Flutamide counteracts the antiproliferative effects of antiprogestins in the primate endometrium

In addition to blocking progesterone (P) action, antiprogestins (APs) also inhibit estrogen-stimulated endometrial cell proliferation in nonhuman primates and women. This effect is paradoxical because APs do not bind to estrogen receptors (ER), and AP + estradiol (E(2)) treatment leads to elevation of ER levels, a recognized action of estrogen in the endometrium. Recently, we showed that APs (RU 486, ZK 137 316 and ZK 230 211) also elevate endometrial androgen receptor (AR) in macaques and women and we hypothesized that over expression of AR may play a role in the antiproliferative actions of APs. We now report that cotreatment with the specific antiandrogen flutamide (FLU) blocked the suppressive effects of APs on estrogen action in the endometrium. We treated ovariectomized rhesus macaques with either E(2) alone, E(2) + ZK 137 316 or E(2) + ZK 137 316 + FLU daily for 28 days. Endometrial wet weight (mean +/- SE) from one-half of the endometrium was as follows: E(2)-treated controls, 360 +/- 32 mg; E(2) + ZK 137 316, 64 +/- 10 mg; and E(2) + ZK 137 316 + FLU, 265 +/- 92 mg (P < 0.05). Mean mitoses/1000 epithelial cells +/- SE was: E(2) alone, 6.25 +/- 0.6; E(2) + ZK 137 316, 0.3 +/- 0.25; and E(2) + ZK 137 316 + FLU, 5.1 +/- 3.8 (P < 0.05). FLU also blocked the hyalinizing degradation of the spiral arteries typically induced by APs. These results indicate that many of the antiendometrial effects of APs in primates may involve the AR.