Endocrine Abstracts

The brain is an important target of progesterone. Already earlier studies consistently reported the presence of progesterone receptors (PR) throughout the brain. The wide distribution of brain PR has subsequently been confirmed by mRNA analysis, immunohistochemistry and more recently by immunoelectron microscopy. Surprisingly, the significance of the wide distribution of PR in the brain has largely remained unexplored, and only hypothalamic receptors have been extensively studied for their role in the regulation of female reproductive behavior. This lack of information about the brain functions of PR is unexpected, as progesterone is known to exert multiple effects on neural cells. Moreover, the neuroprotective effects of progesterone have recently received much attention. A reason why so little interest has been devoted to the brain functions of PR may be the widely accepted assumption that non-reproductive functions of progesterone may be mainly mediated by its metabolite allopregnanolone, which does not bind to PR, but to membrane γ-aminobutyric acid type A (GABA_A) receptors, a major inhibitory neurotransmitter receptor. It is indeed widely acknowledged that allopregnanolone has anxiolytic, anesthetic, antidepressant and anticonvulsant actions by modulating GABA_A receptors. Our recent experimental studies demonstrate a key role for PR in neuronal survival after stroke, induced by the transient occlusion of the middle cerebral artery (MCAO) in mice. Importantly, we show that PR deficiency, and even haploinsufficiency, markedly increases the vulnerability of the brain to ischemic injury, resulting in increased infarct volume and poor functional outcomes. Identification of PR as a drug target for neuroprotection opens new therapeutic indications for selective synthetic progestins, already validated for contraception or hormone therapy. Thus, the neuroprotective effect of progesterone therapy could be mimicked by administration of a low dose of the potent 19-norprogesterone derivative Nestorone.