Fuhrmann U, Krattenmacher R, Slater E P, Fritzemeier K H
Research Laboratories of Schering AG, Berlin, Germany.
Contraception. 1996 Oct;54(4):243-51. doi: 10.1016/s0010-7824(96)00195-3.
Drospirenone is a novel progestin under clinical development that is similar to the natural hormone progesterone, combining potent progestogenic with antimineralocorticoid and antiandrogenic activities. This specific pharmacological profile of drospirenone is defined by its pattern of binding affinities to a variety of steroid hormone receptors. In the present study the affinity of drospirenone to the progesterone receptor (PR), the androgen receptor (AR), the glucocorticoid receptor (GR), the mineralocorticoid receptor (MR), and the estrogen receptor (ER) was re-evaluated by steroid binding assays and compared to those obtained for the natural hormone progesterone. Drospirenone displayed high affinity to PR and MR and low binding to AR, similar to progesterone. Unlike progesterone, which showed considerable binding to GR, drospirenone exhibited only low binding to this receptor. Neither drospirenone nor progesterone did bind to the ER. In addition to receptor binding studies, transactivation assays were carried out to investigate the effects of drospirenone and progesterone on AR-, GR-, and MR-mediated induction of transcription. Both progestins showed no androgenic but antiandrogenic activity by inhibiting AR-mediated transcription in a dose-dependent manner. This observation could be confirmed by in vivo experiments carried out with orchiectomized male rats, where the antiandrogenic potency of drospirenone was found to be about five- to ten-fold higher than that of progesterone. In contrast to progesterone, drospirenone was devoid of glucocorticoid activity. Both progestins did not show any antiglucocorticoid action. Furthermore, drospirenone and progesterone both showed considerable antimineralocorticoid activity and weak mineralocorticoid activity.
屈螺酮是一种正在临床开发中的新型孕激素，与天然激素孕酮相似，兼具强效孕激素活性以及抗盐皮质激素和抗雄激素活性。屈螺酮这种特定的药理特性是由其与多种甾体激素受体的结合亲和力模式所决定的。在本研究中，通过甾体结合试验重新评估了屈螺酮与孕激素受体（PR）、雄激素受体（AR）、糖皮质激素受体（GR）、盐皮质激素受体（MR）和雌激素受体（ER）的亲和力，并与天然激素孕酮的亲和力进行了比较。屈螺酮对PR和MR显示出高亲和力，对AR的结合力低，这与孕酮相似。与对GR有相当程度结合的孕酮不同，屈螺酮对该受体仅表现出低结合力。屈螺酮和孕酮均不与ER结合。除了受体结合研究外，还进行了反式激活试验，以研究屈螺酮和孕酮对AR、GR和MR介导的转录诱导作用的影响。两种孕激素均未表现出雄激素活性，而是通过剂量依赖性抑制AR介导的转录表现出抗雄激素活性。用去势雄性大鼠进行的体内实验证实了这一观察结果，其中发现屈螺酮的抗雄激素效力比孕酮高约五至十倍。与孕酮不同，屈螺酮没有糖皮质激素活性。两种孕激素均未表现出任何抗糖皮质激素作用。此外，屈螺酮和孕酮均表现出相当程度的抗盐皮质激素活性和较弱的盐皮质激素活性。
