Long and irregular menstrual cycles, polycystic ovary syndrome, and ovarian cancer risk in a population-based case-control study.

Long and irregular menstrual cycles, a hallmark of polycystic ovary syndrome (PCOS), have been associated with higher androgen and lower sex hormone binding globulin levels and this altered hormonal environment may increase the risk of specific histologic subtypes of ovarian cancer. We investigated whether menstrual cycle characteristics and self-reported PCOS were associated with ovarian cancer risk among 2,041 women with epithelial ovarian cancer and 2,100 controls in the New England Case-Control Study (1992-2008). Menstrual cycle irregularity, menstrual cycle length, and PCOS were collected through in-person interview. Unconditional logistic regression models were used to calculate odds ratios (OR) and 95% confidence intervals (95% CIs) for ovarian cancer risk overall, and polytomous logistic regression to evaluate whether risk differed between histologic subtypes. Overall, we observed no elevation in ovarian cancer risk for women who reported periods that were never regular or for those reporting a menstrual cycle length of >35 days with ORs of 0.87 (95% CI = 0.69-1.10) and 0.83 (95% CI = 0.44-1.54), respectively. We observed no overall association between self-reported PCOS and ovarian cancer (OR = 0.97; 95% CI = 0.61-1.56). However, we observed significant differences in the association with menstrual cycle irregularity and risk of ovarian cancer subtypes (pheterogeneity = 0.03) as well as by BMI and OC use (pinteraction < 0.01). Most notable, menstrual cycle irregularity was associated with a decreased risk of high grade serous tumors but an increased risk of serous borderline tumors among women who had never used OCs and those who were overweight. Future research in a large collaborative consortium may help clarify these associations.

Obesity and survival among women with ovarian cancer: results from the Ovarian Cancer Association Consortium.

BACKGROUND: Observational studies have reported a modest association between obesity and risk of ovarian cancer; however, whether it is also associated with survival and whether this association varies for the different histologic subtypes are not clear. We undertook an international collaborative analysis to assess the association between body mass index (BMI), assessed shortly before diagnosis, progression-free survival (PFS), ovarian cancer-specific survival and overall survival (OS) among women with invasive ovarian cancer. METHODS: We used original data from 21 studies, which included 12 390 women with ovarian carcinoma. We combined study-specific adjusted hazard ratios (HRs) using random-effects models to estimate pooled HRs (pHR). We further explored associations by histologic subtype. RESULTS: Overall, 6715 (54%) deaths occurred during follow-up. A significant OS disadvantage was observed for women who were obese (BMI: 30-34.9, pHR: 1.10 (95% confidence intervals (CIs): 0.99-1.23); BMI: ⩾35, pHR: 1.12 (95% CI: 1.01-1.25)). Results were similar for PFS and ovarian cancer-specific survival. In analyses stratified by histologic subtype, associations were strongest for women with low-grade serous (pHR: 1.12 per 5 kg m(-2)) and endometrioid subtypes (pHR: 1.08 per 5 kg m(-2)), and more modest for the high-grade serous (pHR: 1.04 per 5 kg m(-2)) subtype, but only the association with high-grade serous cancers was significant. CONCLUSIONS: Higher BMI is associated with adverse survival among the majority of women with ovarian cancer.

Dietary fat intake and risk of epithelial ovarian cancer by tumour histology.

BACKGROUND: Studies of fat intake and epithelial ovarian cancer (EOC) risk have reported inconsistent findings, hence we hypothesised that associations may vary by histologic subtype. METHODS: We evaluated fat intake in a New England case-control study including 1872 cases and 1978 population-based controls (1992-2008). Epithelial ovarian cancer risk factors and diet were assessed using a food frequency questionnaire at enrolment. Logistic regression was used to estimate associations between fat intake and EOC risk and polytomous logistic regression was used to test whether associations varied by histologic subtype. RESULTS: We observed a decreased risk of EOC when comparing the highest vs lowest quartiles of intake of omega-3 (odds ratio (OR)=0.79, 95% confidence interval (CI) 0.66-0.96, P-trend=0.01) and omega-6 (OR=0.77, 95% CI 0.64-0.94, P-trend=0.02) and an increased risk with high consumption of trans fat (OR=1.30, 95% CI 1.08-1.57, P-trend=0.002). There was no significant heterogeneity by tumour histologic subtype; however, we observed a strong decreased risk for endometrioid invasive tumours with high intake of omega-3 (quartile (Q) 4 vs Q1, OR=0.58, 95% CI 0.41-0.82, P-trend=0.003). CONCLUSIONS: These findings suggest that higher intake of omega-3 may be protective for EOC overall and endometrioid tumours in particular, whereas greater consumption of trans fat may increase risk of EOC overall.

