David Cohen, M.D.·Published 6 June 2008·13 min read
Key points
Several lines of evidence have long suggested that sex hormones play a central role in the etiology of breast cancer.
Methodologic Issues in Studies of Endogenous Hormones and Breast Cancer Risk In contrast to clinical determinations, in which discerning grossly abnormal from normal hormone levels is the focus, epidemiologic studies are usually aimed at detecting modest differences within the normal range of levels.
Several hormones, particularly estrogens, fluctuate markedly over the menstrual cycle.
For both logistic and financial reasons, in most epidemiologic studies, only a single blood sample can be collected per study subject.
Several lines of evidence have long suggested that sex hormones play a central role in the etiology of breast cancer. As noted in the section Age-Incidence Curve of Breast Cancer Risk, rates of breast cancer increase rapidly in the premenopausal years, but the rate of increase slows sharply at the time of menopause, when endogenous hormone levels decline rapidly. In addition, several reproductive variables that alter estrogen status affect risk of breast cancer; for example, early age at menarche and late age at menopause are associated with increased risk of breast cancer. After menopause, adipose tissue is the major source of estrogen, and obese postmenopausal women have both higher levels of endogenous estrogen and a higher risk of breast cancer. In animals, estrogens and progesterone promote mammary tumors. Also, hormonal manipulations, such as administration of antiestrogens (e.g., tamoxifen citrate), are useful in the treatment of breast cancer and reduce breast cancer incidence in high-risk women. Despite this strong body of evidence suggesting a central role of endogenous estrogen, studies directly relating blood or urinary hormone levels to risk of breast cancer have largely been inconsistent. Only with the availability of large prospective studies has a clearer picture emerged.
Methodologic Issues in Studies of Endogenous Hormones and Breast Cancer Risk In contrast to clinical determinations, in which discerning grossly abnormal from normal hormone levels is the focus, epidemiologic studies are usually aimed at detecting modest differences within the normal range of levels. Considerable laboratory error has been reported in studies of assay reproducibility, and several hormones are measured quite poorly by some laboratories. Low reproducibility could result in failure to detect true (and important) exposure-disease associations. Varying sensitivities and specificities of different laboratory assays also have made comparison of results between studies difficult. For example, in studies of plasma estradiol levels, mean levels in control subjects have ranged from 9 pg per mL81 to 28 pg per mL. Although these differences may result in part from differences in the characteristics of study subjects (i.e., differences in adiposity), a substantial component is probably due to the use of varying laboratory methods.
Several hormones, particularly estrogens, fluctuate markedly over the menstrual cycle. In some early studies, hormone levels were measured in samples collected without regard to the menstrual cycle phase, thus adding considerable noise to the comparison of hormone levelsbetween breast cancer cases and controls. This noise could mask true associations or, because of chance differences in the distribution of cycle phase between cases and controls, could result in associations that do not truly exist. Wih better understanding of such methodologic issues, studies have begun to collect all samples at approximately the same time in the cycle, have matched on cycle day, or have carefully controlled for cycle day in the analysis - all appropriate strategies.
Written and revised by
David Cohen, M.D.
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For both logistic and financial reasons, in most epidemiologic studies, only a single blood sample can be collected per study subject. Whether a single sample can reflect long-term hormone levels (generally the exposure of greatest etiologic interest) is therefore an important issue. In several studies, repeated blood samples were collected over a 1- to 3-year period in postmenopausal women, and the correlation between the samples was calculated. Overall, levels of steroid hormones were reasonably stable, with intraclass correlations ranging from 0.5 to 0.9. This level of reproducibility is similar to that found for other biological variables, such as blood pressure and serum cholesterol measurements, all parameters that are considered reasonably measured and that are consistent predictors of disease in epidemiologic studies. Data on premenopausal women are much more limited, although androgen levels have been noted to be reasonably correlated over a several-year period.
