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Prenatal Programming of Reproductive Neuroendocrine Function: Fetal Androgen Exposure Produces Progressive Disruption of Reproductive Cycles in Sheep

Laboratory of Neuroendocrinology, Department of Neurobiology, The Babraham Institute (R.A.B., W.P.U., J.E.R.), Cambridge CB2 4AT, United Kingdom; and Departments of Pediatrics (V.P.), Obstetrics and Gynecology, and Ecology and Evolutionary Biology (D.L.F.) and the Reproductive Sciences Program (V.P., D.L.F.), University of Michigan, Ann Arbor, Michigan 48109

Address all correspondence and requests for reprints to: Dr. Jane E. Robinson, Department of Preclinical Veterinary Studies, University of Glasgow Veterinary School, Bearsden Road, Glasgow G61 1QH, United Kingdom.

In the agonadal, androgenized ewe testosterone before birth produces a precocious pubertal rise in circulating LH and abolishes the LH surge mechanism. The present study tested two predictions from this model in the ovary-intact female: 1) prenatal androgen exposure produces early ovarian stimulation; and 2) despite early ovarian stimulation, progestogenic cycles would not occur because of the abolition or disruption of the LH surge. Pregnant ewes were injected with testosterone propionate twice per week from either d 30–90 (T60 group; 100 mg/injection) or d 60–90 (T30 group; 80 mg/injection) of gestation (term, 147 d). Control ewes received no injections. At birth, the androgenized and control lambs were divided into two groups: ovary-intact to determine the effects of prenatal androgen on the timing of puberty and subsequent ovarian function, and ovariectomized to assess the timing of the pubertal decrease in sensitivity to estrogen negative feedback and the subsequent increase in LH. Neonatally orchidectomized, estrogen-treated males were included for comparison of the timing of this pubertal rise in LH secretion. Neuroendocrine puberty (determined on the basis of LH increase) was advanced in the androgenized females to a similar age as in males. Repeated progesterone cycles of the same duration and number occurred in the ovary-intact ewes, and they began at the same time as for control females, thus negating both predictions. Differences appeared during the second breeding season, when reproductive cycles were either absent (T60) or disrupted (T30 group). Our findings reveal that exposure to androgens in utero causes a progressive loss of cyclic function in adulthood.

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