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5. Discussion

The goal of this pilot study was to evaluate the effect of I supplementation in caucasian american women, a population with a high incidence of FDB and breast cancer (23,24,25), using daily I intake comparable to average daily I consumption in Japanese women living in Japan, a country with a very low incidence of FDB and breast cancer (25,26). The parameters evaluated were: thyroid volume by ultrasonometry; thyroid function tests; and evidence of toxicity based on urine analysis, hematology and blood chemistry.

The mean thyroid volume (± SD) in our 10 subjects (7.7 ± 3.6 ml) is comparable to the mean thyroid volumes measured using the same method, in normal euthyroid women from Sweden (7.7 ml), Holland (8.7 ml) and Hong Kong (8.9 ml); but 60% of the mean thyroid volume from Ireland (12.9 ml): and 47% of the mean thyroid volume from Germany (16.5 ml) (15,16,27). The high mean thyroid volumes observed in Irish and German women could be due to their low I intake and high prevalence of goiter (15,16). Two subjects (#1 and #10) had an elevated TSH level prior to intervention and in both cases, I supplementation suppressed markedly TSH levels; in subject #1, from 7.8 to 1.4 mIU/L; and in subject #10, from 21.5 to 11.9 mIU/L (Table VII). Subclinical hypothyroidism is defined as clinical euthyroidism with normal levels of thyroid hormones, but with elevated TSH levels above 6 mIU/L (20-22). By this classification, subject #1 would be classified as subclinical hypothyroid before I supplementation, and reclassified as normal 3 months after starting the ingestion of I in daily amount of 12.5 mg, 80 times RDA levels. It is likely that subject #10, if continued on this program, would have reached TSH levels within the normal range. It is estimated that close to 8 million american women suffer from subclinical hypothyroidism (21), which is a risk factor for coronary heart disease and possibly peripheral arterial diseases (21). If the above findings can be confirmed in a larger group of subjects with subclinical hypothyroidism, the solution to this problem could be very simple: increase daily I intake using I supplement in these individuals to levels consumed from seaweed by Japanese women living in Japan. At the least, a therapeutic trial of I supplementation could identify a subgroup of subclinical hypothyroid subjects who would be responsive to such an approach.

We have reviewed published studies in Russia and Canada showing a beneficial effect of I intake at several mg a day on FDB both subjectively in terms of mastodynia and objectively on breast cysts nodularity and induration (9,10). In the present study, there was a significant improvement in the mean score of mastodynia in 7 subjects experiencing this symptom following 3 months of I supplementation. Of interest is the observation that 3 months after termination of I intake, the beneficial effect on mastodynia was still present in those subjects. Based on an extensive review of breast cancer epidemiological studies, R.A. Wiseman (28) came to the following conclusions: 92-96% of breast cancer cases are sporadic; There is a single cause for the majority of cases; The causative agent is deficiency of a micronutrient that is depleted by a high fat diet; If such an agent is detected, intervention studies with supplementation should lead to a decline in the incidence of breast cancer. Several authors have proposed that this protective micronutrient is the essential element I (5,6,10,29,30). Some of the mechanisms by which I could prevent breast cancer are: the antioxidant properties of iodides (31); the ability of I to markedly enhance the excited singlet to triplet radiationless transition (32). Reactive oxygen species causing oxidative damage to DNA are usually excited singlet with a high energy content released rapidly and characterized by fluorescence whereas the corresponding triplet state releases its lower energy at a slower rate expressed as phosphorescence. Such an effect of I would depend on its concentration in the intra- and extracellular fluids. Other possible mechanisms involved were reviewed by Derry (29): the apoptotic properties of I and its ability to trigger differentiation, moving the cell cycle away from the undifferenticated characteristic of breast cancer, for that matter, of all cancers. The above properties of I are totally independent of thyroid hormones. A recent study in female rats (33) has demonstrated an effect of I deficiency independent of thyroid hormones, on the response of the hypothalamo-pituitary-adrenal axis to stress. There was an attenuation of this axis to stress, following I deficiency, and this attenuation persisted after functional recovery of the thyroid axis.

The significant increase in urine pH following I-supplementation, with mean (± SD) values of 6.05 ± 0.69 and 7.00 ± 0.85 for pre- and post- intervention respectively, is suggestive of increased reducing equivalents in biological fluids. This effect could be due to the 7.5 mg of iodide ingested daily (31). However, an effect of I on the enhancement of singlet ® triplet transition (32) would decrease the oxydative burden of the body and such an effect would result also in an increase of urine pH. To our knowledge, this effect of I supplementation on urine pH has not been previously reported.

