Transdermal estradiol (TE2) treatment was found to reduce symptoms of anxiety and anhedonia in a population of perimenopausal women, according to results of a study published in Psychoneuroendocrinology.

This randomized, double-blind, placebo-controlled trial recruited 73 healthy women aged 46-60 years in the early or late menopause transition between 2017 and 2020. Baseline estradiol (E2)-sensitivity strength was measured from 8 weekly blood draws. Participants were randomized to receive TE2 (n=35) or placebo (n=38) for 8 weeks. Anxiety was evaluated using State-Trait Anxiety Inventory (STAI) and anhedonia using Snaith-Hamilton Pleasure Scale (SHAPS).

The intervention and control cohorts comprised women aged mean 48.7 (SD, 2.9) and 49.9 (SD, 2.6) years, BMI was 28.17 (SD, 8.4) and 27.25 (SD, 4.5) kg/m2, STAI was 30.89 (SD, 7.83) and 34.21 (SD, 9.84), and SHAPS was 19.62 (SD, 5.62) and 21.95 (SD, 5.77), respectively.

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E2 fluctuations across the predrug phase of the study tended to predict symptoms of anxiety (β, 0.017; P =.08) and significantly predicted anhedonia (β, 0.019; P =.002). There was a significant interaction effect of stressful life events on symptoms of anhedonia and E2 fluctuations (β, 0.09; P <.001).

Baseline E2 fluctuations also predicted Trier Social Stress Test (TSST) cortisol area under the curve (AUC; β, 0.17; P =.012) and TSST interleukin (IL)-6 AUC (β, -0.147; P =.02).

E2 increased from baseline among TE2 recipients (mean, 72.39 vs 143.62 pg/ml; P <.001), but not among placebo recipients (mean, 87.09 vs 74.15 pg/ml; P =.105).

In the active cohort, anxiety (β, -2.61; P <.001) and anhedonia (β, -2.38; P <.001) decreased significantly after treatment.

The baseline E2-anxiety sensitivity strength interaction predicted posttreatment anxiety (β, -18.50; P =.001), in which the greatest benefit was observed among women with high baseline E2-sensitivity. Similarly, benefits for somatic symptoms were observed among the subset of women with high E2-sensitivity (β, -2.76; P =.05).

No interaction was observed for baseline E2-anhedonia sensitivity.

This study did not evaluate symptoms of depression. Additional study would be needed to interrogate the role of E2 in depression among perimenopausal women.

The study authors concluded, “This is the first study to show that E2 fluctuations during the menopause transition predict dysregulation in cortisol and proinflammatory cytokine stress reactivity. This study confirms the beneficial effect of TE2 treatment, relative to placebo, for perimenopausal affective symptoms, particularly anxiety and anhedonia.”


Lozza-Fiacco S, Gordon JL, Andersen EH, et al. Baseline anxiety-sensitivity to estradiol fluctuations predicts anxiety symptom response to transdermal estradiol treatment in perimenopausal women – A randomized clinical trial. Psychoneuroendocrinology. 2022;143:105851. doi:10.1016/j.psyneuen.2022.105851

This article originally appeared on Psychiatry Advisor