Progesterone antagonists increase androgen receptor expression in the rhesus macaque and human endometrium

Antiprogestins (APs) inhibit estradiol (E-2)-stimulated endometrial growth in women and nonhuman primates, but the mechanism of this "antiestrogenic" action is unknown. Here, we report that APs upregulate endometrial androgen receptor (AR) in both women and macaques, an effect that might play a role in the antiproliferative effects of APs on the primate endometrium. In add ition, because there are discrepancies in the literature on the regulation and localization of AR in the primate endometrium, we used both in situ hyb ridization and immunocytochemistry to evaluate hormonal influences on endom etrial AR in women and macaques. In ovariectomized macaques, the following treatments were given for 4 weeks each: E-2 alone, E-2 + progesterone (P), E-2 + mifepristone (RU 486), and E-2 + P + RU 486. In women, samples were o btained during the normal menstrual cycle and after treatment with either R U 486 for 30 days at 2 mg/day, or after a single oral administration of 200 mg RU 486 on cycle day LH + 2. In macaques, E-2 significantly increased AR expression above vehicle controls; E-2 + RU 486 increased binding further; E-2 + P decreased AR binding; and E, + P + RU 486 treatment caused an inte rmediate elevation in AR binding. In macaques treated with E, alone, stroma l AR staining was predominant, and P treatment suppressed that staining. E- 2 + RU 486 or E-2 + P + RU 486 treatment produced a striking up-regulation of glandular epithelial AR staining and enhanced the stromal AR signal. rn situ hybridization analyses confirmed the immunocytochemistry data. Similar induction of glandular AB staining and enhanced stromal AR staining were o btained in macaques treated with ZK 137 316 and ZK 230 211. During the natu ral cycle in women, stromal AR staining predominated and was greater in the proliferative than the late secretory phase. RU 486 treatment of women up- regulated glandular epithelial AR staining after either daily treatment for 30 days with 2 mg/day or after a single oral dose of 200 mg. In summary, e ndometrial AR was highest in the stroma during the human proliferative phas e (or during E-2 treatment in macaques) and lowest during the late secretor y phase in women (or after E-2 + P treatment in macaques). In both species, RU 486 induced AR expression in the glands and enhanced AR expression in s tromal cells. Because androgens can antagonize E-2 action, enhanced endomet rial AR expression induced by APs could play a role in the antiproliferativ e, "antiestrogenic" effects of APs in primates.