More Information on Soy

Contents

Summary

There is a great deal of controversy surrounding soy foods, mostly due to their isoflavones which can bind to estrogen receptors and affect thyroid hormone.

There is significant evidence that eating moderate amounts (one to two servings per day) of traditional soy foods, whether fermented or not, can reduce the risk of prostate cancer and can lower LDL cholesterol.

People have been concerned that moderate amounts of soy could increase the risk of breast cancer or be harmful to women with breast cancer, especially if their cancer is estrogen receptor positive. However, the research to date has been quite reassuring, showing mostly benefits for breast cancer prevention.

Everyone who eats soy should make sure they are getting enough iodine. People with hypothyroidism might need their synthetic thyroid hormone dosage adjusted if they start eating more soy due to the possibility that soy might interfere with it. There is some concern that eating soy could push some people with subclinical hypothyroidism into overt hypothyroidism, so limiting soy for such people might be a good idea.

Soy infant formula has been shown to be safe except possibly for infants with congenital hypothyroidism, whose thyroid function should be monitored. Soy formula is not intended for pre-term infants.

While one observational study found that tempeh was linked to better cognition in older people, tofu has been associated with worse cognition. This is most likely due to confounding variables, including tofu being processed with formaldehyde in Indonesia. Many clinical studies have found that soy increases cognition. Unless you are in Indonesia, you do not need to worry about tofu harming cognition.

Some soy meats or foods containing isolated soy protein are processed with hexane and there may be small amounts of hexane residues in the final product. It is not known if this is harmful, but it might be a good idea to use soy foods from companies who do not use hexane in their processing methods (linked to below).

The phytates in soy can lower the absorption of calcium, zinc, iron, and magnesium. However, you do absorb these minerals from soy foods and eating moderate amounts of soy should not cause deficiencies.

At moderate amounts, soy does not cause feminine characteristics in men. At high amounts, as in twelve servings a day or more, a small percentage of men who are particularly sensitive to soy might develop tender, enlarged breast tissue.

Introduction—Why the Fuss?

By far, soy is the most controversial of plant foods, with gluten taking a distant second place.

Much of the controversy is due to some fairly unique components of soy, isoflavones. Isoflavones are also called phytoestrogens or “plant estrogens”, because they can attach to estrogen receptors in cells. The estrogenicity of soy has raised questions of potential benefits, such as for bone health of post-menopausal women, as well as concerns such as for women with estrogen receptor positive breast cancer.

In addition to the isoflavones, soy also contains phytates that can bind minerals and lower their absorption from foods.

Between 1990 and 2010, there were over 10,000 peer-reviewed journal articles on soy (122). A large percentage of these were conducted in animals which can make the results irrelevant to humans because species differ in how they metabolize soy isoflavones and because the amount of isoflavones given to the animals is often much greater than any human would eat. This much research makes soy one of the most researched foods and also increases the chances of finding results that are outliers – studies that by random chance, or the inability to control variables, could show soy to be harmful (or helpful) when it actually is not. The large number of studies allow people who want to make a case against soy to simply highlight a handful when the bulk of research provides a different view. Of course, someone could make a case in favor of soy in the same way. It is, therefore, important to perform a comprehensive review of the research on any given topic, which I do below for the most important controversies surrounding the potential harm of soy foods.

The Isoflavones

Because some studies look at individual isoflavones, I will give a little background on them. Table 1 shows the breakdown of the typical isoflavone components of soy foods.

Table 1. Typical Isoflavone Content of Soy122 Isoflavone If Fermented % of Total genistin genistein ~40% daidzin daidzein ~40% glycitin glycitein ~5-10%

In addition to the three main soy isoflavones, there is a fourth isoflavone-related compound, equol, that is produced from daidzin by bacteria that about 25% of Westerners and 50% of Asians and vegetarians have in their digestive tracts (130). Equol has somewhat more estrogenic activity than daidzein and genistein, which has made comparing equol producers the subject of some specific research referenced below.

The isoflavones in soy foods are absorbed almost exactly the same as from supplements (131). After ingesting isoflavones, blood concentrations of genistein and daidzein peak after 5.5 and 7.4 hours respectively; they have a half-life of about 8 hours, meaning 50% will be gone after 8 hours, 75% after 16 hours, and 88% after a day (132). However, if you eat them daily, you will have some in your blood all the time.

There are other isoflavones, the most studied of which are the isoflavones in red clover. These are not the same isoflavones as found in soy.

Soy Servings

In the research discussed here, soy is typically described in grams of protein or milligrams of isoflavones. Less frequently, soy is described in grams of total soy foods. To make things more complicated, sometimes the participants in research are given only soy protein concentrate (about 65% protein), the isolated soy protein (about 90% protein), and sometimes only isolated isoflavones.

A rough guide is that one serving of soy equals 1 cup of soymilk, or 1/2 cup of tofu, tempeh, soybeans, or soy meats. This is the rough equivalent of about 8 to 10 grams of soy protein and 25 mg of isoflavones. The more processed soy meats tend to have more protein (but fewer isoflavones per gram of protein).

Soy Foods

Some people who write about soy suggest that fermented soy foods are the most healthy, and that isolated soy proteins are the most unhealthy. Fermented soy foods are tempeh, miso, and natto. As will be discussed below, for the most part, the evidence does not suggest that fermented soy foods are healthier than traditional non-fermented soy foods (such as tofu and soymilk). And much of the research on soy showing benefits has been performed on isolated soy protein.

In the United States, whole soybeans are usually eaten in the form of edamame, tempeh, or soy nuts. Many, but not all, soy meats, as well as texturized soy protein, are made from soy protein concentrate or isolated soy protein. Turtle Island, the makers of Tofurky, use pressed tofu to create their soy meats.

Benefits of Soy

I do not attempt to comprehensively review the benefits of soy in this article. Because they should also be considered, I will briefly cover them.

Lowering Cholesterol

A 2006 review of six meta-analyses on soy and cholesterol levels concluded, “In summary, the systematic reviews suggest that the effect of [a diet containing isolated soy protein with] around 90 mg/day of isoflavones is to reduce LDL cholesterol modestly (by around 5%), without clear effects on triglycerides or HDL cholesterol.” (125)

Prostate Cancer

A 2009 meta-analysis on soy and prostate cancer found that soy, in the highest versus lowest intake categories, was associated with a statistically significant, 26% reduction in prostate cancer risk (0.74, 0.63-0.89) (1). When separately analyzed, studies on non-fermented soy foods yielded a reduced risk of 30% (0.70, 0.56-0.88), and fermented soy foods were not associated with a decreased (or increased) risk of prostate cancer. It should be noted that the highest intake categories in these studies tended to be low, with most being less than one serving per day.

Menopausal Symptoms

A 2009 paper from the 8th International Symposium on the Role of Soy in Health Promotion and Chronic Disease Prevention and Treatment reported that soy isoflavone supplements containing at least 15 mg of genistein per day have been consistently effective at reducing hot flashes (126). If that much genistein is not provided, then there is little benefit, and is the reason why previous reviews, such as a 2006 meta-analysis (5), provided mixed results.

All-Cause Mortality

A 2019 meta-analysis of 23 prospective studies found a significant inverse relationship between soy intake and all-cause mortality (137). Furthermore, higher soy isoflavone intake was associated with a 10% decrease in all-cause mortality (137).

Asian Intakes

Japan and China have lower rates of heart disease and many cancers than do Westerners. People have suggested this could be due to the soy in their diet. In response, soy opponents have often argued that the traditional Asian intake of soy is much lower than is commonly thought. Typical Asian intakes of soy vary among countries and areas. In Japan and Shanghai, China, average intakes are about 1.5 servings per day, but many people consume an average of two or more servings per day. About half the soy eaten in Asia is not fermented.

Below is a review of soy intakes in various Asian countries as described in the 2006 paper by Messina et al, Estimated Asian adult soy protein and isoflavone intakes (116).

Japan

Food disappearance data from the Food and Agricultural Organization (FAO) show that daily per capita soy protein intake for Japan between 1961 and 2002 remained constant, and ranged from a high of 9.7 g/day in 1961 to a low of 8.4 g/day in 1977.

The Japanese National Nutrition Survey (NNS) showed that soy intake remained fairly constant after 1960 at about 65 g/day. However, 65 g/day provides approximately 6.5 g of soy protein, which is about 25% lower than the FAO estimate. The total soy food intake of Japanese adults aged 60–69 years is 91.7 g/day, approximately 50% higher than the mean intake of the overall Japanese population.

In recently conducted surveys of individuals in Japan that reported soy protein intake, daily adult female soy protein intake ranged from 6.0 to 10.5 g/day; the male range was 8.0 to 11.3 g/day. Average isoflavone intake ranged from 22 to 54 mg per day among food frequency surveys, and two studies from Japan suggest that approximately 5% of adults consume as much as 100 mg of isoflavones per day. Three studies show that the upper range (rather than the average) of soy protein intake is 16 to 18 g/day.

One study reported that isoflavone intake among subjects from a rural village was similar to that reported for urban Japanese.

China

Women from the Chinese city of Shanghai have soy intakes about the same as Japan – about 9-10 g/day of soy protein. Isoflavone intake ranged from 33 to 41 mg/day in three studies.

Studies from Hong Kong reported adult female daily soy protein intakes to be 4.9 g/day (2000) and 7.9 g/day (2003). Isoflavone intake ranged from 6 to 30 mg/day in four studies. One study found the upper quartile of women to be consuming 19 g of soy protein per day.

There is evidence to suggest that people in other areas of China may have considerably lower soy intakes, since the national average for total soy food intake in China for 1990 to 1998 was only 17.8 g/day, which represents an isoflavone intake of ≤ 10 mg/day.

Among Chinese women one study found that soymilk, tofu, and processed soy products other than tofu accounted for 81% of total soy protein intake consumed.

Singapore

Two studies from Singapore, from 2000 and 2002, show relatively low (≤ 5.1 g/day) soy protein intakes. One of those studies showed isoflavone intake to be 16 mg/day; the other didn’t report isoflavone intake.

Korea

A 2000 study found average daily isoflavone intake among Korean women aged 35 to 60 years to be 24.4 ± 25.1 mg/day. Intake among pre- and post-menopausal women was 21.8 and 30.1 mg/day, respectively. According to the Korean National Household Survey, the mean daily isoflavone intake (15.1 mg) of individuals living in large cities was almost identical to the isoflavone intake (15.2 mg) of individuals living in rural areas.

Fermentation

In both Japan and China, non-fermented foods provide approximately half of the total soy intake. In Shanghai, nearly all soy is non-fermented.

Breast Cancer

Summary: The vast majority of the evidence is that soy is either neutral or protective against breast cancer, including for women previously diagnosed with estrogen receptor positive breast cancer (tumors stimulated by estrogen contact). This evidence is mostly limited to amounts of two servings per day or less.

