Video Abstract

Video Abstract

Close modal
BACKGROUND AND OBJECTIVES

Puberty onset and development contribute substantially to adolescents’ bone mass and body composition. Our objective with this study was to examine the effects of gonadotropin-releasing hormone agonists (GnRHa) on these puberty-induced changes among youth with gender dysphoria (GD).

METHODS

Medical records of the endocrine diversity clinic in an academic children’s hospital were reviewed for youth with GD seen from January 2006 to April 2017 with at least 1 baseline dual-energy radiograph absorptiometry measurement.

RESULTS

At baseline, transgender females had lower lumbar spine (LS) and left total hip (LTH) areal bone mineral density (aBMD) and LS bone mineral apparent density (BMAD) z scores. Only 44.7% of transgender youth were vitamin D sufficient. Baseline vitamin D status was associated with LS, LTH aBMD, and LS BMAD z scores. Post-GnRHa assessments revealed a significant drop in LS and LTH aBMD z scores (transgender males and transgender females) without fractures and LS BMAD (transgender males), an increase in gynoid (fat percentage), and android (fat percentage) (transgender males and transgender females), and no changes in BMI z score.

CONCLUSIONS

GnRHa monotherapy negatively affected bone mineral density of youth with GD without evidence of fractures or changes in BMI z score. Transgender youth body fat redistribution (android versus gynoid) were in keeping with their affirmed gender. The majority of transgender youth had vitamin D insufficiency or deficiency with baseline status associated with bone mineral density. Vitamin D supplementation should be considered for all youth with GD.

What’s Known on This Subject:

Despite short-term efficacy and safety of gonadotropin-releasing hormone agonist (GnRHa) to suppress puberty in youth with gender dysphoria, evidence on the potential impacts of GnRHa monotherapy on bone mass accrual and body composition and the role of vitamin D status is limited.

What This Study Adds:

GnRHa monotherapy for gender dysphoria negatively affected bone mineral density without changes in BMI z score. Transgender youth fat redistribution (android/gynoid) and transgender females lean body mass and total body fat changes were in keeping with their affirmed gender. Most transgender youth had low vitamin D levels at baseline.

The number of youth with gender dysphoria (GD) seeking gender-affirming care has increased significantly.14  Endocrine Society5  and World Professional Association for Transgender Health6  guidelines recommend gonadotropin-releasing hormone agonists (GnRHas) for puberty suppression in youth with GD who are in Tanner stages 2 to 5. Efficacy and safety of GnRHa to arrest pubertal development in central precocious puberty is well described7  with short-term efficacy and safety of GnRHa in youth with GD.8,9  However, there are concerns about puberty suppression effects on bone mass accrual of youth with GD5,811  because sex steroids are fundamental for bone acquisition during puberty and maintenance of bone mass in adulthood.12,13  In small studies, researchers have found that GnRHa in youth with GD are associated with decreased bone mineral density (BMD) z scores and bone turnover markers.11,1417  Periodic monitoring of BMD by dual-energy radiograph absorptiometry (DXA) in youth with GD is currently recommended by the Endocrine Society5  and International Society for Clinical Densitometry.18  The scarcity of evidence on effects of GnRHa on bone health and body composition of youth with GD motivated us to retrospectively review all youth with GD managed at the endocrine diversity clinic of the Children’s Hospital of Eastern Ontario (CHEO). In addition, we aimed to characterize vitamin D status of youth with GD and its relationship with bone health, as well as assess efficacy of supplemental vitamin D with 1000 to 2000 IU daily.

Medical records of the 198 youth <18 years of age seen at the endocrine diversity clinic at CHEO from January 2006 to April 2017 were retrospectively reviewed, and the 172 youth (86.9%) with at least 1 DXA measurement were included in this study. To allow a minimum follow-up time of 18 months, the study population’s medical records were last reviewed in January 2019. GD diagnosis was based on adolescent medicine specialist assessments, which typically preceded the referral to the endocrine diversity clinic.

Our center uses the GnRHa formulation of leuprolide acetate, historically starting with 3 doses of 7.5 mg intramuscularly every 4 weeks, followed by 11.25 mg intramuscularly every 12 weeks after confirmation of puberty suppression clinically and biochemically. GD management includes areal bone mineral density (aBMD) measurements by DXA with Lunar Prodigy system, and aBMD z scores are determined on the basis of birth-assigned sex, age, and ethnicity. Lumbar spine (LS) (L2–L4) and left total hip (LTH) aBMD z scores are usually assessed at baseline and every 12 months; however, youth with an aBMD z score below 2 SDs or significant drop (≥ 1 SD) in LS aBMD z score undergo BMD every 6 months and a lateral spine radiograph for vertebral fracture assessment. Youth with poor calcium intake are advised to take calcium carbonate 500 mg twice daily to meet the Institute of Medicine’s19  recommended dietary allowance. All youth are advised to take vitamin D 1000 to 2000 IU daily. Serum 25-hydroxyvitamin D (25OHD) levels are assessed at baseline and monitored every 6 to 12 months. Vitamin D status is classified on the basis of 25OHD level, with <30 nmol/L indicating deficiency, 30 to 50 nmol/L indicating insufficiency, and >50 nmol/L indicating sufficiency.20 

Given the retrospective nature of the study and variable timing of baseline and follow-up DXA results relative to GnRHa initiation, pre-GnRHa DXA was defined as DXA scan within “−180 to +30” days of GnRHa initiation. Post-GnRHa DXA was defined as DXA scan at “≥ +180” days of GnRHa initiation, as long as this assessment was completed within 90 days of gender-affirming hormone initiation or GnRHa discontinuation.

