Berthe M. P. Aleman1, Inge M. Krul2, Annemieke W. J. Opstal van Winden2, Cécile P. M. Janus3, Laurien A. Daniëls4, Y. Appelman5, Angela H. E. M. Maas6, Frederika A. van Nimwegen2, Simone de Vries2, Michael Hauptmann2, Katarzyna Józ’wiak2, Flora E. van Leeuwen1
1Department of Radiation Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands,2Department of Epidemiology and Biostatistics, The Netherlands Cancer Institute, Amsterdam, the Netherlands,3Department of Radiation Oncology, Erasmus University MC Cancer Institute, Rotterdam, the Netherlands,4Department of Radiotherapy, Leiden University Medical Center, Leiden, the Netherlands,5Department of Cardiology, Amsterdam University Medical Center, location VUmc, Amsterdam, the Netherlands,6Department of Cardiology, Radboud University Medical Center, Nijmegen, the Netherlands
Background: Female survivors of Hodgkin lymphoma (HL) treated with alkylating chemotherapy (CT) and/or pelvic radiotherapy (RT) have an increased risk of premature ovarian insufficiency (POI). Among women with a natural menopause, POI has been associated with a 1.6-fold increased risk of overall cardiovascular disease (CVD). However, mixed results have been reported for women with POI after surgical menopause, possibly due to the use of hormone replacement therapy (HRT) or the age at surgery.
Objectives: We examined whether treatment-induced POI increases long-term CVD risk in 5-year HL survivors.
Methods: From a large Dutch cohort of 5-year HL survivors, we selected 918 women who were treated before 41 years of age between 1965 and 2000. Data on HL treatment, menopausal status and cardiovascular events (ischemic heart disease (IHD), heart failure (HF) and valvular heart disease (VHD)) were obtained from medical records, general practitioners and patient questionnaires. CVD risks were estimated with Cox regression models using time-dependent covariates.
Results: After a median follow-up of 24 years, 299 out of 918 women had developed POI (median menopausal age, 34 years (interquartile range 28–37). We identified 463 cardiovascular events in 300 women, of whom 85 developed CVD after POI. POI was not associated with subsequent CVD risk (hazard ratio (HR):0.85, 95% CI 0.62–1.16) compared with a menopausal age of ≥40 years. Also a short duration of intact ovarian function after HL treatment (<5 years) did not increase CVD risk compared to a long duration (≥25 years) (HR:0.72, 95% CI 0.44–1.20). Similar results were found in analyses with IHD, HF and VHD as separate outcomes.
Conclusions: POI and duration of post-treatment intact ovarian function did not affect CVD risk in HL survivors, suggesting that an early artificial menopause does not increase CVD risk. Future studies should investigate whether specific genes predispose to both POI and CVD development, or whether an unfavorable CVD risk profile before menopause contributes to POI.