For as long as his parents could remember, 12-year-old Jack acted “female.” He favored Barbies over Transformers, often wore his sister’s underpants, and refused to use urinals.

Similarly, the mother of 14-year-old Janice cannot remember a time when her daughter did not dress androgynously—preferring short haircuts, boxer shorts, and extra-tight sports bras.

Like many young adolescents, Jack and Janice are uncomfortable with their bodies. However, their anguish runs a lot deeper. At 10, Jack attempted to leap out of a rapidly moving car. Janice has had repeated episodes of cutting herself with a razor blade.

Separate psychologists working with Jack and Janice confirmed that the teens have gender identity disorder (GID) and are possibly transgender, a catch-all phrase for individuals whose gender identity is different from their biological sex.

Increasingly, pediatricians and psychologists are challenged by cases like Jack’s and Janice’s in which kids want to be the opposite gender. It is an emotional and confusing time for the family and the children, who often are on the cusp of puberty at the very time they are reject ing their biological gender. One solution specialists recommend is puberty blockers, drugs that delay the onset of puberty and give the children time to sort out their gender identity.

“Pediatric endocrinologists are the only specialists who see children and adolescents who require pubertal blocking drugs in the course of regular practice,” said Norman Spack, a pediatric endocrinologist at Boston Children’s Hospital whose practice mainly focuses on transgender youth. “If they do not get involved in cases where they can be helpful, it is unlikely anyone else will.”

In the course of their practices, pediatric endocrinologists typically use drugs that delay puberty, such as gonadotropinreleasing hormone (GnRH) analogues, to treat conditions such as central precocious puberty and congenital adrenal hyperplasia. The drugs have a good track record, with 30 years of follow-up data showing them to be safe and effective. For transgender patients, the verdict is still out; as transgender patients enter adulthood, data are trickling in as to the benefits and risks of these drugs.

Deciding to treat with such drugs may not be an easy choice, Spack admitted. “It is difficult for pediatric endocrinologists to grasp the idea of treating a child who otherwise seems perfectly normal and may not reveal his/her mental suffering and risk of self-harm. It is all too easy to turn away referred patients with whom the physician has no prior relationship and whose condition may be considered psychiatric.”

Gender fluidity is common among children, but it typically crystallizes during the teenage years. Among preadolescents whomanifest GID traits, 80 percent will “desist” from being transgender before entering adolescence, according to Kenneth Zucker, Ph.D., of the University of Toronto. Half or more of the youths will go on to identify themselves as gay or lesbian.

Despite increased coverage in the popular press, the prevalence of transgenderism is quite low—about one in 10,000–30,000, according to the fourth edition of the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders (DSM IV).

In a recent commentary in Pediatrics, Walter J. Meyer III, a psychiatrist at the University of Texas Medical Branch in Galveston, Texas, whose practice includes young patients with gender identity issues, cautioned pediatricians not to be so quick to diagnose transgender conditions.

“Many of the presentations in the public media concerning childhood GID give the impression that a child with cross-gender behavior needs to change to the new gender or at least should be evaluated for such a change,” he wrote. “Very little information in the public domain talks about the normality of gender questioning and gender role exploration and the rarity of an actual change. The burden of that education is going to fall on the pediatrician.”

Once the pediatrician verifies GID, other specialists need to weigh in.

“Pediatric endocrinologists should work with a mental health professional who will support this diagnosis or who can vet the patient for this diagnosis,” Meyer said in an interview with Endocrine News.

Transgender is not a mindset, it is a condition that is most likely hardwired into a person from the onset.

“A transgender patient says ‘change my body, not my mind,’” explained Milton Diamond, a sexologist with a research focus on transitional and intersex conditions. “A therapist tries to get them to think they’re delusional and they don’t think they are.” Diamond says transgenderism is in a person’s genes. In his research on transexuality in twins, he has found that among identical twins, if one transitions, the other does also in about 40 percent of the cases. With fraternal twins, this usually does not happen—only 4 percent of these twins do.

His studies have also shown that transgenders’ brains are more similar to the gender they want to be than to their biological gender.

“Experiments show that just the way people are rightor left-handed, individuals that are transgender are shown to hear and smell like their preferred gender,” added Diamond. (Except for taste and touch, men generally underperform in the sensory department compared with women.)

Spack, who co-directs the Gender Management Service, or GeMS, at Boston Children’s Hospital, one of the United States’ first gender identity pediatric clinics, champions early treatment before patients reach adulthood.

During his 40-year career, he says he has treated some 200 adult transgender patients who would have benefited from biological clock-stopping drugs. Male-to-female adult patients often suffer physically and psychologically—battling male pattern hair loss, undergoing voice training, having their thyroid cartilage shaved to remove their Adam’s apples, and feeling stuck in a body that’s too big for a typical female. The late transformation can also be expensive. Patients spend thousands of dollars on hair removal, breast augmentation surgery, and facial feminization surgery.

When American women transition to men at an adult age, their height is typically 5 feet 4 inches, considerably below the mean of 5 feet 10 inches for men. Such patients would have menstruated monthly for years and would face complicated breast reduction to attain a flat chest with an appropriately located areola and nipple.

The lack of availability of medical services for transgenders 20 years ago was “a wasteland,” Spack told a packed audience at ENDO 2012 in Houston. In 2009 he co-authored The Endocrine Society Guideline that recommended the use of GnRH analogues in prepubertal, Tanner Stage 2 children and lifetime use of sex-changing hormones with monitoring for potential health risks.

“There was an attitudinal shift to be able to say that The Endocrine Society supports this,” said Spack. Today a dozen pediatric endocrinology transgender programs exist in the United States compared with two or three a few years ago.

