene therapy. These cells can be obtained in a reasonably easy and reproducible manner from otherwise discarded umbilical cord, or readily accessible bone marrow, selecting out the cells using various standard techniques. Fat, amnion, and umbilical cord blood are also sources, from which mesnechymal stem cells can be derived. After a proliferative phase, the cells take up an appearance similar to a carpet of fibroblasts, which can differentiate into bone, cartilage, or fat cells. Although mesenchymal stem cells from the various sources mentioned may look similar, their differentiation potentials are idiosyncratic and differ, which makes it inappropriate and difficult to think of them as a uniform source of target cells. Neonatal amnion cells and umbilical cord cells have low immunogenicity and do not express HLA class II antigens. They also secrete factors that inhibit immune reactions, for example, soluble HLA-G. Although immunogenicity is reduced significantly, they are still not autologous and, therefore, there remains a risk for allograft rejection. They have the advantage that they could be multiplied, frozen, and banked in large numbers and could be used in patients already needing immunosuppressive agents, for examples those having renal transplants.

In Singapore, our studies of umbilical cord-derived amnion cells have shown some success in having expression of insulin and glucagon genes, but little or no secretion of insulin in vitro. Together with insulin gene transfection in vitro, after peritoneal transplantation into sterptozotocin-induced diabetic mice, there was some improvement in glucose levels.[3] Our colleagues in Singapore[4,5] have used another model of autologous hepatocytes from streptozotocin-induced diabetic pigs. These separated hepatocytes were successfully transfected ex-vivo with a human insulin gene construct by electrophoration, and then the cells were injected directly back into the liver parenchyma using multiple separate injections. The pigs were cured of their diabetes for up to nine months - which is a remarkable achievement. As these were autotransplantations, no immunosuppressive drugs were necessary, but the liver cells were obtained from large open surgical biopsies. This necessity of surgical removal of liver tissue would limit its applicability, but nevertheless has been a good proof of concept study. In the context of autoimmune diabetes, the risk of recurrent disease may well persist unless the target of autoimmune attack could be defined and eliminated. In these porcine experiments, the human insulin gene with a glucose sensing promoter EGR-1 was used. There was no virus involved, and the plasmid does not integrate. Division of the transfected cell would dilute gene activity, but large numbers of plasmid can be produced cheaply. The same group of workers successfully transfected bone marrow mesenchymal stem cells with the human insulin gene plasmid using the same EGR-1 promoter and electrophoration. This cured diabetic mice after direct intra-hepatic and intra-peritoneal injection.

Finally, there should be caution in interpreting the results of these and other reports of cell and gene therapy for diabetes. In gene transfection and/or transplantation of insulin-producing cells or clusters in the diabetic rodent, there have been many reports in the literature, but only a few of these claims have been reproduced in independent laboratories. We have suggested the need to satisfy The Seven Pillars of Credibility as essential criteria in the evaluation of claims of success in the use of stem cell and/or gene therapy for diabetes.[1]

Cure of hyperglycemia

Response to glucose tolerance test

Evidence of appropriate C-peptide secretion

Weight gain

Prompt return of diabetes when the transfecting gene and/or insulin producing cells are removed

No islet regeneration of stereptozotocin-treated animals and no re-generation of pancreas in pancreatectomized animals

Presence of insulin storage granules in the treated cells

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Ethical issues in stem cell research and therapy

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Ethical issues in stem cell research and therapy

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Amniotics led consortium selected for EIC-Pathfinder grant of 3.8 million from the European Innovation Council – Marketscreener.com

Amniotics led consortium selected for EIC-Pathfinder grant of 3.8 million from the European Innovation Council  Marketscreener.com

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We created the world’s first donkey embryo using IVF in a bid to save species from extinction – The Conversation

We created the world's first donkey embryo using IVF in a bid to save species from extinction  The Conversation

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‘Ghost heart’: Built from the scaffolding of a pig and the … – CNN

CNN

The first time molecular biologist Doris Taylor saw heart stem cells beat in unison in a petri dish, she was spellbound.

It actually changed my life, said Taylor, who directed regenerative medicine research at Texas Heart Institute in Houston until 2020. I said to myself, Oh my gosh, thats life. I wanted to figure out the how and why, and re-create that to save lives.

That goal has become reality. On Wednesday at the Life Itself conference, a health and wellness event presented in partnership with CNN, Taylor showed the audience the scaffolding of a pigs heart infused with human stem cells creating a viable, beating human heart the body will not reject. Why? Because its made from that persons own tissues.

Now we can truly imagine building a personalized human heart, taking heart transplants from an emergency procedure where youre so sick, to a planned procedure, Taylor told the audience.

That reduces your risk by eliminating the need for (antirejection) drugs, by using your own cells to build that heart it reduces the cost and you arent in the hospital as often so it improves your quality of life, she said.

Debuting on stage with her was BAB, a robot Taylor painstakingly taught to inject stem cells into the chambers of ghost hearts inside a sterile environment. As the audience at Life Itself watched BAB functioning in a sterile environment, Taylor showed videos of the pearly white mass called a ghost heart begin to pinken.

Can we grow a personalized human heart?

Its the first shot at truly curing the number one killer of men, women and children worldwide heart disease. And then I want to make it available to everyone, said Taylor to audience applause.

She never gave up, said Michael Golway, lead inventor of BAB and president and CEO of Advanced Solutions, which designs and creates platforms for building human tissues.

At any point, Dr. Taylor could have easily said Im done, this just isnt going to work. But she persisted for years, fighting setbacks to find the right type of cells in the right quantities and right conditions to enable those cells to be happy and grow.

Taylors fascination with growing hearts began in 1998, when she was part of a team at Duke University that injected cells into a rabbits failed heart, creating new heart muscle. As trials began in humans, however, the process was hit or miss.

We were putting cells into damaged or scarred regions of the heart and hoping that would overcome the existing damage, she told CNN. I started thinking: What if we could get rid of that bad environment and rebuild the house?

Taylors first success came in 2008 when she and a team at the University of Minnesota washed the cells out of a rats heart and began to work with the translucent skeleton left behind.

Soon, she graduated to using pigs hearts, due to their anatomical similarity to human hearts.

We took a pigs heart, and we washed out all the cells with a gentle baby shampoo, she said. What was left was an extracellular matrix, a transparent framework we called the ghost heart.

Then we infused blood vessel cells and let them grow on the matrix for a couple of weeks, Taylor said. That built a way to feed the cells we were going to add because wed reestablished the blood vessels to the heart.

The next step was to begin injecting the immature stem cells into the different regions of the scaffold, and then we had to teach the cells how to grow up.

We must electrically stimulate them, like a pacemaker, but very gently at first, until they get stronger and stronger. First, cells in one spot will twitch, then cells in another spot twitch, but they arent together, Taylor said. Over time they start connecting to each other in the matrix and by about a month, they start beating together as a heart. And let me tell you, its a wow moment!

But thats not the end of the mothering Taylor and her team had to do. Now she must nurture the emerging heart by giving it a blood pressure and teaching it to pump.

We fill the heart chambers with artificial blood and let the heart cells squeeze against it. But we must help them with electrical pumps, or they will die, she explained.

The cells are also fed oxygen from artificial lungs. In the early days all of these steps had to be monitored and coordinated by hand 24 hours a day, 7 days a week, Taylor said.

The heart has to eat every day, and until we built the pieces that made it possible to electronically monitor the hearts someone had to do it person and it didnt matter if it was Christmas or New Years Day or your birthday, she said. Its taken extraordinary groups of people who have worked with me over the years to make this happen.

But once Taylor and her team saw the results of their parenting, any sacrifices they made became insignificant, because then the beauty happens, the magic, she said.

Weve injected the same type of cells everywhere in the heart, so they all started off alike, Taylor said. But now when we look in the left ventricle, we find left ventricle heart cells. If we look in the atrium, they look like atrial heart cells, and if we look in the right ventricle, they are right ventricle heart cells, she said.

So over time theyve developed based on where they find themselves and grown up to work together and become a heart. Nature is amazing, isnt she?

As her creation came to life, Taylor began to dream about a day when her prototypical hearts could be mass produced for the thousands of people on transplant lists, many of whom die while waiting. But how do you scale a heart?

I realized that for every gram of heart tissue we built, we needed a billion heart cells, Taylor said. That meant for an adult-sized human heart we would need up to 400 billion individual cells. Now, most labs work with a million or so cells, and heart cells dont divide, which left us with the dilemma: Where will these cells come from?

The answer arrived when Japanese biomedical researcher Dr. Shinya Yamanaka discovered human adult skin cells could be reprogrammed to behave like embryonic or pluripotent stem cells, capable of developing into any cell in the body. The 2007 discovery won the scientist a Nobel Prize, and his induced pluripotent stem cells (iPS), soon became known as Yamanaka factors.

Now for the first time we could take blood, bone marrow or skin from a person and grow cells from that individual that could turn into heart cells, Taylor said. But the scale was still huge: We needed tens of billions of cells. It took us another 10 years to develop the techniques to do that.

The solution? A bee-like honeycomb of fiber, with thousands of microscopic holes where the cells could attach and be nourished.

The fiber soaks up the nutrients just like a coffee filter, the cells have access to food all around them and that lets them grow in much larger numbers. We can go from about 50 million cells to a billion cells in a week, Taylor said. But we need 40 billion or 50 billion or 100 billion, so part of our science over the last few years has been scaling up the number of cells we can grow.

Another issue: Each heart needed a pristine environment free of contaminants for each step of the process. Every time an intervention had to be done, she and her team ran the risk of opening the heart up to infection and death.

Do you know how long it takes to inject 350 billion cells by hand? Taylor asked the Life Itself audience. What if you touch something? You just contaminated the whole heart.

Once her lab suffered an electrical malfunction and all of the hearts died. Taylor and her team were nearly inconsolable.

When something happens to one of these hearts, its devastating to all of us, Taylor said. And this is going to sound weird coming from a scientist, but I had to learn to bolster my own heart emotionally, mentally, spiritually and physically to get through this process.

Enter BAB, short for BioAssemblyBot, and an uber-sterile cradle created by Advance Solutions that could hold the heart and transport it between each step of the process while preserving a germ-free environment. Taylor has now taught BAB the specific process of injecting the cells she has painstakingly developed over the last decade.

When Dr. Taylor is injecting cells, it has taken her years to figure out where to inject, how much pressure to put on the syringe, and the best speed and pace to add the cells, said BABs creator Golway.

A robot can do that quickly and precisely. And as we know, no two hearts are the same, so BAB can use ultrasound to see inside the vascular pathway of that specific heart, where Dr. Taylor is working blind, so to speak, Golway added. Its exhilarating to watch there are times where the hair on the back of my neck literally stands up.

Taylor left academia in 2020 and is currently working with private investors to bring her creation to the masses. If transplants into humans in upcoming clinical trials are successful, Taylors personalized hybrid hearts could be used to save thousands of lives around the world.

In the US alone, some 3,500 people were on the heart transplant waiting list in 2021.

Thats not counting the people who never make it on the list, due to their age or heath, Taylor said. If youre a small woman, if youre an underrepresented minority, if youre a child, the chances of getting an organ that matches your body are low.

If you do get a heart, many people get sick or otherwise lose their new heart within a decade. We can reduce cost, we can increase access, and we can decrease side effects. Its a win-win-win.

Taylor can even envision a day when people bank their own stem cells at a young age, taking them out of storage when needed to grow a heart and one day even a lung, liver or kidney.

