© The Author 2007. Published by Oxford University Press.
CORRESPONDENCE |
Re: Endogenous Steroid Hormone Concentrations and Risk of Breast Cancer Among Premenopausal Women
Affiliations of authors: Dipartimento di Medicina Preventiva e Predittiva, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italia (AM, GS, EM, VK, EV, FB); Unità di Epidemiologia, Istituto Tumori Regina Elena, Roma, Italia (PM)
Correspondence to: Andrea Micheli, PhD, Dipartimento di Medicina Preventiva e Predittiva, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milano, Italia (e-mail: andrea.micheli{at}istitutotumori.mi.it).
The case–control study nested within the Nurses’ Health Study II by Eliassen et al. (1) provides further evidence that circulating sex hormone levels are associated with breast cancer risk. They found that high prediagnostic estrogen and androgen levels were associated with an increased risk of breast cancer in premenopausal women but that there was no association with progesterone levels. Two prospective studies, Hormones and Diet in the Etiology of Breast Tumors [ORDET; (2)] and European Prospective Investigation into Cancer and Nutrition [EPIC; (3)], also showed that a high androgen level was associated with an increased risk of breast cancer but that progesterone level was inversely associated with breast cancer risk.
It is difficult to investigate associations between breast cancer risk and sex hormones in premenopausal women because hormone levels vary markedly during the menstrual cycle. The approach taken by Eliassen et al. was to separately analyze cryopreserved blood samples that were collected during the luteal and follicular phases of each woman's menstrual cycle. To better synchronize the timing of blood collection within the cycles, they counted backward from the day on which the woman's next menstrual period started to the blood-sampling day and used the number of days counted to adjust estimates of the relative risk of breast cancer.
The ORDET study was designed to assess whether ovarian hyperandrogenism associated with anovulation or luteal inadequacy increased breast cancer risk (4,5); estrogens were not investigated. We controlled for intraindividual hormone variation by collecting blood samples during a narrow window of the menstrual cycle (days 20–24) when most women are in the midluteal phase of their menstrual cycle. Women in the ORDET study also gave the date of their next period and information about their menstrual history. When we plotted the mean levels of progesterone, testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) according the number of days from blood sampling to the start of bleeding in the control subjects, we found that the resulting curves were similar to the familiar blood concentration curves for these substances in the latter half of the cycle. This finding suggested that backward counting is a reliable way of synchronizing when blood was sampled among women who have menstrual cycles of varying length.
However, compared with the control subjects, the ORDET case subjects had shorter times from blood sampling to the start of their next menstrual period, shorter cycles, and distinctly lower LH and FSH levels (2). Because the length of the luteal phase varies less than the length of the follicular phase (6), the implication of these findings is that the timing of blood sample collection in the luteal phase differed between the case subjects and the control subjects. We noticed that, regardless of the timing of blood sample collection relative to subsequent bleeding, the progesterone levels were higher among control subjects who had low LH levels than among control subjects with high LH levels. High LH levels indicate that blood samples were taken close to the ovulatory surge, when the progesterone level was still low. Thus, we concluded that the backward counting method was insufficient to completely synchronize the day of sampling within the cycle. We therefore used gonadotropin levels as additional "synchronizers", by incorporating LH and FSH levels (as well as the number of days from sampling to the next menses) into logistic regression models to estimate the relative risks of breast cancer in relation to hormone levels (2). Table 1 shows relative risks associated with tertiles of progesterone levels in models with different "synchronizing" variables (2) among women with regular cycles (assessed without knowledge of case–control status). Each variable improves the strength of the association between lower breast cancer risk and higher progesterone level. A similar improvement in the strength of the association occurred when women with irregular cycles were included, although the association did not reach statistical significance.
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On the basis of these findings, we suggest that Eliassen et al. retest the association between progesterone level and breast cancer risk by including adjustments for LH and FSH levels in their analysis. It might also be useful to restrict the analysis to women with regular menstrual cycles. We suspect that a relationship between progesterone level and breast cancer risk was obscured in their previous analyses by insufficient synchronization of sampling days between case and control subjects.
REFERENCES
(1) 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.
(2) 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]
(3) Kaaks R, Berrino F, Key T, Rinaldi S, Dossus L, Biessy C, et al. (2005) Serum sex steroids in premenopausal women and breast cancer risk within the European Prospective Investigation into Cancer and Nutrition (EPIC). J Natl Cancer Inst 97:755–65.
(4) Grattarola R. (1964) The premenstrual endometrial pattern of women with breast cancer: a study of progestational activity. Cancer 17:1119–22.[CrossRef][ISI][Medline]
(5) Grattarola R. (1973) Androgens in breast cancer. I. Atypical endometrial hyperplasia and breast cancer in married premenopausal women. Am J Obstet Gynecol 116:423–8.[ISI][Medline]
(6) Sherman BM and Korenmann SG. (1974) Measurement of serum LH, FSH, estradiol and progesterone in disorders of the human menstrual cycle: the inadequate luteal phase. J Clin Endocrinol Metab 39:145–9.[ISI][Medline]
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J Natl Cancer Inst 2007 99: 409-410.
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