Effect of daily ingestion of a tablet containing 5 mg iodine and 7.5 mg iodide as the potassium salt, for a period of 3 months, on the results of thyroid function tests and thyroid volume by ultrasonometry in ten euthyroid Caucasian women.
Guy E. Abraham M.D., Jorge D. Flechas M.D., and John C. Hakala R. Ph.
Note: For the sake of clarity, the element iodine in all its forms will be identified in this manuscript with the letter I, whereas the name iodine will be reserved for the oxidized state [I.sub.2].
According to a recent editorial of the Journal of Clinical Endocrinology and
Metabolism, (1) one-third of the world's population lives in areas of I
deficiency, which is the world's leading cause of intellectual deficiency. (2)
I is an essential element, and its essentiality is
believed to be due to its requirement for the synthesis of the thyroid hormones
thyroxine (T4) and triiodothyronine
(T3). The recommended daily intake of I for adults of
both sexes in
Considering the importance of this element for overall well-being, it is most amazing that no study so far has attempted to answer the very important question: What is the optimal amount of daily I intake that will result in the greatest levels of mental and physical well-being in the majority of a population with a minimum of negative effects? In studies designed to answer this question, consideration should be given to the possibility that I, at levels higher than those required to achieve normal thyroid function tests and absence of simple goiter, may have some very important thyroidal and extrathyroidal (non-T3 ,T4-related) roles in overall well-being.
Some 80 years ago, D. Marine reported the results of his landmark study on
the effect of I supplementation in the prevention and
treatment of iodine-deficiency goiter. Based on extensive studies of goiter in
farm animals, he estimated the amount of I that would be required for human
subjects. He chose a population of adolescent school girls from the fifth to
twelfth grade between the ages of 10 and 18 years residing in
Due to the large consumption of seaweeds in the Japanese diet, this
population ingests several milligrams of I daily without ill effects -- in
fact, with some very good results, evidenced by the very low incidence of
fibrocystic disease of breast (5) and the low mortality rates for cancers of
the female reproductive organs. (6) According to the Japanese Ministry of
Health and Welfare, the average daily intake of seaweed is 4.6 gm. At an
average of 0.3% I content (range = 0.08-0.45%), that is an estimated daily I
intake of 13.8 mg. (7) Japanese living in the coastal areas consume more than
13.8 mg. (7) Studies performed on some of the subjects living in the coastal
areas revealed that the thyroid glands exposed to those levels of I organify more I than they secrete as T3 and T4, and the
levels of T3 and T4 are maintained within a narrow range. The excess I is
secreted as non-hormonal I of unknown chemical composition, mostly as inorganic
B.V. Stadel, from the National Institutes of
Health, proposed in 1976 to test the hypothesis that the lower incidence and
prevalence of breast dysfunctions and breast cancer and the lower mortality
rate from breast, endometrial and ovarian cancers observed in Japanese women
living in Japan versus those women living in Hawaii and the continental US, was
due their I intake. (6) He suggested a prospective study with two groups of
subjects recruited from the same population with a high incidence of the above
pathologies: the control group on intakes of I from a
Western diet at RDA levels, and the intervention group receiving I in amounts
equivalent to that consumed by Japanese women living in
Data are available, however, regarding the effects of I, ingested in daily amounts of several milligrams, on subjective and objective improvements of fibrocystic disease of the breast (FDB). In 1966, two Russian scientists (9) published their results regarding the effect of oral administration of potassium iodide in daily amounts equivalent to 10-20 mg I, on 200 patients with "dyshormonal hyperphasia of mammary glands." They postulated that this form of mastopathy was due to excess estrogens from ovarian follicular cysts which were caused by insufficient consumption of I. The duration of I supplementation of their patients varied from six months to three years. Within three months, there was significant reduction of swelling, pain, diffuse induration, and nodularity of the breast. Out of 167 patients who completed the program, a positive therapeutic effect was observed in 72% of them. In five patients with ovarian follicular cysts, there was a regression of the cystic ovaries following five months to one year of I supplementation. No side effects of I supplementation was reported in those patients.
