Journal
ENDOCRINOLOGY
Volume 153, Issue 9, Pages 4522-4532Publisher
ENDOCRINE SOC
DOI: 10.1210/en.2012-1283
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Funding
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (Specialized Cooperative Centers Program in Reproduction and Infertility Research) [U54 HD28934]
- University of California, San Diego, Histology Core Facility [P30 CA023100]
- National Institutes of Health [R01 DK044838, R01 HD072754, R01 HD020377, P42 ES101337]
- Eunice Kennedy Shriver National Institute of Child Health and Human Development/National Institutes of Health [U54 HD012303]
- Specialized Cooperative Centers Program in Reproduction and Infertility Research
- [R01 HD065856]
- [P30 DK063491]
- [T32 GM008666]
- [T32 DA007315]
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Sex steroid hormone production and feedback mechanisms are critical components of the hypothalamic-pituitary-gonadal (HPG) axis and regulate fetal development, puberty, fertility, and menopause. In female mammals, developmental exposure to excess androgens alters the development of the HPG axis and has pathophysiological effects on adult reproductive function. This study presents an in-depth reproductive analysis of a murine model of prenatal androgenization (PNA) in which females are exposed to a low dose of dihydrotestosterone during late prenatal development on embryonic d 16.5-18.5. We determined that PNA females had advanced pubertal onset and a delay in the time to first litter, compared with vehicle-treated controls. The PNA mice also had elevated testosterone, irregular estrous cyclicity, and advanced reproductive senescence. To assess the importance of the window of androgen exposure, dihydrotestosterone was administered to a separate cohort of female mice on postnatal d 21-23 [prepubertal androgenization (PPA)]. PPA significantly advanced the timing of pubertal onset, as observed by age of the vaginal opening, yet had no effects on testosterone or estrous cycling in adulthood. The absence of kisspeptin receptor in Kiss 1r-null mice did not change the acceleration of puberty by the PNA and PPA paradigms, indicating that kisspeptin signaling is not required for androgens to advance puberty. Thus, prenatal, but not prepubertal, exposure to low levels of androgens disrupts normal reproductive function throughout life from puberty to reproductive senescence. (Endocrinology 153: 4522-4532, 2012)
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