Puberty blocker

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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] Puberty blockers are used to delay puberty in children with precocious puberty. Since the 1990s, they are also used to delay the development of unwanted secondary sex characteristics in transgender children,^[4] so as to allow transgender youth more time to explore their gender identity^[5] under what became known as the "Dutch Protocol".^[6][7] They have been shown to reduce depression and suicidality in transgender and nonbinary youth.^[8][9][10] The same drugs are also used in fertility medicine and to treat some hormone-sensitive cancers in adults.^[11][12][13]

The use of puberty blockers is supported by twelve major American medical associations, including the American Medical Association,^[14] the American Psychological Association,^[15] and the American Academy of Pediatrics.^[16] the American Academy of Child and Adolescent Psychiatry,^[17] the Pediatric Endocrine Society,^[18] the American College of Obstetricians and Gynecologists,^[19] the American Association of Clinical Endocrinologists,^[20] and the American College of Physicians.^[21] In Australia four medical organizations support them,^[22] as does the Endocrine Society,^[23] and the World Professional Association for Transgender Health (WPATH).^[24] The United Kingdom has implemented a ban on prescribing puberty blockers to new patients under 18 for the treatment of gender dysphoria except for use in clinical research trials, as of May 2024.^[25]

In the 2020s, 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 rising scepticism in the field of medicine has led to the rolling back of the use of puberty blockers for transgender children in some countries, with the United Kingdom stopping the routine prescription of puberty blockers^[26] and some states of the United States making their use a criminal offense.^[27][28]

Puberty blockers prevent the development of biological secondary sex characteristics.^[29]

Puberty blockers are commonly used to delay puberty in children with precocious puberty, a condition that activates the hypothalamic-pituitary-gonadal axis prematurely and initiates puberty at an inappropriate age.^[30] The main goal of treatment is to preserve children's adult height potential.^[31] Puberty blockers work by stabilizing puberty symptoms, decreasing growth velocity, and slowing skeletal maturation.^[32] The outcomes of treatment are assessed in terms of height, reproduction, metabolic, and psychosocial measures. The most pronounced effects on height have been seen in children experiencing the onset of puberty before 6 years of age; however there is variability in height outcomes across studies which can be attributed to varying study designs, time of symptom presentation, and time of treatment termination.^[33] A study investigating the effects of puberty blockers on reproductive health showed no significant difference in the number of irregular menstrual cycles, pregnancies, or pregnancy outcomes between women who received treatment for precocious puberty and those who opted out of treatment.^[34] In terms of psychosocial markers, preadolescents and adolescents diagnosed with precocious puberty have shown body image concerns and demonstrated poor emotional regulation and high anxiety.^[35] Individuals with precocious puberty, early adrenarche, and early normal puberty show less stress after treatment compared to individuals without preexisting developmental conditions.^[36]

Moreover, they are utilized in the treatment of central precocious puberty resulting from conditions like hypothalamic hamartomas or congenital adrenal hyperplasia, where early onset of puberty is a symptom. Additionally, puberty blockers can be prescribed for children with severe forms of idiopathic short stature, allowing for more time for growth before the closure of growth plates. These applications illustrate the versatility of puberty blockers in addressing various endocrine and growth-related disorders.^[37][38]

Overall, puberty blockers have demonstrated an excellent safety and efficacy profile in the treatment of precocious puberty. The most common side effects reported include nonspecific headaches, hot flashes, and implant-related skin reactions.^[39]

Puberty blockers are sometimes prescribed to young transgender people with gender dysphoria to temporarily halt the development of secondary sex characteristics.^[40] Puberty blockers are intended to allow patients more time to solidify their gender identity and give them 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.^[6] 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.^[41] A number of subsequent studies appeared to support this treatment as safe and effective at delaying development of secondary sexual characteristics, and it became the standard treatment in the field.^[42] Since then, the use of puberty blockers has evolved as the result of further medical research and development of opinion within the medical community.^[43]

