Follicle-stimulating hormone inhibits granulosa cell 5 alpha-reductase activity. Possible role of 5 alpha-reductase as a steroidogenic pubertal switch.
In order to elucidate the role of 5 alpha-reductase in the ovarian pubertal transition from 5 alpha-reduced to non-5 alpha-reduced steroids, we examined the characteristics and regulation of granulosa cell (GC) 5 alpha-reductase activity. Maximum activity was observed at 37 degrees C and at a pH of 6.5-8.0. Synthetic 4-aza-3-oxosteroids proved to be potent inhibitors (76% inhibition at 0.1 microM) of ovarian 5 alpha-reductase activity, and 20 alpha-DHP was a better substrate than either progesterone or testosterone (4- or 7-fold higher affinity constants, respectively). The Km (20 alpha-DHP) of the enzyme was 0.50 +/- 0.03 microM and 0.75 +/- 0.20 microM in homogenates of whole ovaries and GC, respectively. 17 beta-Estradiol was a non-competitive inhibitor (KI = 6.97 microM). 5 alpha-Reductase activity was 22-fold (immature) to 68-fold (mature) higher in liver than ovary and 4-fold higher in theca-interstitial shells than in isolated GC. Ovarian 5 alpha-reductase activity decreased markedly with age (greater than 60% inhibition in mature, randomly cycling rats as compared to immature rats). In vivo administration of follicle-stimulating hormone (FSH) to immature rats produced a dose-dependent decrease in GC 5 alpha-reductase activity (36 +/- 1.1% and 46 +/- 5.9% inhibition following 12 micrograms and 24 micrograms FSH, respectively). Similarly, the in vitro provision of FSH (100 ng/ml) to cultured GC from immature rats resulted in (36-59%) inhibition in 5 alpha-reduced steroids. Inasmuch as FSH promotes GC development and the advancement of puberty, its ability to "switch-off" ovarian 5 alpha-reductase activity may enhance the formation of biologically potent (i.e. non-5 alpha-reduced) progestins as well as the availability of aromatizable androgens, in the best interests of pubertal steroidogenesis.
Payne
D W
DW
Department of Obstetrics and Gynecology, University of Maryland School of Medicine, Baltimore 21201.
Packman
J N
JN
Adashi
E Y
EY
D000818:Animals; D002478:Cells, Cultured; D042944:Cholestenone 5 alpha-Reductase; D002851:Chromatography, High Pressure Liquid; D005260:Female; D005640:Follicle Stimulating Hormone / Q000494:pharmacology*; D006107:Granulosa Cells / Q000201:enzymology* / Q000378:metabolism; D007700:Kinetics; D008099:Liver / Q000201:enzymology; D009929:Organ Size; D010053:Ovary / Q000187:drug effects / Q000201:enzymology; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D011284:Pregnenolone / Q000378:metabolism; D011374:Progesterone / Q000378:metabolism; D051381:Rats; D013739:Testosterone / Q000378:metabolism; D014599:Uterus / Q000187:drug effects / Q000201:enzymology
D013739:Testosterone; D011374:Progesterone; D011284:Pregnenolone; D005640:Follicle Stimulating Hormone; D010088:Oxidoreductases; D042944:Cholestenone 5 alpha-Reductase