Breast Cancer—Reviews

In their article, Soy and Cancer Risk: Our Expert’s Advice, the American Cancer Society says:

So far, the evidence does not point to any dangers from eating soy in people, and the health benefits appear to outweigh any potential risk. In fact, there is growing evidence that eating traditional soy foods such as tofu, tempeh, edamame, miso, and soymilk may lower the risk of breast cancer, especially among Asian women. Soy foods are excellent sources of protein, especially when they replace other, less healthy foods such as animal fats and red or processed meats. Soy foods have been linked to lower rates of heart disease and may even help lower cholesterol.

In their 2010 review, Hilakivi-Clarke et al. sum up the evidence on soy and breast cancer (40):

Results reviewed here suggest that women consuming moderate amounts of soy throughout their life have lower breast cancer risk than women who do not consume soy; however, this protective effect may originate from soy intake early in life. We also review the literature regarding potential risks genistein poses for breast cancer survivors. Findings obtained in 2 recent human studies show that a moderate consumption of diet containing this isoflavone does not increase the risk of breast cancer recurrence in Western women, and Asian breast cancer survivors exhibit better prognosis if they continue consuming a soy diet.

Breast Cancer—Meta-Analyses

A 2019 dose-response meta-analysis of 23 prospective studies with a total of 330,826 participants found that both soy protein and soy isoflavones have a positive impact on breast cancer mortality (137). A 10 mg/day increase in soy isoflavone intake was associated with a 9% decreased risk of breast cancer mortality, and a 5 g/day increase in soy protein intake was associated with a 12% reduction in breast cancer death (137).

Breast Cancer—Retrospective Studies

In retrospective studies, past diets (provided by memory) of subjects with breast cancer are compared to those without breast cancer. Retrospective studies are less expensive and faster than following people prospectively (forward in time) but are considered less reliable due to inaccuracies in recalling past diet. They generally provide ideas of what connections to investigate prospectively. Nonetheless, the findings from the retrospective studies have shown soy to be either neutral or beneficial in protecting against breast cancer.

California-Hawaii Asian-American Study (2009)

This study looked at childhood soy exposure (18). Women in the top one-third of soy intake during childhood, adolescence, and adulthood had a lower risk of breast cancer than those in the lowest one-third, with the strongest, most consistent effect being for childhood intake. That authors suggest that, “Soy may be a hormonally related, early-life exposure that influences breast cancer incidence.”

Aichi Cancer Center Research Institute, Japan (2008)

This 2008 case control study from Japan found that soy consumption was linked with a significantly reduced risk of estrogen positive breast cancer (8). The risk for the top one-third was .74 (.58 – 0.94).

Nishio et al (2007) sums up the results of the previous restrospective studies (17):

“…seven studies showed no associations [between soy and breast cancer], one study showed protective effects, six studies showed protective associations only in premenopausal women, and one study found [protective] associations only in postmenopausal women.”

Breast Cancer Observational Studies of Women Initially without Cancer

In typical observational studies, you start with people who are apparently healthy and follow them prospectively, without any clinical intervention. The observational studies on soy and breast cancer can be divided into two groups—those done on populations with very low intakes and those done on populations with higher intakes.

The studies done on populations with very low intakes do not provide much evidence. Since 2001 there have been six observational studies on such populations. One of those studies, EPIC-Norfolk (2004), did find an association between soy intake and breast cancer, but the intake of soy was so small as to make the finding likely due to random chance.

EPIC-Norfolk, Phytoestrogens (2010)

The European Prospective Investigation into Cancer and Nutrition (EPIC), Norfolk chapter, measured phytoestrogen content of all foods (not only soy) and compared intakes to breast cancer rates (19). They found no association between phytoestrogens and breast cancer.

French Cohort (2006)

Women were followed from 1990-1991 through July 2002. No relationship between isoflavone intake and breast cancer risk was found. Isoflavone intake was extremely low with the highest group in the range of .03 to .1 mg/day (25).

EPIC-Norfolk (2004)

EPIC-Norfolk performed a nested case-control study measuring isoflavone intake and risk of breast cancer. Women were recruited from 1993-1997 and followed through July 2001 (20). Isoflavone intake was very low, with an average intake of .4 mg/day. Urine and serum isoflavone levels (taken at the beginning of the study) were compared to breast cancer rates. Exposure to equol and daidzein was associated with a statistically significant increased risk of breast cancer. This is the only prospective finding in which soy was associated with an increased risk of breast cancer; because the intakes of soy were so low, the finding is most likely an anomaly.

The Netherlands (2004)

This study found no association between soy intake and breast cancer. Intake of soy was very small, only 4.9 g of soy foods per day in the highest one-fourth (29).

California Teachers Study (2002)

This study, that took place in Los Angeles, found no association between soy intake and breast cancer, but it only had two years of follow-up and isoflavone intake was 2 mg/day at the 80th percentile – just a fraction of a serving per day (28).

The Netherlands (2001)

This nested case-control study found that urinary genistein levels collected 1 to 9 years before post-menopausal breast cancer was diagnosed was not associated with risk (27).

Observational Studies with Higher Soy Intakes

Of the studies done on populations with higher soy intakes (about one to two servings per day as a typical upper intake amount), the Singapore Chinese Health Study (21), the Shanghai Women’s Study (22, 23), and the Japan Public Health Center (26) study all found that higher intakes of soy were associated with a reduced risk of cancer. The Japan Collaborative Cohort Study (17) and the Japan Life Span Study (30) found no association. European Prospective Investigation into Cancer-Oxford (24) which contained a large number of vegetarians, also found no association, but this could be because exposure to soy might be more protective when breast tissue is developing during adolescence, while Western vegetarians often come to the diet as adults.

Singapore Chinese Health Study (2010)

This report of the Singapore Chinese Health Study was a bit different (than the 2008 report below) in that it examined dietary patterns, and not just soy intake (21). There were two diet patterns which had previously been identified as common among Asian women: “vegetable-fruit-soy” and “meat–dim sum.” The women were recruited from 1993 to 1998, had a median age of 55 years, and were followed through 2005. Women who ate closer to the vegetable-fruit-soy pattern had a lower risk of breast cancer, but this result was limited to women who were post-menopausal at the beginning of the study. There were a number of non-statistically significant trends towards less risk, including for soy and isoflavone intake, fruit intake, vegetable intake, and vegetable-fruit-soy intake for estrogen receptor positive breast cancer.

Shanghai Women’s Study (2009)

The Shanghai Women’s Study (SWS) found that among pre-menopausal women, higher soy intake was associated with a lower risk of breast cancer (23). A soy protein intake of 16 g/day was associated with an almost 60% reduced risk when compared to the lowest intake of soy protein of 3.5 g/day or less. SWS also surveyed soy intake during adolescence (based on the participants’ memory) and found it to be associated with a lower risk of pre-menopausal breast cancer.

Singapore Chinese Health Study (2008)

Women were recruited from 1993 to 1998 and followed through the end of 2005 (22). The women were divided into those eating less than 10.6 mg of isoflavones per 1,000 calories and those eating 10.6 mg or more. Women in the higher intake group had a lower risk of breast cancer (.82, .70-.97). When divided by pre- and post-menopausal, the post-menopausal women (only) had a lower risk (.74, .61 – .90). Post-menopausal women who ate more soy had a lower risk of estrogen receptor positive cancer (.67, .49–.91). The authors noted that “There are seven common soy products in the Singapore Chinese diet and all are nonfermented.”

EPIC-Oxford (2008)

EPIC-Oxford followed 37,600 British women, 31% of whom were vegetarian, for 7.4 years (24). There was no difference in risk of breast cancer between high isoflavone intake (average of 31.6 mg/day) and low isoflavone intake (.2 mg/day). No significant associations were observed when separated into pre- and post-menopausal groups.

Japan Collaborative Cohort Study (2007)

The Japan Collaborative Cohort Study found no correlation between the consumption of tofu, boiled beans, or miso soup and the risk of breast cancer (17).

Japan Public Health Center (2003)

The Japan Public Health Center-Based Prospective Study on Cancer and Cardiovascular Diseases found that people in the highest one-fourth of genistein intake of 24 mg/day had only half the risk of breast cancer compared to those in the lowest genistein intake of 7 mg/day (26). Those in the highest soyfoods intake category (“almost every day”) didn’t have a lower risk compared to those in the lowest (“less than 2 times per week”). Upon further analysis, the finding for isoflavones being protective was limited to post-menopausal women, for whom there was a 68% lower risk in the highest isoflavone intake category.

Life Span Study, Japan (1999)

The Life Span Study cohort in Hiroshima and Nagasaki found no association between tofu and miso with breast cancer risk. The highest soy intake category was 5 or more servings per week (30).

Breast Cancer Survival and Recurrence

The Women’s Healthy Eating and Living (2011) study is a randomized controlled trial of a high fruit-vegetable-fiber and low fat dietary intervention in early stage breast cancer survivors (121). It had a median follow-up of 7.3 years from the time of enrollment. Soy intake was measured post-diagnosis (median 2 years, range: 2 months to 4 years) using a food frequency questionnaire that included specific items for “Meat Substitutes (such as Tofu, Veggie Burgers),” and “Soy Milk”, as well as an opportunity to include other soy foods and supplements.

Isoflavone intake (the marker for soy) was unrelated to the risk of recurrence regardless of hormone receptor status or Tamoxifen use. No significant increased or decreased risk was associated with any specific level of intake. Risk of death tended to be lower as isoflavone intake increased (p for trend=0.02). Women at the highest levels of isoflavone intake (>16.3 mg/day isoflavones; equivalent to at least 1⁄2 cup soymilk or 2 oz tofu) had a non-significant 54% reduction in risk of death compared to the lowest one-fifth of soy intake.

The authors state:

Our study is the third epidemiological study to report no adverse effects of soy foods on breast cancer prognosis. These studies, taken together, which vary in ethnic composition (two from the US and one from China) and by level and type of soy consumption, provide the necessary epidemiological evidence that clinicians no longer need to advise against soy consumption for women diagnosed with breast cancer.

Of the other studies, one from the Cancer Hospital of Harbin Medical University, China (2010) (31), the Shanghai Breast Cancer Survival Study (2009) (11), and the Long Island Breast Cancer Study (2007) (32) found soy to be associated with a lower risk of breast cancer or death in some subgroups. Neither those studies nor the Shanghai Breast Cancer Study (2005) (33) or the Life After Cancer Epidemiology Study from Northern California and Utah (2009) (34) found any statistically significant increase in breast cancer, including among women with estrogen positive breast cancer (11, 33, 34).

Breast Tissue and Nipple Aspirate

Non-lactating nipple aspirate might be a risk for breast cancer, although the data is mixed, and it is likely that what is more important is whether certain types of cells are found in the aspirate (129).

There have been three studies measuring the effects of soy on nipple aspirate. One was conducted in women diagnosed with breast cancer and it found increased aspirate after two weeks in the high soy diet, although there was no increase in breast cell proliferation (35). In two longer term studies of six months on women without a diagnosis of breast cancer, one study found increased nipple aspirate in women while on a higher soy diet of 45 mg of isoflavones per day (there was no placebo group) (37). The other found no increase in nipple aspirate on the high soy diet (2 servings per day) when compared to the low soy diet (< 3 servings per week) (129). At this time, it appears that there is little concern regarding soy and nipple aspirate in amounts up to two servings per day.