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.^[44][45][46] Puberty blockers are associated with such positive outcomes as decreased suicidality in adulthood, improved affect and psychological functioning, and improved social life.^[40] Puberty blockers have clearly beneficial, lifesaving impacts on a scale of up to six years, but research is lacking beyond that time frame.^[47] The World Professional Association for Transgender Health's Standards of Care 8, published in 2022, declared 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, because longitudinal data shows improved outcomes for transgender patients who receive them.^[48]

Puberty blocker medications are used to delay the physical changes associated with puberty, offering individuals more time to explore their gender identity. The most common type of puberty blockers are GnRH (gonadotropin-releasing hormone) analogues, such as leuprolide acetate and histrelin acetate, which suppress the release of sex hormones like testosterone and estrogen. These medications are typically administered via injections or implants. Another type of puberty blocker includes progestins, such as medroxyprogesterone acetate, which can be taken orally or by injection and work by reducing the body's production of sex hormones. In some cases, aromatase inhibitors are used off-label to block the conversion of androgens into estrogens, although they are less commonly prescribed. Each type of medication has specific benefits and potential side effects, and the choice of which to use depends on the individual's medical needs and the advice of their healthcare provider.^[49][50]

A number of different drugs are used as puberty blockers.^[51][52]

• Gonadotropin-releasing hormone (GnRH) agonists: Specific examples include: buserelin, histrelin, leuprorelin, nafarelin, and triptorelin.^[51][52] 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.^[51][52]
• GnRH antagonists are also expected to be effective at delaying puberty but have not yet been widely studied or used for this purpose.^[51][53] Examples of GnRh antagonists include ganirelix and cetrorelix, drugs that are typically used to treat infertility.
• 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.^[51] They are not as effective as GnRH agonists and have more side effects.^[51]
• Antiandrogens: Bicalutamide has been used as an alternative puberty blocker in transgender girls for whom GnRH agonists were denied by insurance.^[54][55] The antiandrogens spironolactone and cyproterone acetate are not as strong.^[55]

In the United States, the main providers of puberty blockers are Endo International and AbbVie.^[56] Endo International creates histerelin acetate (Vantas) while AbbVie manufactures leuprolide acetate (Lupron Depot).^[57][58] Other companies within the United States are also in the mix such as Pfizer who distributes histerelin acetate (Supprelin LA) and Tolmar Pharmaceuticals who create their own leuprolide acetate (Fensolvi).^[59][60] Outside of the United States, companies such as Ferring Pharmaceuticals, Ipsen, Takeda Pharmaceutical Company, Astellas Pharma, Sandoz, and Sun Pharmaceutical Industries supply much of the rest of the world with the various puberty blockers. Ferring Pharmaceuticals, based out of Switzerland, generate two separate products of triptorelin (Decapeptyl and Gonapeptyl).^[61] Originating in France, Ipsen also produces triptorelin (Decapeptyl).^[62] German/Swiss company Sandoz makes leuprorelin (Leuprorelin Acetate, Lucrin, Eligard).^[63] In Japan, Takeda Pharmaceutical Company and Astellas Pharma create leuprorelin (Lupron Depot) and goserelin (Zoladex).^[58][64] Indian company Sun Pharmaceutical Industries mainly produces leuprolide acetate generic injectables.^[65] AbbVie is also a player internationally.^[66]

In the short term, they are generally considered safe and well-tolerated by most individuals. One of the primary effects is the suppression of secondary sexual characteristics, such as breast development in assigned females at birth or deepening of the voice in assigned males at birth. This can significantly alleviate the distress associated with gender dysphoria in transgender youth. Additionally, by halting the rapid growth spurts of puberty, these medications provide more time for growth in stature, particularly beneficial for children diagnosed with idiopathic short stature or central precocious puberty. Common short-term side effects may include injection site reactions, headaches, mood swings, changes in weight or appetite, fatigue, insomnia, muscle aches and changes in breast tissue, but these are usually manageable.^[67][68][69]

