Treatment of iodine deficiency diseases

This invention relates to a composition for use in the treatment of iodine deficiency diseases such as fibrocystic dysplasia of the breast, breast cancer, endometriosis and premenstrual syndrome. The composition may also be used for the prophylaxis of breast cancer. More particularly, this invention relates to a composition for the treatment of iodine deficiency diseases, the composition comprising a solution of elemental iodine (I.sub.2) which may also be referred to as metallic iodine or iodine metal. The elemental iodine is soluble in water which leaves it thermodynamically free. The term "aqueous iodine" may also be used to refer to such an aqueous solution.

BACKGROUND OF THE INVENTION 
The nomenclature of iodine deficiency breast syndrome has a varied past 
with Reclus in France, Schimmellbusch in Germany and Bloodgood in the 
United States contributing to the confusion. Pathological nomenclature was 
popular for a time with the terms fibroepitheliosis, fibroadenosis and 
epithelial adenosis reported in the literature. Recently, the most common 
named applied seems to be fibrocystic disease. It is generally agreed, 
that all of these terms, and several more, apply to an entity 
characterized by painful nodular breasts and supported pathologically with 
cystic spaces, epithelial hyperplasia or apocrine metaplasia and 
interacinar fibrosis. 
The etiology of the condition has remained obscure with various theories in 
ascendancy at any one time. These have included a prolonged luteal phase, 
a reversal of the estrone/estriol ratio, increased median prolactin 
levels, or any upset in these complex interrelationships. All of these 
etiological theories are supported by good research data. More recent 
suggestions have implicated caffeine in coffee, tea and chocolate users 
and the increased estrogen intake in milk drinkers. 
It is the inventors' position that there is a common denominator in all of 
these concepts and this is specific iodine ion deficient state. In this 
state, it is further postulated that the secreting cells of the breast are 
sensitized to various stimuli to produce the changes noted. This 
sensitization can progress to overt malignancy if a carcinogen is added to 
the rat model and possibly to the human female. 
Clinically, the fibrocystic syndrome is the most common breast disease that 
affects North American women. The Cancer Committee of the American Academy 
of Pathology (1985) estimated the incidence at 50-80% of the adult female 
population. 
Parallel findings indicate that at least fifty percent of all North 
American and European women of child bearing age are suffering from 
fibrocystic disease (fibrocystic dysplasia). Painful breasts are common 
prior to the onset of menstruation and fibrocystic disease accentuates 
this tendency. Some women suffering from this disease have hard areas of 
thickening with small pellet sized masses scattered throughout the breast 
while other patients have marble sized cyst development. Fibrocystic 
disease of the breast affects one in two women between the ages of 16 and 
60. 
The link between iodine deficiency states and an increased incidence of 
breast cancer is statistically valid on a geographical basis. Demographic 
evidence indicates that rates of morbidity and mortality due to breast 
cancer are higher in areas of iodine inadequacy than in regions where 
iodine is readily available. Demographic surveys of Japan and Iceland show 
low incidences of endemic non-toxic goiter and breast cancer, while Mexico 
and Thailand show high incidences of goiter and breast cancer. In 
addition, increased breast cancer in specific endemic-goiter regions in 
Poland, Switzerland, Australia, and the Soviet Union have been described 
in various publications. Similarly, in the United States and Canada iodine 
deficient regions (described by the World Health Organization) show a high 
census of breast disease. 
The treatment of fibrocystic disease in the past has included neglect, 
hormonal manipulation with birth control pills, danazol (a masculinizing 
hormone), withdrawal of caffeine and cow's milk, or subcutaneous 
mastectomy. The treatment of this syndrome by a non-surgical technique 
with very low side effects would be more desirable and is offered by this 
invention. 
Previously, iodine, a trace element in the basic physiology of humans, has 
received much attention in its application to thyroid function. This led, 
in 1929, to the addition of potassium iodide to all salt sold in Canada. 
The addition resulted in a marked decrease in the iodine deficiency 
disorders (I.D.D.) known as cretinism and endemic goiter and a drop in the 
incidence of hypothyroid states. 
Iodides and protein-bound iodines have been used to treat various other 
human diseases, including hypercholesteremia, hyperlipemia, diabetes and 
tuberculosis. U.S. Pat. Nos. 4,187,294, 4,338,304 and 4,394,376, all to 
Kamimae et al. disclose a composite containing a high amount of 
protein-bound iodine for the treatment of hypercholesteremia, diabetes and 
hyperlipemia, respectively. U.S. Pat. No. 4,259,322 to Lim discloses 
tuberculosis medication containing sodium iodide administered by 
intramuscular or intravenous injections. 
Recent investigations have indicated that the iodine molecule is involved 
in the function of various organs in the body, including the salivary 
glands, the stomach, the liver, the ovaries, endometrial tissues and the 
human female breast. Iodine deficiency appears to cause an increase in 
carcinogenesis when a known breast carcinogen is given to susceptible 
rats. In some studies, earlier onset of cancer is seen, and in others, a 
greater number of breast tumor sites and an increased size of tumor have 
been described. 
Yunbing et al. related hyperplastic cystic disease of the breast 
etiologically to dysfunction of the ovaries with elevated estrogen level 
coupled with decreased progesterone level and abnormal reactivity of 
breast tissue to estrogen. Treatment of mammary dysplasia was directed to 
restoring normal ovarian function and hormonal balance of the gonad using 
traditional Chinese medicines. These medicines include Sargassum which 
contains a high iodide concentration principally in the form of potassium 
iodide. Among those patients treated solely with traditional medicine, 
Yunbing et al. reported a cure rate of 65.4 percent. This is much below 
the rate quoted for this invention and not substantiated by animal 
testing. 
