Prenatal Programming of Reproductive Neuroendocrine Function: The Effect of Prenatal Androgens on the Development of Estrogen Positive Feedback and Ovarian Cycles in the Ewe1

Exposure of the female ovine fetus to male hormones during a sensitive window of in utero life causes disruption to reproductive function. In some animals, androgen exposure completely abolishes reproductive cycles, but in others, cycles are progressively lost with age. The present study tested two predictions: that noncycling, androgenized animals are unable to respond to estrogen with a preovulatory-like surge of LH (estrogen positive feedback), and that the androgenized animals that exhibit a progressive loss of cycles also show a progressive loss of estrogen positive feedback. Androgenized ewes were generated by injection of their mothers with testosterone propionate twice per week from Day 30 to Day 90 of pregnancy (term, 147 days). Control ewes received no injections. Whether ewes could exhibit estrogen positive feedback was tested on five occasions before puberty (30 wk) and once during the anestrous period. All control animals had repeated reproductive cycles in both the first and second breeding season, and all showed robust LH surges during test periods. Despite the fact that 64% of androgenized animals showed reproductive cycles, estrogen positive feedback could be demonstrated in only 6.1% of trials. Subsequent experiments revealed that the lack of response to estrogen in androgenized animals was not because of pituitary insensitivity to GnRH, a requirement for higher concentrations of estrogen, or a surge that was delayed relative to the time of estrogen administration. The mechanisms by which some androgenized ewes can produce normal reproductive cycles in the apparent absence of estrogen positive feedback are currently unknown.