In two other studies of breast tissue, no difference was found between the high and low soy diet groups (38, 39)

Thyroid

Almost everyone who has a reliable source of iodine can safely eat soy without it causing thyroid problems. Although most studies that have measured thyroid function and soy intake have found no problems, a 2011 study (78) of people with subclinical hypothyroidism found an increased rate of progression to overt hypothyroidism. For such people, it might be wise to limit soy. People with overt hypothyroidism who substantially change their soy intake might need to talk to their doctor about adjusting their synthetic thyroid medication.

Introduction

The thyroid gland produces hormones, triiodothyronine (T3) and thyroxine (T4), that regulate metabolism. Thyroid stimulating hormone (TSH), made by the anterior pituitary gland, increases in response to the body’s need for more T3 or T4.

Isoflavones in soy can inhibit thyroid peroxidase (TPO) (77), an enzyme involved in the synthesis of the thyroid hormones. This mostly happens when someone is deficient in iodine. If left unchecked, this can lead to hypothyroidism and even an enlarged thyroid gland, known as a goiter.

Reviews

In their 2006 review article, Messina and Redmond write (77):

The preponderance of evidence from clinical trials involving healthy adult men and women indicates that neither soy protein nor isoflavones adversely affect thyroid function. As noted the adverse effects reported by one Japanese study [Ishizuki Thyroid Clinic, (67)] are biologically implausible and contrast with the results of 13 other trials. Thus, despite their ability to [inhibit thyroid peroxidase] in vitro and in vivo in rodents, isoflavones do not appear to cause thyroid hormone abnormalities in euthyroid individuals [people with genetically normal thyroid function]. Nevertheless, research aimed at determining whether further depression of thyroid function in individuals with pre-existing subclinical hypothyroidism occurs in response to soy intake is warranted.

Messina and Redmond also point out that soy might interfere with the absorption of synthetic thyroid hormone.

In their 2002 review article, Doerge and Sheehan write (76):

Iodine deficiency is an emerging concern in elderly Americans. Consumption of iodized salt, the primary source of dietary iodine, may decrease with the desire or need to reduce the possible hypertensive effects of high salt intake. The data presented here suggest that elderly women need to be aware of, and monitored for, possible thyroid problems resulting from consumption of soy products. Those post-menopausal women who consume large amounts of soy products may be at higher risk.

Primary Studies

Hull Royal Infirmary, United Kingdom (2011)

This study was done on people who were found to have subclinical hypothyroidism (defined as a TSH value between 5 and 15 mU/liter; normal range is 0.5–4.7 mU/liter) (78).

It was a randomized, double-blinded, crossover study of 60 patients (8 men, 52 women), ages 44–70. The two study periods lasted eight weeks each and consisted of 30 g of soy protein that provided either 2 mg of isoflavones or 16 mg of isoflavones with an eight week washout period in between. An isoflavone intake of 2 mg per day is typical of Western populations, while 16 mg is typical of vegetarian intakes. The subjects had normal iodine levels ( >100 µg/liter).

Six patients, all women, developed overt hypothyroidism after the 16 mg isoflavone phase, while none did after the 2 mg phase. The overt hypothyroidism appeared permanent, with no reversal on isoflavone withdrawal, although to determine this fully they should have discontinued thyroid hormone for a period, which they did not do. The underlying cause is unclear, although acceleration of an underlying autoimmune process is a possibility.

The authors state:

In a prospective study looking into the spontaneous course of hypothyroidism in females, the rate of progression of subclinical hypothyroidism to overt hypothyroidism was 5.6%/yr. Extrapolating the data from this 8-wk study to give a rate of progression per year, it was expected that in our study population, 3.36 cases per year would progress to overt hypothyroidism; this translates into a standardized rate ratio of 3.6 (95% confidence interval = 1.9, 6.2), i.e. supplementation with 16 mg phytoestrogen caused a 3-fold increase in progression from subclinical to overt hypothyroidism in this study….There are currently no data to guide what effect longer periods of exposure would have on thyroid function, with the possibilities that more overt hypothyroidism may result, stabilization may occur, or thyroid function could improve with thyroid adaptation to the phytoestrogen load.

The authors conclude that female vegetarian patients with subclinical hypothyroidism may need careful monitoring.

The good news was that the high isoflavone phase produced a significant reduction of blood pressure, c-reactive protein, and insulin resistance. It should also be noted that this is just one study which is rarely enough to be considered conclusive.

Secondary Studies

The studies below, while not primarily looking at thyroid function, did measure it while studying other effects of soy.

Studies showing no effects on thyroid hormone were:

54 mg/day genistein in post-menopausal women for 3 years (13)

76 mg/day isoflavones in post-menopausal women for 2 years (75)

10 mg/day of equol in post-menopausal women for 1 year (63)

90 mg/day isoflavones on post-menopausal women for 6 months (60)

65 mg/day isoflavones in men and women for 3 months (69)

48 mg/day isoflavones on children for 2 months (66)

62 mg isoflavones on men for 2 months (68)

54 mg/day isoflavones on post-menopausal women for 7 weeks (71)

A study on soy’s effects on protein synthesis by the liver showed no effect on thyroid binding globulin (TBG) after 118 mg/day isoflavones for 3 months in post-menopausal women (72).

The following studies showed minor changes in thyroid hormone but were not believed to be of physiological significance:

90 mg/day isoflavones in post-menopausal women for 6 months (73)

132 mg/day isoflavones in post-menopausal women for 3 months (70)

128 mg/day isoflavones in pre- and post-menopausal women for 3 months (61)

40 mg/day isoflavones in pre-menopausal women for 1 month (74)

140 g/day soybeans in female students for 1 week (65)

One study of 50 g/day soy protein in men for 4 weeks found that T4 changed from baseline, but did not differ from the placebo group (64).

Finally, one study found that 30 g/day of pickled soybeans didn’t change thyroid hormone levels but caused a goiter in half the subjects.

Infant Formula

Both the National Institutes of Health (NIH) and the American Academy of Pediatrics (AAP) consider soy formula safe for term infants.

The AAP specifically recommends soy formula for those seeking a vegetarian or vegan diet for term infants (147).

In 2009, the NIH’s National Toxicology Program Center for the Evaluation of Risks to Human Reproduction convened an expert panel to evaluate soy infant formula. After evaluating the available scientific evidence, the panel concluded that there was “minimal concern for adverse developmental effects in infants fed soy infant formula” (145). In 2010, the NIH’s National Toxicology Program Board of Scientific Counselors voted in support of the conclusion (146).

Research on Soy Formula and Health

The Beginnings Study is an ongoing study examining the effects of formula on development. It now has findings from children 5 years old and to date, no negative effects of soy have been found on growth, sex organs, or neurological development compared to children who were breastfed or who received cow’s milk formula (138). The researchers recommend choosing a soy formula with DHA and emphasize that soy formula isn’t intended for pre-term infants.

Other research includes:

Three case studies of infants with goiter in 1960, before soy formula was fortified with iodine (80).

A 1990 case-control study found a correlation between receiving soy formula in infancy and autoimmune thyroid disease diagnosis in childhood (81), but the study didn’t control for allergies which is often a reason for children receiving soy formula and which also may lead to autoimmune thyroid disease (82).

A 2001 study of young men and women who had been given soy infant formula found no reason to be concerned about thyroid or reproductive function, although the women had a slightly longer duration and greater discomfort of menstrual bleeding (95).

A 2008 cross-sectional study found a correlation between female toddlers who received soy formula and more breast bud tissue at age 2 (93). While this is a concern, the most relevant study to date, a 2008 case-control study, found no increased risk of breast cancer for girls fed soy formula (144).

A 2008 cross-sectional study found girls on soy formula had a higher maturation index which the authors thought should be examined in future studies (94).

A 2009 cross-sectional study found no difference in sex hormone levels in children fed soy formula (83).

A 2010 study found that women who had received soy formula as infants had a higher rate of non-cancerous uterine fibroids, but the finding wasn’t statistically significant (RR = 1.25; 95% CI, 0.971-1.61). (92).

A 2017 cross-sectional study found boys who were fed soy formula did not experience suppressed testosterone as infants (as had been previously reported in animal studies) (141).

A 2018 longitudinal study found girls exclusively fed soy formula in infancy had greater vaginal and uterine maturation indices, but no difference in breast bud diameter or hormone concentrations compared to those receiving cow-based formula (142).

A 2019 case-control study found no association between the use of soy formula and age of onset of puberty (143).

A 2019 retrospective study on African-American women found that women fed soy formula as infants were more likely to report moderate/severe menstrual discomfort/pain with ‘most periods’, but not with ‘every period’, during early adulthood compared to women never fed soy formula (139). Mark Messina, PhD, of the Soy Nutrition Institute, says there’s not enough research on the impact of soy formula consumption on menstrual pain later in life to draw any meaningful conclusions (140).

Feeding Pre-Term Infants

The American Academy of Pediatrics does not recommend soy infant formulas for pre-term infants due to studies showing poor bone growth in pre-term infants on soy formula compared to cow’s milk formulas designed for pre-term infants.

There’s also a concern that aluminum levels in soy formula could be a problem for infants with undeveloped kidneys but not for full-term infants.

Feeding Infants with Thyroid Issues

According to a 2008 paper by the American Academy of Pediatrics Committee on Nutrition:

Consumption of soy products by infants with congenital hypothyroidism complicates their management, as evidenced by a prolonged increase in thyroid-stimulating hormone when compared with infants not fed soy formula; the authors of 2 studies suggested closer monitoring and a possible need for an increased dose of levothyroxine (84).

Cognition

Summary: There have been 12 short-term clinical trials looking at the impact of soy on cognition, and all have shown soy to be helpful or neutral. A longitudinal study found tempeh to be associated with improved cognition. Three reports from longitudinal studies have associated tofu with reduced cognition in some groups, but increased cognition in another group, and neutral in others. This is likely due to confounding. Based on the research to date, there should be little concern about eating soy, including tofu, with regards to cognitive decline.

Long-term Studies

In the Honolulu-Asia Aging Study (2000) of older Asian men living in Hawaii, food intake was collected once at baseline (1965–1967) and one more time during 1971–1974. Cognitive function was then measured in 1991–1993, and brain size was measured in those who had died (2).

Midlife tofu consumption by itself (controlling for no other factors) explained 2.3% of the variation in mental cognition scores. A linear regression model that included only age, education and history of a prior stroke explained 27.8% of the variation. After controlling for these three most important factors, midlife tofu consumption remained statistically significant even though it then explained only 0.8% of the variance in test scores. Despite this, the researchers state that, “In this study population, 20% to 25% of the burden of cognitive impairment appears attributable to midlife tofu consumption — an effect size of enormous public health importance…”

Upon autopsy of those who died, smaller brain size was associated with increased tofu consumption.

