CORRESPONDENCE

Re: Plasma Sex Steroid Hormone Levels and Risk of Breast Cancer in Postmenopausal Women

Joanne F. Dorgan, Christopher Longcope, Frank Z. Stanczyk, Hugh E. Stephenson, Jr., Robert N. Hoover

Affiliations of authors: J. F. Dorgan, R. N. Hoover, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD; C. Longcope, Departments of Obstetrics and Gynecology and Medicine, University of Massachusetts Medical School, Worcester; F. Z. Stanczyk, Department of Obstetrics and Gynecology, University of Southern California School of Medicine, Los Angeles; H. E. Stephenson, Jr., Department of Surgery, University of Missouri Health Sciences Center, Columbia.

Correspondence to: Joanne F. Dorgan, M.P.H., Ph.D., National Institutes of Health, Executive Plaza South, Rm. 7082, Bethesda, MD 20892-7234 (e-mail: jd7g{at}nih.gov).

Sex steroid hormone concentrations in serum (or plasma) have been positively related to postmenopausal breast cancer in several cohorts. Most recently, Hankinson et al. (1) reported in the Journal that postmenopausal women in the Nurses' Health Study with elevated levels of plasma estradiol, testosterone, and dehydroepiandrosterone (DHEA) sulfate were at a significantly increased risk when the relationship of each hormone to breast cancer was analyzed separately. However, when estradiol was included in statistical models, risk estimates for testosterone were substantially attenuated and no longer statistically significant, whereas risk estimates for DHEA sulfate and estradiol were reduced only modestly. The authors concluded that plasma estradiol is probably causally related to breast cancer risk in postmenopausal women, whereas testosterone is more likely to be indirectly related to risk through its conversion to estradiol. Potential mechanisms of action for DHEA sulfate were explored.

We previously reported (2,3) an increased risk of breast cancer among postmenopausal women in the Columbia, MO, Breast Cancer Serum Bank cohort with elevated serum levels of non-sex hormone-binding globulin (SHBG)-bound estradiol, testosterone, and DHEA. We did not, however, control for estradiol when evaluating relationships of androgens with risk. Our study included 71 case subjects with two control subjects per case subject matched on age and on date and time of day of blood collection. All participants were postmenopausal women who were free of cancer and not taking exogenous estrogens when they donated blood to the serum bank. The median age of the participants at blood collection was 62 years, and the time from blood collection to diagnosis ranged from less than 1 year to 9.5 years. Written informed consent was obtained from all participants.

Serum concentrations of non-SHBG-bound estradiol, testosterone, and DHEA were significantly correlated (Spearman r = .29-.38). Relative risks (RRs) associated with these hormones both with and without mutual adjustment are summarized in Table 1.Go When all were included in a single model, the apparent association with breast cancer was attenuated slightly and similarly for estradiol and testosterone but more so for DHEA (e.g., 43%, 31%, and 83% reductions in the excess RR for the top quartiles of estradiol, testosterone, and DHEA, respectively).


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Table 1. Relative risks (RRs) (95% confidence intervals [CI]) for breast cancer by quartile of serum hormone concentrations*

 
Thus, within the limitations of our sample size, estradiol, testosterone, and possibly DHEA appeared to have independent positive effects on breast cancer risk. These results are similar to those from the ORDET (hormones and diet in the etiology of breast tumors) study (4), where mutual adjustment resulted in persistence of a testosterone effect but weakening of estradiol and DHEA sulfate effects. On the other hand, a result for testosterone similar to that of Hankinson et al. (1) was found in another cohort study (5). Differences between these studies in the specific analytes associated with risk, in the strength and consistency of the associations, and in the underlying distributions of hormone concentrations could contribute to differing results, as could the inherent difficulty in disentangling the effects of correlated variables. What is clear from these recent cohort studies, as well as from a number of case-control investigations, is that androgens are consistently found to be related to breast cancer risk. Clarification of the underlying mechanism(s) for this observation (via estrogenic and/or independent pathways) could substantially increase our understanding of the specific hormonal basis of this disease.

REFERENCES

1 Hankinson SE, Willett WC, Manson JE, Colditz GA, Hunter DJ, Spiegelman D, et al. Plasma sex steroid hormone levels and risk of breast cancer in postmenopausal women. J Natl Cancer Inst 1998;90:1292-9.[Abstract/Free Full Text]

2 Dorgan JF, Longcope C, Stephenson HE Jr, Falk RT, Miller R, Franz C, et al. Relation of prediagnostic serum estrogen and androgen levels to breast cancer risk.Cancer Epidemiol Biomarkers Prev 1996;5:533-9.[Abstract]

3 Dorgan JF, Stanczyk FZ, Longcope C, Stephenson HE Jr, Chang L, Miller R, et al. Relationship of serum dehydroepiandrosterone (DHEA), DHEA sulfate, and 5-androstene-3ß,17ß-diol to risk of breast cancer in postmenopausal women. Cancer Epidemiol Biomarkers Prev 1997;6:177-81.[Abstract]

4 Berrino F, Muti P, Micheli A, Bolelli G, Krogh V, Sciajno R, et al. Serum sex hormone levels after menopause and subsequent breast cancer. J Natl Cancer Inst 1996;88:291-6.[Abstract/Free Full Text]

5 Zeleniuch-Jacquotte A, Bruning PF, Bonfrer JM, Koenig KL, Shore RE, Kim MY, et al. Relation of serum levels of testosterone and dehydroepiandrosterone sulfate to risk of breast cancer in postmenopausal women. Am J Epidemiol 1997;145:1030-8.[Abstract]


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