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Objective: To determine whether isoflavones exert estrogen-like effects in men by lowering bioavailable T through evaluation of the effects of soy protein or isoflavone intake on T, sex hormone-binding globulin (SHBG), free T, and free androgen index (FAI) in men., Design: PubMed and CAB Abstracts databases were searched through July 1, 2008, with use of controlled vocabulary specific to the databases, such as soy, isoflavones, genistein, phytoestrogens, red clover, androgen, testosterone, and SHBG. Peer-reviewed studies published in English were selected if [1] adult men consumed soy foods, isolated soy protein, or isoflavone extracts (from soy or red clover) and [2] circulating T, SHBG, free T, or calculated FAI was assessed. Data were extracted by two independent reviewers. Isoflavone exposure was abstracted directly from studies., Main Outcome Measure(s): Fifteen placebo-controlled treatment groups with baseline and ending measures were analyzed. In addition, 32 reports involving 36 treatment groups were assessed in simpler models to ascertain the results., Result(s): No significant effects of soy protein or isoflavone intake on T, SHBG, free T, or FAI were detected regardless of statistical model., Conclusion(s): The results of this meta-analysis suggest that neither soy foods nor isoflavone supplements alter measures of bioavailable T concentrations in men., (Copyright (c) 2010 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

BACKGROUND Hormonal effects of soy and isoflavones have been investigated in numerous trials with equivocal findings. We aimed to systematically assess the effects of soy and isoflavones on circulating estrogen and other hormones in pre- and post-menopausal women. METHODS The Cochrane Library, MEDLINE and EMBASE (plus reviews and experts) were searched to December 2007. Inclusion of randomized or residential crossover trials of soy or isoflavones for 4 or more weeks on estrogens, SHBG, FSH, LH, progesterone and thyroid hormones in women was assessed independently in duplicate. Six percent of papers assessed were included. Data concerning participants, interventions, outcomes, potential effect modifiers and trial quality characteristics were extracted independently in duplicate. RESULTS Forty-seven studies (11 of pre-, 35 of post- and 1 of perimenopausal women) were included. In premenopausal women, meta-analysis suggested that soy or isoflavone consumption did not affect primary outcomes estradiol, estrone or SHBG concentrations, but significantly reduced secondary outcomes FSH and LH [by approximately 20% using standardized mean difference (SMD), P = 0.01 and 0.05, respectively]. Menstrual cycle length was increased by 1.05 days (95% CI 0.13, 1.97, 10 studies). In post-menopausal women, there were no statistically significant effects on estradiol, estrone, SHBG, FSH or LH, although there was a small statistically non-significant increase in total estradiol with soy or isoflavones ( approximately 14%, SMD, P = 0.07, 21 studies). CONCLUSIONS Isoflavone-rich soy products decrease FSH and LH in premenopausal women and may increase estradiol in post-menopausal women. The clinical implications of these modest hormonal changes remain to be determined.

Objective: To confirm the results of an earlier study showing premenopausal equol excretors to have hormone profiles associated with reduced breast cancer risk, and to investigate whether equol excretion status and plasma hormone concentrations can be influenced by consumption of probiotics., Design: A randomized, single-blinded, placebo-controlled, parallel-arm trial., Subjects: In all, 34 of the initially enrolled 37 subjects completed all requirements., Intervention: All subjects were followed for two full menstrual cycles and the first seven days of a third cycle. During menstrual cycle 1, plasma concentrations of estradiol (E(2)), estrone (E(1)), estrone-sulfate (E(1)-S), testosterone (T), androstenedione (A), dehydroepiandrosterone-sulfate (DHEA-S), and sex-hormone-binding globulin (SHBG) were measured on cycle day 2, 3, or 4, and urinary equol measured on day 7 after a 4-day soy challenge. Subjects then received either probiotic capsules (containing Lactobacillus acidophilus and Bifidobacterium longum) or placebo capsules through day 7 of menstrual cycle 3, at which time both the plasma hormone concentrations and the post-soy challenge urinary equol measurements were repeated., Results: During menstrual cycle 1, equol excretors and non-excretors were not significantly different with respect to subject characteristics, diet, or hormone concentrations. Significant inverse correlations were found between E(2) and body mass index (BMI) (P=0.02), SHBG and BMI (P=0.01), DHEA-S and dietary fiber (P=0.04), and A and protein:carbohydrate ratio (P=0.02). Probiotic consumption failed to significantly alter equol excretor status or hormone concentrations during menstrual cycle 3, although there were trends towards decreased concentrations of T (P=0.14) and SHBG (P=0.10) in the probiotic group., Conclusions: We were unable to verify a previously reported finding of premenopausal equol excretors having plasma hormone concentrations different from those of nonexcretors. Furthermore, a 2-month intervention with probiotic capsules did not significantly alter equol excretion or plasma hormone concentrations.

