. 2025 Mar 18:zwaf051.

doi: 10.1093/eurjpc/zwaf051. Online ahead of print.

Reassessing the association between age at menarche and cardiovascular disease: observational and Mendelian randomization analyses

Lena Tschiderer¹, Sanne A E Peters^{2

3

4}, Yvonne T van der Schouw², Stephen Burgess^{5

6

7}, Janneke Luijken², Cheyenne Bijmolt², Houda Soliman², Adam S Butterworth^{5

6

8

9

10}, Angela M Wood^{8

10

11

12

13}, Tammy Y N Tong¹⁴, Christina C Dahm¹⁵, Lisa Seekircher¹, Anne Tjønneland^{16

17}, Lene Mellemkjær¹⁶, Matthias B Schulze^{18

19}, Giovanna Masala²⁰, Sabina Sieri²¹, Salvatore Panico²², Carlotta Sacerdote²³, Jolanda M A Boer²⁴, W M Monique Verschuren^{2

24}, Carlota Castro-Espin^{25

26}, Dafina Petrova^{27

28

29}, Sandra M Colorado-Yohar^{29

30

31}, Conchi Moreno-Iribas^{29

32

33}, Elisabete Weiderpass³⁴, Alicia K Heath³⁵, Ioanna Tzoulaki^{35

36}, Peter Willeit^{1

5}, N Charlotte Onland-Moret²

Affiliations

¹ Institute of Clinical Epidemiology, Public Health, Health Economics, Medical Statistics and Informatics, Medical University of Innsbruck, Anichstraße 35, Innsbruck 6020, Austria.
² Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands.
³ The George Institute for Global Health, School of Public Health, Imperial College London, London, UK.
⁴ The George Institute for Global Health, University of New South Wales, Sydney, New South Wales, Australia.
⁵ Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
⁶ Heart and Lung Research Institute, University of Cambridge, Cambridge, UK.
⁷ MRC Biostatistics Unit, School of Clinical Medicine, University of Cambridge, Cambridge, UK.
⁸ NIHR Blood and Transplant Research Unit in Donor Health and Behaviour, University of Cambridge, Cambridge, UK.
⁹ BHF Centre of Research Excellence, School of Clinical Medicine, Addenbrooke's Hospital, Cambridge, UK.
¹⁰ Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge, UK.
¹¹ British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
¹² Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge, UK.
¹³ British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge, UK.
¹⁴ Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
¹⁵ Department of Public Health, Aarhus University, Aarhus, Denmark.
¹⁶ Danish Cancer Institute, Strandboulevarden 49, Copenhagen 2100, Denmark.
¹⁷ Department of Public Health, Section of Environmental Health, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen DK-1353, Denmark.
¹⁸ Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany.
¹⁹ Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany.
²⁰ Clinical Epidemiology Unit, Institute for cancer research, prevention and clinical network (ISPRO), Florence, Italy.
²¹ Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy.
²² School of Medicine, Federico II University, Naples, Italy.
²³ Unit of Cancer Epidemiology, AOU Città della Salute e della Scienza University Hospital, Turin, Italy.
²⁴ National Institute for Public Health and the Environment, Bilthoven, the Netherlands.
²⁵ Unit of Nutrition and Cancer, Catalan Institute of Oncology-ICO, L'Hospitalet de Llobregat, Barcelona, Spain.
²⁶ Nutrition and Cancer Group, Epidemiology, Public Health, Cancer Prevention and Palliative Care Program, Bellvitge Biomedical Research Institute-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.
²⁷ Escuela Andaluza de Salud Pública (EASP), Granada 18011, Spain.
²⁸ Instituto de Investigación Biosanitaria ibs.GRANADA, Granada 18012, Spain.
²⁹ Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Madrid 28029, Spain.
³⁰ Department of Epidemiology, Murcia Regional Health Council, IMIB-Arrixaca, Murcia, Spain.
³¹ Research Group on Demography and Health, National Faculty of Public Health, University of Antioquia, Medellín, Colombia.
³² Instituto de Salud Pública y Laboral de Navarra, Pamplona 31003, Spain.
³³ Navarra Institute for Health Research (IdiSNA), Pamplona 31008, Spain.
³⁴ International Agency for Research on Cancer, World Health Organization, Lyon, France.
³⁵ Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.
³⁶ Biomedical Research institute, Academy of Athens, Athens, Greece.

