S. A. Khan et al. (1) in their case-control study on serum estradiol and progesterone levels and expression of estrogen and progesterone receptors and epithelial proliferation observed an inverse correlation of serum estradiol with estrogen receptor only in control women and a direct association of estradiol with progesterone receptor only in cases. Furthermore, they did not find association of both serum estradiol and progesterone with epithelial proliferation in both cases and controls.

The report addresses a very relevant issue for epidemiological and clinical studies linking hormones to breast cancer etiology; however,the authors did not consider important methodological issues related to control of biological hormone variability that may explain such controversial results.

The first issue concerns the control of two relevant sources of hormone biological variability: (a) hormone fluctuations during the menstrual cycle; and (b) circadian rhythm. In the authors’study, blood samples were collected before surgery or during the procedure; however, there is no mention if and/or how the two sources of variability were taken into consideration. Production of hormones is characterized by strong fluctuations during the menstrual cycle (in premenopausal women). Relevant circadian variation in serum hormone concentration has been detected in premenopausal and postmenopausal women between early, late morning, and early afternoon (2). Adjustment for phase of menstrual cycle and exact time at which blood was drawn (not mentioned in the authors’ paper)could help in controlling for this possible source of error (3). Furthermore, hormone fluctuation according to ovarian cycle may also potentially affect hormone receptor expression.

The second issue concerns the technical variability in hormone, hormone receptor, and epithelial proliferation determinations. The authors did not mention the size of the error in measurement for all biomarkers,and they did not address how it was taken into consideration in the study design or in the study analysis (4).

In conclusion, study of the relation between hormones and diseases is made particularly difficult by numerous sources of variability. Careful attention should be paid to these before conclusive statements can be made regarding presence or absence of potential associations.

1
Khan S. A., Sachdeva A., Naim S., Meguid M. M., Marx W., Simon H., Halverson J. D., Numann P. J. The normal breast epithelium of women with breast cancer displays an aberrant response to estradiol.
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1999
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Panico S., Pisani P., Muti P., Recchione C., Cavalleri A., Totis A., et al Diurnal variation in testosterone and estradiol: a source of bias in comparative studies on breast cancer.
J. Endocrinol. Investig.
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1990
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Berrino F., Muti P., Micheli A., Bolelli G. F., Krogh V., Sciajno R., Pisani P., Panico S., Secreto G. Serum sex hormone levels after menopause and subsequent breast cancer.
J. Natl. Cancer Inst.
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1996
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4
McShane L. M., Dorgan J. F., Greenhut S., Damato J. J. Reliability and validity of serum hormone measurements.
Cancer Epidemiol. Biomark. Prev.
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1996
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