The neuroactive steroid allopregnanolone suppresses hypothalamic gonadotrophin-releasing hormone release through a mechanism mediated by the GABAA receptor

A E Calogero, M A Palumbo1, A M J Bosboom2, N Burrello, E Ferrara, G Palumbo1, F Petraglia3 and R D'Agata

Division of Andrology, Department of Internal Medicine, University of Catania, Catania, Italy, 1Department of Obstetrics and Gynaecological Endocrinology, University of Catania, Catania, Italy, 2Department of Andrology III, Erasmus University, Rotterdam, The Netherlands and 3Department of Gynaecology, Obstetrics and Paediatric Sciences, University of Modena, Modena, Italy

(Requests for offprints should be addressed to A E Calogero, Istituto di Medicina Interna e Specialità Internistiche, Ospedale Garibaldi, Piazza S.M. di Gesù, 95123 Catania, Italy)

Abstract

The central nervous system (CNS) is able to synthesize and/or metabolize steroid hormones. These neuroactive steroids are capable of modulating several brain functions and, among these, they seem to regulate the hypothalamic-pituitary-gonadal (HPG) axis. Indeed, recent observations showed that 5alpha-pregnane-3alpha-ol-20-one (allopregnanolone), one of the most abundant naturally occurring neuroactive steroids, suppresses ovulation and sexual behaviour when administered within the CNS. The present study was undertaken to evaluate the effects of allopregnanolone and its inactive stereoisomer, 5alpha-pregnane-3ß-ol-20-one, upon the release of gonadotrophin-releasing hormone (GnRH) from individually- incubated hemi-hypothalami. Allopregnanolone suppressed GnRH release in a concentration-dependent manner with maximal activity in the nanomolar range, a range at which this neurosteroid is capable of playing a biological action. The specificity of allopregnanolone suppression of GnRH release was provided by the lack of effect of its known inactive stereoisomer. To evaluate the involvement of GABAA receptor, we examined the effects of two neurosteroids with GABA-antagonistic properties, pregnanolone sulfate (PREG-S) and dehydroepiandrosterone sulfate (DHEAS), and of bicuculline, a selective antagonist of the GABA binding site on the GABAA receptor, on allopregnanolone (10 nM)-suppressed GnRH release. Both PREG-S and bicuculline overcame the inhibitory effects of allopregnanolone on GnRH release, whereas DHEAS did not. To further substantiate the involvement of the GABAA receptor, we tested the effects of muscimol, a selective agonist for this receptor, which suppressed GnRH release.

In conclusion, allopregnanolone suppressed hypothalamic GnRH release in vitro and this effect appeared to be mediated by an interaction with the GABAA receptor. We speculate that the inhibitory effect of allopregnanolone on the HPG axis may be also caused by its ability to suppress hypothalamic GnRH release.

Download the FULL TEXT of this article in Acrobat PDF format.

If you have not previously downloaded PDF files we suggest you access our Advice page for further information.

Journal of Endocrinology

Return to the Contents List - Vol. 158 Part 1