Evidence review: Gonadotrophin releasing hormone analogues for children and adolescents with gender dysphoria
National Institute for Health and Care Excellence – NICE
The results of the studies that reported impact on the critical outcomes of gender dysphoria and mental health (depression, anger and anxiety), and the important outcomes of body image and psychosocial impact (global and psychosocial functioning) in children and adolescents with gender dysphoria are of very low certainty using modified GRADE. They suggest little change with GnRH analogues from baseline to follow-up.
Studies that found differences in outcomes could represent changes that are either of questionable clinical value, or the studies themselves are not reliable and changes could be due to confounding, bias or chance. 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. One study reported statistically significant reductions in the Child Behaviour Checklist/Youth Self-Report (CBCL/YSR) scores from baseline to follow up, and given that the purpose of GnRH analogues is to reduce distress caused by the development of secondary sexual characteristics and the CBCL/YSR in part measures distress, this could be an important finding. However, as the studies all lack reasonable controls not receiving GnRH analogues, the natural history of the outcomes measured in the studies is not known and any positive changes could be a regression to mean.
The results of the studies that reported bone density outcomes suggest that GnRH analogues may reduce the increase in bone density which is expected during puberty. However, as the studies themselves are not reliable, the results could be due to confounding, bias or chance. While controlled trials may not be possible, comparative studies are needed to understand this association and whether the effects of GnRH analogues on bone density are seen after treatment is stopped. All the studies that reported safety outcomes provided very low certainty evidence.
No cost-effectiveness evidence was found to determine whether or not GnRH analogues are cost-effective for children and adolescents with gender dysphoria.
The results of the studies that reported outcomes for subgroups of children and adolescents with gender dysphoria, suggest there may be differences between sex assigned at birth males (transfemales) and sex assigned at birth females (transmales). Read more
National Institute for Health and Care Excellence – NICE
This evidence review found limited evidence for the effectiveness and safety of gender-affirming hormones in children and adolescents with gender dysphoria, with all studies being uncontrolled, observational studies, and all outcomes of very low certainty. Any potential benefits of treatment must be weighed against the largely unknown long-term safety profile of these treatments.
The results from 5 uncontrolled, observational studies (Achille et al. 2020, Allen et al. 2019, Kaltiala et al. 2020. Kuper et al. 2020, Lopez de Lara et al. 2020) suggest that, in children and adolescents with gender dysphoria, gender-affirming hormones are likely to improve symptoms of gender dysphoria, and may also improve depression, anxiety, quality of life, suicidality, and psychosocial functioning. The impact of treatment on body image is unclear. All results were of very low certainty. The clinical relevance of any improvements to the person is difficult to determine because most outcomes do not have a recognised minimal clinically important difference, and the authors do not present statistical analysis for some outcomes.
A further 5 uncontrolled, observational studies (Khatchadourian et al. 2014, Klaver et al. 2020, Klink et al. 2015, Stoffers et al. 2019 and Vlot et al. 2017) reported on safety outcomes, all of which provided very low certainty evidence. Statistically significant increases in some measures of bone density were seen following treatment with gender-affirming hormones, although results varied by bone region (lumber spine versus femoral neck) and by population (transfemales versus transmales). However, z-scores suggest that bone density remained lower in transfemales and transmales compared with an equivalent cisgender population. Results from 1 study of gender-affirming hormones started during adolescence reported statistically significant increases in blood pressure and body mass index, and worsening of the lipid profile (in transmales) at age 22 years, although longer term studies that report on cardiovascular event rates are needed. Adverse events and discontinuation rates associated with gender-affirming hormones were only reported in 1 study, and no conclusions can be made on these outcomes. Read more
International clinical practice guidelines for gender minority/trans people: systematic review and quality assessment
Sara Dahlen, Dean Connolly, Isra Arif, Muhammad Hyder Junejo, Susan Bewley, Catherine Meads
Objectives To identify and critically appraise published clinical practice guidelines (CPGs) regarding healthcare of gender minority/trans people.
Design Systematic review and quality appraisal using AGREE II (Appraisal of Guidelines for Research and Evaluation tool), including stakeholder domain prioritisation.
Setting Six databases and six CPG websites were searched, and international key opinion leaders approached.
Participants CPGs relating to adults and/or children who are gender minority/trans with no exclusions due to comorbidities, except differences in sex development.
Intervention Any health-related intervention connected to the care of gender minority/trans people.
Main outcome measures Number and quality of international CPGs addressing the health of gender minority/trans people, information on estimated changes in mortality or quality of life (QoL), consistency of recommended interventions across CPGs, and appraisal of key messages for patients.