Adverse effects on bone mineralization are a potential risk of pubertal suppression in gender dysphoric youth treated with GnRH agonists.^[45][70] To protect against lower bone density, doctors recommend exercise, calcium, and Vitamin D.^[71]

Despite their benefits, there are some considerations regarding the short-term use of puberty blockers. One concern is the potential impact on bone density. Since puberty is a critical period for bone development, delaying it may temporarily reduce bone mineral density, which could be monitored through regular bone density scans. Another consideration is the potential impact on psychological well-being. While many individuals experience relief from gender dysphoria, the delay in physical development might also cause anxiety or social difficulties in some cases, particularly in environments where peers are progressing through puberty. It is crucial for healthcare providers to closely monitor the physical and emotional well-being of individuals on puberty blockers, ensuring that the benefits outweigh any short-term risks or discomforts.^[72][73][74]

In 2016, the FDA ordered drugmakers to add warning labels to puberty blocker drugs that states: "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.^[56]

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.^[75] 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.^[76] 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.^[77] 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".^[78]

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.^{[40][79][80][81]} There is 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.^[82]

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)."^[46]

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 getting 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.^[7][83]

Research on the long-term effects on brain development and cognitive function is limited.^[56][84][85] According to a 2024 systematic review, no conclusions can be drawn about the effects of puberty blockers on cognitive development.^[82] Another 2024 systematic review, using both human and animal studies found some evidence of sex-specific impact on cognitive function in mammals, and no evidence that cognitive effects were fully reversible.^[86]

Research on the long-term effects on fertility and sexual function is limited.^[56][84][85] The long-term use of puberty blockers presents several uncertainties, particularly concerning fertility and sexual function. Since these medications suppress the production of sex hormones during a critical period of sexual maturation, their extended use may impact the development of reproductive organs and future fertility. For instance, individuals assigned male at birth who take puberty blockers might experience underdeveloped testes, potentially affecting sperm production later in life. Similarly, individuals assigned female at birth might have impaired ovarian function, impacting their ability to conceive. Additionally, there is concern that prolonged suppression of puberty may influence sexual function, including libido and the ability to achieve sexual arousal and satisfaction. These potential effects underscore the importance of careful, individualized medical counseling and consideration of fertility preservation options, such as sperm or egg banking, before initiating long-term puberty blocker treatment. Ongoing research is crucial to better understand these long-term impacts and to provide clearer guidance to patients and their families.^[42][87] Additionally, genital tissue in transgender women may not be optimal for potential vaginoplasty later in life due to underdevelopment of the penis when using penile inversion vaginoplasty.^[88] Several other methods such as bowel vaginoplasty, which uses part of the sigmoid colon to form the canal instead,^[89][90] or a peritoneal pull-through vaginoplasty which harvests a skin graft from the peritoneum are not affected by this as they do not require the penile tissue to form the vaginal canal.^[91][92]

A systematic review of studies investigating the long-term effects of treating precocious puberty with GnRH agonists found that bone mineral density decreases during treatment but normalizes afterward, with no lasting effects on peak bone mass.^[93] A review focused on the treatment of adolescents experiencing gender dysphoria found that bone health may be compromised during treatment, although the long-term outcomes of puberty suppression alone were not possible to determine.^[82]

A study published in the Journal of the American Medical Association in 2022 found a 60% reduction in moderate to severe depression and a 73% reduction in suicidality in trans and nonbinary youth prescribed puberty blockers.^[8]

A multi-year study published in September 2024 found that restrictions to transgender care, including restriction on access to gender-affirming puberty blockers, showed a direct link to negative mental health outcomes for transgender youth. The study followed the enactment of several laws in US states on restricting such access, which led to an increase of suicide attempts of 7-72% in transgender youth within one to two years following the enactment of laws restricting access.^[9][10]

