Genetic evidence for causal relationships between age at natural menopause and the risk of aging-associated adverse health outcomes

Abstract BackgroundA later age at natural menopause (ANM) has been linked to several aging-associated traits including an increased risk of breast and endometrial cancer and a decreased risk of lung cancer, osteoporosis, and Alzheimer disease. However, ANM is also related to several proxies for overall health that may confound these associations. MethodsWe investigated the causal association of ANM with these clinical outcomes using Mendelian randomization (MR). Participants and outcomes analyzed were restricted to post-menopausal females. We conducted a one-sample MR analysis in both the Women’s Health Initiative (WHI) and the UK Biobank (UKB). We further analyzed and integrated several additional datasets of post-menopausal women using a two-sample MR design. We used up to 55 genetic variants previously discovered to be associated with ANM as our instrumental variable. ResultsA five year increase in ANM was causally associated with a decreased risk of osteoporosis (OR=0.80 [0.70, 0.92]) and fractures (OR=0.76 [0.62, 0.94]) as well as an increased risk of lung cancer (OR=1.35 [1.06, 1.71]). Other associations including atherosclerosis related outcomes were null. ConclusionsOur study confirms that the decline in bone density with menopause causally translates to fracture and osteoporosis. Additionally, this is the first causal epidemiologic analysis to our knowledge to find an increased risk of lung cancer with ANM. This finding is consistent with molecular and epidemiologic studies suggesting estrogen dependent growth of lung tumors. Randomized controlled trials of anti-estrogen therapies in the prevention or treatment of lung cancer should be considered if additional MR studies are confirmatory. Key MessagesAs in prior literature, the age of natural menopause (ANM) was observationally associated with increased risk of breast cancer, endometrial cancer, and ovarian cancer, and with a decreased risk of lung cancer, coronary heart disease, ischemic stroke, fracture, osteoporosis, and Alzheimer disease in the Women’s Health Initiative and UK Biobank.However, these associations may be confounded by overall markers of health, such as smoking, so we used a genetic instrument variable to look at the causality of ANM on these adverse outcomes using Mendelian randomization.A five year increase in ANM was causally associated with decreased risk of fracture and osteoporosis, but with an increase lung cancer.This increase in ANM was not significantly associated with other outcomes; notably, there was no causal association of ANM with coronary heart disease or ischemic stroke.Given the increase in lung cancer risk and prior molecular studies linking lung cancer to estrogen receptor expression, randomized controlled trials of anti-estrogen therapies for prevention or treatment of lung cancer should be considered, should these results be replicated in additional studies.