Reproductive characteristics in relation to ovarian cancer risk by histologic pathways.

STUDY QUESTION: Do reproductive risk factor associations differ across subgroups of invasive epithelial ovarian cancer (EOC) defined by the dualistic model (type I/II) or a histologic pathway-based classification? SUMMARY ANSWER: Associations with parity, history of endometriosis, tubal ligation and hysterectomy were found to differ in the context of the type I/II and the histologic pathways classification of ovarian cancer. WHAT IS KNOWN ALREADY: Shared molecular alterations and candidate precursor lesions suggest that tumor histology and grade may be used to classify ovarian tumors into likely etiologic pathways. DESIGN: This case-control study included 1571 women diagnosed with invasive EOC and 2100 population-based controls that were enrolled from 1992 to 2008. Reproductive risk factors as well as other putative risk factors for ovarian cancer were assessed through in-person interviews. PARTICIPANTS/MATERIALS, SETTING, METHODS: Eligible cases were diagnosed with incident ovarian cancer, were aged 18 and above and resided in eastern Massachusetts or New Hampshire, USA. Controls were identified through random digit dialing, drivers' license and town resident lists and were frequency matched with the cases based on age and study center. MAIN RESULTS AND THE ROLE OF CHANCE: We used polytomous logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for type I/II EOC or using a pathway-based grouping of histologic subtypes. In multivariate analyses, we observed that having a history of endometriosis (OR = 1.92, 95% CI: 1.36-2.71) increased the risk for a type I tumor. Factors that were strongly inversely associated with risk for a type I tumor included parity (≥ 3 versus 0 children, OR = 0.15, 95% CI: 0.11-0.21), having a previous tubal ligation (OR = 0.40, 95% CI: 0.26-0.60) and more weakly hysterectomy (OR = 0.71, 95% CI: 0.45-1.13). In analyses of histologic pathways, parity (≥ 3 versus 0 children, OR = 0.13, 95% CI: 0.10-0.18) and having a previous tubal ligation (OR = 0.41, 95% CI: 0.28-0.60) or hysterectomy (OR = 0.54, 95% CI: 0.34-0.86) were inversely associated with risk of endometrioid/clear cell tumors. Having a history of endometriosis strongly increased the risk for endometrioid/clear cell tumors (OR = 2.41, 95% CI: 1.78-3.26). We did not observe significant differences in the risk associations across these tumor classifications for age at menarche, menstrual cycle length or infertility. LIMITATIONS, REASONS FOR CAUTION: A potential limitation of this study is that dividing the cases into subgroups may limit the power of these analyses, particularly for the less common tumor types. Since cases were enrolled after their diagnosis, it is possible that the most aggressive cases were not included in the study. WIDER IMPLICATIONS OF THE FINDINGS: This study provides insights about the role of reproductive factors in relation to risk of pathway-based subgroups of ovarian cancer that with further confirmation may assist with the development of improved strategies for the prevention of these different tumor types. STUDY FUNDING/COMPETING INTEREST(S): This research is funded by grants from the National Cancer Institute, the Department of Defense Ovarian Cancer Research Program and the Ovarian Cancer Research Fund. The authors have no competing interests to declare. TRIAL REGISTRATION NUMBER: Not applicable.

Validating genetic risk associations for ovarian cancer through the international Ovarian Cancer Association Consortium.