Results Twelve international CPGs address gender minority/trans people’s healthcare as complete (n=5), partial (n=4) or marginal (n=3) focus of guidance. The quality scores have a wide range and heterogeneity whichever AGREE II domain is prioritised. Five higher-quality CPGs focus on HIV and other blood-borne infections (overall assessment scores 69%–94%). Six lower-quality CPGs concern transition-specific interventions (overall assessment scores 11%–56%). None deal with primary care, mental health or longer-term medical issues. Sparse information on estimated changes in mortality and QoL is conflicting. Consistency between CPGs could not be examined due to unclear recommendations within the World Professional Association for Transgender Health Standards of Care Version 7 and a lack of overlap between other CPGs. None provide key messages for patients.
Conclusions A paucity of high-quality guidance for gender minority/trans people exists, largely limited to HIV and transition, but not wider aspects of healthcare, mortality or QoL. Reference to AGREE II, use of systematic reviews, independent external review, stakeholder participation and patient facing material might improve future CPG quality. Read more
Short-term outcomes of pubertal suppression in a selected cohort of 12 to 15 year old young people with persistent gender dysphoria in the UK
Polly Carmichael, Gary Butler, Una Masic, Tim J. Cole, Bianca L. De Stavola, Sarah Davidson, Elin M. Skageberg, Sophie Khadr, Russell M. Viner
Background In adolescents with severe and persistent gender dysphoria (GD), gonadotropin releasing hormone analogues (GnRHa) are used from early/middle puberty with the aim of delaying irreversible and unwanted pubertal body changes. Evidence of outcomes of pubertal suppression in GD is limited.
Methods We undertook an uncontrolled prospective observational study of GnRHa as monotherapy in 44 12–15 year olds with persistent and severe GD. Prespecified analyses were limited to key outcomes: bone mineral content (BMC) and bone mineral density (BMD); Child Behaviour CheckList (CBCL) total t-score; Youth Self-Report (YSR) total t-score; CBCL and YSR self-harm indices; at 12, 24 and 36 months. Semistructured interviews were conducted on GnRHa.
Results 44 patients had data at 12 months follow-up, 24 at 24 months and 14 at 36 months. All had normal karyotype and endocrinology consistent with birth-registered sex. All achieved suppression of gonadotropins by 6 months. At the end of the study one ceased GnRHa and 43 (98%) elected to start cross-sex hormones.
There was no change from baseline in spine BMD at 12 months nor in hip BMD at 24 and 36 months, but at 24 months lumbar spine BMC and BMD were higher than at baseline (BMC +6.0 (95% CI: 4.0, 7.9); BMD +0.05 (0.03, 0.07)). There were no changes from baseline to 12 or 24 months in CBCL or YSR total t-scores or for CBCL or YSR self-harm indices, nor for CBCL total t-score or self-harm index at 36 months. Most participants reported positive or a mixture of positive and negative life changes on GnRHa. Anticipated adverse events were common.
Conclusions Overall patient experience of changes on GnRHa treatment was positive. We identified no changes in psychological function. Changes in BMD were consistent with suppression of growth. Larger and longer-term prospective studies using a range of designs are needed to more fully quantify the benefits and harms of pubertal suppression in GD. Read more
Lucy Griffin, Katie Clyde, Richard Byng, Susan Bewley
In the past decade there has been a rapid increase in gender diversity, particularly in children and young people, with referrals to specialist gender clinics rising. In this article, the evolving terminology around transgender health is considered and the role of psychiatry is explored now that this condition is no longer classified as a mental illness. The concept of conversion therapy with reference to alternative gender identities is examined critically and with reference to psychiatry’s historical relationship with conversion therapy for homosexuality. The authors consider the uncertainties that clinicians face when dealing with something that is no longer a disorder nor a mental condition and yet for which medical interventions are frequently sought and in which mental health comorbidities are common. Read more
Paul W. Hruz, Lawrence S. Mayer and Paul R. McHugh
Public controversies about how institutions should treat individuals who identify as a gender that does not correspond to their biological sex have recently been debated in the halls of government, in courtrooms, and on TV talk shows. Should males who identify as women have access to women’s restrooms? Which school locker room should girls who identify as boys be permitted, or required, to use? Should teachers be compelled to use a student’s preferred pronoun, or even a gender-neutral pronoun such as “ze” instead of “he” or “she”?
