The novel progestin drospirenone and its natural counterpart progesterone: biochemical profile and antiandrogenic potential.
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.
Fuhrmann
U
U
Research Laboratories of Schering AG, Berlin, Germany.
Krattenmacher
R
R
Slater
E P
EP
Fritzemeier
K H
KH
D000736:Androstenes / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists / Q000378:metabolism / Q000494:pharmacology*; D009919:Orchiectomy; D011374:Progesterone / Q000378:metabolism / Q000494:pharmacology*; D045167:Progesterone Congeners / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011944:Receptors, Androgen / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D011960:Receptors, Estrogen / Q000187:drug effects / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D018161:Receptors, Mineralocorticoid / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D011980:Receptors, Progesterone / Q000187:drug effects / Q000378:metabolism; D011987:Receptors, Steroid / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D013739:Testosterone / Q000494:pharmacology; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics; D014162:Transfection / Q000187:drug effects / Q000235:genetics
D000736:Androstenes; D000451:Mineralocorticoid Receptor Antagonists; D045167:Progesterone Congeners; D011944:Receptors, Androgen; D011960:Receptors, Estrogen; D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid; D011980:Receptors, Progesterone; D011987:Receptors, Steroid; D013739:Testosterone; D011374:Progesterone; C035144:drospirenone