The first mention of the thyroid/iodine associated with the human female 
breast was made in 1896, by Dr. Beatson, who treated metastatic breast 
cancer, with some success, using desiccated thyroid in large doses. 
Desiccated thyroid contains an abundance of protein-bound iodine in 
addition to the active hormone thyroxine. 
Carcinoma of the breast is less prevalent in patients with hyperthyroidism 
than patients with hypothyroidism, and the survival rate in the former 
group is enhanced as compared to hypo or euthyroid patients. 
The first association of an iodine deficiency state and benign breast 
dysplasia was reported by Vishnyakova and Murivieva in 1966 from Russia. 
They reported a 71% improvement rate in women with dysplastic mastodynia 
treated with potassium iodide (inorganic iodine). 
Studies on rats have included iodine replacement therapy in animals made 
iodine deficient by a Remington iodine-free diet. Employing iodide 
inorganic salts (sodium iodide) in food at both normal and excessive 
levels as replacement, the breast dysplasia appeared to abate with a 
partial subsidence of epithelial hyperplasia and a loss of cystic spaces 
but with a continuation of the fibrosis of the syndrome. 
Laboratory support for the relationship of benign fibrocystic disease and 
iodine deficiency was furnished by Eskin reported in 1970 in the New York 
Academy of Sciences Journal, which is incorporated herein by reference. 
Eskin was attempting to produce carcinoma in a rat model with iodine 
deficiency, hypothyroidism, estrogen addition and a carcinogen. These 
laboratory studies were successful, but in the cellular steps to final 
neoplasia, microscopic changes resembling those of fibrocystic disease 
were produced. These changes included epithelial hyperplasia associated 
with mammary ducts and acinar cells, cyst formation and an increase in 
interacinar fibrosis. All previous animal models produced with hormonal 
manipulation produced hyperplasia with some cystic dilation but without 
the interacinar fibrosis that is characteristic of the human condition. 
Other iodine-deficient disease states for which effective treatments have 
not been discovered include endometriosis and premenstrual syndrome. 
Endometriosis is characterized by hormonally responsive endometrial tissue 
implants in extra-uterine sites. The etiology of endometriosis is thought 
to be the transplantation of uterine lining cells through the fallopian 
tubes, the lymph channels and/or the blood stream to the abdominal cavity. 
Another suggested theory is that the peritoneum undergoes metaplasia to 
produce endometrial cells without direct access to cellular transplants. 
The transplanted or transformed islands of endometrial tissue act in a 
similar fashion to the uterine cells, with swelling and then bleeding at 
the time of menstruation. 
Current treatment modalities for endometriosis are directed at the normal 
fluctuations of the estrogen/progesterone complex. Medications include 
birth control pills, masculinizing hormones such as danazol, or estrogen 
suppression drugs such as tamoxifen. In older age groups, total abdominal 
hysterectomy is the only therapy that is effective. All of the medical 
therapies are aimed at masculinizing the female concerned. 
Premenstrual syndrome is defined as the cyclic recurrence in the luteal 
phase of the menstrual cycle of a combination of distressing physical, 
psychological and/or behavioral changes, of sufficient severity to result 
in deterioration of interpersonal relationship and/or interference with 
normal activities. The symptoms of premenstrual syndrome include breast 
pain, swelling and tenderness, lower abdominal bloating, constipation, 
increased appetite with cravings for salt or chocolate, fatigue, emotional 
lability with temper tantrums, anger or crying, depression, anxiety with 
tension, irritability with tendency to seek confrontations, aversion to 
sexual relations, insomnia, confusion and/or violence. 
Although premenstrual syndrome has been classified as a psychiatric 
instability in the premenstrual phase, psychiatric counselling has not 
proven to be an effective treatment. Other treatment modalities include 
progesterone administration, tranquilizers and pain control medication, 
surgical removal of the ovaries and naloxone administration. However, 
these other treatment modalities are also ineffective. 
The nomenclature of iodine-containing compositions is ambiguous, and often 
misleading. Iodine is most often administered in an inorganic iodide form 
or as protein-bound iodine. Both of these forms utilize the I.sup.- ion 
and are not elemental iodine (I.sub.2). 
However, in the literature, both of these forms have been referred to as 
iodine, which to the unskilled reader might connote the use of elemental 
iodine (I.sub.2). Prior to its use by the current inventors, elemental 
iodine (I.sub.2) in a pure solution has not been administered as a 
medication to treat iodine deficiency states. 
Elemental iodine in a suspension form (i.e. containing micro and macro 
particles of iodine) has been used to treat thyroid conditions as taught 
by Polley in U.S. Pat. No. 4,384,960. However, such a suspension is an 
undesirable form of iodine. The iodine particles cause the suspension to 
be of unknown strength. Furthermore, the iodine particles cause the 
unwanted side effects of nausea, vomiting and diarrhea when the suspension 
is administered to patients. The iodine particles are present in the 
Polley suspension due to the method of manufacture which comprises direct 
exposure of iodine pellets, crystals or dust to water through a porous 
container. 
SUMMARY OF THE INVENTION 
This invention relates to a composition for use in the treatment of 
fibrocystic dysplasia which reduces or dissipates cyst and fibrous tissue 
formation in the female breast and alleviates the pain and discomfort 
associated with this disease. More particularly, this invention relates to 
a composition for the treatment of fibrocystic dysplasia which is 
comprised of a pure solution of elemental iodine (I.sub.2). For the 
purposes of this application, elemental iodine refers to diatomic iodine 
(I.sub.2) which may also be referred to as metallic iodine or iodine 
metal. The elemental iodine is a solution of I.sub.2 in water, and is 
thermodynamically free. The term "aqueous iodine" may also be used to 
refer to such an aqueous solution. 
