Biosynthesis of the neurosteroid 3 alpha-hydroxy-4-pregnen-20-one (3 alpha hp), a specific inhibitor of FSH release

Endocrinology
L D Griffin, Synthia H Mellon

Abstract

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 ...Continue Reading

References

Nov 11, 1999·Proceedings of the National Academy of Sciences of the United States of America·L D Griffin, S H Mellon
Jan 5, 2000·The Journal of Steroid Biochemistry and Molecular Biology·H K LinT M Penning
Jan 6, 2000·The Journal of Steroid Biochemistry and Molecular Biology·W P EechauteJ M Kaufman
Jan 12, 2000·Alcoholism, Clinical and Experimental Research·A L MorrowK A Grant

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Citations

Oct 16, 2010·Alcoholism, Clinical and Experimental Research·Joyce BesheerA Leslie Morrow
Aug 3, 2013·Alcoholism, Clinical and Experimental Research·Jason B CookA Leslie Morrow
Feb 24, 2005·Gynecological Endocrinology : the Official Journal of the International Society of Gynecological Endocrinology·M J SmithD R Rubinow

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