The search for genetic variants associated with ovarian cancer risk has focused on pathways including sex steroid hormones, DNA repair, and cell cycle control. The Ovarian Cancer Association Consortium (OCAC) identified 10 single-nucleotide polymorphisms (SNPs) in genes in these pathways, which had been genotyped by Consortium members and a pooled analysis of these data was conducted. Three of the 10 SNPs showed evidence of an association with ovarian cancer at P< or =0.10 in a log-additive model: rs2740574 in CYP3A4 (P=0.011), rs1805386 in LIG4 (P=0.007), and rs3218536 in XRCC2 (P=0.095). Additional genotyping in other OCAC studies was undertaken and only the variant in CYP3A4, rs2740574, continued to show an association in the replication data among homozygous carriers: OR(homozygous(hom))=2.50 (95% CI 0.54-11.57, P=0.24) with 1406 cases and 2827 controls. Overall, in the combined data the odds ratio was 2.81 among carriers of two copies of the minor allele (95% CI 1.20-6.56, P=0.017, p(het) across studies=0.42) with 1969 cases and 3491 controls. There was no association among heterozygous carriers. CYP3A4 encodes a key enzyme in oestrogen metabolism and our finding between rs2740574 and risk of ovarian cancer suggests that this pathway may be involved in ovarian carcinogenesis. Additional follow-up is warranted.

Determinants of ovarian cancer risk. II. Inferences regarding pathogenesis.

Entrapment of surface epithelium within the ovarian stroma was proposed as an initial event in the pathogenesis of cystadenocarcinoma of the ovary. Subsequent events, including differentiation, proliferation, and eventual malignant transformation of the entrapped epithelium, may occur as a consequence of stimulation by estrogen or estrogen precursors. These events were more likely when the steroid producing stroma itself had been stimulated by high gonadotropins. Animal experiments suggested that gonadotropin excess and stromal stimulation may result by disturbing normal feedback inhibition between ovary and pituitary or by destroying ovarian follicles. By analogy, in humans, a number of common chemicals and drugs may increase gonadotropins by enhancing estrogen degradation in the liver or by directly stimulating production by the pituitary. Elevated gonadotropins may also result via mechanisms that cause primary ovarian failure including pelvic irradiation, exposure to chemicals or metabolites toxic to follicles, or ovarian infections such as mumps.

Determinants of ovarian cancer risk. I. Reproductive experiences and family history.

Reproductive experiences and family history were assessed in 215 white females with epithelial ovarian cancer and in 215 control women matched by age, race, and residence. Pregnancy exerted a strong protective effect against ovarian cancer, which increased with the number of live-born children. After adjustment for parity, an effect of age at first live birth and breast-feeding was not apparent. Menstrual events did not differ significantly between cases and controls, although cases were more likely to have had an earlier menopause and less likely to have had a surgical menopause. Women with ovarian cancer had more frequently used menopausal hormones in cyclic fashion compared to controls. Regarding family history, women with ovarian cancer more frequently reported consanguinity in their ancestry and a highly frequency of primary relatives with cancer of the colon, lung, ovary, and prostate gland.

Prospective study of talc use and ovarian cancer.

BACKGROUND: Perineal talc use has been associated with an increased risk of ovarian cancer in a number of case-control studies; however, this association remains controversial because of limited supporting biologic evidence and the potential for recall bias or selection bias in case-control studies. In this study, we conducted a prospective analysis of perineal talc use and the risk of ovarian cancer. METHODS: The Nurses' Health Study is a prospective study of 121 700 female registered nurses in the United States who were aged 30-55 years at enrollment in 1976. Talc use was ascertained in 1982 by use of a self-administered questionnaire: after exclusions, 78 630 women formed the cohort for analysis. Three hundred seven epithelial ovarian cancers subsequently diagnosed in this cohort through June 1, 1996, were confirmed by medical record review and met inclusion criteria. Proportional hazards models by use of pooled logistic regression were used to derive relative risks (RRs) and 95% confidence intervals (CIs). RESULTS: In 1982, 40.4% (n = 31 789) of the cohort reported ever using talc, and 14.5% (n = 11 411) reported ever using talc daily. We observed no overall association with ever talc use and epithelial ovarian cancer (multivariate RR = 1.09; 95% CI = 0.86-1.37) and no increase in risk of ovarian cancer with increasing frequency of use. There was a modest elevation in risk for ever talc use and invasive serous ovarian cancer (multivariate RR = 1.40; 95% CI = 1.02-1.91). The risk of epithelial ovarian cancer for talc users was not greater among women who had never had a tubal ligation (multivariate RR = 0.97; 95% CI = 0.71-1.32). CONCLUSION: Our results provide little support for any substantial association between perineal talc use and ovarian cancer risk overall; however, perineal talc use may modestly increase the risk of invasive serous ovarian cancer.

Prostasin, a potential serum marker for ovarian cancer: identification through microarray technology.

