Indomethacin inhibits lordosis induced by ring a-reduced progestins: Possible role of 3 alpha-oxoreduction in progestin-facilitated lordosis

Progestins with a delta-4-3-keto configuration bind to the progestin recept or (PR) and facilitate estrous behavior in estrogen-primed rats. Some ring A-reduced progestins [5 alpha-dihydroprogesterone (alpha DHP), allopregnano lone, and epipregnanolone] are more potent estrus-inducing agents than prog esterone when iv injected despite their lower affinity for the PR. Yet the estrus-inducing action of such progestins is reduced by the antiprogestin R U486, suggesting that binding to the PR is required for this effect. Becaus e allo- and epi-pregnanolone are oxidized to alpha- and beta DHP, respectiv ely, by 3 alpha-hydroxysteroid oxo-reductase (3 alpha HSOR), part of their estrus-inducing action may occur through the binding of such DHPs to the PR . Conversely, because 3 alpha HSOR reduces alpha- and beta DHP 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 po ssibilities we assessed the effect of indomethacin, a blocker of 3 alpha HS OR, on the estrus-inducing action of such progestins. Because indomethacin also inhibits cyclooxygenases, we selected a dose and treatment schedule th at does not interfere with prostaglandin-mediated brain processes (e.g., LH RH release). Indomethacin did not significantly modify the effect of proges terone or megestrol acetate on lordosis. Yet, it significantly reduced the action of all ring A-reduced progestins. Results suggest that: (a) oxidatio n is essential for lordosis facilitation by 3 alpha-pregnanolones and (b) r eduction of 3-keto progestins generates 3 alpha-hydroxy metabolites which s ynergize with processes triggered by occupation of the PR by 3-keto progest ins. The possible participation in this response of other events influenced by indomethacin (e.g., prostaglandin or melatonin synthesis) is discussed. (C) 1999 Academic Press.