The complexity and expense of hormone assays, coupled with the need to collect urine or blood samples from study subjects (and timed samples in premenopausal subjects) have resulted in both a limited number of epidemiologic studies of these issues and small sample sizes. These factors, in conjunction with error in the laboratory assays, have likely contributed to the lack of consistent findings. A summary, which relies when possible predominantly on the larger studies and those using a prospective design, is provided in the sections below.
Estrogens Estradiol, considered the most biologically active endogenous estrogen, circulates in blood either unbound ("free") or bound to sex hormone-binding globulin or albumin. Free or bioavailable (free plus albumin-bound) estradiol is thought to be readily available to breast tissue and thus may be more strongly related to risk than total estradiol. Postmenopausally, estrone is the source of most circulating estradiol, and estrone sulfate is the most abundant circulating estrogen. Both normal and malignant breast cells have sulfatase and aromatase activity, so estrone and estrone sulfate could serve as a ready source of intracellular estradiol.
Among postmenopausal women, the most consistent finding is a positive relationship between total estradiol and risk of breast cancer. In a meta-analysis of six prospective studies, breast cancer patients had mean estradiol levels that were 15% higher (p <.001) than those of healthy controls. Similarly, among 16 case control studies, breast cancer patients were noted to have mean levels 24% higher than levels in controls, although substantial heterogeneity in results was noted among these studies.
Results of the largest prospective study have been published since this meta-analysis. Blood samples were collected from 32,826 women in the Nurses' Health Study from 1989 to 1990; among postmenopausal women not using hormone replacement therapy at blood collection, 156 women were diagnosed with breast cancer after blood collection. Two controls were selected per case, matched on age, menopausal status, and time of blood collection. A significant positive association between plasma estradiol level and risk of breast cancer was seen (top versus bottom quartile comparisons: multivariate relative risk, 1.9; 95% confidence interval, 1.2 to 3.5). Among women with no prior use of postmenopausal hormone therapy (for whom the single plasma hormone measure would best reflect past hormone levels), the association was markedly stronger (relative risk, 3.8; 95% confidence interval, 1.6 to 8.7). The comparable relative risk for women with high levels of plasma estrone sulfate was 4.3 (95% confidence interval, 1.9 to 10.1).
Other estrogens and estrogen fractions have not been as thoroughly evaluated as total estradiol. Percent free estradiol has been assessed in four prospective studies; a positive relationship was noted in three but not in the fourth. Percent bioavailable estradiol was positively associated with risk in one study but not in a second. Higher estrone levels were significantly associated with increased breast cancer risk in several studies but not in all. Similarly, findings for estrone sulfate (evaluated in only three studies) have been somewhat inconsistent.
Overall, the epidemiologic data now provide strong evidence for an influence of plasma estrogens on breast cancerrisk in postmenopausal women based largely on the substantial evidence for total estradiol. However, the specific estrogens and estrogen fractions most related to risk, and the dose-response relationship, remain to be defined.
Data on premenopausal estrogen levels and breast cancer risk are more limited, in large part because of the complexities related to sampling during the menstrual cycle. Data from several case control studies, but not others, suggest that high levels of estradiol in premenopausal women increase the risk of breast cancer. In the largest prospective analysis to date, involving 61 cases, estradiol levels were 12% higher in women who developed breast cancer than in controls. A second prospective study, with 22 cases, reported a nonsignificant increased risk for women with higher estrone and estradiol levels in the follicular phase but not the luteal phase of the menstrual cycle, whereas a third study found no association. To date, few studies have evaluated free or bioavailable estradiol levels in premenopausal women.{pagebreak}
Estrogen Metabolites A woman's pattern of estrogen metabolism has also been hypothesized to influence her breast cancer risk. Estradiol and estrone can be metabolized through one of two mutually exclusive pathways, the 16a and 2-hydroxy pathways. Products of these two pathways have markedly different biological properties, and opposing hypotheses have been proposed concerning their influence on risk.
