Puberty blockers (also called puberty inhibitors or hormone blockers) are medicines used to postpone puberty in children. The most commonly used puberty blockers are gonadotropin-releasing hormone (GnRH) agonists, which suppress the natural production of sex hormones, such as androgens (e.g. testosterone) and estrogens (e.g. estradiol).[1][2][3] In addition to their use in treating precocious puberty, which involves puberty occurring at an unusually early age (and sometimes idiopathic short stature) in children, puberty blockers are also used for transgender children to delay the development of unwanted sex characteristics,[4] so as to allow transgender youth more time to explore their gender identity.[5]
The use of puberty blockers in transgender youth is supported by twelve major American medical associations, including the American Medical Association,[6] the American Psychological Association,[7] the American Academy of Pediatrics,[8] along with four Australian medical organizations,[9] the Endocrine Society,[10] the European Society for Sexual Medicine,[11]:573 and the World Professional Association for Transgender Health (WPATH).[12]
As of 2024[update], the provision of puberty blockers for gender dysphoria in children has become the subject of public controversy. A combination of shifts in public opinion, political lobbying, and scepticism from some in the field of medicine has led to the rolling back of the use of puberty blockers for transgender children in several countries, with results ranging from some health systems stopping the routine use of puberty blockers until higher-quality research evidence is available,[13] to the provision of puberty blockers to children being made a criminal offence in some states of the United States.[14][15]
Delaying or temporarily suspending puberty is a medical treatment for children whose puberty started abnormally early (precocious puberty).[16] Puberty blockers have been used on-label since the 1980s to treat precocious puberty in children,[17] and were approved for use in treating precocious puberty in children by the U.S. Food and Drug Administration (FDA) in 1993.[18] Puberty blockers are also commonly used for children with idiopathic short stature, for whom these medications can be used to promote development of long bones and increase adult height.[16] In adults, the same drugs have a range of different medical uses, including the treatment of endometriosis, breast and prostate cancer, and polycystic ovary syndrome.[19]
Puberty blockers prevent the development of biological secondary sex characteristics.[20]
Puberty blockers are sometimes prescribed to young transgender people, to temporarily halt the development of secondary sex characteristics and treat gender dysphoria in children.[4]
Puberty blockers are intended to allow patients more time to solidify their gender identity, without developing secondary sex characteristics, and give transgender youth a smoother transition into their desired gender identity as an adult.[5] If a child later decides not to transition to another gender the medication can be stopped, allowing puberty to proceed.
The "Dutch Protocol" was the first example of the use puberty blockers to treat gender dysphoria in children. It was developed by Peggy Cohen-Kettenis in the 1990s.[21] The statement was made that the treatment was fully reversible, and that a study of 70 children showed evidence that it had an overall positive outcome for those treated.[22] A number of subsequent studies appeared to support this treatment as safe and effective, and it became the standard treatment in the field.[23]
Since then, the use of puberty blockers has evolved as the result of further medical research and development of opinion within the medical community.
