GFINAL DYSPHORIA– the terrible feeling of being at odds with one’s sex – is one of the fastest growing medical complaints among children. America had a pediatric gender clinic in 2007. It now has at least 50. The only pediatric gender clinic in England and Wales, known by its acronym, GIDS, saw referrals increase 30 times in a decade. A similar pattern is evident throughout the wealthy world.
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Many who attend these clinics receive gonadotropin-releasing hormone (GNRH) agonists or “puberty blockers”. These drugs, licensed to treat breast and prostate cancer, endometriosis and “central precocious puberty” – a rare condition in which puberty begins long before normal – are prescribed off-label to stop the signals that stimulate the testicles or ovaries to rise increase the production of sex hormones. The idea is to delay puberty, saving time for patients to decide whether to do cross-sex hormones and surgery in order to “pass” adult members of the opposite sex.
All drugs offer a combination of harms and benefits. But despite its popularity, the effects of puberty blockers remain unclear. As they are not licensed for gender medicine, pharmaceutical companies have not conducted tests. Record keeping in many clinics is deficient. A 2018 review by researchers at the University of Melbourne described the evidence for its use as “low quality”. In December, British judges also signaled the lack of a “solid evidence base” when deciding that children were unlikely to be able to give meaningful consent to take them. Britain’s National Health Service recently dropped a claim, still made elsewhere, that its effects are “fully reversible”.
The studies that exist are both weak and worrying. The day after the court’s decision, GIDS published a study that concluded that children were happy to receive the drugs. But there was little other evidence of benefit – not even a reduction in gender dysphoria. Two older studies of Dutch patients who received puberty blockers in the 1990s found that gender dysphoria later declined. But without a control group, it is impossible to say how patients would feel if they had not taken the drugs.
A 2020 article looked at responses to an online survey and found that people who took puberty blockers were less prone to suicidal thoughts. But online surveys capture convenient, unrepresentative samples. People can respond repeatedly or randomly. Much of the data appeared to have been reported incorrectly: many of those who said they had taken puberty blockers were too old to have done so plausibly.
In the absence of direct and robust evidence, researchers can try to extrapolate from other findings. Off-label prescription is common in pediatric medicine, because pharmaceutical companies generally don’t like testing children. Therefore, doctors look for second-hand evidence elsewhere to guide their decisions. One source is studies that examine how GNRH agonists are used to treat other conditions.
Interrupting normal adolescence is not the same as treating cancer, endometriosis or precocious puberty. However, data on these conditions signaled unpleasant side effects. Men who take GNRH agonists lose energy and sexual desire. (This is why some countries prescribe them for sex offenders.) Women are pushed into artificial menopause, an experience unpleasant enough that, in endometriosis, drugs are prescribed for a maximum period of six months. Several lawsuits have been filed against pharmaceutical companies by adults who used puberty blockers for early puberty. They allege cognitive deficits, brittle bones and chronic pain in adulthood, although none have reached court.
Animal studies suggest that these concerns are worth investigating. A 2017 study looked at sheep, which are experiencing a development spurt similar to human adolescence. Sheep that received puberty blockers performed worse than controls in a maze navigation task, suggesting that their spatial memory was inferior. A 2020 article looking at mice found, among other things, that women who received puberty blockers were more shy in unfamiliar surroundings and earlier gave up on a “forced swim” test that is commonly used to assess whether antidepressants work.
A major concern is that puberty blockers appear to safely lead to cross-sex hormones, in what doctors call a “cascade of interventions”. The best estimate, from studies started in the 1970s, is that about 80% of children with gender dysfunction who can express themselves as they wish, but who do not make a social transition – change clothes, pronouns and the like to if they present themselves as members of the opposite sex – they will, as they grow up, be reconciled to their biological sex. However, puberty blockers seem to prevent this reconciliation. In European clinics that report numbers, this happens to only 2 to 4% of the children who receive the drugs. American clinics rarely publish numbers, but anecdotally the picture is similar.
These figures led British judges to decide that the effects of these subsequent treatments should be taken into account when assessing puberty blockers. In addition to the intended effects, such as breast or facial hair growth, cross-sex hormones also cause side effects. A 2018 study found that women who take testosterone are more likely to suffer from cardiovascular disease, while men who take estrogen are at higher risk for blood clots and strokes. The additional risk increased the longer the patients remained on the hormones.
Some doctors worry about osteoporosis. Bone density increases dramatically during puberty, but blockers stop this process. If they are followed by cross-sex hormones, they are very likely to impair fertility, even if the hormones are stopped later – although the lack of studies means no one knows how much, says Will Malone, an American endocrinologist and a member of the Society for Evidence – Based Gender Medicine, a new group. If the cascade of intervention ends with the removal of the testicles or ovaries, sterility will result.
Despite the uncertainties, professional bodies have endorsed the drugs. In a 2018 position paper, the American Association of Paediatrics (AAP) described “gender-based” care as the only ethical approach. Not everyone is convinced. James Cantor, a Canadian clinical psychologist, published an article accusing the AAP to distort the content of his quotes, which “repeatedly said the opposite of what the AAP assigned to them ”. (Asked for comment, the AAP reaffirmed his position.) Marcus Evans, a psychoanalyst, resigned from the council that oversees GIDS about concerns about “experimental” treatments.
The best way to resolve these disputes is the same as in any other part of medicine: a large, well-conducted clinical trial. So far, despite the increasing number of cases and puberty blockers being prescribed for decades, no one is planning to conduct one.■
This article appeared in the Science and Technology section of the print edition under the title “Development halted”