High-dose estradiol restores vertebral micro-architecture and strength in an adolescent mouse model of male-to-female transition — ASN Events
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  3. High-dose estradiol restores vertebral micro-architecture and strength in an adolescent mouse model of male-to-female transition

High-dose estradiol restores vertebral micro-architecture and strength in an adolescent mouse model of male-to-female transition (#3)

Varun S Venkatesh 1 2 , Ellen Davies 1 , Hugo Teixeira Rodeia 3 , Kai Wright 1 , Suzanne Golub 1 2 , Reena Desai 4 , David J Handelsman 4 , Kathryn S Stok 3 , Rachel A Davey 1
  1. Department of Medicine, Austin Health, University of Melbourne, Heidelberg, Victoria, Australia
  2. Department of Endocrinology, Austin Health, Heidelberg, Victoria, Australia
  3. Department of Biomedical Engineering, University of Melbourne, Parkville, Victoria, Australia
  4. ANZAC Research Institute, University of Sydney, Concord, New South Wales, Australia

In transgender (trans) girls, pubertal suppression with gonadotropin-releasing hormone analogues (GnRHa) reduces peak bone mass. While subsequent feminising gender affirming hormone therapy (GAHT) with estradiol restores bone density at the femoral neck, deficits persist at the lumbar spine (1), raising concern for future vertebral fracture risk. We previously developed a preclinical adolescent male-to-female model of pubertal suppression and GAHT and showed that high-dose estradiol is anabolic, not only restoring the deficit in peak bone mass but increasing bone accrual and strength at the femur compared to intact male controls (2). Given the vulnerability of the lumbar spine to fracture due to its high trabecular bone content, we sought to determine whether these anabolic effects extend to the lumbar vertebrae.

To model adolescent male-to-female transition, male mice were orchidectomised (Orx) at 5 weeks, followed by 12 weeks of high-dose estradiol commencing at 8 weeks of age (~0.85 mg, intraperitoneal silastic implant) to model pubertal suppression and subsequent feminising GAHT. The L1 vertebrae was analysed by high-resolution micro-computed tomography and compression testing was performed on the L5 vertebrae to assess strength.

Orx reduced trabecular bone volume (BV/TV) by 0.7-fold relative to sham controls (p<0.0001) due to decreases in trabecular number (Tb.N) and thickness (Tb.Th). High-dose estradiol increased BV/TV 2-fold versus Orx controls and 1.2-fold versus intact males (p<0.0001), with concurrent increases in Tb.N and Tb.Th, consistent with our previous findings of increased bone formation in the femur. This translated to a 2.7-fold increase in maximal compressive force versus Orx controls (p<0.01), restoring strength to intact male control levels. Histomorphometric analyses are ongoing to quantify bone formation and resorption parameters. While findings were concordant with femoral data, the magnitude of change in BV/TV and strength was attenuated in the vertebrae, suggesting site-specific differences in the anabolic response to estradiol.

Taken together, high-dose estradiol following pubertal suppression exerts anabolic effects at the lumbar vertebrae, restoring bone accrual and strength. These findings support defining the estradiol dose threshold required to drive bone anabolism, providing a foundation for optimising hormone therapy in trans girls and informing broader strategies to prevent fragility fractures.

  1. (1) van der Loos M, Vlot MC, Klink DT, Hannema SE, den Heijer M, Wiepjes CM (2023) Bone Mineral Density in Transgender Adolescents Treated With Puberty Suppression and Subsequent Gender-Affirming Hormones. JAMA Pediatr 177, 1332–1341.
  2. (2) Nie T, Venkatesh VS, Golub S, Stok KS, Hemmatian H, Desai R, . . . Davey RA (2024) Estradiol increases cortical and trabecular bone accrual and bone strength in an adolescent male-to-female mouse model of gender-affirming hormone therapy. Bone Res 12, 1.