Say they have heart disease in their family, she said. We can plan ahead: Grow their cells to the numbers we need and freeze them, then when they are diagnosed with heart failure pull a scaffold off the shelf and build the heart within two months.

Im just humbled and privileged to do this work, and proud of where we are, she added. The technology is ready. I hope everyone is going to be along with us for the ride because this is game-changing.

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'Ghost heart': Built from the scaffolding of a pig and the ... - CNN

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Stem Cells International | Hindawi

Research Article

09 Nov 2022

Aucubin Impeded Preosteoclast Fusion and Enhanced CD31hi EMCNhi Vessel Angiogenesis in Ovariectomized Mice

Ziyi Li|Chang Liu|...|Peng Xue

Osteogenesis is tightly correlated with angiogenesis during the process of bone development, regeneration, and remodeling. In addition to providing nutrients and oxygen for bone tissue, blood vessels around bone tissue also secrete some factors to regulate bone formation. Type H vessels which were regulated by platelet-derived growth factor-BB (PDGF-BB) were confirmed to couple angiogenesis and osteogenesis. Recently, preosteoclasts have been identified as the most important source of PDGF-BB. Therefore, inhibiting osteoclast maturation, improving PDGF-BB secretion, stimulating type H angiogenesis, and subsequently accelerating bone regeneration may be potent treatments for bone loss disease. In the present study, aucubin, an iridoid glycoside extracted from Aucuba japonica and Eucommia ulmoides, was found to inhibit bone loss in ovariectomized mice. We further confirmed that aucubin could inhibit the fusion of tartrate-resistant acid phosphatase (TRAP)+ preosteoclasts into mature osteoclasts and indirectly increasing angiogenesis of type H vessel. The underlying mechanism is the aucubin-induced inhibition of MAPK/NF-B signaling, which increases the preosteoclast number and subsequently promotes angiogenesis via PDGF-BB. These results prompted that aucubin could be an antiosteoporosis drug candidate, which needs further research.

Review Article

07 Nov 2022

The Influence of Intervertebral Disc Microenvironment on the Biological Behavior of Engrafted Mesenchymal Stem Cells

Jing Zhang|Wentao Zhang|...|Zhonghai Li

Intervertebral disc degeneration is the main cause of low back pain. Traditional treatment methods cannot repair degenerated intervertebral disc tissue. The emergence of stem cell therapy makes it possible to regenerate and repair degenerated intervertebral disc tissue. At present, mesenchymal stem cells are the most studied, and different types of mesenchymal stem cells have their own characteristics. However, due to the harsh and complex internal microenvironment of the intervertebral disc, it will affect the biological behaviors of the implanted mesenchymal stem cells, such as viability, proliferation, migration, and chondrogenic differentiation, thereby affecting the therapeutic effect. This review is aimed at summarizing the influence of each intervertebral disc microenvironmental factor on the biological behavior of mesenchymal stem cells, so as to provide new ideas for using tissue engineering technology to assist stem cells to overcome the influence of the microenvironment in the future.

Research Article

07 Nov 2022

CD44v6+ Hepatocellular Carcinoma Cells Maintain Stemness Properties through Met/cJun/Nanog Signaling

Wei Chen|Ronghua Wang|...|Bin Cheng

Cancer stem cells (CSCs) are characterized by their self-renewal and differentiation abilities. CD44v6 is a novel CSC marker that can activate various signaling pathways. Here, we hypothesized that the HGF/Met signaling pathway promotes stemness properties in CD44v6+ hepatocellular carcinoma (HCC) cells via overexpression of the transcription factor, cJun, thus representing a valuable target for HCC therapy. Magnetic activated cell sorting was used to separate the CD44v6+ from CD44v6- cells, and Met levels were regulated using lentiviral particles and the selective Met inhibitor, PHA665752. An orthotopic liver xenograft tumor model was used to assess the self-renewal ability of CD44v6+ cells in immunodeficient NOD/SCID mice. Luciferase reporter and chromatin immunoprecipitation assays were also conducted using cJun-overexpressing 293 T cells to identify the exact binding site of cJun in the Nanog promoter. Our data demonstrate that CD44v6 is an ideal surface marker of liver CSCs. CD44v6+ HCC cells express higher levels of Met and possess self-renewal and tumor growth abilities. Xenograft liver tumors were smaller in nude mice injected with shMet HCC cells. Immunohistochemical analysis of liver tissue specimens revealed that high Met levels in HCC cells were associated with poor patient prognosis. Further, a cJun binding site was identified 1700 bp upstream of the Nanog transcription start site and mutation of the cJun binding site reduced Nanog expression. In conclusion, the HGF/Met signaling pathway is important for maintenance of stemness in CD44v6+ HCC cells by enhancing expression of cJun, which binds 1700 bp upstream of the Nanog transcription start site.

Research Article

26 Oct 2022

Stage-Dependent Regulation of Dental Pulp Stem Cell Odontogenic Differentiation by Transforming Growth Factor-1

Yu Bai|Xin Liu|...|Wenxi He

Transforming growth factor-1 (TGF-1) is an important multifunctional cytokine with dual effects on stem cell differentiation. However, the role of TGF-1 on odontogenic differentiation of dental pulp stem cells (DPSCs) remains to be entirely elucidated. In the present study, we initially investigated the effect of TGF-1 at a range of concentrations (0.1-5ng/mL) on the proliferation, cell cycle, and apoptosis of DPSCs. Subsequently, to determine the effect of TGF-1 on odontogenic differentiation, alkaline phosphatase (ALP) activity and Alizarin Red S (ARS) staining assays at different concentrations and time points were performed. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot analysis were used to determine the levels of odonto-/osteo-genic differentiation-related gene and protein expression, respectively. For in vivo studies, newly formed tissue was assessed by Massons trichrome and von Kossa staining. Data indicated that TGF-1 inhibited DPSCs proliferation in a concentration-and time-dependent manner () and induced cell cycle arrest but did not affect apoptosis. ALP activity was enhanced, while ARS reduced gradually with increasing TGF-1 concentrations, accompanied by increased expression of early marker genes of odonto-/osteo-genic differentiation and decreased expression of late-stage mineralization marker genes (). ALP expression was elevated in the TGF-1-treatment group until 14 days, and the intensity of ARS staining was attenuated at days 14 and 21 (). Compared with the control group, abundant collagen but no mineralized tissues were observed in the TGF-1-treatment group in vivo. Overall, these findings indicate that TGF-1 promotes odontogenic differentiation of DPSCs at early-stage while inhibiting later-stage mineralization processes.

Research Article

20 Oct 2022

miR-31 from Mesenchymal Stem Cell-Derived Extracellular Vesicles Alleviates Intervertebral Disc Degeneration by Inhibiting NFAT5 and Upregulating the Wnt/-Catenin Pathway

Baodong Wang|Na Xu|...|Yang Cao

In this study, we explored the regulatory mechanism of intervertebral disc degeneration (IDD) that involves miR-31 shuttled by bone marrow mesenchymal stem cell-derived extracellular vesicles (BMSC-EVs) and its downstream signaling molecules. Nucleus pulposus cells (NPCs) were isolated and treated with TNF- to simulate IDD in vitro. The TNF--exposed NPCs were then cocultured with hBMSCs or hBMSC-EVs in vitro to detect the effects of hBMSC-EVs on NPC viability, apoptosis, and ECM degradation. Binding between miR-31 and NFAT5 was determined. A mouse model of IDD was prepared by vertebral disc puncture and injected with EVs from hBMSCs with miR-31 knockdown to discern the function of miR-31 in vivo. The results demonstrated that hBMSC-EVs delivered miR-31 into NPCs. hBMSC-EVs enhanced NPC proliferation and suppressed cell apoptosis and ECM degradation, which was associated with the transfer of miR-31 into NPCs. In NPCs, miR-31 bound to the 3UTR of NFAT5 and inhibited NFAT5 expression, leading to activation of the Wnt/-catenin pathway and thus promoting NPC proliferation and reducing cell apoptosis and ECM degradation. In addition, miR-31 in hBMSC-EVs alleviated the IDD in mouse models. Taken together, miR-31 in hBMSC-EVs can alleviate IDD by targeting NFAT5 and activating the Wnt/-catenin pathway.

Review Article

20 Oct 2022

Variability in Platelet-Rich Plasma Preparations Used in Regenerative Medicine: A Comparative Analysis

Raghvendra Vikram Tey|Pallavi Haldankar|...|Ravindra Maradi

Background. Platelet-rich plasma (PRP) and its derivatives are used in several aesthetic, dental, and musculoskeletal procedures. Their efficacy is primarily due to the release of various growth factors (GF), interleukins, cytokines, and white blood cells. However, the PRP preparation methods are highly variable, and studies lack consistency in reporting complete procedures to prepare PRP and characterize PRP and its derivatives. Also, all the tissue-specific (in vivo and in vitro) interactions and functional properties of the various derivatives/factors of the PRP have not been taken into consideration by any study so far. This creates a potential space for further standardization of the PRP preparation methods and customization of PRP/PRP derivatives targeted at tissue-specific/pathology specific requirements that would enable efficacious and widely acceptable usage of PRP as main therapy, rather than being used as adjuvant therapy. The main objective of our study was to investigate the variability in PRP preparation methods and to analyze their efficacy and reliability. Method. This study considered articles published in the last 5 years, highlighting the variability in their PRP preparation methods and characterization of PRP. Following the PRISMA protocol, we selected 13 articles for the study. The selected articles were assessed using NHLBI quality assessment tool. Results. We noted differences in (1) approaches to producing PRP, (2) extent of characterization of PRP, (3) small scale and large-scale preparation methods, (4) in vitro and in vivo studies. Conclusion. We identified two studies describing the procedures which are simple, reproducible, economical, provide a good yield of platelets, and therefore can be considered methods for further tissue-specific and pathology-specific standardizations of PRP and its derivatives. We recommend further randomized studies to understand the full therapeutic potential of the constituents of PRP and its derivatives.

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Stem Cells International | Hindawi

Recommendation and review posted by Bethany Smith

Ono Exercises Option to HER2-targeted CAR T-Cell Product Candidate for Solid Tumors Generated from the Collaboration with Fate Therapeutics -…

Ono Exercises Option to HER2-targeted CAR T-Cell Product Candidate for Solid Tumors Generated from the Collaboration with Fate Therapeutics  Marketscreener.com

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Ono Exercises Option to HER2-targeted CAR T-Cell Product Candidate for Solid Tumors Generated from the Collaboration with Fate Therapeutics -...

Recommendation and review posted by Bethany Smith

Diagnosis of Hypogonadism: Clinical Assessments and Laboratory Tests

Rev Urol. 2004; 6(Suppl 6): S3S8.

Auxilium Pharmaceuticals, Inc., Norristown, PA

Hypogonadism can be of hypothalamic-pituitary origin or of testicular origin, or a combination of both, which is increasingly common in the aging male population. In the postpubertal male, testosterone replacement therapy can be used to treat the signs and symptoms of low testosterone, which include loss of libido, erectile dysfunction, diminished intellectual capacity, depression, lethargy, osteoporosis, loss of muscle mass and strength, and some regression of secondary sexual characteristics. Before initiation of testosterone replacement therapy, an examination of the prostate and assessment of prostate symptoms should be performed, and both the hematocrit and lipid profile should be measured. Absolute contraindications to testosterone replacement therapy are prostate or breast cancer, a hematocrit of 55% or greater, or sensitivity to the testosterone formulation.

