Interest in phytoestrogens derived from the observation that Eastern women in menopausal age have a lower incidence of symptoms of menopause, cardiovascular disease, hormone-dependent cancers (eg breast, endometrium) and osteoporosis than Western women. Among the several factors which, presumably, could cause these differences are included genetic, dietary and cultural factors.
Although the observation that in people of Asian origin moved to the United States the incidence of “Western” degenerative diseases becomes, within 1 or 2 generations, similar to that of the local population led to downplay the role of genetic factors and to pay attention to dietary factors. Comparing feeding of Asian populations with that of the West, one of the most significant differences was found to be the major soy consumption, since soy is rich in phytoestrogens.
Phytoestrogens are plant-derived xenoestrogens functioning as the primary female sex hormone not generated within the endocrine system. Also called "dietary estrogens", they are a diverse group of naturally occurring nonsteroidal plant compounds that, because of their structural similarity with estradiol (17-β-estradiol), have the ability to cause estrogenic or/and antiestrogenic effects.
Chemical structures of the most common phytoestrogens found in plants (top and middle) compared with estrogen (bottom):
The key structural elements that enable phytoestrogens to bind with high affinity to estrogen receptors and display estradiol-like effects are:
• The phenolic ring that is indispensable for binding to estrogen receptor
• The ring of isoflavones mimicking a ring of estrogens at the receptors binding site
• Low molecular weight similar to estrogens (MW=272)
• Distance between two hydroxyl groups at the isoflavones nucleus similar to that occurring in estradiol
• Optimal hydroxylation pattern
ESTROGEN RECEPTOR
Phytoestrogens exert their effects primarily through binding to estrogen receptors (ER). There are two variants of these: alpha (ER-α) and beta (ER-β) and many phytoestrogens display somewhat higher affinity for ER-β compared to ER-α, while endogenous estrogens such as 17-β-estradiol show equal affinity for the two types of receptors.
Both ERs belong to the nuclear receptor (NR) gene family of transcription factors. The gene product contains an N-terminal DNA binding domain and C-terminal ligand binding domain.
PHYTOESTROGENS AND MENOPAUSE
The onset of climacteric symptoms (hot flashes and night sweats) is the primary reason for perimenopausal women to start hormone therapy. As said, the association of a lower incidence of postmenopausal symptoms with high intake of soybeans in Asian women suggests that phytoestrogens are an alternative to estrogen therapy, however most of the trials conducted so far to ascertain their effectiveness were small, of short duration and poor quality.
Some of them found a slight reduction in hot flushes and night sweats with phytoestrogen-based treatment but overall there was no indication that phytoestrogens worked any better than no treatment.
Phytoestrogens for vasomotor menopausal symptoms, 2009
OSTEOPOROSIS
There have been several studies regarding the potential beneficial effects of isoflavones on Bone Mineral Density (BMD) reduction: phytoestrogens have not or just poorly proven to be able to improve this parameter which, moreover, is not very relevant from a clinical point of view, since the primary objective is instead the reduction of fractures.
Actually the main hypothesis is that trabecular bone would be more responsive to isoflavone treatment than cortical or composite bone, since it is the trabecular bone which is preferentially lost with estrogen deprivation, however soy isoflavones proved to be little effective also in mitigating postmenopausal cortical bone loss, this may suggest an effect that is dissimilar to estrogen.
Some trials suggest also that the efficacy is proven only in case of simultaneous supply of exogenous calcium to the diet. On the contrary it is possible that high dietary phosphorus may lessen any potential protective effect soy isoflavones might exert on BMD, in part because high phosphorus diets may stimulate bone resorption through increased parathyroid hormone secretion.
The Soy Isoflavones for Reducing Bone Loss (SIRBL) Study: Three year effects on pQCT bone mineral density and strength measures in postmenopausal women, 2011
CARDIOVASCULAR DISEASE
All findings suggest the protective role of dietary soy intake against cardiovascular disease (risk factors) in postmenopausal women.
