Prenatal androgens time neuroendocrine sexual maturation

Abstract

The present study determined whether exposure to gonadal steroids in utero dictates the postnatal control of gonadotropin secretion in the lamb. There is a marked sex difference in the timing of neuroendocrine sexual maturation in sheep; while male lambs undergo a reduction in sensitivity to inhibitory gonadal steroid feedback by 10 weeks of age, females remain hypersensitive until 30 weeks. The hypothesis was tested that prenatal androgens advance the time of the decrease in feedback sensitivity, and hence the pubertal increase in pulsatile gonadotropin secretion. Pregnant ewes were injected each week with 100 mg testosterone cypionate im from 30-90 days of gestation (term is approximately 150 days). Five female lambs were born with masculinized external genitalia (penis and scrotum). These females, together with eight androgenized males, eight control males, and eight control females, were gonadectomized at 2 weeks of age and implanted with a Silastic capsule of estradiol to produce a constant steroid feedback signal. Blood samples were collected twice weekly to monitor trends in LH secretion. For determination of LH pulse frequency, samples were collected frequently (every 12 min for 4 h) at various intervals between 5 and 32 weeks of age. In males, a sustained increase in LH from biweekly blood samples, indicative of reduced sensitivity to inhibitory steroid feedback, began at 10.1 +/- 1.4 weeks (mean +/- SE) of age in control males and at 5.4 +/- 0.1 weeks in androgenized males. By contrast, control females remained hypersensitive much longer as evidenced by the delay in the LH rise until 27.2 +/- 0.8 weeks. The response of the five androgenized females was intermediate; LH increased at 4, 7, 16, 20, and 21 weeks of age with an early increase of LH being associated with more pronounced masculinization of the genitalia. Patterns of pulsatile LH secretion reflected differences in serum LH measured from biweekly blood samples. For example, at 20 weeks of age, before the pubertal LH rise in female lambs, no pulses were evident in control females, whereas LH pulse frequency averaged 1.6 +/- 0.7 pulses/4 h in androgenized females. At this age, postpubertal males had 2.8 +/- 0.5 LH pulses/4 h. These results lead to the conclusion that in the sheep, prenatal androgens can masculinize patterns of gonadotropin secretion, and that the timing of reproductive neuroendocrine maturation after birth is programmed by androgens in utero.