The novel progestin drospirenone and its natural counterpart progesterone: biochemical profile and antiandrogenic potential.
Fuhrmann U, Krattenmacher R, Slater EP, Fritzemeier KH.
Research Laboratories of Schering AG, Berlin, Germany.
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.
PIP: In various research laboratories in Germany, researchers conducted receptor binding studies and transactivation assays in vitro and studied antiandrogenic activity in juvenile castrated male rats of the new progestin drospirenone and of the natural hormone progesterone. Drospirenone exhibited high affinity to the progesterone receptor (PR) and the mineralocorticoid receptor (MR), while it exhibited low affinity to the androgen receptor (AR). Progesterone also had low affinity to AR. Neither the new progestin nor progesterone bound to the estrogen receptor (ER). Neither drospirenone nor progesterone displayed androgenic activity. On the other hand, they thwarted AR-mediated transcription in a dose-dependent manner, therefore displaying antiandrogenic activity. The in vivo studies confirmed the antiandrogenic activity of drospirenone and progesterone.
In fact, these studies revealed that drospirenone had an antiandrogenic potency 5-10 times greater than progesterone. Unlike progesterone, drospirenone exhibited no glucocorticoid activity, but both drospirenone and progesterone exhibited antiglucocorticoid activity. They also displayed strong antimineralocorticoid activity and weak mineralocorticoid activity.
Bron:
http://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=8 922878&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pu bmed.Pubmed