Little is known about the long-term side effects of hormone or puberty blockers in children with gender dysphoria. Although puberty blockers are known to be safe and physically reversible treatment if stopped in the short term, it is also not known whether hormone blockers affect the development of factors like bone mineral density, brain development and fertility in transgender patients.[24][25][26][27]
Puberty blockers have not received FDA approval for use on children who are transgender, and are instead issued "off-label".[28] The practice of off-label prescription is common in children's medicine because many drugs lack pediatric-specific information in their marketing authorisation or approval. Doctors use their professional judgment to decide how to use these drugs, and the term 'off-label' itself does not indicate an improper, illegal, or experimental use of medicine.[29] According to pediatric endocrinology expert Brad Miller, pharmaceutical companies that make puberty blocker drugs for children with gender dysphoria have refused to submit them for FDA approval because doing so would cost too much money and "because (transgender treatment) was a political hot potato."[28]
While few studies have examined the effects of puberty blockers for gender non-conforming and transgender adolescents, the studies that have been conducted generally indicate that these treatments are reasonably safe, are reversible, and can improve psychological well-being in these individuals.[30][31][32] A 2020 review published in Child and Adolescent Mental Health found that puberty blockers are associated with such positive outcomes as decreased suicidality in adulthood, improved affect and psychological functioning, and improved social life.[24] A 2022 review published in the Annual Review of Medicine found clearly beneficial, lifesaving impacts of puberty blockers on a scale of up to six years, but found research lacking beyond that time frame.[citation needed] The World Professional Association for Transgender Health's Standards of Care 8, published in 2022, found puberty-blocking medication to be "medically necessary" and recommends them for usage in transgender adolescents once the patient has reached Tanner stage 2 of development, and state that longitudinal data shows improved outcomes for transgender patients who receive them.[33]
A 2020 commissioned review published by the UK's National Institute for Health and Care Excellence concluded that the quality of evidence for puberty blocker outcomes (for mental health, quality of life and impact on gender dysphoria) was of very low certainty based on a modified GRADE approach, but that "it is plausible, however, that a lack of difference in scores from baseline to follow-up is the effect of GnRH analogues in children and adolescents with gender dysphoria, in whom the development of secondary sexual characteristics might be expected to be associated with an increased impact on gender dysphoria, depression, anxiety, anger and distress over time without treatment."[34] A 2024 systematic review using the same approach re-affirmed the conclusions of the NICE report, concluding that the currently available studies have "significant conceptual and methodological flaws".[35][36]
The NICE review has been criticized by WPATH and EPATH for excluding studies combining puberty blockers and hormone therapy and by parents of transgender youth for excluding evidence of its safety when used by cisgender youth undergoing precocious puberty.[37][38] The review has also been criticized for prioritization of "high quality" evidence according to the GRADE approach, which designates randomized control trials (RCTs) as "high quality", since RCTs are widely considered unfeasible and unethical for transgender youth due to the fact those in the control group would have to be denied treatment.[37] The review also deviated from GRADE guidance which states that "low or very low quality evidence can lead to a strong recommendation" by not taking the low-quality studies into account when forming evidence review recommendations.[37]
The longest follow-up study followed a transgender man who began taking puberty blockers at age 13 in 1998, before later taking hormone treatments, and later got gender confirmation surgery as an adult. His health was monitored for 22 years and at age 35 in 2010 was well-functioning, in good physical health with normal metabolic, endocrine, and bone mineral density levels. There were no clinical signs of a negative impact on brain development from taking puberty blockers.[39][40]
A 2024 systematic review by University of York published as part of the Cass Review found limited high-quality research on puberty suppression among adolescents experiencing gender dysphoria or incongruence. No conclusions on impact on gender dysphoria, mental health and cognitive development could be drawn. Bone health may be compromised during treatment, although the long-term outcomes of puberty suppression alone were not possible to determine.[41]
The use of puberty blockers for gender affirming care has attracted some criticism, due primarily to the lack of randomized controlled trials within the research base.[42][43] However, randomized controlled trials are not regarded as feasible or ethical in the case of research for gender-affirming care.[44][45]
