Steroid hormones play an influential role in neural development. In addition to androgens and estrogens of fetal and neonatal origin, the developing brain may also be exposed to progesterone. In this regard, identifying forebrain nuclei that are sensitive to progesterone during neural development may elucidate the impact of progesterone on the developing brain. Using immunocytochemistry, the present study documented the distribution of progesterone receptor (PR) expression in the rat forebrain from embryonic day (E) 17 through postnatal day (P) 28. The results indicate that PR expression in the developing brain is extensive, present in numerous forebrain nuclei, but transient, in that PR expression was absent in most nuclei by P28. Regions displaying the highest levels of PR-immunoreactivity (PRir) were found in preoptic and hypothalamic nuclei including the medial preoptic, anteroventral periventricular, arcuate, and ventromedial nuclei. PRir was moderately abundant in the limbic region, particularly in subdivisions of the amygdala, the bed nucleus of the stria terminalis, and hippocampus. The choroid plexus and neocortex were additional structures that demonstrated relatively abundant levels of PRir. The presence PR expression in the developing forebrain implicates the involvement of progesterone and PR in fundamental mechanisms of neural development.

The differential exposure of males and females to testosterone (T) and its metabolite estradiol (E) contributes to the development of sex differences in the brain. However, the mechanisms by which T and E permanently alter neural development remain virtually unknown. Two regions of the rat preoptic area, the anteroventral periventricular nucleus (AVPv) and the medial preoptic nucleus (MPN), are sexually dimorphic and serve as models for studying the hormonal mechanisms of sexual differentiation. Around birth, these regions express dramatically higher levels of progesterone receptor immunoreactivity (PRir) in males than they do in females. The present study examined the possibility that sexually dimorphic induction of PR expression in these two regions constitutes a potential mechanism of E-mediated sexual differentiation. Prenatal exposure to either T propionate or the synthetic estrogen, diethylstilbestrol, but not dihydrotestosterone propionate, significantly increased PRir levels in the MPN and AVPv of fetal females compared with controls. Prenatal exposure to the aromatase inhibitor, 1,4,6-androstatriene-3,17-dione, significantly reduced PRir in the MPN and AVPv of fetal males, whereas the androgen receptor antagonist flutamide had no effect. This suggests that aromatization of T into E is crucial for the sex difference in PR expression in the MPN and AVPv during development.

Around the time of birth, male rats express higher levels of progesterone receptors in the medial preoptic nucleus (MPN) than female rats, suggesting that the MPN may be differentially sensitive to maternal hormones in developing males and females. Preliminary evidence suggests that this sex difference depends on the activation of estrogen receptors around birth. To test whether estrogen receptor alpha (ER alpha) is involved, we compared progesterone receptor immunoreactivity (PRir) in the brains of male and female neonatal mice that lacked a functional ER alpha gene or were wild type for the disrupted gene. We demonstrate that males express much higher levels of PRir in the MPN and the ventromedial nucleus of the neonatal mouse brain than females, and that PRir expression is dependent on the expression of ER alpha in these regions. In contrast, PRir levels in neocortex are not altered by ER alpha gene disruption. The results of this study suggest that the induction of PR via ER alpha may render specific regions of the developing male brain more sensitive to progesterone than the developing female brain, and may thereby underlie sexual differentiation of these regions.

To assess the relative roles of sex chromosome genes and gonadal steroid hormones in producing sex differences in progesterone receptor (PR) expression in the forebrain of neonatal mice, we used mice in which the Sry gene had been deleted from the Y-chromosome and inserted as a transgene on an autosome in both XX and XY genotypes. Levels of PR immunoreactivity (PRir) in the anteroventral periventricular nucleus, the medial preoptic nucleus, and the ventromedial nucleus were significantly higher in mice that possessed an Sry transgene compared with mice that lacked an Sry transgene, regardless of their complement of sex chromosomes (XX vs. XY). This result suggests that sexual differentiation of PR expression in these regions is likely controlled mainly by gonadal hormones, not by the genetic sex of the brain cells. No differences in PRir were detected between wild-type XY mice with the Sry gene on the Y-chromosome and XY mice with the Sry transgene, suggesting that testicular hormones produced in these two genotypes have comparable effects on neural tissue.