Article Text

Interventions to suppress puberty in adolescents experiencing gender dysphoria or incongruence: a systematic review
  1. Jo Taylor,
  2. Alex Mitchell,
  3. Ruth Hall,
  4. Claire Heathcote,
  5. Trilby Langton,
  6. Lorna Fraser,
  7. Catherine Elizabeth Hewitt
  1. Department of Health Sciences, University of York, York, UK
  1. Correspondence to Dr Jo Taylor, Health Sciences, University of York, York, North Yorkshire, UK; dohs-gender-research{at}york.ac.uk

Abstract

Background Treatment to suppress or lessen effects of puberty are outlined in clinical guidelines for adolescents experiencing gender dysphoria/incongruence. Robust evidence concerning risks and benefits is lacking and there is a need to aggregate evidence as new studies are published.

Aim To identify and synthesise studies assessing the outcomes of puberty suppression in adolescents experiencing gender dysphoria/incongruence.

Methods A systematic review and narrative synthesis. Database searches (Medline, Embase, CINAHL, PsycINFO, Web of Science) were performed in April 2022, with results assessed independently by two reviewers. An adapted version of the Newcastle-Ottawa Scale for cohort studies was used to appraise study quality. Only moderate-quality and high-quality studies were synthesised. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guidelines were used.

Results 11 cohort, 8 cross-sectional and 31 pre-post studies were included (n=50). One cross-sectional study was high quality, 25 studies were moderate quality (including 5 cohort studies) and 24 were low quality. Synthesis of moderate-quality and high-quality studies showed consistent evidence demonstrating efficacy for suppressing puberty. Height increased in multiple studies, although not in line with expected growth. Multiple studies reported reductions in bone density during treatment. Limited and/or inconsistent evidence was found in relation to gender dysphoria, psychological and psychosocial health, body satisfaction, cardiometabolic risk, cognitive development and fertility.

Conclusions There is a lack of high-quality research assessing puberty suppression in adolescents experiencing gender dysphoria/incongruence. No conclusions can be drawn about the impact on gender dysphoria, mental and psychosocial health or cognitive development. Bone health and height may be compromised during treatment. More recent studies published since April 2022 until January 2024 also support the conclusions of this review.

PROSPERO registration number CRD42021289659.

Data availability statement

Data sharing not applicable as no datasets generated and/or analysed for this study.

http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

Statistics from Altmetric.com

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

WHAT IS ALREADY KNOWN ON THIS TOPIC

  • Increasing numbers of children and adolescents experiencing gender dysphoria/incongruence are being referred to specialist gender services.

  • National and international guidelines have changed over time and outline that medications to suppress puberty can be considered for adolescents experiencing gender dysphoria/incongruence.

  • Several systematic reviews report a limited evidence base for these treatments, and uncertainty about the benefits, risks and long-term effects.

WHAT THIS STUDY ADDS

  • No high-quality studies were identified that used an appropriate study design to assess the outcomes of puberty suppression in adolescents experiencing gender dysphoria/incongruence.

  • There is insufficient and/or inconsistent evidence about the effects of puberty suppression on gender-related outcomes, mental and psychosocial health, cognitive development, cardiometabolic risk, and fertility.

  • There is consistent moderate-quality evidence, although from mainly pre-post studies, that bone density and height may be compromised during treatment.

HOW THIS STUDY MIGHT AFFECT RESEARCH, POLICY OR PRACTICE

  • There is a lack of high-quality evidence to support the use of puberty suppression in adolescents experiencing gender dysphoria/incongruence, and large well-designed research is needed.

Introduction

Over the last 10-15 years, increasing numbers of children and adolescents experiencing gender dysphoria/incongruence are being referred to specialist paediatric gender services.1 2

Gender dysphoria/incongruence in childhood is associated with high rates of co-occurring mental health and psychosocial difficulties, which can affect health and well-being.3 Clinical guidelines recommend psychosocial care to alleviate gender-related distress and any co-occurring difficulties. For pubertal adolescents, medications to suppress or lessen effects of puberty are also outlined. Gonadotropin-releasing hormone analogues (GnRH-a) are used as first-line treatment, although other drugs with anti-androgenic properties including progestins and spironolactone are used in this population.4 5 The effects differ depending on whether they are initiated in early puberty or mid-puberty, as well as the type of intervention used, with GnRH-a suppressing puberty when started early or suspending further progression when initiated in mid-puberty, and anti-androgens instead blocking specific downstream effects of sex hormones.4