Key words: Hypogonadism, Testosterone replacement therapy, Serum hormone-binding globulin, Luteinizing hormone, Follicle-stimulating hormone

Hypogonadism is a lack of testosterone in male patients and can be of central (hypothalamic or pituitary) or testicular origin, or a combination of both. Hypogonadism in male patients with testicular failure due to genetic disorders (eg, Klinefelters syndrome), orchitis, trauma, radiation, chemotherapy, or undescended testes, is known as hypergonadotropic hypogonadism or primary hypogonadism. Hypogonadism in male patients with gonadotropin deficiency or dysfunction as a result of disease or damage to the hypothalamic-pituitary axis is known as hypogonadotropic hypogonadism, central hypogonadism, or secondary hypogonadism. This might be due to Kallmanns syndrome, tumor, trauma, radiation, sarcoidosis, or tuberculosis. In addition, men older than 50 years might have low testosterone levels with functional abnormalities at multiple levels of the hypothalamic-pituitary-testicular axis.1,2,3

The prevalence of hypogonadism has increased in recent years. It has been reported that 12%, 19%, 28%, and 49% of men greater than 50, 60, 70, or 80 years of age, respectively, fit the criteria of hypogonadism.4

During puberty, testosterone is required for the development of male secondary sexual characteristics, stimulation of sexual behavior and function, and initiation of sperm production.5,6 In adult males, testosterone is involved in maintaining muscle mass and strength, fat distribution, bone mass, red blood cell production, male hair pattern, libido and potency, and spermatogenesis.13,5,6

In men, the major gonadal steroid hormone is testosterone. Testosterone circulates in 3 major forms: unbound, or free, testosterone; tightly bound testosterone, which is bound to sex hormone-binding globulin (SHBG); and weakly bound testosterone, which is bound to albumin. Only free and weakly bound testosterone is bioavailable or able to bind to the androgen receptor.2,3

In males, serum testosterone levels show a circadian variation, with the highest levels in the morning and lowest levels in the late afternoon. In young men, the variation in testosterone levels is approximately 35%. Although the normal range for serum testosterone might vary between different laboratories, the normal range for early morning total testosterone in healthy adult males is approximately 300 ng/dL to 1000 ng/dL.7,8

To determine whether a patient is testosterone deficient, a clinician must consider clinical signs and symptoms in conjunction with laboratory values. The initial clinical picture will vary depending on the age of the patient at the onset of the disorder.

In the normal male, the start of puberty is apparent by enlargement of the testes and the appearance of pubic hair, followed by the appearance of auxiliary and facial hair. At puberty there is also increased penile length and the onset of spermatogenesis. If signs of puberty are not evident in boys by 14 years of age, a workup for delayed puberty is warranted.

In the prepubertal age group, hypogonadism might be either primary hypogonadism or secondary hypogonadism. To differentiate primary from secondary hypogonadism, early morning luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels must be obtained. Because LH and FSH are secreted during the early morning at the beginning of puberty, it is necessary to measure these hormones in the early morning (8:0010:00 AM). Primary hypogonadism is associated with low levels of testosterone and high-normal to high levels of LH and FSH. Secondary hypogonadism is associated with low levels of testosterone and normal to low levels of LH and FSH.5,6

The signs and symptoms of low testosterone in postpubertal adult males can be more difficult to diagnose and might include loss of libido, erectile dysfunction, diminished intellectual capacity, depression, lethargy, osteoporosis, loss of muscle mass and strength, and some regression of secondary sexual characteristics.13 At the initial visit, the first objective is to distinguish between primary gonadal failure, in which low testosterone is accompanied by increased FSH and increased LH, and hypothalamic-pituitary disorders (secondary hypogonadism), with low testosterone and low to normal FSH and LH levels.

Initial laboratory testing should include early morning (8:0010:00 AM) measurement of serum testosterone, prolactin, FSH, and LH levels. For the diagnosis of primary hypogonadism, FSH measurement is particularly important because FSH has a longer half life, is more sensitive, and demonstrates less variability than LH.2,3

The aging male patient can present with signs and symptoms of low testosterone, including loss of libido, erectile dysfunction, diminished intellectual capacity, depression, lethargy, osteoporosis, and loss of muscle mass and strength.13 At the initial visit, laboratory testing should include early morning (8:0010:00 AM) measurement of serum testosterone. In elderly men, testosterone levels decrease between 15% and 20% over the course of 24 hours.8

Total testosterone levels might be normal with hypogonadism if the SHBG levels are increased.79 Levels of SHBG increase with age, causing a decrease in bioavailable testosterone.9 If testosterone levels are low-normal but the clinical symptoms and signs indicate hypogonadism, measurement of serum total testosterone levels should be repeated and an SHBG level should be determined. With the total testosterone and SHBG levels, a bioavailable testosterone value can be calculated. A bioavailable testosterone calculator is available at http://www.issam.ch/freetesto.htm.

It is usually not necessary to determine FSH or LH levels in the aging male.

It is well accepted that testosterone levels should be measured in the early morning, when they are at their peak level. However, in community practice the choice of which testosterone parameter to measure is still debatable.

Total testosterone assay is widely available and inexpensive to perform. Although the ranges and methods vary, physicians can consult their local laboratories for the applicable values in their clinical practice. Total testosterone values, however, must be interpreted carefully in the aging male because SHBG levels might be elevated. If the total testosterone level is normal in the aging male presenting signs of hypogonadism, the clinician can measure free testosterone or measure SHBG and calculate bioavailable testosterone.9

Free testosterone can be measured by equilibrium dialysis or ultrafiltration, which are difficult to perform and largely unavailable but reliable. In contrast, the radioimmunoassay for free testosterone is widely available but unreliable. Because total testosterone and SHBG assays are readily available and cheap, calculating bioavailable testosterone might be a good compromise. Whichever method is chosen, if the early morning testosterone level is at or below the lower limit of normal for the individual laboratory, then a repeat measurement of the early morning testosterone level should be performed to confirm the result. Because testosterone is secreted in a pulsatile fashion, it is important to obtain 2 early morning testosterone levels.

In selected patients, FSH, LH, and prolactin can be measured. If the FSH and LH levels are raised, this suggests a primary testicular cause, and if levels are low or normal, a hypothalamic or pituitary cause should be considered. A raised prolactin level suggests that further investigation of the pituitary gland should be undertaken.1,2

The clinical signs and symptoms of hypogonadism will vary depending on whether the patient presents before or after puberty. Depending on the age of the patient, the degree of pubertal development is important for establishing the differential diagnosis.

Boys aged 14 years or older should be suspected of being hypogonadal if on examination they have underdeveloped testes, lack of penile enlargement, and absence of pubic, auxiliary, and facial hair.

In patients with primary hypogonadism, history might reveal the cause for primary testicular failure, such as familial autoimmune disease, physical trauma to the testes, or trauma to the testes caused by radiation, chemotherapy, or infection.

A karyotype should be obtained to diagnose chromosomal abnormalities, such as Klinefelters syndrome, and a physical examination will reveal small or absent testes resulting from anorchia, Noonans syndrome, or other testicular disorders.

Hypothalamic or pituitary deficiency might be transitory or permanent. Transient secondary hypogonadism might be related to malnutrition or stress states and can be diagnosed by physical examination and evaluation of the patients growth chart. If permanent hypothalamic or pituitary hormone deficiency is suspected, serum levels of pituitary hormones and magnetic resonance imaging of the brain and pituitary should be obtained to screen for hypothalamic or pituitary disease.

If both physical examination and serum chemistry tests are normal, then by exclusion a diagnosis of constitutional pubertal delay must be considered.

To establish a diagnosis of hypogonadism, it is important to take a careful history to determine whether there have been major medical problems, toxic exposure, concomitant drug therapy that might cause hypogonadism, or fertility problems.

Low libido, impotence, fatigue, impaired concentration, and sexual dysfunction are important clinical problems that might not be raised by the patient in the clinic. Therefore, these symptoms need to be asked about specifically if hypogonadism is suspected.13

Formal assessment of intellectual changes, mood, and cognitive changes can be performed. Changes in lean body mass will be apparent from the medical history and examination, as will changes in hair, skin, and fat distribution. Decreases in bone mineral density might be apparent from a history of recent fractures but can only be confirmed by dual energy x-ray absorptiometry (DEXA).1

Physical examination should include testicular examination, including size and consistency. The distribution and amount of body hair should also be noted. Penile size is not affected by postpubertal testosterone deficiency. An assessment of the prostate by digital rectal examination (DRE) should be performed and a prostate-specific antigen (PSA) value obtained.3

To establish a diagnosis of hypogonadism in the aging male, it is important to assess the patient carefully for signs and symptoms. Low libido, impotence, fatigue, impaired concentration, and sexual dysfunction are important clinical problems that might not be raised by the patient in the clinic, especially by an aging patient. Therefore, as with the younger postpubertal patient, these symptoms need to be asked about specifically if hypogonadism is suspected.1,2 As with the postpubertal patient (see previous section), changes in intellectual functioning; mood; lean body mass; and hair, skin, and fat distribution should all be assessed, and DEXA can be used to confirm decreases in bone mineral density.1

In older patients, an important part of the physical examination includes an assessment of the prostate by DRE and PSA assay. In addition, an assessment of prostate-related symptoms should be undertaken. The presence of gynecomastia or carcinoma of the breast are important physical findings.

In cases of primary and permanent secondary hypogonadism diagnosed in the prepubertal male, life long testosterone treatment is needed. The usual treatment is initiation of therapy with small doses of testosterone (50100 mg IM) every 3 to 4 weeks at the appropriate psychosocial stage in development. When a final adult height is thought to have been obtained, the adult dose of testosterone replacement is inaugurated.

In the postpubertal period, once the diagnosis of testosterone deficiency has been made, replacement therapy should be considered in light of the clinical signs and symptoms in conjunction with the laboratory values. The objective of testosterone replacement therapy is to normalize serum testosterone and maintain the level within the eugonadal state. In addition, treatment objectives might include improving sexual dysfunction, intellectual capacity, depression, and lethargy; maintaining bone mineral density and possibly reducing fracture risk; increasing muscle mass and strength; and enhancing the quality of life.13,9

Although the normal range for serum testosterone might vary between different laboratories, the normal range for early morning testosterone in male adults is approximately 300 ng/dL to 1000 ng/dL.7 An early morning total serum testosterone level of less than 300 ng/dL clearly indicates hypogonadism, and under most circumstances benefit will be derived from testosterone replacement therapy. A healthy male adult patient with a serum testosterone level greater than 400 ng/dL is unlikely to be testosterone deficient, and therefore clinical judgment should be exercised if he has symptoms suggestive of testosterone deficiency.

There are some absolute contraindications to testosterone replacement therapy. These include prostate cancer, which must be assessed by history and clinical examination. If on DRE the prostate is enlarged or if the PSA level is greater than 4.0 ng/mL, biopsy of the prostate should be undertaken to confirm a diagnosis of prostate cancer or benign prostatic hyperplasia (BPH).3

An existing or prior history of breast cancer is also an absolute contraindication to testosterone replacement therapy. Testosterone therapy is known to increase the hematocrit, and therefore a pre-existing hematocrit of 55% or greater is an absolute contraindication to replacement therapy.

