Antigonadotropic and antisteroidogenic actions of peroxide in rat granulosa cells.
Reactive oxygen species are produced in the ovary. In luteal cells, peroxide abruptly inhibits LH-sensitive cAMP and progesterone production, and may serve a role as a mediator of luteolysis by such mechanisms. The objective of the present studies was to evaluate the acute actions of peroxide in rat granulosa cells. Peroxide at concentrations in the low micromolar range produced a marked and dose-dependent inhibition of FSH-sensitive cAMP accumulation and progesterone production, and depleted cell levels of ATP within 1 min. Longer treatment with peroxide (60 min) caused complete abrogation of the actions of FSH. Peroxide-induced depletion of ATP was prevented by 3-aminobenzamide, an inhibitor of DNA repair, but maintenance of cell levels of ATP did not prevent the anti-FSH effects of peroxide. Peroxide also abrogated cAMP accumulation and progesterone production in response to LH in granulosa cells. Unlike that seen with LH, inhibition of FSH-sensitive cyclic AMP accumulation by peroxide was partially reversed with isobutylmethyl xanthine, an inhibitor of cyclic AMP phosphodiesterase. Although peroxide inhibited cAMP accumulation in response to cholera toxin, it did not inhibit this same response to forskolin, which indicates that peroxide may interfere with G-protein-dependent activation of adenylate cyclase. Peroxide inhibited steroidogenesis in response to cholera toxin, forskolin, and 8-bromo-cAMP. The marked inhibitory actions of peroxide on gonadotropic hormone action and steroidogenesis in granulosa cells raise the possibility that peroxide may mediate events associated with loss of follicular function.
Department of Obstetrics/Gynecology, Yale University School of Medicine, New Haven, Connecticut 06510.
Y
Y
Margolin
R F
RF
Aten
H R
HR
Behrman
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002772:Cholera Toxin / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000096:biosynthesis; D004260:DNA Repair / Q000187:drug effects; D005260:Female; D005640:Follicle Stimulating Hormone / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D005609:Free Radicals; D006107:Granulosa Cells / Q000187:drug effects / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D007986:Luteinizing Hormone / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D010100:Oxygen / Q000378:metabolism; D011374:Progesterone / Q000096:biosynthesis*; D051381:Rats
D001549:Benzamides; D005609:Free Radicals; D005576:Colforsin; D015124:8-Bromo Cyclic Adenosine Monophosphate; D011374:Progesterone; C025160:3-aminobenzamide; D000255:Adenosine Triphosphate; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone; D002772:Cholera Toxin; D006861:Hydrogen Peroxide; D000242:Cyclic AMP; D010100:Oxygen; D015056:1-Methyl-3-isobutylxanthine