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Past Oral Contraceptive Use and Current Dietary Soy Isoflavones Influence Estrogen Metabolism in Postmenopausal Monkeys (Macaca fascicularis)

¹ Department of Pathology, Section on Comparative Medicine, and ² Department of Public Health Sciences, Section on Biostatistics, Wake Forest University School of Medicine, Winston-Salem, North Carolina; and ³ Laboratory of Proteomics and Analytical Technologies, Advanced Technology Program, Science Applications International Corporation-Frederick, Inc., Frederick, Maryland

Requests for reprints: Latanya M. Scott or J. Mark Cline, Department of Pathology/Comparative Medicine, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157. Phone: 336-971-2527; Fax: 336-716-1515. E-mail: lmscott{at}wfubmc.edu or jmcline{at}wfubmc.edu

Estrogen metabolism may play an important role in mammary carcinogenesis in postmenopausal women. We evaluated the effects of prior oral contraceptive (OC) treatment and current soy isoflavone consumption on endogenous estrogen metabolite concentration and biomarkers of tissue estrogen exposure in a monkey model. One hundred eighty-one female cynomolgus macaques were randomized to receive OC or placebo for 26 months premenopausally, then ovariectomized and randomized to one of three diets for 36 months: an isoflavone-depleted soy protein isolate (Soy–) diet, a diet containing soy protein isolate with a human equivalent of 129 mg isoflavone/d (Soy+), or a Soy– diet supplemented with conjugated equine estrogens (CEE+) at a human equivalent dose of 0.625 mg/d. Reverse-phase high-performance liquid chromatography directly coupled with tandem mass spectrometry was used to measure the concentrations of estrogen species in urine samples. Generally, prior OC treatment was associated with significantly reduced urinary estrogen metabolites (25-55% reduction; P < 0.05 for each versus OC–). Animals that consumed isoflavones postmenopausally had increased urinary 2-hydroxyestrone and 16-hydroxyestrone (50% and 56% increases, respectively), but reduced levels of 2-hydroxyestradiol, 2-methoxyestradiol, and 17-epiestriol (92%, 63%, and 66%, respectively), compared with animals fed a Soy– diet. Isoflavones did not have widespread effects on uterine or mammary proliferation biomarkers, whereas prior OC significantly reduced two of three proliferation end points in the endometrium. Premenopausal OCs may have long-term systemic effects on response to estrogen and its metabolism whereas postmenopausal dietary isoflavones may alter endogenous estrogen metabolism in a modest but selective manner. (Cancer Epidemiol Biomarkers Prev 2008;17(10):2594–602)