Although several extrathyroidal organs and tissues have the capability to concentrate and organify

I (34-36), the most compelling evidence for an extra thyroidal function of I is its effects on the mammary gland. Eskin et al have published the results of their extensive and excellent studies on the rat model of FDB and breast cancer and the importance of iodine as an essential element for breast normality and for protection against FDB and breast cancer (30,37,38). The amount of I required for breast normality in the female rats was equivalent based on body weight, to the amounts required clinically to improve signs and symptoms of FDB (9,10). Eskin’s findings on the protective effect of iodine against breast cancer in the rat model were recently confirmed by Japanese workers (39).

Of interest is the findings of Eskin et al (40) that the thyroid gland preferentially concentrate iodide whereas the mammary gland favors iodine. In the I-deficient female rats, histological abnormalities of the mammary gland were corrected more completely and in a larger number of rats treated with iodine than iodide given orally at equivalent doses. Recent textbooks of endocrinology continue the tradition of the past, reaffirming that iodine is reduced to iodide prior to absorption in the intestinal tract, referring to a study by Cohn (41), published in 1932, using segments of the gastrointestinal tract of dogs, washed clean of all food particles prior to the application of I in the lumen. However, Thrall and Bull (42) observed that in both fasted and fed rats, the thyroid gland and the skin contained significantly more I when rats were fed with iodide than with iodine; whereas the stomach walls and stomach contents had a significantly greater level of I in iodine-fed rats than iodide-fed animals. Peripheral levels of inorganic I were different with different patterns, when rats were fed with these 2 forms of I. The authors concluded: "These data lead us to question the view that iodide and iodine are essentially interchangeable". Based on the above findings, I supplementation should contain both iodine and iodide.

Regarding the potential adverse effects of I supplementation at the levels used in the present study, they are threefold: iodism, I-induced hyperthyroidism (IIH) and I-induced goiter (IIG). Iodism is dose-related and the symptoms are: unpleasant brassy taste, increased salivation, coryza, sneezing, and headache originating in frontal sinuses. Skin lesions are mildly acneiform and distributed in the seborrheic areas (11,43). Those symptoms disappear spontaneously within a few days after stopping the administration of I. As of this writing, no iodism and for that matter, no side effect has been reported in more than 150 subjects who underwent I supplementation at 12.5 mg/day. It has been suggested 100 years ago that iodism may be due to small amounts of bromine contaminant in the iodine preparations and trace amount of iodate and iodic acid in the iodide solutions (43). With greater purity of USP grade materials now available, iodism may no longer be a problem at the level of I used in the present study.

The next potential complication is IIH, which occurs predominately in population with I-deficiency during the early period of I replacement (45). In the 8th Edition of Werner and Ingbar’s The Thyroid, published in 2000, Delange (46) stated: "The possible reason for the development of IIH after iodine supplementation has now been identified: iodine deficiency increases thyrocyte proliferation and mutation rates. Possible consequences are the development of hyperfunctioning autonomous nodules in the thyroid, … and hyperthyroidism after iodine supplementation. Therefore, IIH is an IDD (Iodine Deficiency Disorder)." The prevalence of goiter in the United States is about 3.1% (46). In non-endemic goiter areas, IIH occurs predominantly in elderly subjects with nodular goiter, which could be detected by ultrasonography.

The last of the 3 adverse effects of I supplementation is I-induced goiter (IIG) and hypothyroidism. Most patients with IIG have received large amounts of I (up to 2 gm per day) for prolonged period of time, usually as an expectorant for asthma, chronic bronchitis and emphysema (11,47). In the 10th Edition of Goodman and Gilman’s The Pharmacological Basis of Therapeutics, published in 2001, Farwell and Braverman wrote: "In euthyroid individuals, the administration of doses of I from 1.5 to 150 mg daily results in small decreases in plasma thyroxine and triodothyronine concentrations and small compensatory increases in serum TSH values, with all values remaining in the normal range" (48). However, in patients with underlying thyroid disorders, IIG with hypothyroidism could be induced, mainly by I-containing drugs. Predisposing factors to I-induced hypothyroidism are: treated Graves’ disease, Hashimoto’s thyroiditis, post-partum lymphocytic thyroiditis, subacute painful thyroiditis, and lobectomy for benign nodules (47). Needless to stress the importance of medical supervision during the implementation of I supplementation for FDB and other conditions. A careful history should reveal previous and current thyroid disorders. Ultrasonography, although not required, is highly recommended prior to I-supplementation to detect abnormal echopatterns. Serum thyroid autoantibodies would supplement finding from history and physical examination. Reevaluation is recommended every 3 months to assess response to I-supplementation and to monitor possible side effects.

