Functional Hypothalamic Amenorrhea Phenotype and Cardiovascular Disease Risk.

CONTEXT: Menstrual irregularities have been associated with cardiovascular disease (CVD) risk, but underlying etiologies may confer distinct risk profiles. Functional hypothalamic amenorrhea (FHA) has not been evaluated as a separate risk phenotype.

OBJECTIVE

To assess the association between FHA phenotype and incident CVD and cardiometabolic risk factors.

DESIGN

Prospective cohort study with biennial follow-up from 1993 to 2019.

SETTING

Nurses' Health Study II cohort.

PARTICIPANTS

The sample included 52,655 premenopausal women free of CVD in 1993. FHA phenotype was defined as irregular or absent cycles without PCOS traits combined with low body mass index and/or high physical activity.

INTERVENTION: None.

MAIN OUTCOME MEASURES: Incident CVD (coronary heart disease [CHD; myocardial infarction or coronary revascularization] and stroke) and incident elevated cholesterol, hypertension, and type 2 diabetes (T2DM).

RESULTS

During up to 26 years of follow-up, 1,007 CVD events occurred. Among women who developed CVD, the median time to the first CVD event was 17.0 years (IQR, 11.3-21.0). FHA phenotype in mid-adulthood was associated with a 62% higher risk of CVD (95% confidence interval [CI]: 1.01-2.59), driven by an almost two-fold higher risk of CHD (hazard ratio [HR] = 1.91; 95% CI: 1.11-3.27), compared with women with regular cycles. FHA was also associated with T2DM (HR = 1.86; 95% CI: 1.41-2.47), but not hypertension or elevated cholesterol. Non-FHA menstrual irregularity was associated with elevated cholesterol, hypertension, and T2DM, but not CVD. FHA in early adulthood was not associated with outcomes.

CONCLUSIONS

FHA phenotype in mid-adulthood was associated with increased CHD risk independent of traditional risk factors. Menstrual history may serve as an early marker of cardiometabolic risk.