Annotated References:
Investigating the Relationship Between Iodine and the Breast
PART 1: WHAT IS THE BACKGROUND OF IODINE AND BREAST DISEASE RISK?

  • Geographical Areas of Iodine Deficiency Lead to Increased Risk of Breast Cancer

Editor's Note: The author below found that from 1990-1993, the US had 22.3 deaths per
100,000 women of breast cancer, placing them in 45th place in the world, while in Japan, where
they have high dietary iodine, there were 6.6 deaths per 100,000, placing them in 13th place
(Cancer Statistics, 1997). These findings tally with the study below finding that the low intake of
dietary iodine, found due to geographical differences, leads to a risk of breast, endometrial,
and ovarian cancer.

Lancet. 1976 Apr 24;1(7965):890-1.
Dietary Iodine and Risk of Breast, Endometrial, and Ovarian Cancer
by Stadel BV

Geographic differences in the rates of breast, endometrial, and ovarian cancer appear to be
inversely correlated with dietary iodine intake.  Endocrinological considerations suggest that a
low dietary iodine intake may produce a state of increased effective gonadotrophin stimulation,
which in turn may produce a hyperoestrogenic state characterised by relatively high production
of oestrone and oestradiol and a relatively low oestriol to oestrone plus oestradiol ratio.  This
altered endocrine state may increase the risk of breast, endometrial, and ovarian cancer.
Increasing dietary iodine intake may reduce the risk of these cancers.

  • Estrogen Receptors More Sensitive to Estrogen When Iodine Deficient

Editor's Note: The author below found iodine-deficient breasts show changes in RNA/DNA
ratios, estrogen receptor proteins, and cytosol iodine levels. Iodine is a necessary element for
breast tissue growth and development.  

Adv Exp Med Biol. 1977,91:293-304
Iodine and mammary cancer.
by Eskin BA.

From laboratory studies presented, iodine appears to be a requisite for the normalcy of breast
tissue in higher vertebrates. When lacking, the parenchyma in rodents and humans show
atypia, dysplasia, and even neoplasia. Iodine-deficient breast tissues are also more
susceptible to carcinogen action and promote lesions earlier and in greater profusion.
Metabolically, iodine-deficient breasts show changes in RNA/DNA ratios, estrogen receptor
proteins, and cytosol iodine levels. Clinically, radionuclide studies have shown that breast
atypia and malignancy have increased radioactive iodine uptakes. Imaging of the breasts in
high-risk women has localized breast tumors. The potential use of breast iodine determination
to determine estrogen dependence of breast cancer has been considered and the role of
iodide therapy discussed. In conclusion, iodine appears to be a compulsory element for the
breast tissue growth and development. It presents great potential for its use in research
directed toward the prevention, diagnosis, and treatment of breast cancer.   


  • Iodine Deficiency Increases Ovarian Production of  Estrogen

Editor's Note: The 2005 study below found that ovarian estrogen production increases during
an iodine-deficient state, while changes in the estrogen receptors in iodine-deficient breasts
make them more sensitive to circulating estrogens (Eskin above).  A diet low in iodine can lead
to a hyperestrogen state with high estrone and estradiol and a low estriol to estrone ratio that
can lead to cancer (Stadel above).


Domest Anim Endocrinol. 2005 Jul;29(1):97-103. Epub 2005 Apr 7.
Ovarian iodide uptake and triiodothyronine generation in follicular fluid. The enigma of the
thyroid ovary interaction.
by Slebodzinski AB.

Polish Academy of Sciences, ul. Promienista 166A/34, 60-157 Poznan, Poland.

Since 1928, the iodine concentration in the ovary has been known to be higher than in every
other organs except the thyroid. The ovarian iodide uptake varies with sexual activities, is
enhanced by estrogens and a hypothyroid state and blocked by goitrogens. The recent
discovery of a sodium iodide symporter (NIS) in ovaries has offered a possible mechanism for
ovarian iodide uptake and other functional similarities to its thyroid counterpart. Nevertheless,
the physiological significance of ovarian iodine uptake and accumulation remains unknown.
The presence of thyroid hormones (TH) in follicular fluid (FF) has been established recently.
Our preliminary studies on TH in FF (1996-1998) in rabbits, pigs, horses showed that the
concentration of T4 is generally lower than that in serum and that for T3 is within the normal
range or higher. A positive correlation exists between the T4 levels in FF and serum but not
between the corresponding T3 levels. These studies revealed, for the first time, the presence
of the ovarian 5'-monodeiodinase system in FF capable of generating T3 (ovary-born T3) by
outer ring deiodination of T4. In mares, seasonal polyestrus, ovarian 5'-monodeiodinase (MD)
activity and FF T3 levels have been found to be higher during the ovulatory period than in the
anovulatory one. The exact physiological significance of this system generating T3 and
coexisting with isoforms of TH receptors in granulosa cells has not been elucidated. A direct
role of T3 for the early follicular development, differentiation and for the steroidogenic capability
of granulosa cells, although strongly suggested by data obtained from in vitro studies, has to
be elucidated.


