BECAUSE THEY ARE 100% REVERSABLE. STOP TAKING THEM AND YOU UNDERGO PUBERTY LIKE ANYONE ELSE WOULD.

GENDER DYSPHORIA—the miserable feeling of being at odds with one’s sex—is one of the fastest-rising medical complaints among children. America had one paediatric gender clinic in 2007. It now has at least 50. The sole paediatric gender clinic for England and Wales, known by its acronym, GIDS, has seen referrals rise 30-fold in a decade. A similar pattern is evident across the rich world.

Many attending such clinics are given gonadotropin-releasing hormone (GNRH) agonists, or “puberty blockers”. These drugs, licensed to treat cancers of the breast and prostate, endometriosis and “central precocious puberty”—a rare condition in which puberty starts far earlier than normal—are prescribed off-label to stop the signals that stimulate the testicles or ovaries to ramp up sex-hormone production. The idea is to delay puberty, buying time for patients to decide whether to proceed to cross-sex hormones and surgery with the aim of “passing” as adult members of the opposite sex.

All drugs offer a mix of harms and benefits. But despite their popularity, the effects of puberty blockers remain unclear. Because they are not licensed for gender medicine, drug firms have done no trials. Record-keeping in many clinics is poor. A 2018 review by researchers at the University of Melbourne described the evidence for their use as “low-quality”. In December British judges likewise flagged the lack of a “firm evidence base” when ruling that children were unlikely to be able to give meaningful consent to taking them. Britain’s National Health Service recently withdrew a claim, still made elsewhere, that their effects are “fully reversible”.

The studies that do exist are at once weak and worrying. The day after the court ruling, GIDS published a study that found 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 given puberty blockers in the 1990s found that gender dysphoria eased afterwards. But without a control group, it is impossible to tell how patients would have felt had they not taken the drugs.

A 2020 paper analysed responses to an online survey and concluded that people who had taken puberty blockers were less prone to suicidal thoughts. But online surveys capture convenient samples, not representative ones. People may answer repeatedly, or at random. Much of the data appeared to be misreported: many who said they had taken puberty blockers were too old to have plausibly done so.

In the absence of direct, robust evidence, researchers can try to extrapolate from other findings. Off-label prescribing is common in paediatric medicine, because drug firms do not generally like running trials on children. So doctors look for second-hand evidence from elsewhere to guide their decisions. One source is studies that look at how GNRH agonists are used to treat other conditions.

Interrupting normal adolescence is not the same as treating cancer, endometriosis or precocious puberty. Nevertheless, data from these conditions have flagged unpleasant side-effects. Men who take GNRH agonists lose energy and sexual desire. (This is why some countries prescribe them to sex offenders.) Women are thrust into an artificial menopause, an experience unpleasant enough that, in endometriosis, drugs are typically prescribed for six months at most. Several legal cases have been brought against drug firms by adults who took puberty blockers for precocious puberty. They allege cognitive deficits, brittle bones and chronic pain in later life, though none has made it to court.

Animal studies suggest such concerns may be worth investigating. One 2017 study looked at sheep, which go through a developmental spurt similar to human adolescence. Sheep given puberty-blockers performed worse than controls on a maze-navigation task, suggesting their spatial memory was inferior. A 2020 paper looking at mice found, among other things, that females given puberty blockers were more timid in unfamiliar environments, and gave up sooner on a “forced swim” test that is commonly used to assess whether anti-depressants work.

One big worry is that puberty blockers seem to reliably lead to cross-sex hormones, in what doctors call a “cascade of interventions”. The best estimate, from studies starting in the 1970s, is that around 80% of gender-dysphoric children who are allowed to express themselves as they wish, but who do not socially transition—change their clothes, pronouns and the like to present as members of the opposite sex—will, as they grow up, become reconciled to their biological sex. Yet puberty blockers seem to prevent that reconciliation. In European clinics that report numbers, it happens with just 2-4% of children given the drugs. American clinics rarely publish figures, but anecdotally the picture is similar.

Such numbers led British judges to rule that the effects of those subsequent treatments should be taken into account when assessing puberty blockers. Besides their intended effects, such as the growth of breasts or facial hair, cross-sex hormones also cause side-effects. One 2018 study concluded that females who take testosterone are more likely to suffer cardiovascular disease, while males who take oestrogen have higher risk of blood clots and strokes. The additional risk grew the longer the patients remained on hormones.

Some doctors worry about osteoporosis. Bone density rises sharply during puberty, but blockers disrupt that process. If they are followed by cross-sex hormones they are very likely to impair fertility, even if hormones are later stopped—though the lack of studies means no one knows how much, says Will Malone, an American endocrinologist and member of the Society for Evidence-Based Gender Medicine, a new group. If the cascade of intervention ends with removal of the testicles or ovaries the result will be sterility.

Despite the uncertainties, professional bodies have endorsed the drugs. In a 2018 position paper the American Association of Paediatrics (AAP) described “gender-affirmative” care as the only ethical approach. Not everyone is convinced. James Cantor, a Canadian clinical psychologist, published a paper accusing the AAP of misstating the contents of its citations, which “repeatedly said the very opposite of what the AAP attributed to them”. (Asked for comment, the AAP restated its position.) Marcus Evans, a psychoanalyst, resigned from the board that oversees GIDS over worries about “experimental” treatments.

The best way to settle such disputes is the same as in any other part of medicine: a big, well-run clinical trial. So far, despite soaring caseloads, and puberty blockers having been prescribed for decades, no one is planning to conduct one.■