It's Complicated: Docs Say Gender-Questioning Kids Need Better Science

Three separate groups of physicians have recently written to leading medical journals questioning hormonal treatment of children and adolescents with gender dysphoria in countries such as the United States, Canada, Australia, and certain European countries.

They are extremely concerned that current practice is outpacing the science, citing a lack of robust clinical trial evidence to support existing recommendations from groups such as the Endocrine Society, American Academy of Pediatrics, and Royal Children's Hospital Melbourne, which all support "gender affirmation."

If deemed appropriate, this allows for treatment with puberty blockers (also called hormonal suppression) as early as age 11 in children who insist that they are not the gender associated with their birth sex, effectively halting puberty associated with the latter. Most of them then proceed to 'cross-sex' hormones; that is, they will take estrogen if transitioning from male to female (trans female) or testosterone if they are transitioning from female to male (trans male).

Gender reassignment surgery may follow. This used to be reserved for those over the age of 18, but some procedures are now being performed at even younger ages. Just last year, for example, an article published in JAMA Pediatrics described adolescents aged 13 undergoing double mastectomies, transitioning from female to male.^[1]

This issue has come much more to the forefront in the past few years because the number of youth seeking help for gender dysphoria has mushroomed throughout the Western world.

Some healthcare professionals are thus becoming increasingly uncomfortable with how clinical practice in this field is evolving, arguing that it is proceeding without full consideration of potential harms and in the absence of any long-term evidence of benefit. In effect, they contend that some children are being used as guinea pigs in the rush to embrace early medical treatment of many youths with gender dysphoria.

They call instead for psychotherapy, social transitioning (ie, dressing as and passing for the opposite gender), and/or watchful waiting.

Not surprisingly, many in the transgender community, and experts in the field, are skeptical of those who focus on the negative outcomes of the medical treatment involved in transitioning, arguing that such objections put transgender kids at risk for self-harm and mental distress, setting back all of the recent gains made in acceptance of transgender individuals, at least in Western society.

And, they argue, most of these "armchair critics" have little direct experience treating these kids.

But the consequences of not pausing a moment to figure out the path forward could be significant.

"Some teenagers, in the years ahead, are going to rush into physically transitioning and may regret it," warned Jesse Singal in a detailed feature article on the topic published in The Atlantic last year. "Other teens will be prevented from accessing hormones and will suffer great anguish as a result. Along the way, a heartbreaking number of trans and gender-nonconforming teens will be bullied and ostracized, and will even end their own lives," he writes.

Tip of the Iceberg: Number of Transgender Children Grows

Because of the growing number of children presenting with gender dysphoria, specialist clinics in Western countries are often heavily oversubscribed, with long waiting lists.

At the UK Gender Identity Development Service (GIDS), for example, there has been a massive increase in referrals in the past decade or so, as described by Gary Butler, MD, department of pediatrics and adolescents at University College London Hospitals, UK, and colleagues in a leading article in Archives of Disease in Childhood last year.^[2]

In 2017-2018, 2500 children sought care at GIDS, a 25% increase from the previous year and a 50-fold increase from 12 years prior, according to their latest statistics.^[3]

Psychiatrist Annelou de Vries, MD, PhD, of the Center of Expertise on Gender Dysphoria at VU University Medical Center in Amsterdam, the Netherlands — also known as The Dutch Clinic, whose group pioneered the use of puberty blockers for gender dysphoria — told Medscape Medical News that they have seen a doubling of referrals every year. They now have 50 children seeking care per month, or 600 a year, at their one center alone.

Similar increases have been noted in other Western European countries and in the United States, Canada, and Australia.

It is now believed that around 0.5% of children and adolescents will meet the criteria for gender dysphoria and may require medically affirming therapies. de Vries says this indicates that this is just the tip of the iceberg and that gender dysphoria "is not such a rare condition anymore," as greater tolerance develops with regard to gender-diverse expression in Westernized society.

Butler and colleagues observe in their article that the reasons for the exponential increase in referrals of such children "are not fully explicable."

