Beyer C, Gonzalez-Flores O, Gonzalez-Mariscal G
Centro de Investigación en Reproducción Animal, CINVESTAV-Universidad Autónoma de Tlaxcala, México.
Physiol Behav. 1995 Nov;58(5):985-93. doi: 10.1016/0031-9384(95)00141-5.
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.
在切除卵巢并用雌激素预处理的大鼠（在给予孕激素前40小时注射5微克苯甲酸雌二醇，EB）中，研究了C5和C3位A环还原对孕酮（P）分子刺激发情行为能力的影响。构建了P及其所有A环还原代谢产物的脊柱前凸商（LQ）、脊柱前凸评分（LS）和接受性的剂量-反应曲线（剂量范围：0.75 - 200微克）：5α-孕烷二酮（αDHP）、5β-孕烷二酮（βDHP）、3α,5α-孕烷醇酮（3α,5α-Pgl）、3α,5β-孕烷醇酮（3α,5β-Pgl）、3β,5α-孕烷醇酮（3β,5α-Pgl）和3β,5β-孕烷醇酮（3β,5β-Pgl）。将孕激素溶解在丙二醇中，通过留置的颈静脉导管静脉注射。在注射孕激素后5、30和120分钟进行脊柱前凸和接受性测试。在注射某些孕激素后5分钟观察到了较弱但显著的脊柱前凸行为，特别是孕烷醇酮类。所有孕激素在注射后120分钟获得最大反应。αDHP和两种3α-孕烷醇酮的LQ、LS和接受性的剂量反应曲线呈二元性，高剂量时反应较小。相对效价分析表明，αDHP、3α,5β-Pgl、3β,5α-Pgl和3α,5α-Pgl在引发脊柱前凸方面比P的效力显著更高（分别为14倍、13.7倍、9倍和4倍）。对于LS和接受性也发现了相同的相对效价顺序。3β,5β-Pgl和βDHP仅比P稍有效（分别为2倍和1.5倍）。在第二项研究中，在四种选定的孕激素（αDHP、3α,5α-Pgl、3α,5β-Pgl和3β,5β-Pgl）之一注射前60分钟皮下注射抗孕激素RU486（5毫克），在注射后60和120分钟测试时，显著抑制了它们对发情行为（脊柱前凸和接受性）的作用。另一方面，RU486未能抑制在注射3α,5α-Pgl和3α,5β-Pgl后5和30分钟获得的早期脊柱前凸反应。同样，RU486在仅用雌二醇治疗的切除卵巢的大鼠（每天3微克EB，共7天）中抑制脊柱前凸无效。数据表明：（i）P分子的A环还原在大鼠发情行为的正常促进中起重要作用；（ii）A环还原的孕激素至少部分通过孕激素受体起作用引发这种效应。