Ghent et al (10) extended the Russian study further, using different amounts of different forms of I in women with FDB. Beginning in 1975, these Canadian investigators tested various amounts of various forms of I in three open trials. Lugol 5% solution was used in 233 patients for two years in daily amounts ranging from 3162 mg I. They achieved clinical improvement in 70% of the patients. Thyroid function tests were affected in 4% of the patients and iodism was present in 3% of them. In 588 patients, using iodine caseinate at 10 mg/day for five years, only 40% success rate was achieved. In 1,365 patients, using an aqueous saturated solution of iodine in daily amount based on body weight, estimated at 3-6 mg I/day, 74% of the patients had clinical improvements, both subjectively from breast pain and objectively from breast induration and nodularity. Iodism was present in only 0.1% in this last group. In a double-blind study of 23 patients ingesting aqueous solution of iodine in amounts of 3-6 mg/day for a mean of 191 days, 65% showed objective and subjective improvement, whereas in 33 patients on a placebo, 3% experienced worsening of objective signs and 35% experienced improvement in subjective breast pain. These data are summarized in Table 1. Although the percentage of subjects reporting side effects in Ghent's studies appear high, ranging from 7-10.9%, the authors stated that the incidence of iodism was relatively low, and most complaints were minor, such as increased breast pain at the onset of I supplementation, and complaint about the unpleasant taste of iodine.
When the data from Marine's, Klinger's and Ghent's studies (3,10) were evaluated regarding the incidence of iodism in relation to the daily amount of I ingested, a positive correlation was found between those two parameters: 0% iodism at a daily amount of 1.4-2 mg; 0.1% iodism with 3-6 mg daily; 0.5% with 9 mg and 3% with 31-62 mg (Table 2).
In the 19th edition of Remington's Science and Practice of Pharmacy,
published in 1995, (11) the recommended daily oral intake of Lugol 5% solution for I supplementation was 0.1-0.3 ml.
This time-tested Lugol solution has been available
since 1829, when it was introduced by French physician Jean Lugol.
The 5% Lugol solution contains 50 mg iodine and 100
mg potassium iodide per ml, with a total of 125 mg I/ml. The suggested daily
amount of 0.1 ml is equivalent to 12.5 mg of I, with 5
mg iodine and 7.5 mg of iodide as the potassium salt. This amount of I is very
close to 13.8 mg, the estimated daily intake of I in Japanese subjects living
This lengthy introduction could be justified in the present context by stating that the background information was necessary to set the stage for the present study. If indeed, as suggested by Ghent et al, the amount of I required for breast normality is much higher than the RDA for I which is based on thyroid function tests and thyroid volume, (10) then the next question is: What is the optimal amount of I that will restore and maintain normal breast function and histology, without any significant side effects and negative impact on thyroid functions? From the studies referred to (9,10) and Table 1, the range of daily I intake in the management of FDB was 31-62 mg. From Table 2, we observe that the incidence of iodism increased progressively from 0% at 2 mg to 3% at 31-62 mg.
Our goal was to assess the effect of a standardized, fixed amount of I, within the range of daily amount of I previously used in FDB, on blood chemistry, hematology, thyroid volume and function tests, first in clinically euthyroid women with normal thyroid volume by ultrasonometry, and subsequently in women with FDB if there was no evidence of adverse effects or toxicity on the thyroid gland. The equivalent of 0.1 ml of a 5% Lugol solution, that is 12.5 mg I was chosen, a value close to the average intake of 13.8 mg consumed in Japan, (7) a country with a very low incidence of FDB; (5) slightly higher than the 9 mg amount used in Marine's original study (3) of adolescents, with a very low incidence (0.5%) of iodism following this level of I supplementation; also within the range of 10-20 mg used in the Russian study of FDB, without any side effects reported; (8) and five times less than the largest amount of 62 mg used in Ghent's studies with a 3% iodism reported. (10)
Because administration of I in liquid solution is not very accurate, may stain clothing, has an unpleasant taste, and causes gastric irritation, we decided to use a precisely quantified tablet form containing 5 mg iodine and 7.5 mg iodide as the potassium salt. To prevent gastric irritation, the iodine/iodide preparation was absorbed into a colloidal silica excipient; and to eliminate the unpleasant taste of iodine, the tablets were coated with a thin film of pharmaceutical glaze. Ten clinically euthyroid caucasian women were evaluated before and three months after ingesting a tablet daily. The evaluation included thyroid function tests and assessments of thyroid volume by ultrasonometry. The results suggest that this form and amount of I administered daily for three months to euthyroid women had no detrimental effect on thyroid volume and functions. Some statistically significant changes were observed in the mean values of certain tests of urine analysis, thyroid function, hematology, and blood chemistry fol lowing I supplementation. These mean values were within the reference range, except for mean platelet volume (MPV), with a mean value below the reference range prior to supplementation, but within the normal range following I supplementation. In two subjects, baseline TSH levels were above 5.6 mIU/L, the upper limit for the reference range of the clinical laboratory used in this study. In both subjects, I supplementation markedly suppressed TSH levels.