Another intriguing aspect of this phenomenon is the dramatic switch in the ratio of genders of those being referred, particularly in children older than age 11.^[4]

Numerous clinics are reporting that they are seeing a ratio of around three birth-assigned females to every one birth-assigned male, particularly among those first presenting as teenagers/adolescents. In a contentious publication last year,^[5] this was dubbed "rapid-onset gender dysphoria" (ROGD); experts are divided as to whether this represents a new subgroup of patients or not (see Box).

Distress Must Be Taken Seriously, but Powerful Interventions Need Assessment

Voicing concern publicly is contentious by virtue of the fact that the subject of gender dysphoria has become highly politicized.

And yet, a number of groups felt compelled to do so.

In a letter to The Lancet at the end of last year,^[6] Richard Byng, MB BCh, PhD, of the Community and Primary Care Research Group, University of Plymouth, UK, and colleagues wrote, "Distress about gender identity must be taken seriously and support should be put in place for these children and young people, but the impacts of powerful innovative interventions should be rigorously assessed.

"The evidence of medium-term benefit from hormonal treatment and puberty blockers is based on weak follow-up studies," they stress. And guidelines do "not consider longer term effects, including the difficult issue of de-transition.

"Patients need high quality research into the benefits and harms of all psychological, medical, and surgical treatments, as well as so-called wait-and-see strategies," they maintain.

In correspondence^[7] to the Archives of Disease in Childhood, published last month in response to the article by Butler and colleagues, Christopher Richards, MBBS, of the Royal Victoria Infirmary, Newcastle upon Tyne, UK, and colleagues say, "To halt the natural process of puberty is an intervention of momentous proportions with lifelong medical, psychological, and emotional implications.

"We contend that this practice should be curtailed until we are able to apply the same scientific rigor that is demanded of other medical interventions."

And in a similar vein, Michael Laidlaw, MD, and coauthors penned a letter^[8] to the official journal of the Endocrine Society, the Journal of Clinical Endocrinology & Metabolism (JCEM), published online last October and recently in print.

Laidlaw, an adult endocrinologist who concedes that he has never treated individuals with gender dysphoria, told Medscape Medical News, "If we're talking about [transgender] adults [who have gone through puberty of their biological sex] and who can make a decision — if they have been truly notified of the risks and benefits [of cross-sex hormones] and have also had psychological evaluation, and they decide, 'This is still the right course for me,' then I don't have any objection."

But considering the use of cross-sex hormones in children and adolescents is "quite a different story," he contends. 

"The health consequences of gender affirmative therapy [for youth] are not trivial and include potential sterility, sexual dysfunction, thromboembolic and cardiovascular disease, and malignancy," he and his coauthors stated in their letter.  

Especially when "the stated quality of evidence...is low...how can a child, adolescent, or even parent provide genuine consent to such a treatment?"

Affirmative Therapy 'Prevents Mental Distress,' but Little Research Published

Proponents of gender-affirming therapy argue, however, that hormonal treatment of children who have been rigorously assessed and in whom it is deemed that the gender dysphoria will persist, is the best way forward for many to avoid becoming too mentally distressed.

de Vries told Medscape Medical News, "It's really clear that the mental health of children [with gender dysphoria who use puberty blockers] becomes so much better once they start them."

Indeed, their mental health is "so much better than when we wait and see transgender individuals in adult clinics," she emphasized. 

And Joshua Safer, MD, an adult endocrinologist who is executive director of the Mount Sinai Center for Transgender Medicine and Surgery in New York City, and a spokesperson on transgender issues for the Endocrine Society, told Medscape Medical News, "The medical consensus is that harms from short-term puberty blockade and from hormone therapy...seem to be modest, while the harms from failure to treat transgender people are great."

The problem, however, is that there is little published research to support these assertions. Rather, the evidence is anecdotal, although it is garnered from experts who had been taking care of such children and their families for many years.

"More study is desperately needed, but the difference in relative harm already seems quite large," Safer added. 

