Ovarian-derived estrogens are not the only compounds that can activate ER. Phytoestrogens are plant compounds with intrinsic estrogen-like biological activity mainly due to the presence of a phenolic A ring, which is crucial for receptor binding.[87,88] The two major classes of phytoestrogens are lignans and isoflavones. Soy protein contains the isoflavones genistein and diadzein. Phytoestrogens are believed to signal predominantly via ERβ, and genistein in particular has a 20-fold higher binding affinity for ERβ compared with ERα.[12,90–92] Feeding estrogen-depleted ArKO mice diets containing either soy or genistein in part ameliorated the reproductive phenotype of female mice. Ovarian and uterine weights increased, although not to wild-type levels, and hemorrhagic cysts disappeared with the addition of genistein. These effects of genistein are thought to be mediated via ERβ, which is supported by the identification of ERβ in the uterus and evidence that estrogen is directly responsible for the development of hemorrhagic cysts (and not elevated LH levels).[30,93–97] Adverse effects of genistein on rodent reproductive function have also been reported, notably reduced fertility, the formation of polyovular follicles, and altered estrous cycles.[32,98] The doses of genistein given neonatally to mice in these studies were high, although environmentally relevant, and led to the manifestation of reproductive abnormalities in adult life.
Exposure of adult females to estrogen either via the environment or clinically can have consequences for reproductive function. Adult rats treated with estradiol valerate had abnormal estrus cycles, and the ovaries contained reduced numbers of CL, developed follicular cysts, and theca cell hyperplasia, and there was an increase in apoptosis of granulosa cells from primary and secondary follicles. ERβ and PR proteins expressed by granulosa cells declined in follicles larger than secondary follicles, suggesting abnormal differentiation of the granulosa cells.
Women exposed to endocrine-disrupting chemicals have impaired fertility, irregular menstrual cycles, and experience pregnancy loss.[101,102] Methoxychlor (MXC), an organochlorine pesticide with estrogenic activity mediated primarily via ERβ, caused ovarian dysfunction in the adult rodent following exposure to rats during the fetal or neonatal period.[12,103] Follicle composition was altered with more preantral and early antral follicles present and fewer CL. ERβ expression declined, and there was reduced expression of LH receptor and P450SCC mRNAs. Accelerated entry into puberty and to first estrus, irregular cyclicity, and reduced litter sizes were also reported. The bisphenol demethylated form HPTE is believed to be responsible for the estrogenic activity of MXC. HPTE analogs act as ERα agonists and ERβ antagonists in a range of cell lines.[107,108] ERβ was found to be hypermethylated (i.e., inactivated), whereas ERα was not.
Bisphenol A (BPA) exposure results from interactions with polycarbonate plastics or epoxy resins in food packaging. BPA acts as an agonist of estrogen via ERβ, whereas it acts as both an agonist and antagonist in some cell types via ERα. The effect of BPA is likely to be determined on a tissue-specific basis.[108,110] Neonatal exposure to DES or BPA induces anovulation and persistent estrus in female rodents and induces polyovular follicles.[31,111–113] The observed anovulation and induced estrus is thought to be mediated via ERα, given that diarylpropionitrile, an ERβ selective agonist, had no effect on these parameters.
Resveratrol (RES), a phytoestrogen found in grapes, binds equally to ERα and ERβ. RES decreased body weight and induced ovarian hypertrophy potentially via ERβ in gonadally intact rats. RES-liganded ERβ induced significantly higher levels of transcriptional activity than estradiol-liganded ERβ, suggesting that tissues expressing ERβ will be more transcriptionally active in response to RES than those expressing ERα.
Semin Reprod Med. 2012;30(1):32-38. © 2012 Thieme Medical Publishers