In utero exposure of female lambs to testosterone reduces the sensitivity of the gonadotropin-releasing hormone neuronal network to inhibition by progesterone.

Exposure of the female ovine fetus to exogenous androgens during early gestation permanently masculinizes the reproductive anatomy, physiology, and behavior of the adult ewe. In utero testosterone exposure has been shown to act centrally on the GnRH neuronal network to alter the response to both the stimulatory and inhibitory actions of estrogen. It is currently unknown whether fetal androgens alter other mechanisms that are critical for the regulation of GnRH release and, specifically, other important regulatory steroid feedback loops. Three studies were performed on gonadectomized postpubertal sheep to determine whether the inhibitory actions of progesterone on episodic LH release are also sex-specific and engendered by early in utero exposure to testosterone. In each study, the pulsatile pattern of LH release was determined both before and after the sc implantation of a progesterone releasing CIDR device. The studies involved 7 female, 7 male, and 12 androgenized female sheep (T60 (n = 7) and T30 (n = 5) groups; 200 mg testosterone propionate/week im to the mother for 60 or 30 days, respectively, from day 30-90 or 60-90 of pregnancy). The first two studies were performed in the anestrous season in the presence (Exp 1) or absence (Exp 2) of a low circulating concentration of estradiol. Exp 3 was carried out in the breeding season in the absence of exogenous estrogen. In all three studies progesterone inhibited LH pulse frequency only in the females. Progesterone had no action on mean LH concentrations or the frequency or amplitude of LH pulses in the males or either group of androgenized ewes. We conclude that the inhibition of episodic LH release by progesterone is sexually differentiated in the sheep, males being less responsive than females to steroid negative feedback. Further, these sex differences are a consequence of in utero exposure to androgens for a period as short as 30 days between days 60 and 90 of a 147-day pregnancy.