Subjects and Methods
The female subjects were recruited from the private patients of one of the authors (JDF) and from staff members of a medical clinic. They were ambulatory, without any serious medical problems, clinically euthyroid, and on no medication known to affect thyroid functions. Informed consent was obtained from all subjects. Of 12 subjects recruited, two were dropped from the data analyzed. One subject had a diffusely enlarged thyroid with a volume of 43 ml by ultrasonometry, (14) significantly higher than the upper normal of 18 ml. (14,15) Even though the thyroid function tests were within the normal limits for this subject, we decided to exclude her from this study; however, she was placed on the same I supplementation and reevaluated every three months. The other subject did not return for follow-up. The clinical information on the 10 Women selected are displayed in Table 3. Mastodynia (breast pain) was initially the only symptom evaluated pre- and post-I supplementation. However, some of the subjects volunteered information regarding improvement of restless leg and tremor while on the program, so we included these two symptoms also.
The tablets containing 5 mg iodine and 7.5 mg of iodide as the potassium salt were prepared by one of the authors (JCH). A 5% Lugol solution, prepared with USP grade iodine crystals and potassium iodide powder in purified water, was added to a colloidal silica excipient under mixing, and the preparation was calibrated to contain the above amounts per tablet. The excess water was evaporated under low heat and the resulting dried preparation compressed into tablets which were coated with a thin film of pharmaceutical glaze. There was no loss of I due to evaporation since triplicate analysis by a commercial laboratory (Weber Laboratories, New Port Beach, CA) of tablets taken from the batch used in the present study, revealed quantitative recovery, with I concentrations of 12.5, 12.5 and 12.6 mg per tablet. After initial evaluation, each subject was supplied with a bottle of 90 tablets (registered under the name lodoral[TM]), with instruction to ingest one tablet a day for 90 days and to report any adverse effec ts.
The following laboratory evaluations were performed prior to and after three months of I supplementation: Complete blood count (CBC) was obtained from an Abbott Cell-Dyn[R] 1200; the metabolic panel and thyroid profile were performed by Lab Corporation of America; urine analysis was processed at the clinic with Multistix 10SG Reagent Strips, read on a Clinitek 100 that was calibrated daily. Measurement of thyroid volume by ultrasonometry was performed at the clinic by a registered sonographer using a portable Biosound Esaote Megas System unit with a frequency of 7.5 megaHertz, according to the procedure described by Brunn et al. (14) The volume of each lobe of the thyroid gland was calculated according to the formula: V (mL) = W(cm) x D(cm) x L(cm) x 0.479. (14) The thyroid volume was the sum of the volumes of both lobes, taking 18 ml as the upper limit for normal thyroid volume in women living in a non-endemic goiter area. (16) Body compositional analysis was performed at the clinic by near infrared technol ogy, (17) using a Futrex 5000: muscle mass, fat mass, percent fat, and total body water. The body mass index (BMI) is the ratio of body weight divided by height squared, using the metric units of kilogram (kg) for weight and meter (in) for height. (18) Based on the classification of overweight and obesity by BMI, the normal range is 18.5-24.9 kg/[m.sup.2], with less than 18.5 as underweight; between 25-29.9 as overweight, and 30 and above as obese. The latest NHANES III study (1988-1994) revealed that 25% of American women are overweight and 25% obese. (18) Based on this classification, five subjects were within the normal range, two were overweight, and three were obese (Table 3). Therefore, these subjects are a good representation of our "normal" population. Statistical analysis of the data, comparing pre- and post-I supplementation values within patients, was done by paired data analysis. (19)
Clinically, there were significant improvements of mastodynia (p0.004), tremor (p=0.048), and restless leg (p0.009) (Table 3). There was no statistically significant effect of I supplementation on blood pressure, body temperature and body composition (Table 4). Percent body fat reached a near significant drop (p=0.075).