Alongside these questions of public concern, however, there are quieter matters of medicine and wellbeing. How should medical and mental health professionals care for patients who identify as the opposite sex, and how should families support loved ones who do so? The stakes are high: as detailed in a recent report in these pages, people who identify as transgender are disproportionately likely to suffer from a variety of mental health problems, including depression, anxiety, suicide attempts, and suicide. Read more
A reduction in long-term spatial memory persists after discontinuation of peripubertal GnRH agonist treatment in sheep
D. Hough, M. Bellingham, I.R. Haraldsen, M. McLaughlin, J.E. Robinson, A.K. Solbakk, N.P. Evans
Chronic gonadotropin-releasing hormone agonist (GnRHa) administration is used where suppression of hypothalamic-pituitary-gonadal axis activity is beneficial, such as steroid-dependent cancers, early onset gender dysphoria, central precocious puberty and as a reversible contraceptive in veterinary medicine. GnRH receptors, however, are expressed outside the reproductive axis, e.g. brain areas such as the hippocampus which is crucial for learning and memory processes.
Previous work, using an ovine model, has demonstrated that long-term spatial memory is reduced in adult rams (45 weeks of age), following peripubertal blockade of GnRH signaling (GnRHa: goserelin acetate), and this was independent of the associated loss of gonadal steroid signaling.
The current study investigated whether this effect is reversed after discontinuation of GnRHa-treatment. The results demonstrate that peripubertal GnRHa-treatment suppressed reproductive function in rams, which was restored after cessation of GnRHa-treatment at 44 weeks of age, as indicated by similar testes size (relative to body weight) in both GnRHa-Recovery and Control rams at 81 weeks of age. Rams in which GnRHa-treatment was discontinued (GnRHa-Recovery) had comparable spatial maze traverse times to Controls, during spatial orientation and learning assessments at 85 and 99 weeks of age. Former GnRHa-treatment altered how quickly the rams progressed beyond a specific point in the spatial maze at 83 and 99 weeks of age, and the direction of this effect depended on gonadal steroid exposure, i.e. GnRHa-Recovery rams progressed quicker during breeding season and slower during non-breeding season, compared to Controls. The long-term spatial memory performance of GnRHa-Recovery rams remained reduced (P < 0.05, 1.5-fold slower) after discontinuation of GnRHa, compared to Controls.
This result suggests that the time at which puberty normally occurs may represent a critical period of hippocampal plasticity. Perturbing normal hippocampal formation in this peripubertal period may also have long lasting effects on other brain areas and aspects of cognitive function. Read more
Behavioral and neurobiological effects of GnRH agonist treatment in mice—potential implications for puberty suppression in transgender individuals
Christoph Anacker, Ezra Sydnor, Briana K. Chen, Christina C. LaGamma, Josephine C. McGowan, Alessia Mastrodonato, Holly C. Hunsberger, Ryan Shores, Rushell S. Dixon, Bruce S. McEwen, William Byne, Heino F. L. Meyer-Bahlburg, Walter Bockting, Anke A. Ehrhardt, Christine A. Denny
In the United States, ~1.4 million individuals identify as transgender. Many transgender adolescents experience gender dysphoria related to incongruence between their gender identity and sex assigned at birth. This dysphoria may worsen as puberty progresses. Puberty suppression by gonadotropin-releasing hormone agonists (GnRHa), such as leuprolide, can help alleviate gender dysphoria and provide additional time before irreversible changes in secondary sex characteristics may be initiated through feminizing or masculinizing hormone therapy congruent with the adolescent’s gender experience. However, the effects of GnRH agonists on brain function and mental health are not well understood.
Here, we investigated the effects of leuprolide on reproductive function, social and affective behavior, cognition, and brain activity in a rodent model. Six-week-old male and female C57BL/6J mice were injected daily with saline or leuprolide (20 μg) for 6 weeks and tested in several behavioral assays. We found that leuprolide increases hyperlocomotion, changes social preference, and increases neuroendocrine stress responses in male mice, while the same treatment increases hyponeophagia and despair-like behavior in females. Neuronal hyperactivity was found in the dentate gyrus (DG) of leuprolide-treated females, but not males, consistent with the elevation in hyponeophagia and despair-like behavior in females.
These data show for the first time that GnRH agonist treatment after puberty onset exerts sex-specific effects on social- and affective behavior, stress regulation, and neural activity. Investigating the behavioral and neurobiological effects of GnRH agonists in mice will be important to better guide the investigation of potential consequences of this treatment for youth experiencing gender dysphoria. Read more
Gender Dysphoria in children and young people: The implications for clinical staff of the Bell V’s Tavistock Judicial Review and Appeal Ruling
Sinead Helyar BSc, PG Dip, MSc, PhD, RN, Laura Jackson MSc, BN, Leanne Patrick RMN, MSc, Andy Hill BA, MPhil, Grad Dip CBT, RMN, Robin Ion RMN, MSc, PhD
In the past few years, there has been a very significant rise in the number of children and young people seeking treatment for gender dysphoria
This area is the subject of much discussion, as evidenced in a recent court case in the UK which examined competence and capacity of young people to consent to potentially irreversible interventions.