Birth-assigned sex, affirmed gender, Tanner stage at initial assessment, and anthropometrics (height and weight) at baseline and follow-up visits were retrieved from medical records. BMI z score was calculated on the basis of 2014 revised World Health Organization growth charts for Canada.21 

Pre- and post-GnRHa DXA results were used to retrieve aBMD (grams per square centimeters) of LS, LTH, and total body less head (TBLH). Volumetric BMD was calculated as bone mineral apparent density (BMAD) (grams per cubic centimeters) at LS by using the method of Kroger et al22  as “LS aBMD × [4/(π × width)].” LS BMAD z score was calculated on the basis of available reference for age-matched birth-assigned gender BMAD mean and SD.23 

DXA is the most readily available and valid method of 3 compartmental body analyses.24  In this study, we used pre- and post-GnRHa DXA results to extract the following variables: lean body mass (LBM) (kilograms), total body fat (TBF) (percentage), TBF (kilograms), regional fat mass ratios (ie, trunk/total, legs/total, and extremities/total), fat distribution in the form of android (fat percentage) and gynoid (fat percentage), as well as bone mineral content (BMC) (kilograms) and BMC z score. TBF (percentage) z score was calculated on the basis of age-matched birth-assigned sex TBF (percentage), with mean and SD as “logarithm natural (Ln) TBF (%) – (Ln TBF (%) mean/Ln TBF (%) SD)” for transgender females and Ln “(TBF (%) +10) – (Ln TBF (%) mean/Ln TBF (%) SD)” for transgender males.23  LBM z score was calculated on the basis of age-matched birth-assigned sex LBM mean and SD.23 

Normally distributed data were expressed as mean ± SD and compared with the paired sample t test. Data that were not normally distributed were expressed as median and interquartile range and the Wilcoxon rank test used for comparison. P < .05 was considered statistically significant. However, bond percolation threshold was also used to determine statistical significance, corrected for multiple testing.

The study included 172 youth with GD; 119 (69.2%) youth self-identified as transgender males (age 15.2 ± 1.8 [SD] years; 90.7% Tanner 4–5), 51 (29.7%) youth as transgender females (age 15.4 ± 2.0 years; 80.3% Tanner 4–5), and 2 (1.1%) youth as nonbinary. Baseline body composition and BMD profiles are summarized in Table 1; transgender females had lower z scores at LS aBMD, LS BMAD, LTH aBMD, and BMC than transgender males.

TABLE 1

Baseline Body Composition and BMD Profiles at LS and LTH

Transgender Males (n = 119)Transgender Females (n = 51)Pa
Mean (SD)Median (IQR)Mean (SD)Median (IQR)
LS      
 aBMD, g/cm2 1.13 (0.17) 1.16 (1.04 to 1.25) 0.98 (0.18) 0.968 (0.84 to 1.13) <.001 
 aBMD z score 0.04 (1.10) 0.1 (−0.70 to 0.70) −0.84 (1.29) −0.9 (−1.8 to 0.00) <.001 
 BMAD, g/cm3 0.37 (0.46) 0.38 (0.33 to 0.41) 0.31 (0.04) 0.31 (0.29 to 0.34) <.001 
 BMAD z score −0.10 (1.00) 0.01 (−0.88 to 0.64) −0.22 (1.41) −0.08 (−0.99 to 0.64) <.001 
LTH      
 aBMD, g/cm2 1.00 (0.15) 1.02 (0.90 to 1.11) 0.95 (0.16) 0.94 (0.813 to 1.10) NS 
 aBMD z score 0.10 (1.06) 0.2 (−0.70 to 0.90) −0.44 (1.39) −0.5 (−1.60 to 0.30) <.001 
BMC, kg 2.40 (0.54) 2.40 (2.00 to 2.74) 2.39 (0.65) 2.27 (1.96 to 2.83) NS 
BMC z score 0.05 (1.30) 0.05 (−0.86 to 0.93) −0.66 (1.35) −0.91 (−1.58 to 0.13) .001 
LBM, kg 36.24 (56.14) 36.46 (32.81 to 39.75) 45.74 (9.98) 44.66 (39.27 to 53.55) .005 
LBM z score −1.03 (1.22) −1.15 (−1.86 to −0.34) −1.19 (1.45) −1.41 (−2.4 to −0.24) NS 
TBF, % 37.14 (10.46) 37 (29.10 to 45.80) 24.45 (12.48) 24.2 (14.60 to 37) <.001 
TBF z score, % 1.68 (0.96) 1.76 (1.04 to 2.44) 1.42 (1.02) 1.58 (0.62 to 2.38) NS 
BMI 24.04 (5.17) 22.99 (20.04 to 27.66) 23.22 (6.33) 20.38 (18.30 to 26.61) NS 
BMI z score 0.89 (1.25) 0.86 (0.07 to 1.85) 0.62 (1.67) 0.72 (−0.67 to 2.04) NS 
Transgender Males (n = 119)Transgender Females (n = 51)Pa
Mean (SD)Median (IQR)Mean (SD)Median (IQR)
LS      
 aBMD, g/cm2 1.13 (0.17) 1.16 (1.04 to 1.25) 0.98 (0.18) 0.968 (0.84 to 1.13) <.001 
 aBMD z score 0.04 (1.10) 0.1 (−0.70 to 0.70) −0.84 (1.29) −0.9 (−1.8 to 0.00) <.001 
 BMAD, g/cm3 0.37 (0.46) 0.38 (0.33 to 0.41) 0.31 (0.04) 0.31 (0.29 to 0.34) <.001 
 BMAD z score −0.10 (1.00) 0.01 (−0.88 to 0.64) −0.22 (1.41) −0.08 (−0.99 to 0.64) <.001 
LTH      
 aBMD, g/cm2 1.00 (0.15) 1.02 (0.90 to 1.11) 0.95 (0.16) 0.94 (0.813 to 1.10) NS 
 aBMD z score 0.10 (1.06) 0.2 (−0.70 to 0.90) −0.44 (1.39) −0.5 (−1.60 to 0.30) <.001 
BMC, kg 2.40 (0.54) 2.40 (2.00 to 2.74) 2.39 (0.65) 2.27 (1.96 to 2.83) NS 
BMC z score 0.05 (1.30) 0.05 (−0.86 to 0.93) −0.66 (1.35) −0.91 (−1.58 to 0.13) .001 
LBM, kg 36.24 (56.14) 36.46 (32.81 to 39.75) 45.74 (9.98) 44.66 (39.27 to 53.55) .005 
LBM z score −1.03 (1.22) −1.15 (−1.86 to −0.34) −1.19 (1.45) −1.41 (−2.4 to −0.24) NS 
TBF, % 37.14 (10.46) 37 (29.10 to 45.80) 24.45 (12.48) 24.2 (14.60 to 37) <.001 
TBF z score, % 1.68 (0.96) 1.76 (1.04 to 2.44) 1.42 (1.02) 1.58 (0.62 to 2.38) NS 
BMI 24.04 (5.17) 22.99 (20.04 to 27.66) 23.22 (6.33) 20.38 (18.30 to 26.61) NS 
BMI z score 0.89 (1.25) 0.86 (0.07 to 1.85) 0.62 (1.67) 0.72 (−0.67 to 2.04) NS 