Phyto-oestrogens are oestrogenic compounds found in plants and consist of isoflavones, lignans and coumestans. Epidemiological studies provide evidence for a protective role of isoflavones, and to a lesser extent lignans, against the development of numerous chronic diseases, including several cancers, cardiovascular disease and osteoporosis. The structural similarity of phyto-oestrogens to endogenous oestrogens has prompted the hypothesis that phyto-oestrogens exert hormonal or anti-hormonal effects relevant to the risk of hormone-dependent disease and/or their suitability as a dietary alternative to hormone replacement therapy. The many human studies that have evaluated the effects of isoflavones and lignans on various endpoints relating to risk of various diseases have greatly increased knowledge of how these compounds behave. At the same time, additional questions have been generated. For example, the increasing interest in extracting isoflavones from the soybean for incorporation into dietary supplements has raised important concerns regarding safety and efficacy. Overall, it is clear that phyto-oestrogens are an area of active and advancing research with great potential to continue to affect human health.

Isoflavonic phytoestrogens, or isoflavones, constitute a class of phytoestrogens that have properties similar to selective estrogen receptor modulators, and have attracted a substantial degree of attention in recent years, particularly as a possible alternative to the conventional hormone replacement therapy regimens used by postmenopausal women. Despite great promise, it is difficult to make many specific recommendations about their use at the current time, in light of the many outstanding questions that hopefully will be answered in the future by focused interventional studies involving humans. Studies to date indicate that the use of isoflavones to address vasomotor symptoms provides at most small benefits beyond a placebo effect, and no benefit for genital atrophy. As for postmenopausal women whose primary concern is cardiovascular disease, the recommendation of the American Heart Association to include soy protein foods as part of an otherwise healthy diet is well justified, and similarly the substitution of supplements containing soy protein for animal protein can also be recommended. The use of purified isoflavone supplements not containing soy protein may have some cardiovascular benefits, but these appear to be less substantial in degree than those provided by soy protein with isoflavones. In particular, more research is needed to assess the effects of isoflavones on osteoporosis, for which no recommendation regarding isoflavones can be made based on the current data. Also, isoflavones should not be taken by postmenopausal women for the specific purpose of decreasing their risk of breast or endometrial cancer, although, at least for those without pre-existing disease or at high risk, it seems quite unlikely that isoflavone use is harmful in this regard.

Objective: To assess the effect of soy isoflavone ingestion on plasma leptin concentrations in premenopausal and postmenopausal women., Design: Randomized, crossover studies, with blinding of participants and laboratory personnel., Setting: Procedures involving free-living individuals were carried out at the University of Minnesota General Clinical Research Center., Patient(s): Fourteen regularly cycling premenopausal women, and 18 postmenopausal women., Intervention(s): Each premenopausal participant consumed, on a daily basis, each of three soy protein powders containing different levels of isoflavones for three menstrual cycles plus 9 days, with plasma samples collected every other day the last 6 weeks of each diet period. Similarly, each postmenopausal participant consumed each of the three powders for 93 days, with plasma samples collected daily on days 64 to 66 and 92 to 94 of each diet period. The powders, dosed on a per-kilogram body weight basis, provided mean isoflavone intakes of 8, 65, and 130 mg/day, for the control, low-isoflavone, and high-isoflavone diet periods, respectively., Main Outcome Measure(s): Plasma leptin concentrations., Result(s): Isoflavone intake had essentially no effect on leptin concentrations in either premenopausal or postmenopausal participants. Concentrations in the premenopausal women were higher during the periovulatory and midluteal phases as compared to the early follicular and midfollicular phases., Conclusion(s): Despite the well-documented effect of estrogens to enhance leptin production, even high levels of isoflavone consumption do not alter leptin concentrations in women. Further studies are needed to more precisely delineate the nature of estrogenic and/or antiestrogenic effects of isoflavones in humans.