In an accompanying editorial, Grodstein et al, write (41):

Clearly, these results are interesting, although must be considered preliminary; relatively few subjects consumed tofu at high levels, and the confidence intervals around the estimates of effect presented are wide, indicating the limited precision of these results… Importantly, we do not know if tofu itself was the cause of these numerous indications of accelerated brain aging or if tofu is merely a marker for some other unfavorable exposure. For example, in this population, men with higher tofu intake (and more traditional diets) likely came from poorer immigrant families and perhaps experienced more childhood privation, which may be related to their brain development and subsequent cognitive function.

In 2010, Hogervorst et al, reference this study (42):

People of low socioeconomic status were hypothesized to eat more soy (as an animal protein substitute because it is cheaper). However, low socioeconomic status in itself is associated with a faster cognitive decline and an earlier onset of dementia and could thus have mediated the association between high soy intake and low memory function.

The Kame Project (King County, Washington, 2000) is a prospective study of Japanese Americans aged 65 years or older living in King County, WA (53). Cognitive ability was measured at the beginning and after two years. Tofu consumption was categorized as low (<1/wk), moderate (1–2/wk), and high (3+/wk). At the beginning of the study, among women taking estrogen replacement therapy, high tofu consumption was associated with lower cognitive scores. No other statistically significant differences were found at baseline, and all analyses were adjusted for age, education, and language spoken. Upon testing at two years, tofu consumption was not associated with the rate of cognitive change either among men, women, or women on estrogen replacement therapy.

The Tofu and Tempeh Study, a 2008 study from Indonesia found that among people aged 52 to 98, tempeh intake was associated with slightly better memory scores (9). The authors suggested that tempeh might be good for memory because the bacteria used in the tempeh starter, Rhizopus oligosporus, produce folate which is thought to protect memory.

However, increased tofu consumption was linked to slightly worse memory scores (-0.18, p = .05). The authors state that, “According to the Departments of Public Health at the Universities of Jakarta and Yogyakarta, formaldehyde is often added to tofu (but not tempeh) to preserve its freshness. Formaldehyde can induce oxidative damage to the frontal cortex and hippocampal tissue….” As of January 2011, the Indonesian government was still trying to end the practice of adding formaldehyde to tofu (43).

In 2010, this research group published a follow-up paper (42). It was a cross-sectional study of 151 men and women (most from the previous report) over the age of 56. Both immediate and delayed recall were tested. Median and mean tempeh and tofu consumption was seven times a week, ranging from never to three times a day. Before adjusting for age, sex, and education, tempeh and tofu were associated with better immediate recall; after adjusting, the associations were no longer significant. In the group younger than 73 years, higher tofu consumption was significantly associated with better immediate recall even after the adjustments.

There are a lot of theories as to why this follow-up study had opposite findings of their first study (one being that the older people who were eating more tofu had died), but it is an indication that tofu, itself, does not cause cognitive decline.

In a 1993 study of California Seventh-day Adventists (SDA) ages 65 and over, those who hadn’t eaten meat in the previous 30 years were about one-third as likely to develop dementia as their regular meat-eating counterparts (58). While soy intake was not compared to dementia rates, another study (59) of California Seventh-day Adventists showed SDA vegetarians to eat an average of 3.5 servings of meat substitutes (which usually contain soy) per week compared to only 1.4 servings by their meat-eating counterparts.

Clinical Trials

There has been a plethora of short-term (lasting one week to a year) clinical trials on soy and cognitive function. Four studies found that soy had benefits compared to the placebo (44, 45, 48, 49). One study found no decline in cognitive function in the soy group, whereas the placebo declined (47). Four studies found a benefit to soy but there was no placebo group (50, 54, 55, 56). Three studies found no benefit of soy (51, 52, 57). No study found the placebo group to do better than the soy group on any measurement of cognitive function.

Conclusion

The short-term clinical trials have been very favorable towards soy and cognitive function. The one long-term study that assessed a non-tofu soy food, tempeh, found a protective effect in the first analysis, and no effect after adjustments in a follow-up.

The main concern appears to be tofu which has recently been prepared with formaldehyde in Indonesia and was a food traditionally eaten by poorer people with less education. The research can be summarized as follows:

The Honolulu-Asia Aging Study found tofu consumption during the 1960s and 1970s was associated with cognitive decline in the 1990s (2).

An Indonesian study of older people found that tofu was associated with slightly lower memory scores, possibly due to formaldehyde in processing (9). A follow-up report found that tofu was linked with better memory scores among the younger subjects (42).

The Kame Project, a study of older Japanese Americans found that at baseline, and only among women taking estrogen replacement therapy, tofu consumption was associated with lower cognitive scores. Testing again two years later, this association was no longer there (53).

It seems safe to assume that tofu does not have an appreciable effect on cognitive function and that these associations are due to confounding variables. A study on non-Asians and tofu consumption (where it cannot be linked to lower socioeconomic status or formaldehyde) could shed more light on this subject.

Hexane

There is little evidence to determine whether the hexane residues in some processed soy meats are safe over the long term, though hexane processing can be harmful to workers and the environment. It seems prudent to buy most of your processed soy from companies that do not use hexane extraction.

Hexane is sometimes used by the soy industry to separate the oil from the protein in soybeans. The protein is then used for soy meats and other products that contain soy protein extract. This process inevitably leaves some hexane residues in the products.

The Cornucopia Institute is a public interest group that promotes organic agriculture. In November 2010, they released a report Toxic Chemicals: Banned In Organics But Common in “Natural” Food Production. The report makes a persuasive argument that hexane use is dangerous to workers and the environment (the evaluation of which is beyond the scope of this article), and for those reasons alone it seems better to use soy meats processed without hexane. Luckily, there are soy meats available that do not use hexane such as Tofurky, Field Roast, Wildwood, Amy’s Kitchen, and some (though not all) Boca products (link). Foods certified as “USDA Organic” are produced without using hexane extraction.

There is not much evidence that the amount of hexane found in most veggie burgers is harmful. The U.S. Food and Drug Administration has not set an upper limit on how much hexane residue can be in foods, whereas the European Union prohibits hexane residues greater than “30 mg/kg [30 ppm] in the defatted soya products as sold to the final consumer” (118). The Cornucopia Institute found some soy ingredients to have hexane levels as high as 21 ppm, but did not provide details on the average hexane levels they found in any final food products.

More info on hexane in soyfoods:

Hexane in Soy Food – Berkeley Wellness • May 01, 2012

Do Veggie Burgers Contain Hexane? – Shereen Jegtvig, MS • Updated Feb 07, 2014

Mineral Absorption

Eating a few servings of soy per day is unlikely to result in calcium, zinc, iron, or magnesium deficiency. Soybeans contain phytic acid, also known as phytate, which can inhibit the absorption of calcium, zinc, iron, and possibly magnesium. Many whole plant foods contain phytate, but soy has more than most. Hidvegi and Lasztity estimated the phytate content per 100 grams of food (97) in Table 2.

Table 2. Phytate Content of Selected Foods97 Food Range or Average g/100 g Wheat 0.52 – 1.05 Corn 0.62 – 1.17 Barley 0.85 – 1.18 Oats 0.90 – 1.42 Peas 0.72 – 1.23 Soybean 1.20 – 1.75 Soy isolate 0.82 Lupine bean 0.76 – 1.63 Vital gluten 1.90

While phytic acid has a bad reputation, it has some benefits. In their 2002 review, Minerals and Phytic Acid Interactions: Is It a Real Problem for Human Nutrition?, Lopez et al point out that phytates can prevent lipid peroxidation, iron oxidation of colorectal tissue, and calcium-based kidney stones (98).

Calcium

Three studies on adults (99, 100, 101) have shown calcium to be absorbed from soy at rates comparable to that of cow’s milk. One study on Chinese boys found calcium from soy milk to be absorbed at 43% while calcium from cow’s milk was absorbed at 64% (109, see Table 3).

A study from Victoria University (2010) found calcium absorption to be the same from fortified soymilk as from cow’s milk in post-menopausal women (101).

A study from Purdue University (2005) found that the calcium in soymilk fortified with calcium carbonate was absorbed at the same rate (21%) as the calcium in cow’s milk (100). The calcium in soymilk fortified with tricalcium phosphate was absorbed at a lower rate of 18%.

In a study from Creighton University (1991), soybeans, grown in different mediums to produce a different phytate content, were used to determine calcium absorption (99). They found that calcium from high-phytate soybeans was absorbed at 31%, while calcium from low-phytate soybeans was absorbed at 41%. Calcium from milk was absorbed at 38%.

Table 3. Mineral Absorption Rates in Chinese Boys109 Food Calcium

(%) Zinc

(%) Iron

(%) Soy milk 43.5 11.3 6.7 Cow’s milk 64.2 31.2 15.5 Dephytinized soy milk 50.9 20.1 20.6

Soy and Bones

Although a 2010 (3) and 2008 (4) meta-analysis each found that soy isoflavone supplements of 82 and 90 mg/day, respectively, increases bone mineral density in menopausal women, a more recent, clinical trial found little benefit from 80 or 120 mg of soy isoflavone supplements for three years (6).

There is a plethora of evidence that soy does not harm bones; including a cross-sectional study from the Chinese University of Hong Kong (2003) which found that women who ate the most soy (10 g/day of soy protein or more) had greater bone mineral density than those in the lower intake groups (104).

Zinc

Studies have shown that the zinc in soy is absorbed at a rate of about 10–20%.

A 2004 study from Switzerland showed that removing the phytic acid from a wheat and soy flour increased zinc absorption from 22.8% to 33.6% in healthy adults (108). Copper absorption was unaffected.

Table 2 shows results from a 2003 absorption study on Chinese boys (109). Zinc absorption rates were lower from soymilk than cow’s milk.

A study from University of Gothenburg in Sweden (1987), found that adding milk to a meal with meat sauce reduced zinc absorption from 25.2% to 20.7% (110). Adding soy to a meal with meat sauce decreased zinc absorption to 18-20%. Meals of only soy had zinc absorption rates of 14-21%.

Iron

Iron from plant foods is generally not absorbed as well as iron from meat. But a type of iron in soy, ferritin iron, is absorbed at about 30% among people with low iron stores, and this is a high rate of absorption. Ferritin iron makes up a large percentage of the iron found in soybeans; up to 90% (127). Some soy foods have a decent amount of iron, including extra firm tofu (3.35 mg per 1/2 cup), edamame (1.75 mg per 1/2 cup), and soy nuts (1.7 mg per 1/4 cup). There is no reason to worry that moderate amounts of soy might cause iron deficiency.

Also note that adding vitamin C to a meal (in a dose of about 100 mg) has been shown to significantly increase absorption of the iron in plant foods in numerous studies. I found no studies on vitamin C’s effect on iron absorption from soy foods in adults, but two showed that it significantly increased iron absorption from soy formula in infants (114, 115).

Magnesium

I found no studies looking at the effect of soy on magnesium absorption. Phytates have been shown to bind magnesium, so it would be no surprise if the magnesium in soy is absorbed at a lower rate than from other foods. Leafy green vegetables, whole grains, nuts, and seeds are the best sources of magnesium and people eating such foods while adding a few servings of soy per day should not be in danger of magnesium deficiency.