NS, nonsignificant.

a

t test.

At baseline, the majority (55.2%) of transgender youth were found to have vitamin D deficiency or insufficiency (Table 2). Baseline vitamin D status was associated with baseline LS aBMD, LS BMAD, and LTH z scores (Fig 1). Supplementation with 1000 to 2000 IU of vitamin D daily improved the vitamin D status with no case of vitamin D toxicity (Table 2).

FIGURE 1

Pre-GnRHa BMD profiles and baseline vitamin D status.

FIGURE 1

Pre-GnRHa BMD profiles and baseline vitamin D status.

Close modal
TABLE 2

Vitamin D Status Among Youth With GD

nVitamin D Status, n (%)
DeficiencyaInsufficiencybSufficiencyc
Baseline 170 30 (17.6) 64 (37.6) 76 (44.6) 
First follow-up 146 5 (3.4) 26 (17.8) 115 (78.8) 
Second follow-up 110 4 (3.6) 19 (17.3) 87 (79.1) 
Third follow-up 63 1 (1.6) 7 (11.1) 55 (87.3) 
nVitamin D Status, n (%)
DeficiencyaInsufficiencybSufficiencyc
Baseline 170 30 (17.6) 64 (37.6) 76 (44.6) 
First follow-up 146 5 (3.4) 26 (17.8) 115 (78.8) 
Second follow-up 110 4 (3.6) 19 (17.3) 87 (79.1) 
Third follow-up 63 1 (1.6) 7 (11.1) 55 (87.3) 
a

25OHD <30 nmol/L.

b

25OHD 30 to 50 nmol/L.

c

25OHD >50 to 250 nmol/L.

A subgroup of the study population, namely, 36 (30.5%) transgender females and 80 (67.8%) transgender males with pre- and post-GnRHa DXA, was analyzed for GnRHa-associated changes. Pre-GnRHa DXA was done −51.4 ± 41.3 days (range −158 to +28 days) relative to GnRHa initiation; post-GnRHa DXA was done 355.2 ± 96.7 days or median of 352.5 (294.5, 385.8) days (range 188–676 days) after GnRHa initiation. The mean time interval between pre- and post-DXA scans was 406.7 ± 98.3 days (range 210–720 days).

BMD profiles and body composition after GnRHa as well as corresponding changes relative to baseline characteristics are summarized in Table 3. LS, LTH, and TBLH aBMD z scores dropped significantly among both transgender males and transgender females, whereas LS BMAD z scores decreased significantly among transgender males. Considering the limited number of transgender youth at early stages of puberty,2,3  no statistical comparison of subgroups based on puberty status was done.

