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In rats, fetal testosterone directs sexual differentiation of the brain. However, fetuses are also exposed to maternal progesterone. Here we report that progestin receptor immunoreactivity in the medial preoptic nucleus (MPN) of fetal and neonatal rats is high in males but virtually absent in females. The MPN is one of the most sexually dimorphic structures in the rat brain and mediates several sexually differentiated behaviors. This suggests that progesterone may play a previously overlooked role in the development of sex differences in the brain and behavior. Henceforth, a novel function of the mother in the sexual differentiation of the CNS must be considered.
Unexpected patterns of progesterone receptor expression in fetal and newborn rats break the rules of sexual differentiation, according to a researcher at the Experimental Biology 2002 conference. Contrary to current dogma, progesterone from maternal circulation binds to progesterone receptors in the fetal cortex.
Christine Wagner, assistant professor of psychology at the University at Albany, explained at the meeting that progesterone receptors clearly influence neuronal development in previously unthought ways.
In the classical brain development paradigm, fetal hormones drive the sexual differentiation of the developing brain. But Wagner now reports that maternal progesterone binds to fetal progesterone receptors.
The results, Wagner says, reveal a novel role of the mother in the development of the fetal central nervous system: A possible source of progesterone receptor ligand.
In males, fetal testosterone aromatises to oestradiol and masculinises the fetal brain. Without testosterone, the fetal brain is female. Wagner and her team previously reported that certain areas of the fetal rat brain, notably the medial preoptic nucleus (MPN) – an area that mediates sexually differentiated behaviours in adulthood – express the progesterone receptor well before birth.
On the day of birth, expression of the progesterone receptor (PR) in the MPN is high in males but virtually absent in females, a difference likely produced by differential exposure to oestradiol.
In contrast, Wagner has found that PR expression in another part of the developing rat brain, the ventral medial nucleus (VMN), is higher in females than males, an observation not readily explained by perinatal exposure to gonadal hormones.
Wagner says she believes the source of fetal PR receptor ligand is maternal ovarian progesterone, which is present in extremely high levels during pregnancy.
To test this hypothesis, Wagner and her colleagues manipulated fetal and postnatal hormonal exposure. They found that prenatal testosterone treatment in females, or castration of males upon birth, abolished the sex difference in PR expression. Sex differences in PR expression were also absent in mice lacking a functional oestrogen receptor-alpha.
In another finding, prenatal treatment with the aromatase inhibitor ATD reduced PR expression in both the male and female MPN. In contrast, prenatal treatment with flutamide, an androgen receptor antagonist, had no apparent effect on PR expression.
Neonatal treatment with the PR antagonist RU486 also abolished subsequent sexual behaviour in most adult males and attenuated the masculinising effects of testosterone on the MPN structure in females.
This surprising finding – the strikingly opposite effects of RU486 in males and females given identical doses – suggests, Wagner explained, that males and females come to the day of birth already substantially differentiated in ways postnatal testosterone cannot counter.
The findings also suggest progesterone is capable of both pro- and anti-apoptotic effects in the developing brain.
23 April 2002