Tomas Riman

Review of epidemiological evidence for reproductive and hormonal factors in relation to the risk of epithelial ovarian malignancies

Ovarian cancer is the leading cause of mortality related to gynecologic malignancies in Sweden but there is no current screening program. Based upon epidemiological research there is evidence that certain reproductive factors are associated with ovarian cancer risk. Most studies generally indicate that each childbirth incurs a 15–20% risk reduction. Women who have used oral contraceptives for 5 years or longer experience about half the risk of ovarian cancer compared with never users. Breastfeeding seems to be protective while age at menarche and at menopause are less consistent risk predictors. Tubal ligation and hysterectomy seem to reduce ovarian cancer risk by up to 80%. Although some studies found endometriosis, polycystic ovarian syndrome (PCOS) and pelvic inflammatory disease (PID) to be positively related to ovarian cancer, the role of these factors is not yet established. Most recent studies observed an approximately 50% ovarian cancer risk increase among ever users of hormone replacement therapy (HRT) compared with never users, and the risk increased further with long‐term use. There is less information concerning separate estrogen and progestin effects of HRT and ovarian cancer risk. Although the cause of ovarian cancer remains obscure, hypotheses relating to “incessant” ovulation, excessive gonadotropin secretion, retrograde carcinogen transportation, apoptosis and estrogen/progestin imbalance have been invoked as etiological explanations. All these hypotheses find various epidemiological support. The aim of this review is to summarize the epidemiological findings on reproductive factors and ovarian cancer risk. These findings are considered in the context of etiologic hypotheses and some new research areas are suggested.

Some life-style factors and the risk of invasive epithelial ovarian cancer in Swedish women

The objective of this nationwide case-control study was to examine body mass index (BMI), alcohol use, coffee consumption, cigarette smoking, and leisure-time physical activity in relation to epithelial ovarian cancer (EOC) risk. Subjects were 655 newly diagnosed EOC cases and 3899 population controls, all 50-74 years of age at recruitment between 1993 and 1995. Data were collected through mailed questionnaires. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression. Women with a BMI ≥ 30 kg/m2 compared with those with a BMI < 22 kg/m2 appeared to have an elevated EOC risk (OR = 1.37, 95% CI: 1.01-1.85), particularly of mucinous (OR = 2.76, 95% CI: 1.15-6.61) and clear-cell histologies (OR = 2.68, 95% CI: 0.96-7.48). The OR for EOC among coffee users reporting ≥ 6 daily cups compared with non-users was 0.68 (95% CI: 0.42-1.10). Alcohol consumption was unrelated to EOC risk. Compared to non-smokers the ORs of EOC among current smokers were 0.70 (95% CI: 0.52-0.94) for those who smoked 1-10 cigarettes/day and 0.74 (95% CI: 0.53-1.02) for heavier smokers, while former smokers were at an unaltered risk (OR = 0.83, 95% CI: 0.66-1.04). Reduced EOC risks were observed among women in the highest compared with the lowest physical activity levels both at age 18-30 years (OR = 0.67, 95% CI: 0.52-0.87) and during the last years preceding study enrollment (OR = 0.68, 95% CI: 0.53-0.87). We conclude that women may avoid an excess risk of EOC through maintaining a normal BMI and reduce their risk by participation in leisure-time physical activity. The use of coffee, alcohol, or cigarette smoking does not appear␣to increase the risk of EOC.

Use of hormone replacement therapy before and after ovarian cancer diagnosis and ovarian cancer survival

Use of hormone replacement therapy (HRT) has been hypothesized to affect survival of epithelial ovarian cancer (EOC). We studied 5‐year survival in patients with invasive EOC and borderline ovarian tumors (BOT) according to HRT use before and after diagnosis in a prospective nation‐wide cohort study of 799 women diagnosed with EOC (n = 649) and BOT (n = 150) aged 50–74 years in 1993–1995 in Sweden. Cox regression was used to obtain multivariate age‐adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). Multivariate models included indicator variables for age, tumor stage, grade and histological subtype. After 5 years of follow‐up, 45% of the patients with EOC and 93% of the patients with BOT were alive. For women with BOT there were no associations between HRT‐use pre‐ or postdiagnosis and survival. There was no overall difference in 5‐year EOC survival according to use HRT before diagnosis (multivariate HR = 0.83, 95% CI = 0.65–1.08), except for serous EOC (HR = 0.69, 95% CI = 0.48–0.98). Analyses of different HRT preparations, duration and recency of use did not reveal any variations in pattern of survival. We observed a better survival for EOC‐patients who used HRT after diagnosis (multivariate HR = 0.57, 95% CI = 0.42–0.78). We conclude that HRT‐use prior to diagnosis of EOC does not affect 5‐year survival, except for a possible survival advantage in serous EOC. Women using HRT after diagnosis had a better survival than women with no use, but we cannot rule out that this latter finding may reflect a subtle selection process.

