It is also well known that post-menopausal estrogen use and endogenous hormonal exposures during pregnancy and related reproductive events are involved in endometrial cancer etiology. In addition, although unopposed estrogens continued to be used widely, a growing proportion of post- menopausal estrogen use is in combination with progestins, as the combination of estrogen and progestin therapy, when used cyclically (or sequentially), is thought to confer protection against the development of endometrial cancer by causing a monthly sloughing of endometrial tissue. Yet, with the more recent administration of post-menopausal hormone therapy in the form of daily pills combining estrogens and progestins (i.e., continuous use), the mechanism postulating a beneficial effect from sloughing of endometrial tissue is no longer valid, and proof of its protective effect is even more critical. If progestins are not effective in preventing endometrial cancer, their use should be abandoned If progestins are e are effective in preventing endometrial cancer, then use of unopposed estrogens should perhaps be reduced. Further, a recently identified variant in the CYP3A4 gene may serve as a biomarker of the susceptibility to endometrial cancer because of its important role in the metabolism of estrogen and progesterone. Women who have a decreased capacity to metabolize exogenous hormones because of an inherited variant in the CYP3A4 (nifedipine) specific element (NFSE) gene may have a different susceptibility to endometrial cancer compared to women who have not inherited this genetic variant. To data, sufficient data are not available on the effects of post-menopausal progestins, in any regimen. In addition, knowledge about whether this inherited variant in the CYP3A4 NFSE genotype modifies individuals' susceptibility to exogenous hormone exposure could help inform clinical decision-making about prescribing these drugs in the future. For this reason, a case-control study is planned to examine three primary associations. First, the association between HRT and endometrial cancer, as expressed by the following specific hypothesis: 1) the risk of developing endometrial carcinoma in women using unopposed estrogens is greater than the risk in women using no post-menopausal hormones; 2) the risk of developing endometrial carcinoma in women who use estrogen/progestin combination drugs is greater than women using no post- menopausal hormones; and 3) the risk of developing endometrial carcinoma in women who use post-menopausal estrogen/progestin combination drugs is lower than that in women using unopposed estrogens. Second, the association between exposure to post-menopausal hormones and inherited genotype, and how this might affect the risk of endometrial cancer. Third, the association between parity (because of a protected period from unopposed estrogens) and inherited genotype, and how this might affect the risk of endometrial cancer. We are planning a population-based case-control study in the Greater Delaware Valley that will include 999 hospitalized incident cases of endometrial cancer. These cases will be recruited from the Delaware Valley Case-Control Network, which includes virtually all hospitals in this area that has a population of over 5 million individuals. An equal-sized population-based age- and race-matched control group will be recruited using random digit dialing. Both the case group and the control group will be interviewed by telephone to evaluate their exposures to post-menopausal HRT, their reproductive history, and other possible risk factors for this disease, and DNA will be collected using a non-invasive cheek swab method. Medical records will be reviewed for validation of the diagnosis in the cases. Matched analyses, including calculation of odds ration with confidence intervals, will be followed by multiple conditional logistic regression, to evaluate the relative importance of each variables as a risk factor.