Indomethacin inhibits lordosis induced by ring A-reduced progestins: possible role of 3alpha-oxoreduction in progestin-facilitated lordosis.
Progestins with a delta-4-3-keto configuration bind to the progestin receptor (PR) and facilitate estrous behavior in estrogen-primed rats. Some ring A-reduced progestins [5alpha-dihydroprogesterone (alphaDHP), allopregnanolone, and epipregnanolone] are more potent estrus-inducing agents than progesterone when iv injected despite their lower affinity for the PR. Yet the estrus-inducing action of such progestins is reduced by the antiprogestin RU486, suggesting that binding to the PR is required for this effect. Because allo- and epi-pregnanolone are oxidized to alpha- and betaDHP, respectively, by 3alpha-hydroxysteroid oxo-reductase (3alphaHSOR), part of their estrus-inducing action may occur through the binding of such DHPs to the PR. Conversely, because 3alphaHSOR reduces alpha- and betaDHP to allo- or epi-pregnanolone, both of which exert membrane effects, the estrus-inducing effect of DHPs may involve actions independent of the PR. To test these possibilities we assessed the effect of indomethacin, a blocker of 3alphaHSOR, on the estrus-inducing action of such progestins. Because indomethacin also inhibits cyclooxygenases, we selected a dose and treatment schedule that does not interfere with prostaglandin-mediated brain processes (e.g., LHRH release). Indomethacin did not significantly modify the effect of progesterone or megestrol acetate on lordosis. Yet, it significantly reduced the action of all ring A-reduced progestins. Results suggest that: (a) oxidation is essential for lordosis facilitation by 3alpha-pregnanolones and (b) reduction of 3-keto progestins generates 3alpha-hydroxy metabolites which synergize with processes triggered by occupation of the PR by 3-keto progestins. The possible participation in this response of other events influenced by indomethacin (e.g., prostaglandin or melatonin synthesis) is discussed.
CINVESTAV-Universidad Autónoma de Tlaxcala, Tlaxcala, Tlax, 90,000, México. gabriela@tlax.net.mx
C
C
Beyer
O
O
González-Flores
J M
JM
Ramírez-Orduña
G
G
González-Mariscal
D015096:3-Hydroxysteroid Dehydrogenases / Q000378:metabolism; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific); D000818:Animals; D001921:Brain / Q000201:enzymology; D001923:Brain Chemistry / Q000502:physiology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004971:Estrus / Q000187:drug effects / Q000502:physiology; D005260:Female; D006120:Grooming / Q000187:drug effects; D007213:Indomethacin / Q000494:pharmacology*; D008297:Male; D010084:Oxidation-Reduction; D011187:Posture / Q000502:physiology*; D011280:Pregnanolone / Q000378:metabolism / Q000494:pharmacology; D011372:Progestins / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D011980:Receptors, Progesterone / Q000378:metabolism; D012726:Sexual Behavior, Animal / Q000187:drug effects*
D016861:Cyclooxygenase Inhibitors; D011372:Progestins; D011980:Receptors, Progesterone; D011280:Pregnanolone; D015096:3-Hydroxysteroid Dehydrogenases; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific); D007213:Indomethacin