Clinicians involved in gaining consent to puberty blockers for gender dysphoric young people, must understand the evidence in this area and be aware of the heavy burden of accountability placed upon them. Read more
Lucy Thompson, Darko Sarovic, Philip Wilson, Angela Sämfjord, Christopher Gillberg
It is unclear whether the research literature on adolescent gender dysphoria (GD) provides sufficient evidence to adequately inform clinical decision making. In the first of a series of three papers, this study sought to systematically review published evidence regarding: the prevalence of GD in adolescence; the proportions of natal males/females with GD in adolescence and whether this changed over time; and the pattern of age at (a) onset (b) referral and (c) assessment.
Having searched PROSPERO and the Cochrane library for existing systematic reviews (and finding none), we searched Ovid Medline 1946 –October week 4 2020, Embase 1947–present (updated daily), CINAHL 1983–2020, and PsycInfo 1914–2020. The final search was carried out on the 2nd November 2020 using a core strategy including search terms for ‘adolescence’ and ‘gender dysphoria’ which was adapted according to the structure of each database. Papers were excluded if they did not clearly report on clinically-verified gender dysphoria, if they were focused on adult populations, if they did not include original data (epidemiological, clinical, or survey) on adolescents (aged at least 12 and under 18 years), or if they were not peer-reviewed journal publications.
From 6202 potentially relevant articles (post de-duplication), 38 papers from 11 countries representing between 3000 and 4000 participants were included in our final sample. Most studies were observational cohort studies, usually using retrospective record review (26). A few compared to normative or population datasets; most (31) were published in the past 5 years. There was significant overlap of study samples (accounted for in our quantitative synthesis). No population studies are available, so prevalence is not possible to ascertain.
There is evidence of an increase in frequency of presentation to services, and of a shift in the natal sex of referred cases: those assigned female at birth are now in the majority. No data were available on age of onset. Within the included samples the average age was 13 years at referral, 15 years at assessment. All papers were rated by two reviewers using the Crowe Critical Appraisal Tool v1·4 (CCAT). The CCAT quality ratings ranged from 45% to 96%, with a mean of 78%.
Almost half the included studies emerged from two treatment centres: there was considerable sample overlap and it is unclear how representative these are of the adolescent GD community more broadly. The increase in clinical presentations of GD, particularly among natal female adolescents, warrants further investigation. Whole population studies using administrative datasets reporting on GD / gender non-conformity may be necessary, along with inter-disciplinary research evaluating the lived experience of adolescents with GD. Read more
Lucy Thompson, Darko Sarovic, Philip Wilson, Angela Sämfjord, Christopher Gillberg
It is unclear whether the literature on adolescent gender dysphoria (GD) provides sufficient evidence to inform clinical decision making adequately. In the second of a series of three papers, we sought to review published evidence systematically regarding the extent and nature of mental health problems recorded in adolescents presenting for clinical intervention for GD.
Having searched PROSPERO and the Cochrane library for existing systematic reviews (and finding none), we searched Ovid Medline 1946 –October week 4 2020, Embase 1947–present (updated daily), CINAHL 1983–2020, and PsycInfo 1914–2020. The final search was carried out on the 2nd November 2020 using a core strategy including search terms for ‘adolescence’ and ‘gender dysphoria’ which was adapted according to the structure of each database. Papers were excluded if they did not clearly report on clinically-likely gender dysphoria, if they were focused on adult populations, if they did not include original data (epidemiological, clinical, or survey) on adolescents (aged at least 12 and under 18 years), or if they were not peer-reviewed journal publications.
From 6202 potentially relevant articles (post deduplication), 32 papers from 11 countries representing between 3000 and 4000 participants were included in our final sample. Most studies were observational cohort studies, usually using retrospective record review (21). A few compared cohorts to normative or population datasets; most (27) were published in the past 5 years. There was significant overlap of study samples (accounted for in our quantitative synthesis). All papers were rated by two reviewers using the Crowe Critical Appraisal Tool v1·4 (CCAT). The CCAT quality ratings ranged from 45% to 96%, with a mean of 81%.
More than a third of the included studies emerged from two treatment centres: there was considerable sample overlap and it is unclear how representative these are of the adolescent GD community more broadly. Adolescents presenting for GD intervention experience a high rate of mental health problems, but study findings were diverse. Researchers and clinicians need to work together to improve the quality of assessment and research, not least in making studies more inclusive and ensuring long-term follow-up regardless of treatment uptake. Whole population studies using administrative datasets reporting on GD / gender non-conformity may be necessary, along with inter-disciplinary research evaluating the lived experience of adolescents with GD. Read more