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Biosynthesis of the Neurosteroid 3-Hydroxy-4-pregnen-20-one (3HP), a Specific Inhibitor of FSH Release

Departments of Neurology (L.D.G.) and Obstetrics and Gynecology (S.H.M.), and Center for Reproductive Endocrinology (S.H.M.), University of California, San Francisco, California 94143

Address all correspondence and requests for reprints to: Synthia H. Mellon, Ph.D., Box 0556, University of California, San Francisco, California 94143-0556. E-mail: mellon{at}cgl.ucsf.edu

The gonadal steroid 3-hydroxy-4-pregnen-20-one (3HP) is a neuroactive steroid with anxiolytic and analgesic actions. In addition, 3HP has been shown to inhibit GnRH activity on gonadotropes and selectively suppress FSH release from pituitary cells, without an effect on LH. The enzyme 3-hydroxysteroid dehydrogenase (3HSD) has been presumed to be the enzyme responsible for the conversion of progesterone to 3HP, but this has never been confirmed in vitro or in vivo. We have now determined the mechanism of 3HP synthesis in vivo using specific enzyme inhibitors and in vitro using recombinant proteins. Incubation of [³H]progesterone with purified recombinant rat and human 3HSD isoforms showed that both the rat 3HSD and the human type 2_brain 3HSD converted progesterone to 3HP. Age-dependent 3HP production was demonstrated in pituitary and cortex. Incubation of both tissues with indomethacin, a known 3HSD inhibitor, decreased the conversion of progesterone to 3HP by at least 70%, indicating that 3HSD was responsible for this conversion. As human type 2 3HSD is expressed in a region-specific fashion in the brain, 3HP may only be made in specific regions of the brain. Furthermore, the data suggest that the pituitary has the capacity for 3HP production, which may provide an additional mechanism for regulation of GnRH action.

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