Su‑Min Jeong^1,2,3†, Jung Eun Yoo^4†, Keun Hye Jeon⁵, Kyungdo Han⁶, Heesun Lee⁷, Dong‑Yun Lee⁸ and Dong Wook Shin^9,10*

¹Department of Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea. 
²Department of Family Medicine, Seoul National University Health Service Center, Seoul, Republic of Korea. 
³Department of Family Medicine, Seoul National University Hospital, Seoul, Republic of Korea. 
⁴Department of Family Medicine, Healthcare System Gangnam Center, Seoul National University Hospital, Seoul, Republic of Korea. 
⁵Department of Family Medicine, CHA Gumi Medical Center, CHA University, Gumi, Republic of Korea. 
⁶Department of Statistics and Actuarial Science, Soongsil University, Seoul, Republic of Korea. 
⁷Department of Cardiology, Healthcare System Gangnam Center, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea. 
⁸Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. 
⁹Department of Family Medicine/Supportive Care Center, Samsung Medical Center, Seoul, Republic of Korea. 
¹⁰Department of Clinical Research Design & Evaluation, Samsung Advanced Institute for Health Science and Technology (SAIHST), Sungkyunkwan University, 81 Irwon‑Ro, Gangnam‑Gu, Seoul 06351, Republic of Korea. 

^†Su-Min Jeong and Jung Eun Yoo are co-frst authors.
^*Correspondence: Dong Wook Shin

Background: To assess the association between the reproductive factors of age at menarche, age at menopause, and reproductive span and the incidence of myocardial infarction (MI) and ischemic stroke (IS).

Methods: We used a population-based retrospective cohort study from the National Health Insurance Service database of Korea including a total of 1,224,547 postmenopausal women. Associations between age at menarche (≤ 12, 13-14 [reference], 15, 16, and ≥ 17 years), age at menopause (< 40, 40-45, 46-50, 51-54 [reference], and ≥ 55 years), and reproductive span (< 30, 30-33, 34-36, 37-40 [reference], and ≥ 41 years) and the incidence of MI and IS were assessed by Cox proportional hazard models with adjustment for traditional cardiovascular risk factors and various reproductive factors.

Results: During a median follow-up of 8.4 years, 25,181 MI and 38,996 IS cases were identified. Late menarche (≥ 16 years), early menopause (≤ 50 years), and short reproductive span (≤ 36 years) were linearly associated with a 6%, 12-40%, and 12-32% higher risk of MI, respectively. Meanwhile, a U-shaped association between age at menarche and risk of IS was found, with a 16% higher risk in early menarche (≤ 12 years) and a 7-9% higher risk in late menarche (≥ 16 years). Short reproductive span was linearly associated with an increased risk of MI, whereas both shorter and longer reproductive spans were associated with an increased risk of IS.

Conclusions: This study demonstrated different patterns of association between age at menarche and incidence of MI and IS: a linear association for MI versus a U-shaped association for IS. Female reproductive factors in addition to traditional cardiovascular risk factors should be considered when assessing overall cardiovascular risk in postmenopausal women.