Pediatric endocrinologist Stephen Rosenthal, MD, from the University of California San Francisco (UCSF), told Medscape Medical News in an interview last year, "It is generally accepted that if young people meet the [DSM-5 diagnosis for gender dysphoria] during early puberty, then they are more likely to be transgender as adults.

"Not intervening is not an option, and saying that we can't do anything until we have the data means we will never do anything and never have the data."

There is some published evidence in support of the gender-affirming approach, albeit very short-term because puberty-blocking therapy was only broadly initiated for this purpose within the past decade.

One 2015 study showed that psychological support and puberty suppression were both associated with improved global psychosocial functioning in adolescents with gender dysphoria.^[9]

And in a 2014 report by de Vries and colleagues,^[10] puberty blocking (at a mean age of 13.6 years) followed by cross-sex hormones (mean age, 16.7 years) and gender reassignment surgery (mean age, 20.7 years) relieved gender dysphoria and improved psychological functioning in 55 young transgender adolescents to the extent that they "were comparable to same age peers," said de Vries.

However, follow-up was only 1-year post surgery, and the researchers noted that "this study did not focus on physical side effects of treatment."

Evidence of Increased Suicide Among Transitioned Adults

Meanwhile, a 2011 study from Sweden^[11] — the only country to have consistently tracked its transgender population — doesn't predict very good long-term outcomes for these individuals, at least not among those who transitioned as adults.

Of 324 adults who had taken cross-sex hormones and had gender reassignment surgery between 1973 and 2003, mortality was doubled among the sex-reassigned persons compared with controls of the same birth sex (adjusted hazard ratio [aHR], 2.1). This was particularly true of deaths by suicide, which were almost 20-fold higher in treated individuals (aHR, 19.1).

de Vries says the Swedish study is comparable to a similar Dutch long-term follow-up study on mortality rates of treated transgender adults, which also found an increased suicide rate.^[12]

"It is difficult to make conclusions from these studies; they show that transgender individuals remain to have mental health difficulties and lifestyle issues after gender-affirming treatment," she told Medscape Medical News.

"[The reasons for that are] not explained by these studies, but an association with stigma, discrimination, and a life-long history of being uncomfortable is likely," she added.

"We can only hypothesize that current referrals and transgender adolescents treated at a young age who grow up in a more supportive environment will have an easier life," she predicts.

de Vries said her team is now planning a long-term follow-up of their 2014 cohort, who were recruited in 2000-2008. "They will be able to report on what life is like for them in their 20s and early 30s."

She stresses that at her clinic no one has yet returned and indicated regret about their choice.

Looking Long-Term: Do Transgender People Change Their Minds?

There are people who have chosen to "de-transition" back to their original gender. Such individuals often post online anonymously, but more and more are now choosing to go public.

James Caspian, UKCP, a psychotherapist from the UK with 10 years' experience in treating transgender adults, has tried unsuccessfully to conduct a research project on this group of individuals. "I [initially] enrolled at Bath Spa University [in the UK] to do a Master's thesis on the experiences of people who had reversed gender assignment surgery," Caspian told Medscape Medical News.

It was, however, "difficult to get people who had reversed their surgery to talk," he explained. He later amended his project to include a number of young women, primarily from the United States, with whom he had communicated online, who had reversed their gender transition [from female to male and then back again] but without necessarily reversing any surgery.

"At that point, the university said they couldn't continue with the research...because it might attract criticism [from the trans community] on social media. This is a conversation that is being suppressed — this is a conversation that needs to be had," he says.

Caspian used crowdfunding to challenge the university's decision to veto his research. After battling for more than 2 years, he has won the right to a first hearing at the High Court in London, to be held on February 19.

Caspian says that the problem with statistics on long-term outcomes among transgender individuals is that these people tended to disappear, at least until recently. "No clinic has kept tabs on their patients," he says.

In the only country to have done so, Sweden, a 2014 study of several hundred adults who had undergone sex reassignment surgery indicated that 2.2% of individuals regretted their choice.^[13]

Puberty Blockers Limit Fertility; Concerns About Bones, Brains

Puberty blockers have traditionally been used by pediatric endocrinologists to delay precocious puberty in young children and stopped when they reach an appropriate age to enter puberty, allowing them to progress through this change at a similar time as their peers.

