Risk of prostate cancer in men who are childless

In an uniquely large population-based data set obtained from a nationwide record linkage and including 48,850 cases of prostate cancer diagnosed in Sweden between 1958 and 1998, Giwercman et al.1 found an odds ratio (OR) of 0.93 (95 CI = 0.90–0.96) in men who fathered only 1 child and of 0.83 (95% CI = 0.81–0.86) in childless men compared to men who fathered 2 or more children. No further change in risk was found with increasing number of children. Since prostate cancer has been associated to high androgen levels, the authors suggest that testicular failure, the main cause of male infertility, may be associated to long-term androgen deficiency and therefore to low prostate cancer risk. However, a meta-analysis of 18 epidemiologic studies of prostate cancer failed to find a similar association.2 The estimated overall ORs were 1.02 (95% CI = 0.99–1.04), 1.03 (95% CI = 0.99–1.09), 1.05 (95% CI = 0.98–1.13) and 1.07 (95% CI = 0.97–1.18), respectively, in men with 1, 2, 3 and 4 children compared to childless men. Results were, however, significantly heterogeneous: the OR for men with 2 children compared to childless men was 1.16 (95% CI = 1.06–1.28) in hospital-based case-control studies (10 studies), 0.99 (95% CI = 0.94–1.05) in population-based case-control studies (7 studies) and 1.01 (95% CI = 0.84–1.21) in 1 cohort study. A previous Italian study did not find a clear association between the number of children and prostate cancer risk.3 To investigate the relation between the number of children and prostate cancer risk, we have analyzed data from a case-control study conducted between 1991 and 2002 in 4 Italian areas, including greater Milan and the provinces of Pordenone and Gorizia in northern Italy, the province of Latina in central Italy and the urban area of Naples in southern Italy.4 Briefly, this included 1,294 patients (median age, 66 years; range, 46–74) with incident, histologically confirmed carcinoma of the prostate, admitted to major teaching and general hospitals in the areas under study, and 1,451 controls (median age, 63 years; range, 46–74) selected among patients admitted to the same hospitals as cases for a wide spectrum of acute and nonneoplastic conditions. Less than 5% of both cases and controls refused to participate. Twenty-one percent of the controls were admitted for traumas, 32% for other orthopedic disorders, 17% for acute surgical conditions and 29% for miscellaneous other illnesses, including eye, nose, ear, skin, or dental disorders. Cases and controls were interviewed during their hospital stay using a standard questionnaire, including information on sociodemographic characteristics, anthropometric measures, lifestyle habits, a validated food-frequency section, personal medical history and family history of cancer in first-degree relatives. The sociodemographic section collected also information on marital status, age at marriage and number of children. Two cases and 2 controls had missing information on number of children and were eliminated from the analysis. ORs and the corresponding 95% confidence intervals were estimated using unconditional multiple logistic regression models,5 including terms for age and study center (OR1), plus marital status and age at marriage (OR2), plus education, body mass index, physical activity, smoking, alcohol intake and family history of prostate cancer (OR3). Compared to men with 2 or more children, the OR for childless men was 0.95 (95% CI = 0.73–1.24) when adjusting only for age and center, and 1.10 (95% CI = 0.74–1.62) after further adjustment for marital status and age at marriage (OR2) (Table I). For the latter model, the OR was 1.00 (95% CI = 0.67–1.50) when unmarried (69 cases and 98 controls) and separated/divorced (27 cases and 35 controls) men were excluded, 1.09 (95% CI = 0.57–2.07) below age 65 years and 1.13 (95% CI = 0.69–1.86) above age 65 years. The OR for men with only 1 child compared to men who reported 2 or more children was 1.17 (95% CI = 0.94–1.47). Although our study is among the largest epidemiologic studies on the topic,2 it is much smaller than the Swedish record linkage study,1 and we were not able to exclude an inverse association of the order of the one reported in the Swedish study. However, in our study there was no indication that childless men were at lower risk of prostate cancer, in line with the meta-analysis of published data.2 In this study, we were not able to distinguish between biologic and adopted children, and this may have introduced some misclassification. On the other hand, we were able to adjust for marital status, which was strongly associated with being childless (5% among married men and 94% among never-married men). Allowance for marital status led to a change in the OR for childless men from 0.95 to 1.10, suggesting that marital status may at least in part explain the inverse relation observed in the Swedish data. Thus, the epidemiologic evidence on the relation between the number of children and prostate cancer risk remains controversial, and specific studies investigating infertility in men are needed to test the intriguing hypothesis of a relation between this condition and prostate cancer. The authors thank Mrs. I. Garimoldi for editorial assistance. Yours sincerely, Eva Negri, Renato Talamini, Cristina Bosetti, Maurizio Montella, Silvia Franceschi, Carlo La Vecchia.