RING-A-REDUCED-PROGESTINS POTENTLY STIMULATE ESTROUS BEHAVIOR IN RATS- PARADOXICAL EFFECT THROUGH THE PROGESTERONE-RECEPTOR

The effect of ring A reductions at C5 and C3 on the capacity of the pr ogesterone (P) molecule to stimulate estrous behavior was studied in o variectomized estrogen primed rats (5 mu g estradiol benzoate, EB, 40 h before progestin administration). Dose-response curves (dose range: 0.75-200 mu g) for the lordosis quotient (LQ), lordosis score (LS), an d proceptivity were constructed for P and all its ring A reduced metab olites: 5 alpha-pregnanedione (alpha DHP), 5 beta-pregnanedione (beta DHP), 3 alpha,5 alpha-pregnanolone (3 alpha,5 alpha-Pgl), 3 alpha,5 be ta-pregnanolone (3 alpha,5 beta-Pgl), 3 beta,5 alpha-pregnanolone (3 b eta,5 alpha-Pgl), and 3 beta,5 beta-pregnanolone (3 beta,5 beta-Pgl). Progestins were dissolved in propylene glycol and IV injected through an indwelling jugular catheter. Tests for lordosis and proceptivity we re made at 5, 30, and 120 min after progestin injection. Weak, though significant lordosis behavior was observed at 5 min following the inje ction of some of the progestins, particularly the pregnanolones. Maxim al responses were obtained at 120 min postinjection for all progestins . Dose response curves of the LQ, LS, and proceptivity were dualistic for alpha DHP and both 3 alpha pregnanolones, smaller responses being observed with high doses. Relative potency analysis revealed that alph a DHP, 3 alpha,5 beta-Pgl, 3 beta,5 alpha-Pgl, and 3 alpha,5 alpha-Pgl were considerably more potent for eliciting lordosis than P (14, 13.7 , 9, and 4-fold, respectively). The same order of relative potencies w as found for both LS and proceptivity. 3 beta,5 beta-Pgl and beta DHP were only slightly more potent than P (2 and 1.5-fold, respectively). In a second study, the antiprogestin RU486 (5 mg, SC), injected 60 min before one of four selected progestins (alpha DHP, 3 alpha,5 alpha-Pg l, 3 alpha,5 beta-Pgl, and 3 beta,5 beta-Pgl), significantly inhibited their action on estrous behavior (lordosis and proceptivity) when tes ted at 60 and 120 min postinjection. On the other hand, RU486 failed t o inhibit early lordotic responses obtained at 5 and 30 min following 3 alpha,5 alpha-Pgl and 3 alpha,5 beta-Pgl. Similarly RU486 was ineffe ctive in inhibiting lordosis in ovariectomized rats treated only with estradiol (3 mu g of EB/day for 7 days). Data suggest that: (i) ring A reduction of the P molecule plays an important role in the normal fac ilitation of estrous behavior in the rat; and (ii) ring A reduced prog estins provoke this effect by acting, at least partially, through the progesterone receptor.