© The Author 2007. Published by Oxford University Press.
CORRESPONDENCE |
Response: Re: Endogenous Steroid Hormone Concentrations and Risk of Breast Cancer Among Premenopausal Women
Affiliations of authors: Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (AHE, SEH); Department of Epidemiology, Harvard School of Public Health, Boston, MA (AHE, SEH); Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (RLB)
Correspondence to: A. Heather Eliassen, ScD, Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 181 Longwood Ave, Boston, MA 02115 (e-mail: heather.eliassen{at}channing.harvard.edu).
We appreciate the comments by Micheli et al. The data they present are intriguing, particularly the stronger association they found between progesterone level and breast cancer risk after further adjustment for luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels. We agree with Micheli et al. that the timing of hormone measurements within the menstrual cycle is of critical importance in assessing the relationship between hormone levels that vary cyclically, such as progesterone, and breast cancer risk.
A number of important differences exist between the Hormones and Diet in the Etiology of Breast Tumors (ORDET) study and our analysis in the Nurses’ Health Study II (NHSII) that may have contributed to our discrepant findings, including differences between case and control subjects within each study (1,2). Given the fluctuation in progesterone level across the menstrual cycle, if case and control subjects are sampled at differing times in the cycle, spurious associations could be detected or a true association could be hidden. In this regard, it is essential to match case and control subjects on the day within the menstrual cycle that their hormone levels were sampled. In the ORDET study, although blood was collected between the 20th and 24th days of the menstrual cycle, the length of the menstrual cycle, and therefore the number of days to the next cycle, differed between the case and control subjects. Case subjects had shorter cycles than control subjects (27.7 versus 29.4 days) and fewer days between blood collection and the start of the next cycle (7.1 versus 9.1 days) (1). As Micheli et al. stated, the follicular phase is much more likely to differ between individuals than the luteal phase (3). Thus, blood collected 7 days before the next cycle is likely to represent levels later in the luteal phase than blood collected 9 days before the next cycle. By contrast, in the NHSII, control subjects were matched to case subjects on luteal day (counting backward from the start of the next cycle). Given this matching, the number of days between blood collection and the start of the next cycle was nearly identical for case and control subjects (7.6 versus 7.7 days) (2).
To compensate for the difference in sample timing between case and control subjects, Micheli et al. adjusted for the number of days to the start of the next menstrual cycle in their analysis and further attempted to "synchronize" case and control subjects by additionally adjusting for LH and FSH levels. We feel this is an innovative approach to control for menstrual cycle day differences between case and control subjects, but one that may not apply in our study, given that we matched case and control subjects on luteal day (counting backwards).
Micheli et al. also suggested that we reanalyze our data by restricting the analysis to women with regular menstrual cycles. To achieve this restriction, we excluded women who 1) had anovulatory cycles when blood was collected, 2) had either short (<3 days) or long (>21 days) time from blood collection to the start of the next cycle, or 3) reported having irregular cycles between the ages of 18 and 22 years. Among the remaining 126 case subjects and 260 control subjects, progesterone level was still not inversely associated with the risk of breast cancer (relative risk = 1.4, 95% confidence interval = 0.7 to 2.8; Ptrend = .11).
REFERENCES
(1) Micheli A, Muti P, Secreto G, Krogh V, Meneghini E, Venturelli E, et al. (2004) Endogenous sex hormones and subsequent breast cancer in premenopausal women. Int J Cancer 112:312–8.[CrossRef][ISI][Medline]
(2) Eliassen AH, Missmer SA, Tworoger SS, Spiegelman D, Barbieri RL, Dowsett M, et al. (2006) Endogenous steroid hormone concentrations and risk of breast cancer among premenopausal women. J Natl Cancer Inst 98:1406–15.
(3) Waller K, Swan SH, Windham GC, Fenster L, Elkin EP, Lasley BL. (1998) Use of urine biomarkers to evaluate menstrual function in healthy premenopausal women. Am J Epidemiol 147:1071–80.
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J Natl Cancer Inst 2007 99: 408-409.
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