Assessment of hormonally active agents in the reproductive tract of femalenonhuman primates

Using the ovariectomized macaque model of postmenopausal women's health, we investigated the effects of long-term treatments (5 weeks-3 years) with es tradiol, conjugated equine estrogens (CEE), esterified estrogens, progestin s such as medroxyprogesterone acetate (MPA) and nomegestrol acetate, CEE MPA, tamoxifen, soybean phytoestrogens (SPEs), a variety of putative select ive estrogen receptor modulators (SERMs), and androgens. Agents tested were selected on the basis of beneficial effects on arteries and/or bone. Doses were scaled on a caloric or serum-concentration basis to approximate human clinical doses. We evaluated endometrial and mammary gland histopathology and morphometry and used immunohistochemistry to evaluate cell proliferatio n and expression of estrogen receptor alpha and progesterone receptor (PR). Both estradiol and CEE induced endometrial hyperplasia. MPA antagonized ep ithelial proliferation induced by CEE in endometrium and induced pseudodeci dual stromal hyperplasia in some animals. Tamoxifen induced endometrial pol yps, cystic hyperplasia, stromal fibrosis, and PR expression but not Ki-67 expression. SPEs were not estrogenic at dietary doses and antagonized estro gen-induced proliferation in the endometrium and breast. Nandrolone induced mucometra and an adenomyosis-like change. The potential SERM 17 alpha dihy droequilenin did not have uterotrophic or mammotrophic effects. In general, experimental findings in macaques have been predictive of outcomes in huma n clinical trials of the same agents.