The Differential Effects of Sex Hormones on the Bone Metabolism in Mice with Androgen Receptor Deficiency

Abstract

Male mice with androgen receptor knock-out (ARKO) have shown significant bone loss at a young age. However, whether sex hormones actions influence bone homeostasis in aged male and female mice through regulation of androgen receptor (AR) activity remain unclear. Here we aimed to evaluate the effects of sex hormone treatments on bone microarchitectures in male and female ARKO mice. These mice were classified according to their sex gender, AR status, and types of surgery and sex hormone implants. Sex hormone supplements, including dihydrotestosterone (DHT), dehydroepiandrostendione (DHEA), or 17β-estradiol (E2), were given to gonadectomized control and ARKO mice in both males and females at 18 weeks old and the effects were evaluated at 30 weeks old by micro-computed tomography. The results showed while bone mass decreased in both male and female ARKO mice at 6, 18, and 30 weeks old, loss of AR has a greater effect on bone microstructure in males than female mice at 6 weeks old. Gonadectomy did not further worse the bone microstructure in ARKO mice at 18 weeks of age. Bone strength and stiffness decreased in female and male ARKO mice, respectively. While none of the hormones significantly increased bone strength, E2 but not DHT or DHEA treatment rescued trabecular bone mass in both sexes of gonadectomized ARKO mice. E2 supplementation also increased bone stiffness in male mice. In conclusion, AR plays important roles on bone stiffness, bone strength and trabecular bone mass in both genders of ARKO mice, respectively. E2 supplementation can rescue the trabecular bone loss in mice with AR deficiency. Given that androgen replacement therapy is not an option for patients treated with hormone deprivation therapy for prostate cancer and patients with androgen insensitive syndrome, our results suggest that effectiveness of E2 treatment on restoring the bone loss and improving bone quality might represent a novel approach potentially useful to control male osteoporosis.