The Finnish government commissioned a review of the research evidence for treatment of transgender minors and the Finnish Ministry of Health concluded that there are no research-based health care methods for minors with gender dysphoria.[46] However the Finnish Ministry supports the use of puberty blockers for minors on a case-by-case basis.[47]
Short-term side effects of puberty blockers include headaches, fatigue, insomnia, muscle aches and changes in breast tissue, mood, and weight.[48]
Adverse effects on bone mineralization and compromised fertility are potential risks of pubertal suppression in gender dysphoric youth treated with GnRH agonists.[31][49] To protect against lower bone density, doctors recommend exercise, calcium, and Vitamin D.[50] Additionally, genital tissue in transgender women may not be optimal for potential vaginoplasty later in life due to underdevelopment of the penis.[51]
Research on the long-term effects on brain development, cognitive function, fertility, and sexual function is limited.[28][52][53] A 2020 study conducted by John Strang and other researchers suggested that "pubertal suppression may prevent key aspects of development during a sensitive period of brain organization", adding that "we need high-quality research to understand the impacts of this treatment – impacts which may be positive in some ways and potentially negative in others."[28] The Endocrine Society Guidelines, while endorsing the use of puberty blockers for treatment of gender dysphoria, underscores the need for more rigorous safety and effectiveness evaluations and careful assessment of "the effects of prolonged delay of puberty in adolescents on bone health, gonadal function, and the brain (including effects on cognitive, emotional, social, and sexual development)."[32]
In 2016, the FDA ordered drugmakers to add warning labels to puberty blocker drugs being used to treat children with precocious puberty stating: "Psychiatric events have been reported in patients", including symptoms "such as crying, irritability, impatience, anger and aggression." The warning labels were added after the FDA received reports of 10 children who had suicidal thoughts, including one attempt at suicide. One of these children, a 14-year-old, was taking a puberty blocker drug for gender dysphoria.[28]
In 2017, it was reported that the FDA had received more than 10,000 reports of adverse events from women who took Lupron in order to grow taller.[54]
In 2022, the FDA reported that there have been six cases of idiopathic intracranial hypertension in 5 to 12-year-old children assigned female at birth taking puberty blockers.[55] Five who experienced the side effect were receiving treatment for precocious puberty and one who experienced the side effect was transgender and was receiving treatment for gender dysphoria.[56] Morissa Ladinsky, a pediatrician with University of Alabama-Birmingham who works with transgender youth, said that "[Idiopathic intracranial hypertension] is an inordinately well-known side effect that can happen for many, many different medications, most commonly, oral birth control pills." Referring to the six reported side effects, Ladinsky said that "It doesn't even approach any semblance of what we call in medicine, statistical significance".[57]
A 2024 University College London review of the impact of suppressing puberty on psychological function found some evidence of a detrimental effect on IQ, and no evidence that cognitive effects were fully reversible.[58]
A number of different puberty blockers are used.[59][60] These include the GnRH agonists buserelin, histrelin, leuprorelin, nafarelin, and triptorelin.[59][60] GnRH agonists are available and used as daily subcutaneous injections, depot subcutaneous or intramuscular injections lasting 1 to 6 months, implants lasting 12 months, and nasal sprays used multiple times per day.[59][60] GnRH antagonists are also expected to be effective as puberty blockers but have not yet been widely studied or used for this purpose.[59][61] Progestogens used at high doses such as medroxyprogesterone acetate and cyproterone acetate have been used as puberty blockers in the past or when GnRH agonists are not possible.[59] They are not as effective as GnRH agonists and have more side effects.[59] The antiandrogen bicalutamide has been used as an alternative puberty blocker in transgender girls for whom GnRH agonists were denied by insurance.[62][63]
Centrally acting puberty blockers such as GnRH agonists are ineffective in peripheral precocious puberty, which is gonadotropin-independent.[64] In this situation, direct inhibitors of sex hormone action and/or synthesis must be employed instead.[64] Treatment options for peripheral precocious puberty in girls, such as in McCune–Albright syndrome, include ketoconazole, the aromatase inhibitors testolactone, fadrozole, anastrozole, and letrozole, and the antiestrogens tamoxifen and fulvestrant.[64] Treatment possibilities for peripheral precocious puberty in boys, such as in familial male-limited precocious puberty, include the antiandrogens bicalutamide, spironolactone, and cyproterone acetate, ketoconazole, and the aromatase inhibitors testolactone, anastrozole, and letrozole.[64]