TABLE 3

Body Composition Analysis and BMD Profile of Youth With GD After GnRHa

Transgender Males (n = 80)P,a SSbTransgender Females (n = 36)P, SS
Post-GnRHa Mean (SD)Δ Post-Pre Mean (95% CI)Post-GnRHa Mean (SD)Δ Post-Pre Mean (95% CI)
BMD changes       
 LS aBMD z score −0.72 (0.97) −0.74 (−0.85 to −0.63) <.001 S −1.33 (1.39) −0.33 (−0.46 to −0.19) <.001 S 
 LS BMAD z score −0.76 (0.93) −0.59 (−0.74 to −0.45) <.001 S −0.76 (1.48) −0.37 (−0.61 to −0.14) .003 NS 
 LTH aBMD z score −0.31 (0.99) −0.33 (−0.40 to −0.26) <.001 S −1.03 (1.64) −0.46 (−0.60 to −0.31) <.001 S 
 TBLH aBMD z score 0.03 (1.05) −0.34 (−0.43 to −0.25) <.001 S −0.48 (1.49) −0.34 (−0.48 to −0.21) <.001 S 
Body composition changes       
 BMI 25.12 (6.04) 1.36 (0.75 to 1.97) <.001 S 23.18 (6.64) 0.57 (−0.46 to 1.60) .120 
 BMI z score 0.99 (1.30) 0.15 (0.01 to 0.29) .083 0.45 (1.69) −0.10 (−0.38 to 0.17) .475 
 TT-FMR 0.49 (0.04) 0.00 (−0.01 to 0.01) 1.0 0.48 (0.05) −0.02 (−0.03 to 0.00) .010 NS 
 LT-FMR 0.38 (0.04) 0.00 (−0.01 to 0.00) .209 0.39 (0.04) 0.01 (0.00 to 0.02) .013 NS 
 ET-FMR 0.97 (0.17) 0.00 (−0.02 to 0.02) .813 1.03 (0.19) 0.08 (0.02 to 0.13) .004 NS 
 Android, fat % 42.21 (12.36) 2.75 (1.21 to 4.28) <.001 S 33.41 (13.97) 4.18 (1.09 to 7.28) .002 NS 
 Gynoid, fat % 46.76 (7.81) 1.83 (0.77 to 2.88) <.001 S 38.70 (9.30) 7.17 (4.64 to 9.69) <.001 S 
 TBF, kg 25.00 (12.48) 2.19 (0.75 to 3.63) .001 S 20.44 (13.57) 4.41 (2.22 to 6.60) <.001 S 
 TBF, % 39.93 (10.03) 2.21 (0.99 to 3.43) <.001 S 31.14 (11.62) 5.36 (2.83 to 7.88) <.001 S 
 TBF, z score, % 1.78 (0.90) 0.13 (0.00 to 0.25) .053 2.46 (0.51) 1.05 (0.79 to 1.32) <.001 S 
 LBM, kg 37.45 (5.55) 1.05 (0.45 to 1.64) <.001 S 43.17 (7.86) −1.58 (−3.0 to −0.15) .006 NS 
 LBM z score −1.01 (1.28) −0.02 (−0.16 to 0.12) .891 −1.99 (1.58) −0.73 (−0.95 to −0.5) <.001 S 
 BMC, kg 2.37 (0.43) 0.006 (−0.03 to 0.04) .998 2.40 (0.46) 0.15 (0.10 to 0.20) <.001 S 
 BMC z score −0.39 (1.12) −0.39 (−0.51 to −0.28) <.001 S −0.99 (1.18) −0.12 (−0.26 to 0.02) .059 
Transgender Males (n = 80)P,a SSbTransgender Females (n = 36)P, SS
Post-GnRHa Mean (SD)Δ Post-Pre Mean (95% CI)Post-GnRHa Mean (SD)Δ Post-Pre Mean (95% CI)
BMD changes       
 LS aBMD z score −0.72 (0.97) −0.74 (−0.85 to −0.63) <.001 S −1.33 (1.39) −0.33 (−0.46 to −0.19) <.001 S 
 LS BMAD z score −0.76 (0.93) −0.59 (−0.74 to −0.45) <.001 S −0.76 (1.48) −0.37 (−0.61 to −0.14) .003 NS 
 LTH aBMD z score −0.31 (0.99) −0.33 (−0.40 to −0.26) <.001 S −1.03 (1.64) −0.46 (−0.60 to −0.31) <.001 S 
 TBLH aBMD z score 0.03 (1.05) −0.34 (−0.43 to −0.25) <.001 S −0.48 (1.49) −0.34 (−0.48 to −0.21) <.001 S 
Body composition changes       
 BMI 25.12 (6.04) 1.36 (0.75 to 1.97) <.001 S 23.18 (6.64) 0.57 (−0.46 to 1.60) .120 
 BMI z score 0.99 (1.30) 0.15 (0.01 to 0.29) .083 0.45 (1.69) −0.10 (−0.38 to 0.17) .475 
 TT-FMR 0.49 (0.04) 0.00 (−0.01 to 0.01) 1.0 0.48 (0.05) −0.02 (−0.03 to 0.00) .010 NS 
 LT-FMR 0.38 (0.04) 0.00 (−0.01 to 0.00) .209 0.39 (0.04) 0.01 (0.00 to 0.02) .013 NS 
 ET-FMR 0.97 (0.17) 0.00 (−0.02 to 0.02) .813 1.03 (0.19) 0.08 (0.02 to 0.13) .004 NS 
 Android, fat % 42.21 (12.36) 2.75 (1.21 to 4.28) <.001 S 33.41 (13.97) 4.18 (1.09 to 7.28) .002 NS 
 Gynoid, fat % 46.76 (7.81) 1.83 (0.77 to 2.88) <.001 S 38.70 (9.30) 7.17 (4.64 to 9.69) <.001 S 
 TBF, kg 25.00 (12.48) 2.19 (0.75 to 3.63) .001 S 20.44 (13.57) 4.41 (2.22 to 6.60) <.001 S 
 TBF, % 39.93 (10.03) 2.21 (0.99 to 3.43) <.001 S 31.14 (11.62) 5.36 (2.83 to 7.88) <.001 S 
 TBF, z score, % 1.78 (0.90) 0.13 (0.00 to 0.25) .053 2.46 (0.51) 1.05 (0.79 to 1.32) <.001 S 
 LBM, kg 37.45 (5.55) 1.05 (0.45 to 1.64) <.001 S 43.17 (7.86) −1.58 (−3.0 to −0.15) .006 NS 
 LBM z score −1.01 (1.28) −0.02 (−0.16 to 0.12) .891 −1.99 (1.58) −0.73 (−0.95 to −0.5) <.001 S 
 BMC, kg 2.37 (0.43) 0.006 (−0.03 to 0.04) .998 2.40 (0.46) 0.15 (0.10 to 0.20) <.001 S 
 BMC z score −0.39 (1.12) −0.39 (−0.51 to −0.28) <.001 S −0.99 (1.18) −0.12 (−0.26 to 0.02) .059 