But Laidlaw contends that just because puberty blockers appear safe in precocious puberty it is a "terrible justification" for using them in children with gender dysphoria.  

"One of the reasons we wrote the letter to the editor of JCEM...is because what I'm seeing from proponents of 'affirmative care' is that no one is talking about the harms of stopping puberty. There is a dearth of questioning."

Transgender children can begin puberty blockers as early as Tanner Stage 2 (around age 11, although it can be younger), which means that they will not undergo sperm maturation or ovum release. If they then proceed straight to cross-sex hormones to transition to their desired gender, they will "have no prospect of biological" children, as Laidlaw and his colleagues point out in their letter.

In 15 or 20 years' time, they may regret this decision, argues Laidlaw.

de Vries acknowledges that fertility is a very thorny subject. "Most [transgender children and adolescents] will say, 'I don't want to have children anyway, or I will adopt.'"

"It is a problem to figure out at what age, if any, they are mature enough to make this kind of decision that will impact upon their future," she told Medscape Medical News. 

Indeed, research shows that even among adolescents receiving gender affirming therapy for whom fertility preservation is a possibility, only 5% will attempt it.^[14]

Similarly, such children will not have normal sexual function as adults, Laidlaw argues. "When you have someone who is stunted at an early age of genital growth, you are not going to have normal adult sexual function. Can you really make a choice about that at that age?" he commented.

There are also important questions about the effects of puberty blockers on bone health and the development of the adolescent brain; very little long-term research has been done on either of these outcomes.

Work is ongoing, and several academic groups worldwide are following their pediatric patients with gender dysphoria, as UCSF's Rosenthal explained to Medscape Medical News last year. "On the one hand, it's important to do the best we can with the information available. On the other, it is the responsibility of academic centers to conduct progressive research to discover what is best for our patients."

However, long-term results will not be known for some time.

Puberty Blockers Versus Watchful Waiting

It is thought that around 60% to 70% of children attending gender dysphoria clinics are referred for puberty blockers, although exact figures are difficult to come by.

Ken Zucker, PhD, CPsych, a psychologist from the University of Toronto, Ontario, Canada, who has treated transgender children for many years and whose group was the first to use puberty blockers in North America, told Medscape Medical News, "When we in our Toronto clinic published a study in 2011, the percentage of adolescents [attending our clinic] that we were recommending for hormonal suppression [puberty blocking] was about 60%."

"But now, in 2019, what percentage of children and adolescents across all the [gender identity] centers [in the Western world] are being recommended for hormonal [puberty] blockers? I don't know," he acknowledged

Laidlaw and colleagues — and the authors of the other letters — argue that there is another way, citing evidence of social transitioning or "watchful waiting" relieving much of the psychological distress associated with gender dysphoria.

Existing care models based on psychological therapy "have been shown to alleviate gender dysphoria in children, thus avoiding the radical changes and health risks of gender affirming therapy. This is an obvious and preferred therapy, as it does the least harm with the most benefit."

But, says de Vries, using the term "watchful waiting", at least when referring to adolescents, is "confusing." 

It is a phrase that she and her colleagues coined back in 2011 and "that was primarily used...for prepubertal children who were [back then] advised not to socially transition at a (very) early age but to wait until the first signs of puberty evolved,” she explained. 

And Zucker stressed that, in adolescents, "there is no evidence that 'watchful waiting' relieves the distress."

And similarly in adolescents who go through the puberty associated with their birth sex, social transitioning per se does not always "alleviate the incongruence between the felt gender and somatic sex, particularly in girls who have large breasts or boys who are virilized (body hair, deep voice, etc)," he explains. 

Yet Laidlaw and colleagues go on to say that in many instances children who have gone through natural puberty will "desist" from their gender dysphoria, eventually accepting their birth sex. "Our concern is that the use of puberty blockers may prevent some young people with gender dysphoria from finally becoming comfortable with their birth sex."