BACKGROUND: Screening biomarkers for ovarian cancer are needed because of its late stage at diagnosis and poor survival. We used microarray technology to identify overexpressed genes for secretory proteins as potential serum biomarkers and selected prostasin, a serine protease normally secreted by the prostate gland, for further study. METHODS: RNA was isolated and pooled from three ovarian cancer cell lines and from three normal human ovarian surface epithelial (HOSE) cell lines. Complementary DNA generated from these pools was hybridized to a microarray slide, and genes overexpressed in the cancer cells were identified. Real-time quantitative polymerase chain reaction was used to examine prostasin gene expression in ovarian cancer and HOSE cell lines. Anti-prostasin antibodies were used to examine prostasin expression and to measure serum prostasin by an enzyme-linked immunosorbent assay in 64 case patients with ovarian cancer and in 137 control subjects. Previously determined levels of CA 125, an ovarian cancer marker, were available from about 70% of all subjects. All statistical tests were two-sided. RESULTS: Prostasin was detected by immunostaining more strongly in cancerous ovarian epithelial cells and stroma than in normal ovarian tissue. The mean level of serum prostasin was 13.7 microg/mL (95% confidence interval [CI] = 10.5 to 16.9 microg/mL) in 64 case patients with ovarian cancer and 7.5 microg/mL (95% CI = 6.6 to 8.3 microg/mL) in 137 control subjects (P<.001, after adjustment for the subject's age, year of collection, and specimen quality). In 14 of 16 case patients with both preoperative and postoperative serum samples, postoperative prostasin levels were statistically significantly lower than preoperative levels (P =.004). In 37 case patients with nonmucinous ovarian cancer and in 100 control subjects for whom levels of CA 125 and prostasin were available, the combination of markers gave a sensitivity of 92% (95% CI = 78.1% to 98.3%) and a specificity of 94% (95% CI = 87.4% to 97.7%) for detecting ovarian cancer. CONCLUSIONS: Prostasin is overexpressed in epithelial ovarian cancer and should be investigated further as a screening or tumor marker, alone and in combination with CA 125.

Multiple births and risk of epithelial ovarian cancer.

BACKGROUND AND METHODS: Prevailing hypotheses about the causes of ovarian carcinogenesis predict that women with a history of multiple births (twins, triplets, etc.) should be at increased risk of epithelial ovarian cancer. However, the scant available evidence suggests that they may actually be at lower risk. To resolve this issue, we pooled data from eight studies involving 2859 parous women with epithelial ovarian cancer (case patients) and 7434 parous women without ovarian cancer (control women). In addition to assessing their history of multiple births (and the sex of the children, where available), we obtained information on age, parity, oral contraceptive use, and other reproductive factors for each woman. Details of tumor histology were available for all case patients. We estimated the relative risks of various histologic types of ovarian cancers associated with multiple births by using multivariable logistic regression analysis, adjusting for matching and confounding variables. RESULTS: Among these parous women, 73 case patients (2. 6%) and 257 control women (3.5%) had a history of multiple births. The adjusted summary odds ratio (OR) for developing all types of epithelial ovarian cancer that are associated with multiple births was 0.81 (95% confidence interval [CI] = 0.61-1.08). We found no evidence that risks associated with multiple births differed among women with borderline or invasive tumors and among women with same-sex and opposite-sex offspring from multiple births. The risk reductions appeared specific for nonmucinous tumors (n = 2453; summary adjusted OR = 0.71 [95% CI = 0.52-0.98]); in contrast, associations with mucinous tumors (n = 406) were heterogeneous across studies. CONCLUSIONS: Parous women with nonmucinous ovarian cancer are no more likely to have a history of multiple births than other parous women, counter to the predictions of current hypotheses for causes of ovarian cancer.

Frequency of the BRCA1 185delAG mutation among Jewish women with ovarian cancer and matched population controls.