Sensitivity to any of the ingredients in the testosterone formulation would also be an absolute contraindication. Relative contraindications include an increased hematocrit, untreated sleep apnea, severe obstructive symptoms of BPH, and advanced congestive cardiac failure.2,3

The goal of replacement therapy is to maintain testosterone in the normal physiological range; therefore, a combination of clinical and biochemical measures should be monitored 6 to 12 weeks after initiating therapy. In most cases, an early morning serum total testosterone level is adequate to determine whether dosage adjustment is necessary. However, patients receiving injections of testosterone enanthate or cypionate every 2 weeks will require an earlier measurement of serum testosterone at 1 to 2 weeks after commencement of therapy.3

Examination of the prostate should be performed routinely, although the exact frequency after initiation of testosterone replacement is still debatable. Digital rectal examination of the prostate and PSA assay should be performed before initiation of therapy, along with an assessment of prostate-related symptoms. In elderly men, a DRE and PSA assay should be performed at 3 and 6 months after commencing testosterone therapy and then annually thereafter.3 A high PSA level should be further evaluated with a highly specific PSA assay, if available. A patient should be referred to a urologist if his PSA level increases over time or if he has a PSA level greater than 4.0 ng/mL.3

It is known that testosterone stimulates bone marrow production of erythrocytes, which might result in an increased hematocrit in some men, and therefore this should be checked at the same time as the PSA level.2,3

Lipid disturbances in testosterone-treated male patients are generally not a problem because the ratio of high-density lipoprotein to total cholesterol usually remains constant. An initial lipid profile should be performed before therapy, and a follow-up profile should be obtained after 6 to 12 months of therapy and annually thereafter.3

Hypogonadism can be of hypothalamic-pituitary origin or of testicular origin, or a combination of both, which is increasingly common in the aging male population. It can be easily diagnosed with measurement of the early morning serum total testosterone level, which should be repeated if the value is low. Follicle-stimulating hormone, LH, and prolactin might also need to be measured. If the clinical signs and symptoms suggest hypogonadism but the serum testosterone level is near normal, then assay of serum testosterone should be repeated in conjunction with SHBG because serum testosterone might be normal in the presence of hypogonadism if the SHBG level is raised, which commonly occurs in elderly male patients.

Before initiation of testosterone replacement therapy, an examination of the prostate, including DRE, PSA assay, and assessment of prostate symptoms should be undertaken, and both the hematocrit and lipid profile should be measured. There are few absolute contraindications to testosterone replacement therapy other than prostate or breast cancer, a hematocrit of 55% or greater, or sensitivity to the testosterone formulation. Monitoring of the prostate (assessed with DRE and PSA assay) and hematocrit and lipid profile should be repeated during testosterone replacement therapy.

The benefits of testosterone replacement therapy may include restoring metabolic parameters to the eugonadal state; improving psychosexual function and intellectual capacity, including depression and lethargy; maintaining bone mineral density and reducing bone fractures; improving muscle mass and strength; and enhancing quality of life.

Hypogonadism is a lack of testosterone in male patients and can be of central (hypothalamic or pituitary) or testicular origin, or a combination of both.

Boys ages 14 years or older should be suspected of being hypogonadal if on examination they have underdeveloped testes, a lack of penile enlargement, and an absence of pubic, auxiliary, and facial hair.

In pre- and postpubertal male patients, primary hypogonadism is associated with low levels of testosterone and high-normal to high levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH); secondary hypogonadism is associated with low levels of testosterone and normal to low levels of LH and FSH.

In the aging male patient, signs and symptoms of hypogonadism can include loss of libido, erectile dysfunction, diminished intellectual capacity, depression, lethargy, osteoporosis, and loss of muscle mass and strength.

For aging men, laboratory testing should include early morning (8:0010:00 AM) measurement of serum testosterone; levels less than 300 ng/dL clearly indicate hypogonadism, and under most circumstances benefit will be derived from testosterone replacement therapy.

Before initiation of testosterone replacement therapy, an examination of the prostate and assessment of prostate symptoms should be performed, and both the hematocrit and lipid profile should be measured.

There are few absolute contraindications to testosterone replacement therapy other than prostate or breast cancer, a hematocrit of 55% or greater, or sensitivity to the testosterone formulation.

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Diagnosis of Hypogonadism: Clinical Assessments and Laboratory Tests

Recommendation and review posted by Bethany Smith

Approach to the Patient With Hypogonadotropic Hypogonadism

Hypogonadotropic hypogonadism (HH) or secondary hypogonadism is defined as a clinical syndrome that results from gonadal failure due to abnormal pituitary gonadotropin levels. HH may result from either absent or inadequate hypothalamic GnRH secretion or failure of pituitary gonadotropin secretion. Several congenital and acquired causes, including functional and organic forms, have been associated with this condition. One important aspect of the HH diagnosis is that it may reflect the presence of a tumor of the hypothalamic pituitary region or even a systemic disease. On the other hand, functional forms of HH, characterized by a transient defect in GnRH secretion, are relatively common in women, in response to significant weight loss, exercise, or stress leading to hypothalamic amenorrhea. HH is typically characterized by low circulating sexual steroids associated with low or inappropriately normal gonadotropin levels. The precise and early diagnosis of HH can prevent negative physical and psychological sequelae, preserve normal peak bone mass, and restore the fertility in affected patients.

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The Endocrine Society is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The Endocrine Society has achieved Accreditation with Commendation.

The Endocrine Society designates this JCEM Journal-based CME activity for a maximum of 1 AMA PRA Category 1 Credits. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Learning Objectives

Upon completion of this educational activity, participants should be able to:

Recognize the symptoms and signs of hypogonadism throughout different phases of life.

Identify the congenital and acquired causes of hypogonadotropic hypogonadism.

Diagnose hypogonadotropic hypogonadism.

Disclosure Policy

Authors, editors, and Endocrine Society staff involved in planning this JCEM Journal-based CME activity are required to disclose to The Endocrine Society and to learners any relevant financial relationship(s) of the individual or spouse/partner that have occurred within the last 12 months with any commercial interest(s) whose products or services are discussed in the CME content. The Endocrine Society has reviewed all disclosures and resolved all identified conflicts of interest.

The following authors reported no relevant financial relationships:

Leticia Ferreira Gontijo Silveira, M.D., Ph.D, and Ana Claudia Latronico, M.D., Ph.D., have no relevant financial relationships.

The following JCEM Editors reported relevant financial relationships:

The Editor-in-Chief, Leonard Wartofsky, M.D., is a Consultant for Asurogen, Genzyme, and IBSA, and is on the Speaker's Bureau for Genzyme. Kenneth Burman, M.D., is a Consultant for Medscape and UpToDate; a Reviewer for the Endocrine Fellows Foundation; and has received Institutional Grants for Research from Amgen, Eisei, and Pfizer. Samuel Dagogo-Jack, M.D., is a Consultant for Merck and Novo Nordisk; a Grantee for the American Diabetes Association, AstraZeneca, Boehringer Ingelheim, National Institutes of Health, and Novo Nordisk; and a Grant Reviewer for the American Diabetes Association and National Institutes of Health. Silvio Inzucchi, M.D., is a Consultant/Advisor for Boehringer Ingelheim, Genentech, Janssen, Merck, and Takeda; has DSMB Activity with Amgen, Esai, and Gilead; and receives CME support from Abbott, Amylin, Boeringher-Ingelheim, Merck, and Takeda. Kieren Mather, M.D., received an Investigator-initiated Grant from Novo Nordisk. Lynnette Nieman, M.D., is an Author/Editor for UpToDate, and receives Research Support from HRA-Pharmaceutical.

The following JCEM Editors reported no relevant financial relationships: Paolo Beck-Peccoz, M.D.; David Ehrmann, M.D.; David Handelsman, Ph.D.; Michael Kleerekoper, M.D.; Merrily Poth, M.D.; Constantine Stratakis, M.D.

Endocrine Society staff associated with the development of content for this activity reported no relevant financial relationships.

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A 19 year-old female, born from nonconsanguineous parents, was referred to the Endocrinology Unit due to primary amenorrhea and poor breast development. Spontaneous partial pubarche and thelarche occurred at 13 and 15 years, respectively. The patient did not report eating disorders or vigorous physical activity. She had no olfactory complaints. She had 2 older brothers with a history of normal pubertal development. At physical examination, she had eunuchoid habitus (height, 155 cm; arm span, 160 cm), weight of 60.7 kg, with normal body mass index of 23 kg/m2. Pubic hair and breast development were Tanner stage II. She had ogival palate and cavus feet, and no other stigmata were observed. Basal hormonal evaluation revealed low serum estradiol (6.8 pg/ml) and suppressed LH (<0.6 IU/L) and FSH (<1.0 IU/L) levels. Upon acute GnRH stimulation test (100 mg iv), peak LH was 1.4 IU/L and peak FSH was 1.7 IU/L. Anterior pituitary function was otherwise normal, including prolactin (9 ng/mL) and thyroid function (TSH, 1.5 IU/L; free T4, 1.1 ng/dL). A formal olfactory test was applied and confirmed normal sense of smell. Her bone age was 13 years. No abnormalities were noticed on abdominal ultrasound examination. Pelvic ultrasound revealed infantile uterus (1.5 cc) and small ovaries (right, 2.6 cc; left, 1.3 cc). Her bone mineral density, corrected for bone age, was reduced, showing osteopenia. Magnetic resonance imaging scan of the hypothalamic-pituitary region was normal.

Pulsatile secretion of GnRH by hypothalamic neurons is a crucial element of the reproductive cascade, initiating the release of pituitary gonadotropins, gonadal secretion of sex steroids, pubertal development, and gametogenesis. Hypogonadotropic hypogonadism (HH) is characterized by failure of gonadal function secondary to deficient gonadotropin secretion (1). This condition is commonly seen in association with other pituitary hormone deficiency states caused by structural lesions of the hypothalamic-pituitary region. However, congenital, acquired, and functional causes have been associated with isolated GnRH deficiency (Tables 1 and 2) (2).

Genes and Their Protein Products Associated With Congenital IHH Phenotype

Genes and Their Protein Products Associated With Congenital IHH Phenotype

Congenital isolated HH (IHH) is characterized by partial or complete lack of pubertal development, secondary to deficient GnRH-induced gonadotropin secretion, in the absence of anatomical abnormalities in the hypothalamic and pituitary region, and normal baseline and reserve testing of the remaining pituitary hormones (1). This genetic condition is classically divided in 2 groups based on the presence or absence of olfaction dysfunction. Around 5060% of the affected individuals exhibit anosmia or hyposmia in association with IHH, defining Kallmann syndrome. Patients with Kallmann syndrome may have additional phenotypic abnormalities including craniofacial defects (cleft lip/palate, high-arched palate, ocular hypertelorism, dental agenesis), neurosensory deafness, digital anomalies (clinodactyly, syndactyly, camptodactyly), unilateral renal agenesis, and neurological defects (oculomotor abnormalities, bimanual synkinesis or mirror hand movements, cerebellar ataxia), whereas normosmic IHH is usually not associated with any other malformations (nonsyndromic condition) (3). In Kallmann syndrome, anosmia is related to hypoplasia or aplasia of the olfactory bulbs, whereas the hypogonadism is due to GnRH deficiency, due to defective migration of olfactory and GnRH neurons. In most vertebrates, the olfactory and GnRH neurons share a common origin in the nasal placode and migrate together across the cribiform plate toward the developing olfactory bulb, explaining the association of HH with olfactory abnormalities (4, 5).

Congenital IHH is a clinically and genetically heterogeneous disorder. Although sporadic cases are the most frequent, families with congenital IHH have been reported with X-linked, autosomal dominant or recessive inheritance. The prevalence of IHH has been estimated at 1/4000 to 1/10 000 males, and it is reported to be 2 to 5 times less frequent in females. The reason for this marked gender discrepancy is not known, and the prevalence of the disease is probably underestimated in females. Male preponderance can be only partially explained by the contribution of men with X-linked disease to the total number of cases (1, 6, 7). Other factors, such as incomplete penetrance, biased referral patterns, with male patients being seen by endocrinologists as opposed to more females being referred and treated by gynecologists, should also be considered.