In September 2024, the New South Wales government in Australia released an independent review into puberty blockers that they commissioned which found that the benefits of puberty blockers outweigh any possible risks. The review concluded that puberty blockers are "safe, effective and reversible".^[94]

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.^[95][96][97]

A 2020 commissioned review published by the UK's National Institute for Health and Care Excellence (NICE) 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 was plausible that the outcomes would have been worse without treatment.^[98] A subsequent systematic review re-affirmed the conclusions of the NICE report, concluding that the currently available studies have "significant conceptual and methodological flaws".^[99][43] A 2024 review of evidence on behalf of the Cass Review came to a similar conclusion.^[100]

The NICE review has been criticized by organizations that support the use of puberty blockers such as WPATH and EPATH, and in an WPATH's International Journal of Transgender Health article by Cal Horton for excluding studies combining puberty blockers and hormone therapy, and also by parents of transgender youth for excluding evidence of its safety when used, albeit at a much younger age, by cisgender youth being treated for precocious puberty.^[101][102] Horton criticised the review for prioritizing high-quality evidence according to the GRADE approach, which designates randomized control trials (RCTs) as "high quality", since RCTs are widely considered infeasible and unethical for transgender youth if those in the control group are denied medical treatment.^[101] Horton also argued that it had not followed 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.^[101]

The Finnish Ministry of Health also concluded that there are no research-based health care methods for minors with gender dysphoria.^[103] Their guidelines permit the use of puberty blockers for minors on a case-by-case basis.^[104]

Puberty blockers have not received FDA approval for use on children who are transgender, and are instead issued "off-label".^[56] 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.^[105] 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."^[56]

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The prescription of puberty blockers has been a polarizing issue on an international scale. On the one hand, opponents for the use of puberty blockers argue that minors are unable to provide informed consent, treatment interferes with typical gender identity development, and there are high rates of detransitioning after puberty, rendering treatment ineffective.^{[106][107][108]} On the other hand, proponents argue that there are psychological and developmental benefits of puberty blockers which may outweigh the risks associated with treatment, such as a lower risk of depression and reduced behavioral issues.^[109][107] In the United States, the growing disarray between opponents and proponents has led to the dissemination of misinformation and consequently the establishment of anti-transgender ("anti-trans") legislation.^{[110][111][112][113]}

Informed consent:

Groups continue building on the discussion on informed consent. A 2019 study found that a "multidisciplinary approach" is necessary "to ensure meaningful consent" is acquired and treatment is initiated with a strong ethical foundation.^[114] A 2021 editorial adds a pragmatic perspective, claiming that "disproportionate emphasis is given to young people's inability to provide medical consent" and that "what matters ethically is whether an individual has a good enough reason for wanting treatment".^[115] Bioethicist Maura Priest shares this perspective. She claims 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 and that the psychological costs associated with untreated gender dysphoria in children are avoidable.^[109] Another bioethicist, Florence Ashley, adds that counseling and educating the parents of transgender youth could also be beneficial to familial relationships.^[116]

Puberty blockers in the US:

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.^[117][118] 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.^[119] The Alabama law was partially blocked by a federal judge a few days after the law took effect.^[120][121] In August 2022, Florida banned Medicaid from covering gender affirming care, including puberty blockers.^[122]

As of July 2024, 26 states have enacted some form of ban on gender-affirming care for minors, but not all of these ban puberty blockers. Currently, only 18 of the 26 states have complete bans which are fully in effect. Six states have only partial bans and two are currently blocked from taking effect. While some states have banned all forms of medical transition, others have banned only specific types such as surgery. Six states have exceptions which allow minors who were already receiving gender affirming care prior to the ban to continue their treatments.^[123] Currently, all 26 states make exceptions for puberty blockers, hormones and surgery for cisgender and intersex children.^[123] Only one state, West Virginia, makes exceptions in cases of "severe dysphoria". There is also currently only one state, Missouri, that has a ban which is set to expire after a certain period of time. Nearly all states with restrictions include specific provisions with penalties for providers and 4 states include provisions directed at parents or guardians.^[123] An additional 4 states include laws/policies that impact school officials such as teachers and counselors, among others.^[123]