Fermentation

In their 2007 review, Hotz and Gibson say that fermentation can reduce the amount of zinc and iron-binding phytates in soybeans and should, therefore, increase the amount of zinc and iron absorbed from fermented soy foods such as tempeh and miso (111).

The effects of fermenting soy foods on rates of zinc absorption have not been tested in humans, but one study from the University of the Witwatersrand, South Africa (1990) found that the iron in tempeh was absorbed better than from other soy foods, at a rate of 10 – 15%; the iron from tofu was absorbed at a range of about 3 to 8% (113). Again, absorption rates of plant iron vary greatly according to someone’s current iron status and the amount of iron in the food, which can account for a large range of absorption amounts.

Feminizing Characteristics

It requires twelve servings of soy (and probably much more for most men) to have any sort of noticeable feminizing effects. While one epidemiological study raised concerns about soy and sperm quantity (14), two clinical studies have shown no effects of soy on sperm quality or quantity (15, 126).

In 2011, there was a case report of a 19-year old vegan male who was eating a great deal of soy foods – enough to provide 360 mg of isoflavones per day, the equivalent of about 14 servings (10). He also had type 1 diabetes. After eating this way for a year, he developed low free testosterone levels and erectile dysfunction. After ceasing the soy products (and the vegan diet), his symptoms normalized within a year. There was no reason why he needed to stop being vegan rather than just cutting way down on, or eliminating for a period, soy foods.

A 2008 case report described a 60 year old man who developed gynecomastia (the enlargement of the mammary glands in a male) after drinking 3 quarts of soymilk (the equivalent of 12 servings) a day (123). His breasts returned to normal after discontinuing the soymilk.

Gynecomastia – Male Breasts

In contrast to the case report above, in a 2004 study, 20 men with prostate cancer were given either 450 mg (amount found in about 18 servings of soy) or 900 mg (amount found in about 36 servings of soy) of isoflavones for 84 days (124). Two of the men, who had no gynecomastia at baseline, receiving the 900 mg developed mild cases of gynecomastia. One man was taking a drug that likely increased the gynecomastia. Two men had hot flashes probably related to the isoflavones. Given the very large amounts of isoflavones they were taking, this study should allay fears of feminization in men rather than cause any sort of alarm.

Sperm Health

A 2008 epidemiological study found that men attending a fertility clinic had lower sperm concentrations if they ate more soy, but the amount of soy was very small (≥ .3 servings/day) and part of the difference could be explained by a higher ejaculate volume (14). Two more recent clinical trials using 62 mg/day of isoflavones for two months and 480 mg/day of isoflavones for three months found no difference in sperm count, concentration, or motility.

Review

Messina sums up the rest of the literature on soy and feminizing characteristics in men in his 2010 review (122):

In contrast to the results of some rodent studies, findings from a recently published metaanalysis and subsequently published studies show that neither isoflavone supplements nor isoflavone-rich soy affect total or free testosterone (T) levels. Similarly, there is essentially no evidence from the nine identified clinical studies that isoflavone exposure affects circulating estrogen levels in men. Clinical evidence also indicates that isoflavones have no effect on sperm or semen parameters, although only three intervention studies were identified and none were longer than 3 months in duration. Finally, findings from animal studies suggesting that isoflavones increase the risk of erectile dysfunction are not applicable to men, because of differences in isoflavone metabolism between rodents and humans and the excessively high amount of isoflavones to which the animals were exposed. The intervention data indicate that isoflavones do not exert feminizing effects on men at intake levels equal to and even considerably higher than are typical for Asian males.

Endometrium

A 2009 meta-analysis of five retrospective and two prospective studies found that participants with a higher soy intake (roughly one serving per day) had a reduced risk for endometrial cancer and ovarian cancer, when compared with lower soy intakes. Two other studies of three years in duration found that soy isoflavones in the amounts of 70, 80, and 120 mg/day did not have a negative effect on the endometrium. However, one study using 90 mg of isoflavones for five years (equivalent to 3.5 servings of soy per day) did result in cell growth (though non-cancerous) of the endometrium among some subjects. Women at risk for endometrial cancer might use caution in eating more than one serving per day of soy.

Ovarian Function

A 2010 review by Wendy N. Jefferson of the Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, summarized the literature on soy and ovarian function (117):

For the most part, the studies conducted to date suggest that a diet containing lower levels of soy, e.g. 1–2 servings of soy/d, as part of a well-balanced diet should not pose harmful effects on the function of the ovary as it relates to ovulation. These levels are similar to that found in a traditional Asian diet (10–25 mg/day isoflavones) and even up to 50 mg/day isoflavones has little impact on serum circulating levels of hormones involved in reproduction. Although the levels of phytoestrogens typically found in soy foods pose minimal risk in the adult female, the female reproductive system is dependent on hormones for proper function and phytoestrogens at very high levels can interfere with this process.

Additionally, a 2009 meta-analysis of five retrospective and two prospective studies found that participants with a higher soy intake (roughly one serving per day) had a reduced risk for endometrial cancer and ovarian cancer, when compared with lower soy intakes (119).

Fertility

A 2014 cross-sectional study from Adventist Health Study-2 found that a higher intake of isoflavones was associated with an increased rate of never becoming pregnant and of being childless (136). Among the highest soy intake category of > 50 mg/day (average of 79 mg/day or about three servings), compared to those in the lowest intake category (average of 3.7 mg/day), there was a 15% higher rate of being childless (1.15, 1.02-1.29). This finding was adjusted for age, educational level, and marital status.

The authors did not distinguish between involuntary and voluntary childlessness.

This issue warrants further attention, but given that it is a cross-sectional study and the findings were rather weak, it seems unlikely that isoflavones cause childlessness.

Glutamate

Isolated soy protein is rumored by some to have unusually large amounts of MSG (it doesn’t), and MSG, in turn, is rumored to be an excitotoxin (for practical purposes, it’s not) that will destroy brain cells. I cover this topic in some blog posts at JackNorrisRD.com (link).

Hypospadias

Two studies have examined soy intake and risk of hypospadias. Neither found a statically significant risk with more soy intake. It appears that factors other than soy are the most likely the cause of hypospadias, although more studies are warranted.

Hypospadias is a male birth defect in which the opening of the urethra (the tube through which urine passes) is not located at the tip of the penis as it should be. The milder forms of hypospadias, which are by far the largest number of cases, are relatively easy to repair which usually results in a penis with normal or near-normal function and appearance, and no future problems (135).

A 2004 case-control study from the Netherlands (133) found no link between maternal soy intake and an increased risk of hypospadias. Women who had a soy protein intake of 20 g or more had the exact same risk as those eating no soy (1.0, 0.5-2.2).

A 2000 UK prospective study, of 7,928 boys born to mothers taking part in the Avon Longitudinal Study of Pregnancy and Childhood, found 51 cases of hypospadias (134). There was a trend of more soy meats and soy milk being associated with an increased risk for hypospadias, but the findings were not statistically significant, nor were the results adjusted for any confounding variables.

Two of three studies have found an increased risk of hypospadias if the mothers were vegetarian; more information can be found in Hypospadias and Vegetarian Diets.

Last updated March 2011

References

1. Yan L, Spitznagel EL. Soy consumption and prostate cancer risk in men: a revisit of a meta-analysis. Am J Clin Nutr. 2009 Apr;89(4):1155-63.

2. White LR, Petrovitch H, Ross GW, Masaki K, Hardman J, Nelson J, Davis D, Markesbery W. Brain aging and midlife tofu consumption. J Am Coll Nutr. 2000 Apr;19(2):242-55.

3. Taku K, Melby MK, Takebayashi J, Mizuno S, Ishimi Y, Omori T, Watanabe S. Effect of soy isoflavone extract supplements on bone mineral density in menopausal women: meta-analysis of randomized controlled trials. Asia Pac J Clin Nutr. 2010;19(1):33-42.

4. Ma DF, Qin LQ, Wang PY, Katoh R. Soy isoflavone intake increases bone mineral density in the spine of menopausal women: meta-analysis of randomized controlled trials. Clin Nutr. 2008 Feb;27(1):57-64.

5. Nelson HD, Vesco KK, Haney E, Fu R, Nedrow A, Miller J, Nicolaidis C, Walker M, Humphrey L. Nonhormonal therapies for menopausal hot flashes: systematic review and meta-analysis. JAMA. 2006 May 3;295(17):2057-71.

6. Alekel DL, Van Loan MD, Koehler KJ, Hanson LN, Stewart JW, Hanson KB, Kurzer MS, Peterson CT. The soy isoflavones for reducing bone loss (SIRBL) study: a 3-y randomized controlled trial in postmenopausal women. Am J Clin Nutr. 2010 Jan;91(1):218-30.

8. Suzuki T, Matsuo K, Tsunoda N, Hirose K, Hiraki A, Kawase T, Yamashita T, Iwata H, Tanaka H, Tajima K. Effect of soybean on breast cancer according to receptor status: a case-control study in Japan. Int J Cancer. 2008 Oct 1;123(7):1674-80. (Abstract)

9. Hogervorst E, Sadjimim T, Yesufu A, Kreager P, Rahardjo TB. High tofu intake is associated with worse memory in elderly Indonesian men and women. Dement Geriatr Cogn Disord. 2008;26(1):50-7. Epub 2008 Jun 27.

10. Siepmann T, Roofeh J, Kiefer FW, Edelson DG. Hypogonadism and erectile dysfunction associated with soy product consumption. Nutrition. 2011 Feb 23.

11. Shu XO, Zheng Y, Cai H, Gu K, Chen Z, Zheng W, Lu W. Soy food intake and breast cancer survival. JAMA. 2009 Dec 9;302(22):2437-43.

13. USDA Database for the Isoflavone Content of Selected Foods Release 2.0. 2008.

14. Chavarro JE, Toth TL, Sadio SM, Hauser R. Soy food and isoflavone intake in relation to semen quality parameters among men from an infertility clinic. Hum Reprod. 2008 Nov;23(11):2584-90.

15. Beaton LK, McVeigh BL, Dillingham BL, Lampe JW, Duncan AM. Soy protein isolates of varying isoflavone content do not adversely affect semen quality in healthy young men. Fertil Steril. 2010 Oct;94(5):1717-22.

17. Nishio K, Niwa Y, Toyoshima H, Tamakoshi K, Kondo T, Yatsuya H, Yamamoto A, Suzuki S, Tokudome S, Lin Y, Wakai K, Hamajima N, Tamakoshi A. Consumption of soy foods and the risk of breast cancer: findings from the Japan Collaborative Cohort (JACC) Study. Cancer Causes Control. 2007 Oct;18(8):801-8.

18. Korde LA, Wu AH, Fears T, Nomura AM, West DW, Kolonel LN, Pike MC, Hoover RN, Ziegler RG. Childhood soy intake and breast cancer risk in Asian American women. Cancer Epidemiol Biomarkers Prev. 2009 Apr;18(4):1050-9.

19. Ward HA, Kuhnle GG, Mulligan AA, Lentjes MA, Luben RN, Khaw KT. Breast, colorectal, and prostate cancer risk in the European Prospective Investigation into Cancer and Nutrition-Norfolk in relation to phytoestrogen intake derived from an improved database. Am J Clin Nutr. 2010 Feb;91(2):440-8.

