Perinatal testosterone surge is required for normal adult bone size but not for normal bone remodeling

1 Department of Medicine at St. Vincent's Hospital, The University of Melbourne and St. Vincent's Institute, Fitzroy, Victoria; and 2 ANZAC Research Institute, University of Sydney, Sydney, New South Wales, Australia Submitted 11 July 2005 ; accepted in final form 3 October 2005 Although testosterone (T) has striking effects on mature skeletal size and structure, it is not clear whether this depends exclusively on adult circulating levels of T or whether additional early-life factors also play a role. We have compared the androgen-deficient hypogonadal ( hpg ) mutant mouse with intact, orchidectomized, and T-treated non- hpg mice to determine relative contributions of adult and perinatal T to bone growth and development. At 3 wk of age, although trabecular and cortical bone structure was normal, bone turnover was significantly altered in hpg male mice; osteoid volume (OV/BV) and osteoblast surface (ObS/BS) were significantly lower and osteoclast surface (OcS/BS) significantly higher in hpg mice compared with age-matched non- hpg mice, pointing to a role for the perinatal T surge in determining bone turnover levels before sexual maturity. At 9 wk of age, the hpg bone phenotype mimicked closely that of age-matched non- hpg mice that had been orchidectomized at 3 wk of age, including low trabecular bone mass and high bone turnover. These bone phenotypes of hpg and orchidectomized non- hpg mice were all prevented by replacement doses of T or dihydrotestosterone (DHT), suggesting that these are determined by adult sex steroid hormones. In contrast, a short bone phenotype that could not be prevented by T or DHT treatment was observed in 9-wk-old hpg mice yet not in intact or castrated non- hpg mice. These data suggest a role for the perinatal T surge in determining adult bone length and confirms that adult circulating T determines adult bone density. hypogonadism; skeleton; androgens Address for reprint requests and other correspondence: N. Sims, Dept. of Medicine at St. Vincent's Hospital, 41 Victoria Pde, Fitzroy VIC 3065, Australia (e-mail: nsims{at}unimelb.edu.au )