Clinicians Push for Increased Study of Gender-Affirming Care

As the Supreme Court considers individual states’ ability to prevent puberty blockers and hormone therapy for gender-diverse youth, clinicians advocate for more research on the best ways to treat this population.

Current guidelines developed by the World Professional Association for Transgender Health (WPATH) and the Endocrine Society are based on what is considered weak evidence, leaving some clinicians to make their own determinations on how to provide care for gender-diverse youth.

For instance, the recommendations for stepping up doses of gender-affirming hormones at different stages of puberty in the guidelines are a weak spot, said Ralph Vetters, MD, MPH, medical director, Sidney Borum Jr Health Center at Fenway Health, Boston.

Following these recommendations is “impossible to do,” Vetters said. His clinic developed its own protocols.

Current guidelines recommend starting with minimum doses and increasing slowly — much slower than a natal puberty. This recommendation would put trans kids developmentally behind their peers, he said. To create their own dosing schedule, Fenway Health clinicians collaborated with endocrinologists who prescribe hormones to adolescents with nonfunctional gonads.

More research is needed to better inform clinicians on how to treat gender-diverse youth and provide additional evidence for clinical guideline updates, Vetters said. Such research also could better equip physicians to inform patients and their families about treatment during adolescence and beyond.

The Endocrine Society guidelines were cosponsored by the American Association of Clinical Endocrinologists, the American Society of Andrology, the European Society of Endocrinology, the European Society for Paediatric Endocrinology, the Pediatric Endocrine Society, and WPATH. Other medical associations expressing support for gender-affirming care for youth include the American Academy of Pediatrics, the American Medical Association, and the American Psychiatric Association.

All have issued statements denouncing the politicization of the issue, insisting gender-affirming care is a medical issue.

Despite the support from the medical community, restrictions or bans against gender-affirming care have been established in 26 US states and in some countries, and continue to be foremost among the challenges complicating the situation for physicians and their patients.

On January 28, President Donald J. Trump signed an executive order banning transgender care to those less than 19 years old. This order specifically prohibits the use of puberty-blocking hormones and surgical procedures “that transform an individual’s physical appearance to align with an identity that differs from his or her sex.”

The order also cited the WPATH guidelines as lacking “scientific integrity,” and stated that agencies shall “rescind or amend all policies that rely on WPATH guidelines.”

On March 4, a federal judge extended a nationwide block on Trump’s executive order stopping federal funding for those providing gender-affirming care for patients less than19 years.

The Research Clinicians Want to See

Although the political issues remain, clinicians agree there is a need for additional research for this population. Specifically, research addressing the effect of puberty blockers on bone density, how gender-affirming hormones affect adult height, how hormone therapy affects the brain, how high-risk behaviors like vaping impact trans youth, and how to best counsel transitioning youth on fertility preservation.

A Wisconsin-based pediatric endocrinologist, who asked to remain anonymous, said she would be excited to see additional prospective studies but disagreed about the need for more guidance on gender-affirming hormone dosing because individual needs vary. For example, some youth may be more sensitive to testosterone therapy than their peers and need a lower dose.

“I don’t think there is a one-size-fits-all standard recommendation around how quickly one should step up hormones,” she said.

Endocrinologists should rely on their own expertise and that of their collaborators, she added.

Kade Goepferd, MD, a pediatrician and medical director of Children’s Minnesota Gender Health Program in Minneapolis wants to see research on the well-being of gender-diverse youth who live in states that ban gender-affirming care compared with those who don’t.

That research is just beginning to be published, with one recent study showing that anti-transgender laws, including those limiting access to gender-affirming care, cause an increase in suicide attempts in transgender and nonbinary youth aged 13-17 years.

“What we need to combat a lot of the legislative attacks and misinformation is some good data on how that’s impacting the health of kids,” Goepferd said.

According to the Wisconsin endocrinologist, one area that doesn’t need more research is the need for care. “There’s plenty of excellent data that says having gender-affirming medical care available to adolescent patients saves lives and is an important part of healthcare, just like any other aspect of healthcare that we provide to youth.”

Both the WPATH standards and the Endocrine Society guidelines, updated in 2017, support social transition in prepubescent gender-diverse children. They agree that providers should consider puberty blockers for gender-diverse adolescents at the onset of puberty to delay irreversible changes like breast development or voice deepening. They also recommend gender-affirming hormone therapy and some, but not all, types of gender-affirming surgery to treat transgender youth with persistent and consistent gender dysphoria. Both emphasize the need for individualized treatment plans rather than a one-size-fits-all approach.

The American Academy of Pediatrics guidelines, which are currently being updated, are fairly consistent with those from WPATH and the Endocrine Society.

However, the Cass Review, published in April 2024, gained attention for making recommendations conflicting with widely accepted medical society guidelines. It criticizes many of those guidelines as too often relying on weak evidence, including the results of studies that aren’t randomized control trials (RCTs). The UK’s National Health Service, which commissioned the review, has used it to justify a national ban on puberty blockers. It contends that the treatment has “very substantial risks and very narrow benefits.”

Challenges in Research for Trans Youth

Although RCTs typically get high ratings for the quality of their evidence in clinical guidelines, they are difficult to run in the field of gender-affirming care.