20. Grace PB, Taylor JI, Low YL, Luben RN, Mulligan AA, Botting NP, Dowsett M, Welch AA, Khaw KT, Wareham NJ, Day NE, Bingham SA. Phytoestrogen concentrations in serum and spot urine as biomarkers for dietary phytoestrogen intake and their relation to breast cancer risk in European prospective investigation of cancer and nutrition-norfolk. Cancer Epidemiol Biomarkers Prev. 2004 May;13(5):698-708.

21. Butler LM, Wu AH, Wang R, Koh WP, Yuan JM, Yu MC. A vegetable-fruit-soy dietary pattern protects against breast cancer among postmenopausal Singapore Chinese women. Am J Clin Nutr. 2010 Apr;91(4):1013-9.

22. Wu AH, Koh WP, Wang R, Lee HP, Yu MC (2008) Soy intake and breast cancer risk in Singapore Chinese health study. Br J Cancer 99(1):196–200.

23. Lee SA, Shu XO, Li H, Yang G, Cai H, Wen W, Ji BT, Gao J, Gao YT, Zheng W. Adolescent and adult soy food intake and breast cancer risk: results from the Shanghai Women’s Health Study. Am J Clin Nutr. 2009 Jun;89(6):1920-6.

24. Travis RC, Allen NE, Appleby PN, Spencer EA, Roddam AW, Key TJ. A prospective study of vegetarianism and isoflavone intake in relation to breast cancer risk in British women. Int J Cancer. 2008 Feb 1;122(3):705-10.

25. Touillaud MS, Thiébaut AC, Niravong M, Boutron-Ruault MC, Clavel-Chapelon F. No association between dietary phytoestrogens and risk of premenopausal breast cancer in a French cohort study. Cancer Epidemiol Biomarkers Prev. 2006 Dec;15(12):2574-6.

26. Yamamoto S, Sobue T, Kobayashi M, Sasaki S, Tsugane S; Japan Public Health Center-Based Prospective Study on Cancer Cardiovascular Diseases Group. Soy, isoflavones, and breast cancer risk in Japan. J Natl Cancer Inst. 2003 Jun 18;95(12):906-13.

27. den Tonkelaar I, Keinan-Boker L, Veer PV, Arts CJ, Adlercreutz H, Thijssen JH, Peeters PH. Urinary phytoestrogens and postmenopausal breast cancer risk. Cancer Epidemiol Biomarkers Prev. 2001 Mar;10(3):223-8.

28. Horn-Ross PL, Hoggatt KJ, West DW, Krone MR, Stewart SL, Anton H, Bernstei CL, Deapen D, Peel D, Pinder R, Reynolds P, Ross RK, Wright W, Ziogas A. Recent diet and breast cancer risk: the California Teachers Study (USA). Cancer Causes Control. 2002 Jun;13(5):407-15.

29. Keinan-Boker L, van Der Schouw YT, Grobbee DE, Peeters PH. Dietary phytoestrogens and breast cancer risk. Am J Clin Nutr. 2004 Feb;79(2):282-8.

30. Key TJ, Sharp GB, Appleby PN, Beral V, Goodman MT, Soda M, Mabuchi K. Soya foods and breast cancer risk: a prospective study in Hiroshima and Nagasaki, Japan. Br J Cancer. 1999 Dec;81(7):1248-56.

31. Kang X, Zhang Q, Wang S, Huang X, Jin S. Effect of soy isoflavones on breast cancer recurrence and death for patients receiving adjuvant endocrine therapy. CMAJ. 2010 Nov 23;182(17):1857-62.

32. Fink BN, Steck SE, Wolff MS, Britton JA, Kabat GC, Gaudet MM, Abrahamson PE, Bell P, Schroeder JC, Teitelbaum SL, Neugut AI, Gammon MD. Dietary flavonoid intake and breast cancer survival among women on Long Island. Cancer Epidemiol Biomarkers Prev. 2007 Nov;16(11):2285-92.

33. Boyapati SM, Shu XO, Ruan ZX, Dai Q, Cai Q, Gao YT, Zheng W. Soyfood intake and breast cancer survival: a followup of the Shanghai Breast Cancer Study. Breast Cancer Res Treat. 2005 Jul;92(1):11-7.

34. Guha N, Kwan ML, Quesenberry CP Jr, Weltzien EK, Castillo AL, Caan BJ. Soy isoflavones and risk of cancer recurrence in a cohort of breast cancer survivors: the Life After Cancer Epidemiology study. Breast Cancer Res Treat. 2009 Nov;118(2):395-405.

35. Hargreaves DF, Potten CS, Harding C, Shaw LE, Morton MS, Roberts SA, Howell A, Bundred NJ. Two-week dietary soy supplementation has an estrogenic effect on normal premenopausal breast. J Clin Endocrinol Metab. 1999 Nov;84(11):4017-24.

36. McMichael-Phillips DF, Harding C, Morton M, Roberts SA, Howell A, Potten CS, Bundred NJ. Effects of soy-protein supplementation on epithelial proliferation in the histologically normal human breast. Am J Clin Nutr. 1998 Dec;68(6 Suppl):1431S-1435S.

37. Petrakis NL, Barnes S, King EB, Lowenstein J, Wiencke J, Lee MM, Miike R, Kirk M, Coward L. Stimulatory influence of soy protein isolate on breast secretion in pre- and postmenopausal women. Cancer Epidemiol Biomarkers Prev. 1996 Oct;5(10):785-94.

38. Cheng G, Wilczek B, Warner M, Gustafsson JA, Landgren BM. Isoflavone treatment for acute menopausal symptoms. Menopause 2007; 14:468–73.

39. Maskarinec G, Williams AE, Carlin L. Mammographic densities in a one-year isoflavone intervention. Eur J Cancer Prev 2003;12:165–9.

40. Hilakivi-Clarke L, Andrade JE, Helferich W. Is soy consumption good or bad for the breast? J Nutr. 2010 Dec;140(12):2326S-2334S.

41. Grodstein F, Mayeux R, Stampfer MJ. Tofu and cognitive function: food for thought. J Am Coll Nutr. 2000 Apr;19(2):207-9.

42. Hogervorst E, Mursjid F, Priandini D, Setyawan H, Ismael RI, Bandelow S, Rahardjo TB. Borobudur revisited: Soy consumption may be associated with better recall in younger, but not in older, rural Indonesian elderly. Brain Res. 2010 Oct 28. (Epub ahead of print)

43. Agency wants control on formaldehyde. The Jakarta Post. Wed, 01/05/2011 9:53 AM. Accessed January 6, 2011.

44. File SE, Jarrett N, Fluck E, Duffy R, Casey K, Wiseman H. Eating soya improves human memory. Psychopharmacology (Berl) 2001; 157:430-6.

45. Duffy R, Wiseman H, File SE. Improved cognitive function in postmenopausal women after 12 weeks of consumption of a soya extract containing isoflavones. Pharmacol Biochem Behav. 2003 Jun;75(3):721-9.

47. Fournier LR, Ryan Borchers TA, Robison LM, Wiediger M, Park JS, Chew BP, McGuire MK, Sclar DA, Skaer TL, Beerman KA. The effects of soy milk and isoflavone supplements on cognitive performance in healthy, postmenopausal women. J Nutr Health Aging. 2007 Mar-Apr;11(2):155-64.

48. Thorp AA, Sinn N, Buckley JD, Coates AM, Howe PR. Soya isoflavone supplementation enhances spatial working memory in men. Br J Nutr. 2009 Nov;102(9):1348-54.

49. Kritz-Silverstein D, Von Mühlen D, Barrett-Connor E, Bressel MA. Isoflavones and cognitive function in older women: the Soy and Postmenopausal Health In Aging (SOPHIA) Study. Menopause. 2003 May-Jun;10(3):196-202.

50. Islam F, Sparkes C, Roodenrys S, Astheimer L. Short-term changes in endogenous estrogen levels and consumption of soy isoflavones affect working and verbal memory in young adult females. Nutr Neurosci. 2008 Dec;11(6):251-62.

51. Kreijkamp-Kaspers, S., Kok, L., Grobbee, D.E., de Haan, E.H.F., Aleman, A., Lampe, J.W., van der Schouw, Y.T. Effect of soy protein containing isoflavones on cognitive function, bone mineral density, and plasma lipids in postmenopausal women: A randomized controlled trial, JAMA. 2004;292:65-74.

52. Ho SC, Chan AS, Ho YP, So EK, Sham A, Zee B, Woo JL. Effects of soy isoflavone supplementation on cognitive function in Chinese postmenopausal women: a double-blind, randomized, controlled trial. Menopause. 2007 May-Jun;14(3 Pt 1):489-99.

53. Rice MM, Graves AN, McCurry SM, Larson EB. Tofu consumption and cognition in older Japanese American men and women. J Nutr 2000(Suppl):676S. (Published only as abstract)

54. Celec P, Ostatnikova D, Hodosy J, Putz Z, Kúdela M. Increased one week soybean consumption affects spatial abilities but not sex hormone status in men. Int J Food Sci Nutr. 2007 Sep;58(6):424-8.

55. Ostatníková D, Celec P, Hodosy J, Hampl R, Putz Z, Kúdela M. Short-term soybean intake and its effect on steroid sex hormones and cognitive abilities. Fertil Steril. 2007 Dec;88(6):1632-6.

56. Celec P, Ostatníková D, Cagánová M, Zuchová S, Hodosy J, Putz Z, Bernadic M, Kúdela M. Endocrine and cognitive effects of short-time soybean consumption in women. Gynecol Obstet Invest. 2005;59(2):62-6.

57. Pilsáková L, Riecanský I, Ostatníková D, Jagla F. Missing evidence for the effect one-week phytoestrogen-rich diet on mental rotation in two dimensions. Neuro Endocrinol Lett. 2009 Mar;30(1):125-30.

58. Giem P, Beeson WL, Fraser GE. The incidence of dementia and intake of animal products: preliminary findings from the Adventist Health Study. Neuroepidemiology 1993; 12:28-36.

59. Fraser GE. Associations between diet and cancer, ischemic heart disease, and all-cause mortality in non-Hispanic white California Seventh-day Adventists. Am J Clin Nutr. 1999 Sep;70(3 Suppl):532S-538S.

60. Bruce B, Messina M, Spiller GA. Isoflavone supplements do not affect thyroid function in iodine-replete postmenopausal women. J Med Food. 2003 Winter;6(4):309-16.

61. Duncan AM, Merz BE, Xu X, Nagel TC, Phipps WR, Kurzer MS. Soy isoflavones exert modest hormonal effects in premenopausal women. J Clin Endocrinol Metab. 1999 Jan;84(1):192-7.

63. Tousen Y, Ezaki J, Fujii Y, Ueno T, Nishimuta M, Ishimi Y. Natural S-equol decreases bone resorption in postmenopausal, non-equol-producing Japanese women: a pilot randomized, placebo-controlled trial. Menopause. 2011 Jan 19. (Epub ahead of print)

64. Ham JO, Chapman KM, Essex-Sorlie D, Bakhit RM, Prabhudesal M, Winter L, Erdman JW, Potter S. Endocrinological response to soy protein and fiber in mildly hypercholesterolemic men. Nutr Res 1993; 13:873-884.