In response to these bans, many Democrat-controlled states have gone in the opposite direction and enacted laws protecting access to gender affirming care for minors and adults. These laws, often called "shield" laws, often explicitly combine protections for gender-affirming care and abortion and cover a variety of protections including protecting both providers and patients from being punished, mandating insurance providers to cover the procedures and acting as "sanctuary states" that protect patients traveling to the state from other states that have banned such treatments among other things.^[124] As of June 2024, 16 states and the District of Columbia have enacted "shield" laws.

The UK's Cass Review was cited in the Indiana legislation to ban puberty blockers.^[125]

Some US state bans on gender affirming care including puberty blockers have been declared unconstitutional.^[126] 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.^[127][128] 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.^{[129][130][131]}

Puberty blockers in Italy:

The Italian National Bioethics Committee and the Italian Medicines Agency have demonstrated support for the use of puberty blockers in adolescents with gender dysphoria, expanding coverage by adding them to the list of medications covered by the National Health Service.^[132] Still, challenges with accessing puberty blocker medications persist. Specific clinical criteria must be satisfied for treatment including comprehensive medical evaluations, parental consent, and the exhaustion of all other clinical interventions.^[132]

Puberty blockers in Canada:

The British Columbia Infants Act of 1996 grants minors legal decision-making authority if they can consent to a clinical intervention and their healthcare provider believes it is in their best interest.^[133] As a result, providers are required to evaluate if their patients have a robust and realistic understanding of hormone therapy, risks, benefits, and alternatives. Although some incorporate the gender-affirming care model into practice, others demonstrate reluctance to prescribe puberty blockers.^[134]

A qualitative study investigating the experience of trans youth in seeking and receiving gender-affirming care at Canadian specialty clinics shows a mix of positive and negative outcomes.^[135] People reported improvements in their well-being, frustrations with treatment protocols and wait lists, and concerns with their transition journey.^[135]

More than a dozen major American and Australian medical associations, as well as the World Professional Association for Transgender Health (WPATH),^[136] and the Endocrine Society^[137] 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, discouraging or limiting the use of puberty blockers.^[138][56] However, these countries have not outright banned or criminalized the treatment unlike many US States.^{[139][140][141][142][143]}

Access to puberty blockers for transgender youth in Australia is supported by:

• The Royal Australasian College of Physicians,
• The Royal Australian College of General Practitioners,
• The Australian Endocrine Society,
• AusPATH.^[22]

An independent review into gender-affirming care for minors commissioned by the New South Wales government and released in September 2024 found that puberty blockers are "safe, effective and reversible", while acknowledging that the evidence for this and other interventions "remains weak due to poor study designs, low participant numbers and single-centre recruitment", calling for more long-term research.^[144][145]

According to the Canadian Pediatric Society in 2024, "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."^[146]

The following medical organizations have expressed their support for puberty blockers for transgender children and adolescents:

• The Chilean Pediatric Society
• The Chilean Society of Psychiatry and Neurology of Childhood and Adolescence
• The Chilean Society of Childhood and Adolescent Gynecology^[147]

Danish guidelines published in 2023 recommend the use of puberty blockers on transgender patients at either Tanner stage two or three, as a means of buying time for patients to consider their gender more fully before making a decision.^[148]

In 2020, Finland revised its guidelines to prioritise psychotherapy over medical transition,^[149] 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.^[150][151]

Transgender children in France are eligible for puberty blockers with parental permission at any age, and usually receive them at age 15 or 16.^[152]

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".^[153][152] This change to the guidelines has not changed actual practice.^[152]

In late 2024, the French Society of Pediatric Endocrinology and Diabetology released the country's first ever guidelines for medical care of trans youth, in which they recommended patients who have hit at least Tanner stage 2 to receive puberty blockers along with calcium and vitamin D supplements.^[154]

