Premenopausal Estradiol Levels and the Risk of Breast Cancer: A New Method of Controlling for Day of the Menstrual Cycle

Abstract

Levels of total estradiol in premenopausal women vary widely over the course of the menstrual cycle with a spike at the time of ovulation and dissimilar patterns pre- and post-ovulation. Evaluating the association between breast cancer and premenopausal measurements of total estradiol when the measurements cannot be taken on a uniform day of the cycle is therefore a difficult methodological challenge. In a matched case-control study of breast cancer nested within a prospective study, premenopausal serum samples obtained up to 7 years before breast cancer diagnosis were available for total estradiol assay. By fitting a three-piece spline model that regressed the logarithm of total estradiol (ln estradiol) on day of menstrual cycle, the authors were able to adjust the measurements for day of the cycle on which they were collected by expressing them in terms of the number of standard deviations above or below the fitted ln estradiol value for that day. Applying the adjusted measurements to the nested case-control study, they found evidence of a 1.5 to 2-fold risk for women in the upper two tertiles of ln estradiol relative to women in the lowest tertile. Conditional logistic regression analysis for day-of-cycle-adjusted ln estradiol treated as a continuous variable resulted in a relative risk estimate of 1.19 (95% confidence interval 0.91-1.55) per standard-deviation increase in adjusted ln estradiol.

Dehydroepiandrosterone intake protects against 7,12-dimethylbenz(a)anthracene-induced mammary tumor development in the obese Zucker rat model

“…In rats and mice, DHEA feeding reduces fat accumulation in both genetic-and diet-induced obesity models and has protective effects against insulin resistance induced by a high-fat diet (33,42). Studies have reported an association between low levels of serum or urine DHEA or DHEA metabolites and increased breast cancer risk in premenopausal women (48)(49)(50)(51)(52)(53). The relationship between endogenous androgens, such as DHEA, and breast cancer risk is less clear with both epidemiological and experimental data providing conflicting results.…”

A prospective study of endogenous serum hormone concentrations and breast cancer risk in premenopausal women on the island of Guernsey

“…The influence of the disease on serum hormone concentrations can only be excluded by prospective studies. Only three prospective studies have reported oestradiol concentrations in premenopausal women and none found a statistically significant association between serum oestradiol concentration and risk of developing breast cancer (Wysowski et al, 1987;Helzlsouer et al, 1994;Rosenberg et al, 1994).…”

Endogenous 6-Hydroxymelatonin Excretion and Subsequent Risk of Breast Cancer: A Prospective Study

“…The opposite was previously found by Wysowski et al [29], in the same cohort study. Rosenberg et al [30] reported, in a case-control study nested in the New York University Women's Health Study, similar estradiol levels in cases and controls (although further adjustments for stage of menstrual cycle at blood drawing suggested that estradiol was on average non-significantly higher in cases). Kabuto et al [22] found in the prospective cohort study conducted in Japan higher levels ofbioavailable estradiol in breast cancer cases than in controls.…”

“…Results from the prospective study conducted in the island of Guernsey (UK) by Key and colleagues showed that premenopausal breast cancer cases excreted less estrogen than controls when estrogens were determined in urine [31] and that estrogen levels were higher in cases than in controls when the hormones were determined in blood, although the difference was small and not statistically significant [32]. The number of breast cancer cases in those studies ranged between 22 [25] and 79 [30]. Several of those studies tried to control the ovarian phase variability using time interval between the date at specimen collection and the date at the subsequent menstrual period either as a matching variable or variable to adjust for in the analysis [30][31][32].…”

“…The number of breast cancer cases in those studies ranged between 22 [25] and 79 [30]. Several of those studies tried to control the ovarian phase variability using time interval between the date at specimen collection and the date at the subsequent menstrual period either as a matching variable or variable to adjust for in the analysis [30][31][32]. On the contrary, Wysowski et al [29] and Helzlsouer et al [25] used the time interval between date at the menstrual period preceding the blood collection and the date at blood drawing, while Kabuto et al [22] did not control for menstrual phase.…”