Introduction: We sought to explore iodine status (expressed as urine iodine excretion) in a group of women with a variety of breast diseases to characterize the relationship between iodine and breast physiology. Methods: Demographic and clinical data were recorded and random urine iodine levels were checked in 415 euthyroid patients over 5 years during clinic visits. Results: Pre menopausal women excreted less iodine in their urine than post menopausal women. Post menopausal women who took hormone supplementation had an excretion level similar to pre menopausal women. Women with breast cancer excreted less iodine than those without, and iodine excretion increased after treatment with aromatase inhibitors. Conclusions: These results demonstrate that there is a relationship between estrogen status and iodine excretion in euthyroid women. This suggests that there may be a threshold for total body iodine required for prevention of breast disease.
Breast Cancer; Iodine; Iodide; Estrogen1. Introduction
There is a great deal of epidemiologic, clinical and basic science data to support the fact that iodine plays a role in breast physiology [1-7]. Iodine is essential for lactation and there is an association between thyroid disease and breast disease [8-10]. Animal models have suggested that iodine deficiency increases the incidence of breast dysplasia and lowers the threshold for breast carcinogenesis [2,11-14]. Several clinical trials have looked at iodine supplementation to treat fibrocystic disease and breast pain [12,15].
While the World Health Organization has established a normal daily iodine intake to avoid goiter [16] and the National Institutes of Health has determined what constitutes a normal urine iodine level [17], changes in these parameters have not been reported for women with breast disease. It is well known that variations in diet can cause fluctuations in urinary iodine levels, but only in chronic conditions. Knowing that iodine is important in breast physiology, we sought to explore iodine status (expressed as urine iodine excretion) in a group of euthyroid women with a variety of breast diseases.
2. Study Design and Methods
The Drexel University College of Medicine Institutional Review Board approved our study protocol. In adherence to this protocol, a total of 415 patients presenting to the Drexel University Women’s Health Program provided consent to participate in the study and for the results of the study to be published and were enrolled in the study between 2004 and 2009. Patients were screened and were excluded for any history of thyroid disease, surgery, or thyroid medications. Random urine iodine levels were checked during clinic visits and patient data including presentation, gynecologic history, medications, breast cancer risk factors, diagnosis, and treatment were recorded. Many women gave urine samples on 2 or more occasions, often before and after treatment for breast cancer. Some healthy volunteers gave 4 weekly specimens for our menstrual cycle study.
Urine specimens were stored in a freezer at –20˚C until batches were processed using the ion-selective electrode assay (ISE) method. This procedure involves isolation of urinary iodine by anion exchange chromatography that is then quantified by measuring the electromotive force generated at an iodide-selective electrode. The details of this procedure have been previously described [18].
Data were stored on a secure server, de-identified, and analyzed using SPSS software. Chi square, t-test, paired t-test and ANOVA were used where appropriate.
3. Results
Between 2004 and 2009, 415 patients were enrolled in the study with 451 evaluable urine specimens obtained. The demographics are reported in Table 1 with the patients separated into 2 groups based on menopausal status. The two populations are significantly different in ethnicity and prevalence of cancer. Many patients gave more than one sample during the study period, usually after a cancer diagnosis had been obtained and treatment had begun.
In order to explore the relationship between hormone status and urine iodine levels, the data was evaluated in two ways. First the urine iodine levels were compared in relation to reported menopausal state (Figure 1). Then women who were using hormone replacement therapy were moved from the post menopausal group to the pre menopausal group (high estrogen). It is clear from the graph that there was a trend towards lower urine iodine excretion in women labeled as “pre menopause”/“high” vs. “post menopause”/“low” estrogen state. The results of the analysis are reported for all women in the group, and then women without a cancer diagnosis are analyzed separately.
Looking at the urine iodine excretion in patients diagnosed with cancer vs that seen in other women, there is a trend towards lower urine iodine excretion in pre menopausal women diagnosed with cancer. When the same analysis is done for high vs low estrogen state (Figure 2), the difference becomes more apparent in the high estrogen patients.
