| Summary: | Endometrial cancer is the most common gynecologic cancer in women in the United States, and to date many risk factors have been identified, most of which result in increased exposure to estrogens unopposed by progesterone. Androgens, which are precursors to estrogens, have been shown to increase the risk of endometrial cancer in postmenopausal women. Their role in premenopausal women has not yet been determined. We hypothesized that androgens increase the risk of endometrial cancer in premenopausal women by either acting directly via the androgen receptor or indirectly by causing anovulation which results in progesterone deficiency and increased exposure to unopposed estrogens. We conducted a nested case-control study within three cohorts, the New York University Women's Health Study (NYUWHS), the Northern Sweden Health and Disease Study (NSHDS), and the Hormones and Diet in the Etiology of Breast Cancer Study (ORDET) in order to examine the association of androgens in premenopausal women with risk of endometrial cancer. The study included 101 cases and 181 controls matched on cohort and age and date at blood donation. Overall, we found no association between androgens or sex hormone bindingglobulin (SHBG) in premenopausal women and risk of endometrial cancer. However, after stratifying by age at diagnosis (< 55, ≥55 years), we found that, although no association was seen between androgens or SHBG in the younger (premenopausal) women at diagnosis, total testosterone, free testosterone, and androstanediol glucuronide were statistically significantly associated with risk of endometrial cancer in the older women, who were mostly later premenopausal at the time of blood donation and postmenopausal at time of diagnosis. This association remained after controlling for body mass index (BMI). We also examined the association of menstrual cycle length, as a surrogate measure of progesterone levels with the risk of endometrial cancer. However, no conclusions could be drawn due to the small sample size of our study. We did observe that women reporting irregular menstrual cycles had statistically significant higher levels of dehydroepiandrosterone sulfate (DHEAS) and androstanediol glucuronide (Adiol) than women reporting normal menstrual cycles. While our study did not find evidence that androgens or SHBG increase the risk of endometrial cancer in premenopausal women, we did find that later premenopausal levels of androgens are associated with the risk of endometrial cancer after menopause. Due to the correlation between later premenopausal and postmenopausal levels of androgens, it is possible that our later premenopausal androgen measurements provided an estimate of the women's exposure to postmenopausal androgens, which are known to increase the risk of endometrial cancer.
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