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This version published online on June 23, 2005
Endocrinology, doi:10.1210/en.2005-0322
A more recent version of this article appeared on October 1, 2005
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*Compound via MeSH
*Substance via MeSH
Hazardous Substances DB
*ESTRADIOL
*MENOTROPINS
*TESTOSTERONE

Submitted on March 17, 2005
Accepted on June 16, 2005

FETAL PROGRAMMING: EXCESS PRENATAL TESTOSTERONE REDUCES POSTNATAL LH, BUT NOT FSH RESPONSIVENESS TO ESTRADIOL NEGATIVE FEEDBACK IN THE FEMALE*

Hirendra N Sarma, Mohan Manikkam, Carol Herkimer, James Dell'Orco, Kathleen B Welch, Douglas L Foster, and Vasantha Padmanabhan*

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

* To whom correspondence should be addressed. E-mail: vasantha{at}umich.edu.

Exposure of female sheep fetuses to excess testosterone (T) during early-mid gestation 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) twice weekly from days 30-90 of gestation or vehicle. Responsiveness to E2 negative feedback was assessed at 12 and 24 weeks 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 and every 10 min at 24 weeks before treatment, during and after GnRH-A treatment both before and after E2 implant. GnRH-A ablated LH pulsatility, reduced FSH by ~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.
Key words: Neuroendocrinology • PCOS • gonadotropins




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