Abstract
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.
Highlights
In order to elucidate the roleof 5a-reductase in the indispensable for proper reproductive function
Ba-reduced steroids, we examined the characteristics and regulation of granulosa cell( G C )5a-reductase activity
A4-3-oxosteroids are in ample supply in the mature animal, Sa-reduced steroids predominate in the immature(prepubertal) state (Lerner and Eckstein, 1976; Karakawa et al, 1976; Toorop et al, 1984). the precisecellularmechanism(s) underlying this pubertal “switch” remain unknown, it is highly likely that this steroidogenic shift is due to the deactivation of ovaria5na-reductas(eEC
Summary
In order to elucidate the roleof 5a-reductase in the indispensable for proper reproductive function. Ba-reduced steroids, we examined the characteristics and regulation of granulosa cell( G C )5a-reductase activity. T o begin to elucidate the regulation of ovarian 5a-reductase activityinthe course of thepubertaltransition, we have examined its biochemical characteristics, cellular localization, reductase activity decreased markedly with This inhibition in mature, randomly cycling rats as com- approach was prompted by the recognition that ovarian 5aparedtoimmaturerats). Inasmuch as FSH promotes GC development and theadvancement of puberty, its ability to “switch-off” ovarian 5a-reductase activity may enhance the formationof biologically potent (Le. non-5a-reduced)progestins as well as the availability of aromatizable androgens, in thebest interests of pubertal steroidogenesis.
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