Rationales for puberty suppression in the Dutch treatment protocol, which has informed practice internationally, were to alleviate worsening gender dysphoria, allow time for gender exploration, and pause development of secondary sex characteristics to make passing in the desired gender role easier.6 Practice guidelines propose other indications for puberty suppression, including allowing time and/or capacity for decision-making about masculinising or feminising hormone interventions, and improving quality of life.4 7 8

Criteria in early treatment protocols for puberty suppression specified adolescents be at least age 12 years, at Tanner stage 2 in puberty, experienced gender dysphoria in childhood which persisted and intensified during puberty and met criteria for diagnosis of gender dysphoria.6 It was also expected that any psychosocial difficulties that could interfere with treatment were managed.6 The World Professional Association for Transgender Health standards of care4 and other practice guidelines5 8 9 have broadened these criteria, for example, removing minimum age. However, other recent guidelines have taken a more cautious approach and restricted inclusion criteria in response to uncertainties in the evidence base.7 10

Systematic reviews have consistently found mainly low-quality evidence, limited data on key outcomes or long-term follow-up.11–16 These reviews report that while puberty suppression may offer some benefit, there are concerns about the impact on bone health, and uncertainty regarding cognitive development, psychosocial outcomes and cardiometabolic health. They conclude there is insufficient evidence to support clinical recommendations.

The proliferation of research in this area and lack of evidence to support practice means there is an ongoing need to aggregate evidence. This systematic review aims to synthesise evidence published to April 2022 that reports outcomes of puberty suppression in adolescents experiencing gender dysphoria/incongruence.

Methods

The review forms part of a linked series examining the epidemiology, care pathways, outcomes and experiences for children and adolescents experiencing gender dysphoria/incongruence and is reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.17 The protocol was registered on PROSPERO (CRD42021289659.18

Search strategy

A single search strategy was used to identify studies comprising two combined concepts: ‘children’, which included all terms for children and adolescents and ‘gender dysphoria’, which included associated terms such as gender-related distress and gender incongruence, and gender identity terms including transgender, gender diverse and non-binary.

MEDLINE (online supplemental table S1), EMBASE and PsycINFO through OVID, CINAHL Complete through EBSCO, and Web of Science (Social Science Citation Index) were searched (13–23 May 2021 and updated on 27 April 2022).

Reference lists of included studies and relevant systematic reviews were assessed for inclusion.11–16 19 20

Inclusion criteria

The review included published research that reported outcomes of interventions used to suppress puberty for children and/or adolescents experiencing gender dysphoria/incongruence (table 1).

Table 1

Inclusion and exclusion criteria

Selection process

The results of database and other searches were uploaded to Covidence21 and screened independently by two reviewers. Full texts of potentially relevant articles were retrieved and reviewed against inclusion criteria by two reviewers independently. Disagreements were resolved through discussion and inclusion of a third reviewer.

Data extraction

Data on study characteristics, methods and reported outcomes were extracted into prepiloted data extraction templates by one reviewer and second-checked by another.

Study quality

Critical appraisal was undertaken by two reviewers independently, with consensus reached through discussion and involvement of a third reviewer where necessary.

Quality was assessed using a modified version (online supplemental file 1) of the Newcastle-Ottawa Scale for cohort studies, a validated scale of eight items covering three domains: selection, comparability and outcome.22 Scale modification included not scoring certain question(s) for cross-sectional and single-group designs, or particular outcomes; specification of key confounders to assess comparability of cohorts; guidance regarding sufficiency of follow-up and use of numerical scores for items and overall (maximum score 9 for cohorts, 8 for pre-post and cross-sectional studies with comparator). Total scores were calculated as percentages to account for different total scores (≤50% low quality, >50%–75% moderate quality, >75% high quality).

Synthesis

Narrative synthesis methods were used because of heterogeneity in study design, intervention, comparator, outcome and measurement. Due to high risk of bias in low-quality studies, these were excluded from the synthesis.

