Annotated References:
Investigating the Relationship Between Iodine and the Breast
Breastcancerchoices.org
Innovative Research and Patient Advocacy
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.