Among women of Ashkenazi Jewish origin, a frameshift mutation of the BRCA1 gene, designated 185delAG, occurs with a carrier frequency of approximately 1% and is estimated to account for about 39% of ovarian cancer cases occurring prior to age 50 years. To determine the actual frequency of this mutation among Jewish women with ovarian cancer, we tested DNA collected as part of an ongoing population-based case-control study of genetic and environmental factors for epithelial ovarian cancer in eastern Massachusetts. Using single-stranded conformational polymorphism analysis followed by direct sequencing, we found that 6 (19.4%) of 31 Jewish patients were carriers for a 185delAG mutation compared to 0 of 23 Jewish controls (P=0.03) Using empiric logic [correction of logits], the estimated relative risk for ovarian cancer associated with a 185delAG mutation is 12.0. The average age of the 6 patients with mutations was 48.3 years, significantly younger than the average of 57.4 years observed for the 25 patients without the mutation (P-0.05). For ovarian cancer diagnosed prior to age 50 years, three (37.5%) of eight patients carried the mutation. None of the six patients with the mutation had a history consistent with hereditary breast ovarian cancer syndrome, although two had a personal history of prior cancer. Our results provide empiric conformation of the estimated prevalence of 185delAG mutations among Jewish women with ovarian cancer.

Occult ovarian tumors in women with BRCA1 or BRCA2 mutations undergoing prophylactic oophorectomy.

PURPOSE: To review the findings at prophylactic oophorectomy of a series of women who presented to a familial breast and ovarian cancer clinic. MATERIALS AND METHODS: Data from medical charts, operative notes, and pathology reports were collected on women who had undergone prophylactic oophorectomies because of the elevated risk of ovarian cancer. Because only a subset of patients underwent BRCA1 and BRCA2 testing, each patient's risk of hereditary predisposition was calculated using the Berry-Parmigiani model and family history data. RESULTS: From June 1989 to December 1998, 50 women seen at our clinic underwent prophylactic oophorectomy, 33 of whom had a calculated risk of carrying a germline BRCA1 or BRCA2 mutation greater than 25%. Among this group, four incidental tumors were found (four of 33, or 12%); one tumor was noted at the time of surgery and three were noted only in the final pathology. Two patients had microscopic, poorly differentiated serous adenocarcinomas in multiple sites on both ovaries. A third patient had a bilateral serous borderline tumor with micropapillary features. The fourth patient had a microscopic serous borderline ovarian tumor. All four patients had germline BRCA1 or BRCA2 mutations, and three had unremarkable transvaginal ultrasonography examinations within 6 months before prophylactic surgery. CONCLUSION: Foci of malignant tumor are not uncommon in prophylactic oophorectomies performed in women at very high risk for ovarian cancer and may not be detected on ultrasonograms. Surgeons should have a high suspicion of finding cancer in these women at the time of prophylactic surgery, and careful pathologic assessment of the specimens should be conducted.

Prevalence and predictors of depressive symptoms in older premenopausal women: the Harvard Study of Moods and Cycles.

BACKGROUND: The Harvard Study of Moods and Cycles is a community-based cohort study designed to evaluate the relationship between major depression and changes in menstrual and ovarian function. METHODS: All women aged 36 to 44 years with a verifiable address from 7 Boston, Mass, metropolitan communities were selected from the Massachusetts Town Books. A self-administered questionnaire assessed demographic characteristics and menstrual history, depression history, and current depressive symptoms (Center for Epidemiologic Studies Depression Scale [CES-D]) in 4161 women. RESULTS: We observed a score of 16 or more on the CES-D in 22.4% of women surveyed, and 8.6% scored 25 or more. Widowed, divorced, or separated women were twice as likely as married women to have depression scores greater than 16 (95% confidence interval, 1.6-2.8), and smokers in the upper tertile of pack-years were 1.9 times more likely to have CES-D scores of 16 or more (95% confidence interval, 1.5-2.3). Relative to nulliparous women, those with 1 or 2 children had a 30% lower risk of historic mood disorder, and those with 3 or more children had an even greater reduction in risk (odds ratio, 0.4; 95% confidence interval, 0.3-0.6). Menstrual cycle irregularities were largely unassociated with current or past depression. However, 5 of 8 premenstrual symptoms were significantly associated with CES-D scores of 16 or more. CONCLUSIONS: These findings corroborate the prevalence of depression reported by other community-based studies, and also support a relationship between depressive symptoms and marital status, cigarette smoking, nulliparity, and premenstrual symptoms.

Ethnic background and in vitro fertilization outcomes.