  • Effect of Blocking Iodine in Rats Causes Human-Like Fibrocystic Changes

Editor's Note: The authors below found that blocking dietary iodine and imposing a chemical
blockade of iodine in female rats, from the midreproductive to perimenopausal years,
progressively caused human-like fibrocystic disease in the rats. The older 52-week-old rats
exhibited atypical lobules, papillomas, sclerosing adenosis, calcifications, and lobular
dysplasia.


Arch Pathol Lab Med. 1979 Nov;103(12):631-4.
Age-related changes resembling fibrocystic disease in iodine-blocked rat breasts
by Krouse TB, Eskin BA, Mobini J.

It has been reported that dietary restriction and chemical blockade of iodine causes
histopathologic changes in peripubertal female rat breasts. This study extended the age range
to include midreproductive life and perimenopausal rats; there is a wider spectrum of structural
alterations that are associated with the older breast, with sodium perchlorate as the blocking
agent. In 16-week-old rats, breasts showed general increased parenchymal activity and
growth, regressing after removal of the block. In 42-week-old rats, breasts showed noticeable
calcospherite deposition, intralobular fibrosis, and cystic changes resembling human
fibrocystic disease. In 52-week-old rats, breasts exhibited atypical lobules cytologically,
papillomatosis, sclerosing adenosis, calcifications, and a lobular transformation of a
histologically dysplastic type. It is the older rat that experiments will more closely parallel the
human condition.


  • Iodine, as Opposed to Iodide,  Effective in Diminishing Ductal Hyperplasia and
    Perilobular Fibrosis Secondary to Iodine Deficiency

Editor's Note: The authors below observed that for iodine-deficient rats that manifest atypical
breast and thyroid tissues, supplementing with iodine helped with the breast and iodide helped
with the thyroid.

Biol Trace Elem Res.  1995.Jul;49(1):9-19
Different tissue responses for iodine and iodide in rat thyroid and mammary glands
by Eskin BA, Grotkowski CE, Connolly CP, Ghent WR.

Department of Obstetrics and Gynecology, Medical College of Pennsylvania, Philadelphia
19129, USA.

This research describes the effects of short-term elemental iodine (I2) and iodide (I-)
replacement on thyroid glands and mammary glands of iodine-deficient (ID) Sprague-Dawley
female rats. Iodine deficiency causes atypical tissue and physiologic changes in both glands.
Tissue histopathology and the endocrine metabolic parameters, such as serum TT4, tissue
and body weights, and vaginal smears, are compared. A moderate reduction in thyroid size
from the ID control (IDC) was noted with both I- and I2, whereas serum total thyroxine
approached the normal control with both I- and I2, but was lower in IDC. Thyroid gland IDC
hyperplasia was reduced modestly with I2, but eliminated with I-. Lobular hyperplasia of the
mammary glands decreased with I2 and increased with I- when compared with the IDC;
extraductal secretions remained the same as IDC with I2, but increased with I-; and periductal
fibrosis was markedly reduced with I2, but remained severe with I-. Thus, orally administered
I2 or I- in trace doses with similar iodine availability caused different histopathological and
endocrine patterns in thyroid and mammary glands of ID rats. The significance of this is that
replacement therapy with various forms of iodine are tissue-specific.

  • Benefits of Supplementing  Iodine in Women with Fibrocystic Disease: Breast
    Reduction + Reduced Symptoms

Editor's Note: As cited above, for iodine-deficient rats, iodine was more beneficial than iodide
for the mammary gland. Similarly, for  humans with fibrocystics breasts, the patients incurred
more benefits from supplementing with iodine rather than iodide.  The benefits included a
reduction in breast size and remission of disease symptoms.

Can J Surg.1993 Oct;36(5):453-60.  
Iodine replacement in fibrocystic disease of the breast.
by Ghent WR, Eskin BA, Low DA, Hill LP.

Department of Surgery, Queen's University, Hotel Dieu Hospital, Kingston, Ont.