The invention also relates to a composition of elemental iodine (I.sub.2) 
for the treatment of endometriosis, the treatment of premenstrual syndrome 
and the treatment or prophylaxis of breast cancer.

DETAILED DESCRIPTION OF THE INVENTION 
A. Iodine Treatment of Fibrocystic Dysplasia 
The present invention provides a method and composition for use in the 
treatment of fibrocystic dysplasia which results in not only the relief of 
pain associated with the disease, the regression of epithelial hyperplasia 
and the dissipation of cysts, but additionally the control and dissolution 
of the fibrous tissue. The invention also provides a method and 
composition for use in the treatment of fibrocystic dysplasia which is 
comprised of the use of a pure solution of elemental iodine. A further 
aspect of the invention is the provision of a method and composition for 
the treatment of fibrocystic dysplasia, including the use of an aqueous 
solution of elemental iodine wherein the composition is in a form for oral 
administration. 
In an effort to overcome the disadvantages of the prior art, the present 
invention provides a composition for the treatment of fibrocystic 
dysplasia, including the use of an aqueous solution of elemental iodine 
which may be administered orally without the vile taste of previous iodine 
replacement compositions, notably Lugol's iodine (potassium iodide in 
aqueous solution), and without the side effects associated with various 
prior art treatments. 
The pure solution of elemental iodine is produced by a unique method which 
prevents any micro or macro particles of iodine from being present in the 
solution. Iodine crystals are placed in a sealed plastic bag or container 
which is exposed to water at about 20.degree. C. The iodine crystals 
sublime, and iodine vapor passes through the plastic and into the water to 
produce a pure solution of elemental iodine without any particulate 
matter. 
The particular plastic composition used must be penetrable by iodine vapor 
but impermeable to water and micro or macro particles of iodine. The 
inventors have found that suitable plastics include polyethylene, 
polypropylene polybutylene and related plastic compositions. A preferred 
plastic composition is a 1 millimeter thick film of linear, low density 
polyethylene. 
The concentration of the pure solution after the iodine vapor has passed 
through the plastic to the water is about 270 milligrams elemental iodine 
per liter of solution to about 350 milligrams of elemental iodine per 
liter of solution. A preferred concentration is 300 mg of elemental iodine 
per liter of solution. 
As stated above, the pure solution with the required concentration is 
obtained by exposing a plastic container of prilled iodine to water for an 
amount of time sufficient to yield a pure iodine solution with a 
concentration of about 270 to about 350 milligrams elemental iodine per 
liter of solution. The temperature of the water effects the rate of 
sublimation of the prilled iodine, and therefore effects the time to 
stabilization of the pure solution at the required concentration. 
Preferably, 7 grams of prilled iodine is placed in a polyethylene 
container, and submerged in 100 ml of distilled water at about 20.degree. 
C. for about 18 hours to produce a pure iodine solution having the 
required concentration (about 270 to about 350 milligrams elemental iodine 
per liter of solution). 
Alternatively, the polyethylene container with 7 grams of prilled iodine is 
submerged in 100 ml of distilled water at about 50.degree. C. for about 30 
minutes to obtain the pure solution having the required concentration. At 
50.degree. C., the prilled iodine sublimes at a much faster rate. 
Once the pure solution has been produced, it is an easy process for the 
patient to replenish the solution after use. Refilling a partially used 
dispenser of the solution with distilled water at 20.degree. C. results in 
further sublimation of the prilled iodine in the polyethylene container, 
and stabilization of the solution at the required concentration occurs in 
about 6 hours. 
The pure elemental iodine solution produced by the above-described methods 
allows an accurate dosage regime to be maintained, and reduces the 
unwanted side effects of nausea, vomiting and diarrhea. Both of these 
advantages are attributable to the lack of particulate iodine in the 
solution. 
Breast dysplasia and neoplasia are influenced by the available iodine ion. 
Carcinogenesis occurs early in estrogen therapies in association with 
iodine deficiency. 
The subsequent addition of iodine to iodine-deficient diets in rat 
experiments reversed breast dysplasia. Once breast lesions were 
established, only chronic iodine replacement manages the dysplasia that is 
formed. 
The first iodine product used in the reversal experiment was sodium iodide. 
The use of sodium iodide resulted in reversal of the pathological changes 
to a degree with the partial subsidence of cyst formation, epithelial 
hyperplasia and fibrosis. The interacinar fibrosis remained. 
Iodine caseinate, an organified form of iodine was next tested based on the 
proven ability of the breast tissue to deorganify iodine to secrete iodine 
as in organic potassium iodide in milk. The breasts' ability to organify 
inorganic iodine with the addition of protein molecules, some in the form 
of thyroxin, was proven by Eskin and reported in "Iodine in Breast 
Cancer-A 1982 Update" in Biological Trace Element Research 538. 
The testing of iodine caseinate on the rat model, which first began in 
1974, resulted in a reversal of the cyst formation and the epithelial 
hyperplasia. The interacinar fibrosis remained as a hallmark of continuing 
pathology. 
Iodine replacement therapy investigations have been limited to animal 
experimentation until recently. Since the basic research had shown changes 
resembling fibrocystic disease in women when iodine was deficient, the 
clinical analogy became apparent. The clinical application of this basic 
research was started in 1969. Clinical treatment of women with fibrocystic 
disease was carried out using Lugol's solution (Strong Iodine Solution, 
U.S.P.), which is a solution containing 5% by weight iodine and 10% by 
weight potassium iodide. Undesirable characteristics of Lugol's iodine are 
that it has a vile taste and has the potential to disrupt thyroid function 
because of the presence of large quantities of sodium iodide. With the 
discovery of iodine caseinate as a viable replacement for Lugol's 
solution, it became the basic treatment modality beginning in 1974. 