Regarding laboratory evaluation of the subjects, results of urine analysis
were normal in all subjects pre- and post-I supplementation. The only
statistically significant effect of I was on urine pH (p0.0 12) with pre- and
post-I values (mean [+ or -] SD) respectively of 6.05[+ or -]0.69
and 7.00[+ or -]0.85. (
The data on thyroid function tests and thyroid volume are displayed in Table 7. Thyroid volume in all the subjects were below 18 ml, the upper limit of normal values reported, (14, 15) suggesting that their intake of I prior to this study was adequate to prevent enlargement of the thyroid gland, and to maintain normal thyroid hormones, since all these values were within normal limits. Serum T4 levels dropped significantly (p<0.01) from a mean of 8.8 (SD=1.3) to 7.2 ug/dL (SD=1.1). However, all individual values remained within the reference range (Table 7). Mean serum TSH levels decreased following I intake from 4.4 mIU/L to 3.2 mIU/ L. This non-significant decrease was due to the marked fall in subjects #1 and #10, with 16 mIU/L decrease between these two subjects. Using the classification of subclinical hypothyrodism as clinical euthyroidism with normal levels of thyroid hormones but elevated TSH above 6 mIU/L, (20,22) subjects #1 and #10 would be classified as subclinical hypothyroid before I supplementati on. >
The goal of this pilot study was to evaluate the effect of I supplementation in American Caucasian women, a population with a high incidence of FDB and breast (23,24,25) cancer, 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 ([+ or -] SD) in our 10 subjects (7.7[+ or -]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. In both cases, I
supplementation markedly suppressed 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 7). Subclinical hypothyroidism is defined as clinical euthyroidism with normal levels of thyroid hormones, but
with elevated TSH levels above 6 mIU/L. (20,21,22) By
this classification, subject #1 would be classified as subclinical
hypothyroid before I supplementation, and reclassified as normal three months
after starting the ingestion of I in daily amount of 12.5 mg, 80 times the RDA
level. It is likely that subject #10, if maintained 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 supplements in these individuals to levels consumed from
seaweed by Japanese women living in
We have reviewed published studies in
The significant increase in urine pH following I supplementation, with mean ([+ or -] SD) values of 6.05[+ or -]0.69 and 7.00[+ or -]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 [right arrow] triplet transition (32) is to decrease the oxidative burden of the body; 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 extrathyroidal 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 researchers. (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 two 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.
The potentially adverse effects of I supplementation at the levels used in the present study 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 the 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 was 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
The last of the three 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 periods 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, postpartum lymphocytic thyroiditis, subacute painful thyroiditis, and lobectomy for beni gn nodules. (47) It is not necessary 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 echo patterns. Serum thyroid autoantibodies would supplement finding from history and physical examination. Reevaluation is recommended every three 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 7), 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 sensitivit y 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 microgram amounts to the milligram amounts ingested by Japanese with a very low incidence of FDB and breast cancer, (25,26) and iodophilia in the therapeutic range, prescribing excessively large amounts of I in gram 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, is 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/[m.sup.2]/day was required
to achieve the 5% goal. These auth ors 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
The benefits of I supplementation within the range used in FDB outweigh 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.
Summary of results obtained by Vishnyakova et al (9) and Ghent et al
(10) for objective and subjective improvements of fibrocystic disease of
the breast in response to various dosages of various forms of I.
Study Design # pts Duration Form of I Daily Dosage
Open Trial 200 3 years Potassium 10-20 mg
Open Trial 233 2 years Lugol 5% * 5-10 drops
(31-62 mg I)
Open Trial 588 5 years Iodine 10 mg
Open Trial 1365 18 months Aqueous 0.08 mg/kg BW
Double Blind [P.sub.L] = 33 mean of Aqueous 0.08 mg/kg BW
191 days Solution of
[I.sub.2] = 23 Iodine
Study Design % of pts with % of pts with
clin. improvement side effects
Open Trial 72% none
Open Trial 70% 7%
Open Trial 40% 9.5%
Open Trial 74% 10.9%
Double Blind Object. Subject. N/A
[P.sub.L] = -3% 33%
[I.sub.2] = 65% 65%
* 5% Lugol solution contains 5% iodine and 10% potassium iodide with a
total 1 of 125 mg/ml, consisting of 50 mg iodine and 75 mg iodide. At 20
drops per ml, 5-10 drops represent .25-.5 ml, or 31-62 mg I.