Predictors of ovarian cancer survival: a population-based prospective study in Sweden.

Ovarian cancer is the leading cause of death from gynecologic malignancies among women worldwide. Little is known about reproductive factors or lifestyle determinants and ovarian cancer prognosis. The objective of this study was to examine whether ovarian cancer survival is influenced by reproductive history, anthropometric characteristics, prediagnostic life‐style factors and family history of breast or ovarian cancer. The study population consisted of 635 epithelial ovarian cancer (EOC) cases derived from a nationwide population‐based case‐control study conducted in Sweden between 1993 and 1995. Exposure data on prediagnostic factors of interest were collected through questionnaires at the beginning of the parent study. Clinical data were abstracted from medical records. Cases were followed‐up by means of record linkage to nationwide registers until December 31, 2002. Cox proportional hazard regression model was used to estimate the prognostic effect of each factor in terms of hazard ratios (HR) and 95% confidence intervals (CI), following adjustment for age at diagnosis, FIGO tumor stage and WHO grade of tumor differentiation. Tumor characteristics significantly influenced the risk of death from EOC. After adjustment for these, no clear associations were detected between reproductive history (parity, age at first or last birth, oral contraceptive use, age at menarche or menopause), anthropometric characteristics (body size and shape in different periods of life), lifestyle factors before diagnosis (alcohol consumption, smoking and physical activity over lifetime), nor family history of breast cancer or ovarian cancer and EOC survival. Our findings indicate that these prediagnostic factors do not influence the EOC survival. Nevertheless, among women with early stage disease (FIGO stage I and II), there was some indication that overweight in young adulthood or recent years increased the risk of death, while physical activity in young adult life appeared to reduce the risk of death due to EOC.

Gestational Age and Fetal Growth in Relation to Maternal Ovarian Cancer Risk in a Swedish Cohort

Background: Pregnancy influences subsequent maternal ovarian cancer risk. To date, there is limited evidence whether two characteristics of pregnancy, gestational age and birth weight, could modify risk. Materials and Methods: We studied 1.1 million Swedish women who delivered singleton births between 1973 and 2001. Information on infant gestational age and birth weight was abstracted from the nationwide Swedish Birth Register. Women were followed prospectively through linkage with other population-based registers for occurrence of ovarian cancer, death, or emigration through 2001. Hazard ratios [relative risk (RR), 95% confidence interval (95% CI)] from Cox models were used to estimate associations between gestational age, birth weight, and epithelial ovarian cancer risk. Results: During 12.6 million person-years, 1,017 epithelial ovarian cancers occurred. Mean age at diagnosis was 43 years. Compared with women with term deliveries (≥40 weeks), women with moderately (35-36 weeks) or very (<35 weeks) preterm deliveries had increased risks of epithelial ovarian cancer (RR 1.4, 95% CI 1.0-2.0 and RR 2.3, 95% CI 1.3-3.8, respectively). In contrast, women giving birth to small-for-gestational-age babies had a reduced risk (RR 0.7, 95% CI 0.4-1.0). Stratifying on birth weight and gestational age, there was a strong protective effect of low birth weight on maternal risk of epithelial ovarian cancer among term deliveries, whereas birth weight seemed to have little effect among preterm births (Pinteraction = 0.022). Conclusions: Our results lend further support that the hormonal milieu of a pregnancy may modify long-term risk of developing ovarian cancer. (Cancer Epidemiol Biomarkers Prev 2007;16(9):1828–32)

Gender of Offspring and Maternal Risk of Invasive Epithelial Ovarian Cancer

Gender of a fetus is associated with maternal hormonal milieu and may therefore modify maternal risk of ovarian cancer following a birth. We evaluated the relation between gender of offspring and maternal risk of epithelial ovarian cancer in a large case-control study nested within a nationwide cohort. Cohort members were identified in the Swedish Fertility Register. Cases of invasive epithelial ovarian cancer were identified in the Swedish National Cancer Register from 1961 to 2001. Five controls were matched by age to each case. A total of 7,407 cases and 37,658 controls with only singleton births were included in the analysis. We fit logistic regression models to study the association between gender of offspring and ovarian cancer risk, controlling for covariates. Maternal risk of ovarian cancer was reduced with increasing numbers of male offspring and increased with number of female offspring. Compared with women who gave birth to only girls, multivariate odds ratios (95% confidence interval) of invasive epithelial ovarian cancer were 0.92 (0.87-0.98) for those who gave birth to one boy, 0.87 (0.80-0.94) for two boys, and 0.82 (0.73-0.94) for three or more boys (P value test for trend < 0.001). There was a positive but nonsignificant association with number of girls. Similar results were observed when restricting the analysis to women born before 1935. Our findings suggest that hormonal and physiologic conditions in pregnancy with male, but not with female, offspring are associated with a lowered maternal risk of invasive epithelial ovarian cancer. (Cancer Epidemiol Biomarkers Prev 2007;16(11):2314–20)

