Goitrogens

4.1. Definition 

Plant-derived goitrogens are another set of compounds which have received attention among nutrition researchers and health professionals. The term ‘goitrogen’ broadly refers to agents that interfere with thyroid function, thus increase the risk of goiter and other thyroid diseases [78]. Sources of these compounds include medications, environmental toxins, as well as certain foods [79,80]. Glucosinolates, a diverse class of over 120 compounds, are dietary goitrogens found primarily in the Brassica family, as well as other plant foods [81]. Upon mastication and ingestion, the enzyme myrosinase (activated in damaged plant tissue and produced by human microflora) converts glucosinolates to a variety of other compounds, including thiocyanates, nitriles, isothiocyanates and sulforaphane [80,81]. Much research surrounding glucosinolates and associated analogues have focused on their potential to prevent cancer, induce phase II detoxification enzymes, induce apoptosis, regulate redox reactions, and inhibit Phase I detoxification enzymes [81–87]. Despite the potential beneficial effects of glucosinolates, some evidence suggests that goitrin, produced from the glucosinolate precursor, progoitrin, as well as thiocyanate (an indole glucosinolate degradation product), may have adverse effects on the thyroid (Table 1). Early animal and cell models demonstrated goitrin and thiocyanate ions to inhibit the thyroid’s utilization and uptake of iodine [80,88,89]. 

4.2. Background 

Vegetables in the Brassica genus are the most well-known goitrogen containing foods, although there is an enormous variation of these compounds between species, and even varietals [80]. Kale (Brassica oleracea acephala and B. napus) and Brussels sprout (B. oleracea gemmifera) varietals have been shown to contain the largest amounts of indole glucosinolates and progoitrin, 840 µmol/100 g FW total, and 400.33 µmol/100 g FW total, respectively [80]. However, other studies have found kale to contain very little concentrations of indole glucosinolates and progoitrin [80]. Red Russian kale (B. napus) and Siberian kale (B. napus ssp pabularia) were reported to contain 365.9 µmol/100 g, and 148.1 µmol/100 g FW of progoitrin, respectively. Kale (B. oleracea acephala) also contained higher concentrations of glucoraphanin (sulforaphane precursor) than Russian or Siberian species (B. napus ssp) [80]. Glucoraphanin is metabolized to sulforaphane and is found to be a potent inducer of Phase II enzymes [82–86,90]. Broccoli, often accused of being high in goitrogens, was actually reported to contain low levels of progoitrin and indole glucosinolates, while being rich in beneficial glucoraphanin [80]. Broccoli sprouts may be an even richer source of glucoraphanin than mature plants, while still containing only negligible amounts of progoitrin [91]. In addition to glucosinolates, resveratrol, isoflavones, and flavonoids may also have goitrogenic effects, though much of the research is based on in vitro or in vivo animal models [92–94]. Isoflavones (genistein and daidzein) are found almost exclusively in soy, while resveratrol and other flavonoids are widespread throughout the plant kingdom [95,96]. Millet also contains goitrogenic compounds called C-glycosylflavones, which have been shown in in-vitro models to inhibit thyroid peroxidase (TPO) [97,98]. 

4.3. Effects of Cooking/Processing 

Factors such as soil conditions, weather, growing location, use of plant growth regulators or pesticides, pathogen challenges, plant stressors, as well as date of harvest and storage time all can impact glucosinolate content [81,99]. The processing of foods, such as cooking, and fermenting, may lower total glucosinolate concentration (Table 2). However, cooking will also remove beneficial glucosinolates. One study found that steaming broccoli for just 5 min reduced glucoraphanin and total glucosinolate content by 57%, and 51%, respectively [100]. Therefore, it is important to evaluate the current evidence of dietary goitrogens on thyroid and human health, before eliminating or modifying phytonutrient rich plant foods from the diet. 