When synthesising results by outcome domains, care was taken to differentiate between different study designs, comparators and interventions. Where possible, potential differences in effects by birth-registered sex, treatment duration or treatment in early puberty versus late puberty were examined.

Results

The database search yielded 28 147 records, 3181 of which were identified as potentially relevant for the linked systematic reviews and full texts reviewed. From these, 50 studies met inclusion criteria for this review (figure 1).

Study characteristics

Studies were published from 2006 to 2022 with the majority published in 2020–2022 (n=29). Studies were conducted in the Netherlands (n=17),23–39 the US (n=15),40–54 the UK (n=6),55–60 Canada (n=4),61–64 three in Belgium65–67 and Israel68–70 and one in Brazil71 and Germany72 (online supplemental table S2).

The 50 studies included 11 cohorts comparing adolescents experiencing gender dysphoria/incongruence receiving puberty suppression with a comparator,35 39–42 45 49 50 52 56 72 8 cross-sectional with a comparator23 33 37 47 51 53 60 71 and 31 pre-post single group studies.24–32 34 36 38 43 44 46 48 54 55 57–59 61–70 More than half of studies (n=29) used retrospective chart review.

All but 4 studies selected adolescents experiencing gender dysphoria/incongruence from specialist gender or endocrinology services: 43 from single services (in Belgium, Israel, the Netherlands and the UK these were large regional or national services) and 3 from multiple US services.48–50 The other four included three US studies (national survey recruiting via community settings,53 clinical and community settings,51 US Military Healthcare Data Repository54) and a study from Brazil recruiting via Facebook.71

Overall, studies included 10 673 participants: 9404 were adolescents experiencing gender dysphoria/incongruence (4702 received puberty suppression, 4702 did not) and 1269 other comparators. Comparator groups included adolescents or adults experiencing gender dysphoria/incongruence who had not received puberty suppression,35 39 40 42 51–53 60 71 72 untreated adolescents not experiencing gender dysphoria/incongruence,36 47 50 both of these comparators23 33 37 56 or adolescents receiving treatment for a different medical reason.41 45 49

Most studies (n=39) assessed GnRH-a. In one, some participants received GnRH-a and some (birth-registered males) spironolactone.62 In another, GnRH-a or progestins/anti-androgens were used but numbers taking each were not reported.40 Among the other 11 studies, 5 assessed effects of progestins (cyproterone acetate,66 67 lynestrenol,65 66 medroxyprogesterone44 and levonorgestrel-releasing intrauterine system41) as alternatives to GnRH-a,41 44 65–67 1 assessed bicalutamide46 and 5 did not specify.43 52–54 71

Of the 50 studies, 29 reported outcomes for feminising or masculinising hormones as well as for puberty suppression, either by including a mixed sample of those receiving the two different interventions or by assessing those who progressed to hormones following puberty suppression.

The most frequently measured outcomes were puberty suppression (n=30) and physical health outcomes (n=27) (figure 2, online supplemental table S3). Gender-related outcomes and body image were measured in five and four studies, respectively. Psychological health was measured in 13 studies, psychosocial in 9 studies and cognitive/neurodevelopmental outcomes in 3 studies. Side effects were reported in six, bone health in nine, and one study measured fertility.

Figure 2

Outcome categories by study quality and design.

Study quality

One cross-sectional study was rated high quality,37 25 moderate quality23 24 29–32 34–36 39 48–51 54–59 64 65 67–69 and 24 low quality.25–28 33 38 40–47 52 53 60–63 66 70–72 Of the 11 cohort studies, which were the only studies to include a comparator and assess outcomes over time, only 5 were rated moderate quality (figure 2, online supplemental table S4).35 39 49 50 56

In most studies, there were concerns about sample representativeness due to single site recruitment, inclusion of a selected group and/or poor reporting of the eligible population. In studies including a comparator, most did not report or control for key differences between groups and only four used matched controls.23 33 41 47 Most studies presented results for birth-registered males and females separately or controlled for this. Few studies controlled for age or Tanner stage or co-interventions that could influence outcomes.

