LACK OF ESTROGENIC POTENTIAL OF PROGESTERONE OR 19-NOR-PROGESTERONE-DERIVED PROGESTINS AS OPPOSED TO TESTOSTERONE OR 19-NOR-TESTOSTERONE DERIVATIVES ON ENDOMETRIAL ISHIKAWA CELLS

Estrogen receptors of human endometrial cancer Ishikawa cells were fou nd to be present in moderate amounts (160-200 fmol/mg protein), and to specifically bind moxestrol (R2858) with a very high affinity charact erized by a K-d around 60 pM, when measured under equilibrium conditio ns. The binding specificity respected a decreasing order as follows: e stradiol (E(2): 100%) > 4-hydroxy-tamoxifen (40HTAM: 52.7%) > estriol (E(1): 5.7%) > estrone (E(1): 2.1%)>TAM (0.2%). The induction of alkal ine phosphatase activity (APase) used as an estrogen-specific response , confirmed the intrinsic estrogenicity of progestins derived from 19- nor-testosterone (19NT): norethindrone (NOR), norethynodrel and levono rgestrel, at concentrations ranging from 10(-8) to 10(-6) M. The effec t of NOR was partially blocked by the antiestrogen 40HTAM, which was a lso partially agonistic in this model, but neither by the antiprogesti n mifepristone (RU486) nor by the aromatase inhibitor aminoglutethimid e. A simulatory effect was also detected at 10(-7) or 10(-6) M with et hindrone, the testosterone- (T) derived progestin homologous to NOR, a nd with both androgenic parent-compounds, i.e. T and 19NT themselves. In contrast, progesterone (P) derivatives like medroxyprogesterone ace tate (MPA) and chlormadinone acetate (CMA) remained totally inactive, as well as 19-nor-progesterone (19NP) itself or its progestagenic deri vatives: ORG 2058 and nomegestrol acetate (NOM). Structure-activity re lationships deduced from these studies suggest that it is not the abse nce of the 19-methyl group which can account for the estrogenic potent ial of the so-called ''19-norprogestins'', but rather their steroid st ructure derived from T in a broad sense (including the 19NT derivative s), as opposed to the non-estrogenic therapeutic progestins derived fr om P like MPA or CMA, or from 19NP like NOM.