Relationship between the amount of I ingested and percentage of
students/patients with iodism
Author(s) Populatin Number Form of I Daily Amount Duration
Marine (3) students 760 iodine 1.4 - 2 mg 15 mos.
(10) patients 1368 iodine 3 - 6 mg 9.9 mos. Ghent
Marine (3) students 2190 sodium 9 mg 30 mos.
(10) patients 233 Lugol (5%) 31 - 62 mg 24 mos. Ghent
Author(s) % of stud/pts
Marine (3) 0
(10) 0.1 Ghent
Marine (3) 0.5
(10) 3.0 Ghent
Clinical data on the 10 subjects
Subject Age Height Weight BMI menstrual
# (years) (inches) (lbs.) (kg/[m.sup.2]
1 31 68 152 23.2 Pre-Menopausal
2 49 70 216 30.9 Pre-Menopausal
3 49 63 161 28.5 Pre-Menopausal
4 49 66 202 32.5 Pre-Menopausal
5 43 65 146 24.3 Pre-Menopausal
6 35 67 149 23.4 Pre-Menopausal
7 44 62 115 21.2 Pre-Menopausal
8 47 69 168 24.9 Pre-Menopausal
9 59 69 196 29 Post-Menopausal
10 53 66 219 35.2 Post-Menopausal
x 45.9 66.50 172 27.3
SD 8.2 2.64 34.3 4.6
Subject medications Symptoms assessed in response to
I supplementation * (pre-I /post-I
# Mastodynia Tremor Restless legs
1 O.C. 1/.5 1/.5 1/.5
2 Diuretics 0/0 0/0 1/0
3 Anti-Anx. 1/0 1/0 0/0
4 Anti-Dep. 1/0 1/1 1/1
5 None 1/.5 0/0 0/0
6 Ritalin 1/1 1/0 0/0
7 None 0/0 0/0 1/0
8 None 1/0 0/0 0/0
9 Anti-Histamine 0/0 0/0 1/0
10 ERT 1/0 0/0 1/0
x x 0.70/.20 0.4/0.15 0.6/0.15
SD p value 0.004 0.048 0.009
* 1 = present; 0 = absent; 0.5 = improved
Effect of I supplementation in daily amount of 12.5 mg for 3 consecutive
months on blood pressure, body temperature, weight and composition.
Reference Pre- I Post-I
Units Range x SD x
Temp (oral) [degrees]F -- 97.5 0.99 97.3
Body weight kg -- 78 15.4 78.3
Height m -- 1.7 0.1 1.7
BMI kg/[m.sup.2] 18.5-24.9 27.3 4.6 27.1
Systolic BP mm Hg <140 127 21 124.2 Diastolic BP mm Hg ><90 80.4 12 78.2 Muscle mass kg -- 53.1 7.8 53.5 Fat kg -- 25.1 8.8 24.3 % Fat % -- 31.3 5.9 30.6 Water liters -- 40.9 6.2 40.8 Post-I SD p value Temp (oral) 1.1 0.20 Body weight 15.1 0.46 Height 0.1 -- BMI 4.2 0.31 Systolic BP 13.5 0.23 Diastolic BP 8.6 0.24 Muscle mass 7.3 0.24 Fat 8.5 0.45 % Fat 6.0 0.075 Water 5.9 0.43 Table 5 Effect of I supplementation in daily amount of 12.5 mg for 3 consecutive months on blood chemistry Reference Pre-I Post-I Units Range X SD X SD Glu mg/dL 65-109 76.6 19 78.4 20.4 BUN mg/dL 5-26 12.8 4.2 11.9 2.9 Creat mg/dL 0.5-1.5 0.85 0.12 0.73 0.07 BUN/Creat - - 14.6 4.7 15.9 3.9 Na mMole/L 135-148 140 3.8 144 2.6 K mMole/L 3.5-5.5 4.7 0.54 4.7 