OBJECTIVE: To compare IVF outcomes among women of different ethnic backgrounds. METHOD: This was a retrospective cohort study. Between August 1994 and March 1998, the first IVF cycles of 1039 white, 43 African American, 18 Hispanic, and 35 Asian women were examined. RESULT: Ages and day 3 FSH levels did not differ significantly among patients. African Americans weighed more than other ethnic groups and were also more likely to have tubal factor infertility than whites. IVF cycle characteristics did not vary among the ethnic groups with the exception that African Americans had a higher level of estradiol on day of HCG than whites. Pregnancy outcomes did not differ among the ethnic groups. The percentage of ectopic pregnancies, spontaneous abortions, and successful live births was similar among the groups. CONCLUSION: Our data showed no significant difference in pregnancy outcomes with IVF among the ethnic groups.

Determinants of basal follicle-stimulating hormone levels in premenopausal women.

The (basal) level of FSH measured during early menses is emerging as a predictor of ovarian competence. In this study, correlates of basal FSH were examined in 222 premenopausal women who were not using oral contraceptives and selected from either the general population or a clinic for women with family histories of ovarian cancer. Using analysis of variance, the effect on FSH by age, smoking history, and reproductive variables was examined. Dietary galactose (as a potential oocyte toxin) was estimated, and red cell activity of galactose-1-phosphate uridyl transferase (GALT) was measured. Qualitative features of GALT were described by its electrophoretic or molecular genetic patterns. Possession of GALT polymorphisms previously linked with low GALT activity, including the Q188R mutation of classic galactosemia or N314D mutation of the Duarte galactosemia variant, was associated with significantly higher FSH, even in the heterozygous state. Other factors significantly influencing FSH included age, smoking history, cycle length, and cycle regularity. No effect of current galactose consumption was found, and GALT activity was only weakly correlated (inversely) with FSH. Applying multiple linear regression, variables independently predictive of high FSH were age of 40 yr or more, current smoking, and possession of a GALT polymorphism.

Psychotropic medication use and risk of epithelial ovarian cancer.

Long-term use of psychotropic medication may increase the risk for epithelial ovarian cancer through increased gonadotropin secretion or direct ovarian stimulation of adrenergic receptors, effects which may affect ovarian cancer pathogenesis. An earlier case-control study found that prior use of antidepressants or benzodiazepine tranquilizers was associated with a 2-fold increase in risk of epithelial ovarian cancer. However, that study lacked details on all types of psychotropic medications, length of use, and the categorization of the specific action of these medications on the hypothalamic-pituitary-ovarian axis. In a new case-control study conducted in eastern Massachusetts (MA) and all of New Hampshire (NH), we identified all women with newly diagnosed ovarian cancer between May 1992 and March 1997. We interviewed 563 women diagnosed with malignant or borderline epithelial ovarian tumors and 523 controls identified through random digit dialing and the use of Town Books (residential listings by name, age, and precinct). Participants were asked to provide the name of medications used for 6 months or longer, the age at first use, and total months or years of use. Psychotropic medications included amphetamines, sedatives, barbiturates/anticonvulsants, antidepressants, and antipsychotics. Self-reported use of psychotropic medication for 6 months or longer was associated with a statistically significant increase in risk of invasive ovarian cancer [odds ratio (OR), 1.6; 95% confidence interval (CI), 1.1-2.3]. Relative to nonusers, risk was greatest in those whose first use occurred premenopausally for more than 2 years (OR, 2.9; CI, 1.3-6.6). The association was largely confined to use of medications that operate through dopaminergic mechanisms (OR, 2.9; CI, 1.3-6.4) or gabaergic pathways (OR, 1.5; CI, 0.9-2.5) as opposed to serotoninergic pathways (OR, 1.0; CI, 0.4-2.1). These results are consistent with the hypothesis that psychotropic medications induce gonadotropin secretion, which in turn may increase ovarian cancer risk. However, until other studies confirm our findings and determine whether they apply to medications with specific neuroendocrine actions, it is premature to advise a change in clinical practice and conclude that these medications indeed play a role in the etiology of ovarian cancer.

A case-control study of galactose consumption and metabolism in relation to ovarian cancer.