Overall, studies used appropriate methods to ascertain exposure and assess outcomes. Adequacy of follow-up was evident in 18 studies, with multiple studies not reporting treatment duration, including participants receiving treatment at baseline, and not aligning follow-up with treatment initiation. Missing data at follow-up/analysis or poor reporting of this affected many studies.

Four studies did not report separate outcome data for adolescents receiving puberty suppression or masculinising/feminising hormones.39 54 60 71 Two of these were of moderate quality and not included in the synthesis,39 54 one of which was the only study to assess fertility outcomes.39 One moderate-quality study assessed amplitude of click-evoked otoacoustic emissions.23 This was excluded from the synthesis on the basis of not being clinically relevant.

Synthesis of outcomes

Gender dysphoria and body satisfaction

Two pre-post studies measured gender dysphoria and body satisfaction (with primary and secondary sex or neutral body characteristics) and reported no change before and after receiving treatment24 55 (table 2).

Table 2

Gender-related, body image, psychological, psychosocial, and cognitive/neurodevelopmental outcomes

Psychological health

One cross-sectional37 and two pre-post studies24 55 measured symptoms of depression (n=1), anxiety (n=1), anger (n=1), internalising and externalising symptoms (n=3), suicide and/or self-harm (n=2) and psychological functioning (n=2).

Three studies assessed internalising and externalising symptoms with one reporting improvements in both (pre-post24), one improvement in internalising but not externalising symptoms when compared with adolescents under assessment by a gender service (cross-sectional37) and one observed no change in either (pre-post).55

For other psychological outcomes, there was either a single study, or two studies showing inconsistent results, with studies reporting either a small to moderate significant improvement or no change (table 2).

Psychosocial outcomes

One cohort56 and two pre-post24 55 studies measured psychosocial functioning, one pre-post study assessed quality of life55 and one cross-sectional study measured peer-relations (table 2).37

For psychosocial functioning, both pre-post studies reported no clinically significant change at follow-up.24 55 The cohort study compared adolescents who were not immediately eligible for puberty suppression and received psychological support only, and adolescents who additionally received GnRH-a after 6 months.56 Improvements were seen in both groups after 6 months of psychological support. This improvement was maintained over time for those receiving psychological support only. For those receiving GnRH-a, further improvements were observed at 12 and 18 months. At 18 months, psychosocial functioning in this group was considerably higher than in those still waiting for puberty suppression, and similar to adolescents not experiencing gender dysphoria/incongruence. However, there were considerably fewer participants included at final follow-up.

There was no change in quality of life pre-post,55 and treated adolescents had better peer-relations compared with adolescents under assessment at a gender service but poorer peer-relations than adolescents not experiencing gender dysphoria/incongruence.37

Cognitive/neurodevelopmental outcomes

One cross-sectional study measured executive functioning and found no difference between adolescents who were treated for <1 year compared with those not treated, but worse executive functioning in those treated for >1 year compared with those not treated.51 A pre-post study found no differences in features typically associated with autism spectrum condition after treatment (table 2).59

Physical health outcomes

Bone health

Five studies found decreases in bone mineral apparent density and z-scores pre-post treatment; however, absolute measures generally remained stable or increased/decreased slightly.29 32 34 55 58 Results were similar across birth-registered males and females.29 32 55 58 One study considered timing of treatment, and found similar decreases among those starting GnRH-a in early or late puberty (table 3).32

Table 3

Physical health outcomes and side effects

Cardiometabolic health

Twelve pre-post studies measured body mass index (BMI), and in 10 studies there was no evidence of a clinically significant change in BMI and/or BMI SD score.29 30 32 34 55 57 65 67–69 In one study, BMI increased for birth-registered males but not females.58 Another study found BMI increased for birth-registered females who started GnRH-a in early puberty or mid-puberty, and birth-registered males in early puberty.36

Three studies assessed cholesterol markers, one after GnRH-a (no changes),34 one after cyproterone acetate (decrease in high-density lipoprotein (HDL) and triglycerides)67 and one after lynestrenol (decrease in HDL, increase in low-density lipoprotein).65 Three studies assessing GnRH-a reported blood pressure: two found similar systolic and diastolic blood pressure before and after treatment,34 68 and one found a non-clinically significant increase in diastolic but not systolic blood pressure.69 Two studies measured markers of diabetes (fasting glucose, HbA1c and/or insulin) and noted no changes.65 67