ET-FMR, extremities/trunk fat mass ratio; LT-FMR, legs/total fat mass ratio; NS, not significant; S, statistically significant; TT-FMR, trunk/total fat mass ratio.

a

Wilcoxon rank test.

b

Statistical significance of .0011 to correct for multiple testing.

Four transgender youth (one birth-assigned girl and 3 birth-assigned males) had a baseline LS aBMD z score below 2 SDs, with 20 transgender youth (all transgender males) having >1-SD drop (1.37 ± 0.26) in their follow-up LS aBMD z score. Each of these youth had a subsequent lateral spine radiograph, none of which revealed a vertebral fracture.

Transgender males’ post-GnRHa body composition analysis revealed significant increases in BMI, LBM (kilograms), TBF (percentage), android (fat percentage), and gynoid (fat percentage); there was no significant change in BMI z score, LBM z score, or TBF (%) z score. Transgender females showed a significant increase in TBF (percentage), TBF (percentage) z score, and gynoid (fat percentage), as well as a drop in LBM z score. GnRHa-associated changes in body compartment z scores and BMI z score were not different between transgender youth with baseline BMI percentiles above and below the obesity risk (85%) cutoff percentile (Table 4).

TABLE 4

GnRHa-Induced Body Compartment and BMI Changes Among Transgender Youth Subdivided by Baseline BMI Percentile at Cutoff for Obesity Risk

BMI ≤85 PercentileBMI >85 PercentileDifference (95% CI)Pa Value, SSb
nMean (SD)nMean (SD)
Δ BMI z score 71 0.11 (0.62) 47 0.00 (0.79) 0.11 (−0.14 to 0.37) 0.867, NS 
Δ TBF z score, % 71 0.58 (0.91) 47 0.19 (0.44) 0.39 (0.11 to 0.67) 0.050, NS 
Δ LBM z score 71 −0.31 (0.66) 47 −0.15 (0.81) −0.15 (−0.42 to 0.11) 0.292, NS 
Δ BMC z score 71 −0.26 (0.49) 47 −0.37 (0.49) 0.11 (−0.07 to 0.30) 0.326, NS 
BMI ≤85 PercentileBMI >85 PercentileDifference (95% CI)Pa Value, SSb
nMean (SD)nMean (SD)
Δ BMI z score 71 0.11 (0.62) 47 0.00 (0.79) 0.11 (−0.14 to 0.37) 0.867, NS 
Δ TBF z score, % 71 0.58 (0.91) 47 0.19 (0.44) 0.39 (0.11 to 0.67) 0.050, NS 
Δ LBM z score 71 −0.31 (0.66) 47 −0.15 (0.81) −0.15 (−0.42 to 0.11) 0.292, NS 
Δ BMC z score 71 −0.26 (0.49) 47 −0.37 (0.49) 0.11 (−0.07 to 0.30) 0.326, NS 

NS, nonsignificant.

a

Wilcoxon rank test.

b

Statistical significance of .01 to correct for multiple testing.

With this study, we reviewed BMD and body composition changes in youth with GD after 355.2 ± 96.7 days of GnRHa monotherapy. Youth identifying as transgender males constituted 69.2% of study population in keeping with the current trend of overrepresentation (50%–90%) of birth-assigned female patients in GD clinics.3,25,26 

Baseline BMD characteristics were remarkable for transgender females’ lower LS aBMD and BMAD z scores compared with those of transgender males. Similar baseline differences were previously observed in studies among youth11,14,15,17  and adult27  transgender females. Klink et al15  suggested that lower engagement in physical activities, as is typical for transgender females, is a factor, as well as pubertal stage. Despite lack of consistent records of physical activity among our study population, literature supports reduced involvement of sexual minorities in moderate to vigorous physical activities and team sports.28  We believe it is prudent to consider evaluating physical activity level as part of baseline and follow-up assessments of youth with GD, although lack of objective scales or specific recommendations from the Endocrine Society or World Professional Association for Transgender Health5,6  are challenges in clinical practice.