In an effort to explore the link between hormone status, malignancy, and urinary iodine excretion a little further, we looked at our patients who gave us a second sample after they had undergone treatment for their cancer and compared them to other women who gave us multiple samples over time with no cancer diagnosis. In this analysis we identified 15 women (11 post menopausal) who gave one sample before and at least one after treatment over a median interval of 12 months (range 1 - 29). We also identified 7 women (5 post menopausal) with benign breast complaints with at least 2 samples (over a median interval of 9 months (range 4 - 11). In benign patients, the mean starting iodine level was 140 mg/l and the mean follow up level was 150 mg/l with a mean difference of 10 mg/l. In patients with a cancer diagnosis, the starting urine iodine level was 120 mg/l and increased to mean of 230 mg/l with a mean difference of 120 mg/l. (p < 0.05).
Looking specifically at the urine iodine levels in women with cancer we found that in both pre and post menopausal women, there was a trend towards lower urinary iodine levels in women with estrogen receptor (ER) positive cancers (Figure 3). The results are similar for progesterone receptor (PR) status in the group with PR positive pre menopausal women trending to have lower urinary iodine excretion than those with PR positive tumors.
Figure 4 is a graph representing the urinary iodine excretion for women with various estrogen states. The urinary iodine levels are lowest for pre menopausal women
ReferencesB. A. Eskin, H. I. Jacobson, V. Bolmarich and J. A. Murray, “Breast Atypia in Altered Iodine States: Intracellular Changes,” Senologia, Vol. 2, 1977, pp. 61-65.H. Funahashi, T. Imai, Y. Tanaka, et al., “Suppressive Effect of Iodine on DMBA-Induced Breast Tumor Growth in the Rat,” Journal of Surgical Oncology, Vol. 61, No. 3, 1996, pp. 209-213.
doi:10.1002/(SICI)1096-9098(199603)61:3<209::AID-JSO9>3.0.CO;2-FP. Garcia-Solis, Y. Alfaro, B. Anguiano, et al., “Inhibition of N-Methyl-N-Nitrosourea-Induced Mammary Carcinogenesis by Molecular Iodine (I2) but Not by Iodide (I-) Treatment Evidence That I2 Prevents Cancer Promotion,” Molecular and Cellular Endocrinology, Vol. 236, No. 1-2, 2005, pp. 49-57.B. A. Eskin, R. Shuman, T. Krouse and J. A. Merion, “Rat Mammary Gland Atypia Produced by Iodine Blockade with Perchlorate,” Cancer Research, Vol. 35, 1975, pp. 2332-2339.P. S. Yang, T. L. Yang, C. L. Liu, C. W. Wu and C. Y. Shen, “A Case-Control Study of Breast Cancer in Taiwan—A Low-Incidence Area,” British Journal of Cancer, Vol. 75, No. 5, 1997, pp. 752-756.
doi:10.1038/bjc.1997.133K. Brown-Grant, “The Iodide Concentrating Mechanism of the Mammary Gland,” Journal of Physiology, Vol. 135, No. 3, 1957, pp. 644-654.O. I. Alatise and G.N. Schrauzer, “Lead Exposure: A Contributing Cause of the Current Breast Cancer Epidemic in Nigerian Women,” Biological Trace Element Research, Vol. 136, No. 2, 2010, pp. 127-139.
doi:10.1007/s12011-010-8608-2B. A. Eskin, S. A. Murphey and M. R. Dunn, “Induction of Breast Cancer in Altered Thyroid States,” Nature, Vol. 218, No. 5147, 1968, p. 1162. doi:10.1038/2181162a0P. R. K. Bhargav, A. Mishra, G. Agarwal, A. Agarwal, A. K. Verma and S. K. Mishra, “Prevalence of Hypothyroidism in Benign Breast Disorders and Effect of Thyroxine Replacement on the Clinical Outcome,” World Journal of Surgery, Vol. 33, No. 10, 2009, pp. 2087-2093.
doi:10.1007/s00268-009-0143-yA. Vivacqua, D. Bonofiglio, L. Albanito, et al., “17betaEstradiol, Genistein, and 4-Hydroxytamoxifen Induce the Proliferation of Thyroid Cancer Cells through the g Protein-Coupled Receptor GPR30,” Molecular Pharmacology, Vol. 70, 2006, pp. 1414-1423.