0.58 Cl mMole/L 96-109 101 3.6 102 2.9 [CO.sub.2] mMole/L 20-32 23.2 4.2 26.1 4.2 CA mg/dL 8.5-10.6 9.6 0.45 9.2 0.32 Prot gm/L 6-8.5 7.1 0.42 7.1 0.32 Alb gm/L 3.5-5.5 4.5 0.16 4.1 0.17 Glob gmlL 1.5-4.5 2.6 0.41 2.9 0.19 A/G ratio - 1.1-2.5 1.7 0.29 1.38 0.08 Total Bil mg/dL 0.1-1.2 0.58 0.37 0.59 0.5 Alk Phos I.U/L 25-165 84.8 24.7 77.5 21.9 SGOT I.U/L 0-40 18.5 3.4 21.3 6.9 SGPT I.U/L 0-40 13.8 2.5 19.9 4.6 p value Glu 0.41 BUN 0.18 Creat ><0.01 BUN/Creat 0.13 Na 0.01 K 0.46 Cl 0.08 [CO.sub.2] 0.02 CA 0.04 Prot 0.47 Alb ><0.01 Glob 0.01 A/G ratio ><0.01 Total Bil 0.43 Alk Phos ><0.01 SGOT 0.08 SGPT ><0.01 Table 6 Effect of I supplementation in daily amount of 12.5 mg for 3 consecutive months on Units Reference Pre-I Post-I Range X SD X WBC [10.sup.3]/uL 4.6-10.2 6.04 1.7 6.05 Lymph % 12-51 33.4 8.5 32.4 Mid % 0-12 6.3 1.2 6.1 Gran % 43-85 60.3 7.8 61.6 RBC [10.sup.6]/uL 3.8-6.5 4.35 0.33 4.53 Hb g/dL 11.5-18 13.5 0.83 13.7 Hct % 37-54 38 2.2 38.8 MCV fL 80-100 87.4 4.2 85.7 MCH pg 27-32 31.2 2.2 30.1 MCHC g/dL 31-36 35.6 1.3 35.1 RWD % 11.5-14.5 11.4 0.48 11.4 PLAT [10.sup.3]/uL 150-400 282 47 274 MPV fL 8.2-10.0 7.5 1.03 8.2 Post-I p value SD WBC 1.72 0.49 Lymph 6 0.23 Mid 1.9 0.33 Gran 5 0.22 RBC 0.25 0.09 Hb 0.96 0.35 Hct 2.6 0.23 MCV 3.9 ><0.01 MCH 1.7 ><0.01 MCHC 0.6 0.05 RWD 0.6 0.35 PLAT 77 0.33 MPV 1.3 0.04 Table 7 Effect of I supplementation in daily amount of 12.5 mg for 3 consecutive months on thyroid volume and thyroid function tests Thyr.Vol. TSH [T.sub.4] Subject # (mL) (mIU/L) ([micro]/dL) Pre Post Pre Post Pre 1 4.35 3.6 7.8 1.4 9.2 2 5.5 5.5 2.0 2.2 10.7 3 4.7 5.6 3.4 5.1 9.6 4 5.9 12 2.7 6.1 8.7 5 5.7 8.9 1.4 1.1 6.3 6 11.6 9.5 1.0 0.34 7.5 7 7.0 6.1 1.4 2.3 8.2 8 6.7 7.5 2.3 1.3 9.4 9 15.8 14.7 0.76 0.53 9.7 10 9.2 7.7 21.5 11.9 8.3 x 7.7 8.1 4.4 3.2 8.8 SD 3.6 3.3 6.34 3.6 1.3 p value .29 0.18 ><.01 Ref. Range >< 18 0.35-5.5 4.5-12
[T.sub.4] [FT.sub.4] [FT.sub.3]
Subject # ([micro]/d (ng/dL) (pg/mL)
Post Pre Post Pre Post
1 7.9 0.85 1.3 2.9 2.5
2 8.9 1.1 1.1 2.5 2.5
3 6.4 1.1 1.1 2.7 2.8
4 8.0 1.2 1.2 3.0 3.2
5 6.3 1.0 1.2 2.9 2.9
6 6.9 1.2 1.1 2.9 2.7
7 6.0 1.0 0.84 2.9 2.7
8 7.4 1.0 1.15 2.7 3.1
9 8.0 1.2 1.3 3.1 3.4
10 5.4 1.2 0.9 2.8 2.6
x 7.1 1.1 1.1 2.8 2.8
SD 1.1 0.12 .16 .17 .31
p value 0.34 0.50
Ref. Range 0.61-1.76 2.3-4.2
(1.) Dunn JT. Editorial: "What's happening to our iodine?" J Clinical Endocrinology and Metabolism, 1998; 83:3398-3400.