Soy isoflavones are hypothesized to exert hormonal effects in women and thus may play a role in bone metabolism throughout life. In 2 randomized, cross-over studies, 14 pre- and 17 postmenopausal women were given 3 soy protein isolates containing different amounts of isoflavones [control, 0.13; low isoflavone (low-iso), 1.00; and high-iso, 2.01 mg/kg body wt/day, averaging 8, 65, and 130 mg/day, respectively], for over 3 months each. Food records, blood samples, and 24-h urine collections were obtained throughout the studies. The endpoints evaluated included plasma or serum concentrations of bone-specific alkaline phosphatase, osteocalcin, insulin-like growth factor-I (IGFI), IGF binding protein-3 (IGFBP3), and urine concentrations of deoxypyridinoline cross-links and carboxy-terminal telopeptide of type I collagen. In premenopausal women, IGFI and IGFBP3 concentrations were increased by the low-iso diet, and deoxypyridinoline cross-links was increased by both the low- and high-iso diets during certain phases of the menstrual cycle. In postmenopausal women, bone-specific alkaline phosphatase was decreased by both the low- and high-iso diets, and there were trends toward decreased osteocalcin, IGFI, and IGFBP3 concentrations with increasing isoflavone consumption. Although soy isoflavones do affect markers of bone turnover, the changes observed were of small magnitude and not likely to be clinically relevant. These data do not support the hypothesis that dietary isoflavones per se exert beneficial effects on bone turnover in women.

Increased urinary excretion of equol, a metabolite of the isoflavone daidzein, has been associated with a reduced risk of breast cancer. This risk reduction has generally been presumed to be a consequence of increased isoflavone consumption. However, only 30-40% of the population excretes more than trace amounts of equol, regardless of isoflavone intake. Accordingly, we hypothesized that the observed apparent protective effect of equol is at least in part attributable to hormonal differences between equol excretors and non-excretors, and that these differences are largely independent of isoflavone intake. We measured plasma hormone and sex hormone binding globulin (SHBG) concentrations in 14 normally cycling premenopausal women during each of three diet periods in which they consumed differing isoflavone doses (0.15, 1.0, and 2.0 mg/kg of body weight/day) as a component of soy protein isolate. The plasma hormone and SHBG concentrations of equol excretors (n = 5) were then compared with those of the non-excretors (n = 9). Results showed that even at the lowest dose, urinary equol excretion values for excretors far exceeded those for non-excretors consuming the highest dose. At all doses, equol excretors generally had lower concentrations of estrone, estrone-sulfate, testosterone, androstenedione, dehydroepiandrosterone (DHEA), DHEA-sulfate, and cortisol and higher concentrations of SHBG and midluteal progesterone, a hormonal pattern overall consistent with lowered breast cancer risk. In conclusion, the association of equol excretion and lowered breast cancer risk may largely reflect the tendency of equol excretors to have more favorable hormonal profiles, as opposed to merely reflecting increased isoflavone intake. Equol may be a marker for the presence of colonic bacterial enzymatic activity that increases fecal steroid excretion. Alternatively, equol itself, even with very modest isoflavone intake, may exert beneficial effects on the regulation of endogenous hormones.