Baseline body composition comparison of transgender males and transgender females was remarkable for lower BMC z score among transgender females and no difference in LBM and TBF (percentage) z scores. Of note, both transgender males and transgender females had higher baseline TBF and lower baseline LBM relative to the birth-assigned sex population; however, only transgender females had a lower baseline BMC z score. The latter is likely secondary to factors like physical activity, LBM, and BMI rather than delayed bone accrual, and the noted higher TBF among transgender females may have contributed to it, as some evidence suggests that higher body fat attenuates bone density in males while supporting bone density in females.29 

At baseline, the majority (55.2%) of transgender youth had vitamin D deficiency or insufficiency with vitamin D status associated with BMD at LS and LTH. Some evidence suggests potential bone protective effects of physical activity in the presence of very low serum 25OHD.30  However, the conceivably lower physical activity in transgender youth may heighten vitamin D deficiency effects on BMD. In addition, the combination of low vitamin D and low calcium intake (<600 mg/day) may impair LS mineralization in postmenarchal females.31  These all suggest that vitamin D and calcium supplementation should be considered for all youth with GD regardless of whether they are considering puberty suppression.

GnRHa monotherapy negatively affected transgender youth aBMD z scores at LS, LTH, and TBLH levels and transgender males’ LS BMAD z scores. The most pronounced decrease in z score (>0.5) was noted in transgender males’ LS aBMD and BMAD. The majority of the youth were late pubertal; this observed decrease is in line with other studies11,14  and explained by the significant decrease of estrogen on the trabecular rich bone at the spine. Transgender males at early stages of puberty seemed to have less pronounced LS aBMD z score changes. Schagen et al11  found that transgender youth in both early and late stages of puberty had a drop in aBMD z scores after 24 months of GnRHa regardless of puberty status, but this was more pronounced in transgender males in late puberty, assessing BMD z scores on the basis of sex assigned at birth. Similarly, because we were assessing the effect of GnRHa monotherapy, BMD z scores were based on sex assigned at birth. In future studies, researchers should consider whether to use sex assigned at birth or identified gender when assessing the effect of gender-affirming hormones on bone health in transgender youth. Given the limited evidence on transgender youth in early puberty, the degree of BMD changes after puberty suppression in early puberty is not known. This is an important clinical concern for transgender youth in early stages of puberty who are treated with a longer course of GnRHa therapy before gender-affirming hormones are considered.5,6 

Current evidence on GnRHa effects on body composition of youth with GD suggests a stable or slightly increased BMI z score, as well as an increase in fat percentage and drop in LBM.8,15,16,32  In our study, GnRHa was not associated with any significant changes in BMI z score. Among transgender females, GnRHa was associated with a significant increase in TBF (percentage) z score and drop in LBM z score. If transgender females were on GnRHa longer, a significant change in BMI and TBF (percentage) z scores could occur because of loss of testosterone effects on LBM and TBF33,34  at advanced stages of puberty. The observed fat redistribution (android versus gynoid) is in keeping with youth affirmed gender’s typical fat distribution.3335 

Evidence on GnRHa-associated changes in body composition and BMD will help health care professionals involved in the care of youth with GD to counsel appropriately and optimize their bone health. Given the absence of vertebral fractures detected in those with significant decreases in their LS z scores, the significance of BMD effects of GnRHa in transgender youth needs further study, as well as whether future spine radiographs are needed on the basis of BMD trajectory. This study can advance clinical practice guidelines and research in the field.

The study strengths include the large study population with baseline assessments and pre-post GnRHa subgroup analysis. This is the first study used to examine vitamin D status and provide a comprehensive assessment of body composition after GnRHa monotherapy. Lack of consistent records of physical activity at baseline and follow-up visits limited analysis of physical activity’s role as a potential contributing factor to bone health and body composition. The small sample size of youth in early puberty prevented comparison of GnRHa effects in early versus late puberty.

BMI z score does not appear to increase significantly in transgender youth on GnRHa monotherapy; however, it is associated with an increase in TBF (percentage) z score and reduction in LBM z score of transgender females. Transgender youth body fat redistribution (android versus gynoid) after GnRHa and transgender females’ body composition changes after GnRHa were in keeping with youth affirmed gender. GnRHa monotherapy in transgender youth is associated with a decrease in LS, LTH, and TBLH aBMD z scores. Vitamin D sufficiency was uncommon among transgender youth. Vitamin D and calcium supplementation should be considered for all youth with GD, particularly those who seek pubertal suppression. Given the negative effects of GnRHa monotherapy on BMD, bone density and 25OHD should be considered at baseline and follow-up care of adolescents with GD on GnRHa monotherapy.

FUNDING: No external funding for this study.

COMPANION PAPER: A companion to this article can be found online at www.pediatrics.org/cgi/doi/10.1542/peds.2021-051137.