It is still quite unclear whether the benefits obtained are to be attributed to isoflavonic component or to other components of soybean. In this study three of them are compared: Effects of soy isoflavones on atherosclerosis: potential mechanisms, 1998 and there was find evidence of the major effect of the intact soy protein versus the alcohol-extractable components of soy on cardiovascular disease.
Potential mechanisms by which soy isoflavones may have a positive effect on the postmenopausal risk of atherosclerosis and arterial degeneration include their antioxidative effects on LDL cholesterol and their ability to maintain normal vascular reactivity.
Higher Usual Dietary Intake of Phytoestrogens Is Associated With Lower Aortic Stiffness in Postmenopausal Women, 2002
In this trial they found that the association between dietary intake of phytoestrogens and aortic stiffness was more pronounced in older women with longer postmenopausal time spans (20 to 30 years). Several explanations are posed. A first possible explanation for this finding is that women with shorter postmenopausal time spans still have higher plasma estradiol levels than women with longer postmenopausal time spans, therefore, the effect of phytoestrogens is possibly overshadowed in the first group, and the latter group could have more estrogen receptors available.
However, until now the most widely accepted explanation for the differences found in the effects of phytoestrogens between both postmenopausal time-span groups might be that the initial level of aortic PWV (Pulse Wave Velocity that is a measure of arterial stiffness) might have a powerful effect on changes in aortic PWV: a higher initial PWV may be lowered more strongly than a lower initial PWV. Because women with a longer postmenopausal time span are significantly older and have a significantly higher initial PWV, an effect of phytoestrogens on PWV is perhaps shown sooner than in women with a shorter postmenopausal time span, who are younger and have lower (and therefore better) initial aortic stiffness.
PHYTOESTROGENES AND BREAST CANCER
It remains uncertain whether these plant compounds are chemoprotective or whether they may produce adverse outcomes related to breast carcinogenesis.
Those who support the protective role of phytoestrogens on the initiation or progression of breast cancer try to provide a detailed description of the possible mechanisms of action of phytoestrogens:
Firstly they have found evidence of phytoestrogens to inhibit the local production of estrogens from circulating precursors in breast tissue, through inhibition of the involved enzymes.
In fact the majority of breast cancers are estrogen dependent and in postmenopausal women the supply of estrogens in breast tissue is derived from the peripheral conversion of circulating androgens.
Enzymes involved in the major steroidogenic pathways that can generate biologically active estrone and estradiol are hydroxysteroid dehydrogenase, aromatase, 17β-Hydroxysteroid dehydrogenases (17β-HSD) types 3 and 5 which convert androstenedione to testosterone and 17β-HSD types 1, 7, and 12 that convert estrone to estradiol:
Moreover ERβ isoforms have been tested to inhibit cell proliferation in breast tumors, whilst activation of ERα is known to promote growth.
Infact the ratio of ERα:ERβ is increased in carcinogenesis and expression of ERβ was associated with lower breast tumor aggressiveness and improved disease-free survival rates compared with those ERβ-negative tumors. One theory for the effects of ERβ on the growth of breast tumors is that it may dimerize with ERα and silence its activation functions and that loss of ERβ in cancer cells could signal the stage of estrogen-dependent tumor progression.
Phytoestrogens seem to have an enancher effect on the ERβ activity in two ways:
1)Their differential affinities for ER-α and ER-β suggest that physiologic concentrations of phytoestrogens may be enough to activate ER-β but not ER-α, implying that rather than acting via the classical ER-α pathway, phytoestrogens may activate ER-β and induce its antiproliferative effects
2)It seems that they are able to induce the expression of the beta isoform of the receptor.
Phytoestrogens and breast cancer –promoters or protectors?, 2006
Phytoestrogens and Breast Cancer Prevention: Possible Mechanisms of Action, 2008
On the contrary very few studies have focused on the posible negative effect of phytoestrogens on estrogen-induced breast cancers. In any case, increased soy intake in patients with breast cancer can be counterproductive since it has been suggested also that isoflavones may compromise the effect of Tamoxifen, an used drug for the treatment of ER+ breast cancer (estrogen receptor positive, meaning those cancers the growth of which is estrogen dependent).