A Prospective Study of the Transient Decrease in Ovarian Cancer Risk Following Childbirth

Epidemiologic evidence shows that the risk of ovarian cancer is decreased following childbirth. We examined the time points when the decreased risk of postpartum maternal ovarian cancer reaches the lowest point and whether the protective effect diminishes over time. A case-control study nested within the Swedish Fertility Register included 10,086 cases of epithelial ovarian cancer recorded in the Swedish Cancer Register from 1961 to 2001. From the Fertility Register, 49,249 eligible subjects matched to the cases by age were selected as controls. The analysis contrasted risk between adjacent parities through logistic regression models that included indicator variables representing each year of age, age at delivery, and time since delivery. Compared with nulliparous women, uniparous women had a transient decrease in maternal ovarian cancer risk at 2 years after delivery (spline-derived odds ratio, 0.71; 95% confidence interval, 0.53-0.95, for those delivered at age 25 years) and maintained a lower risk for 4 years postpartum. Similar transient decreases were observed in biparous women compared with uniparous women and in women with three parities compared with biparous women. The protective effect of childbearing seemed to diminish with time. The transient decrease in postpartum ovarian cancer risk may define the latent period required for pregnancy hormones in clearing out ovarian cells that have undergone early stages of malignant transformation. The period before the risk increases again could indicate the period required for ovarian cancer induction. (Cancer Epidemiol Biomarkers Prev 2006;15(12):2508–13)

Hormone replacement therapy and ovarian cancer risk – any news?

The publication of data from the Women’s Health Initiative (WHI) randomised controlled trial, where increased risks of breast cancer and cardiovascular events appeared among users of hormone replacement therapy (HRT), set off a change in attitude towards HRT use among both practitioners and health care consumers (1). It is estimated that HRT prescriptions have declined by 40 60% since the first WHI report in 2002 (2,3). The clinical question, to initiate or continue HRT in the management of menopausal symptoms, necessitates a careful risk benefit assessment, which, to date, has only marginally incorporated the risk of ovarian cancer among users of HRT. Two large, well conducted, cohort studies recently provided new information on ovarian cancer risks among HRT users (4,5), which may be added to the decision-making process whether to prescribe HRT or not. Further, particularly the US cohort study examines the effects of estrogen and progestin components of HRT in relation to ovarian cancer risk, a research area that has been incompletely evaluated (6). Between 1996 and 2001, Beral et al. in the UK Million Women Study recruited a cohort of 948,576 postmenopausal women, half of whom were current (30%) or past (20%) users of HRT (4). The results pertaining to HRT and the risk of ovarian cancer were published in the Lancet Online of 19 April. After an average follow-up of 5.3 years for incident disease, and 6.7 years for fatal ovarian cancer, 2,273 incident ovarian cancers were detected, and 1,591 deaths were attributed to the malignancy. Current users of HRT were more likely to develop ovarian cancer, with a relative risk of 1.20 (95% CI: 1.09 1.32) compared with HRT never users, and the incidence of ovarian cancer increased with increasing duration of use. A relative risk of 1.31 (95% CI: 1.12 1.53) was reported among those who had used HRT for ]10 years. Compared with never users of any HRT, current users of unopposed estrogens and estrogen-progestin combinations, who were on the medications for ]5 years, had relative risks for incident ovarian cancer of 1.53 (95% CI: 1.27 1.84) and 1.17 (95% CI: 1.02 1.34), respectively. The relative risks of developing ovarian cancer among current users of estrogen-progestin combinations were 1.14 (95% CI: 0.98 1.32) for sequential regimens, and 1.13 (95% CI: 0.95 1.33) for continuous regimens, when compared with HRT never users. No duration data were presented for the sequential and continuous estrogen-progestin combinations. Over time, women may use different HRT regimens, and the authors did not specify if the analyses were restricted to groups of women who had only used one regimen or if any statistical adjustments had been made to allow for use of 2 or more consecutive types of HRT regimens. No residual risk of incident ovarian cancer was observed among past HRT users (RR: 0.98; 95% CI: 0.88 1.11). In the same study, current users of HRT had a higher relative risk for fatal ovarian cancer of 1.23 (95% CI: 1.09 1.38) than never users, a risk that did not persist among past users (RR: 0.97; 95% CI: 0.84 1.11). Standardised incidence and mortality rates for ovarian cancer per 1,000 women in the study population were 2.2 and 1.3 among HRT never users, respectively, and 2.6 and 1.6 in current HRT users, respectively. The authors concluded that if the differences in rates between never users and current users are due to HRT, the study results imply that over a 5-year period, use of HRT resulted in