65. Hampl R, Ostatnikova D, Celec P, Putz Z, Lapcík O, Matucha P. Short-term effect of soy consumption on thyroid hormone levels and correlation with phytoestrogen level in healthy subjects. Endocr Regul. 2008 Jun;42(2-3):53-61.

66. Zung A, Shachar S, Zadik Z, Kerem Z. Soy-derived isoflavones treatment in children with hypercholesterolemia: a pilot study. J Pediatr Endocrinol Metab. 2010 Jan-Feb;23(1-2):133-41.

67. Ishizuki Y, Hirooka Y, Murata Y, Togashi K. [The effects on the thyroid gland of soybeans administered experimentally in healthy subjects]. Nippon Naibunpi Gakkai Zasshi. 1991 May 20;67(5):622-9. Japanese. (Abstract)

68. Dillingham BL, McVeigh BL, Lampe JW, Duncan AM. Soy protein isolates of varied isoflavone content do not influence serum thyroid hormones in healthy young men. Thyroid. 2007 Feb;17(2):131-7.

69. Mackey R, Ekangaki A, Eden JA. The effects of soy protein in women and men with elevated plasma lipids. Biofactors. 2000;12(1-4):251-7.

70. Jayagopal V, Albertazzi P, Kilpatrick ES, Howarth EM, Jennings PE, Hepburn DA, Atkin SL. Beneficial effects of soy phytoestrogen intake in postmenopausal women with type 2 diabetes. Diabetes Care. 2002 Oct;25(10):1709-14.

71. Roughead ZK, Hunt JR, Johnson LK, Badger TM, Lykken GI. Controlled substitution of soy protein for meat protein: effects on calcium retention, bone, and cardiovascular health indices in postmenopausal women. J Clin Endocrinol Metab. 2005 Jan;90(1):181-9.

72. Teede HJ, Dalais FS, McGrath BP. Dietary soy containing phytoestrogens does not have detectable estrogenic effects on hepatic protein synthesis in postmenopausal women. Am J Clin Nutr. 2004 Mar;79(3):396-401.

73. Persky VW, Turyk ME, Wang L, Freels S, Chatterton R Jr, Barnes S, Erdman J Jr, Sepkovic DW, Bradlow HL, Potter S. Effect of soy protein on endogenous hormones in postmenopausal women. Am J Clin Nutr. 2002 Jan;75(1):145-53.

74. Watanabe S, Terashima K, Sato Y, Arai S, Eboshida A. Effects of isoflavone supplement on healthy women. Biofactors. 2000;12(1-4):233-41.

75. Lydeking-Olsen E, Beck-Jensen JE, Setchell KD, Holm-Jensen T. Soymilk or progesterone for prevention of bone loss–a 2 year randomized, placebo-controlled trial. Eur J Nutr. 2004 Aug;43(4):246-57.

76. Doerge DR, Sheehan DM. Goitrogenic and estrogenic activity of soy isoflavones. Environ Health Perspect. 2002 Jun;110 Suppl 3:349-53.

77. Messina M, Redmond G. Effects of soy protein and soybean isoflavones on thyroid function in healthy adults and hypothyroid patients: a review of the relevant literature. Thyroid. 2006;16(3):249 –258.

78. Sathyapalan T, Manuchehri AM, Thatcher NJ, Rigby AS, Chapman T, Kilpatrick ES, Atkin SL. The Effect of Soy Phytoestrogen Supplementation on Thyroid Status and Cardiovascular Risk Markers in Patients with Subclinical Hypothyroidism: A Randomized, Double-Blind, Crossover Study. J Clin Endocrinol Metab. 2011 Feb 16. (Epub ahead of print)

79. Setchell KD, Zimmer-Nechemias L, Cai J, Heubi JE. Exposure of infants to phyto-oestrogens from soy-based infant formula. Lancet. 1997 Jul 5;350(9070):23-7.

80. Shepard TH, Pyne GE, Kirschvink JF, McLean CM. Soybean goiter. N Engl J Med 1960;262:1099–1103.

81. Fort P, Moses N, Fasano M, Goldberg T, Lifshitz F. Breast and soy-formula feedings in early infancy and the prevalence of autoimmune thyroid disease in children. J Am Coll Nutr. 1990 Apr;9(2):164-7.

82. Merritt RJ, Jenks BH. Safety of soy-based infant formulas containing isoflavones: the clinical evidence. J Nutr. 2004 May;134(5):1220S-1224S.

83. Cao Y, Calafat AM, Doerge DR, Umbach DM, Bernbaum JC, Twaddle NC, Ye X, Rogan WJ. Isoflavones in urine, saliva, and blood of infants: data from a pilot study on the estrogenic activity of soy formula. J Expo Sci Environ Epidemiol. 2009 Feb;19(2):223-34.

84. Bhatia J, Greer F; American Academy of Pediatrics Committee on Nutrition. Use of soy protein-based formulas in infant feeding. Pediatrics. 2008 May;121(5):1062-8.

92. D’Aloisio AA, Baird DD, DeRoo LA, Sandler DP. Association of intrauterine and early-life exposures with diagnosis of uterine leiomyomata by 35 years of age in the sister study. Environ Health Perspect. 2010 Mar;118(3):375-81. Erratum in: Environ Health Perspect. 2010 Mar;118(3):380.

93. Zung A, Glaser T, Kerem Z, Zadik Z. Breast development in the first 2 years of life: an association with soy-based infant formulas. J Pediatr Gastroenterol Nutr. 2008 Feb;46(2):191-5.

94. Bernbaum JC, Umbach DM, Ragan NB, Ballard JL, Archer JI, Schmidt-Davis H, Rogan WJ. Pilot studies of estrogen-related physical findings in infants. Environ Health Perspect. 2008 Mar;116(3):416-20.

95. Strom BL, Schinnar R, Ziegler EE, Barnhart KT, Sammel MD, Macones GA, Stallings VA, Drulis JM, Nelson SE, Hanson SA. Exposure to soy-based formula in infancy and endocrinological and reproductive outcomes in young adulthood. JAMA. 2001 Aug 15;286(7):807-14.

96. Strom BL, Schinnar R, Barnhart KT, Sammel MD, Macones GA, Stallings VA. Exposure to soy-based formula in infancy—reply. JAMA. 2001 Nov 21;286(19):2402-3.

97. Hidvegi M, Lasztity R. Phytic acid content of cereals and legumes and interaction with proteins. Periodica Polytechnica Ser. Chem. Eng. 2002;46(1–2):59–64.

98. Lopez HW, Leenhardt F, Coudray C, Remesy C. Minerals and phytic acid interactions: is it a real problem for human nutrition?. International Journal of Food Science & Technology, 2002;37:727–739.

99. Heaney RP, Weaver CM, Fitzsimmons ML. Soybean phytate content: effect on calcium absorption. Am J Clin Nutr. 1991 Mar;53(3):745-7.

100. Zhao Y, Martin BR, Weaver CM. Calcium bioavailability of calcium carbonate fortified soymilk is equivalent to cow’s milk in young women. J Nutr. 2005 Oct;135(10):2379-82.

101. Tang AL, Walker KZ, Wilcox G, Strauss BJ, Ashton JF, Stojanovska L. Calcium absorption in Australian osteopenic post-menopausal women: an acute comparative study of fortified soymilk to cows’ milk. Asia Pac J Clin Nutr. 2010;19(2):243-9. (Abstract)

104. Ho SC, Woo J, Lam S, Chen Y, Sham A, Lau J. Soy protein consumption and bone mass in early postmenopausal Chinese women. Osteoporos Int. 2003 Oct;14(10):835-42.

108. Egli I, Davidsson L, Zeder C, Walczyk T, Hurrell R. Dephytinization of a complementary food based on wheat and soy increases zinc, but not copper, apparent absorption in adults. J Nutr. 2004 May;134(5):1077-80.

109. Zhao XF, Hao LY, Yin SA, Kastenmayor P, Barclay D. [A study on absorption and utilization of calcium, iron and zinc in mineral-fortified and dephytinized soy milk powder consumed by boys aged 12 to 14 years]. Zhonghua Yu Fang Yi Xue Za Zhi. 2003 Jan;37(1):5-8. Chinese. (Abstract)

110. Sandström B, Kivistö B, Cederblad A. Absorption of zinc from soy protein meals in humans. J Nutr. 1987 Feb;117(2):321-7.

111. Hotz C, Gibson RS. Traditional food-processing and preparation practices to enhance the bioavailability of micronutrients in plant-based diets. J Nutr. 2007 Apr;137(4):1097-100.

113. Macfarlane BJ, van der Riet WB, Bothwell TH, Baynes RD, Siegenberg D, Schmidt U, Tal A, Taylor JR, Mayet F. Effect of traditional oriental soy products on iron absorption. Am J Clin Nutr. 1990 May;51(5):873-80.

114. Gillooly M, Torrance JD, Bothwell TH, MacPhail AP, Derman D, Mills W, Mayet F. The relative effect of ascorbic acid on iron absorption from soy-based and milk-based infant formulas. Am J Clin Nutr. 1984 Sep;40(3):522-7.

115. Derman DP, Ballot D, Bothwell TH, MacFarlane BJ, Baynes RD, MacPhail AP, Gillooly M, Bothwell JE, Bezwoda WR, Mayet F. Factors influencing the absorption of iron from soya-bean protein products. Br J Nutr. 1987 May;57(3):345-53. (Abstract)

116. Messina M, Nagata C, Wu AH. Estimated Asian adult soy protein and isoflavone intakes. Nutr Cancer. 2006;55(1):1-12.

117. Jefferson WN. Adult ovarian function can be affected by high levels of soy. J Nutr. 2010 Dec;140(12):2322S-2325S.

118. Directive 2009/32/EC of the European Parliament and of the Council of 23 April 2009 on the approximation of the laws of the member states on extraction solvents used in the production of foodstuffs and food ingredients. Official Journal of the European Union.

119. Palacios S, Pornel B, Vázquez F, Aubert L, Chantre P, Marès P. Long-term endometrial and breast safety of a specific, standardized soy extract. Climacteric. 2010 Aug;13(4):368-75.

121. Caan BJ, Natarajan L, Parker BA, Gold EB, Thomson CA, Newman VA, Rock CL, Pu M, Al-Delaimy WK, Pierce JP. Soy Food Consumption and Breast Cancer Prognosis. Cancer Epidemiol Biomarkers Prev. 2011 Feb 25.

122. Messina M. Soybean isoflavone exposure does not have feminizing effects on men: a critical examination of the clinical evidence. Fertil Steril. 2010 May 1;93(7):2095-104. Epub 2010 Apr 8.

123. Martinez J, Lewi JE. An unusual case of gynecomastia associated with soy product consumption. Endocr Pract 2008;14:415–8. (Abstract)

124. Fischer L, Mahoney C, Jeffcoat AR, Koch MA, Thomas BE, Valentine JL, et al. Clinical characteristics and pharmacokinetics of purified soy isoflavones: multiple-dose administration to men with prostate neoplasia. Nutr Cancer 2004;48(2):160–70.