Richards and colleagues concur, saying in their letter that use of puberty blockers "leaves a young person in developmental limbo without the benefit of pubertal hormones or secondary sexual characteristics, which would tend to consolidate gender identity."

Zucker says he can "see the argument a bit" when it comes to blocking puberty from a very young age. "Why not give the adolescents at least some time to experience puberty as opposed to suppressing it from the get go?" But, he stresses, "this is a complex matter."

"Armchair Critics" Lack Experience Treating Transgender Kids

When gender-questioning children end up becoming comfortable with their birth sex, this is known as desisting from gender dysphoria, and there is much debate as to what percentage of kids who have been referred to a gender identity clinic will eventually desist and what number will "persist" in their gender dysphoria.

Published figures for desistance vary from 60% to 100% of kids referred to such clinics.

However, some say that these numbers are wide open to interpretation because it depends on which kids you use as your baseline research group.

Drilling down into those whose gender dysphoria has persisted for some time despite psychotherapy and other approaches will reveal lower percentages of children who eventually change their minds, they argue.

Zucker says, "If I was seeing an 11-year-old for the first time who had not started to develop gender dysphoria until the last couple of years and had never had any type of psychotherapy to explore their gender identity, I would want to know a lot more about that kid [before recommending puberty blockers]."

But "suppose you had a child who, for whatever reason, had socially transitioned at age 4 — and who had persisted in their gender dysphoria until age 11, and then entered puberty and was feeling distressed about his or her developing body, then given the long history of gender dysphoria, I can see making an argument for hormonal suppression [puberty blockers], as it's very unlikely that the gender dysphoria is going to go away."

And it is precisely these kids — the ones who 'persist' in their gender dysphoria — whom experts in transgender care believe will benefit most from puberty blockers.

Zucker adds that "as much as I understand their concerns, one of the big problems I have with" Laidlaw et al and others "is that they are armchair critics, with little direct experience with this population."

But Laidlaw, who does acknowledge he has never treated youth with gender dysphoria, pointed out to Medscape Medical News, "We are opening this up to the whole world of pediatric endocrinologists, nurse practitioners, physician assistants [and others]."

Will they be able to properly ascertain who is going to persist in their gender dysphoria, he wonders: "Do they all have this special ability?"

He is also concerned that not all gender identity clinics popping up, particularly in the United States, may be so scrupulous in their assessment criteria. There are now approximately 50 such multidisciplinary gender identity clinics, mainly in the Northeast and on the West coast. But other smaller clinics exist, too, and he is afraid that greed might potentially blind some healthcare professionals in this field.  

UK Adopts "Gatekeeping" Approach

Meanwhile, back at GIDS in the UK, Butler and colleagues are proceeding a little more cautiously than many other institutions around the world; approximately 40% of youth receiving care in their service will ultimately be referred to their endocrine clinic. 

These "are...precisely the [kids] most likely to persist in their atypical gender identity, as they have only been recommended for medical assessment following a thorough period of exploration in which the likely stability of their gender feelings has been established by the psychosocial team," they observe in a recent editorial^[16] written in response to the letter by Richards and colleagues.

"Puberty blockade is only considered when the risks of nonintervention are considered the worse option in the patient's best interest. Risks are always fully explained, including any potential effect on emotional development and decision making, and the effects on reproduction," they explain.

The UK physicians also differ in the percentage of children on puberty blockers that they immediately transition to cross-sex hormones, thought to be 90% to 100% at most gender identity clinics.

"We do not go directly to prescribing cross-sex hormones, as is the practice in some European countries [for kids] from age 15 years, and even as young as 14 years in the United States."

"We do not think it is advisable without good supportive evidence to go straight into irreversible treatment."

"We know the blocker is reversible physically, buys time, and reduces distress. We also do not know the comparable risks of being on cross-sex hormones, started early and continued for a lifetime," they concede.

"Therefore, we continue to adopt a cautious 'gatekeeping' approach with detailed scientific observation until we know more."

