Testosterone Restores Body Composition, Bone Mass, and Bone Strength Following Early Puberty Suppression in a Mouse Model Mimicking the Clinical Strategy in Trans Boys

Abstract

Transgender youth increasingly present at pediatric gender services. Some of them receive long‐term puberty suppression with gonadotropin‐releasing hormone analogues (GnRHa) before starting gender‐affirming hormones (GAH). The impact of GnRHa use started in early puberty on bone composition and bone mass accrual is unexplored. It is furthermore unclear whether subsequent GAH fully restore GnRHa effects and whether the timing of GAH introduction matters. To answer these questions, we developed a mouse model mimicking the clinical strategy applied in trans boys. Prepubertal 4‐week‐old female mice were treated with GnRHa alone or with GnRHa supplemented with testosterone (T) from 6 weeks (early puberty) or 8 weeks (late puberty) onward. Outcomes were analyzed at 16 weeks and compared with untreated mice of both sexes. GnRHa markedly increased total body fat mass, decreased lean body mass, and had a modest negative impact on grip strength. Both early and late T administration shaped body composition to adult male levels, whereas grip strength was restored to female values. GnRHa‐treated animals showed lower trabecular bone volume and reduced cortical bone mass and strength. These changes were reversed by T to female levels (cortical bone mass and strength) irrespective of the time of administration or even fully up to adult male control values (trabecular parameters) in case of earlier T start. The lower bone mass in GnRHa‐treated mice was associated with increased bone marrow adiposity, also reversed by T. In conclusion, prolonged GnRHa use started in prepubertal female mice modifies body composition toward more fat and less lean mass and impairs bone mass acquisition and strength. Subsequent T administration counteracts GnRHa impact on these parameters, shaping body composition and trabecular parameters to male values while restoring cortical bone architecture and strength up to female but not male control levels. These findings could help guide clinical strategies in transgender care. © 2023 American Society for Bone and Mineral Research (ASBMR).

Bone quality following peripubertal growth in a mouse model of transmasculine gender-affirming hormone therapy

“…While the effect of sex hormones on bone morphology and properties have been heavily studied, the impact of induction of the hypoestrogenic state in combination with T treatment in peripubertal mice such as that used in GAHT has not been explored extensively. In a model like ours, Dubois et al reports that GnRHa administration reduced bone mass acquisition, and bone strength in female to male (transmasculine) mice (8). This effect was also reversed by administration of T, achieving parameters equal to control female mice and in some cases male control (8).…”

“…Puberty suppression in transgender and gender diverse adolescents has been used historically to lessen the psychological burden of gender dysmorphia by making physical secondary sex characteristics more congruent with the experienced gender (8–10). One way this is accomplished is through administration of a GnRH agonist (GnRHa).…”

“…Within the HPG-axis GnRHa will suppress the production and section of luteinizing hormone (LH) and follicle stimulating hormone (FSH), which results in arrested ovarian folliculogenesis and steroidogenesis. Adolescent patients at Tanner Stage 2-3, with persistent feelings of gender dysphoria that worsens at the onset of puberty, are eligible for GnRHa treatment according to International Guidelines (8,11,12). GnRHa can be prescribed as early as 10-11 yrs for trans boys and 11-12yrs for trans girls.…”

“…GnRHa can be prescribed as early as 10-11 yrs for trans boys and 11-12yrs for trans girls. Around 15-16 yrs of age, T or E can be used as gender affirming hormone therapy (GAHT) for full hormonal transitioning in consenting sufficiently capacitated patients (8,11,12). While much of what we know about GAHT in humans has focused on cardiovascular health and metabolic risk (13), the effect of delayed or prolonged pubertal suppression transitioned into GAHT on bone health is underappreciated.…”

Dermatological considerations for transgender and gender diverse patients: An Australian perspective

“…6,20,21 The primary concern with the commencement of GnRH analogues in early adolescence is diminished bone density due to sex steroid deficiency 22 ; however, recent data suggest that this appears to be restored after commencement of GAH. 23 Australian guidelines recommend an initial assessment of bone mineral density and monitoring throughout treatment. 6 Criteria for adolescent commencement of puberty suppression are outlined in Australian standards of care.…”