The epidemiologic studies that evaluated associations between levels of estrogen metabolites and breast cancer risk have been small (the largest had 42 cases), and results are inconsistent. In the only study of premenopausal women (with 19 cases), the 2-hydroxyestrone to 16a-hydroxyestrone ratio was not associated with breast cancer risk, although in postmenopausal women an inverse relation was observed. In another study of perimenopausal and postmenopausal women, percent oxidation by 16a-hydroxylation was significantly greater and oxidation by 2-hydroxylation nonsignificantly greater in cases than in controls. Similar results were observed in several, but not all, other case control studies of postmenopausal women. These associations have not been evaluated in prospective studies. Overall, limited data exist to address these hypotheses, and no conclusions can yet be drawn.
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Androgens Androgens have been hypothesized to increase breast cancer risk either directly, by increasing the growth and proliferation of breast cancer cells, or indirectly, by their conversion to estrogen. Administration of dehydroepiandrosterone (DHEA) to rodents can decrease the risk of spontaneous and chemically induced cancers. In humans, DHEA may act like an antiestrogen premenopausally but an estrogen postmenopausally in stimulating cell growth, in part because of the estrogenic effect of its metabolite, 5-androstene-3b,17b-diol, which also can bind to the estrogen receptor.
In postmenopausal women, higher testosterone levels have been positively associated with breast cancer in most, but not all, studies. The association has tended to be attenuated, however, after plasma estrogen levels are taken into account. In the largest prospective study, the modest, nonsignificant association with testosterone level was substantially attenuated after the investigators controlled for estrogen levels. Postmenopausal dehydroepiandrosulfate (DHEAS) levels were generally associated with either significant or nonsignificant increases in breast cancer risk in previous prospective studies. In three previous prospective assessments of DHEA, significant positive associations were observed in two,106,107 whereas no association was observed in the third.81 In the only previous study of 5-androstene-3b,17b-diol among postmenopausal women, women in the top quartile of levels had a significant threefold higher risk of breast cancer; women in the highest quartile for both DHEA and 5-androstene-3b,17b-diol (compared with the lowest for both) had a sixfold higher risk.
Overall, higher levels of testosterone may have a modest, but probably indirect, association with postmenopausal breast cancer through its conversion to estradiol. Most studies have noted at least a modest positive association with DHEA and DHEAS; further delineation of the exact nature of these associations is required.
Among premenopausal women, no association was found between testosterone level and breast cancer risk in two prospective studies. Strong positive associations have been noted in several case control studies, with RRs ranging from 3.4 to 10.2 for women in the top category of plasma testosterone. Results from studies addressing androstenedione levels and breast cancer are inconsistent. The only prospective study of DHEA and DHEAS levels and breast cancer in premenopausal women had just 15 cases. Again, the data are too limited to draw any firm conclusions relating androgen levels to breast cancer risk in premenopausal women.{pagebreak}
Progesterone Progesterone exerts powerful influences on breast physiology and can influence tumor development in rodents. Based largely on indirect evidence, progesterone has been hypothesized both to decrease breast cancer risk by opposing estrogenic stimulation of the breast and to increase risk because breast mitotic rates are highest in the luteal (high-progesterone) phase of the menstrual cycle. In one prospective study, serum progesterone was 95% higher in cases compared with controls in the luteal phase and 20% higher in the follicular phase; however, the study was small (22 cases), and the differences were not statistically significant. A nonsignificant inverse association between progesterone and breast cancer has been reported in an additionalprospective analysis. Additional larger studies are needed to address this relationship in detail.
Prolactin Indirect evidence suggests that prolactin could play a role in breast carcinogenesis. Prolactin receptors have been found in more than 50% of breast tumors, and prolactin increases the growth of both normal and malignant breast cells in vitro, although these findings have not been entirely consistent. Prolactin administration is well documented to increase mammary tumor rates in mice.
A number of case control studies of prolactin levels and breast cancer risk have been conducted, although the largest of these included just 66 cases. Also, because prolactin is influenced by both physical and emotional stress, levels in women with breast cancer may not reflect their predisease levels. Thus, evaluation of this association in prospective studies is particularly important. Only two prospective studies have been conducted. In the first, which included 40 postmenopausal breast cancer cases, women in the top quintile of prolactin levels had a nonsignificant 63% higher risk of breast cancer compared with those in the bottom quintile. In a prospective analysis of prolactin and breast cancer risk from the Nurses' Health Study that included 306 postmenopausal cases and 448 postmenopausal controls, a significant positive association was seen (top versus bottom quartile comparison: relative risk, 2.0; 95% confidence interval, 1.2 to 3.3; p for trend = .01).