A growing list of genes has been implicated in the molecular pathogenesis of the congenital IHH, pointing up the heterogeneity and complexity of the genetic basis of this condition (Table 2). These genes encode neuropeptides and proteins involved in the development and migration of GnRH neurons, or in the control of different stages of GnRH function. Mutations in KAL1, FGFR1/FGF8, PROK2/PROKR2, NELF, CHD7, HS6ST1, WDR11, and SEMA3A are associated with defects in neuronal migration, leading to Kallmann syndrome (810). Notably, defects in FGFR1, FGF8, PROKR2, CHD7, and WDR11 have also been associated with normosmic IHH, although in a lower frequency (8, 10). Mutations in KISS1/KISS1R, TAC3/TACR3, and GNRH1/GNRHR, genes that interfere in the secretion and action of GnRH, are described exclusively in patients with normosmic IHH (8, 11). Despite these recent and great advances, the genetic basis of most cases of congenital IHH remains unknown, with the molecular basis of this condition being identified in approximately 30% of patients.

Congenital IHH has been historically defined in traditional Mendelian terms and considered a monogenic disease. However, this concept has been recently reviewed. Pedigrees with great phenotypic variability have been described, and complex genetic transmission (digenic or oligogenic inheritance) has been recently demonstrated (12, 13). Substantial variation in clinical expression of the same genetic defect in families of patients with IHH has been observed, with affected members presenting with Kallmann syndrome, normosmic IHH, isolated anosmia, isolated clefting, simple pubertal delay, or even apparent phenotypic normality, suggesting the possibility that Kallmann syndrome and normosmic IHH may take part of a wider spectrum of disease (3, 10, 13). This variability has been observed mainly in kindreds with mutations in FGF8/FGFR1 and in PROK2/PROKR2 ligand-receptor pairs (3, 13). This type of phenotypic heterogeneity may be ascribed to environmental or epigenetic effects. A second explanation is the coexistence within families of defects in 2 or more different genes that interact functionally, as it has recently been described in a number of families (10, 13).

Acquired causes of HH are mostly due to structural or functional abnormalities involving the hypothalamic-pituitary axis, and most of these patients have multiple pituitary hormone deficiencies. These conditions include infiltrative disorders of the hypothalamic-pituitary tract, such as sarcoidosis, lymphocytic hypophysitis and histiocytosis, space-occupying lesions such as pituitary adenomas, craniopharyngiomas, and other central nervous system tumors (2).

Adult-onset isolated gonadotropin deficiency can be secondary to systemic disorders, drugs, functional abnormalities, or idiopathic. One of the most frequent causes of acquired isolated HH is hyperprolactinemia. Elevated prolactin levels can result mainly from the use of drugs that interfere with the dopaminergic system, lactotroph adenomas (prolactinomas), or from any hypothalamic or pituitary stalk disorder that interrupts hypothalamic inhibition of prolactin secretion. The possibility of nutritional disorders or an undiagnosed chronic illness that may affect the hypothalamic GnRH pulse generator should be evaluated in patients with HH. Hypothyroidism should be ruled out, particularly if growth velocity is below expected and bone age markedly delayed. Hemochromatosis can affect the hypothalamic and pituitary region, leading to progressive isolated gonadotropin deficiency, and should always be ruled out by the presence of normal serum ferritin concentrations. Drugs that can reversibly suppress sex steroid levels include opiates, glucocorticoid, and psychotropic agents such as phenothiazines.

The idiopathic form of adult-onset HH is a rare disorder characterized by an isolated failure of gonadotropin secretion occurring after an otherwise normal sexual maturation in men in whom anatomical, systemic, or functional causes had been ruled out (14). No genetic defect in genes associated with congenital IHH has been identified in this group of patients (15). Long-term follow-up of adult-onset HH individuals revealed that the clinical and hormonal characteristics of these patients did not change over a decade, all of them remaining severely hypogonadal, with testosterone levels below 130 ng/dL, with no spontaneous reversals (15). It is important to differentiate adult-onset HH, characterized by frankly low serum testosterone levels in the presence of low or normal gonadotropins, from the progressive testosterone deficiency observed in a small minority of aging men, known as late-onset hypogonadism. This latter condition has been defined as a syndrome in middle-aged and elderly men reporting sexual symptoms in the presence of moderately low total testosterone levels (<320 ng/dL), with variable levels of gonadotropins, which involves central and mostly gonadal components in its pathogenesis (16, 17).

Functional hypothalamic amenorrhea is a reversible form of GnRH deficiency, usually triggered by stressors such as excessive exercise, nutritional deficits, or psychological distress. Regardless of the specific trigger, functional hypothalamic amenorrhea is characterized by the suppression of GnRH pulsatility (18). Functional hypothalamic amenorrhea is a frequent cause of acquired female infertility, typically manifested as amenorrhea of 6-month duration or longer, low or normal gonadotropin levels, and hypoestrogenemia without organic abnormalities (19, 20). Interestingly, rare variants in the genes associated with congenital IHH were recently found in women with hypothalamic amenorrhea, suggesting that these mutations may contribute to the variable susceptibility of women to functional changes in GnRH secretion (20). Moreover, the importance of low levels of leptin, a hormone secreted by adipocytes that regulates energy homeostasis, in the pathophysiology of hypothalamic amenorrhea was clearly demonstrated by evidence of a significant improvement of the reproductive and neuroendocrine functions in women with hypothalamic amenorrhea after exogenous recombinant leptin replacement (21, 22). Although primarily a disease of females, eating disorders such as anorexia nervosa are increasingly being recognized in males and are associated with hypogonadism. Population-based studies reported that 515% of all patients with anorexia nervosa are males (23, 24).

Clinical presentation of HH depends on the time of onset (ie, congenital vs acquired), the severity of the defect, and the presence of associated conditions. Typically the diagnosis of congenital IHH is made during the second or third decade of life, when the patients present with delayed pubertal onset, absent or poorly developed secondary sexual characteristics, primary amenorrhea, eunuchoid proportions, or infertility. In some cases, the diagnosis may be suspected before puberty. The occurrence of micropenis and/or unilateral or bilateral cryptorchidism in boys, as well as the presence of other associated congenital abnormalities, such as midline defects, suggests congenital GnRH deficiency, especially in the context of a positive family history (25, 26). In contrast, newborn girls have no obvious abnormal findings that might provide clues to the diagnosis. Most commonly, however, the diagnosis cannot be confirmed until the expected time of puberty onset, except in the neonatal period, when gonadotropin and sexual steroid levels are expected to be elevated. The presence of anosmia is suggestive of Kallmann syndrome, and if the child is too young to undergo olfaction tests, magnetic resonance imaging (MRI) scan showing absent or abnormal olfactory bulbs or sulci strongly suggests the diagnosis. Nevertheless, it is important to note that a normal MRI does not rule out the disease because normal olfactory bulbs can be present in up to 20% of Kallmann syndrome patients (2, 3). Adult-onset HH is characterized in women by secondary amenorrhea, decreased libido, infertility, and osteoporosis; in men, symptoms of decreased libido, lack of morning erection, erectile dysfunction, inability to perform vigorous activity, depression, fatigue, and infertility are observed.

The evidence of low/normal gonadotropin levels in the setting of low concentrations of testosterone in men and estradiol in women indicates the diagnosis of HH. Rarely, selective deficiency of LH or FSH can occur due to inactivating mutations of the specific -subunits (2729). The measurement of morning total testosterone by a reliable assay is strongly recommended in the initial diagnosis test (30). In some men, in whom total testosterone is near the lower limit of normal or in whom SHBG abnormality is suspected, measurement of free or bioavailable testosterone levels is then recommended (23). Anterior pituitary function must be investigated to rule out a more complex endocrine disorder with multiple hormone deficiencies.

Although widely used, the practical value of the GnRH test has been questionable because of its low cost-effectiveness. Indeed, the GnRH test provides no extra diagnostic information relative to baseline gonadotropin levels. In HH patients, the response to GnRH test is highly variable and depends on the severity of the gonadotropin deficiency, which is often reflected by the clinical phenotype. Similarly, the pituitary function can be first evaluated by basal hormonal levels (measured by ultrasensitive assays). Thyroid function should be assessed by TSH combined with free T4. IGF-I can be used to evaluate the somatotropic axis, whereas secondary adrenal deficiency can be assessed by measuring a morning cortisol and ACTH. The stimulatory tests should be reserved for the situations in which the basal hormone measurements are not helpful or if there is strong clinical evidence of a multiple pituitary hormone deficiency.

Anosmia can be easily diagnosed by questioning the patient, whereas olfactometry, such as University of Pennsylvania Smell Identification Test, is necessary to determine reliably whether olfaction is normal or partially defective. Indeed, IHH patients display a broad spectrum of olfactory function, with a significant hyposmic phenotype. Accurate olfactory phenotyping in IHH subjects can inform the pathophysiology of this condition and guide genetic testing (31).

MRI of the hypothalamo-pituitary region is very useful in the management of HH. MRI can demonstrate a malformation, an expansive or infiltrative disorder of the hypothalamo-pituitary region. However, the cost-effectiveness of MRI scan to exclude pituitary and/or hypothalamic tumors is unknown according to the recent clinical practice guideline (30). Pituitary and/or hypothalamic tumors should be investigated by MRI in patients with serum testosterone less than 150 ng/dL, multiple pituitary hormone deficiency, persistent hyperprolactinemia, or symptoms of tumor mass effect (headache, visual impairment, or visual field defect). In the presence of suspected functional causes of HH, such as severe obesity, nutritional disorders, and drugs, MRI is not indicated. Additionally, MRI with specific cuts for evaluating the olfactory tract can be helpful in the diagnosis of Kallmann syndrome. Evidence of unilateral or bilateral hypoplastic/agenesis olfactory bulbs and hypoplastic anterior pituitary is pathognomonic of Kallmann syndrome.

Renal ultrasound examination is usually recommended to patients with syndromic IHH, such as Kallmann syndrome, independent of the genetic basis, although it is well known that unilateral kidney agenesis may be more prevalent in patients with KAL1 defects. The genetic study is usually the last step in the congenital IHH investigation, and complete clinical characterization could certainly help in the gene selection. Bone mineral density of the lumbar spine, femoral neck, and hip is recommended at the initial diagnosis of HH and after 1 to 2 years of sex steroid therapy in hypogonadal patients with osteoporosis or low trauma fracture (30).

The goals of therapy for hypogonadal adolescents or young adults are the induction and maintenance of normal puberty and induction of fertility when the patient desires. testosterone therapy for adult men with symptomatic androgen deficiency is recommended to improve sexual function and sense of well-being and to increase muscle mass and strength and BMD. Testosterone is the primary treatment modality used to induce and maintain secondary sexual characteristics and sexual function in men with HH, but it does not restore fertility.

Intramuscular injections of long-acting testosterone esters (testosterone cypionate or enanthate) are commonly used. In adolescents, the initial dose of testosterone esters to induce puberty is 5075 mg/month, which should be gradually increased every 6 months to 100150 mg/month. The maintenance dose for adult males is 200250 mg im every 23 weeks or 1000 mg of testosterone undecanoate every 3 months. Other options are transdermal preparations, including gel formulations (510 g/d) or 5 mg testosterone patches applied nightly over the nongenital skin (30). The long-term goals of testosterone therapy are to maintain the serum concentrations of sex steroids in the midnormal adult range. Testosterone therapy is not indicated in patients with breast or prostate cancer, a palpable prostate nodule, or indurations, or prostate-specific antigen greater than 4 ng/mL or greater than 3 ng/mL in men at high risk for prostate cancer, hematocrit greater than 50%, untreated severe obstructive sleep apnea, severe lower urinary tract symptoms, or uncontrolled or poorly controlled heart failure (30).

