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Fetal Programming: Excess Prenatal Testosterone Reduces Postnatal Luteinizing Hormone, But Not Follicle-Stimulating Hormone Responsiveness, to Estradiol Negative Feedback in the Female

Departments of Pediatrics (H.N.S., C.H., M.M., J.D., V.P.), Obstetrics and Gynecology (D.L.F., V.P.), Molecular and Integrative Physiology (V.P.), and Ecology and Evolutionary Biology (D.L.F.), Reproductive Sciences Program (H.S., M.M., C.H., J.D., D.L.F., V.P.), and Center for Statistical Consultation and Research (K.B.W.), University of Michigan, Ann Arbor, Michigan 48109

Address all correspondence and requests for reprints to: Vasantha Padmanabhan, Reproductive Sciences Program, 300 North Ingalls Building, Room 1109 SW, Ann Arbor, Michigan 48109-0404. E-mail: vasantha{at}umich.edu.

Exposure of female sheep fetuses to excess testosterone (T) during early to midgestation produces postnatal hypergonadotropism manifest as a selective increase in LH. This hypergonadotropism may result from reduced sensitivity to estradiol (E₂) negative feedback and/or increased pituitary sensitivity to GnRH. We tested the hypothesis that excess T before birth reduces responsiveness of LH and FSH to E₂ negative feedback after birth. Pregnant ewes were treated with T propionate (100 mg/kg in cotton seed oil) or vehicle twice weekly from d 30–90 gestation. Responsiveness to E₂ negative feedback was assessed at 12 and 24 wk of age in the ovary-intact female offspring. Our experimental strategy was first to arrest follicular growth and reduce endogenous E₂ by administering the GnRH antagonist (GnRH-A), Nal-Glu (50 µg/kg sc every 12 h for 72 h), and then provide a fixed amount of exogenous E₂ via an implant. Blood samples were obtained every 20 min at 12 wk and every 10 min at 24 wk before treatment, during and after GnRH-A treatment both before and after E₂ implant. GnRH-A ablated LH pulsatility, reduced FSH by approximately 25%, and E₂ production diminished to near detection limit of assay at both ages in both groups. Prenatal T treatment produced a precocious and selective reduction in responsiveness of LH but not FSH to E₂ negative feedback, which was manifest mainly at the level of LH/GnRH pulse frequency. Collectively, these findings support the hypothesis that prenatal exposure to excess T decreases postnatal responsiveness to E₂ inhibitory feedback of LH/GnRH secretion to contribute to the development of hypergonadotropism.

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