This protein-bound iodine, Caseoiodine-lodaminol was administered in doses 
of 10 mg per day and resulted in an improvement rate of over 90%. These 
therapeutic trials by Ghent were enlarged in 1985 to 588 Caseoiodine 
patients. The patients treated with iodine caseinate experienced definite 
improvement both subjectively and objectively. Forty-three percent were 
symptom free and their breasts had returned to normal. Fifty percent had 
residual premenstrual discomfort and fibrous tissue collections on 
examination. (Caseoiodine has a small amount of free I.sub.2 in its 
composition). In addition to the very favorable results obtained through 
the treatment of fibrocystic disease by iodine replacement therapy, 
Ghent's patients did not have the massive side effects reported by 
Greenblatt in his treatment of mammary dysplasia with danazol, as reported 
in Fertil, Steril 34, 1980. 
Most recently (in August of 1984), clinical testing was begun by Ghent for 
the treatment of fibrocystic dysplasia using an oral administration of 
elemental iodine. As a result of treatment with aqueous iodine, 90% of 
patients treated have experienced dramatic reduction in breast size caused 
by cystic formation and reduction of the fibrosis and pain associated with 
this syndrome. 
These clinical results parallel the laboratory results obtained in tests 
run concurrently by Eskin in Philadelphia. Thin section photomicrographs 
of breast tissue from female rats show not only the control of cysts, 
including the abatement of epithelial hyperplasia but additionally, the 
control and dissolution of the fibrous tissue characteristic of 
fibrocystic disease. Heretofore, the complete reversal of fibrocystic 
disease was not experienced using iodine replacement therapy. Only 
treatment with aqueous iodine resulted in the complete reversal of the 
fibrocystic dysplasia, including the control of fibrosis and thus a return 
to normal. 
FIG. 1 is a photomicrograph of the breast tissue of a human female. This 
photomicrograph illustrates epithelial hyperplasia, cyst formation and 
increased fibrous tissue associated with fibrocystic disease. Laboratory 
studies on rats by Eskin allow for a comparative study of the relative 
effect of the various prior art iodine replacement therapy, including 
sodium iodide, iodine caseinate, and elemental iodine as a treatment for 
fibrocystic disease, as illustrated by the other Figures. 
FIG. 2 is a photomicrograph of a normal female rat illustrating normal 
cellular configuration. The breast tissue includes a predominance of 
adipose tissue with no exhibition of epithelial hyperplasia, cyst spaces 
or fibrous tissue. 
In comparison, FIG. 3 illustrates rat breast tissue rendered iodine 
deficient. The iodine deficient breast tissue shows cystic spaces, 
epithelial hyperplasia and increased fibrous tissue characteristic of 
fibrocystic dysplasia. The comparison of FIGS. 2 and 3 support Eskin's 
previous findings relating iodine deficiency to fibrocystic disease first 
reported in 1970 in the New York Academy of Sciences Journal, Series II, 
Volume 32, 1970; 911-947 and updated in Iodine and Breast Cancer--A 1982 
Update, Biological Trace Element Research, Volume 5, 1983, 399-412. The 
material disclosed in these articles is incorporated herein by reference. 
FIGS. 4 and 5 show the effect of estrogens on the breast tissue from a 
female rat which was on an iodine deficient diet. FIG. 4 illustrates an 
enhancement of cystic spaces, marked increase in epithelial hyperplasia 
and increased fibrosis between the secreting acini. This is consistent 
with the findings of Fratkin reported in the paper entitled "The 
Hyperoestrogen State" presented at North Pacific Surgery Meeting in 
Tacoma, Wash., in 1980. A correlation was established between fibrocystic 
dysplasia and increased estrogen intake in milk drinkers. FIG. 5 is 
illustrative of the effect of estrogens when added to the breast tissue 
from a female rat which was on a normal iodine containing diet. The 
control rat shows some cyst formation and epithelial hyperplasia but 
without the fibrosis present in the tissue of the rat on the iodine 
deficient diet. 
The addition of the carcinogen, in this case dimethyl benzanthracene, to 
the breast tissue from a female rat on an iodine deficient diet, results 
in the progression from the benign state of fibrocystic dysplasia to overt 
malignancy as seen in FIG. 6. This finding is supportive of the inventors' 
contention that fibrocystic disease enhances the risk of breast cancer 
causing sensitization of the breast tissue to various stimuli, including 
carcinogens. This sensitization process may explain the increased 
incidence of breast cancer in women in areas of deficient iodine intake, 
reported by Moosa et al. in "Thyroid Status and Breast Cancer", Royal 
College of Surgeons, England, 53, 1975. 
FIG. 7 illustrates the effect of sodium iodine as a replacement treatment 
on breast tissue from a female rat which was on an iodine deficient diet. 
The epithelial hyperplasia regressed and the cystic spaces disappeared, 
but the fibrous tissue remained. This is consistent with the inventors' 
initial research on iodine replacement therapy for fibrocystic dysplasia 
beginning in 1969. 
The effect of iodine caseinate on the morphology of rat breast tissue is 
illustrated in FIG. 8. This figure shows the subsidence of the epithelial 
hyperplasia and the reduction in cystic spaces, however the fibrosis 
remains unchanged. 
In comparison, replacement treatment with elemental iodine is shown in FIG. 