PMID: 40099743
PMCID: PMC7618008
DOI: 10.1093/eurjpc/zwaf051

Reassessing the association between age at menarche and cardiovascular disease: observational and Mendelian randomization analyses

Lena Tschiderer et al. Eur J Prev Cardiol. 2025.

. 2025 Mar 18:zwaf051.

doi: 10.1093/eurjpc/zwaf051. Online ahead of print.

Authors

Affiliations

¹ Institute of Clinical Epidemiology, Public Health, Health Economics, Medical Statistics and Informatics, Medical University of Innsbruck, Anichstraße 35, Innsbruck 6020, Austria.
² Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands.
³ The George Institute for Global Health, School of Public Health, Imperial College London, London, UK.
⁴ The George Institute for Global Health, University of New South Wales, Sydney, New South Wales, Australia.
⁵ Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
⁶ Heart and Lung Research Institute, University of Cambridge, Cambridge, UK.
⁷ MRC Biostatistics Unit, School of Clinical Medicine, University of Cambridge, Cambridge, UK.
⁸ NIHR Blood and Transplant Research Unit in Donor Health and Behaviour, University of Cambridge, Cambridge, UK.
⁹ BHF Centre of Research Excellence, School of Clinical Medicine, Addenbrooke's Hospital, Cambridge, UK.
¹⁰ Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge, UK.
¹¹ British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
¹² Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge, UK.
¹³ British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge, UK.
¹⁴ Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
¹⁵ Department of Public Health, Aarhus University, Aarhus, Denmark.
¹⁶ Danish Cancer Institute, Strandboulevarden 49, Copenhagen 2100, Denmark.
¹⁷ Department of Public Health, Section of Environmental Health, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen DK-1353, Denmark.
¹⁸ Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany.
¹⁹ Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany.
²⁰ Clinical Epidemiology Unit, Institute for cancer research, prevention and clinical network (ISPRO), Florence, Italy.
²¹ Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy.
²² School of Medicine, Federico II University, Naples, Italy.
²³ Unit of Cancer Epidemiology, AOU Città della Salute e della Scienza University Hospital, Turin, Italy.
²⁴ National Institute for Public Health and the Environment, Bilthoven, the Netherlands.
²⁵ Unit of Nutrition and Cancer, Catalan Institute of Oncology-ICO, L'Hospitalet de Llobregat, Barcelona, Spain.
²⁶ Nutrition and Cancer Group, Epidemiology, Public Health, Cancer Prevention and Palliative Care Program, Bellvitge Biomedical Research Institute-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.
²⁷ Escuela Andaluza de Salud Pública (EASP), Granada 18011, Spain.
²⁸ Instituto de Investigación Biosanitaria ibs.GRANADA, Granada 18012, Spain.
²⁹ Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Madrid 28029, Spain.
³⁰ Department of Epidemiology, Murcia Regional Health Council, IMIB-Arrixaca, Murcia, Spain.
³¹ Research Group on Demography and Health, National Faculty of Public Health, University of Antioquia, Medellín, Colombia.
³² Instituto de Salud Pública y Laboral de Navarra, Pamplona 31003, Spain.
³³ Navarra Institute for Health Research (IdiSNA), Pamplona 31008, Spain.
³⁴ International Agency for Research on Cancer, World Health Organization, Lyon, France.
³⁵ Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.
³⁶ Biomedical Research institute, Academy of Athens, Athens, Greece.

PMID: 40099743
PMCID: PMC7618008
DOI: 10.1093/eurjpc/zwaf051

Abstract

Aims: Observational studies have shown a U-shaped association between age at menarche (AAM) and cardiovascular disease (CVD). We assessed non-linearity of the observational association and the potential causal relationship between AAM and CVD using data from the European Prospective Investigation into Cancer and Nutrition-Cardiovascular Disease (EPIC-CVD) study and the UK Biobank.

