Bone Development in Transgender Adolescents Treated With GnRH Analogues and Subsequent Gender-affirming Hormones

Sebastian E. E. Schagen; Femke M. Wouters; Peggy T. Cohen-Kettenis; Louis J. Gooren; Sabine E. Hannema


J Clin Endocrinol Metab. 2020;105(12) 

In This Article

Abstract and Introduction


Context: Hormonal interventions in adolescents with gender dysphoria may have adverse effects, such as reduced bone mineral accrual.

Objective: To describe bone mass development in adolescents with gender dysphoria treated with gonadotropin-releasing hormone analogues (GnRHa), subsequently combined with gender-affirming hormones.

Design: Observational prospective study.

Subjects: 51 transgirls and 70 transboys receiving GnRHa and 36 transgirls and 42 transboys receiving GnRHa and gender-affirming hormones, subdivided into early- and late-pubertal groups.

Main Outcome Measures: Bone mineral apparent density (BMAD), age- and sex-specific BMAD z-scores, and serum bone markers.

Results: At the start of GnRHa treatment, mean areal bone mineral density (aBMD) and BMAD values were within the normal range in all groups. In transgirls, the mean z-scores were well below the population mean. During 2 years of GnRHa treatment, BMAD stabilized or showed a small decrease, whereas z-scores decreased in all groups. During 3 years of combined administration of GnRHa and gender-affirming hormones, a significant increase of BMAD was found. Z-scores normalized in transboys but remained below zero in transgirls. In transgirls and early pubertal transboys, all bone markers decreased during GnRHa treatment.

Conclusions: BMAD z-scores decreased during GnRHa treatment and increased during gender-affirming hormone treatment. Transboys had normal z-scores at baseline and at the end of the study. However, transgirls had relatively low z-scores, both at baseline and after 3 years of estrogen treatment. It is currently unclear whether this results in adverse outcomes, such as increased fracture risk, in transgirls as they grow older.


Over the last decades, children diagnosed with gender dysphoria have increasingly come to the attention of the psychomedical care system and clinicians recognize their suffering, aggravated by the somatic changes of puberty.[1,2] The development of secondary sex characteristics can be temporarily halted with gonadotropin-releasing hormone analogue (GnRHa) treatment.[3] This offers the adolescent the opportunity to explore their wish to pursue gender-affirming treatment, while no longer experiencing the agonizing development of secondary sex characteristics due to endogenous puberty, which are incongruent with gender identity. Birth-assigned girls must be at least in Tanner breast stage 2 with clear palpable mammary tissue, while birth-assigned boys must have reached Tanner stage G2 before initiating treatment with GnRHa.[3,4] If no contraindications exist, sex steroids consistent with the affirmed gender are added to the GnRHa treatment at an age where adolescents can give informed consent to such treatment, usually at approximately 16 years.[3] There is much discussion about this age, since 16 years is considered a late age to induce puberty in adolescents.

In young adults, peak bone mass (PBM) is higher in men than in women.[5] Sex steroids play an essential role in the establishment of gender differences in bone mass, both through direct effects and indirect effects, for example, via differences in muscle mass and insulin-like growth factor.[6] Puberty is an important period in determining adult bone mineral content.[6] Together, these findings strengthen the notion that maximizing bone mineral accrual during adolescence may be important in the prevention of osteoporosis and fractures at older age.

One of the primary concerns when using GnRHa in adolescents for a prolonged period of time is the potential decrease in bone mineral density (BMD).[3,7] The suppression of the endogenous sex steroids to stop pubertal development, as recommended by current guidelines, may potentially interfere with the normal pubertal bone mass increment and reduce PBM. Therefore, assessment of BMD every 1 to 2 years is recommended.[3] Three studies in adolescents diagnosed with gender dysphoria receiving GnRHa and gender-affirming hormone treatment reported decreases in areal BMD (aBMD) and bone mineral apparent density (BMAD) z-scores during GnRHa treatment, although not all significant.[8–10] Little difference was noted in change of BMAD z-scores between early- and late-pubertal groups as defined by bone age.[8] Catch-up of bone mineral accrual during subsequent gender-affirming hormone treatment may be incomplete.[8–10] One study investigated bone markers and showed a decrease of carboxyterminal cross-linked telopeptide of type I collagen (1CTP) and N-terminal propeptide of type-1 collagen (P1NP) during GnRHa and during subsequent gender-affirming hormone treatment which was interpreted as evidence of decreased bone turnover.[8] All these studies compared data at the start of GnRHa treatment, at the start of gender-affirming hormones and one endpoint, either 12–24 months after the start of gender-affirming hormone therapy or age 22 years. However, this does not provide information on the course of BMD during treatment. Do BMD z-scores continue to decline with prolonged use of GnRHa? How long do BMD z-scores continue to increase during GAH treatment? These questions remain unanswered. Now that increasing numbers of adolescents undergo this treatment, possibly starting at younger ages, there is a clear need for such data. Therefore we set out to describe the course of BMD during 2 years of GnRHa therapy and during 3 years of subsequent gender-affirming hormone treatment in a large group of adolescents diagnosed with gender dysphoria, with measurements at yearly intervals. We also investigated whether the outcome was influenced by the pubertal stage, as defined by Tanner stage, at which GnRHa treatment was started. In addition, we report data from a small subgroup with more prolonged GnRHa treatment.