**3. Soy, estrogen, and breast cancer**

Breast cancer is one of the most common cancers diagnosed in women in the United States, and is the second leading cause of death after lung cancer in women [33]. Breast cancer is strongly linked to ovarian hormones and estrogen levels [34]. Factors like high endogenous estrogen levels and hormone therapy have been implicated in increasing breast cancer risk [35]. Indeed, 2/3 of breast cancer cases are estrogen receptor (ER) positive [36].

Because soy isoflavones closely resemble estrogen, many health practitioners warn against soy consumption in women, women with breast cancer, and postmenopausal women for fear that soy will behave like an estrogen molecule. In our opinion, this idea is misconceived, as soy isoflavones would likely compete with endogenous estrogen for binding receptor sites in the breast, thereby reducing estrogen-stimulated growth and proliferation in the breast tissue, and may reduce endogenous estrogen concentrations [37]. Indeed, it has been shown that soy isoflavones may act as an estrogen antagonist in estrogen rich environments, and an estrogen agonist in low estrogen environments [38]; there is also evidence that the bioavailability of soy isoflavones may be inversely related to estrogen levels [39].

Epidemiological studies have shown that soy isoflavones do exert a protective effect on breast cancer risk, indicating a 16% risk reduction per 10 mg of daily isoflavone consumed [40]. A Dutch study [41] found that high levels of plasma genistein were associated with up to a 32% decreased risk of breast cancer. A 2009 study [42] that investigated soy food intake and breast cancer survival found that soy food consumption was associated with a marked decreased risk of both mortality and recurrence of breast cancer.

A 1997 study [43] found that genistein is a potent estrogen agonist and exhibited cell growth-inhibitory actions in breast cancer cells *in vitro*. A more recent study [44] also found that genistein works to inhibit topoisomerase II activity, thus resulting in the inhibition of breast cancer growth. Davis et al. [45] investigated the radioprotective effects of genistein by injecting female mice with the isoflavone 24 h prior to receiving a toxic dose of radiation, and found that genistein treated mice expressed fewer DNA damage responsive and cell cycle checkpoint genes than untreated mice. Magee et al. [46] investigated the effect of coumestrol, glycitein, daidzein, and the metabolites equol and O-desmethylangolensin on MDA-MB-231 cells, finding that each inhibited invasion by approximately 30% at the lowest dose, while genistein and coumestrol exerted the most potent inhibitory effects on invasion at the highest dose.

A clinical trial by Shike et al. [47] supplementing soy isoflavones in women with breast cancer found that soy consumption did alter gene expression in breast cancer tumors, specifically in FANCC and UGT2A1 which have both been implicated in the development of breast cancer tumors. There was a subset of tumors with upregulated FGFR2 expression, which is a marker of poor prognosis in breast cancer patients, and overall soy intake did not significantly change cell proliferation and apoptosis indices compared with the placebo group. While this initially sounds discouraging, the article points out that the clinical ramifications of this minor upregulation have yet to be determined.

Another common concern about soy supplementation in post-menopausal women, specifically, is that it causes lymphocytopenia, which is the condition of having low levels of lymphocytes in the blood. Some of these concerns stem from a multicenter study [48] published in 2001 where postmenopausal women supplemented 600 mg of ipriflavone, a synthetic isoflavone, for 3 years. Out of 234 women, 13.2% developed subclinical lymphocytopenia (<0.5 × 103 /mm3 ). Another 2 year study [49] found that 3% of their participants also developed abnormal

**29**

**5. Soy, leptin, and OA**

*Evidence for the Effectiveness of Soy in Aging and Improving Quality of Life*

lymphocyte numbers. Another study by Ben-Hurt et al. [50] found that postmenopausal women also had higher monocyte levels, indicating that menopause

A rat study [51] by our lab refutes these results. Our study not only found that ovariectomy increased lymphocyte, monocyte, eosinophil, and basophil differential counts, but that soy isoflavones retuned leukocyte counts to pre-surgery levels. To test the truth of this in human populations, our lab also investigated the extent to which 1 year of 25 g soy protein containing 60 mg isoflavones supplementation alters lymphocyte counts in postmenopausal women [52]. This study indicated no effect on total and differential white blood cell counts in postmenopausal women, which may be due to the fact that the estimated isoflavone content of the soy protein

Because leukocyte counts tend to go up with menopause, it is not necessarily a bad side effect for pharmaceutical doses of soy to bring down white blood cell counts. Additionally, the supplementation of soy protein did not have a significant impact on leukocyte levels, indicating that soy supplementation is generally safe for