Methods and results: We included women without pre-existing myocardial infarction (MI) or stroke at baseline. We estimated hazard ratios for incident MI, ischaemic and haemorrhagic stroke later in life using Cox regression in observational analyses and conducted non-linear Mendelian randomization (MR) based on fractional polynomials and linear MR based on inverse-variance weighted regression. We analysed 283 210 women with a median AAM of 13 (IQR 12-14) years in both EPIC-CVD and the UK Biobank, of which 8468 experienced a MI, 5501 an ischaemic and 1887 a haemorrhagic stroke. The association between AAM and MI and ischaemic stroke was U-shaped with higher risks in women aged ≤12 and ≥16 compared with those aged 13 years at menarche. Our MR analyses found no evidence for non-linearity between genetically proxied AAM and any CVD endpoint later in life, but each year higher genetically proxied AAM was related to a lower risk of MI (hazard ratio 0.92 [95% CI 0.86-0.99]), but not to ischaemic and haemorrhagic stroke.

Conclusion: This study supported non-linear observational associations between AAM and MI and ischaemic stroke. MR analyses suggested a causal relationship between higher AAM and risk of MI without an indication for non-linearity. There was no support for a potential causal link with ischaemic and haemorrhagic stroke.

Keywords: Age at menarche; Cardiovascular risk; Individual participant data meta-analysis; Mendelian randomization; Non-linearity.

Plain language summary

This study reassessed the relationship between age at menarche and risk of cardiovascular disease based on observational analyses and Mendelian randomization studies.In observational analyses, the association between age at menarche and myocardial infarction and ischaemic stroke was U-shaped, which was not confirmed by Mendelian randomization studies.This study contributes valuable insights into the shape of association between age at menarche and risk of cardiovascular disease, which ultimately leads to an improved understanding of the development of cardiovascular disease in women.

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Conflict of interest statement

Conflict of interest: none declared.

Figures

**Figure 1. Flow diagram**
Abbreviations: CHD, coronary heart disease; EPIC-CVD, European Prospective Investigation into Cancer and Nutrition – Cardiovascular Disease; MI, myocardial infarction; QC, quality control.

**Figure 2. Observational results for the associations between age at menarche and risks of myocardial infarction and ischaemic and haemorrhagic stroke.**
The models were adjusted for age, education (high, medium versus low), smoking status (current, ex versus never), and body mass index (kg/m²). For EPIC-CVD, models were stratified by country. Results are presented based on quasi variances using 13 years at menarche as reference category.

**Figure 3. Mendelian Randomisation analysis for the relationships between age at menarche and risks of myocardial infarction and ischaemic and haemorrhagic stroke based on fractional polynomials.**
The P-value for non-linearity is based on a fractional polynomial non-linearity test comparing a non-linear fractional polynomial model with a linear model.^, For EPIC-CVD, models were adjusted for age, genotyping array, and the first 10 genetic principal components, and stratified by country. For the UK Biobank, models were adjusted for age, genotyping array, and the first 16 genetic principal components.

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Comment in

Age at Menarche and Cardiovascular Risk: A Moving Target of Risk Assessment in Women.
Dastmalchi LN, Gulati M. Dastmalchi LN, et al. Eur J Prev Cardiol. 2025 Jun 5:zwaf318. doi: 10.1093/eurjpc/zwaf318. Online ahead of print. Eur J Prev Cardiol. 2025. PMID: 40468995 No abstract available.

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Reassessing the association between age at menarche and cardiovascular disease: observational and Mendelian randomization analyses

Affiliations

Reassessing the association between age at menarche and cardiovascular disease: observational and Mendelian randomization analyses

Authors

Affiliations

Abstract

Plain language summary

Conflict of interest statement

Figures

Comment in

References

Grants and funding

LinkOut - more resources

Full Text Sources