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. 2025 Jun 18:dgaf364.
doi: 10.1210/clinem/dgaf364. Online ahead of print.

Impact of Estrogen Replacement on Endothelial Dysfunction and Psychological Health in Women with Hypothalamic Amenorrhea

Chrisandra L Shufelt  1   2   3 , Nancy Safwan  1   2 , Mariam Saadedine  1   2 , Galen Cook-Wiens  4 , Jenna Maughan  5 , Margareta D Pisarska  6   7 , JoAnn E Manson  8   9 , Sarah L Berga  10 , Stephanie S Faubion  1   2   3 , Prediman K Shah  5 , C Noel Bairey Merz  5
Affiliations

Impact of Estrogen Replacement on Endothelial Dysfunction and Psychological Health in Women with Hypothalamic Amenorrhea

Chrisandra L Shufelt et al. J Clin Endocrinol Metab. .

Abstract

Context: Endothelial dysfunction and altered psychological measures have been identified in women with functional hypothalamic amenorrhea (FHA). Estradiol (E2) replacement, a known vasodilator, may potentially reverse vascular dysfunction and improve psychological health.

Objective: To evaluate 12-weeks of physiologic E2 replacement on vascular, hormonal and psychological outcomes in women with FHA.

Intervention, design, setting, and participants: A randomized, double-blinded, placebo-controlled trial was conducted in 29 women with FHA with 0.1 mg/day transdermal E2 (n=14) or placebo patch (n=15) twice weekly for 12 weeks. FHA was defined as amenorrhea ≥3 consecutive months, E2 <50 pg/mL, FSH and LH <10 mIU/L, LH:FSH <1, excluding other etiologies.

Main outcome measure: Reactive hyperemic index (RHI) ≤1.67 measurement of endothelial dysfunction. Hormonal and psychological measures were also assessed.

Results: Women with FHA had a mean age of 26.2 ± 6.3 years, BMI of 21.5 ± 3.3 kg/m2, with 63% being non-Hispanic Whites. Baseline characteristics did not differ between groups. After 12 weeks, E2 levels were significantly higher in the E2 group (112.0 vs 36.5 pg/ml, p=0.0002). However, there were no significant differences in vascular, hormonal, or psychological outcomes between E2 and placebo groups at week 12. Cortisol levels showed a near-significant decrease in the E2 group compared to an increase with placebo (-0.4 vs 3.1 µg/dL, p=0.05).

Conclusions: In women with FHA, 12 weeks of transdermal E2 increased serum E2 levels but did not improve vascular or psychological health measures. Further studies with larger sample sizes and longer follow-up are needed to explore the long-term effects of E2 therapy on cardiovascular and mental health outcomes in this population.

Keywords: cardiovascular disease; endothelial dysfunction; estradiol; functional hypothalamic amenorrhea; psychological health.

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