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.

Genomics of Preterm Birth

“…An alternative hypothesis could be that some of the newly evolved roles of P4, such as those in embryonic development or in maternal metabolism, preclude systemic P4 withdrawal before birth. P4 has been shown to play a role in lung development (Beyer et al 2003;Trotter et al 2006Trotter et al , 2009 as well as in neurological development (Wagner 2008;Yawno et al 2014). These two organs manifest prolonged development in humans (and in guinea pig; Sosenko and Frank 1987), as evidenced by a majority of the defects from preterm birth being of neurological and pulmonary nature.…”

Sex-specific effects of early neonatal progesterone treatment on dopamine and serotonin metabolism in rat striatum and frontal cortex

“…The current data suggest that the frontal cortex does not have sexually dimorphic features in terms of sensitivity to neonatal neurosteroids. This result might be relevant to observations of a lack of sex difference in PROG receptor expression in fetal and neonatal cortex in contrast to sex-specific expression in other regions, including the preoptic sexually dimorphic area (Wagner, 2008). Unique findings in neonatally PROG-treated animals that are not also identified in neonatally ALLO-treated animals might be attributed to the genomic action of PROG through a binding to intracellular PROG receptors or other PROG-specific actions.…”

“…Animal studies indicate that the brain is sensitive to PROG during development and PROG receptors transiently express in the cerebral cortex during perinatal period Life Sciences 87 (2010) 738-742 (Jahagirdar and Wagner, 2010). Furthermore, there are sex differences in PROG receptor expression (Wagner, 2008). These evidence suggests that PROG may play an important role in the sexual differentiation of brain.…”

“…A role for PROG in the development of the brain is beginning to be investigated despite that cases of PROG exposure on the developing human brain is increasing (Wagner, 2008); PROG is used for the prevention of premature birth (Ness et al, 2006) and the treatment of premature infants (Trotter et al, 2007). In addition, breast-fed infants may be exposed to progestins from the use by lactating women as contraceptives (Wagner, 2008).…”

“…In addition, breast-fed infants may be exposed to progestins from the use by lactating women as contraceptives (Wagner, 2008). Animal studies indicate that the brain is sensitive to PROG during development and PROG receptors transiently express in the cerebral cortex during perinatal period Life Sciences 87 (2010) 738-742 (Jahagirdar and Wagner, 2010).…”