Background: Soy consumption is known to reduce plasma total cholesterol and LDL cholesterol in hypercholesterolemic subjects, but the responsible soy components and the effects in normocholesterolemic subjects remain unclear., Objective: The effects of soy isoflavone consumption on plasma total cholesterol, HDL-cholesterol, LDL-cholesterol, triacylglycerol, apolipoprotein A-I, apolipoprotein B, and lipoprotein(a) concentrations and on LDL peak particle diameter were examined in normocholesterolemic, premenopausal women., Design: Thirteen healthy, normocholesterolemic, free-living, premenopausal female volunteers took part in this randomized, crossover-controlled trial. Each subject acted as her own control. Three soy isoflavone intakes (control: 10.0 +/- 1.1; low: 64.7 +/- 9.4; and high: 128.7 +/- 15.7 mg/d), provided as soy protein isolate, were consumed for 3 menstrual cycles each. Total cholesterol, HDL cholesterol, LDL cholesterol, and triacylglycerol were measured over the menstrual cycle. Apolipoprotein A-I, apolipoprotein B, lipoprotein(a), and LDL peak particle diameter were evaluated in the midluteal phase., Results: Total cholesterol, HDL-cholesterol, and LDL-cholesterol concentrations changed significantly across menstrual cycle phases (P < 0.005). During specific phases of the cycle, the high-isoflavone diet lowered LDL cholesterol by 7.6-10.0% (P < 0.05), the ratio of total cholesterol to HDL cholesterol by 10.2% (P < 0.005), and the ratio of LDL to HDL cholesterol by 13.8% (P < 0.002)., Conclusions: Isoflavones significantly improved the lipid profile across the menstrual cycle in normocholesterolemic, premenopausal women. Although of small magnitude, these effects could contribute to a lower risk of developing coronary heart disease in healthy people who consume soy over many years.

Soy isoflavones have been hypothesized to exert hormonal effects in postmenopausal women. To test this hypothesis, we studied the effects of three soy powders containing different levels of isoflavones in 18 postmenopausal women. Isoflavones were consumed relative to bodyweight [control: 0.11 +/- 0.01; low isoflavone (low-iso): 1.00 +/- 0.01; high isoflavone (high-iso): 2.00 +/- 0.02 mg/kg/day] for 93 days each in a randomized crossover design. Blood was collected on day 1 of the study (baseline) and days 36-38, 64-66, and 92-94 of each diet period, for analysis of estrogens, androgens, gonadotropins, sex hormone binding globulin (SHBG), prolactin, insulin, cortisol, and thyroid hormones. Vaginal cytology specimens were obtained at baseline and at the end of each diet period, and endometrial biopsies were performed at baseline and at the end of the high-iso diet period, to provide additional measures of estrogen action. Overall, compared with the control diet, the effects of the low-iso and high-iso diets were modest in degree. The high-iso diet resulted in a small but significant decrease in estrone-sulfate (E1-S), a trend toward lower estradiol (E2) and estrone (E1), and a small but significant increase in SHBG. For the other hormones, the few significant changes noted were also small and probably not of physiological importance. There were no significant effects of the low-iso or high-iso diets on vaginal cytology or endometrial biopsy results. These data suggest that effects of isoflavones on plasma hormones per se are not significant mechanisms by which soy consumption may exert estrogen-like effects in postmenopausal women. These data also show that neither isoflavones nor soy exert clinically important estrogenic effects on vaginal epithelium or endometrium.

Soy isoflavones are hypothesized to be responsible for changes in hormone action associated with reduced breast cancer risk. To test this hypothesis, we studied the effects of isoflavone consumption in 14 premenopausal women. Isoflavones were consumed in soy protein powders and provided relative to body weight (control diet, 10 +/- 1.1; low isoflavone diet, 64 +/- 9.2; high isoflavone diet, 128 +/- 16 mg/day) for three menstrual cycles plus 9 days in a randomized cross-over design. During the last 6 weeks of each diet period, plasma was collected every other day for analysis of estrogens, progesterone, LH, and FSH. Diet effects were assessed during each of four distinctly defined menstrual cycle phases. Plasma from the early follicular phase was analyzed for androgens, cortisol, thyroid hormones, insulin, PRL, and sex hormone-binding globulin. The low isoflavone diet decreased LH (P = 0.009) and FSH (P = 0.04) levels during the periovulatory phase. The high isoflavone diet decreased free T3 (P = 0.02) and dehydroepiandrosterone sulfate (P = 0.02) levels during the early follicular phase and estrone levels during the midfollicular phase (P = 0.02). No other significant changes were observed in hormone concentrations or in the length of the menstrual cycle, follicular phase, or luteal phase. Endometrial biopsies performed in the luteal phase of cycle 3 of each diet period revealed no effect of isoflavone consumption on histological dating. These data suggest that effects on plasma hormones and the menstrual cycle are not likely to be the primary mechanisms by which isoflavones may prevent cancer in premenopausal women.