Reproductive Factors, Exogenous Hormone Use, and Risk of B-Cell Non-Hodgkin Lymphoma in a Cohort of Women From the European Prospective Investigation Into Cancer and Nutrition

Laura Costas; Leila Lujan-Barroso; Yolanda Benavente; Naomi E. Allen; Pilar Amiano; Eva Ardanaz; Caroline Besson; Heiner Boeing; Bas Bueno-de-Mesquita; Iris Cervenka; Renée T. Fortner; Agnès Fournier; Marc Gunter; Sophia Harlid; José María Huerta; Mats Jerkeman; Karin Jirström; Rudolf Kaaks; Anna Karakatsani; Kay-Tee Khaw; Anastasia Kotanidou; Eiliv Lund; Giovanna Masala; Amalia Mattiello; Beatrice Melin; Virginia Menéndez; Neil Murphy; Alexandra Nieters; Kim Overvad; Elio Riboli; Carlotta Sacerdote; Maria-Jose Sánchez; Julie A. Schmidt; Sabina Sieri; Anne Tjønneland; Antonia Trichopoulou; Rosario Tumino; Roel Vermeulen; Elisabete Weiderpass; Silvia de Sanjosé; Antonio Agudo; Delphine Casabonne


Am J Epidemiol. 2019;188(2):274-281. 

In This Article

Abstract and Introduction


The role of hormonal factors in the etiology of lymphoid neoplasms remains unclear. Previous studies have yielded conflicting results, have lacked sufficient statistical power to assess many lymphoma subtypes, or have lacked detailed information on relevant exposures. Within the European Prospective Investigation Into Cancer and Nutrition cohort, we analyzed comprehensive data on reproductive factors and exogenous hormone use collected at baseline (1992–2000) among 343,458 women, including data on 1,427 incident cases of B-cell non-Hodgkin lymphoma (NHL) and its major subtypes identified after a mean follow-up period of 14 years (through 2015). We estimated hazard ratios and 95% confidence intervals using multivariable proportional hazards modeling. Overall, we observed no statistically significant associations between parity, age at first birth, breastfeeding, oral contraceptive use, or ever use of postmenopausal hormone therapy and risk of B-cell NHL or its subtypes. Women who had undergone surgical menopause had a 51% higher risk of B-cell NHL (based on 67 cases) than women with natural menopause (hazard ratio = 1.51, 95% confidence interval: 1.17, 1.94). Given that this result may have been due to chance, our results provide little support for the hypothesis that sex hormones play a role in lymphomagenesis.


Non-Hodgkin lymphoma (NHL) is a heterogeneous group of hematological malignancies, the incidence of which has risen in some Western countries since the 1970s, although it seems to have reached a plateau during the last few decades. Incidence rates of NHL are higher in men than in women for most NHL subtypes.[1] Reproductive hormones interact with the immune system in numerous ways,[2,3] and women produce a more vigorous cellular and humoral response than men.[4] Increasing evidence suggests a role of estrogens in hematological malignancies.[5] While normal human peripheral blood cells express both estrogen receptor α and estrogen receptor β, lymphoid neoplasms express and up-regulate estrogen receptor β.[6,7] Furthermore, estrogen receptor β agonists have been shown to strongly inhibit the growth of lymphoma and leukemia cells in mice.[8,9]

Although the interaction between the endocrine and immune systems is complex, hormonal influences in NHL etiology seem biologically plausible. However, analyses that have examined the association of reproductive factors with NHL risk have been inconsistent, probably because of study limitations,[10] including lack of detailed data on hormonal factors and limited statistical power to examine these associations for different NHL subtypes, which may have different etiologies.[11] We therefore investigated the roles of reproductive factors and exogenous hormone use in risk of B-cell NHL using detailed data from a large cohort study, the European Prospective Investigation Into Cancer and Nutrition (EPIC).