9. This figure shows a reversal of tissue morphology to near normal with 
the return of normal adipose tissue components, subsidence of the 
epithelial hyperplasia and cyst spaces, and most notably, subsidence of 
the fibrosis (see also FIG. 2 for comparison). Heretofore, other forms of 
iodine replacement treatment of fibrocystic dysplasia have not been 
successful in the control and reversal of fibrosis. This was clearly an 
unexpected result. 
Parallel clinical testing by Ghent supports the laboratory findings of 
Eskin. Iodine replacement therapy with elemental iodine began in August of 
1984. At that time, 142 women with fibrocystic disease were treated with 
aqueous iodine. Eighty of these women were patients who had been on iodine 
caseinate therapy for varying periods of time and had a resolution of the 
cystic component but with the continued existence of fibrosis. The 
remainder of the sample group were patients who were started on aqueous 
iodine replacement therapy as the first form of treatment. 
Clinical observations of the 142 cases of fibrocystic dysplasia indicated 
that both groups of patients had uniformly good results. The first group 
still had some residual discomfort and some lumpiness from the fibrosis 
during their treatment with iodine caseinate. However, the pain was 
relieved in 90% of the patients in 4 to 16 months after being switched to 
aqueous iodine treatment. In addition, the patients indicated that their 
breasts were softer and had reduced in size by 1/4 to 2 cups in brassiere 
size. This is indicative of the reversal of the fibrosis. 
The second group consisting of de novo patients, had similar dramatic 
results in 4 to 16 months with control of pain, control of cysts, and 
control of fibrosis. These patients also noted a decrease in breast size 
by 1/4 to 11/2 cups (brassiere size). This result was obtained in 90% of 
the patients treated. 
The initial results of elemental iodine therapy were encouraging with a 
resolution of all the elements of the triad (see FIG. 9). These results 
initiated further clinical testing on human volunteers suffering from 
fibrocystic disease. Of these, two hundred fifty-three to date have had 
sufficient follow-up to allow analysis. 
It has been found that a daily dose of about 1.2 milligrams to about 6 
milligrams and preferably about 3 milligrams to about 6 milligrams of 
elemental iodine (I.sub.2) is effective to cause subsidence of fibrosis in 
breast tissue. This daily dose is calculated from a dosage rate of about 
0.07 milligram to about 0.09 milligram elemental iodine (I.sub.2) per 
kilogram body weight of the patient. The daily dose of elemental iodine 
(I.sub.2) is preferably administered as an aqueous solution. The aqueous 
solution preferably contains about 0.3 milligrams of elemental iodine per 
milliliter of solution. 
EXAMPLE 1 
Elemental Iodine Therapy Study 
The subjects of this study were volunteers who had been referred with 
nodular, painful, swollen breasts. The diagnosis of fibrocystic disease 
was made on clinical examination, thermography and mammography when the 
age of the patient permitted such diagnosis. 
As shown in FIG. 12, the study group was divided into two sections. The 
first group, the de novo group, numbered 108 and had not been treated 
previously for fibrocystic disease. The second group, the transfer group, 
numbered 145 and had been on iodine replacement therapy with caseoiodine 
for a mean of thirty months but had experienced residual discomfort and 
fibrosis. The treatment of the transfer group was suspended and all 
patients in the series received 3-6 mg of elemental iodine daily. 
In establishing the dosage of aqueous iodine required to effectively 
control all symptoms associated with fibrocystic disease, Dr. Ghent 
established a dosage range of about 1.2 milligrams to about 6 milligrams 
per day of elemental iodine in aqueous solution with 3-6 milligrams per 
day being the most effective dose as noted above. These dosages were based 
on a dosing rate of about 0.07 milligram to about 0.09 milligram of 
elemental iodine (I.sub.2) per kilogram of the patient's body weight. 
FIG. 10 shows the solubility of iodine in water and illustrates the 
relationship of iodine concentration as a function of temperature. This 
solubility curve was used to calculate the dosage range by Ghent and is 
taken from Black et al., "Use of Iodine For Disinfection" from Journal of 
American Waterworks Association, Volume 37, No. 11, November 1965. 
Further, the half life of I.sub.2 in the human appears to be eight hours 
and therefore a daily dose is necessary. This is supported by clinical 
evidence wherein 10 cases were reduced to a twice-weekly dose and within 
two weeks had a recurrence of symptoms. These clinical findings are 
supported by the inventors' previous clinical testing wherein 89.5% of 
patients who stopped iodine replacement therapy had a recurrence of 
symptoms within a nine-month period. 
The patients of the study group were reassessed at four months and sixteen 
months. As shown in FIGS. 13 and 14 the results of the study were 
classified in four classes with Class 1 representing a subjective and 
objective return to normal. The patents of Class 2 had some residual 
discomfort and some residual fibrosis. Classes 3 and 4 were considered as 
poor results with continued pain, fibrosis and cysts. 
The results in the de novo patients (FIG. 13) showed a complete subjective 
relief of breast pain and a clinical return to normal in 72% of patients 
with 26% retaining a small residual plaque of fibrosis at the fourth month 
level. As objective confirmation of the patients' changed mammary status, 
76% showed a reduction in breast size that varied from 1/4 to 2 cups in 
brassiere size. 
The transfer group illustrated the most significant results with a loss of 
residual breast discomfort and a complete resolution of fibrosis in 74% of 
the cases. A smaller percentage of patients (21%) were of Class 2 
experiencing minor cyclical pain and some remaining soft fibrosis (see 
FIG. 4). It seems that the longer the duration of the fibrocystic 
syndrome, the longer the time required for comfort and normalcy. Reduction 
in breast size was as significant as the de novo group (FIG. 13). 
