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Toxicologic Pathology
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Assessment of Hormonally Active Agents in the Reproductive Tract of Female Nonhuman Primates

J. Mark Cline

Department of Pathology, Section on Comparative Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27151-1040, USA, jmcline{at}wfubmc.edu

Gunnar Söderqvist

Department of Women's and Children's Health, Karolinska Institute, Stockholm, Sweden

Thomas C. Register

Department of Pathology, Section on Comparative Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27151-1040, USA

J. Koudy Williams

Department of Pathology, Section on Comparative Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27151-1040, USA

Michael R. Adams

Department of Pathology, Section on Comparative Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27151-1040, USA

Bo Von Schoultz

Department of Women's and Children's Health, Karolinska Institute, Stockholm, Sweden

Using the ovariectomized macaque model of postmenopausal women's health, we investigated the effects of long-term treatments (5 weeks—3 years) with estradiol, conjugated equine estrogens (CEE), esterified estrogens, progestins such as medroxyprogesterone acetate (MPA) and nomegestrol acetate, CEE + MPA, tamoxifen, soybean phytoestrogens (SPEs), a variety of putative selective 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 proliferation and expression of estrogen receptor alpha and progesterone receptor (PR). Both estradiol and CEE induced endometrial hyperplasia. MPA antagonized epithelial proliferation induced by CEE in endometrium and induced pseudodecidual stromal hyperplasia in some animals. Tamoxifen induced endometrial polyps, cystic hyperplasia, stromal fi brosis, and PR expression but not Ki-67 expression. SPEs were not estrogenic at dietary doses and antagonized estrogen-induced proliferation in the endometrium and breast. Nandrolone induced mucometra and an adenomyosis-like change. The potential SERM 17 alpha dihydroequilenin did not have uterotrophic or mammotrophic effects. In general, experimental findings in macaques have been predictive of outcomes in human clinical trials of the same agents.

Key Words: Endometrium • vagina • macaque • estrogen • tamoxifen • estrogen receptor • progesterone receptor

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Toxicologic Pathology, Vol. 29, No. 1, 84-90 (2001)
DOI: 10.1080/019262301301418883
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