(2.) Hollowell J, Staehling N, Hannon W, Flanders D, Gunter E, and Maberly G. "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 Clinical Endocrinology and Metabolism, 1998; 83:3401-3408.
(3.) Marine D. "Prevention and treatment of simple goiter." Atl Med J, 1923; 26:437-442.
(4.) Marine D and Kimball BS. "The prevention of simple goiter in man." J Lab Clin Med, 1917; 3:40-48.
(5.) Cann S, Netten J, and Netten C. "Hypothesis: Iodine, selenium and the development of breast cancer." Cancer Causes and Control, 2000; 11:121-127.
(6.) Stadel B. "Dietary iodine and risk of breast, endometrial, and ovarian cancer." The Lancet, 1976; 1:890-891.
(7.) Nagataki S, Shizume K, and Nakao K. "Thyroid function in chronic excess iodide ingestion: Comparison of thyroidal absolute iodine uptake and degradation of thyroxine in euthyroid Japanese subjects." J Clin Endo, 1967; 27:638-647.
(8.) Konno N, Yuri K, Miura K, Kumagai M, and Murakami S. "Clinical evaluation of the iodide/creatinine ratio of casual urine samples as an index of daily iodide excretion in a population study." Endocrine Journal, 1993; 40:163-169.
(9.) Vishnyakova VV and Murav'yeva NL. "On the treatment of dyshormonal hyperplasia of mammary glands." Vestn Akad Med Nauk SSSR, 1966; 21:19-22.
(10.) Ghent W, Eskin B, Low D, and Hill L. "Iodine replacement in fibrocystic disease of the breast." Can J Surg, 1993; 36:453-460.
(11.) Gennaro AR. Remington: The Science and Practice of Pharmacy, 19th edition, Mack Publishing Co, 1995; 976, 1267.
(12.) Sem BC. "Pathologico-anatomical and clinical investigations of fibroadenomatosis cystica mammae and its relations to other pathological conditions in mammae especially cancer." Acta ChirScand, 1928; 10:1-48.
(13.) Kramer WM and Rubin BF. "Mammary duct proliferation in the elderly: A histopathologic study." Cancer, 1973; 31:130-137.
(14.) Brunn J, Riock U, Rui G, and Bon T. "Volumentrioder Schiiddrusenlappen mittela Real-time-Sonographic." Dusche Med, 1981; 106:1338-1340.
(15.) Gutekunst R, Smolarek
H, Hasenpusch U, and Stubbe
P. "Goitre epidemiology: thyroid volume, iodine
excretion, thyroglobulin and thyrotropin
(16.) Smyth P. "Thyroid disease and breast cancer." J Endo Int, 1993; 16:396-401.
(17.) Cassady S. "Reliability of near infrared body composition analysis." Card Pulm Phy Ther, 1996; 7:8-12.
(18.) Amatruda J and Linemeyer D. "Obesity." In: Endocrinology & Metabolism. Felig P and Frohman L, Editors. McGraw-Hill, Inc., 2001; 945-991.
(19.) Goldstein A. "Comparison of paired observations by t-test."
In: Biostatistics: An Introductory Text. The Macmillan Co.,
(20.) Staub JJ, Noel R, Grani E, and Gemsenjager E. "The relationship of serum thyrotropin (TSH) to the thyroid hormones after oral TSH-releasing hormone in patients with preclinical hypothyroidism." J Clin Endo and Metabolism, 1983; 86:449.
(21.) Staub J, Althaus B, Engler H, and Ryff A. "Spectrum of subclinical and overt hypothyroidism: Effect on thyrotropin, prolactin, and thyroid reserve, and metabolic impact on peripheral target tissues." Am J Med, 1992; 92:631-642.
(22.) Muller B, Zulewski H, Huber P, and Ratcliffe G. "Impaired action of thyroid hormone associated with smoking in women with hypothyroidism." NFJM, 1995; 333:964-969.
(23.) Love SM, Gelman RS, and Silen W. "Fibrocystic 'disease' of the breast--a nondisease?" NFJM, 1982; 307:1010-1014.
(24.) Devitt JE. "Abandoning fibrocystic disease of the breast: Timely end of an era" Can Med Assoc J, 1986; 134:217-218.
(25.) Parker S, Tong T, Bolden S, and Wingo PA. "Cancer statistics." CA Cancer J Clin, 1997; 47:6-27.
