The cellular mechanism of the antiandrogenic action of nomegestrol acetate, a new 19-nor progestagen, on the rat prostate.
Nomegestrol acetate, like other synthetic progestins such as medroxyprogesterone acetate (MPA), chlormadinone acetate, megestrol acetate and cyproterone acetate, is able to modify the physiological actions of androgens. In the present study, the effects of nomegestrol acetate and other antiandrogens on the binding of androgen to the androgen receptor (AR) and on the 'activation' of this receptor were investigated, using rat ventral prostate as target model. Relative binding affinities (RBA) for AR were first estimated in vitro with respect to [3H]testosterone for a series of structurally-related compounds. The values obtained ranged as follows: dihydrotestosterone (DHT) much greater than megestrol acetate greater than or equal to testosterone (T) greater than nomegestrol acetate greater than 19-nor progesterone (19NP) greater than progesterone (P). An assay was established, using two different incubation times (3 h and 24 h) to further investigate relationships between binding affinity and androgenic, or antiandrogenic, activity. The following order (as %) was obtained for progestins as against [3H]mibolerone (DMNT): 1) DMNT (100) much greater than nomegestrol acetate (42) greater than megestrol acetate (29) greater than chlormadinone acetate (9) greater than MPA (8) greater than cyproterone acetate (6) after 3 h and 2) DMNT (100) much greater than MPA (53) much greater than nomegestrol acetate (19) greater than megestrol acetate (12) greater than chlormadinone acetate (14) and cyproterone acetate (8) after 24 h. Since the RBA of nomegestrol acetate declined with time, these results indicate that this substance may act like an antiandrogen rather than an androgen, while the contrary prevails concerning MPA.(ABSTRACT TRUNCATED AT 250 WORDS)
D000726:Androgen Antagonists / Q000494:pharmacology; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D008297:Male; D008535:Megestrol; D009649:Norpregnadienes / Q000494:pharmacology*; D009919:Orchiectomy; D011374:Progesterone / Q000378:metabolism; D011372:Progestins / Q000494:pharmacology; D011467:Prostate / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D011944:Receptors, Androgen / Q000378:metabolism*; D013739:Testosterone / Q000378:metabolism
D000726:Androgen Antagonists; D009649:Norpregnadienes; D011372:Progestins; D011944:Receptors, Androgen; D013739:Testosterone; D011374:Progesterone; C038501:nomegestrol acetate; D008535:Megestrol