The effect of ring A reductions at C5 and C3 on the capacity of the
progesterone (P) molecule to stimulate estrous behavior was studied in ovariectomized
estrogen primed rats (5 micrograms
estradiol benzoate, EB, 40 h before
progestin administration). Dose-response curves (dose range: 0.75-200 micrograms) for the
lordosis quotient (LQ),
lordosis score (LS), and proceptivity were constructed for P and all its ring A reduced metabolites:
5 alpha-pregnanedione (alpha DHP), 5 beta-pregnanedione (beta DHP), 3 alpha,5 alpha-
pregnanolone (3 alpha,5 alpha-Pgl), 3 alpha,5 beta-
pregnanolone (3 alpha,5 beta-Pgl), 3 beta,5 alpha-
pregnanolone (3 beta,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 were made at 5, 30, and 120 min after
progestin injection. Weak, though significant
lordosis behavior was observed at 5 min following the injection of some of the
progestins, particularly the pregnanolones. Maximal 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 alpha 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 was 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-Pgl, 3 alpha,5 beta-Pgl, and 3 beta,5 beta-Pgl), significantly inhibited their action on estrous behavior (
lordosis and proceptivity) when tested at 60 and 120 min postinjection. On the other hand,
RU486 failed to 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 ineffective in inhibiting
lordosis in ovariectomized rats treated only with
estradiol (3 micrograms of EB/day for 7 days). Data suggest that: (i) ring A reduction of the P molecule plays an important role in the normal facilitation of estrous behavior in the rat; and (ii) ring A reduced
progestins provoke this effect by acting, at least partially, through the
progesterone receptor.