EXAMPLE 2 
Comparative Study of Caseoiodine Treatment 
As noted above, Ghent and Eskin in 1985 enlarged their series of 
caseoiodine patents to 588 with an improvement rate of 93.4%. As shown in 
FIG. 11, this improvement rate was categorized originally in four classes, 
1-4. The first group accounted for 43% of a subjective and objective 
return to normal. The second group (50.4%) had some residual premenstrual 
discomfort and had fibrosis that at best was only worrisome but at worst 
could mask early malignant changes both clinically and mammographically. 
A comparison of the results obtained with caseoiodine therapy and with 
elemental iodine therapy is revealing as shown in FIG. 14. The caseoiodine 
therapy resulted in the return to normal without pain in 5.4% of patients 
(class 1), while 85.8% of patients experienced some residual premenstrual 
pain and fibrosis (class 2). The results after the patients were 
transferred to elemental iodine therapy were significant with 73.7% of 
patients returning to complete normalcy (class 1) and 21.3% again 
experiencing residual premenstrual pain and some fibrosis (class 2) at 
four months evaluation. This increased to over 90% at the 16-month 
evaluation. 
The various complications of iodine replacement therapy are listed in FIG. 
15. These include acne, nausea, diarrhea, hair thinning, hyper- and 
hypothyroidism, skin rash and iodism. An increase of pain was also 
experienced by patients: 18.5% of the de novo group and 1.3% of the 
transfer group during the treatment cycle. This pain occurred three to six 
weeks into the treatment regime and lasted from one to three weeks. The 
manifestation of pain seemed to coincide with a decrease in breast size 
and a sudden softening of the fibrosis. Once this pain had subsided it did 
not recur. 
Based on the two series of clinical patients and in consideration of the 
various complications above, elemental iodine replacement therapy has been 
found to be an effective treatment regime, more effective than other forms 
of iodine replacement therapy, including treatment using caseoiodine. 
Iodine replacement therapy generally should be considered before 
mastectomy, hormonal manipulation or neglect. 
B. Iodine As Treatment and Prophylaxis for Breast Cancer 
The present invention further provides a method and composition for the 
treatment and prophylaxis of breast cancer. Particularly, elemental iodine 
interacts with breast estrogen receptors to reduce the prevalence of 
breast cancer in susceptible animals and halt neoplastic changes in 
animals with malignant breast cancer. Published clinical studies which 
include those of the inventors, have shown evidence of iodine metabolism 
within the ducts and particularly in the terminal ducts (acini) of the 
breast (Eskin, B. A., Iodine Metabolism and Breast Cancer, Trans N.Y. Acad 
Sciences, 32: 911, 1970; Strum, J. M. et al., "Resting Human Female Breast 
Tissue Produces Iodinate Protein", J. Ultrastructure Res, 84: 130, 1983). 
The infrastructures of breast secretory cells have been shown to both 
organify iodides and to produce tyrosine/iodine compounds. 
One prominent facet obtained from this research with iodine is the effect 
of iodine deficient conditions on rat mammary glands. This deficiency can 
be obtained either through the use of an iodine deficient diet and/or 
through perchlorate treatment. Iodine deficient, but euthyroid, rats 
exhibit mammary gland abnormalities which pass through transitional 
histological steps and resemble the fibrocystic, adenomatous, and fibrotic 
diseases present in women. In both rats and women these conditions are 
benign. Thus, the rat mammary gland serves as an excellent animal model 
for breast diseases. 
Iodine deficiency causes a functional decrease in breast estrogen receptor 
activities, which disappears upon iodine replacement Intracellular 
biochemical pathways appear to be responsible for this result. The 
biochemical pathway seems to be an intracellular attraction by iodine for 
estrogen receptors. The pathway also calls for the presence of a small, 
intermediate protein which has been shown to function in active breast 
cells in combination with the iodine/tyrosine products. Thus, cell 
metabolism is altered when there is "inadequate" iodine present. 
Iodides can be oxidized to iodine in the thyroid without difficulty. 
However, in the breast the peroxidase necessary for this transition may be 
lacking or inactivated (DeSombre, E. R., et al., "Identifications, 
Subcellular Localizations and E.sub.2 Regulation of Peroxidase", Cancer 
Research, 35: 172, 1975). Further basic research in this direction 
indicates that a unique iodine treatment for the breast has the capability 
of providing normal intracellular responses. 
Several iodinated compounds and chemical forms of iodine, such as 
caseoiodine, sodium iodide (NaI) and potassium iodide (KI) have been tried 
for treating the resulting histopathologies from iodine deficiency over 
the past ten years with only minimal success. However, the inventors have 
found that when aqueous or diatomic iodine is used, the histopathology in 
the breast becomes normal. 
Trials were first performed on a rat model, and then on women for this 
benign condition. The results show that diatomic iodine should be 
considered efficacious for the treatment of the fibrocystic diseases of 
the breast (Eskin, B. A., et al., "Etiology of Mammary Gland 
Pathophysiology Induced By Iodine Deficiency", Frontiers in Thyroidology 
(Eds: Madiero-Noto, G. and Gatan, E.), New York: Plenum, 1986, p. 1027; 
Ghent, W. R., et al., "Fibrocystic Breast Dysplasia: A Deficiency 
Syndrome", Clin Invest Med (Canada), 9: A66 (R406), 1986; Ghent, W. R., et 
al., "Elemental Iodine Supplementation in Clinical Breast Dysplasia", Proc 
Am Asso Ca Res. 27: 189 (751), 1986)). 