Dr Navabi conceptualized and designed the study, collected data, conducted initial analyses, drafted the initial manuscript, and reviewed and revised the manuscript; Dr Tang conducted the analyses and reviewed and revised the manuscript; Dr Khatchadourian reviewed and revised the manuscript; Dr Lawson conceptualized and designed the study, coordinated and supervised data collection, and critically reviewed and revised the manuscript for important intellectual content; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

     
  • aBMD

    areal bone mineral density

  •  
  • BMAD

    bone mineral apparent density

  •  
  • BMC

    bone mineral content

  •  
  • BMD

    bone mineral density

  •  
  • CHEO

    Children’s Hospital of Eastern Ontario

  •  
  • DXA

    dual-energy radiograph absorptiometry

  •  
  • GD

    gender dysphoria

  •  
  • GnRHa

    gonadotropin-releasing hormone agonist

  •  
  • LBM

    lean body mass

  •  
  • Ln

    logarithm natural

  •  
  • LS

    lumbar spine

  •  
  • LTH

    left total hip

  •  
  • TBF

    total body fat

  •  
  • TBLH

    total body less head

  •  
  • 25OHD

    25-hydroxyvitamin D

1
Olson-Kennedy
J
,
Chan
YM
,
Rosenthal
S
, et al
.
Creating the Trans Youth Research Network: a collaborative research endeavor
.
Transgend Health
.
2019
;
4
(
1
):
304
312
2
Chen
M
,
Fuqua
J
,
Eugster
EA
.
Characteristics of referrals for gender dysphoria over a 13-year period
.
J Adolesc Health
.
2016
;
58
(
3
):
369
371
3
Kaltiala-Heino
R
,
Bergman
H
,
Työläjärvi
M
,
Frisén
L
.
Gender dysphoria in adolescence: current perspectives
.
Adolesc Health Med Ther
.
2018
;
9
:
31
41
4
Zucker
KJ
,
Bradley
SJ
,
Owen-Anderson
A
,
Kibblewhite
SJ
,
Cantor
JM
.
Is gender identity disorder in adolescents coming out of the closet?
J Sex Marital Ther
.
2008
;
34
(
4
):
287
290
5
Hembree
WC
,
Cohen-Kettenis
PT
,
Gooren
L
, et al
.
Endocrine treatment of gender-dysphoric/gender-incongruent persons: An Endocrine Society clinical practice guideline. [published correction appears in J Clin Endocrinol Metab. 2018;103(7):2758–2759]
.
J Clin Endocrinol Metab
.
2017
;
102
(
11
):
3869
3903
6
The World Professional Association for Transgender Health
.
Standards of care for the health of transsexual, transgender, and gender nonconforming people, 7th version
.
2011. Available at: www.wpath.org/. Accessed February 10, 2021
7
Carel
JC
,
Eugster
EA
,
Rogol
A
, et al;
ESPE-LWPES GnRH Analogs Consensus Conference Group
.
Consensus statement on the use of gonadotropin-releasing hormone analogs in children
.
Pediatrics
.
2009
;
123
(
4
):
e752
e762
8
Schagen
SE
,
Cohen-Kettenis
PT
,
Delemarre-van de Waal
HA
,
Hannema
SE
.
Efficacy and safety of gonadotropin-releasing hormone agonist treatment to suppress puberty in gender dysphoric adolescents
.
J Sex Med
.
2016
;
13
(
7
):
1125
1132
9
Chew
D
,
Anderson
J
,
Williams
K
,
May
T
,
Pang
K
.
Hormonal treatment in young people with gender dysphoria: a systematic review. [published correction appears in Pediatrics. 2020;146(4):e2020021303]
.
Pediatrics
.
2018
;
141
(
4
):
e20173742
10
Mahfouda
S
,
Moore
JK
,
Siafarikas
A
,
Zepf
FD
,
Lin
A
.
Puberty suppression in transgender children and adolescents
.
Lancet Diabetes Endocrinol
.
2017
;
5
(
10
):
816
826
11
Schagen
SEE
,
Wouters
FM
,
Cohen-Kettenis
PT
,
Gooren
LJ
,
Hannema
SE
.
Bone development in transgender adolescents treated with GnRH analogues and subsequent gender-affirming hormones
.
J Clin Endocrinol Metab
.
2020
;
105
(
12
):
e4252
e4263
12
Weaver
CM
,
Gordon
CM
,
Janz
KF
, et al
.
The National Osteoporosis Foundation’s position statement on peak bone mass development and lifestyle factors: a systematic review and implementation recommendations
.
Osteoporos Int
.
2016
;
27
(
4
):
1281
1386
13
Khosla
S
,
Monroe
DG
.
Regulation of bone metabolism by sex steroids
.
Cold Spring Harb Perspect Med
.
2018
;
8
(
1
):
a031211
14
Vlot
MC
,
Klink
DT
,
den Heijer
M
,
Blankenstein
MA
,
Rotteveel
J
,
Heijboer
AC
.
Effect of pubertal suppression and cross-sex hormone therapy on bone turnover markers and bone mineral apparent density (BMAD) in transgender adolescents
.
Bone
.
2017
;
95
:
11
19
15
Klink
D
,
Caris
M
,
Heijboer
A
,
van Trotsenburg
M
,
Rotteveel
J
.
