Gonadotropins have been indicted in ovarian carcinogenesis but direct evidence has been limited and inconsistent. The aim of this study was to determine the association between prediagnostic levels of follicle stimulating hormone (FSH) and subsequent development of invasive epithelial ovarian cancer. A nested case-control study was conducted using cases and controls drawn from three cohorts: CLUE I and CLUE II of Washington County, MD, and the Island of Guernsey Study, United Kingdom. In total, 67 incident invasive epithelial ovarian cancer cases were each matched to 1 to 2 controls on age, menopausal status, time since last menstrual period, current hormone use and other relevant factors. FSH concentrations were classified into ranked thirds of low, medium or high based on the distribution among controls. Conditional logistic regression was used to estimate the odds ratio (OR) across increasing thirds of FSH concentrations. Results of the analysis showed that ovarian cancer risk decreased with higher FSH concentrations (p-trend 5 0.005). Compared with the lowest third of FSH concentrations, the OR among those in the middle and highest thirds were 0.45 [95% Confidence Interval (CI): 0.20-1.00] and 0.26 (95% CI: 0.10-0.70), respectively. Associations persisted after excluding cases diagnosed within 5 years of follow-up. In conclusion, a reduction in subsequent risk of invasive epithelial ovarian cancer was observed among women with higher circulating FSH concentrations. These findings contradict the hypothesized role of FSH as a risk factor in ovarian carcinogenesis. ' 2009 UICC Key words: follicle stimulating hormone (FSH); ovarian cancer; gonadotropins; epidemiology; cohort study Exposure of the ovarian surface epithelium to elevated gonadotropin levels has been proposed to play a deleterious role in ovarian carcinogenesis.1 This view is based on the concept that postovulatory inclusion cysts formed from invagination of the ovarian surface epithelium (OSE) are exposed to excessive substromal stimulation by gonadotropins and estrogen in the premenopausal period, resulting in increased cellular proliferation with eventual progression to malignant transformation. The hypothesis is largely based on observations in animal models in which various means of increased production of gonadotropins [follicle-stimulating hormone (FSH) and/or luteinizing hormone (LH)] was associated with ovarian tumor development.1 In humans, epidemiologic evidence in support of this hypothesis includes the decreased risk observed with oral contraceptive use, pregnancy and possibly lactation. All of these factors, which suppress gonadotropin-releasing hormone (GnRH) signaling for synthesis and secretion of both FSH and LH, are in agreement with this hypothesis.
2Only 2 studies of actual prediagnostic circulating concentrations of gonadotropin in relation to ovarian cancer risk have been reported and their results do not, overall, support the ''gonadotropin hypothesis.'' 1,3 A small nested-case-control study of 31 cases (of whom 14 were prem...