Other physiological parameters

Five pre-post studies assessed other parameters from blood tests undertaken at baseline and follow-up,30 31 34 65 67 three in those treated with GnRH-a,30 31 34 one lynestrenol65 and one cyproterone acetate.67 Measurements included haemoglobin count (n=3), haematocrit percentage (n=3), creatinine (n=4), aspartate aminotransferase (n=3), alanine aminotransferase (n=3), γ-glutamyl transferase (n=1), alkaline phosphatase (n=2), prolactin (n=2), free thyroxin (n=3), thyroid-stimulating hormone (n=3), sex hormone binding globulin (n=3), vitamin D levels (n=1), dehydroepiandrosterone sulfate (n=3) and androstenedione (n=2). For most outcomes, no changes were reported. Where there were changes, these were not consistent in direction across studies.

One pre-post study assessing GnRH-a reported QTc prolongation,64 and found no change in mean QTc, with no participants outside normal range.

Side effects

A cohort study of GnRH-a reported side effects including mild headaches or hot flushes (~20%) and moderate/severe headaches or hot flushes, mild fatigue, mood swings, weight gain and sleep problems (<10%) (table 3).55

Two studies assessed other medications and reported headaches and hot flushes as common and an increase in acne in a sample of birth-registered females receiving lynestrenol,65 and complaints of fatigue in birth-registered males receiving cyproterone acetate.67

Puberty suppression

Hormone levels

Hormone levels were reported in nine studies of GnRH-a (two cohort,49 50 seven pre-post30 34 36 48 55 68 69), two in birth-registered females,34 69 one in birth-registered males68 and six including both (table 4).30 36 48–50 55

Table 4

Puberty suppression outcomes

Five studies reported decreases in luteinising hormone, follicle-stimulating hormone, oestradiol and testosterone after receiving GnRH-a.30 34 48 68 69 Another study, which reported luteinising and follicle-stimulating hormones, also found decreases in both pre-post.55 One study reported that where baseline levels were high due to puberty starting, decreases were reported in testosterone and oestradiol.36 One cohort study reporting pre-post data found smaller decreases in luteinising hormone, follicle-stimulating hormone, oestradiol and testosterone compared with other studies; however, it included a younger population, some of who were likely prepubertal.50 The other cohort study included a comparator of adolescents with precocious puberty and found similar decreases in luteinising hormone and oestradiol.49

One pre-post study of lynestrenol (birth-registered females) found a decrease in luteinising hormones but not follicle-stimulating hormone, oestradiol or testosterone.65 One study of cyproterone acetate (birth-registered males) found no changes in luteinising hormone, follicle-stimulating hormone or oestradiol, but a decrease in total testosterone.67

Pubertal progression

Puberty development was reported in four studies (two cohort, two pre-post).30 35 49 67 One only included birth-registered males,67 and three included both birth-registered males and females.30 35 49

A cohort study assessing GnRH-a reported clinical pubertal escape in 2/21 adolescents treated for gender dysphoria/incongruence, in the form of breast enlargement or testicular enlargement together with deepening of voice, compared with no children treated for precocious puberty.49 A pre-post study reported a decrease in testicular volume in birth-registered males, but unclear results with regard to breast development in birth-registered females (most started treatment at Tanner stage 4–5).30 A pre-post study of birth-registered males using cyproterone acetate reported decreases in facial shaving and spontaneous erections.67

A cohort study assessed whether secondary sex characteristics differed depending on receipt or timing of GnRH-a, and whether this affected which surgical interventions/techniques were later used.35 The study found breast size was smallest in birth-registered females who received GnRH-a in Tanner stage 2/3 and largest in untreated participants. Those treated early in puberty were less likely to require a mastectomy and when surgery was required it was less burdensome. In birth-registered males, penile length was greater in those who received GnRH-a at Tanner stage 4/5 compared with Tanner stage 2/3, and greatest in untreated participants.35 Those who received GnRH-a early required more invasive vaginoplasty techniques than those who received it later or not at all.