OBJECTIVE: To determine the response of patients with fibrocystic breast disease to iodine
replacement therapy. DESIGN: Review of three clinical studies beginning in 1975: an
uncontrolled study with sodium iodide and protein-bound iodide; a prospective, control,
crossover study from iodide to molecular iodine; and a prospective, control, double-blind study
with molecular iodine. SETTING: University affiliated breast-treatment clinics. PATIENTS: Study
1: 233 volunteers received sodium iodide for 2 years and 588 received protein-bound iodide for
5 years. Study 2: the treatment of 145 patients from study 1 treated with protein-bound iodide
for several months who still had symptoms was switched to molecular iodine 0.08 mg/kg; 108
volunteers were treated initially with molecular iodine. Study 3: 23 patients received molecular
iodine, 0.07 to 0.09 mg/kg body weight; 33 received an aqueous mixture of brown vegetable
dye and quinine. The numbers in study 2 increased over the review period so that 1365
volunteers were being treated with molecular iodine by 1989. INTERVENTIONS: All patients in
study 3 had pre- and post-treatment mammography and measurement of serum
triiodothyronine, thyroxine and thyroid-stimulating hormone levels. MAIN OUTCOME
MEASURES: Subjective evaluation--freedom from pain--and objective evaluation--resolution of
fibrosis. RESULTS: Study 1: 70% of subjects treated with sodium iodide had clinical
improvement in their breast disease, but the rate of side effects was high; 40% of patients
treated with protein-bound iodide had clinical improvement. Study 2: 74% of patients in the
crossover series had clinical improvement, and objective improvement was noted in 72% of
those who received molecular iodine initially. Study 3: in the treatment group 65% had
subjective and objective improvement; in the control group there was a subjective placebo
effect in 33% and an objective deterioration of 3%. CONCLUSIONS: The fibrocystic breast
reacts differently to sodium iodide, protein-bound iodide and molecular iodine.  Molecular
iodine is nonthytropic and was the most beneficial.

  • Breast Pain Associated with Fibrocystic Disease: Iodine Helped Relieve Symptoms in
    Dose-Dependent Manner

Editor's Note: The author below found patients with breast pain associated with fibrocystic
disease experienced iodine-dependent symptom relief after taking iodine. Of patients taking
1.5 mg., 3.0 mg., or 6.0 mg. a day of iodine for six months for breast pain associated with
fibrocystic disease, more than 50% of patients taking 6.0 mg. for six months reported less
pain. After five months, physician assessment of reduction in pain, tenderness and nodularity
was seen in the women taking 3.0 mg. and 6.0 mg. of iodine a day - but not in the women
taking just 1.5 mg. a day.    

The Breast Journal, Volume 10, Number 4, 2004 328-336
The Effect of Supraphysiologic Levels of iodine on Patients with Cyclic Mastalgia
by Jack H. Kessler, Ph.D.

A randomized, double-blind, placebo-controlled, multicenter clinical trial was conducted with
111 otherwise healthy euthyroid women wiht a history of breast pain.  Patients had to
document moderate or severe breast pain by recording a score> 5 on a visual analog scale
(VAS) of pain for > 6 days per cycle and had to present with fibrosis involving at least 25% of
both breast surfaces.  Subjects could not be effectively treated wiht more conservative
measures such as local heat or nonprescription analgesics.  There was not a stastically
significant difference in the dropout rate for patients on placebo (11.8%), 1.5 mg/day (31.3%),
3.0 mg/day (18.4%), or 6.0 mg/day (25%) of molecular idodine for 6 months.  Physicians
assessed breast pain, tenderness, and nodularity each cycle.  A statistically significant
improvement (p<0.01) associated with dose was observed in the Lewin overall pain scale for
all treated groups compared to placebo.  Reductions in all three physician assessments were
observed in patients after 5 months of therapy in the 3.0 mg/day (7/28; 25%) and 6.0 mg/day
(15/27; 18.5%) treatment groups, but not the 1.5 mg/day or placebo group. Patients recorded
statistically significant decreases in pain by month 3 in the 3.0 and 6.0 mg/day treatment
groups, but not the 1.5 mg/day or placebo group;  more than 50% of the 6.0 mg/day treatment
group recorded a clinically significant reduction in overall pain. All doses were associated with
an acceptable safety profile.  No dose-related increase in any adverse event was observed.

  • Breast Pain Associated with Fibrocystic Disease:  Seaweed Helped 94% of Women
    Reduce Symptoms

Editor's Note: The authors below found 94% of patients taking tablets of brown sea alga
containing iodine, chlorophyll and Omega-3 fats for three months experienced pain relief and
breast cyst regression.