The significant decrease in serum T4 observed in the present study, concomitant with the absence of significant changes in the mean values for TSH, FT3 and FT4, following I supplementation at 12.5 mg/day (Table VII), could be due to either a decreased secretion of T4 by the thyroid gland; or it could be due to lower levels of thyroxine binding globulin (TBG). The synthesis of TBG occurs in the liver and this synthesis is stimulated by estrogens (48). In the female rat, I-deficiency increases the sensitivity of mammary tissue to estrogens (37). I-supplementation to these female rats in amounts equivalent, based on body weight, to amounts of I required in women with FDB for subjective and objective improvement of FDB (10), had an attenuating effect on estrogen stimulation of the mammary tissue in those female rats, decreasing their response to estrogens (41). Therefore, the decreased T4 levels following I-supplementation could be due to a similar mechanism on hepatic synthesis of TBG, by decreasing the sensitivity of hepatic receptors to estrogens, resulting in decreased synthesis and release of TBG by the liver and decreased T4 levels. Since we did not include serum TBG levels in our thyroid profile, the explanation for this decrease of serum T4 levels must await future research.

The amount of I used in the present study would be considered physiological by Japanese standard. In the United States, there is a dichotomy regarding the physician’s attitude toward I: Iodophobia in the physiological range (49), requiring a leap of faith to move up from RDA ug amounts to the mg amounts ingested by Japanese with a very low incidence of FDB, and breast cancer (25,26); and iodophylia in the therapeutic range, prescribing excessively large amounts of I in gm amounts for long periods of time (11,48) as an expectorant in patients with asthma, chronic bronchitis and emphysema, at least up to 1995.

The ranges of I ingested by human subjects for physiological and therapeutic purposes in different countries are displayed in Figure 1. From the lowest amount observed in areas with severe endemic goiter to the highest amount prescribed, a millionfold range. Based on the most recently published literature, we have made an attempt in Figure 1 to display the physiological and therapeutic ranges on the right side of the graph. Within the physiological range, we have displayed first the levels of I necessary for normal thyroid functions, and control of endemic goiter under all physiological

conditions (1,2). Thyroid sufficiency for I is defined according to Saxena et al (50) as the minimal effective daily dose of I required for either maximal suppression of radioactive I uptake by the normal thyroid gland or for a decrease of radioactive I uptake to approximately 5% of the total dose of radioactive I administered. A daily amount of I from 1.5 to 2 mg/m2/day was required to achieve the 5% goal. These authors state: "Thus, for the adult, the minimal effective daily dose of iodide becomes 3 to 4 mg." We have chosen this level of I daily for I sufficiency of the thyroid gland. However, Sternthal et al (51) were able to reduce this mean percent uptake below 5% with higher daily dose of I given for 12 days: 4% at 10 mg; 1.9% at 15 mg; 1.6% at 30 mg; 1.2% at 50 mg; and 0.6% at 100 mg. For breast sufficiency, the average daily consumption of I by Japanese women living in Japan was chosen, a population with the lowest prevalence of FDB and breast cancer (25,26). This value is also within the range of I supplementation used in published studies of FDB (9,10), with the limitation that the number of subjects in these studies were relatively small compared to the Japanese female population. The therapeutic range was divided into two parts based on Farwell and Braverman (47), as quoted in this text: up to 150 mg of I, a range without adverse effects on the normal thyroid gland, and above that quantity, there is a risk for IIG and hypothyroidism, mainly in the presence of thyroid disorders.

The benefits of I supplementation within the range used in FDB outweight the risks, if implemented under medical supervision. We plan to expand this pilot study in order to build a database that could be used to develop a protocol for the implementation of I supplementation in FDB and other conditions such as subclinical hypothyroidism, by interested physicians. There is a need for assays of serum inorganic I levels, to complement urine I levels. Not one of the clinical laboratories contacted offered this service.


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Edited by: _JULEE_ at: 1/3/2009 (10:01)
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