Menstrual suppression

Three studies (one cohort, two pre-post) measured menstrual suppression in birth-registered females, and found full suppression at follow-up,30 49 55 which was similar to the effect seen in those with precocious puberty in the cohort study.49

Height/Growth

Eleven studies (1 cohort,50 10 pre-post29 30 32 34 36 55 57 58 65 67) reported height, nine after GnRH-a,29 30 32 34 36 50 55 57 58 one lynestrenol65 and one cyproterone acetate.67 The cohort study found a similar height velocity between the GnRH-a group and adolescent controls.50 Six studies reported height Z or SD score29 30 34 55 57 67 with two studies finding no change,34 55 two a decrease for birth-registered males but not females,29 57 one a decrease across birth-registered males and females30 and one a decrease in birth-registered males with cyproterone acetate.67 Absolute measures of height generally increased slightly or remained the same.29 30 32 34 36 58 65 67

Body composition

Two studies reported changes in body composition pre-post,30 57 reporting a significant decrease in lean mass SD score57 and percentage30 in males and females. One also measured body fat percentage and reported significant increases in both groups.30

Bone geometry

One pre-post study measured the subperiosteal width and endocortical diameter of the hip bone and found that in birth-registered males these increased in those starting GnRH-a in early puberty and mid-puberty, but only in the early puberty group for birth-registered females.36

Discussion

This systematic review identified 50 studies reporting outcomes relating to puberty suppression in adolescents experiencing gender dysphoria/incongruence. No high-quality studies using an appropriate design were identified, and only four measured gender dysphoria as an outcome. Only 5 of the 11 cohort studies, which were the only studies to compare groups over time, were rated as moderate quality.35 40 49 50 56

There was evidence from multiple mainly pre-post studies that puberty suppression exerts its expected physiological effect, as previously demonstrated in children with precocious puberty.73 In adolescents experiencing gender dysphoria/incongruence, puberty suppression is initiated at different stages of puberty,74 and two studies found that the effects on secondary sex characteristics may vary depending on whether treatment is initiated in early puberty versus mid-puberty, with potentially different outcomes for birth-registered males and females.30 35 Multiple studies also found that bone density is compromised during puberty suppression, and gains in height may lag behind that seen in other adolescents. High-quality research is needed to confirm these findings; however, these potential risks should be explained to adolescents considering puberty suppression.

These findings add to other systematic reviews in concluding there is insufficient and/or inconsistent evidence about the effects of puberty suppression on gender dysphoria, body satisfaction, psychological and psychosocial health, cognitive development, cardiometabolic risk and fertility.11–16 Regarding psychological health, one recent systematic review14 reported some evidence of benefit while others have not. The results in this review found no consistent evidence of benefit. Inclusion of only moderate-quality to high-quality studies may explain this difference, as 8 of the 12 studies reporting psychological outcomes were rated as low-quality.

The lack of representativeness of samples and comparability of selected control groups were key concerns across studies. Only one study attempted to compare puberty suppression with psychosocial care, which is the only other treatment offered for gender dysphoria/incongruence in childhood, and this included a small sample, limited analyses, and little detail about the intervention.56 Other studies lacked information about any psychological care provided to participants, and in studies that included a comparator there was limited information about any differences between groups. Large, well-designed studies with appropriate comparators that enable long-term outcomes of puberty suppression to be measured are needed.

Many studies reported effects of both puberty suppressants and hormones used in later adolescence for feminisation/masculinisation. In adolescents, GnRH-a often continues during hormone treatment,74 or for adolescents who do not receive puberty suppression, GnRH-a or other anti-androgens may be offered at initiation of hormones.66 This makes long-term follow-up of puberty suppression difficult to assess, including any differences between the types of interventions that are offered and when these are initiated, and the few studies reporting long-term outcomes either did not control for this or reported overall effects for both interventions. Although recent studies suggest nearly all adolescents who receive puberty suppression go on to feminising/masculinising hormones,74–76 research is still needed to assess whether suppression will have any lasting effects for those who do not. Aggregation of studies reporting proportions of adolescents who progress to hormones and reasons for discontinuation would also offer useful insights.

Included studies assessed different outcomes across various outcome domains and employed multiple different measures. Agreement about the primary aim and related core outcomes of puberty suppression in this population would help to ensure studies measure key outcomes and facilitate future aggregation of evidence. Expert consensus recommendations to guide the methods and domains for assessing the neurodevelopmental effects of puberty suppression have been developed77; however, there is currently no agreement across other outcome domains.

