Functional hypothalamic amenorrhea and vascular function: is estrogen enough? results from a randomized controlled trial

Functionalhypothalamic amenorrhea (FHA) is a form of anovulation that results in chronic hypoestrogenemia in addition to infertility, which can be prolonged from months to years. Previous studies have identified endothelial dysfunction in women with hypoestrogenemia. We performed a randomized, double-blind placebo-controlled trial of transdermal estradiol to determine if estrogen replacement would improve vascular function in women with FHA. Women with FHA were randomized to 0.1 mg/day transdermal estradiol twice weekly (n=14) vs transdermal placebo twice weekly (n=15) for 12 weeks. FHA was defined as amenorrhea ≥3 consecutive months, estradiol <50 pg/mL, FSH <10 mIU/L, and LH <10 mIU/L, and exclusion of other etiologies. Preclinical CVD was measured using EndoPAT 2000 (Itamar® Medical Ltd) to calculate reactive hyperemic index (RHI) stress to rest pulse amplitude at baseline and week 12. An RHI below 2.0 is suboptimal, and an RHI ≤ 1.67 indicates endothelial dysfunction. Statistical analysis included t-test for normal distributed variables and Wilcoxon rank sum for non-parametric variables. There was no difference in age or BMI in women randomized to estradiol vs placebo (Table). At baseline, 35% of women with FHA had RHI ≤1.67, indicating endothelial dysfunction and there was no difference in baseline RHI between the two randomized groups. After 12 weeks of randomization to continuous patches, no differences were found in mean RHI or in the change in RHI between those randomized to active vs placebo patches. In women with FHA randomized to 12 weeks of physiologic dose replacement of transdermal estradiol, there was no difference in vascular function compared to placebo. Future research will evaluate the role of higher doses of estrogen and other hormones, including cortisol and other hypothalamic-pituitary axis hormones, on vascular health.