Soy Isoflavone Critical Review

By Mark Messina, Ph.D.

There has been much discussion of late over the possible adverse effects of soy consumption on thyroid function in both infants and adults. In fact, researchers from the National Center for Toxicology (NCTR), which is part of the U.S. Food and Drug Administration, have even expressed some concerns. But concerns about the effects of soy on thyroid function are not new.

The first report that soybeans produced goiter in iodine-deficient rodents was published in 1933.1 Subsequent animal studies published in the 1930s and 1940s produced similar findings. However, iodine fortification of the diet was shown to largely eliminate this problem, although soy-fed animals required approximately twice as much iodine to prevent enlarged thyroids as animals fed soy-free diets, and in some cases, slight histological abnormalities of the thyroid gland still persisted.2,3 Heated soy products were shown in some studies to be less goitrogenic than raw soy products although data are mixed on this point.4 Possible explanations for the effect of heat treatment on goitrogenicity include the destruction of heat labile goitrogenic factors and an improvement in overall protein nutriture.

In the late 1950s, 10-15 cases of goiter were identified in infants fed non-iodized soy flour based infant formula. 5,6 However, this type of formula has not been used since the 1960s. Today, soy formula is based on soy protein isolate and is fortified with iodine. No cases of goiter in infants, due to the consumption of soy protein isolate-based iodized formula as is used today, have been reported in the scientific literature. In animals, soy protein isolate (approximately 90 percent soy protein) has been shown to be less goitrogenic than soy flour (approximately 50 percent protein) and, as noted previously, iodine fortification largely overcomes soy-related goitrogenicity.4 Unfortunately, no studies solely designed to study the effect of soy formula on thyroid function in infants have been conducted. Still, given the millions of infants fed soy formula over the past three to four decades, it is reasonable to assume that if a problem existed, more than likely it would have been reported upon by pediatricians in the medical literature.

There are, however, at least limited data suggesting that infants with congenital hypothyroidism who consume soy formula require about 25 percent more synthetic hormone than infants with congenital hypothyroidism on non-soy formulas.7,8 But this may not be a systemic effect, since fiber supplements also necessitate that patients increase their thyroid hormone medication.9 This suggests soy, like fiber, may interfere with either the absorption of thyroid hormone (in the case of medication), or may interfere with reabsorption by interrupting the enterohepatic circulation of thyroid hormone.

There have been many attempts to identify the factors in soy responsible for goitrogenicity in animals but these studies have produced conflicting results. Largely on the basis of in vitro data, NCTR researchers suggested that flavonoids, including isoflavones, are goitrogenic.10,11 And in fact, very recently, dietary genistein (the main soybean isoflavone) was found to inhibit thyroid peroxidase by up to 60 percent in rats.12 Thyroid peroxidase (TPO) is the primary enzyme responsible for the synthesis of thyroid hormone. However, despite inactivation of TPO, the thyroid gland of genistein-fed rats was normal, as were thyroid hormone levels. Furthermore, a recently conducted human trial showed no effects of isoflavone supplements on thyroid function.13 And several other human studies have also found little or no effect of soyfoods (see below).

One study conducted in Japan did find that soy consumption was associated with adverse effects (increase TSH levels) on thyroid function in older women, including an increased incidence of goiter.14 Women in this three-month study consumed 30 g/day of pickled soybeans stored in rice vinegar. However, this study suffers from many design flaws and, although these results should not be ignored, they directly conflict with the results from several, better designed studies.15 For example, recent work from the University of Minnesota indicates that the consumption of isoflavone-rich soy over a three-month period had little effect on thyroid hormone levels in either pre- or postmenopausal women.16 And as already noted, a recently conducted double blind study involving 38 postmenopausal women over the age of 64 who were not on hormone therapy, found no differences in thyroid function, based on measures of thyroid stimulating hormone (TSH), total thyronine (T4), and triiodothyronine (T3), between women given daily either a placebo or a supplement that provided 90 mg of isoflavones (expressed as aglycone units).13

Overall, there appears to be little reason to think that in healthy adults, either soy isoflavone supplements, or soyfoods, will exert adverse effects on thyroid function. Even the NCTR researchers acknowledge that soy is not likely to be a problem in iodine-replete individuals. In contrast, arguably, in people who are predisposed to goiter or who are consuming marginally iodine sufficient diets, soy could conceivably be a risk factor for goiter. So, it is important to note that as many as 10 percent of postmenopausal women may have subclinical hypothyroidism.17 This group may be sensitive to the adverse effects of weak goitrogens.

