Progesterone receptors and neural development: a gap between bench and bedside?

Abstract

Despite a recent increase in the clinical use of progesterone in pregnant women and premature neonates, very little is understood about the potential role of this hormone and its receptors in neural development. Findings from rodent models indicate that the brain is indeed sensitive to progesterone during critical periods of development and maturation. Dramatic sex differences in progesterone receptor (PR) expression, in which males express higher levels of PR than females in specific regions, suggest that PR may play an important role in the sexual differentiation of brain and behavior and that the expression of PR may be one mechanism by which testicular hormones masculinize the brain. PR is also transiently expressed during fetal and neonatal development in areas of the brain associated with cognitive behaviors. PR protein and mRNA are expressed in pyramidal cell layers of perinatal cortex in an anatomically and developmentally specific manner, generating the intriguing hypothesis that progesterone is essential for normal cortical development. Basic research elucidating a potential role for progesterone and PR in developing brain is reviewed in light of the clinical use of this hormone. The necessity for future research integrating findings from the bench and the bedside is evident.

Figure 1

PR activity may be one mechanism by which testicular hormones masculinize neural development and subsequent adult behavior. A, Neonatal treatment of females with the PR antagonist, RU486, attenuated the masculinizing effects of testosterone propionate (TP) on the volume of the SDN-POA (27). *, Significantly different from vehicle group (P < 0.05; **, significantly different from oil-treated females (P < 0.01). B, Neonatal treatment of males with RU486 significantly reduced the percent of males displaying mounting behavior in adulthood (34). *, Significantly different from untreated and vehicle.

Figure 2

There are striking sex differences in PR expression, in which males express much higher levels of PR than females within specific regions of the perinatal rat brain associated with reproductive and/or neuroendocrine function in adulthood. For example, A, PRir in the MPN and the periventricular (PeN) of male and female rats on the day of birth (24). B, PRir in the arcuate nucleus of male and female rats on postnatal d 7. C, PR mRNA, detected by in situ hybridization, in the AVPv of male and female rats on the day of birth. 3V, Third ventricle; AC, anterior commissure.

Figure 3

PR is transiently expressed within specific lamina of perinatal neocortex. PRir nuclei in the subplate of neocortex in a male rat on postnatal d 1 (A) and in cortical layer V (B) in a male rat on postnatal d 7. cc, Corpus callosum; sp, subplate.

Figure 4

Differential regulation and activation of PR across brain regions creates a working model for the actions of P and PR within the MPN and cortex of fetal and neonatal rats. In the MPN of males, testosterone (T), secreted by the fetal and neonatal testes, readily enters the brain, in which it can be aromatized to estradiol (E) or reduced to dihydrotestosterone (DHT). Estradiol activates ERα, which increases the transcription of the PR gene. This results in a developmental period between E18 and approximately postnatal d 10 when PR expression is high in males but not females. P may arise from one or more potential sources creating brain concentrations of P that are dynamic and perhaps locally quite high. P presumably activates PR, which as a transcription factor can initiate a cascade of molecular and cellular events, which, because they occur in the male brain only, lead to sexual differentiation of MPN structure and function. In contrast, PR is expressed in an anatomically and developmentally specific manner in both male and female fetuses and neonates. PR expression in cortex is not regulated by either androgens or estradiol but rather appears to be dependent on maternal thyroid status; expression of PR in developing cortex is reduced by maternal hypothyroidism. P, likely arising from de novo synthesis in cortex, activates PR. Because PR is expressed in cortical subplate neurons and pyramidal cell layers 5 and 2 and 3, it is possible that PR plays an important role in establishing normal thalamocortical connectivity. AR, Androgen receptor; TH, thyroid hormone; THR, thyroid hormone receptor.