Biosynthesis of the neurosteroid 3 alpha-hydroxy-4-pregnen-20-one (3 alpha hp), a specific inhibitor of FSH release.
The gonadal steroid 3 alpha-hydroxy-4-pregnen-20-one (3 alpha HP) is a neuroactive steroid with anxiolytic and analgesic actions. In addition, 3 alpha HP 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 alpha-hydroxysteroid dehydrogenase (3 alpha HSD) has been presumed to be the enzyme responsible for the conversion of progesterone to 3 alpha HP, but this has never been confirmed in vitro or in vivo. We have now determined the mechanism of 3 alpha HP synthesis in vivo using specific enzyme inhibitors and in vitro using recombinant proteins. Incubation of [(3)H]progesterone with purified recombinant rat and human 3 alpha HSD isoforms showed that both the rat 3 alpha HSD and the human type 2(brain) 3 alpha HSD converted progesterone to 3 alpha HP. Age-dependent 3 alpha HP production was demonstrated in pituitary and cortex. Incubation of both tissues with indomethacin, a known 3 alpha HSD inhibitor, decreased the conversion of progesterone to 3 alpha HP by at least 70%, indicating that 3 alpha HSD was responsible for this conversion. As human type 2 3 alpha HSD is expressed in a region-specific fashion in the brain, 3 alpha HP may only be made in specific regions of the brain. Furthermore, the data suggest that the pituitary has the capacity for 3 alpha HP production, which may provide an additional mechanism for regulation of GnRH action.
Griffin
L D
LD
Department of Neurology, University of California, San Francisco, California 94143, USA.
Mellon
S H
SH
D004092:20-alpha-Dihydroprogesterone / Q000031:analogs & derivatives* / Q000096:biosynthesis* / Q000494:pharmacology*; D015096:3-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific); D000818:Animals; D042944:Cholestenone 5 alpha-Reductase; D004798:Enzymes / Q000378:metabolism; D005260:Female; D005473:Fluoxetine / Q000494:pharmacology; D005640:Follicle Stimulating Hormone / Q000037:antagonists & inhibitors*; D006801:Humans; D010088:Oxidoreductases / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D014018:Tissue Distribution
D004092:20-alpha-Dihydroprogesterone; D015096:3-Hydroxysteroid Dehydrogenases; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific); D042944:Cholestenone 5 alpha-Reductase; D004798:Enzymes; D005473:Fluoxetine; D005640:Follicle Stimulating Hormone; D010088:Oxidoreductases; D011994:Recombinant Proteins; D017367:Selective Serotonin Reuptake Inhibitors; C052610:3-hydroxypregn-4-en-20-one