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Prenatal Androgens Time Neuroendocrine Puberty in the Sheep: Effect of Testosterone Dose¹

Reproductive Sciences Program and Departments of Biology (S.S.K., C.H.-E., D.L.F.) and Obstetrics and Gynecology (D.L.F.), University of Michigan, Ann Arbor, Michigan 48109-0404; and the Department of Obstetrics and Gynecology, Yale University (R.I.W.), New Haven, Connecticut 06520-8063

Address all correspondence and requests for reprints to: Dr. Douglas L. Foster, Room 1101, 300 North Ingalls Building, Ann Arbor, Michigan 48109-0404. E-mail: dlfoster{at}umich.edu

In sheep, prenatal exposure to androgens during a critical period for sexual differentiation of the brain (30–90 days of gestation; 145 days is term) can advance the timing of puberty in females and prevent the preovulatory LH surge. The present study tests the hypothesis that in sheep, the timing of neuroendocrine sexual maturation is related to the amount of prenatal steroid exposure. In addition, we determined if different steroid requirements exist for sexual differentiation of the tonic and surge modes of gonadotropin secretion. Testosterone was administered weekly to three groups of pregnant ewes from days 30–90 of gestation at doses of 200, 80, or 32 mg/week. The resulting androgenized female lambs together with control males and females (n = 5–7/group) were gonadectomized at 3 weeks of age, and gonadal steroids were replaced with a SILASTIC brand estradiol-filled capsule. LH concentrations were measured from biweekly blood samples. Sustained increases in circulating LH were considered to reflect the initiation of neuroendocrine puberty. In male lambs, LH secretion started to increase at 8.3 ± 0.9 weeks of age (mean ± SEM). The two highest doses of prenatal androgen advanced the onset of neuroendocrine sexual maturation in females. In the 200 mg androgenized females, the pubertal LH rise (10.2 ± 2.0 weeks) began about the same time as in males. In the 80 mg treatment group, LH concentrations increased at 16.2 ± 1.5 weeks, which was later than in males, but well before that in normal females (27.1 ± 0.7 weeks). For females treated with the lowest dose of androgen (32 mg), the pubertal LH increase (24.6 ± 1.9 weeks) began about the same time as in normal females. To test the function of the LH surge system, LH was measured every 2 h for 60 h after an acute increase in circulating estradiol was produced by implanting additional estrogen capsules. All control females produced a surge in response to acute estradiol stimulation. LH surges did not occur in males, 200 mg androgenized females, or 80 mg androgenized females. Of six females from the 32 mg treatment group, two produced LH surges in response to the stimulatory feedback action of estradiol. We conclude that the greater the amount of prenatal testosterone, the earlier the initiation of the pubertal LH rise. Moreover, the finding that low doses of testosterone (32 mg/week) are capable of abolishing the LH surge without significantly advancing the timing of puberty supports our hypothesis that different steroid requirements exist for sexual differentiation of tonic and surge modes of LH secretion.

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