The therapeutic iodine studies in women were originated after basic 
research in the mammary glands of rats. Iodine in its elemental form shows 
early evidence of effectiveness against neoplasia in the mammary glands. 
The interaction between iodine and the breast is not simply conjecture. 
Morbidity and mortality incidences in iodine deficient regions of the 
world have been shown to be above average for breast diseases (benign and 
malignant). Regions with adequate or excessive iodine levels have much 
lower incidences of breast diseases. Iodine deficient regions in the 
United States and Canada (described by the World Health Organization) 
similarly show a much higher census of breast cancer. 
Early studies conducted by the inventors have shown iodine deficiency 
appears to cause an increase in carcinogenesis when a known breast 
carcinogen is given to susceptible rats. In some studies, earlier onset of 
cancer is seen and in others a greater number of breast tumor sites and an 
increased size of tumor have been described. Early attempts at replacement 
with available iodides were partially responsive but in most cases they 
were actually totally ineffectual. This situation is similar to that seen 
when benign diseases were initially treated using a rat model. 
Iodine seems to be a requirement for normal cellular growth and metabolism 
in the breast. Breast tissues may be iodine deficient, although adequate 
iodides are present for thyroid or other tissue needs. However, the unique 
biochemical pathway found in the breast seems to respond best to 
replacement with diatomic (elemental) iodine (I.sub.2). 
The daily dose of elemental iodine (I.sub.2) for treatment or prophylaxis 
of breast cancer in human is the same as that for treatment of fibrocystic 
breast disease, namely about 1.2 milligrams to about 6 milligrams. A 
preferred daily dose is about 3 milligrams to about 6 milligrams. The 
daily dose is preferably administered as an aqueous solution containing 
about 0.3 milligrams of elemental iodine per milliliter of solution. 
These doses are based on a dosing rate of about 0.07 milligram to about 
0.09 milligram elemental iodine (I.sub.2) per kilogram of patient body 
weight. In the treatment of breast cancer, these daily doses will cause 
the subsidence of neoplastic changes in breast tissue, and when used for 
the prophylaxis of breast cancer, these daily doses will reduce the 
prevalence of breast cancer. 
EXAMPLE 3 
Iodine Treatment of Breast Cancer 
Since several different iodide modalities were used for evaluation without 
success, a preliminary study using iodine (diatomic, elemental) was begun 
by the inventors. This study employed Sprague-Dawley rats under severely 
iodine deficient conditions. The latter was obtained by using both dietary 
and perchlorate treatment together. While most of the histopathology 
obtained in the control rat group was noted to have only severe breast 
dysplasia, approximately 9% had evidence of neoplasia with cytological 
aberrations consistent with malignant alterations. When diatomic iodine 
was administered at a dosage of 0.5 mg per 100 gm body weight (orally or 
intraperitoneally) to the experimental groups, the breasts were noted to 
have improved and there was no evidence of persisting neoplastic changes 
in any of the rats. 
EXAMPLE 4 
Iodine Treatment of Induced Breast Tumors in Rats 
DMBA, a carcinogen, causes mammary gland neoplasia in rats. If these tumors 
contain breast peroxidase, they respond to iodine and estrogen treatment. 
However, as the tumors become less responsive to iodine (hormone 
independent), breast perixodase is found to be lacking. 
The use of perchlorate as a peroxidase-blocking agent increases the 
tumorigenesis and the effectiveness of iodide therapy. Preliminary studies 
with diatomic iodine at a dosage of about 0.5 mg per 100 gm body weight 
(orally or intraperitoneally) have shown the tumors to be more response to 
both diatomic iodine and estrogen. 
In basic research studies, elemental iodine has been shown to be necessary 
for normal estrogen receptor function in rats. A characteristic of breast 
cancer is the change in response to estrogen and estrogen receptor 
variability. 
EXAMPLE 5 
Prophylaxis Against Breast Cancer with Iodine 
Evidence for the diatomic iodine replacement thesis was obtained in a 
prophylactic treatment regime where simultaneous therapy with diatomic 
iodine as described in Example 3 above, was given to a limited number of 
prepared rats. The mammary glands showed no neoplasia secondary to this 
low iodine diet/perchlorate treatment. This preliminary study showed that 
diatomic iodine appears to restrict or abolish neoplastic growth and 
development under extreme iodine deficient conditions, where a significant 
level (9%) of neoplastic changes was predicted from the results of Example 
3. 
C. Iodine Treatment of Endometriosis 
The present invention provides a method and composition for the treatment 
of endometriosis. Particularly, elemental iodine normalizes the ovarian 
function and estrogen production to control endometriosis and alleviate 
its symptoms. 
Endometriosis is characterized by hormonally responsive endometrial tissue 
implants in extra-uterine sites. The etiology of endometriosis is thought 
to be the transplantation of uterine lining cells through the fallopian 
tubes, the lymph channels and/or the blood stream to the abdominal cavity. 
Another suggested theory is that the peritoneum undergoes metaplasia to 
produce endometrial cells without direct access to cellular transplants. 
The transplanted or transformed islands of endometrial tissue act in a 
similar fashion to the uterine cells, with swelling and then bleeding at 
the time of menstruation. 
Current treatment modalities for endometriosis are directed at the normal 
fluctuations of the estrogen/progesterone complex. Medications include 
birth control pills, masculinizing hormones such as danazol, or estrogen 
suppression drugs such as tamoxifen. In older age groups, total abdominal 
hysterectomy is the only therapy that is effective All of the medical 
therapies are aimed at masculinizing the female concerned. 