Vopr Onkol. 2005;51(2):236-41.
Investigation of the drug "Mamoclam" for the treatment of patients with fibroadenomatosis
of the breast
by Bezpalov VG, Barash NIu, Ivanova OA, Semenov II, Aleksandrov VA, Semiglazov VF.

The clinical trial of a new drug "mamoclam" was carried out in patients with benign breast
disease. The drug contains omega-3 polyunsaturated fatty acids, iodine and chlorophyll
derivatives and is produced from the brown sea alga laminaria. The study involved 33 patients
(mean age 42.5 +/- 1.1 yrs). Two tablets were administered thrice a day for three months.
Examination included clinical evaluation of symptoms of mastopathy and dysalgomenorrhea,
breast sonography and mammography. Therapeutic response presented as reduced
mastalgia, premenopausal syndrome, dysmenorrhea and algomenorrhea, breast cyst
regression as well as attenuated pain associated with benign breast disease and palpation.
Positive response was reported in 94%. The drug should be recommended for benign breast
disease treatment.

  • Benign Breast Disease Increases Risk of Developing Breast Cancer

Editor's Note: In the 2005 Mayo Clinic study below,  benign breast disease ,most specifically,
the category of  the benign breast lesion, was found to be an important factor in the subsequent
development of breast cancer. Benign breast lesions, biopsied in over 9,000 women,  were
classified as either nonproliferative,  proliferative without atypia, and atypical hyperplasia, and
these biopsied women were followed for a median of 15 years to see if they developed breast
cancer. All of the women had an increased risk of breast cancer that persisted for at least 25
years after the biopsy.  "One form of benign breast disease, atypical hyperplasia, or atypia, is
characterized by abnormal cell growth and can be precancerous.  Women with this condition
have a four times greater risk of developing breast breast cancer."  Of the 235 women with
atypia (out of the over 9,000 biopsies studied),  41 went on to develop breast cancer in 15-20
years. (Abstract No. 2353, AACR presentation, April 2006.)

N Engl J Med. 2005 Jul 21;353(3):229-37.
Benign breast disease and the risk of breast cancer
by Hartmann LC, Sellers TA, Frost MH, Lingle WL, Degnim AC, Ghosh K, Vierkant RA, Maloney
SD, Pankratz VS, Hillman DW, Suman VJ, Johnson J, Blake C, Tlsty T, Vachon CM, Melton LJ
3rd, Visscher DW. Division of Medical Oncology, Mayo Clinic College of Medicine, Rochester,
MN 55905, USA.

BACKGROUND: Benign breast disease is an important risk factor for breast cancer. We
studied a large group of women with benign breast disease to obtain reliable estimates of this
risk. METHODS: We identified all women who received a diagnosis of benign breast disease
at the Mayo Clinic between 1967 and 1991. Breast-cancer events were obtained from medical
records and questionnaires. To estimate relative risks, we compared the number of observed
breast cancers with the number expected on the basis of the rates of breast cancer in the Iowa
Surveillance, Epidemiology, and End Results registry. RESULTS: We followed 9087 women for
a median of 15 years. The histologic findings were nonproliferative lesions in 67 percent of
women, proliferative lesions without atypia in 30 percent, and atypical hyperplasia in 4 percent.
To date, 707 breast cancers have developed. The relative risk of breast cancer for the cohort
was 1.56 (95 percent confidence interval, 1.45 to 1.68), and this increased risk persisted for at
least 25 years after biopsy. The relative risk associated with atypia was 4.24 (95 percent
confidence interval, 3.26 to 5.41), as compared with a relative risk of 1.88 (95 percent
confidence interval, 1.66 to 2.12) for proliferative changes without atypia and of 1.27 (95 percent
confidence interval, 1.15 to 1.41) for nonproliferative lesions. The strength of the family history
of breast cancer, available for 4808 women, was a risk factor that was independent of
histologic findings. No increased risk was found among women with no family history and
nonproliferative findings. In the first 10 years after the initial biopsy, an excess of cancers
occurred in the same breast, especially in women with atypia. CONCLUSIONS: Risk factors for
breast cancer after the diagnosis of benign breast disease include the histologic classification
of a benign breast lesion and a family history of breast cancer.


CONCLUSION:  Breast Cancer Choices is calling for immediate iodine trials to begin with
women who have benign breast disease to see if supplementing iodine will reduce the
chances of developing breast cancer.
Breastcancerchoices.org
Innovative Research and Patient Advocacy