The phytoestrogens and fungal mycotoxins provide some of the most conclusive data demonstrating that environmental estrogens are toxic to mammalian reproductive function under natural conditions. Naturally occurring compounds with estrogenic and other endocrine activities are widespread in nature. Farnsworth et al.  listed over 400 species of plants that contain potentially estrogenic isoflavonoids or coumestans or were suspected of being estro-
genic based on biological grounds. Plants contain many other compounds in addition to estrogens that can affect reproductive performance , such as the antiandrogenic activity in the oil from saw palmetto.
Although most environmental estrogens are relatively inactive, when compared to steroidal estrogens or DES, the phytoestrogen miroestrol or ethinyl estradiol (EE) are as potent as estradiol in vitro and even more potent than estradiol when administered orally. In addition, many plant estrogens occur in such high concentrations that they induce reproductive alterations in domestic animals . "Clover disease", which is characterized by dystocia, prolapse of the uterus and infertility, is observed in sheep grazed on highly estrogenic clover pastures. Permanent infertility (defeminization) can be produced in ewes by much lower amounts of estrogen over a longer time period than are needed to produce "clover disease". In domestic animals, feeds contaminated with the zearalenone-producing fungus (Fusarium sp.) induce adverse reproductive effects in a wide variety of domestic animals, including impaired fertility in cows and hyperestrogenism in swine and turkeys .
In World War II, people in the Netherlands consumed large quantities of tulip bulbs, containing high levels of estrogenic activity, and many women displayed signs of estrogenism, including uterine bleeding and other abnormalities of the menstrual cycle [48-50]. In addition, an extract from the roots of Pueraria mirifica in Thailand yielded miroestrol, an estrogenic substance that was as potent in increasing uterine weight in rats as DES when administered orally (both of which are orders of magnitude more potent than oral estradiol) and about 70% as active as estradiol when administered by subcutaneous injection . A limited clinical trial with miroestrol was carried out to examine the utility of this plant estrogen for treatment of amenorrhea in women. When miroestrol was administered orally at doses of 1 or 5 mg per day for several days, marked es-trogenic responses were seen, but the onset of effects was slow and in some cases persisted after the cessation of treatment. More recently, Cassidy et al.  reported that addition of 45 mg of dietary isoflavones given for one month to six regularly cycling women increased the duration of the follicular phase or delayed menstruation. Mid-cycle luteinizing hormone (LH) and follicle-stimulating hormone (FSH) surges also were suppressed, suggesting that dietary isoflavones display estrogenic activity on the hypothalamic-pituitary axis.
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