The iodine status of the U.S. population is considered adequate although there is a downward trend in iodine intake and subsets of the population may have marginal intakes.18

In conclusion, there is no reason to restrict soy consumption over concerns about the impact on thyroid function. When counseling patients consuming large amounts of soy, it is important to make sure iodine intake is adequate. But of course, all people, regardless of their dietary pattern, need to consume sufficient amounts of iodine. Any concerns about the effect of soy on thyroid levels can be definitively addressed by having thyroid hormone levels measured. Even this step is not unordinary, since the American Thyroid Association recommends that all people have their thyroid hormone levels checked every five years beginning at the age of 35.19

References

McCarrison R. The goitrogenic action of soya-bean and groundnut. Ind J Med Res 1933;XXI:179-181. Sharpless GR, Pearsons J, Prato GS. Production of goiter in rats with raw and with treated soybean flour. J Nutr 1939; 17:545-555. Kay T, Kimura M, Nishing K, Itokawa Y. Soyabean, goitre, and prevention. J Tropical Med 1988;34:110-113. Block RJ, Mandl RH, Howard HW, Bauer CD, Anderson DW. The curative action of iodine on soybean goiter and the changes in the distribution of iodoamino acids in the serum and in the thyroid gland digests. Arch Biochem Biophyics 1961; 93:15-21. Van Wyk JJ, Arnold MB, Wynn J, Pepper F. The effects of a soybean product on thyroid function in humans. Pediatrics 1959; 24:752-760. Shepard TH, Gordon EP, Kirschvink JF, McLean CM. Soybean goiter. New Engl J Med 1960;262:1099-1103. 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; 96:148-50. Jabbar MA, Larrea J, Shaw RA. Abnormal thyroid function tests in infants with congenital hypothyroidism: the influence of soy-based formula. J Am Coll Nutr 1997; 16:280-2. Liel Y, Harman-Boehm I, Shany S. Evidence for a clinically important adverse effect of fiber enriched diet on the bioavailability of levothyroxine in adult hypothyroid patients. J Clin Endocrinol Metab 1996; 81:857-9. Divi RL, Chang HC, Doerge DR. Anti-thyroid isoflavones from soybean: isolation, characterization, and mechanisms of action. Biochem Pharmacol 1997; 54:1087-96. Divi RL, Doerge DR. Inhibition of thyroid peroxidase by dietary flavonoids. Chem Res Toxicol 1996; 9:16-23. Chang HC, Doerge DR. Dietary genistein inactivates rat thyroid peroxidase in vivo without an apparent hypothyroid effect [In Process Citation]. Toxicol Appl Pharmacol 2000; 168:244-52. Bruce B, Spiller GA, Holloway L. Soy isoflavones do not have an antithyroid effect in postmenopausal women over 64 years of age. Faseb J 2000. Ishizuki Y, Hirooka Y, Murata Y, Togashi K. The effects on the thyroid gland of soybeans administered experimentally to healthy subjects (In Japanese). Nippon Nailbunpu Kashi (Folia Endocrinol) 1991;67:622-629. Ham JO, Chapman KM, Essex-Sorlie D, et al. Endocrinological response to soy protein and fiber in midly hypercholesterolemic men. Nutr Res 1993; 13:873-884. 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; 84:192-7. Hak AE, Pols HA, Visser TJ, Drexhage HA, Hofman A, Witteman JC. Subclinical hypothyroidism is an independent risk factor for atherosclerosis and myocardial infarction in elderly women: the Rotterdam Study. Ann Intern Med 2000; 132:270-8. Hollowell J, G., Staehling NW, Hannon WH, et al. Iodine nutrition in the United States. Trends and public health implications: iodine excretion data from National Health and Nutrition Examination Surveys I and III (1971-1974 and 1988-1994). J Clin Endocrinol Metab 1998;83:3401-3408. Ladenson PW, Singer PA, Ain KB, et al. American Thyroid Association guidelines for detection of thyroid dysfunction. Arch Intern Med 2000; 160:1573-5.