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Department of Epidemiology Graduate School of Public Health Pittsburgh, Pennsylvania 15213
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Introduction |
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 Top Introduction References |
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First, results of the Heart Estrogen/Progestin Replacement Study (HERS) were provocative, raising new questions about hormone replacement therapy (2). HERS was designed to test the hypothesis that combination oral estrogen and progestin therapy reduces the risk for coronary heart disease events in postmenopausal women with established coronary disease. Results showed that treatment with oral estrogen/progestin therapy did not reduce the overall rate of CHD events in these women. However, a pattern of early increase risk of CHD events in the treatment group was followed by a favorable pattern of CHD events after several years of therapy. Fractures were a secondary endpoint of HERS. After 4.1 yr of therapy, there was no difference in fracture incidence between women on hormone therapy and placebo. While confidence intervals did not exclude the possibility of a benefit as large as 20%, and HERS was not designed to look at fractures, the results raise the possibility that observational studies may have overestimated the preventive effects of estrogen on fracture risk, especially among women who are not osteoporotic.
Second, several reports from the Study of Osteoporotic Fractures (SOF), an observational study of 9,704 women, have examined the relationship between endogenous estrogens, and bone mineral density (BMD) (3), bone loss (4), fractures (5), and breast cancer (6). Women with detectable estradiol levels (5–25 pg/mL) had about 6–7% higher BMD at the total hip, calcaneus, proximal radius, and spine than women with undetectable levels (<5 pg/mL) (3). These women suffered significantly less bone loss at the hip and calcaneus than women with undetectable levels: women with a minimum of 10 pg/ml estradiol averaged only 0.1% annual hip bone loss, while women with levels below 5 pg/mL averaged 0.8% annual hip bone loss (4). Women with undetectable serum estradiol concentrations had a relative risk of 2.5 for subsequent hip fracture (95% confidence intervals, 1.4–4.6) and subsequent vertebral fractures (95% confidence interval, 1.4–4.2) (5).
In contrast, women from the same cohort who had the highest estradiol values experienced the greatest risk of developing breast cancer (6). Women with total estradiol concentrations of at least 8 pg/mL had 2.9-fold (95% confidence interval, 1.2–7.2) greater breast cancer risk compared with women with the lowest levels.
These findings are remarkable. The associations between endogenous estradiol and fractures and breast cancer were much stronger than we observed between serum cholesterol and death from cardiovascular disease. In a subset of the SOF cohort recruited from the Pittsburgh, PA (Monongahela Valley) clinic, serum cholesterol was measured in 2,240 women, all 65 years or older. After 9.3 yr of follow-up, there was no association between serum cholesterol and deaths due to cardiovascular disease. The relative risk of dying among women with the highest cholesterol (Quartile 4, >273 mg/dL) was 0.99 (95% confidence intervals (0.68–1.43) compared with women with the lowest cholesterol.
These findings raise the possibility that a single measurement of estradiol could be used to estimate a women’s risk of suffering not only accelerated bone loss and fractures but also breast cancer. Treatments could be targeted depending on the concentration of hormone. Women identified at high risk of breast cancer by the hormone measures might benefit from anti-estrogen treatments for primary prevention of breast cancer (7, 8). On the other hand, women with very low levels of estradiol could consider estrogen replacement therapy. The dose of estrogen replacement therapy could be titrated to the endogenous concentration of estrogen. A lower dose of estrogen could be considered. Replacement with oral conjugated equine estrogen at 0.625 mg/day, the usual dose of replacement in the United States, results in much higher concentrations of estradiol than we observed in our study (9). Several recent reports have also suggested that lower doses of estrogen could be used (10, 11). Use of lower doses might lead to fewer side effects and, perhaps, better adherence to hormone regimens.
It is also possible that nonpharmacologic interventions that either reduce or raise serum estrogen concentrations could thereby influence the risk of disease. For example, in the Women’s Health Trial, a 10- to 20-week low fat dietary intervention was associated with a 17% reduction in estradiol concentrations in healthy postmenopausal women (12). Higher intakes of lutein, a carotenoid abundant in dark green vegetables, was associated with slower rates of bone loss and reduced risk of hip fracture (13). The underlying mechanism for this relationship is unknown, but further studies delineating the effects of dietary factors as well as other lifestyle interventions like physical activity on hormone concentrations may be warranted.
However, specialized endocrine laboratories with highly sensitive assay methods were used for these studies. Assay methods at routine clinical laboratories will need to meet stricter standards to measure hormones at these very low concentrations before they can be incorporated into routine clinical practice.
Finally, the absolute level of estrogens may not be the only
determinant of their biological effects. The manner in which the
circulating estrogens are metabolized may also be important. The two
main pathways of estrogen metabolism consist of the 2-hydroxylation and
the 16
-hydroxylation pathways, with the 2-hydroxylation pathway
leading to less estrogenic activity (14). Women who metabolize
estrogens to the 16 pathway appear to have a higher risk of breast
cancer (15) but lower risk of osteoporosis (16). Hence, future research
on estrogen should also consider its metabolic pathways and include
measurements of estrogen metabolites.
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References |
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TopIntroductionReferences |
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-hydroxylase activity in women with breast
and endometrial cancer. J Steroid Biochem. 20:1077–1081.[CrossRef][Medline]
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