Role of Steroid 5α-Reductase Activity in Sexual Differentiation of the Guinea Pig

Abstract

The possible role of 5α-reduction of steroids in the sexual differentiation of guinea pigs was determined by treating pregnant guinea pigs with a 5α-reductase activity (5αRA) inhibitor (17β-N, N-diethylcarbamoyl-4-methyl-4-aza-5α-androstan-3-one, 4MA, 10 mg/day) from day 30 to 55 of gestation. 5αRA in fetal diencephalon tissue obtained from 4MA-treated mothers on day 55 of gestation was suppressed compared to that of control tissue. Four litters receiving 4MA were carried to term along with an equal number of litters receiving the vehicle alone. Males that received 4MA in utero (n = 6) had altered external genitalia, i.e., hypospadias and reduced anogenital distances, but their adult copulatory behavior did not differ from that of controls (n = 7). In order to evaluate treatment effects on the hypothalamic-pituitary axis, all animals were challenged with estradiol benzoate (EB, 10 µg in oil, s.c.) 2 weeks after gonadectomy. Serial plasma samples were obtained and analyzed for luteinizing hormone (LH) using an heterologous radioimmunoassay. Control females (n= 13) and 4MA-treated females (n = 5) released LH in surge quantities about 42 h after EB treatment. Plasma from 4MA-treated females differed from controls in that it contained greater overall quantities of LH (p < 0.05) and greater amounts at the time of the LH surge (p < 0.05). Regardless of treatment males did not respond to EB. However, 4MA-treatment appeared to blunt the post-castration rise in LH since control plasma (n = 7) contained significantly more LH (p < 0.05) compared to plasma obtained from 4MA-treated animals (n = 6). These data suggest that 5α-reduction of testosterone is not required for androgenization of the male brain but is needed for normal development of external genitalia. The data also suggest that 5α-reduced steroids exert developmental effects on female fetuses since inhibition of 5αRA in fetal life renders them more responsive to the positive feedback action of EB.

Prenatal Inhibition of Aromatase Activity Affects Luteinizing Hormone Feedback Mechanisms and Reproductive Behaviors of Adult Guinea Pigs1

“…These data imply that the cellular events that mediate the organization of positive and negative feedback control mechanisms of gonadotropin release have different hormonal components or dose requirements for estrogen during fetal life. The present results differ from those of similar experiments using a 5oa-reductase inhibitor [11]. In those experiments, fetal guinea pigs of both sexes exposed to a 5ot-reductase inhibitor in utero were capable of responding to the negative feedback action of estrogen on LH secretion in adulthood [11].…”

“…The present results differ from those of similar experiments using a 5oa-reductase inhibitor [11]. In those experiments, fetal guinea pigs of both sexes exposed to a 5ot-reductase inhibitor in utero were capable of responding to the negative feedback action of estrogen on LH secretion in adulthood [11]. Gonadectomized males thus treated, however, possess lower LH levels in their sera than do untreated controls, indicating that the development of mechanisms that control the postcastration rise of gonadotropin is androgen-dependent.…”

“…The part of the guinea pig brain containing the LH surge mechanism is androgenized by endogenous hormones since males will not release LH in response to an estrogen challenge [11,12]. Androgenization of the surge mechanism in females is readily achieved by prenatal treatment with testosterone [10], but the capacity of males to release surge amounts of LH in response to an estrogen challenge was unaffected by exposing the fetus to either a S5a-reductase [11] or an aro- matase (present study) inhibitor during the critical period for sexual development. The reason for this failure is probably that testosterone per se can androgenize the central nervous system without being converted to an active metabolite.…”

Effects of Prenatal Treatment with Antiandrogens on Luteinizing Hormone Secretion and Sex Steroid Concentrations in Adult Spotted Hyenas, Crocuta crocuta1

“…Alternatively, both sexes may respond to an E 2 challenge by releasing surge amounts of LH, as is the case in primates [8]. The effects of an E 2 challenge on LH in our AA-treated hyenas will also be of interest, because Connolly and Resko [43] found that female guinea pigs treated prenatally with a 5␣-reductase inhibitor showed a greater LH response to E 2 treatment. Given the profound organizational effects that prenatal androgens have on the hypothalamic-pituitary unit in a diverse group of female mammals, how the highly virilized female spotted hyena escapes those effects remains an open and intriguing question.…”