Endogenous Oestradiol Regulates Progesterone Receptor Expression in the Brain of Female Rat Fetuses: What is the Source of Oestradiol?

Abstract

Testosterone secreted by male testes during fetal development is aromatized to oestradiol (E(2)) or reduced to the androgen, dihydrotestosteorne (DHT), within specific tissues. The female brain is assumed to develop in the relative absence of gonadal steroid hormones, as the ovary is steroidogenically quiescent until later in postnatal life. However, the proximity of a female fetus to male littermates in utero can increase her exposure to testosterone, and thereby its metabolites. To date, it is has been difficult to dissociate the effects of male-derived E(2) from those of DHT on the developing female brain. In the present study, anogential distance (AGD) in females was used as an androgen-dependent bioassay, whereas progesterone receptor (PR) expression within the medial preoptic nucleus (MPN) was used as an E-dependent measure. Pregnant dams received the aromatase inhibitor, 1,4,6-androstatriene-3,17-dione (ATD), or vehicle from embryonic day 16 (ED16) to ED21. On ED22, AGD and PR-immunoreactivity (-ir) were measured in females that had zero, one, or two males (0-2M) or females that had three, four, or five males (3-5M) in the uterine horn. AGD was significantly greater in 3-5M females compared to 0-2M females, suggesting that male littermates are the source of androgenic exposure in the female fetus. ATD treatment significantly decreased PR-ir in the MPN, demonstrating E(2) regulation of PR. However, the total number of males in the uterine horn did not effect PR expression. There was no correlation between PR-ir and AGD, suggesting that these measures are influenced independently. Together, these results suggest that although male littermates provide a significant source of androgens to female fetuses, the amount of E(2) aromatized from male-derived testosterone may not be the only biologically relevant source of androgens or E(2). Alternative sources of E(2) may be essential in ensuring the normal development of the female brain.