Epidemiologic data on premenopausal prolactin levels and breast cancer risk are more sparse, and results are inconsistent. In the only prospective study, with 71 cases, no relationship was observed, although confidence limits were wide (top versus bottom quintile comparison: relative risk, 1.1; 95% confidence interval, 0.5 to 2.2). Thus, no conclusion can be drawn as to the relationship between prolactin levels and breast cancer risk in premenopausal women.
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Insulinlike Growth Factor Insulinlike growth factor type I (IGF-I) is a polypeptide hormone with structural homology to insulin, and it is regulated primarily by growth hormone. Evidence is increasing that the growth hormone-IGF-I axis stimulates proliferation of both breast cancer and normal breast epithelial cells. Transgenic mice that overexpress growth hormone exhibit a high frequency of breast cancer, and rhesus monkeys treated with growth hormone or IGF-I show histologic evidence of mammary gland hyperplasia. In addition, positive associations have been observed between breast cancer and both birth weight and height, which are both positively correlated with IGF-I level.
The relationships between blood levels of IGF-I and its major binding protein, insulinlike growth factor binding protein 3 (IGFBP-3), have been evaluated in several epidemiologic studies. In two case control studies, a positive relationship was noted between plasma IGF-I levels and breast cancer risk. In the larger of the two studies (with 109 cases), the relationship was strongest among premenopausal women. In the Nurses' Health Study, plasma levels in 397 women with invasive breast cancer (diagnosed after they provided a blood sample) were compared with those of 620 age-matched controls. No association was noted between IGF-I level and risk in postmenopausal women. A positive relationship was observed, however, between premenopausal IGF-I levels and risk (top versus bottom tertile, controlling for IGFBP-3: relative risk, 2.9; 95% confidence interval,1.2 to 6.9); this relationship was particularly strong among premenopausal women under age 50 years (relative risk, 7.3; 95% confidence interval, 2.4 to 22.0), although these analyses included few cases.
The difference in RRs between premenopausal and postmenopausal women, observed in two of the three studies published to date, may reflect a relatively important effect of the growth hormone-IGF-I axis earlier in life after breast development. Alternatively, IGF-I levels may be specifically relevant to risk of premenopausal breast cancer, perhaps because estradiol may enhance IGF-I activity in the breast. Although these findings relating plasma levels of IGF-I (and IGFBP-3) to breast cancer are promising, they require further confirmation in larger studies, particularly in studies among premenopausal women.
Prenatal Risk Factors In utero exposure to circulating hormones has been hypothesized to influence the fetus's breast cancer risk in adulthood, perhaps through the influence of these levels on the number and degree of differentiation of breast stem cells. To address this hypothesis, factors such as birth weight and occurrence of preeclampsia, known to be associated with hormone levels during pregnancy, have been evaluated in relation to breast cancer risk. Data are relatively consistent in showing a positive association between birth weight and breast cancer. Strong inverse associations between preeclampsia and disease risk also have been reported. Findings for other measures of in utero hormone exposure, however (e.g., maternal smoking behavior, birth order), have been less consistent. Overall, increasing evidence suggests some influence of in utero exposures on subsequent risk of breast cancer.
Walter C. Willett, Beverly Rockhill, Susan E. Hankinson, David J. Hunter and Graham A. Colditz
W. C. Willett: Harvard Medical School, Boston, Massachusetts; Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts B. Rockhill: Harvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts S. E. Hankinson: Departments of Medicine and Epidemiology, Harvard Medical School and Harvard School of Public Health, Boston Massachusetts D. J. Hunter: Departments of Epidemiology and Nutrition, Harvard School of Public Health, Boston, Massachussetts G. A. Colditz: Department of Medicine, Harvard Medical School, Boston, Massachussetts
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