“RCTs aren’t always appropriate,” said Ken Pang, PhD, a pediatrician who works with trans kids at Royal Children’s Hospital in Melbourne, Australia, and co-author of the Australian Standards of Care guidelines. For instance, many, if not most, RCTs involve blinding patients so they don’t know whether they’re receiving treatment or a placebo.

“It’s going to be pretty clear, pretty soon whether or not you’ve received the placebo or the treatment,” he said. “If participants realize they aren’t receiving the treatment they desire, there’s a real risk they will drop out of the trial and distort its results.”

Experts also say that RCTs aren’t just difficult to run on trans kids, they might be unethical.

“You’re dealing with a population who is usually in extreme distress when they come in,” said Eli Coleman, PhD, professor emeritus and former director of the Eli Coleman Institute for Sexual and Gender Health at the University of Minnesota, Minneapolis, and past president of WPATH. “When you know that these gender-affirming procedures are effective, to not give them to that control group is a real ethical dilemma.”

Additionally, because these treatments are considered safe and effective, very few trans youth would opt into a study where they might receive a placebo rather than going to a doctor for treatment. For the same reason, many RCTs aren’t conducted in pediatrics generally, so gender-affirming care for trans youth is far from alone in not having support from RCTs, according to the Wisconsin pediatrician.

If enrolling in a RCT is the only way to have a chance at receiving a treatment, as is the case for gender-diverse youth and puberty blockers in England, kids who need it have no choice but to opt into the study, Pang said.

“If your only way of getting blockers is via a research trial, that’s coercive,” he said.

A core tenet of medical research is that researchers should not coerce patients into studies, Pang added.

Coleman considered multicenter longitudinal studies that follow trans youth across the country as they grow up to be the best option for studying gender-affirming care. Unfortunately, not many of these observational studies are available because historically there wasn’t much funding for research on trans youth health, he said.

The National Institutes of Health recently funded one such study in the United States, and the first results from 2 years of follow-up were published in 2023, namely that appearance congruence and life satisfaction increased and depression and anxiety symptoms decreased in the first 2 years after starting hormone therapy.

However, Trump’s budget cuts already have hit healthcare grants for transgender patients, and broader scientific research funding cuts would inevitably affect studies on transgender health.

A few longitudinal studies from countries with centralized healthcare records also show the benefits of gender-affirming care. Clinical guidelines usually don’t count these studies as providing high-quality evidence, although they “supply most of the evidence that guides clinical care across all fields of medicine,” according to a recent report from Yale Law.

Indeed, the Endocrine Society guidelines rate the quality of the evidence backing puberty blockers and hormone therapy for those aged ≥ 16 years as low and hormone therapy for those younger than 16 years as very low.

But low-quality evidence isn’t unusual for informing pediatric care guidelines, or medical guidelines in general, states the Yale Law report, which was written by gender-affirming care experts as a critique of the Cass Review report and its methodology.

“Pediatric care would all but cease if physicians denied treatments for which the evidence base is imperfect,” the authors wrote. Additionally, the quality of evidence in 52 areas of medicine, from breast cancer to obstetrics to stroke, is often not high, they noted.

As researchers publish more studies, the evidence quality for gender-affirming care will increase. But in the meantime, guideline writers must work with what they have. And they can do a lot, even without high-quality evidence, Coleman said.

Other Factors Shaping the Guidelines

Although evidence plays a crucial part in the development of clinical guidelines, it is just one of the criteria that expert panels use to write them.

“We don’t determine best guidelines or best treatments simply based upon what is considered the highest-quality evidence,” Coleman said. “Most of what [doctors] do is based upon their expert opinion and what is considered, in technical language, low-quality evidence. But it doesn’t mean that that is not the best way to treat it.”

In developing guidelines, expert panels also consider the stakeholder opinion and the risks and benefits in providing treatment or not. Both are relevant in the gender nonconforming patient population, according to the Yale Law report; for example, the stakeholder opinion — in this case, the values and preferences of trans youth — favors greater access to gender-affirming care.

Treatments for this patient population present unique benefits and risks that must be balanced. For example, puberty blockers offer benefits, including time during which patients can move through life in the experienced gender before proceeding with partly irreversible hormone therapy or their natural course of puberty, psychological advantages, and improved physical outcome compared with patients who start their transition after puberty has been completed.

But treatment also comes with risk. For example, there is the potential for lower bone density with puberty blockers or an increased risk for cardiovascular issues from hormone therapy.

Not providing treatment also presents risks, such as mental health problems and a higher risk for suicide.

Another potential risk is regret on the part of children after their medical transition. However, this outcome appears uncommon, according to Meredithe McNamara, MD, MS, an adolescent medicine specialist at the Yale School of Medicine, New Haven, Connecticut, and lead author of the Yale Law report.

“We have the highest rates of adherence, continuation, and satisfaction with care than any other field of medicine that I’m familiar with,” McNamara said.

However, in its key findings, the Cass Review, which has been widely criticized by trans patient advocates, contended that the “strengths and weaknesses of the evidence based on the care of children and young people are often misrepresented and overstated, both in scientific publications and social debate.”

Whether the potential benefits outweigh the risks is an individual decision. Providers don’t just take the guidelines at face value, McNamara noted.

“We don’t use guidelines to rotely prescribe care,” McNamara said. “We use guidelines to inform shared decision-making discussions with patients. And we know that there’s no document that uniformly applies to every individual perfectly.”