Functional Hypothalamic Amenorrhea and Preclinical Cardiovascular Disease

Context: Endothelial dysfunction is a preclinical cardiovascular disease (CVD) marker. Due to various neuroendocrine aberrations, functional hypothalamic amenorrhea (FHA) may be a sex-specific risk factor for CVD in young women. Objective: To investigate endothelial function in women with FHA, compared with eumenorrheic controls and recently menopausal women. Methods: We performed a cross-sectional analysis among women with FHA (n = 30), eumenorrheic controls (n = 29), and recently menopausal women (n = 30). FHA was defined as amenorrhea >= 3 consecutive months, estradiol <50 pg/mL, follicle-stimulating hormone (FSH) < 10 mIU/mL, and luteinizing hormone (LH) < 10 mIU/mL, excluding other etiologies. Participants were recruited through obstetrics and gynecology referrals, social media advertising, and review of electronic health records. Preclinical CVD was measured using EndoPAT 2000 to calculate reactive hyperemic index (RHI). RHI <= 1.67 indicates endothelial dysfunction. Results: Mean estradiol levels in women with FHA, as compared with eumenorrheic controls and recently menopausal women, were 29.0 +/- 18.1, 46.4 +/- 15.7, and 10.9 +/- 14.4 pg/mL (P <.0001), respectively. Women with FHA had lower insulin (P =.0095) and higher cortisol (P =.0004) compared with controls. RHI was significantly lower in women with FHA compared with eumenorrheic controls and recently menopausal women (1.8 +/- 0.5 vs 2.2 +/- 0.5 vs 2.2 +/- 0.6, respectively; P =.008), and 35% of women with FHA had RHI <= 1.67, consistent with endothelial dysfunction. Conclusion: These results demonstrate endothelial dysfunction in 1 out of 3 young women with FHA. FHA may be a contributor to preclinical CVD, and it is not explained by hypoestrogenemia alone.