Estrogen/isoflavone interactions in cynomolgus macaques (Macaca fascicularis)

Abstract

Soy isoflavones are phytoestrogenic components of dietary soy, which are widely consumed for their potential health benefits. Soy isoflavones appear to decrease breast and endometrial cancer risk in human observational studies, but paradoxically stimulate growth of breast cancer cells in culture and uterine enlargement in rodents. We have shown that these compounds are not estrogenic in cynomolgus monkeys even at relatively high doses, but that they reduce estrogen-induced proliferative responses of the breast and endometrium. This effect may be mediated through estrogen receptor interactions and/or modulation of endogenous estrogen metabolism. Interindividual variation in isoflavone absorption and metabolism contributes to the degree of estrogen antagonistic effect. Our recent studies have also shown that individual isoflavone metabolites such as glyceollins may have unique selective estrogen receptor modulator-like activity, acting as tissue-specific antagonists without agonist activity. Rodent studies and human epidemiologic data suggest that timing of exposure and dose relative to endogenous estrogen concentrations are important determinants of effect, and studies of dietary soy on breast development and pubertal maturation are under way. Because soy isoflavones are both abundant in standard monkey chow diets and widely available as dietary supplements for human beings, these findings have broad relevance to the health of human and nonhuman primates.

Effects of isoflavones on breast density in pre- and post-menopausal women: a systematic review and meta-analysis of randomized controlled trials

“…Isoflavones may exert their potential protective effects early in life by stimulating breast cell differentiation (Lamartiniere, 2000; Lamartiniere et al ., 2002) but these positive epidemiological data are in contrast to the conflicting experimental data from in vitro models and studies in animal models including the ovarectomized athymic nude mouse model implanted with MCF-7 cells (an estrogen-sensitive breast cancer cell line; Wang et al ., 1996; Hsieh et al ., 1998; Allred et al ., 2001, 2004a, b; Ju et al ., 2001; Kanno et al ., 2003; Power et al ., 2006a, b, 2007; Seo et al ., 2006; Cline and Wood, 2009; Messina et al ., 2009; Messina and Wu, 2009; Saarinen et al ., 2009). Our findings from the available RCTs support the epidemiological data observed for post-menopausal women but not for premenopausal women as we observed a small increase in breast density following isoflavone consumption in the younger women.…”

“…There are conflicting experimental data on the effects of isoflavones on breast cancer cells in vitro and estrogen-sensitive induced mammary tumours in vivo (Hsieh et al ., 1998; Allred et al ., 2001; Kanno et al ., 2003; Messina et al ., 2006, 2009; Cline and Wood, 2009; Power et al ., 2006a, b, 2007; Saarinen et al ., 2009). Isoflavones are not estrogenic in cynomolgus monkeys, even following high isoflavone intake; these reduced estrogen-induced proliferation responses occur via effects on estrogen metabolism, or are mediated through ER interactions (Cline and Wood, 2009).…”

“…Isoflavones are not estrogenic in cynomolgus monkeys, even following high isoflavone intake; these reduced estrogen-induced proliferation responses occur via effects on estrogen metabolism, or are mediated through ER interactions (Cline and Wood, 2009). Paradoxically, in rodents and in vitro cell models isoflavones induce estrogen-like effects in breast cancer cells lines and cause uterine enlargement in rodents (Wang et al ., 1996; Hsieh et al ., 1998; Allred et al ., 2001; Kanno et al ., 2003; Power et al ., 2006a, b, 2007; Seo et al ., 2006; Saarinen et al ., 2009).…”

Molecular and cellular profiling of acute responses to total body radiation exposure in ovariectomized female cynomolgus macaques

“…Cynomolgus macaques are an excellent model for the study of inflammation and cardiovascular disease (Register 2009), cancer risk (Cline and Wood 2009), and other conditions, and may provide a useful addition to our non-human primate animal model portfolio for discovery and development of radiation countermeasures. The effects of radiation exposure on stem cells (Adler and Erbelding 1988), brain electrical activity (Legeza and Turlakov 1991), liver function (Yannam et al 2014), clinical, cardiac, cortisol stress response (Darenskaia et al 1992, 2001), and mitigating effects of gonadotropin hormone releasing hormone (GnRH) antagonism on the testes (Shetty et al 2013) have been studied in this species.…”

Adverse Effects on Female Human Reproductive Health from Exposure to Endocrine Disruptors: Focus on Endometrial Lesions

“…As with other cancers, the timing of exposure is critical to the potential development of uterine cancer; in fact treatment of adult mice with comparable levels of DES does not induce uterine neoplasms [57]. Soy isoflavones inhibit estradiol mediated endometrial proliferation in macaque monkeys [58]; maybe that is due to the dualistic effects of phytoestrogens, acting as SERMs (both estrogenic and antiestrogenic effects All environmental estrogenic chemicals [Polychlorinated Hydroxybiphenyls, DDT and derivatives, alkylphenols, BPA, methoxychlor and chlordecone] compete with E2 for binding to both ER subtypes with a similar preference and degree. In most instances the relative binding affinities are at least 1000-fold lower than that of E2 [66].…”