Consumption or metabolism of dairy sugar and ovarian cancer have been linked based on evidence that galactose may be toxic to ovarian germ cells and that ovarian cancer is induced in animals by depletion of oocytes. We assessed consumption of dairy products and obtained blood for biochemical and molecular genetic assessment of galactose metabolism in 563 women with newly diagnosed epithelial ovarian cancer and 523 control women selected either by random digit dialing or through lists of residents in eastern Massachusetts and New Hampshire. We observed no significant differences between cases and controls in usual consumption of various types of dairy products or total daily lactose (the principal source of galactose in the diet); nor did we find that RBC activity of either galactose-1-phosphate uridyl transferase (GALT) or galactokinase differed. The mean (and SE) activity of uridine diphospho-galactose 4'-epimerase (in micromoles per hour per gram of hemoglobin) was, however, significantly lower (P < 0.005) in cases compared with controls, 20.32 (0.31) versus 21.64 (0.36). Ovarian cancer cases were also more likely to carry the N314D polymorphism of the GALT gene, generally predisposing to lower GALT activity. The difference was most evident for endometrioid and clear cell types of ovarian cancer, in which 3.9% of cases were found to be homozygous for N314D compared with 0.4% of controls, yielding an odds ratio and 95% confidence interval of 14.17 (2.62-76.60). We conclude that, whereas adult consumption of lactose carries no clear risk for the disease, certain genetic or biochemical features of galactose metabolism may influence disease risk for particular types of ovarian cancer.

Epidemiologic evidence for uterine growth factors in the pathogenesis of ovarian cancer.

To examine the association between ovarian cancer and prior hysterectomy or tubal ligation in light of various interpretations, we combined data from two previously conducted case-control studies of ovarian cancer. This included 450 women with histologically verified epithelial ovarian cancer and 454 age-matched women from the general population for whom data on prior pelvic surgery were available to estimate exposure odds ratios. Overall there was a nonsignificant deficit of case patients who had had a hysterectomy or tubal ligation (odds ratio (OR) = 0.9; 95% confidence interval (CI), 0.6 to 1.3). A protective effect of prior hysterectomy or tubal ligation was more apparent among women who had the surgery 20 or more years previously (OR = 0.6; 95% Ci, 0.3 to 1.1), women who had not used talc in their hygiene (OR = 0.6; 95% CI, 0.4 to 1.0), and women with mucinous tumors of the ovary (OR = 0.3; 95% CI, 0.1 to 1.0). Although these data do not clearly establish the validity of or mechanisms for an association between prior pelvic surgery and ovarian cancer, we speculate that such an association exists and may be mediated through absent or reduced uterine growth factors that reach the ovaries through the uteroovarian circulation, with mucinous tumors most dependent on such factors.

Fertility and use of cigarettes, alcohol, marijuana, and cocaine.

This study demonstrated that cigarette smoking was associated with an increase in both time to conception (among 2817 fertile women) and risk of primary infertility (among 1818 infertile women and their primiparous control subjects). The average time to conception was 4.3 months for women who never smoked, 4.6 months for those who smoked in the past, and 5.1 months for those who currently smoked. The delay in conception for current smokers remained significant after adjusting for confounders (risk ratio of 0.9 (0.8 to 1.0)). Additionally, current smokers were at increased risk of primary infertility (odd ratios of 1.9 (1.5 to 2.3)). For alcohol use, the average time to conception and risk of primary infertility did not vary by level of consumption. The average time to conception was significantly shorter for women who had used marijuana regularly and for women who had ever used cocaine than for women who had never used these drugs. Because of the increased use of marijuana and cocaine among young adults, further investigations of these associations are needed.

Epidemiologic determinants of endometriosis: a hospital-based case-control study.

PURPOSE: Risk factors for endometriosis were identified through data obtained from a case-control study at Brigham and Women's Hospital in Boston, Massachusetts. METHODS: Cases were 50 women with infertility-associated endometriosis. The primary control group consisted of 89 fertile women without endometriosis, and an alternate control group consisted of 47 infertile women without endometriosis. RESULTS: The risk of endometriosis was positively associated with height (OR), 2.8 per 10 cam increase; 95% confidence interval (CI), 1.4-5.6) and inversely associated with weight (OR, 0.7 per 10 kg increase; 95% CI, 0.5-1.0) and body mass index (OR, 0.7 per 5 kg/m2 increase; 95% CI, 0.4-1.1). We observed an inverse association with exercise (OR, 0.6; 95% CI, 0.3-1.5), but the effect was limited to women who exercised > or = 4 hours per week (OR, 0.4; 95% CI, 0.2-1.2). Endometriosis was not associated with either smoking or alcohol consumption. CONCLUSIONS: Our findings suggest that the fertility status of controls can strongly influence associations seen with menstrual characteristics. This study is one of few to address the issue of control selection for a case-control study of endometriosis. Specifically, potential problems encountered using fertile and infertile control women are examined and discussed.