When fertility is desired, gonadotropin therapy is necessary to induce spermatogenesis in males with HH (32). Different treatment protocols can be used in male patients with HH. The typical gonadotropin regimen combines human chorionic gonadotropin (hCG) and FSH. One option is to combine hCG 1000 U and FSH 75 U every other day for HH patients without puberty and immature testes (<3 mL). Notably, the intra-subcutaneous route of administration is as effective as im. The hCG doses should be titrated based on testosterone levels, targeting middle normal values. Testosterone levels usually achieve normal range values by 6 months of continuous treatment in most patients, and spermatogenesis is attained in up to 80% of the cases. Another option for patients with partial pubertal development is to start with hCG alone for 6 months and subsequently add FSH if azoospermia persists. Predictive factors of better outcome include larger testicular volume, absence of cryptorchidism, and higher serum inhibin B levels at the initial medical evaluation.

Treatment of adolescent males with exogenous hCG alone or combined with recombinant FSH for induction of puberty may result in testicular growth and hence improvement in potential fertility compared to treatment with testosterone (32). Early induction of spermatogenesis may reduce the time required for appearance of sperm and the need for prolonged cycles of gonadotropin treatment in adult life. Use of hCG alone appears to be less efficient in spermatogenesis induction and final testicular volume when compared to combined treatment with hCG and FSH (32, 33). Side effects of gonadotropin treatment include the inconvenient way of administration, gynecomastia, and the induction of antibodies to hCG, which can impair the response to hCG in the future (34, 35). It is important to note that there are few studies about the use of gonadotropins in adolescents, and most them are small case series of boys with HH who received pubertal induction with gonadotropins at various times, and thus further studies are needed.

The main and most difficult differential diagnosis of congenital IHH in boys is constitutional delay of growth and puberty. Patients with constitutional delay of puberty typically have delayed growth before puberty and delayed bone age, compatible with the height. In contrast, patients with congenital IHH have normal linear growth during childhood, and despite the absence of the pubertal growth spurt, short stature is not a common finding. The absence of long-bone epiphyseal closure explains the presence of eunuchoid proportions and relative high stature. A variety of physiological and stimulation tests have been proposed, such as LH sampling, prolactin response to various stimulating agents, gonadotropin response to GnRH, testosterone response to hCG, and daily urine excretion of FSH and LH (36). Recently, Coutant et al (37) demonstrated that a single measurement of inhibin B level discriminated IHH from constitutional delay of puberty in adolescent boys. The sensibility and specificity were 100% for inhibin B concentration of 35 pg/mL or less in boys with genital stage 1 (testis volume < 3 mL) in this study (26). Other baseline measurements (anti-Mullerian hormone, testosterone, FSH, and LH) were not useful for such discrimination.

It is notable that men with apparent isolated hypothalamic GnRH deficiency may also have primary pituitary and/or testicular defects (a dual defect) as demonstrated by the atypical responses to long-term exogenous pulsatile GnRH treatment (43). The pituitary and/or testicular defects may be initially masked by the GnRH deficiency in these patients. Therefore, the pathophysiology of hypogonadism in a subgroup of patients with IHH could be more complex than previously thought and possibly not limited to an isolated hypothalamic or pituitary defect.

Interestingly, sustained reversal of hypogonadism has been observed in about 10% of congenital IHH patients after discontinuation of treatment. To date, the triggers leading to reversal of IHH are not well understood. Androgen exposure has been suggested to predispose to reversal, and specific genetic backgrounds are especially prone to reversal HH (38). The reversible form of HH should be suspected if testicular volume increases during testosterone administration or in the absence of endocrine therapy. A brief discontinuation of hormonal therapy to assess reversibility is rational in patients with HH. However, the reversibility may not always be lifelong. Interestingly, heterogeneous genetic background (FGFR1, PROK2, GNRH, CHD7, and TAC/TACR3 mutations) has been associated with reversal of congenital HH (38).

Testosterone replacement in older men is another controversial issue in the practice of medicine. Despite the long existence of testosterone as a pharmaceutical medication, few large-scale, double-blind, placebo-controlled, multiple end point studies had been performed on testosterone therapy in men. In fact, older men are more susceptible to risks from testosterone intervention, such as benign prostatic hyperplasia, prostate cancer, and cardiovascular disease. In addition, many men in the middle to older age group do not fit the simple definition of either primary or secondary hypogonadism but have a mixed type of testosterone deficiency with impairment of both testicular and hypothalamic pituitary signals, indicating that the pathogenesis of low testosterone in this group is not well defined (39, 40).

Low gonadotropin and estradiol levels resulting in primary amenorrhea and poor pubertal development suggested the diagnosis of a severe form of HH in this young lady. The normal remaining pituitary function indicated an isolated form of HH. Her history and physical examination ruled out functional hypothalamic amenorrhea. Central anatomic defects and systemic diseases were excluded by routine tests and a normal brain imaging. The early presentation of the hypogonadism, manifesting as primary amenorrhea, and the association with nonreproductive phenotypes (ogival palate and bone abnormalities) contributed to the hypothesis of a congenital defect in this apparently sporadic case of IHH. Additionally, the normal olfaction test confirmed the diagnosis of idiopathic normosmic IHH. More recently, systematic genetic screening revealed a large heterozygous deletion of FGFR1 in this female with IHH (41).

The case depicted here illustrates the typical clinical presentation of severe female GnRH deficiency. Shaw et al (42) recently demonstrated that the clinical presentation of women with GnRH deficiency can vary from primary amenorrhea and absence of any secondary sexual characteristics to spontaneous breast development and occasional menses. In this large series of women with GnRH deficiency, most patients exhibited some degree of breast development (51%), and a small percentage experienced isolated menses (10%). Hypogonadal women with spontaneous thelarche were more likely to have undergone pubarche, suggesting that aromatization of adrenal androgens could contribute to breast development.

Young women with HH are at risk for bone loss and fracture. Congenital hypogonadism may be particularly detrimental to the skeleton because it may lead to failure to achieve peak bone mass, in addition to loss of established bone mass. Estrogen-progesterone replacement, calcium and vitamin D supplementation, and nutritional counseling should be provided. Multiple formulations of estrogen are available and include oral estradiol, oral conjugated estrogen, transdermal estrogen patches, and gel. In patients who have not yet started pubertal development, estrogen therapy should be started at low doses (5 g ethinyl estradiol, 0.3 mg conjugated equine estrogen, or 0.5 mg micronized estradiol daily) to promote breast development. After 6 months or when breakthrough bleeding occurs, cyclical therapy can be initiated by adding a progestogen, and the dose of estrogen is gradually increased over a 2- to 3-year period. Full replacement dose of estrogen and progesterone is attained with 0.6251.25 mg conjugated equine estrogen daily combined with cyclic 510 mg medroxyprogesterone acetate or 200 mg oral micronized progesterone. Other estrogen options are daily 2 mg micronized estradiol orally, 100200 g transdermal 17-estradiol patches or 12 mg estrogen gel. Alternatively, combined contraceptive pills, usually containing ethinyl estradiol, can be conveniently used. However, natural estrogens are preferable to synthetic estrogens because of incomplete metabolization and a greater risk of thromboembolism and arterial hypertension of the synthetic forms. In patients in whom fertility is desired, induction of gonadotropin secretion by pulsatile GnRH or treatment with exogenous gonadotropin is the current hormonal treatment of choice.

Maestre de San Juan was the first to report, in 1856, the association of the absence of olfactory structures in the brain and the presence of small testes in an individual. Although this description took place more than a century ago, the genetics and natural history of Kallmann syndrome are still incompletely understood. Similarly, testosterone has been available as a pharmaceutical medication since 1930, and it has been used since then to treat failure of male secondary sexual development. Definitely, there are still numerous controversial issues in the practice of medicine, requiring individual good sense for taking decisions regarding whom, when, and how to treat. Long-term and well-controlled studies are necessary to solve the current uncertainties in the field of reproductive disorders.

This work was partially supported by a grant from Conselho Nacional de Desenvolvimento Cientfico e Tecnolgico (CNPq, Productivity in Research, process no. 302825/2011-8; to A.C.L.).

Disclosure Summary: The authors have nothing to declare.

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human chorionic gonadotropin

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magnetic resonance imaging.

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Approach to the Patient With Hypogonadotropic Hypogonadism

Recommendation and review posted by Bethany Smith

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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NAD+ Cell Regenerator and Resveratrol Elite – Life Extension

NAD+ Cell Regenerator and Resveratrol Elite combines NIAGEN nicotinamide riboside and ultra-bioavailable forms resveratrol with quercetin and fisetin to create an innovative nutritional supplement for longevity and youthful cellular energy production.

Resveratrol is a well-known longevity and anti-aging supplement.1 Our Resveratrol Elite formulas contains trans-resveratrol, the form associated with beneficial biological effects.2-5 Resveratrol also promotes healthy insulin sensitivity, supports a healthy inflammatory response and has been shown to promote healthy endothelial function for a healthy cardiovascular system.4,6,7

A more bioavailable resveratrol

Weve combined resveratrol with galactomannan fibers from fenugreek seeds. This makes our Resveratrol Elite formulas up to 10 times more bioavailable. This means that the trans-resveratrol in our supplements reaches higher levels in your bloodstream and circulates longer than traditional, unformulated resveratrol.

Resveratrol and heart health

One way that resveratrol promotes heart health is by helping to shield the body from oxidative stress at the cellular level.8 By inhibiting oxidative stress in your cardiovascular system, resveratrol promotes endothelial healthan essential component of living a long, healthy life.9

Resveratrol and brain health

At the same time, resveratrols ability to support cerebrovascular blood flow may also make it good for your brain: there is clinical evidence that resveratrol can help encourage youthful neurological function and with it, things like cognition. Interestingly, this same trial showed that resveratrol promoted healthy glucose metabolismanother essential aspect of healthy longevity.10

Fight general fatigue with NIAGEN

Nicotinamide riboside increases your bodys levels of NAD+, a coenzyme critical to healthy cellular function.11 In a randomized controlled trial published in 2017, older adults taking a daily dose of 250 mg of nicotinamide riboside had a 40% increase in NAD+ levels after just 30 days.2 Studies in preclinical models have shown that increasing NAD+ also encouraged healthy metabolic and cognitive function.3,4

Fisetin and quercetin

Fisetin and quercetin are phytonutrient compounds that augment trans-resveratrols healthy effects, promote cardiovascular health, support healthy cellular function, fight oxidative stress, promote a healthy inflammatory response and more.9,10

Take the fight against aging to the cellular level with NAD+ Cell Regenerator and Resveratrol Elite.

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NAD+ Cell Regenerator and Resveratrol Elite - Life Extension

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State Stem Cell & Gene Therapy Agency Sets up Support Program to Help …

For many patients battling deadly diseases, getting access to a clinical trial can be life-saving, but it can also be very challenging. Today the governing Board of the California Institute for Regenerative Medicine (CIRM) approved a concept plan to make it financially and logistically easier for patients to take part in CIRM-funded clinical trials.

The plan will create a Patient Support Program (PSP) to provide support to California patients being evaluated or enrolled in CIRM-supported clinical trials, with a particular emphasis on helping underserved populations.