Although attitudes about treatment are changing, Spack said transgender kids are not being treated soon enough. In his own practice, he advocates starting puberty blockers earlier than in the Society guidelines of under the age of 16. The best age for boys, he says, is 12–14 years, while they are at Tanner Stage 2, and have a testicular volume of 4–6 cc; girls should come in younger, at age 10–12 years, with Tanner Stage 2 breast development.

“If a biological female comes in at 15, she’s physically a woman and may have been menstruating for three years,” he said. She would have already reached her peak height, which might have been augmented with earlier GnRH analogues. If she starts blockers at ages 10-13, she would not need a mastectomy because Tanner 2/3 breasts recede with treatment.

“It’s becoming clear that the most desirable physical result with the least physical intervention is to prevent pubertal progression in the first place,” Spack said.

Adult transgender genotypic males outnumber genotypic females by a three-to-one ratio while in cohorts under age 21, the sex ratios are equal, he said. The reason for the disparity among transgender adults is mostly cultural; most Westernized countries accept women who are “masculine” in looks and behavior, so a girl may have more difficulty in identifying the depth of her feelings or convincing family and doctors of them.

Spack’s GeMS program is modeled after the Dutch program that was created by Peggy Cohen-Kettenis, Ph.D., in Amsterdam. The premise of both programs is to treat the patient’s natural puberty like an unintended precocity. Dutch physicians administer GnRH analogues to patients at Tanner Stages 2–3, in an attempt to buy more diagnostic time and ensure that patients really want to transition to the other gender.

If at age 16, patients decide to proceed with the transition, they are put on cross-sex steroids such as testosterone and estradiol. The next step is gonadectomies (e.g., oophorectomy, hysterectomy, feminizing genitoplasty with orchiectomies), surgeries that cannot be lawfully performed in the Netherlands and North America until patients are 18. Mental health counseling is continuous and formal evaluations take place at each major decision point in the process.

Before entering Spack’s program, patients must be between Tanner Stages 2and 5 (10 years or above for boys and 9 years or above for girls) and have been in counseling with a gender therapist for six months. The therapist is required to write a referral letter recommending pharmacologic endocrine intervention and stating that other than depression and anxiety associated with gender nonconformity, the patient has no severe psychopathology. Patients must also have the support of both custodial parents.

Once these requirements are established, Spack and his interdisciplinary staffof endocrinologists, urologists, gynecologists, geneticists, psychologists, medical ethicists, and social workers are called into action. Candidates for medication undergo a rigorous five-hour battery of psychological tests and a physical examination to determine pubertal stage.

In his ENDO 2012 lecture, Spack explained that before Tanner 2, most patients are willing to live in both genders. “It’s hard to distinguish whether they will desist or persist in becoming transgender and there is no litmus test before Tanner 2 puberty,” said Spack. Very few of his patients or those in the Dutch program decide to stay their biological gender after beginning pubertal blockers. The Dutch have treated more than 100 patients with GnRH who have reached over 18 years of age. Spack has seen 105 new patients ages 10-19 since 2007; more than a third of his patients (40) have been Tanner Stage 2–3 and have received GnRH treatment.

Once the psychiatrist and endocrinologist have given the greenlight, the patient begins with one of several GnRH analogues, either a depo injection of Leuprolide that lasts one to three months or an inch-long implant of Histerlin that lasts two years. The latter shuts down gonadotrophic secretion very quickly—within a couple of weeks. The patient undergoes a state of biologic limbo, in which secondary sexual characteristics such as breast budding, testicular enlargement, and axillary and torso hair growth are halted. Height and bone mass, however, still proceed at a pre-pubertal rate.

Usually between ages 14 and 16, patients still look prepubertal compared with the maturity of their peers. Although the delay can be psychologically challenging for the patients who may desire to look like their preferred genders, the slowdown gives them an opportunity to reconsider the transition. GnRH analogues are reversible. Cessation of them usually results in patients restarting their genetically intended puberty within six months.

Although the treatments are considered safe, they are not risk-free. Most transgenders become infertile as a result of the hormonal switching medications. Estrogens diminish sperm production in males, and testosterone’s cessation of menses can cause polycystic ovaries in women; these changes usually lead to infertility. Some late-pubertal male patients have opted for sperm banking, but equivalent options for women are limited. Egg freezing is an arduous and expensive procedure requiring ovarian hyperstimulation with HCG, akin to women undergoing in vitro fertilization, and not as likely to be successful, especially if the ovaries are immature when GnRH-suppressed.

“It’s hard to have a conversation about fertility when the patient is 12 or 14 years old,” said Spack. “It’s important for patients to continue to be in psychotherapy during this long diagnostic phase so they can fully understand the implication of taking cross-steroids, even though they are waiting anxiously to get them.”

Another risk is cancer. Girls who have breasts and undergo testosterone treatment need regular mammogram screening as adult men; those who have their uteruses while on testosterone may develop endometrial cancer. Both risks can be mitigated by surgical removal of the organs.

Among the arguments for using pubertal blockers to gain more diagnostic time is that patients will not need as many cross-sex hormones later in the transition process. Fewer estrogens in patients means a decreased risk of blood clotting and pulmonary embolism; fewer androgens reduces the likelihood of hypertension. Another plus, Spack said, is that most male-to-female adult patients who took GnRH analogues end up with appropriate size breasts for their frame and never feel the need to have further reconstructive surgery.

For Jack and Janice, not having options may be a case of life and death. According to Youth Pride Inc., a U.S. advocacy group for lesbian, gay, bisexual, transgender, and questioning youth, about two thirds of transgender youth have reported being verbally, physically, and sexually attacked by either their peers or an adult family member, and one third have attempted suicide.

“A lot of people are concerned that delaying puberty may cause some harm,” said Meyer. “On a whole, much less harm is done by giving blockers than by not giving blockers.”

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