Interestingly, OA is often seen in postmenopausal women, and is three times more likely to be a problem for postmenopausal women rather than men [53]. Cartilage is an estrogen sensitive tissue, which may, in part, explain the gender disparity. Because postmenopausal women experience a severe drop in the production of estrogen, it stands to reason that estrogen may be protective against the development of OA. Some studies [54–56] have found an association between hysterectomy and OA, while others [57, 58] have found no association. A study by Gao et al. [59] found that estradiol (E2) deficiency as well as changes in estrogen metabolites are involved in the pathogenesis of OA. Increased cartilage and bone turnover has been found in multiple animal models of menopause [60], but contrary to a general belief that lack of estrogen in women is the cause of OA, Tsai and colleagues [61] have suggested that excessive level of synovial fluid estrogen is responsible for the development of OA in both men and women. Indeed, some studies have found that the direct administration of estrogen to the knee joint has increased OA instance and progression [62, 63]. Intraarticular estradiol injection to ovariectomized rabbits both upregulated ER and ultimately caused further cartilage degeneration [64]. Soy isoflavones are often referred to as phytoestrogens, and may be helpful in relieving some symptoms of OA, and possibly prevent its progression. The conformational binding of soy isoflavones is similar to that of a SERM, which have been shown to be effective estrogen agonists or antagonists [65]. Genistein is the most potent of the isoflavones, and can therefore hypothetically produce positive effects on cartilage by blocking the action of estrogen. In addition to the possibility of modulating ERs, soy isoflavones may be able to increase IGF-1 production and decrease inflammation while also acting as an antioxidant. IGF-1 is thought to slow cartilage degradation [66]. Because soy isoflavones may serve as a natural modulator of IGF-1 production, it

is probable that consumption of soy would benefit people suffering from OA.

Leptin is of particular interest in the pathology of OA, as the severity of OA is associated with both weight and BMI [67, 68], and leptin is generally elevated in

*DOI: http://dx.doi.org/10.5772/intechopen.85664*

definitively alters hematological parameters.

was lower than the pharmacological dose at 60 mg.

healthy postmenopausal populations.

**4. Soy, estrogen, and OA**

*Evidence for the Effectiveness of Soy in Aging and Improving Quality of Life DOI: http://dx.doi.org/10.5772/intechopen.85664*

lymphocyte numbers. Another study by Ben-Hurt et al. [50] found that postmenopausal women also had higher monocyte levels, indicating that menopause definitively alters hematological parameters.

A rat study [51] by our lab refutes these results. Our study not only found that ovariectomy increased lymphocyte, monocyte, eosinophil, and basophil differential counts, but that soy isoflavones retuned leukocyte counts to pre-surgery levels. To test the truth of this in human populations, our lab also investigated the extent to which 1 year of 25 g soy protein containing 60 mg isoflavones supplementation alters lymphocyte counts in postmenopausal women [52]. This study indicated no effect on total and differential white blood cell counts in postmenopausal women, which may be due to the fact that the estimated isoflavone content of the soy protein was lower than the pharmacological dose at 60 mg.

Because leukocyte counts tend to go up with menopause, it is not necessarily a bad side effect for pharmaceutical doses of soy to bring down white blood cell counts. Additionally, the supplementation of soy protein did not have a significant impact on leukocyte levels, indicating that soy supplementation is generally safe for healthy postmenopausal populations.

## **4. Soy, estrogen, and OA**

Interestingly, OA is often seen in postmenopausal women, and is three times more likely to be a problem for postmenopausal women rather than men [53]. Cartilage is an estrogen sensitive tissue, which may, in part, explain the gender disparity. Because postmenopausal women experience a severe drop in the production of estrogen, it stands to reason that estrogen may be protective against the development of OA. Some studies [54–56] have found an association between hysterectomy and OA, while others [57, 58] have found no association. A study by Gao et al. [59] found that estradiol (E2) deficiency as well as changes in estrogen metabolites are involved in the pathogenesis of OA. Increased cartilage and bone turnover has been found in multiple animal models of menopause [60], but contrary to a general belief that lack of estrogen in women is the cause of OA, Tsai and colleagues [61] have suggested that excessive level of synovial fluid estrogen is responsible for the development of OA in both men and women. Indeed, some studies have found that the direct administration of estrogen to the knee joint has increased OA instance and progression [62, 63]. Intraarticular estradiol injection to ovariectomized rabbits both upregulated ER and ultimately caused further cartilage degeneration [64].

Soy isoflavones are often referred to as phytoestrogens, and may be helpful in relieving some symptoms of OA, and possibly prevent its progression. The conformational binding of soy isoflavones is similar to that of a SERM, which have been shown to be effective estrogen agonists or antagonists [65]. Genistein is the most potent of the isoflavones, and can therefore hypothetically produce positive effects on cartilage by blocking the action of estrogen. In addition to the possibility of modulating ERs, soy isoflavones may be able to increase IGF-1 production and decrease inflammation while also acting as an antioxidant. IGF-1 is thought to slow cartilage degradation [66]. Because soy isoflavones may serve as a natural modulator of IGF-1 production, it is probable that consumption of soy would benefit people suffering from OA.
