The term ‘phyto-estrogen’ – literally, a plant-derived compound able to behave like estrogen and to activate the mammalian estrogen receptor ‑ was coined to describe a group of substances which are found in a large range of grains, seeds, legumes and medicinal plants, as well as some other commonly eaten foods. Typical classes of phyto-estrogens are isoflavones, coumestans and lignans, which are collectively known as phenolic phyto-estrogens, certain flavonoid derivatives, triterpenoid and steroidal saponins found in typical medicinal plants used against menopausal disorders or pre-menstrual syndrome, and phytosterols.
Due to the observation that sheep grazing on red clover developed infertility it had originally been assumed that the phyto-estrogens from red clover are powerful estrogens, acting as a contraceptive due to their hormonal effects (Bennets et al. 1946). This theory has to be questioned in view of the discovery of a new type of estrogen receptor, the estrogen receptor beta (ER-β), which in many aspects is a counter-player of the classical estrogen receptor alpha (ER-α). Anti-fertility effects would be caused by an activation of ER-α. However, it was found that isoflavones from red clover (and likewise those from other sources such as soy) do neither have ER-α mediated effects in humans or other mammals, nor would they cause infertility.
The riddle of the infertility of grazing sheep is still unsolved. It may be related to differences in the metabolism between sheep and other mammals, but it may as well be related to blaming the wrong herb (growing at the same time as red clover, but not recognized) or a hitherto unknown phytochemical present in the specific plant type of the Australian red clover. In fact, red clover is typically present on European pastures and is grazed by sheep and cows. The ingested isoflavones are even passed on to the milk (Antignac et al. 2003; King et al. 1998), and thus also to humans. Infertility as a consequence of cattle grazing on pastures with red clover has never been observed in Europe.
Phyto-estrogens possess a certain structural similarity to the estradiol molecule, which allows them to bind to estrogen receptors. However, binding to estrogen receptors is not the only mechanism of action of phyto-estrogens. The medicinal plant Black cohosh (Cimificuga racemosa), for instance, is known to alleviate menopausal complaints, but its extracts and constituents have no affinity to the estrogen receptors – other than plant preparations from soy, red clover, Puearia, alfalfa (Medicago sativa) or hops (Humulus lupulus).
Affinity to estrogen receptors may, however, be misleading. There are two major types of estrogen receptors in the human organism, which have partly opposite functions: the “classical” estrogen-receptor alpha (ER-α), and the estrogen-receptor beta (ER-β), which was only discovered in 1996 (Kuiper et al. 1996). ER-α is responsible for the growth of hormone-sensitive tissues, and thus has a pivotal role in the female menstrual cycle and in the changes of the body during pregnancy. An over-activation of ER-α is also related to the growth of hormone-sensitive tumours such as breast or uterine and endometrial cancer in women, or prostate cancer in men. Furthermore, ER-α is involved in catabolic bone turnover: an over-activation of ER-α is related to osteoporosis. ER-β, to which estrogen has approximately the same affinity as to ER-α, has the function of a natural counter-player to ER-α-mediated hormonal effects (Huber 2003). Its functions are complex, but in many ways they counteract processes induced by ER-α. The exact outcome of the mix of hormonal activations and de-activations at the various receptors depends on the presence of physiological binding partners in sufficient quantities, and on the receptor distribution in the different organs.
Isoflavones as “phyto-estrogens” have a higher binding affinity to ER-β than to ER-α (Choi et al. 2008). The term “phyto-estrogens” may therefore be considered inadequate. Plant constituents activating ER-α, such as 8-prenyl-naringenin or xanthohumol from hop strobiles, will have typical estrogenic effects, as can be seen by the growth of the breast of male beer drinkers. In contrast, the activation of ER-β as with isoflavones from soy or red clover will rather protect from excessive estrogenic effects (Messina and Wood 2008), which explains the considerably lower rate of breast and prostate cancer in regions with high dietary intake of isoflavones by protecting against the proliferation-enhancing effect of estrogen in hormone-sensitive tissues. Isoflavones are known to positively influence the menstrual cycle (Nagata et al. 2006), to reduce the incidence of estrogen-responsive cancers (Guha et al. 2009; Wu et al. 2008; Wu et al. 2009); and to decrease the frequency and severity of menopausal symptoms (Kurzer 2008).
Unlike estradiol, isoflavones cannot trigger the full range of estrogen-like actions. E.g., physical maturation, ovulation and menstruation – which are typical ER-α-related effects – cannot occur in response to a dietary intake of isoflavones from soy or red clover. Compared with the hormone estradiol, phyto-estrogens have a much more limited biological role and are capable of achieving only some of the consequences associated with endogenous estrogens - such as a reduction in hot flushes, a typical effect mediated by ER-β. “Phyto-estrogens” from soy and red clover are therefore more and more frequently called “Phyto-SERMs”, “selective estrogen receptor modulators”.
References
Bennets, H. W., Underwood, E. J., and Shier, F. L. A. (1946). A specific breeding problem of sheep on subterranean clover pastures in Western Australia. Aust. Vet. J. 22: 2-12.
Huber, J. C. (2003). Das Yin-Yang der Östrogene: Der Alpha- und der Beta-Östrogenrezeptor. Gyne (6): 97-100.