125. Cassidy A, Hooper L. Phytoestrogens and cardiovascular disease. J Br Menopause Soc. 2006 Jun;12(2):49-56.

126. Messina M, Watanabe S, Setchell KD. Report on the 8th International Symposium on the Role of Soy in Health Promotion and Chronic Disease Prevention and Treatment. J Nutr. 2009 Apr;139(4):796S-802S.

127. Murray-Kolb LE, Welch R, Theil EC, Beard JL. Women with low iron stores absorb iron from soybeans. Am J Clin Nutr. 2003 Jan;77(1):180-4.

129. Maskarinec G, Morimoto Y, Conroy SM, Pagano IS, Franke AA. The Volume of Nipple Aspirate Fluid Is Not Affected by 6 Months of Treatment with Soy Foods in Premenopausal Women. J Nutr. 2011 Feb 16. (Epub ahead of print)

130. Setchell KD, Cole SJ. Method of defining equol-producer status and its frequency among vegetarians. J Nutr. 2006 Aug;136(8):2188-93.

131. Anupongsanugool E, Teekachunhatean S, Rojanasthien N, Pongsatha S, Sangdee C. Pharmacokinetics of isoflavones, daidzein and genistein, after ingestion of soy beverage compared with soy extract capsules in postmenopausal Thai women. BMC Clin Pharmacol. 2005 Mar 3;5(1):2.

132. Setchell KD, Faughnan MS, Avades T, Zimmer-Nechemias L, Brown NM, Wolfe BE, Brashear WT, Desai P, Oldfield MF, Botting NP, Cassidy A. Comparing the pharmacokinetics of daidzein and genistein with the use of 13C-labeled tracers in premenopausal women. Am J Clin Nutr. 2003 Feb;77(2):411-9.

133. Pierik FH, Burdorf A, Deddens JA, Juttmann RE, Weber RF. Maternal and paternal risk factors for cryptorchidism and hypospadias: a case-control study in newborn boys. Environ Health Perspect. 2004 Nov;112(15):1570-6.

134. North K, Golding J. A maternal vegetarian diet in pregnancy is associated with hypospadias. The ALSPAC Study Team. Avon Longitudinal Study of Pregnancy and Childhood. BJU Int. 2000 Jan;85(1):107-13.

135. Hypospadias – Diagnosis & treatment. Mayo Clinic. Accessed February 8. 2018.

136. Jacobsen BK, Jaceldo-Siegl K, Knutsen SF, Fan J, Oda K, Fraser GE. Soy isoflavone intake and the likelihood of ever becoming a mother: the Adventist Health Study-2. Int J Womens Health. 2014 Apr 5;6:377-84. doi: 10.2147/IJWH.S57137. eCollection 2014.

137. Nachvak SM, Moradi S, Anjom-Shoae J, Rahmani J, Nasiri M, Maleki V, Sadeghi O. Soy, Soy Isoflavones, and Protein Intake in Relation to Mortality from All Causes, Cancers, and Cardiovascular Diseases: A Systematic Review and Dose-Response Meta-Analysis of Prospective Cohort Studies. J Acad Nutr Diet. 2019 Sep;119(9):1483-1500.e17.

138. Andres A, Moore MB, Linam LE, Casey PH, Cleves MA, Badger TM. Compared with feeding infants breast milk or cow-milk formula, soy formula feeding does not affect subsequent reproductive organ size at 5 years of age. J Nutr. 2015 May;145(5):871-5.

139. Upson K, Adgent MA, Wegienka G, Baird DD. Soy-based infant formula feeding and menstrual pain in a cohort of women aged 23-35 years. Hum Reprod. 2019 Jan 1;34(1):148-154.(Abstract)

140. Messina M. Soy Formula and Menstrual Pain: A Look at the Evidence. Soy Nutrition Institute. Published January 3, 2020.

141. Fang X, Wang L, Wu C et al. Sex Hormones, Gonadotropins, and Sex Hormone-binding Globulin in Infants Fed Breast Milk, Cow Milk Formula, or Soy Formula. Sci Rep. 2017;7:4332.

142. Adgent MA, Umbach DM, Zemel BS, et al. A Longitudinal Study of Estrogen-Responsive Tissues and Hormone Concentrations in Infants Fed Soy Formula. J Clin Endocrinol Metab. 2018;103(5):1899–1909.

143. Sinai T, Ben-Avraham S, Guelmann-Mizrahi I, et al. Consumption of soy-based infant formula is not associated with early onset of puberty. Eur J Nutr. 2019;58(2):681–687.

144. Boucher BA, Cotterchio M, Kreiger N, Thompson LU. Soy Formula and Breast Cancer Risk, Epidemiology. 2008;19(1):165-166.

145. National Institute of Environmental Health Sciences. Expert Panel Evaluation of Soy Infant Formula Meeting Summary & Expert Panel Conclusions. Published 2009. Reviewed November 18, 2019.

146. Mamta B. NTP Tackles Soy Infant Formula Safety. NIEHS Environmental Factor. Published 2010.

147. Where We Stand: Soy Formulas. American Academy of Pediatrics healthychildren.org. Updated 8/7/2018.

Reviewed

Agency wants control on formaldehyde. The Jakarta Post. Wed, 01/05/2011 9:53 AM. Accessed January 6, 2011.

Alekel DL, Germain AS, Peterson CT, Hanson KB, Stewart JW, Toda T. Isoflavone-rich soy protein isolate attenuates bone loss in the lumbar spine of perimenopausal women. Am J Clin Nutr. 2000 Sep;72(3):844-52.

Anderson JJ, Chen X, Boass A, Symons M, Kohlmeier M, Renner JB, Garner SC. Soy isoflavones: no effects on bone mineral content and bone mineral density in healthy, menstruating young adult women after one year. J Am Coll Nutr. 2002 Oct;21(5):388-93.

Arjmandi BH, Lucas EA, Khalil DA, Devareddy L, Smith BJ, McDonald J, Arquitt AB, Payton ME, Mason C. One year soy protein supplementation has positive effects on bone formation markers but not bone density in postmenopausal women. Nutr J. 2005 Feb 23;4:8.

Badger TM, Gilchrist JM, Pivik RT, Andres A, Shankar K, Chen JR, Ronis MJ. The health implications of soy infant formula. Am J Clin Nutr. 2009 May;89(5):1668S-1672S.

Bitto A, Polito F, Atteritano M, Altavilla D, Mazzaferro S, Marini H, Adamo EB, D’Anna R, Granese R, Corrado F, Russo S, Minutoli L, Squadrito F. Genistein aglycone does not affect thyroid function: results from a three-year, randomized, double-blind, placebo-controlled trial. J Clin Endocrinol Metab. 2010 Jun;95(6):3067-72.

Chen YM, Ho SC, Lam SS, Ho SS, Woo JL. Soy isoflavones have a favorable effect on bone loss in Chinese postmenopausal women with lower bone mass: a double-blind, randomized, controlled trial. J Clin Endocrinol Metab. 2003 Oct;88(10):4740-7.

Chorazy PA, Himelhoch S, Hopwood NJ, Greger NG, Postellon DC. Persistent hypothyroidism in an infant receiving a soy formula: case report and review of the literature. Pediatrics. 1995 Jul;96(1 Pt 1):148-50.

Duncan AM, Underhill KE, Xu X, Lavalleur J, Phipps WR, Kurzer MS. Modest hormonal effects of soy isoflavones in postmenopausal women. J Clin Endocrinol Metab. 1999 Oct;84(10):3479-84.

Evans EM, Racette SB, Van Pelt RE, Peterson LR, Villareal DT. Effects of soy protein isolate and moderate exercise on bone turnover and bone mineral density in postmenopausal women. Menopause. 2007 May-Jun;14(3 Pt 1):481-8.

File SE, Hartley DE, Elsabagh S, Duffy R, Wiseman H. Cognitive improvement after 6 weeks of soy supplements in postmenopausal women is limited to frontal lobe function. Menopause. 2005 Mar;12(2):193-201.

Gilchrist JM, Moore MB, Andres A, Estroff JA, Badger TM. Ultrasonographic patterns of reproductive organs in infants fed soy formula: comparisons to infants fed breast milk and milk formula. J Pediatr. 2010 Feb;156(2):215-20.

Hallberg L, Rossander L. Effect of soy protein on nonheme iron absorption in man. Am J Clin Nutr. 1982 Sep;36(3):514-20.

Jing H, Gilchrist JM, Badger TM, Pivik RT. A longitudinal study of differences in electroencephalographic activity among breastfed, milk formula-fed, and soy formula-fed infants during the first year of life. Early Hum Dev. 2010 Feb;86(2):119-25.

Jing H, Pivik RT, Gilchrist JM, Badger TM. No difference indicated in electroencephalographic power spectral analysis in 3- and 6-month-old infants fed soy- or milk-based formula. Matern Child Nutr. 2008 Apr;4(2):136-45.

Koh WP, Wu AH, Wang R, Ang LW, Heng D, Yuan JM, Yu MC. Gender-specific associations between soy and risk of hip fracture in the Singapore Chinese Health Study. Am J Epidemiol. 2009 Oct 1;170(7):901-9. Epub 2009 Aug 31.

Li J, Dykman RA, Jing H, Gilchrist JM, Badger TM, Pivik RT. Cortical responses to speech sounds in 3- and 6-month-old infants fed breast milk, milk formula, or soy formula. Dev Neuropsychol. 2010 Nov;35(6):762-84.

Lönnerdal B, Bryant A, Liu X, Theil EC. Iron absorption from soybean ferritin in nonanemic women. Am J Clin Nutr. 2006 Jan;83(1):103-7.

Messina M, Wu AH. Perspectives on the soy-breast cancer relation. Am J Clin Nutr. 2009 May;89(5):1673S-1679S. Epub 2009 Apr 1.

Myung SK, Ju W, Choi HJ, Kim SC; Korean Meta-Analysis (KORMA) Study Group. Soy intake and risk of endocrine-related gynaecological cancer: a meta-analysis. BJOG. 2009 Dec;116(13):1697-705.

National Toxicology Program Center for the Evaluation of Risks to Human Reproduction. Expert Panel Evaluation of Soy Infant Formula. December 16-18, 2009. Accessed February 23, 2011.

Pivik RT, Dykman RA, Jing H, Gilchrist JM, Badger TM. Early infant diet and the omega 3 fatty acid DHA: effects on resting cardiovascular activity and behavioral development during the first half-year of life. Dev Neuropsychol. 2009;34(2):139-58.

Trock BJ, Hilakivi-Clarke L, Clarke R. Meta-analysis of soy intake and breast cancer risk. J Natl Cancer Inst. 2006 Apr 5;98(7):430-1.

Unfer V, Casini ML, Costabile M, et al. Endometrial effects of long-term treatment with phytoestrogens: a randomized, double-blind, placebo-controlled study. Fertil Steril 2004;82:145–8.