4.4. Safety 

The evidence published thus far investigating the impacts of dietary goitrogens is mixed and may be more complex than initially thought. “Cabbage goiter” was first observed in rabbits fed a diet consisting almost entirely of cabbage [101]. Later, researchers also observed ‘antinutritional’ effects in rats that were fed high-glucosinolate rapeseed meal and purified rapeseed progoitrin for 30 days [102]. An early human study assessed radioactive iodine uptake following goitrin administration and found that 25 mg (194 µmol) of recrystallized goitrin decreased iodine uptake, though 10 mg (70 µmol) resulted in no inhibition [80]. These results, however, cannot be extrapolated for human health, as they are not representative of a balanced human diet. Due to the potential inhibitory effects of goitrogens on iodine uptake, populations with underlying iodine deficiency that consume large amounts of goitrogenic foods, may be more at risk than healthy individuals. In rats consuming an iodine-deficient diet containing pure thiocyanate, they experienced significant reductions in thyroxine (T4) levels, as well as reductions in certain proteins and nucleic acids. Adding iodine back to their diet restored levels of thyroxine, reversing the effects of thiocyanate [103]. In contrast, progoitrin-rich rutabaga sprouts had no impact on thyroid function in healthy rats. Adverse effects of iodine deficiency were only pronounced in rats with preexisting hypothyroidism [104]. 

4.5. Human Studies 

Human studies investigating the effects of dietary goitrogens in healthy individuals are relatively sparse. Some epidemiological evidence supports an association between goitrogen-containing foods and thyroid dysfunction, though mostly only in the presence of low iodine intake. A study on children found only modest associations between genistein levels and increased thyroglobulin autoantibodies and decreased thyroid volume [105]. In Ethiopian children with iodine deficiency, there was a positive association with consumption of goitrogenic foods (such as taro root, cabbage, Abyssinian cabbage and banana), low levels of iodine in the diet, and lower urinary iodine levels [106]. In a study on pregnant Thai women, higher levels of thyroid stimulating hormone (TSH) were associated with thiocyanate exposure, but only in those with low urinary iodine levels [107]. No associations were found between thiocyanate exposure and thyroid function in mildly iodine-deficient pregnant women [108]. Moreover, consumption of cruciferous vegetables, in combination with low iodine intake, was associated with increased risk of thyroid cancer in women from New Caledonia [109]. A 1.5-fold higher risk of thyroid cancer was observed in a Polish sample who frequently consumed cruciferous vegetables [110]. Other epidemiological studies in the United States have demonstrated an inverse relationship between cruciferous vegetable intake and risk of thyroid cancer [110]. While a small handful of epidemiological studies demonstrate potential concern regarding dietary goitrogens in combination with low iodine, other human studies show no correlations. In a three-year trial of genistein, considered an isoflavone goitrogen, no impacts on thyroid function or health were observed [111]. A review on soy isoflavones arrived at similar conclusions, but still advised soy-consuming individuals taking thyroid medication to increase their dosage of thyroid medication, due to the possibility of decreased drug absorption [94]. Vegans are found to contain slightly higher levels of urinary thiocyanates and lower iodine levels than vegetarians, however no association could be made with thyroid function, based on TSH and T4 levels [112]. Foods exist as complex matrix of compounds, which often have synergistic effects, that have yet to be discovered. In this regard, foods considered to be ‘goitrogenic’ also contain thousands of other bioactive compounds that may be protective against thyroid cancer. According to a case-control study in French Polynesia, a traditional Polynesian diet, rich in cassava and cabbage, was significantly associated with a decreased risk of thyroid cancer when compared to a Western style diet [113]. Zhang et al. found similar negative associations between urinary thiocyanate and thyroid cancer [114]. At the same time, several case-control studies and meta-analysis found no relationship between cruciferous vegetable consumption and thyroid cancer risk [115–117]. 

4.6. Conclusions 

Overall, most human studies investigating the effects of goitrogenic foods on thyroid health display neutral effects, although some conflicting results are still present. Evidence seems to suggest that suboptimal iodine status may potentiate any negative impacts of dietary goitrogens on thyroid health. Furthermore, progoitrin content amongst the Brassica genus varies significantly. Items such as broccoli, Chinese cabbages, bok choi, broccoli sprouts, and some kale varietals generally contain progoitrin and thiocyanate-generating glucosinolates at concentrations far below those likely to cause a physiological effect. In fact, consuming these foods as part of a varied, colorful, plant-based diet should not pose significant risks in healthy individuals, and, conversely, may be of great benefit. In addition to beneficial glucosinolates, cruciferous vegetables provide a plethora of other health-promoting phytochemicals, fiber, and essential vitamins and minerals. For those with thyroid disease, or at higher risk of thyroid disease, long-term daily intake of progoitrin-rich items, like Russian kale, broccoli rabe or collard greens may decrease iodine uptake, and should be cooked with iodized salt to avoid reduced iodine uptake.