The Italian National Bioethics Committee and the Italian Medicines Agency have demonstrated support for the use of puberty blockers in adolescents with gender dysphoria, expanding coverage by adding them to the list of medications covered by the National Health Service.^[132] Still, challenges with accessing puberty blocker medications persist. Specific clinical criteria must be satisfied for treatment including comprehensive medical evaluations, parental consent, and the exhaustion of all other clinical interventions.^[132]

Additionally, the use of puberty blockers in transgender youth is supported by:

• The Italian Society of Endocrinology (SIE)
• The Italian Society of Andrology and Sexual Medicine (SIAMS)
• The Italian Society of Gender, Identity and Health (SIGIS)^[155]

The Japanese Society of Psychiatry and Neurology (JSPN) published its updated guidelines in August 2024 on the treatment of gender dysphoria. The guidelines continued to recommend puberty suppression in trans patients, noting it is "self-evident" that, unless puberty is suppressed, development of sex characteristics are irreversible in AMAB individuals. They made recommendations that doctors administering such treatment report more detailed information on outcomes going forward.^[156][157]

In June 2020, the Mexican federal government released "The Protocol for Access without Discrimination to Health Care Services for Lesbian, Gay, Bisexual, Transsexual, Transvestite, Transgender, and Intersex Persons and Specific Care Guidelines." The guidelines are used in healthcare facilities administered by the government. The guidelines state that the process of identifying one's sexual orientation, gender identity and/or expression can occur at early ages. Thus, the guidelines recommend that medical facilities and doctors consider the use of puberty blockers and cross-sex hormones as a treatment for transgender minors when appropriate. In addition to the guidelines, multiple Mexican states have modified their civil codes to recognize gender-affirming healthcare as a right for transgender people under the age of eighteen.^[158]

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.^[159] This guideline, published in 2016, is endorsed by the following Dutch medical organizations:

• Nederlands Internisten Vereniging (Dutch Internists Association)^[159]
• Nederlands Huisartsen Genootschap (Dutch Society of General Practitioners)^[159]
• Nederlands Instituut van Psychologen (Dutch Institute of Psychologists)^[159]
• Nederlandse Vereniging voor Kindergeneeskunde (Dutch Association for Pediatrics)^[159]
• Nederlandse Vereniging voor Obstetrie & Gynaecologie (Dutch Association for Obstetrics & Gynaecology)^[159]
• Nederlandse Vereniging voor Plastische Chirurgie (Dutch Association for Plastic Surgery)^[159]
• Nederlandse Vereniging voor Psychiatrie (Dutch Psychiatry Association)^[159]
• Transvisie (Transvision, a patient organization for transgender patients)^[159]

The use of puberty blockers for transgender people is supported by

• The Professional Association for Transgender Health Aotearoa (PATHA),^[160]
• The Royal Australian and New Zealand College of Psychiatrists (RANZCP),^[161]
• The Australian and New Zealand Professional Association for Transgender Health (ANZPATH),
• The Society of Youth Health Professionals Aotearoa New Zealand (SYHPANZ)
• The New Zealand Sexual Health Society, and
• The New Zealand Society of Endocrinology.^[162]

In November 2024, the Ministry of Health released an evidence brief on puberty blockers. The brief found there to be a lack of evidence for both the efficiency and harms of puberty blockers and recommended "a more precautionary approach".^[163] The country did not ban puberty blockers and one doctor who provides the treatments in New Zealand said it "would not change the way in which he practiced".^{[164][165][166]}

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.^{[167][168][152]}

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 changing to a cautious approach.^[169][170] 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.^{[169][167][152]} Misinformation that Norway had banned gender affirming care proliferated on social media.^[167]

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.^[171] 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".^[172][173]

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.^{[173][174][175]}

As of May 2024, prescription of puberty blockers to new patients under 18 for the treatment of gender dysphoria is banned for both private medical practices (by a law in parliament in May^[176][25]) and the official state healthcare National Health Service (NHS) which stopped their use earlier, in the aftermath of the Cass Review except for use in clinical research trials.^[177]

Previously, on 30 June 2020, the NHS changed its website, replacing the statement that puberty blockers were "fully reversible" and that "treatment can usually be stopped at any time"; with "little is known about the long-term side effects of hormone or puberty blockers in children with gender dysphoria.^[178]

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.