It was found that the therapeutic treatment of human patients with an 
aqueous solution of elemental iodine (I.sub.2) cause a subsidence of the 
nodularity of the patient's pelvic peritoneum. An effective dose of 
elemental iodine (I.sub.2) to cause such a subsidence of nodularity is 
about 0.07 milligram to about 0.09 milligram elemental iodine (I.sub.2) 
per kilogram of patient body weight per day. 
Such a dosing rate yields daily doses of about 1.2 milligrams to about 6 
milligrams of elemental iodine (I.sub.2). A preferred daily dose of 
elemental (I.sub.2) for the treatment of endometriosis is about 3 
milligrams to about 6 milligrams. The daily dose is preferably 
administered as an aqueous solution containing about 0.3 milligrams of 
elemental iodine per milliliter of solution. 
EXAMPLE 6 
Treatment of Endometriosis With Iodine 
In the course of treating patients with diatomic iodine for fibrocystic 
breast dysplasia (Example 1, above) three patients had a coincident 
dramatic decrease in their cyclic lower abdominal pain. Two patients (ages 
17 and 15), both with a diagnosis of endometriosis and both treated with 
birth control pills previously with little result, were treated with 
diatomic iodine for 10 and 18 months, respectively. Both had a complete 
amelioration of their pain within one cycle of starting the medication. 
As a trial, the medication was stopped in these patients, and, within one 
cycle, they had severe pain again, with increasing nodularity of the 
pelvic peritoneum on rectal examination. The subjective symptoms and 
physical findings again improved within one cycle of restarting diatomic 
iodine. 
The third patient (age 36), had proven endometriosis that responded to 
diatomic iodine therapy within two cycles, with complete relief of pelvic 
pain and improvement in the pelvic nodularity on rectal examination. Upon 
stopping her medication, she was asymptomatic for two cycles, and then her 
pain returned. 
This series of patients has responded to diatomic iodine, and during their 
trial therapy were not on any other medication. The mechanism of action of 
the diatomic iodine in control of endometriosis may be through the 
"normalization" of ovarian function and estrogen production, such as seems 
to be the case in the treatment of premenstrual syndrome. 
D. Iodine Treatment of Premenstrual Syndrome 
The present invention further relates to a method and composition for the 
treatment of premenstrual syndrome. Particularly, elemental iodine 
normalizes the ovarian function and estrogen production to alleviate the 
symptoms of premenstrual syndrome. 
Premenstrual syndrome is defined as the cyclic recurrence in the luteal 
phase of the menstrual cycle of a combination of distressing physical, 
psychological and/or behavioral changes, of sufficient severity to result 
in deterioration of interpersonal relationship and/or interference with 
normal activities. The symptoms of premenstrual syndrome include breast 
pain, swelling and tenderness, lower abdominal bloating, constipation, 
increased appetite with cravings for salt or chocolate, fatigue, emotional 
lability with temper tantrums, anger or crying, depression, anxiety with 
tension, irritability with tendency to seek confrontations, aversion to 
sexual relations, insomnia, confusion and/or violence. 
Although premenstrual syndrome has been classified as a psychiatric 
instability in the premenstrual phase, psychiatric counselling has not 
proven to be an effective treatment. Other treatment modalities include 
progesterone administration, tranquilizers and pain control medication, 
surgical removal of the ovaries and naloxone administration. However, 
these other treatment modalities are also ineffective. 
It was found that an effective treatment of premenstrual syndrome in human 
patients entailed the administration of an aqueous solution of elemental 
iodine (I.sub.2). The dose of elemental iodine (I.sub.2) had to be 
sufficient to normalize the patients's ovarian function and estrogen 
production (both of which are abnormal in patients with premenstrual 
syndrome). 
An effective amount of elemental iodine (I.sub.2) to normalize the ovarian 
function and estrogen production is about 1.2 milligram to about 6 
milligrams per day, preferably about 3 milligrams to about 6 milligrams 
per day. These doses are based on a daily dosing rate of about 0.07 
milligram to about 0.09 milligram elemental iodine (I.sub.2) per kilogram 
of patient body weight. The daily dose is preferably administered as an 
aqueous solution containing about 0.3 milligrams of elemental iodine per 
milliliter of solution. 
EXAMPLE 7 
Treatment of Premenstrual Syndrome With Iodine 
Diatomic iodine has been used for the treatment of fibrocystic disease (see 
Example 1, above). During this treatment, ten women not only had 
improvement of their breast pain, but also volunteered that their 
premenstrual syndrome was controlled in part or totally. This was 
significant because premenstrual syndrome was not discussed at their 
initial consultation, but each woman, at her four-month evaluation, 
spontaneously reported amelioration of her premenstrual syndrome within 
two menstrual cycles of beginning treatment. These women varied in age 
from 30 years to 45 years, with an average of 38 years. The dose of 
elemental iodine employed was from about 0.07 mg. to about 0.09 mg. per 
kilogram body weight per day. 
In a retrospective review, the presence of their syndrome was confirmed by 
their family doctor, and all reported failure of control of the 
premenstrual syndrome with various medications. All these patients met the 
research diagnostic criteria for premenstrual syndrome as defined by 
Steiner, Haskett and Carroll. Five were classified as moderate, and five 
as severe. Subsequent follow up has shown continuation of control of the 
syndrome. Three patients stopped their medication and within one menstrual 
cycle had a return of symptoms. 
While the present invention has been described in connection with specific 
embodiments thereof, it will be understood that it is capable of further 
modifications. This disclosure of the invention is intended to cover any 
variations, uses or adaptations of the invention following in general, the 
principles of the invention, and including such departures from the 
present disclosure as come within known and customary practice within the 
art to which the invention pertains.