ESPE Yearbook of Paediatric Endocrinology

Brief Summary: This prospective follow-up cohort study investigated bone mineral density in transgender individuals who had initiated GnRH analogue treatment before age 18 followed by sex hormone treatment for at least 9 years. At a median age 28.2 years, after using testosterone for a median 11.9 years (IQR 10.2-13.8), transmasculine individuals had mean z-scores close to 0 at the lumbar spine, total hip and femoral neck, similar to z-scores at the start of GnRH analogue treatment. In contrast, transfeminine individuals at a median age 28.2 years, after using estradiol for a median 11.6 years (IQR 10.1-14.7) had mean z-scores of −1.34 at the lumbar spine, −0.66 at the total hip, and −0.54 at the femoral neck. Only at the lumbar spine was the z-score lower than that at the start of GnRH analogue treatment (difference −0.87; 95% CI, −1.15 to −0.59).

Concerns exist about the potential long-term impact of puberty suppression with GnRH analogues on bone health. GnRH analogue treatment is known to reduce bone mineral accrual in transgender and gender diverse adolescents, but this study shows that complete catch-up is seen with long-term testosterone treatment. With estradiol treatment, z-scores at the total hip and femoral neck also returned to (below average) pre-treatment values, but not at the lumbar spine. The authors suggest this may be due to insufficient estradiol concentrations. Indeed, a higher estrogen dosage has been found to be associated with a greater increase in lumbar spine BMD Z-scores (1). Since z-scores were already below average before the start of any treatment, lifestyle factors likely also play a role in suboptimal bone health in transfeminine individuals and deserve attention during clinical follow-up.

Animal models are now also being used to assess the impact of hormonal interventions on bone and allow additional aspect of bone health such as bone architecture to be studied. Dubois et al., using a mouse model of puberty suppression followed by testosterone treatment, found that GnRH analogue treatment results in lower trabecular bone volume, cortical bone mass and cortical strength and higher bone marrow adiposity, all of which were restored by testosterone (2). Thus, in transmasculine individuals, GnRH analogue treatment followed by testosterone treatment seems safe with regard to bone health. However, bone health in transfeminine individuals deserves attention, with counseling about the importance of weight-bearing exercise, sufficient calcium intake and vitamin D.

References: 1. Boogers LS, van der Loos MATC, Wiepjes CM, van Trotsenburg ASP, den Heijer M, Hannema SE. The dose-dependent effect of estrogen on bone mineral density in trans girls. Eur J Endocrinol. 2023 Aug 2;189(2):290-296. doi: 10.1093/ejendo/lvad116. PMID: 37590955.2. Dubois V, Ciancia S, Doms S, El Kharraz S, Sommers V, Kim NR, David K, Van Dijck J, Valle-Tenney R, Maes C, Antonio L, Decallonne B, Carmeliet G, Claessens F, Cools M, Vanderschueren D. Testosterone Restores Body Composition, Bone Mass, and Bone Strength Following Early Puberty Suppression in a Mouse Model Mimicking the Clinical Strategy in Trans Boys. J Bone Miner Res. 2023 Oct;38(10):1497-1508. doi: 10.1002/jbmr.4832. Epub 2023 Jun 8. PMID: 37222072.