A major emphasis of this project has been to define the relationship of exogenous hormones to subsequent cancer risk. Our most recent analyses have assesed the relationships of menopausal hormones to gynecologic cancer risk using data from our large, prospective cohort studies. Using data from the NIH-AARP Diet and Health Cohort Study, we have clarified some unresolved issues regarding ovarian cancer risk in women who use menopausal hormone therapy. Increased ovarian cancer risks among women who used unopposed estrogen therapy for 10 or more years provide further evidence to support the hypothesis that increased estrogen levels after menopause can influence the development of ovarian cancer. In addition, this study provided some of the first strong evidence that specifically links estrogen plus progestin use to increased ovarian cancer risk in women with intact uteri. These results reiterate the value of long-term follow-up of existing cohorts to elucidate increased risks of rare outcomes, such as ovarian cancer, among women who exposed to menopausal hormone therapy. This large cohort study has also been used to assess relationships of menopausal hormones to the risk of endometrial cancers. In contrast to some previous suggestions that estrogen plus progestin therapy might protect against this cancer, we found no evidence for such protection. Of note was that neither continuous nor sequential estrogen plus progestin were found to have any statistically significant associations with endometrial cancer risk in this population. <BR><BR>The AARP study has also been useful for evaluating effects on cancer risk of other medications. Current analyses are underway to assess breast cancer risk in relation to non-steroidal anti-inflammatory medications. This is of interest given that inflammation has been proposed as being involved as an etiologic agent for this cancer site. We are also evaluating effects on breast cancer risk of certain medications used in the treatment of cardiovascular diseases that are known to have demethylating effects on DNA.<BR><BR>We have also had an interest in effects of other hormonal exposures, including ovulation stimulating drugs used to treat infertility. A retrospective cohort study was also conducted which allowed an assessment of effects on cancer risk of different causes of infertility and associated therapies. This study involved detailed abstraction of medical records of patients diagnosed as long ago as the 1960's and administration of questionnaires to obtained updated health information. A strength of the study was the detailed information collected on causes of infertility. Analyses showed that type of infertility (primary vs. secondary) was a more important predictor of cancer risk than specific causes of infertility. However, patients with endometriosis were at an especially high risk of developing ovarian cancer. In general, the study provided reassuring results regarding use of ovulation-inducing agents, showing no major increases in cancer risk relating to use of either clomiphene citrate or human menopausal gonadotropins. There were, however, slight increases in risk of both breast cancer and ovarian cancer among the subjects followed for the longest periods of time (15 or 20+ years), supporting the need for additional monitoring of long-term effects of these agents. <BR><BR>Certain medical devices have also been of interest, including the long-term safetly of silicone breast implants. Effects on breast cancer risk has been of concern, given that breast implants can interfere with the mammographic visualization of lesions. However, in a large retrospective study that we conducted, we found no evidence for an alteration in breast cancer risk. These patients also generally did not experience alterations in other cancer sites, although elevations were observed in the risk of lung and brain cancers, the explanation for which remains unclear. In a mortality analysis, implant patients had signficantly elevated risks of death from suicide, but other causes of death were similar to the general population. The patients in this study are continuing to be followed for future mortal events, of importance given the aging nature of the study population. We also recently assessed effects on various connective tissue diseases. In general, the results were fairly reassuring, although this investigation did highlight the complexities of evaluating the associations, given the rarity of most individual diseases, and a variety of diagnostic and reporting difficulties. <BR><BR>Recent cohort studies demonstrated reduced breast cancer risks among women with a history of fractures or low bone mineral density. The impact of the severity and timing of bone loss on risk has not yet been investigated, and the extent to which other risk factors (family history, anthropometric factors, physical activity, and exogenous hormones) modify the relationship with bone density is unknown. To elaborate on these research questions, we have conducted a follow-up study of over 20,000 postmenopausal women who volunteered for a clinical trial of the bone-enhancing drug alendronate. This large cohort includes extensive baseline information on major breast cancer risk factors, and thus is ideal for evaluating potential interactions with bone mineral density and the effects of bone mineral density on other cancer sites. The data collection phase of the study has been completed, and analyses should answer important questions about the relationship between bone density and cancer risk in postmenopausal women.<BR><BR>A number of medical conditions have been suggested as predisposing to the risk of breast cancer, endometrial cancer and ovarian cancer, but most of these studies have relied on patients reports of these prior conditions. To obtain more precise information on the nature of these prior medical conditions, we have conducted a large case-cohort study in Denmark that involves access to details of the conditions as contained in medical records. Results confirm findings elsewhere of an increased risk of ovarian cancer related to a prior diagnosis of endometriosis. Further, the association seems to be specific for endometrioid and clear cell malignancies. In addition, our results suggest that patients with leiomyomas may be an an increased risk of developing subsequent uterine sarcomas. Whether this is due to shared risk factors of the fact that uterine leiomyomas clinically mimic sarcomas deserves additional study. This study also addressed whether a variety of chronic diseases (diabetes, hypertention, thyroid diseases, as well as others) predispose to ovarian and uterine malignancies. Although these diseases did not appear to affect the risk of ovarian malignancies, there was some evidence that thyroid diseases and diagnoses of obesity increased the risk of uterine cancers. Diabetes initially appeared related to uterine cancers, but the association disappeared after adjustment for diagnoses of obesity