Strengths and limitations

Strengths include a published protocol with robust search strategies, use of PRISMA guidelines and comprehensive synthesis of moderate and high quality studies. Poor reporting across studies may have resulted in moderate-quality studies being rated low-quality and excluded from synthesis. As searches were conducted up to April 2022, this review does not include more recently published studies. However, the findings are in line with previous reviews despite the inclusion of numerous additional studies. In an update of the National Institute for Health and Care Excellence evidence review of GnRH-a performed in April 2023,78 nine additional studies were identified, two of which they felt might materially affect their conclusions.72 74 One was already included in this review,72 and the other examined treatment trajectories which was not an outcome of interest.74

Of other studies that we are aware have been published since April 2022 until January 2024, very few used a cohort design or an appropriate comparator and were of a similar low quality to moderate quality as the studies summarised in this review. Of those likely to contribute new data for synthesis, five examined physical growth and development,79–83 one cardiometabolic health84 and one psychological health.85 The latter, a study from the US, found that adolescents who received puberty suppression before assessment for masculinising or feminising hormones had fewer symptoms of depression, anxiety, stress and suicidal thoughts compared with those who had not received puberty suppression. A sensitivity analysis found similar results, although no difference in suicidal thoughts.85 Adding this study would provide no further clarity about whether puberty suppression improves psychological health due to the inconsistency of results between studies, and the limited high-quality research measuring these outcomes.

Two studies from the Netherlands found that height growth and bone maturation both decelerated during GnRH-a treatment,80 81 and a third assessing only bone health found the same.83 A Belgian study found stable height growth in birth-registered females but deceleration in birth-registered males.82 These studies add strength to the conclusion that bone health and adult height may be compromised during GnRH-a, although like in previous studies the participants went on to receive masculinising or feminising hormones, and therefore the long-term outcomes of puberty suppression alone were not possible to determine.

Another new study, also from the Netherlands, assessed changes in body composition.79 This found that in both birth-registered males and females lean mass z-scores decreased during puberty suppression and fat mass z-scores increased, although the rate and duration of change differed by birth-registered sex. These changes were also found in the two studies synthesised,30 57 but as all three included no comparator uncertainty continues about the effect of puberty suppression on body composition.

A large study of adults in the US examined whether receipt of hormone interventions during adolescence was associated with cardiometabolic-related diagnoses, and for GnRH-a found no statistically significant differences for any diagnosis.84 However, the study uses a retrospective cross-sectional design and is the only study to have examined cardiometabolic diagnoses, so no conclusions can be drawn about these outcomes.

To our knowledge, there are no additional moderate-quality or high-quality studies that have measured psychosocial or fertility outcomes, and only a single study assessing cognitive effects which measured a different outcome (white matter microstructure) to those included in this review.86

Conclusions

There are no high-quality studies using an appropriate study design that assess outcomes of puberty suppression in adolescents experiencing gender dysphoria/incongruence. No conclusions can be drawn about the effect on gender-related outcomes, psychological and psychosocial health, cognitive development or fertility. Bone health and height may be compromised during treatment. High-quality research and agreement on the core outcomes of puberty suppression are needed.

Data availability statement

Data sharing not applicable as no datasets generated and/or analysed for this study.

Ethics statements

Patient consent for publication

References

Supplementary materials

Footnotes

  • Contributors LF, CEH, RH, TL and JT contributed to the conception of this review. RH, CEH, CH, AM and JT contributed to screening and selection. AM and JT completed data extraction. CEH, RH, AM and JT contributed to critical appraisal. CEH, AM and JT completed the synthesis and drafted the manuscript. All authors contributed to interpretation and reviewed and approved the manuscript prior to submission. CEH accepts full responsibility for the finished work and/or the conduct of the study, had access to the data, and controlled the decision to publish.

  • Funding This work was funded by NHS England to inform the Cass Review (Independent review of gender identity services for children and young people). The funder and Cass Review team had a role in commissioning the research programme but no role in the study conduct, interpretation or conclusion.

  • Competing interests None declared.

  • Provenance and peer review Commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

Linked Articles