In the United States, the main providers of puberty blockers are Endo International and AbbVie.[28]
The prescription of puberty blockers to transgender children has been subject to misinformation and anti-transgender legislation.[65][66][67][68]
Some opponents of the use of puberty blockers argue that minors are not able to give proper consent.[69] Some advocates for the use of puberty blockers argue that there are psychological and developmental benefits of puberty blockers which are compelling enough to overlook the issue of informed consent in many cases.[70] According to a 2019 study, a "multidisciplinary staged approach" is necessary "to ensure meaningful consent".[71] According to the 2021 editorial, "Disproportionate emphasis is given to young people's inability to provide medical consent, a moot point given that—like any medical care—parental consent is required. ... what matters ethically is whether an individual has a good enough reason for wanting treatment".[72] Bioethicist Maura Priest contends that, even in the absence of parental permission, the use of puberty blockers could mitigate any adverse effects on familial relationships within the home of a transgender child. She posits that there are benefits to having access to puberty blockers, while psychological costs are often associated with untreated gender dysphoria in children.[70] Bioethicist Florence Ashley contends that counseling and educating the parents of transgender youth could also be beneficial to familial relationships.[73]
One study found that the use of puberty blockers decreases the risk of depression and reduces behavioral issues.[51] Opponents have argued that potentially negative "effects may be too subtle to observe during the follow-up sessions by clinical assessment alone".[51]
Opponents of the use of puberty blockers in adolescents argue that gender identity is still fluctuating at this age and that blockers might interfere with gender identity formation and development of a free sexuality, as well as pointing to what they consider to be high rates of desistance after puberty.[51] Opponents also argue that puberty blockers "may alter the course of gender identity development, essentially 'locking in' a gender identity that may have reconciled with biological sex during the natural course of puberty."[74] Almost all (98%) children who took puberty blockers in a significant recent study by the main UK child/adolescent gender clinic continued on to hormone therapy.[75] Similarly, most reviews[32][51] noting psychological benefits refer to the classic Dutch study,[53] which had very stringent requirements for medical treatment.[76]
In April 2021, Arkansas passed a ban on treatment of minors under 18 with puberty blockers, but it was temporarily blocked by a federal judge a week before the law was set to take effect.[77][78] In April 2022, Alabama passed a ban from minors under 19 from obtaining puberty blockers and made it a felony for a doctor to prescribe puberty blockers to a minor with a punishment of up to ten years in prison.[79] The Alabama law was partially blocked by a federal judge a few days after the law took effect.[80][81] In August 2022, Florida banned Medicaid from covering gender affirming care, including puberty blockers.[82]
Puberty blockers have also been banned in Utah,[83] Idaho,[84] Montana,[85] North Dakota,[86] South Dakota,[87] Iowa,[88] Indiana,[89] Kentucky,[90] Mississippi,[91] Florida,[92] West Virginia,[93] Tennessee,[94] and Oklahoma.[95]
Some state bans on gender affirming care including puberty blockers have been declared unconstitutional.[96] Furthermore, bans on puberty blockers have been criticized as governments interfering with the patient-doctor relationship and taking away healthcare decisions from parents and families for their children.[97][98] State level bans on gender affirming care, including puberty blockers, in the United States have led some families with transgender children to move out of their states.[99][100][101]
More than a dozen major American and Australian medical associations, as well as the World Professional Association for Transgender Health (WPATH),[102] and the Endocrine Society[103] generally support puberty blockers for transgender youth and have come out against efforts to restrict their use. In Europe, however, some medical groups and countries have taken a more cautionary stance following systematic reviews of the evidence base, discouraging or limiting the use of puberty blockers.[104][28]
The Royal Australasian College of Physicians, the Royal Australian College of General Practitioners, the Australian Endocrine Society, and AusPATH all support access to puberty blockers for transgender youth.[105]
According to the Canadian Pediatric Society, "Current evidence shows puberty blockers to be safe when used appropriately, and they remain an option to be considered within a wider view of the patient's mental and psychosocial health."[106]
In 2020, Finland revised its guidelines to prioritise psychotherapy over medical transition,[107] but the Council for Choices in Health Care allows the use of puberty blockers in transgender children after a case-by-case assessment if there are no medical contraindications.[108][109]