(26.) Sasano N, Tateno H, and Stemmeermann
GN. "Volume and hyperplastic
lesions of breasts of Japanese women in
(27.) Kung A, Laot T, Chaut 5, Tams F, and Lowt L. "Goitrogenesis during pregnancy and neonatal hypothyroxinaemia in a borderline iodine sufficient area." Clinical Endo, 2000; 53:725-731.
(28.) Wiseman R. "Breast cancer hypothesis: A single cause for the majority of cases." JEpid Comm Health, 2000; 54:851-858.
(29.) Derry D. Breast Cancer and Iodine,
(30.) Eskin B. "Iodine and mammary cancer." Adv Exp Med Biol, 1977; 91:293-304.
(31.) Venturi S, Donati F, Venturi M, Venturi A, Grossi L, and Guidi A. "Role of iodine in evolution and carcinogenesis of thyroid, breast and stomach." Adv Clin Path, 2000; 4:11-17.
(32.) Kasha M. "Collisional perturbation of spin-orbital coupling and the mechanism of fluorescence quenching. A visual demonstration of the perturbation." The Journal of Chemical Physics, 1952; 20:71-74.
(33.) Nolan LA, Windle RJ, Wood SA, and Kershaw YM. "Chronic iodine deprivation attenuates stress-induced and diurnal variation in corticosterone secretion in female wistar rats." Journal of Neuro, 2000; 12:1149-1159.
(34.) Freinkel N and Ingbar S. "The metabolism of I by surviving slices of rat mammary tissue." Endo, 1956; 58:51-56.
(35.) Schiff L, Stevens CD, Molle WE, Steinberg H, Kumpe C, and Stewart P. "Gastric (and salivary) excretion of radioiodine in man (preliminary report)." JNat Can Inst, 1947; 7:349-356.
(36.) Banerjee R, Bose A, Chakraborty T, De 5, and Datta A. "Peroxidase-catalysed iodotyrosine formation in dispersed cell of mouse extrathyroidal tissues, J Endocr, 1985; 106:159-165.
(37.) Eskin B, Bartuska D, Dunn M, Jacob G, and Dratman M. "Mammary gland dysplasia in iodine deficiency." JAMA, 1967; 200:115-119.
(38.) Eskin B. "Iodine metabolism and breast
(39.) Funahashi H, Imaj T, Tanaka Y, et al. "Suppressive effect of iodine on DMBA-induced breast tumor growth in the rat." Journal of Surgical Oncology, 1996; 61:209-213.
(40.) Eskin B, Grotkowski
C, Connolly C, and
(41.) Cohn B. "Absorption of compound solution of iodine from the gastro-intestinal tract." Arch Intern Med, 1932; 49:950-956.
(42.) Thrall K and Bull LU. "Differences in the distribution of iodine and iodide in the Sprague-Dawley rat." Fundamental and Applied Toxicology, 1990; 15:75-81.
(43.) Peacook L and Davison H. "Observations on iodide sensitivity." Ann Allerg, 1957; 15:158-164,
(44.) The Encyclopedia Britannica: 11th edition; Volume XIV. Encyclopedia
(45.) Stanbury J, Ermans A, Bourdoux P, Todd C, Oken E, and Tonglet R. "Iodine-induced hyperthyroidism: Occurrence and epidemiology." Thyroid, 1998; 8:83-100.
(46.) Delange FM. "Iodine Deficiency."
In: Werner and Ingbar 's The Thyroid. Braverman LE and
(47.) Farwell AP and Braverman LE. "Thyroid and antithyroid drugs." In: Goodman and Gilman 's The Pharmacological Basis of Therapeutics. 10th Edition, McGraw-Hill, 2001; 1563-1596.
(48.) Robbins J, Cheng S-Y, Gershengom MC, et al. "Thyroxine transport proteins of plasma: molecular properties and biosynthesis." Recent Prog Horm Res, 1978; 34:477.
(49.) Lee K, Bradley R, Dwyer J, and Lee SL. "Too much or too little:
The implication of current iodine intake in the
(50.) Saxena KM. Chapman EM, and Pryles CV. "Minimal dosage of iodide required to suppress uptake of iodine-131 by normal thyroid." Science, 1962; 138:430-431.
(51.) Sternthal E, Lipworth L, Stanley, et al. "Suppression of thyroid radioiodine uptake by various doses of stable iodide." NEIM, 1980; 303:1083-1088.