In 2022, the British Medical Association opposed restrictions on puberty blockers,^[179] and the NHS restricted their use for children under 16 years of age to centrally administered clinical research.^[180][181]

The April 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, in terms of reducing distress and improving psychological functioning.^[182] This led to a de facto moratorium of the routine provision of puberty blockers for gender dysphoria within NHS England and NHS Scotland outside of clinical trials,^{[183][26][184]} and a subsequent ban on private prescription of puberty blockers in the United Kingdom.^{[185][186][187]}

Children already receiving puberty blockers via NHS England will be able to continue their treatment.^[188] In England, a clinical trial into puberty blockers is planned for early 2025.^[189]

In July 2024, the Royal College of General Practitioners stated that for patients under 18, no general practitioner should prescribe puberty blockers outside of a clinical trial, and the prescription of gender-affirming hormones should be left to specialists. They affirmed they will fully implement the Cass Review recommendations.^[190]

In December 2024, the Northern Ireland Executive announced a permanent ban on puberty blockers for under-18s, with the Executive's Deputy First Minister, Emma Little-Pengelly, saying it was "the right approach, informed by medical and scientific advice. The protection and safety of our young people must be paramount."^{[191][192][193]} The following day, the Health Secretary, Wes Streeting, announced in the House of Commons that the previously enacted ban on puberty blockers in England would be made indefinite and would be reviewed in 2027.^{[194][195][196]}

Since 1993 the US Food and Drug Administration (FDA) has supported the use of puberty blockers to treat precocious puberty.^[197] Currently under FDA regulation the use of puberty blockers is considered on-label for the treatment of central precocious puberty.^[198][199]

For years, the FDA, Endocrine Society, American Academy of Pediatrics (AAP) and many other pediatric associations have supported the use of Gonadotropin-releasing hormone analogs (GnRHas) in central precocious puberty (CPP).^[200] Access to treatment depends on the classification of precocious puberty as well as other guidelines implemented by the Endocrine Society.^[201] To determine if you are experiencing precocious puberty and should receive treatment it is required your doctor take a medical history, physical exam, blood test, and x-rays.^[202]

In 2009, the Lawson Wilkins Pediatric Endocrine Society and European Society for Pediatric Endocrinology published a consensus statement highlighting the effectiveness of Gonadotropin-releasing hormone analogs(GnRHas) in early onset central precocious puberty.^[203] They confirmed that the use of Gonadotropin-releasing hormone analogs (GnRHas) has had a positive effect on increasing adult height.^[203][204] However these Endocrine Societies believe additional research should be conducted before routinely suggesting GnRHAs for other conditions.^[203] There is still some uncertainty surrounding the effectiveness of GnRHas when utilized for other conditions.

Currently under FDA regulation, the use of puberty blockers in pediatrics with gender dysphoria is considered off-label.^[17]

The use of puberty blockers in youth experiencing gender dysphoria has been supported by the following organizations:

• The American Medical Association^[205][206]
• The American Psychological Association^[199]
• The American Academy of Pediatrics^[207]
• The American Academy of Child and Adolescent Psychiatry (AACAP)^[17]
• The American Psychiatric Association^[208]
• The Endocrine Society^[209]
• The Pediatric Endocrine Society^[18]
• The American Association of Clinical Endocrinologists^[20]
• The American College of Obstetricians and Gynecologists^[210]
• The American College of Physicians^[211]

There has been an increase in youth requesting treatment for gender affirming medical care.^[212][213] The increased medical coverage and societal awareness of transgender youth may be shifting accessibility to care.^[4]

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