More Open Discussion Needed

Medscape Medical News contacted a number of pediatric endocrinologists who are experts in gender dysphoria in children for the purpose of this article, as well as the European Association for Paediatric Endocrinology (ESPE) and Pediatric Endocrine Society in the United States.

Bar one brief email response, none responded to requests for interviews.

And herein lies the rub, says Laidlaw, who told Medscape Medical News that his "main aim" in writing to JCEM "is to open up a discussion about what is the optimal way to diagnose these children and to have a look at potential harms of hormonal therapy that aren't being addressed."

"Myself and other colleagues who wrote the letter — and others we know — would like to have a discussion at an Endocrine Society meeting [or similar], where people from both sides of the table can hash this out together...outside of the political realm."

Butler told Medscape Medical News in an email: "It's good that this is debated, but the constant slagging match initiated by do-gooders is unhelpful."

"Science is certainly taking place under my watch, but we need more funding and support."

Rapid-Onset Gender Dysphoria: A Different Subgroup of Kids? The dramatic switch in natal gender of those being referred to gender dysphoria clinics in recent years has been noted by a number of groups. In many places, they are seeing three born females who wish to transition to males for every one born male who wishes to transition to female. Some experts in the field believe that this cohort represents a new subgroup of youth, so-called rapid-onset gender dysphoria (ROGD), but others vehemently disagree. Zucker told Medscape Medical News: "I published in 2015 with the Dutch the first study documenting the change in the sex ratio.[4] It's an amazing social phenomenon that cuts across the Western world. It's unbelievable. There are some clinics with a female-to-male ratio of six to one. It's fascinating." "In my view, this is a subgroup of adolescents — who can be described as late-onset or 'ROGD' — who are very different from the adolescents we have seen over the years, where it was very common for them to have an early onset history of gender dysphoria that persisted into adolescence." "According to the parents [of this new subgroup], and certainly when one interviews the adolescents, a lot of them will say, 'No, I didn't really think about or struggle with my gender identity as a child.'" "So, what if you didn't have gender dysphoria in childhood — what predicts it in these late-onset kids? There are many factors that people need to look at, whether it's co-occurring autism-spectrum disorder or some general psychosocial vulnerability where these kids feel that they just don't fit in and they are looking for a place to find themselves. "Or if they have pervasive mental health problems that are making them feel bad about themselves and they are looking for a way to feel better. "These things need to be looked at carefully before deciding what is the best way to help them," he asserts. "We have no idea if the current standard of practice guidelines, such as considering the role of hormonal suppression, should be easily transferred over to these late-onset kids because we know much less about whether these kids are going to persist [in their gender dysphoria] at the same rate as the more classical kids." "For clinicians who specialize in this area to not think about the fact that this may be a new subgroup of kids with different contributing factors would be a mistake," he asserts. Butler and colleagues at the UK GIDS, too, write in their editorial: "We, as a service, are especially watchful" around this "later-presenting, more troubled group of birth-registered female teens." They go on to cite a study from Finland[16] that shows severe psychopathology commonly precedes the onset of gender dysphoria among these later-presenting born females. "Autism spectrum problems were very common. The findings do not fit the commonly accepted image of a gender dysphoric minor," the Finnish researchers stated. However, the article that originally coined the term ROGD[5] has been criticized because it was a survey of parents, not the children themselves. The Endocrine Society's spokesperson, Safer, reiterated to Medscape Medical News the viewpoint he first expressed last year when this study was published. "There are no data" to support the concept of ROGD. Rather, the article "is a report of a survey of a convenience sample of fearful parents who are worried that there might be such an entity."

Campion, de Vries Laidlaw, and Zucker have reported no relevant financial relationships.

Follow Lisa Nainggolan on Twitter: @lisanainggolan1. For more diabetes and endocrinology news, follow us on Twitter and on Facebook.

Medscape Medical News © 2019 

Cite this: It's Complicated: Docs Say Gender-Questioning Kids Need Better Science - Medscape - Feb 15, 2019.