Table 3.

Unanswered questions and key areas for future research on sex-specific cardiovascular disease risk factors in women.

Menarche and fertility  ● Do unique hormonal or epigenetic mechanisms link early and late menarche and polycystic ovary syndrome with future CVD risk?  ● Are assisted reproductive technologies causally linked to CVD or simply a signal for underlying infertility and associated shared risk factors with CVD?

Pregnancy and adverse pregnancy outcomes  ● What are the shared and unique pathophysiologic pathways underlying the various adverse pregnancy outcomes? How do long-term cardiometabolic implications differ across different adverse pregnancy outcomes and their subtypes?  ● What are the key novel mechanisms and pathways linking adverse pregnancy outcomes with later-life CVD risk?  ● Are associations between parity and CVD risk driven by socio-behavioral or biological effects (or both)?  ● What is the protective mechanism of breastfeeding against CVD, and can this be leveraged therapeutically?

Menopause  ● Do cardiometabolic changes during the menopause transition independently predict future CVD?  ● What are the mechanisms linking premature age of menopause and vasomotor symptoms with CVD?  ● What are the relationships among clonal hematopoiesis of indeterminate potential, premature menopause, and CVD?  ● Is there a role for exogenous estradiol in cardiometabolic and lipid profile improvement in subsets of postmenopausal women?

Overarching questions for future research  ● Can reproductive history prompt targeted cardiometabolic risk-reduction approaches for primordial and primary prevention?  ● Can mechanistic insights into reproductive exposures yield novel preventive strategies and therapeutics?  ● How do associations between reproductive history and CVD differ across racial/ethnic groups?  ● Can sex-specific cardiovascular risk prediction models effectively incorporate reproductive history to refine risk prediction?  ● How can we better educate clinicians about the role of reproductive history in CVD risk?

CVD = cardiovascular disease