Bone mass in young adulthood following gonadotropin-releasing hormone analog treatment and cross-sex hormone treatment in adolescents with gender dysphoria
.
J Clin Endocrinol Metab
.
2015
;
100
(
2
):
E270
E275
16
Delemarre-van de Waal
HA
,
Cohen-Kettenis
PT
.
Clinical management of gender identity disorder in adolescents: a protocol on psychological and paediatric endocrinology aspects
.
Eur J Endocrinol
.
2006
;
155
(
suppl 1
):
S131
S137
17
Joseph
T
,
Ting
J
,
Butler
G
.
The effect of GnRH analogue treatment on bone mineral density in young adolescents with gender dysphoria: findings from a large national cohort
.
J Pediatr Endocrinol Metab
.
2019
;
32
(
10
):
1077
1081
18
Rosen
HN
,
Hamnvik
OR
,
Jaisamrarn
U
, et al
.
Bone densitometry in transgender and gender non-conforming (TGNC) individuals: 2019 ISCD official position
.
J Clin Densitom
.
2019
;
22
(
4
):
544
553
19
Ross
AC
,
Taylor
CL
,
Yaktine
AL
,
Del Valle
HB
, eds;
National Academy of Sciences; Institute of Medicine Committee to Review Dietary Reference Intakes for Vitamin D and Calcium
.
Dietary Reference Intakes for Calcium and Vitamin D)
.
Washington, DC
:
National Academies Press
;
2011
20
Munns
CF
,
Shaw
N
,
Kiely
M
, et al
.
Global consensus recommendations on prevention and management of nutritional rickets
.
J Clin Endocrinol Metab
.
2016
;
101
(
2
):
394
415
21
Dietitians of Canada
.
WHO growth charts for Canada
.
22
Kröger
H
,
Kotaniemi
A
,
Vainio
P
,
Alhava
E
.
Bone densitometry of the spine and femur in children by dual-energy x-ray absorptiometry
.
Bone Miner
.
1992
;
17
(
1
):
75
85
23
van der Sluis
IM
,
de Ridder
MA
,
Boot
AM
,
Krenning
EP
,
de Muinck Keizer-Schrama
SM
.
Reference data for bone density and body composition measured with dual energy x ray absorptiometry in white children and young adults
.
Arch Dis Child
.
2002
;
87
(
4
):
341
347
,
discussion 341–347
24
Andreoli
A
,
Garaci
F
,
Cafarelli
FP
,
Guglielmi
G
.
Body composition in clinical practice
.
Eur J Radiol
.
2016
;
85
(
8
):
1461
1468
25
Kaltiala-Heino
R
,
Sumia
M
,
Työläjärvi
M
,
Lindberg
N
.
Two years of gender identity service for minors: overrepresentation of natal girls with severe problems in adolescent development
.
Child Adolesc Psychiatry Ment Health
.
2015
;
9
:
9
26
Chiniara
LN
,
Bonifacio
HJ
,
Palmert
MR
.
Characteristics of adolescents referred to a gender clinic: are youth seen now different from those in initial reports?
Horm Res Paediatr
.
2018
;
89
(
6
):
434
441
27
Van Caenegem
E
,
Taes
Y
,
Wierckx
K
, et al
.
Low bone mass is prevalent in male-to-female transsexual persons before the start of cross-sex hormonal therapy and gonadectomy
.
Bone
.
2013
;
54
(
1
):
92
97
28
Calzo
JP
,
Roberts
AL
,
Corliss
HL
,
Blood
EA
,
Kroshus
E
,
Austin
SB
.
Physical activity disparities in heterosexual and sexual minority youth ages 12-22 years old: roles of childhood gender nonconformity and athletic self-esteem
.
Ann Behav Med
.
2014
;
47
(
1
):
17
27
29
Mosca
LN
,
Goldberg
TBL
,
da Silva
VN
, et al
.
Excess body fat negatively affects bone mass in adolescents
.
Nutrition
.
2014
;
30
(
7–8
):
847
852
30
Constantini
NW
,
Dubnov-Raz
G
,
Chodick
G
,
Rozen
GS
,
Giladi
A
,
Ish-Shalom
S
.
Physical activity and bone mineral density in adolescents with vitamin D deficiency
.
Med Sci Sports Exerc
.
2010
;
42
(
4
):
646
650
31
Esterle
L
,
Nguyen
M
,
Walrant-Debray
O
,
Sabatier
JP
,
Garabedian
M
.
Adverse interaction of low-calcium diet and low 25(OH)D levels on lumbar spine mineralization in late-pubertal girls
.
J Bone Miner Res
.
2010
;
25
(
11
):
2392
2398
32
Klaver
M
,
de Mutsert
R
,
Wiepjes
CM
, et al
.
Early hormonal treatment affects body composition and body shape in young transgender adolescents
.
J Sex Med
.
2018
;
15
(
2
):
251
260
33
Veldhuis
JD
,
Roemmich
JN
,
Richmond
EJ
, et al
.
Endocrine control of body composition in infancy, childhood, and puberty
.
Endocr Rev
.
2005
;
26
(
1
):
114
146
34
Loomba-Albrecht
LA
,
Styne
DM
.
Effect of puberty on body composition
.
Curr Opin Endocrinol Diabetes Obes
.
2009
;
16
(
1
):
10
15
35
Wells
JCK
.
Sexual dimorphism of body composition
.
Best Pract Res Clin Endocrinol Metab
.
2007
;
21
(
3
):
415
430

Competing Interests

POTENTIAL CONFLICT OF INTEREST: The authors have no potential conflicts of interest to disclose.

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.