doi:10.1124/mol.106.026344B. V. Stadel, “Dietary Iodine and Risk of Breast, Endometrial, and Ovarian Cancer,” Lancet, Vol. 307, No. 7965, 1976, pp. 890-891. doi:10.1016/S0140-6736(76)92102-4W. R. Ghent, B. A. Eskin, D. A. Low and L. P. Hill, “Iodine Replacement in Fibrocystic Disease of the Breast,” Canadian Journal of Surgery, Vol. 36, No. 5, 1993, pp. 453-460.B. A. Eskin, D. G. Bartuska, M. R. Dunn, G. Jacob and M. B. Dratman, “Mammary Gland Dysplasia in Iodine Deficiency. Studies in Rats,” JAMA, Vol. 200, No. 8, 1967, pp. 691-695. doi:10.1001/jama.1967.03120210077014B. A. Eskin, “Dietary Iodine and Cancer Risk,” Lancet, Vol. 2, 1976, pp. 807-808.
doi:10.1016/S0140-6736(76)90646-2J. H. Kessler, “The Effect of Supraphysiologic Levels of Iodine on Patients with Cyclic Mastalgia,” Breast Journal, Vol. 10, No. 4, 2004, pp. 328-336.
doi:10.1111/j.1075-122X.2004.21341.xWHO/UNICEF/ICIDD, “Recommended Iodine Levels in Salt and Guidelines for Monitoring Their Adequacy and Effectiveness,” WHO, Geneva, 1996.K. L. Caldwell, R. Jones and J. G. Hollowell, “Urinary Iodine Concentration: United States National Health and Nutrition Examination Survey 2001-2002,” Thyroid, Vol. 15, No. 7, 2005, pp. 692-699.
doi:10.1089/thy.2005.15.692G. E. Abraham, J. D. Flechas and J. C. Hakala, “Measurement of Urinary Iodide Levels by Ion-Selective Electrode: Improved Sensitivity and Specificity by Chromatography on Anion-Exchange Resin,” The Original Internist, Vol. 11, No. 4, 2004, pp. 19-32B. A. Eskin, C. E. Grotkowski, C. P. Connolly and W. R. Ghent, “Different Tissue Responses for Iodine and Iodide in Rat Thyroid and Mammary Glands,” Biological Trace Element Research, Vol. 49, 1995, pp. 9-19.
doi:10.1007/BF02788999L. C. Sakoda and P. L.Horn-Ross, “Reproductive and Menstrual History and Papillary Thyroid Cancer Risk: The San Francisco Bay Area Thyroid Cancer Study,” Cancer Epidemiology, Biomarkers & Prevention, Vol. 11, 2002, pp. 51-57.I. Lewy-Trenda, “Estrogen and Progesterone Receptors in Neoplastic and Non-Neoplastic Thyroid Lesions,” Polish Journal of Pathology, Vol. 53, 2002, pp. 67-72.C. Aceves, B. Anguiano and G. Delgado, “Is Iodine a Gatekeeper of the Integrity of the Mammary Gland?” Journal of Mammary Gland Biology and Neoplasia, Vol. 10, No. 2, 2005, pp. 189-196.
doi:10.1007/s10911-005-5401-5K. Brown-Grant, “The Iodide Concentrating Mechanism of the Mammary Gland,” Journal of Physiology, Vol. 135, No. 3, 1957, pp. 644-654.K. Brown-Grant, “Iodinated Compounds in Milk after Radio-Iodide Administration,” Biochimica et Biophysica Acta, Vol. 27, 1958, pp. 422-423.
doi:10.1016/0006-3002(58)90358-5B. A. Eskin, J. A. Parker, J. G. Bassett and D. L. George, “Human Breast Uptake of Radioactive Iodine,” Obstetrics & Gynecology, Vol. 44, 1974, pp. 398-402.C. Aceves, P. Garcia-Solis, O. Arroyo-Helguera, L. Vega-Riveroll, G. Delgado and B. Anguiano, “Antineoplastic Effect of Iodine in Mammary Cancer: Participation of 6-Iodolactone (6-IL) and Peroxisome Proliferator-Activated Receptors (PPAR),” Molecular Cancer, Vol. 8, No. 1, 2009, p. 33. doi:10.1186/1476-4598-8-33F. R. Stoddard II, A. D. Brooks, B. A. Eskin and G. J. Johannes, “Iodine Alters Gene Expression in the MCF7 Breast Cancer Cell Line: Evidence for an Anti-Estrogen Effect of Iodine,” International Journal of Medical Sciences, Vol. 5, No. 4, 2008, pp. 189-196.
doi:10.7150/ijms.5.189