Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
VA Palo Alto Health Care System, Palo Alto, CA, USA.
Int J Epidemiol. 2023 Jun 6;52(3):806-816. doi: 10.1093/ije/dyac215.
A later age at natural menopause (ANM) has been linked to several ageing-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.
We investigated the causal association of ANM with these clinical outcomes using Mendelian randomization (MR). Participants and outcomes analysed were restricted to post-menopausal females. We conducted a one-sample MR analysis in both the Women's Health Initiative and UK Biobank. We further analysed and integrated several additional data sets of post-menopausal women using a two-sample MR design. We used ≤55 genetic variants previously discovered to be associated with ANM as our instrumental variable.
A 5-year increase in ANM was causally associated with a decreased risk of osteoporosis [odds ratio (OR) = 0.80, 95% CI (0.70-0.92)] and fractures (OR = 0.76, 95% CI, 0.62-0.94) as well as an increased risk of lung cancer (OR = 1.35, 95% CI, 1.06-1.71). Other associations including atherosclerosis-related outcomes were null.
Our study confirms that the decline in bone density with menopause causally translates into fractures and osteoporosis. Additionally, this is the first causal epidemiological analysis to our knowledge to find an increased risk of lung cancer with increasing ANM. This finding is consistent with molecular and epidemiological studies suggesting oestrogen-dependent growth of lung tumours.
自然绝经年龄（ANM）较晚与多种与衰老相关的特征有关，包括乳腺癌和子宫内膜癌风险增加、肺癌、骨质疏松症和阿尔茨海默病风险降低。然而，ANM 也与整体健康的几个指标有关，这些指标可能会混淆这些关联。
我们使用孟德尔随机化（MR）研究 ANM 与这些临床结局的因果关系。参与者和结局分析仅限于绝经后女性。我们在妇女健康倡议和英国生物库中进行了一次单样本 MR 分析。我们进一步使用两样本 MR 设计分析和整合了几个额外的绝经后女性数据集。我们使用≤55 个先前发现与 ANM 相关的遗传变异作为我们的工具变量。
ANM 每增加 5 年，与骨质疏松症风险降低相关[比值比（OR）=0.80，95%置信区间（CI）（0.70-0.92）]和骨折（OR=0.76，95%CI，0.62-0.94）以及肺癌风险增加相关（OR=1.35，95%CI，1.06-1.71）。其他与动脉粥样硬化相关的结局无关联。
我们的研究证实，绝经后骨密度下降会导致骨折和骨质疏松症。此外，这是我们所知的第一个使用因果流行病学分析方法发现 ANM 增加与肺癌风险增加相关的研究。这一发现与雌激素依赖性肺癌生长的分子和流行病学研究一致。