Helping scientists develop stem cell and gene therapies is just part of what we do at CIRM. If those clinical trials and resulting therapies are not accessible to the people of California, who are making all this possible, then we have not fulfilled our mission. says Maria T. Millan, M.D., President and CEO of CIRM.

The Patient Support Plan will offer a range of services including:

The funds for the PSP are set aside under Proposition 14, the voter-approved initiative that re-funded CIRM in 2020. Under Prop 14 CIRM money that CIRM grantees earn from licensing, inventions or technologies is to be spent offsetting the costs of providing treatments and cures arising from institute-funded research to California patients who have insufficient means to purchase such treatment or cure, including the reimbursement of patient-qualified costs for research participants.

Currently, the CIRM Licensing Revenues and Royalties Fund has a balance of $15.6 million derived from royalty payments.

The patient support program and financial resources will not only help patients in need, it will also help increase the likelihood that these clinical trials will succeed, says Sean Turbeville, Ph.D., Vice President of Medical Affairs and Policy at CIRM. We know cell and gene therapies can be particularly challenging for patients and their families. The financial challenges, the long-distance traveling, extended evaluation, and family commitments can make it difficult to enroll and retain patients. The aim of the PSP is to change that.

The overall objective of this funding opportunity is to establish a statewide program that, over five years, is expected to support hundreds of patients in need as they participate in the growing number of CIRM-supported clinical trials. The program is expected to cost between $300,000 to $500,000 a year. That money will come from the Medical Affairs budget and not out of the patient assistance fund.

The first phase of the program will identify an organization, through a competitive process, that has the expertise to provide patient support services including:

You can find more information about the Patient Support Program on our website here and here.

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State Stem Cell & Gene Therapy Agency Sets up Support Program to Help ...

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What is CRISPR? | New Scientist

CRISPR is a technology that can be used to edit genes and, as such, will likely change the world.

The essence of CRISPR is simple: its a way of finding a specific bit of DNA inside a cell. After that,the next step in CRISPR gene editing is usually to alter that piece of DNA. However, CRISPR has also been adapted to do other things too, such as turning genes on or off without altering their sequence.

There were ways to edit the genomes of some plants and animals before the CRISPR method was unveiled in 2012 but it took years and cost hundreds of thousands of dollars. CRISPR has made it cheap and easy.

CRISPR is already widely used for scientific research, and in the not too distant future many ofthe plantsandanimalsinour farms, gardens or homes may have been altered with CRISPR. In fact, some people already are eating CRISPRed food.

CRISPR technology also has the potential to transform medicine, enabling us to not onlytreatbut alsopreventmany diseases. We may even decide to use it tochange the genomesofour children. An attempt to do this in Chinahasbeen condemned as premature and unethical, but some think it could benefit children in the future.

CRISPR is being used for all kinds of other purposes too, from fingerprinting cells andlogging what happensinside them todirecting evolutionand creatinggene drives.

The key to CRISPR is the many flavours of Cas proteins found in bacteria, where they help defend against viruses. The Cas9 protein is the most widely used by scientists. This protein can easily be programmed to find and bind to almost any desired target sequence, simply by giving it a piece of RNA to guide it in its search.

When the CRISPR Cas9 protein is added to a cell along with a piece of guide RNA, the Cas9 protein hooks up with the guide RNA and then moves along the strands of DNA until it finds and binds to a 20-DNA-letter long sequence that matches part of the guide RNA sequence. Thats impressive, given thatthe DNA packed into each of our cellshas six billion letters and is two metres long.

What happens next can vary. The standard Cas9 protein cuts the DNA at the target. When the cut is repaired, mutations are introduced that usually disable a gene. This is by far the most common use of CRISPR. Its called genome editing or gene editing but usually the results arenot as preciseas that term implies.

CRISPR can also be used tomake precise changessuch as replacing faulty genes true genome editing but this is far more difficult.

Customised Cas proteins have been created that do not cut DNA or alter it in any way,but merely turn genes on or off: CRISPRa and CRISPRi respectively. Yet others, called base editors,change one letter of the DNA code to another.

So why do we call it CRISPR? Cas proteins are used by bacteria to destroy viral DNA. They add bits of viral DNA to their own genome to guide the Cas proteins, and the odd patterns of these bits of DNA are what gave CRISPR its name: clustered regularly interspaced short palindromic repeats. Michael Le Page

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What is CRISPR? | New Scientist

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CRISPR-Cas9 Structures and Mechanisms – PubMed

Many bacterial clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated (Cas) systems employ the dual RNA-guided DNA endonuclease Cas9 to defend against invading phages and conjugative plasmids by introducing site-specific double-stranded breaks in target DNA. Target recognition strictly requires the presence of a short protospacer adjacent motif (PAM) flanking the target site, and subsequent R-loop formation and strand scission are driven by complementary base pairing between the guide RNA and target DNA, Cas9-DNA interactions, and associated conformational changes. The use of CRISPR-Cas9 as an RNA-programmable DNA targeting and editing platform is simplified by a synthetic single-guide RNA (sgRNA) mimicking the natural dual trans-activating CRISPR RNA (tracrRNA)-CRISPR RNA (crRNA) structure. This review aims to provide an in-depth mechanistic and structural understanding of Cas9-mediated RNA-guided DNA targeting and cleavage. Molecular insights from biochemical and structural studies provide a framework for rational engineering aimed at altering catalytic function, guide RNA specificity, and PAM requirements and reducing off-target activity for the development of Cas9-based therapies against genetic diseases.

Keywords: CRISPR; Cas9; genome engineering; mechanism; off-target; structure.

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CRISPR-Cas9 Structures and Mechanisms - PubMed

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A CRISPR cure for HIV? Gene-editing technology may be able stop viral replication in its tracks and wipe out infections – Genetic Literacy Project

In July, an HIV-positive man became the first volunteer in a clinical trial aimed at using Crispr gene editing to snip the AIDS-causing virus out of his cells. For an hour, he was hooked up to an IV bag that pumped the experimental treatment directly into his bloodstream. The one-time infusion is designed to carry the gene-editing tools to the mans infected cells to clear the virus.

Later this month, the volunteer will stop taking the antiretroviral drugs hes been on to keep the virus at undetectable levels. Then, investigators will wait 12 weeks to see if the virus rebounds. If not, theyll consider the experiment a success. What were trying to do is return the cell to a near-normal state, says Daniel Dornbusch, CEO of Excision BioTherapeutics, the San Francisco-based biotech company thats running the trial.

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Crispr isbeing used in several other studiesto treat a handful of conditions that arise from genetic mutations. In those cases, scientists are using Crispr to edit peoples own cells. But for the HIV trial, Excision researchers are turning the gene-editing tool against thevirus. The Crispr infusion contains gene-editing molecules that target two regions in the HIV genome important for viral replication. The virus can only reproduce if its fully intact, so Crispr disrupts that process by cutting out chunks of the genome.

This is an excerpt. Read the full article here

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A CRISPR cure for HIV? Gene-editing technology may be able stop viral replication in its tracks and wipe out infections - Genetic Literacy Project

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Editas Medicine Presents Preclinical Data on EDIT-103 for Rhodopsin-associated Autosomal Dominant Retinitis Pigmentosa at the European Society of Gene…

Studies in non-human primates demonstrated nearly 100% gene editing and knockout of endogenous RHO gene and more than 30% replacement protein levels using a dual vector AAV approach

Treated eyes showed morphological and functional photoreceptor preservation

EDIT-103 advancing towards IND-enabling studies

CAMBRIDGE, Mass., Oct. 13, 2022 (GLOBE NEWSWIRE) -- Editas Medicine, Inc. (Nasdaq: EDIT), a leading genome editing company, today announced ex vivo and in vivo preclinical data supporting its experimental medicine EDIT-103 for the treatment of rhodopsin-associated autosomal dominant retinitis pigmentosa (RHO-adRP). The Company reported these data in an oral presentation today at the European Society of Gene and Cell Therapy 29th Annual Meeting in Edinburgh, Scotland, UK.

EDIT-103 is a mutation-independent CRISPR/Cas9-based, dual AAV5 vectors knockout and replace (KO&R) therapy to treat RHO-adRP. This approach has the potential to treat any of over 150 dominant gain-of-function rhodopsin mutations that cause RHO-adRP with a one-time subretinal administration.

These promising preclinical data demonstrate the potential of EDIT-103 to efficiently remove the defective RHO gene responsible for RHO-adRP while replacing it with an RHO gene capable of producing sufficient levels of RHO to preserve photoreceptor structure and functions. The program is progressing towards the clinic, said Mark S. Shearman, Ph.D., Executive Vice President and Chief Scientific Officer, Editas Medicine. EDIT-103 uses a dual AAV gene editing approach, and also provides initial proof of concept for the treatment of other autosomal dominant disease indications where a gain of negative function needs to be corrected.

Key findings include:

Full details of the Editas Medicine presentations can be accessed in the Posters & Presentations section on the Companys website.

About EDIT-103EDIT-103 is a CRISPR/Cas9-based experimental medicine in preclinical development for the treatment of rhodopsin-associated autosomal dominant retinitis pigmentosa (RHO-adRP), a progressive form of retinal degeneration. EDIT-103 is administered via subretinal injection and uses two adeno-associated virus (AAV) vectors to knockout and replace mutations in the rhodopsin gene to preserve photoreceptor function. This approach can potentially address more than 150 gene mutations that cause RHO-adRP.

AboutEditas MedicineAs a leading genome editing company, Editas Medicine is focused on translating the power and potential of the CRISPR/Cas9 and CRISPR/Cas12a genome editing systems into a robust pipeline of treatments for people living with serious diseases around the world. Editas Medicine aims to discover, develop, manufacture, and commercialize transformative, durable, precision genomic medicines for a broad class of diseases. Editas Medicine is the exclusive licensee of Harvard and Broad Institutes Cas9 patent estates and Broad Institutes Cas12a patent estate for human medicines. For the latest information and scientific presentations, please visit http://www.editasmedicine.com.

Forward-Looking StatementsThis press release contains forward-looking statements and information within the meaning of The Private Securities Litigation Reform Act of 1995. The words "anticipate," "believe," "continue," "could," "estimate," "expect," "intend," "may," "plan," "potential," "predict," "project," "target," "should," "would," and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. The Company may not actually achieve the plans, intentions, or expectations disclosed in these forward-looking statements, and you should not place undue reliance on these forward-looking statements. Actual results or events could differ materially from the plans, intentions and expectations disclosed in these forward-looking statements as a result of various factors, including: uncertainties inherent in the initiation and completion of preclinical studies and clinical trials and clinical development of the Companys product candidates; availability and timing of results from preclinical studies and clinical trials; whether interim results from a clinical trial will be predictive of the final results of the trial or the results of future trials; expectations for regulatory approvals to conduct trials or to market products and availability of funding sufficient for the Companys foreseeable and unforeseeable operating expenses and capital expenditure requirements. These and other risks are described in greater detail under the caption Risk Factors included in the Companys most recent Annual Report on Form 10-K, which is on file with theSecurities and Exchange Commission, as updated by the Companys subsequent filings with theSecurities and Exchange Commission, and in other filings that the Company may make with theSecurities and Exchange Commissionin the future. Any forward-looking statements contained in this press release speak only as of the date hereof, and the Company expressly disclaims any obligation to update any forward-looking statements, whether because of new information, future events or otherwise.

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Editas Medicine Presents Preclinical Data on EDIT-103 for Rhodopsin-associated Autosomal Dominant Retinitis Pigmentosa at the European Society of Gene...

