OR19-6 Functional Hypothalamic Amenorrhea and Preclinical Cardiovascular Disease
Authors: Bairey Merz C Noel , Berga Sarah , Cook-Weins Galen , Pisarska Margareta , Shah Prediman Krishan , Shufelt Chrisandra 
Published: November 2022

Abstract

Background
Functional Hypothalamic Amenorrhea (FHA) is characterized by suppression of central GnRH drive with secondary anovulation and hypoestrogenemia, hypercortisolism, and low leptin that results from a combination of psychosocial stress and metabolic imbalance due to excess physical activity and/or weight loss. Cardiovascular disease (CVD) is the leading killer of women at all ages and CVD mortality rates are unchanged or increasing in young women aged 35-44 years. We investigated relations between FHA and preclinical CVD measured by endothelial dysfunction in premenopausal women with and without FHA, and recently menopausal women not on hormone therapy.

Methods
We studied 31 women with FHA, 29 eumenorrheic controls, and 30 recently menopausal women not on hormone therapy. FHA was defined as amenorrhea ≥3 consecutive months, estradiol &lt;50 pg/mL, FSH &lt;10 mIU/L, and LH &lt;10 mIU/L, and exclusion of other etiologies including polycystic ovary syndrome, prolactinoma, thyroid dysfunction, and pregnancy. Eumenorrheic controls had self-reported monthly menstrual cycles, were not on hormones, with a day 22-24 progesterone level &gt;3 ng/ml to confirm ovulation. Preclinical CVD testing for eumenorrheic controls took place days 3-5 of menses. Recently menopausal women had natural menopause within 3 years, FSH &gt;30, and not on hormone therapy. Preclinical CVD was measured using Endo PAT 2000 (Itamar® Medical Ltd) to calculate reactive hyperemic index (RHI) stress to rest pulse amplitude. RHI ≤1.67 indicates endothelial dysfunction. Statistical analysis included analysis of variance for normal distributed variables and Kruskal Wallis test for non-parametric variables.

Results
The mean age, BMI and estradiol of FHA, no FHA and recent menopause was 26.4 ± 6.2 y, 30.3 ± 3.7 and 53.3 ± 2.6, respectively (p&lt;0.0001); BMI 21.6 ± 6.2 kg/m2, 21.8 ± 2.0, and 23.5 ± 4.2 (p=0.06); and estradiol 29.7±18.2, 46.4 ± 15.7, and 10.9 ± 14.4 pg/ml (p&lt;0.0001), respectively. The median months of FHA amenorrhea was 10.8 months. There were no differences in testosterone (p=0.48), however FHA women had lower leptin (p=0.012) and higher cortisol (p=0.0005) compared to both no FHA and recently menopausal women. Preclinical CVD measured by RHI was significantly lower in FHA compared to no FHA and recently menopausal women (1.8 + 0.5 vs 2.2 + 0.5 vs 2.2 +0.6;p=0.007, respectively). Further 35% of FHA women had RHI ≤1.67 indicating endothelial dysfunction.

Conclusion
Our results demonstrate endothelial dysfunction in young women with FHA women as compared to eumenorrheic women and older recently menopausal women not on hormone therapy. Our findings suggest that FHA may be an important contributor to CVD mortality in younger women and that preclinical CVD in FHA is not likely due to hypoestrogenemia alone. Future studies will focus on identifying potential treatment targets for CVD prevention.
Presentation: Monday, June 13, 2022 12:15 p.m. - 12:30 p.m.