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


This study examined the impact of puberty suppression and subsequent addition of gender-affirming hormones on bone development in adolescents diagnosed with gender dysphoria. At the start of GnRHa treatment, aBMD and BMAD values were within the normal range. However, transgirls had z-scores well below zero, whereas these were close to zero in transboys. This finding is consistent with previous studies[8,10,16–18] and may be explained by differences in lifestyle and exercise intensity between transgirls and transboys. A recent study showed that high-school transgirls have a higher intake of fast-food and are less physically active than transboys.[19] In a different cohort of transgender adolescents we found vitamin D levels <50 nmol/L in 74% of transboys and 78% of transgirls starting GnRHa treatment ([9] and unpublished data). However, these findings do not explain why BMD z-scores are lower in transgirls than in transboys. Alternatively, it may be hypothesized that biological factors that act during intrauterine or early development and are involved in the development of gender dysphoria, are also related to bone development programming. For example, a whole-exome sequencing study in transgender individuals found 21 variants in 19 genes associated with estrogen activated pathways of sexually dimorphic brain development.[20] These variants in estrogen receptor–activated pathways might also play a role in bone mineral acquisition.

During GnRHa treatment we observed a decline of aBMD and BMAD z-scores in line with previous studies.[8–10] In transgirls a decrease of aBMD z-scores was also reported with the use of the anti-androgenic progestin cyproterone acetate.[18] In contrast, 1 study showed that in transboys treated with the progestin lynestrenol for an average of 11.6 months aBMD z-scores were stable or increased.[18] If these results are confirmed, also with more prolonged treatment duration, the better safety profile with regard to bone health is an important point to discuss with adolescents. In particular, older transboys who have already completed breast development may prefer lynestrenol to GnRHa treatment.

In most individuals with prolonged (3–4 years) GnRHa treatment, no further decrease in aBMD z-scores was observed in the last year, suggesting that z-scores might stabilize. Data from a larger cohort of adolescents treated with GnRHa for longer periods of time are needed, especially now that adolescents are presenting at younger ages at gender identity clinics and starting treatment at the onset of puberty.

During gender-affirming hormone treatment, a significant increase in the BMAD of the lumbar spine was found in all groups, and of the femoral neck in all but the late-pubertal transboys. In line with previous studies, BMAD z-scores were close to zero in transboys after 3 years of testosterone treatment.[8–10] The increase in z-scores was most pronounced in the early pubertal transboys whose z-scores were slightly higher after 3 years of androgen treatment than at the start of GnRHa treatment.

The BMAD z-scores remained well below zero in transgirls in line with previous studies.[8,10] However, BMAD z-scores in early-pubertal transgirls increased more during estrogen treatment and were higher after 36 months than the scores reported by Vlot et al after 24 months.[8] This might be due to the extra year of estrogen treatment in the current study, although the z-score of BMAD at the femoral neck no longer seemed to increase between 24 and 36 months. In contrast, the BMAD z-scores of the femoral neck in the late-pubertal transgirls were much lower after 36 months in the current study than previously reported.[8] This may be due to the lower z-scores at the start of GnRHa treatment (−1.01 vs −0.44) and at the start of estrogen treatment (−1.36 vs −0.36) in the current study compared with the study by Vlot et al.

An important limitation of this study is the lack of an untreated control group. As discussed above, z-scores in transgirls were already well below 0 at the start of treatment, and these might have further decreased even without treatment, as low BMD was also observed in adult transwomen before the start of any treatment.[16,17]

Another issue is which reference population should be used to calculate BMD or BMAD z-scores. In transgirls who started treatment in early puberty, bone architecture may be more similar to that of cisgender females than to cisgender males. A recent study did not find changes in cortical bone geometry in response to estrogen treatment in adult transwomen, but the authors suggested that this might have been different if they had started treatment during puberty.[21]

GnRHa are not only used in transgender children, but also in other populations, mainly in children with precocious or early puberty. A recent publication from an international consortium on the use of GnRHa concluded from the available evidence in this group that the treatment was safe with regard to bone mineral density, with attenuated bone mineral accrual reported during treatment but recovery by late adolescence.[22] Different findings in children with precocious puberty compared with transgender adolescents may be due to the different timing of GnRHa treatment, the use of gender-affirming hormones, with current estradiol dose possibly insufficient,[23] versus endogenous puberty, and due to differences in baseline BMD between the groups.

In transgirls and early-pubertal transboys, all bone markers decreased during the first year of GnRHa treatment while BMD levels remained stable. However, in the late-pubertal transboys bone turnover markers were lower at baseline and did not change. This suggests that the decline of the bone markers during GnRHa treatment may not be due to reduced bone mineral accrual but may rather reflect reduced growth velocity after initiating treatment. The late-pubertal transboys had likely already reached (near) adult height, which could explain the lower and stable levels of bone turnover markers. We previously observed a similar decrease of alkaline phosphatase during GnRHa treatment, but only in those who had not yet completed growth.[24] The opposite effect was seen during the first year of treatment with gender-affirming hormones, where bone markers increased in the early pubertal transgirls, who likely had most growth potential. In adults, changes in P1NP were also found to be only weakly correlated to changes in BMD in transwomen and not significantly correlated in transmen.[25] A previous study of bone turnover markers in adolescents observed a similar pattern of changes in P1NP and 1CTP to the current study.[8] However, changes in osteocalcin were only seen in late-pubertal transboys, possibly due to the small number of subjects in that study with large interindividual differences in the changes of osteocalcin levels.[8]

Based on the current study we propose that it is sufficient to perform DXA scans at the start of GnRHa treatment, every 2 years during GnRHa treatment, at the start of gender-affirming hormone treatment, and then every 2 to 3 years. Adolescents should be counseled on the importance of weight-bearing exercise, an adequate dietary calcium intake, sufficient sunlight exposure to ensure adequate vitamin D levels, or vitamin D supplementation.[26] In addition, it is important to ensure an adequate estrogen dose resulting in physiological serum estradiol levels. Routine measurement of bone turnover markers does not seem to be useful for monitoring bone health.

In conclusion, treatment with GnRHa results in a stabilization and maintenance of previously achieved bone mass in the lumbar spine but a small decrease in BMAD of the femoral neck of the nondominant hip. Gender-affirming hormone treatment increases bone accretion and normalizes the age- and sex-specific BMAD z-scores in transboys. Transgirls had lower BMAD z-scores, especially the late-pubertal group, but as z-scores were already lower at baseline, this may be due to other factors than the endocrine treatment, such as lifestyle factors. The consequences of lower BMD for long-term bone health in these individuals remains unclear. Future studies should evaluate peak bone mass in those who started treatment as adolescents and investigate clinically important outcomes such as fracture risk in this population.