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More Foods Will Be Gene-Edited Than You Think – The Epoch Times

Gene editing has long been primarily used for research, treatment, and disease prevention. Currently, this technology is increasingly being applied to modify agricultural products to create more perfect species. More and more genetically edited foods are appearing on the market, including high-nutrient tomatoes and zero-trans-fat soybean oil.

Some argue that gene-edited foods are safer than genetically modified (GM) foods (pdf). The U.S. Department of Agriculture (USDA) specified in 2018 that most genetically edited foods do not need to be regulated. However, are these foods, which will increasingly appear on the table, really risk-free?

In September 2021, the first gene-edited foodSicilian Rouge tomatoesmade with CRISPR-Cas9 technology were officially on sale.

This gene-edited tomato contains high levels of gamma-aminobutyric acid (GABA), which helps lower blood pressure and aids relaxation.

Japanese researchers remove a gene from the genome of the common tomato. After the gene is removed, the activity of an enzyme in tomatoes increases, promoting the production of GABA. The GABA content in this tomato is four to five times higher than that of a regular tomato.

Warren H. J. Kuo, an emeritus professor of the Department of Agronomy at National Taiwan University, explains that both gene editing and transgenic organisms are genetic modification, also known as genetic engineering.

The earliest technique was genetic modification, that is, transgenicin which a plant or animal is being inserted a gene from another species, such as a specific bacterial gene. The purpose of artificially modifying plants and animals is to improve their resistance against diseases and droughts, promote growth rates, increase yields, or improve nutrient content. However, the finished product will exhibit the foreign species genes.

Kuo says that transgenic modification is genetic modification 1.0, while gene editing is genetic modification 2.0. Gene editing is directly modifies the genes of the organism itself, so most of them do not exhibit foreign genes. However, the most common gene editing technique, CRISPR-Cas9, introduces foreign genes as the editing tool, and then removes the transplanted foreign genes.

While gene-edited tomatoes were on the market, Japan also approved two types of fish genetically edited with CRISPRtiger pufferfish and red seabream. These fish are genetically edited to accelerate muscle growth. Among them, the gene-edited tiger pufferfish weighs nearly twice that of the ordinary species.

Back in 2019, the United States had used another earlier gene-editing technique to create soybean oil with zero trans fat and introduced it into the market.

Gene-edited foods which have also been approved for sale worldwide by now include soybeans, corn, mushrooms, canola, and rice.

The number of genetically edited foods on the market is likely to increase. Patent applications relating to CRISPR-edited commercial agricultural products have skyrocketed since the 2014/2015 period.

Proponents ofgenetic modification believe this is a method to perfect agricultural produce and solve problems such as pests, droughts, and nutritional deficiencies. But the technology is still a double-edged sword.

Genetic engineering indeed has its benefits in the short term, but it may bring long-term pitfalls, said Joe Wang, molecular biologist. Wang is currently a columnist with The Epoch Times.

Hornless cattle were once the celebrity of the animal kingdom, appearing in news stories one after another.

Many breeds of dairy cattle have horns, but they are dehorned to prevent them from harming humans and other animals, and to save more feeding trough space. To solve the problem of horns, the gene editing company Recombinetics successfully produced hornless cattle with gene-editing techniques many years ago.

The company simply added a few letters of DNA to the genome of ordinary cattle and their offspring didnt grow horns, either.

However, a few years later, an accident happened.

The FDA found that a modified genetic sequence of a bull contained a stretch of bacterial DNA including a gene conferring antibiotic resistance, which has been one of the global health crises in recent years. Scientists arent clear whether this gene in gene-edited cattle will pose a greater risk than expected or not, and the FDA has stressed that its hazard-free. However, John Heritage, a retired microbiologist from Leeds University, told MIT Technology Review that the antibiotic resistance gene could be absorbed by gut bacteria in cattle and could create unpredictable opportunities for its spread.

In fact, this is one of the currently perceived risks of genetically edited foods.

The problem with unexpected accidents in the genetic modification process occurs in GM foods because transgenic techniques cannot control where the foreign gene is embedded in the chromosome.

Kuo used the example of a study that compared the protein of transgenic soybeans and non-transgenic soybeans. These transgenic soybeans were initially embedded with one foreign gene, and should have had only one protein that didnt exist before. However, the comparison showed that there was a difference of about 40 proteins between the two: Half of the proteins were originally present, but disappeared after transgenic modification; the other half were not present but were added after the transgenic modification.

In contrast, emerging gene editing techniques allow for more precise modification of specific genes (pdf). Its like a tailor modifying a section of a zipper by cutting off a specific segment and replacing it with a new one. However, there may be mistakes and unexpected changes in the process of cutting and repairing, and another similar section of the zipper may also be cut off.

Kuo says that this process may have unforeseen side effects; for example, if during this, new allergy-causing proteins or new toxins are produced.

The genetic engineering procedure, and this includes gene editing, has the potential to damage DNA, said molecular geneticist Dr. Michael Antoniou, head of the Gene Expression and Therapy Group at Kings College London, in an interview in April 2022. If you alter gene function, you automatically alter the biochemistry of the plant included within that altered biochemistry can be the production of novel toxins and allergens that is my main concern.

Another major concern with GM foods is herbicide residue.

Most crops, whether genetically edited or genetically modified, have herbicide-resistant genes incorporated into them. This is done so that when herbicides are applied to crops for weed control, the crops themselves wont be harmed.

When planting herbicide-resistant crops, farmers can use herbicides rather liberally. But, long term, the weeds the farmers are targeting become increasingly herbicide-resistant as well, resulting in a cycle of increased herbicide use and resistance.

Since the introduction of herbicide-resistant GM crops in 1996, herbicides have experienced a significant growth in application every year. The herbicides residue in the crops grown are increasing as well.

One of the most widely used herbicides is glyphosate under the trade name Roundup. The International Agency for Research on Cancer (IARC) classifies glyphosate as a Group 2A carcinogen that is probably carcinogenic to humans.

Massachusetts Institute of Technology (MIT) researcher Stephanie Sene and scientific consultant Anthony Samsel said in their study that 80 percent of GM crops, especially corn, soybeans, canola, cotton, sugar beets, and alfalfa, are specifically introduced with glyphosate resistance genes.

In addition to carcinogenic concerns, glyphosate may have more harmful effects. They have collected and reviewed 286 studies and indicated that glyphosate inhibits the activity of an enzyme in the mitochondria of liver cellscytochrome P450which has the ability to detoxify and decompose foreign toxic substances. Moreover, glyphosate also has adverse effects on the gut microbiota.

These effects are not immediately apparent, but in the long run may contribute to inflammatory bowel disease, obesity, depression, attention deficit hyperactivity disorder (ADHD), autism, Alzheimers, Parkinsons, amyotrophic lateral sclerosis (ALS), multiple sclerosis, cancer, infertility, and developmental abnormalities.

An animal study published in Environmental Health shows that long-term exposure to ultra-low doses of glyphosate still causes liver and kidney diseases in rats.

The debate over whether GM food is safe or not has not yet settled. Many advocates of transgenic modification and gene editing believe that people have been eating GM crops for 20-plus years and still there is no evidence that they have caused problems to human health. Other argue they contribute to long term harm that is still being measured.

Kuo said that GM food is not a highly toxic drug causing immediate problems. Health problems can be the result of something cumulative, and hard to relate back to a single food cause. Whether GM foods are the culprit of such health problems has not been proven, nor ruled out.

At present, various countries have adopted an early warning principle for GM foods, stipulating that merchants label their products. It is the consumers decision to purchase them or not.

Will gene-edited food require specific labeling? Some argue that because these foods do not exhibit foreign genes, there should not be such regulation. Kuo believes this is a misleading argument, given that the tool used to edit the original genes were in fact foreign genes, and the method carries the risk that these foreign genes may not be completely removed.

Currently, the regulations for gene-edited foods in various countries are much looser than those for GM foods.

The USDA has consistently stated that gene-edited agricultural products are not regulated. Plant technologists are usually given the green light within months after submitting inquiries to the agency, allowing them to grow gene-edited foods without oversight.

In addition to the United States, Brazil and Australia and other countries have also adopted similar regulatory approaches. European regulations are still more stringent.

Antoniou argues that since these GM agricultural products are not monitored, the unexpected genes that they carry are released into the environment and will cause harm to it. They may also cause harm to the public due to the scientific communitys insufficient understanding of their risks.

Wang said that scientists who support gene editing believe that what they are doing now will also happen in nature, albeit at a slower pace. They simply speed it up. However, humans are not gods and cannot control everything. When humans do such things, the odds of mistakes and danger are definitely higher than what happens naturally, Wang said.

We humans have violated the laws of nature for a long time, Kuo said.

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Camille Su is a health reporter covering disease, nutrition, and investigative topics. Have a tip? kuanmi.su@epochtimes.com

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More Foods Will Be Gene-Edited Than You Think - The Epoch Times

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Alcor Life Extension Foundation preserves 199 dead bodies in nitrogen – Goa Chronicle

USAs Alcor Life Extension Foundation has claimed that it will soon develop the scientific way to rebirth. The company, in USAs Arizona, has preserved the dead bodies of around 199 people only with the hope that once the technique is developed, they will get respite from their illnesses, and they will come back to life. With this hope of these people getting their lives back, Alcor has reserved their dead bodies in nitrogen tanks and the company calls them patients who lost their lives because of illnesses like cancer, paralysis, amyotrophic lateral sclerosis, etc.

Dead bodies preserved this way are called cryopreserved. Among these bodies, the youngest is that of a Thai child, who had lost her life at the age of 2 because of brain cancer in the year 2015. Alcors CEO, Max Moor has said that both of the childs parents are doctors and despite getting multiple brain surgeries performed on her, nothing helped. Hal Finney, who pioneered bitcoin, is also a patient at Alcor. After he lost his life in 2014 due to paralysis, his body is being preserved here.

The process of cryopreservation is highly different, after the legal announcement of a persons death, the blood and other fluids from the body are ejected out, which are then replaced with special chemicals, which prevent the boy from getting damaged, after which the dead body is preserved in extremely cold temperatures like glass.

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Alcor Life Extension Foundation preserves 199 dead bodies in nitrogen - Goa Chronicle

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Kauai County to hand out thousands of free COVID home test kits – Yahoo News

Oct. 15Kauai County will give out thousands of free home test kits next week at various neighborhood centers.

The county, in partnership with the state Health Department, is offering about 6, 000 COVID-19 tests kits on a first-come, first-served basis, starting Wednesday. There will be a limit of five tests per person or household.

"Mahalo to our partners with the Kauai District Health Office, the Department of Parks and Recreation, and the Kauai Emergency Management Agency for making these free tests available to our community, " said Mayor Derek Kawakami in a news release. "Home test kits are one of the many tools at our disposal to reduce the risk of spreading COVID."

These COVID-19 tests have an expiration date of November 2022, officials said, but have received a seven-month shelf-life extension from the U.S. Food and Drug Administration. They are set to expire in June.

The distribution schedule will be as follows :

Wednesday9 a.m. to noon, Hanalei Neighborhood Center1 to 4 p.m., Kilauea Neighborhood Center Thursday9 a.m. to noon, Waimea Neighborhood Center1 to 4 p.m., Hanapepe Neighborhood Center Friday9 a.m. to noon, Bryan J. Baptiste Sports Complex1 to 4 p.m., Lihue Neighborhood Center COVID-19 testing is also available islandwide on Kauai, with sites listed at.

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Kauai County to hand out thousands of free COVID home test kits - Yahoo News

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