Transgender children in France are eligible for puberty blockers with parental permission at any age, and usually receive them at age 15 or 16.[110]
In 2022, France's Académie Nationale de Médecine urged caution when considering puberty blockers due to potential side effects, including "impact on growth, bone weakening, [and] risk of infertility".[111][110] This change to the guidelines has not changed actual practice.[110]
The use of puberty blockers in transgender youth is supported by:
The Dutch Ministry of Health, Welfare and Sport publishes guidelines recommending the use of puberty blockers in transgender adolescents of at least Tanner Stage II with informed consent and approval of an endocrinologist. [113] This guideline, published in 2016, is endorsed by the following Dutch medical organizations:
Sweden's Karolinska Institute, administrator of the second-largest hospital system in the country, announced in March 2021 that it would discontinue providing puberty blockers or cross-sex hormones to children under 16. Additionally, the Karolinska Institute changed its policy to cease providing puberty blockers or cross-sex hormones to teenagers 16–18, outside of approved clinical trials.[114] On 22 February 2022, Sweden's National Board of Health and Welfare said that puberty blockers should only be used in "exceptional cases" and said that their use is backed by "uncertain science".[115][116]
However, other providers in Sweden continue to provide puberty blockers, and a clinician's professional judgment determines what treatments are recommended or not recommended. Youth are able to access gender-affirming care when doctors deem it medically necessary. The treatment is not banned in Sweden and is offered as part of its national healthcare service.[116][117][118]
In 2020, the Norwegian Directorate for Health, the governmental body that develops health guidelines, released one for gender incongruence recommending puberty blockers between Tanner stage 2 and the age of 16 following an interdisciplinary assessment, stating they were reversible and there is no reliable evidence of adverse long-term effects.[119][120][110]
In 2023, the Norwegian Healthcare Investigation Board, an independent non-governmental organization, issued a non-binding report finding "there is insufficient evidence for the use of puberty blockers and cross sex hormone treatments in young people" and recommending changes in line with the cautious approach of Sweden and Finland.[121][122] The Norwegian Healthcare Investigation Board is not responsible for setting healthcare policy, and the Directorate, which is, has not implemented the recommendations, though they have said they are considering them.[121][119][110] Misinformation that Norway had banned gender affirming care proliferated on social media.[119]
On 30 June 2020, the British National Health Service changed the information it displayed on its website regarding the reversibility of the effects of puberty blockers and their use in the treatment of minors with gender dysphoria. Specifically, the NHS removed language stating that puberty blockers were "fully reversible" and that "treatment can usually be stopped at any time". In its place, the NHS stated that "little is known about the long-term side effects of hormone or puberty blockers in children with gender dysphoria. Although the Gender Identity Development Service (GIDS) advises this is a physically reversible treatment if stopped, it is not known what the psychological effects may be. It's also not known whether hormone blockers affect the development of the teenage brain or children's bones. Side effects may also include hot flushes, fatigue and mood alterations."[123]
The Bell v Tavistock decision by the High Court of Justice for England and Wales ruled children under 16 were not competent to give informed consent to puberty blockers, but this was overturned by the Court of Appeal in September 2021.
Efforts to ban puberty blockers for transgender youth are opposed by the British Medical Association.[124] The National Health Service currently supports the use of puberty blockers for children under 16 years of age only in the context of centrally administered clinical research, and strongly discourages seeking treatment from unregulated sources.[125][126]
The 2024 Cass Review stated that there was inadequate evidence to justify the widespread use of puberty blockers for gender dysphoria, and that more research was needed to provide evidence as to the effectiveness of this treatment.[127] This has led to a de facto moratorium of the routine provision of puberty blockers for gender dysphoria within NHS England outside of clinical trials,[128][13] and political calls for doctors to be prevented from private prescription of puberty blockers in England.[129]
In March 2024, NHS England announced that it would no longer prescribe puberty blockers to minors outside of use in clinical research trials, citing insufficient evidence of safety or clinical effectiveness.[130] Children already receiving puberty blockers via NHS England will be able to continue their treatment.[130] NHS England hopes to have a study into the use of puberty blockers in place by December 2024, with eligibility criteria yet to be decided.[131] Children in England can still be prescribed puberty blockers through some private clinics that are not associated with NHS England.[132][133] In April 2024, it was announced that the Care Quality Commission (CQC) would check whether private clinics were “taking into account the recommendations of the Cass Review” regarding puberty blockers, and may take enforcement action against clinics which prescribe puberty blockers.[134]
The Sandyford clinic in Glasgow, which is the only specialist gender clinic in Scotland, announced in April 2024 that it was pausing the prescription of puberty blockers.[135]
The use of puberty blockers in transgender youth is supported by:
An April 2021 PBS Newshour/NPR/Marist poll with the question "Do you support or oppose legislation that would prohibit gender transition-related medical care for minors" found 66% of Americans would oppose a ban, including 69% of Democrats, 70% of Republicans, and 64% of Independents.[146]
A February 2022 poll by LGBT support service The Trevor Project and Morning Consult found that 52 percent of American adults expressed some level of support for transgender minors having access to puberty blockers if it is recommended by their doctor and supported by their parents.[147][148]
A Washington Post-KFF poll conducted in November 2022 found that 68 percent of adults oppose access to puberty-blocking medication for transgender children ages 10 to 14, and 58 percent oppose access to hormonal treatments for transgender children ages 15 to 17.[149]
In a January 2023 Deseret News/HarrisX poll, 55 percent of Americans supported banning gender hormone therapy for transgender minors with parental or guardian approval, while 45 percent opposed such a ban.[150]
A September 2023 poll by 19th News/SurveyMonkey found that 39 percent of American adults supported transgender minors having access to any kind of gender-affirming care, including puberty blockers, hormones, therapy, and surgery.[151]
To prevent the consequences of going through a puberty that doesn't match a transgender child's identity, healthcare providers may use fully reversible medications that put puberty on hold.
The few studies that have examined the psychological effects of suppressing puberty, as the first stage before possible future commencement of CSH therapy, have shown benefits.
Often, pubertal suppression...reduces the need for later surgery because physical changes that are otherwise irreversible (protrusion of the Adam's apple, male pattern baldness, voice change, breast growth, etc) are prevented. The available data reveal that pubertal suppression in children who identify as TGD generally leads to improved psychological functioning in adolescence and young adulthood.
Treating GD/gender-incongruent adolescents entering puberty with GnRH analogs has been shown to improve psychological functioning in several domains", "In the future, we need more rigorous evaluations of the effectiveness and safety of endocrine and surgical protocols. Specifically, endocrine treatment protocols for GD/gender incongruence should include the careful assessment of the following: (1) the effects of prolonged delay of puberty in adolescents on bone health, gonadal function, and the brain (including effects on cognitive, emotional, social, and sexual development);
Terveydenhuoltolain mukaan (8§) terveydenhuollon toiminnan on perustuttava näyttöön ja hyviin hoito- ja toimintakäytäntöihin. Alaikäisten osalta tutkimusnäyttöön perustuvia terveydenhuollon menetelmiä ei ole.[According to the Health Care Act (Section 8), health care activities must be based on evidence and good care and operating practices. There are no research-based health care methods for minors.]
GnRHa therapy prevents maturation of primary oocytes and spermatogonia and may preclude gamete maturation, and currently there are no proven methods to preserve fertility in early pubertal transgender adolescents.
The primary risks of pubertal suppression in gender dysphoric youth treated with GnRH agonists include adverse effects on bone mineralization, compromised fertility, and unknown effects on brain development.
We found no evidence of change in psychological function with GnRHa treatment as indicated by parent report (CBCL) or self-report (YSR) of overall problems, internalising or externalising problems or self-harm. This is in contrast to the Dutch study which reported improved psychological function across total problems, externalising and internalising scores for both CBCL and YSR and small improvements in CGAS [24].
According to Cohen-Kettenis, Delemarre-van de Waal, and Gooren (2008), these included the following: (1) the presence of gender dysphoria from early childhood on; (2) an exacerbation of the gender dysphoria after the first signs of puberty; (3) the absence of psychiatric comorbidity that would interfere with a diagnostic evaluation or treatment; (4) adequate psychological and social support during treatment; and (5) a demonstration of knowledge of the sex/gender reassignment process.
The BMA called for trans people to receive healthcare "in settings appropriate to their gender identity" and for under-18s to be able to get treatment "in line with existing principles of consent", which requires they fully understand what is involved.