Baseline anxiety-sensitivity to estradiol fluctuations predicts anxiety symptom response to transdermal estradiol treatment in perimenopausal women - A randomized clinical trial

Abstract

Background: The menopausal transition (perimenopause) is associated with an increased risk of major depression, characterized by anxiety and anhedonia phenotypes. Greater estradiol (E2) variability predicts the development of perimenopausal depression, especially within the context of stressful life events (SLEs). While transdermal E2 (TE2) reduces perimenopausal depressive symptoms, the mechanisms underlying TE2 efficacy and predictors of TE2 treatment response remain unknown. This study aimed at determining relationships between E2 fluctuations, mood symptoms, and physiologic stress-reactivity (cortisol and interleukin-6) and whether differences in mood-sensitivity to E2 fluctuations predict mood responses to TE2 treatment.

Methods: This randomized, double-blind, placebo-controlled trial investigated medically healthy women (46-60 years) in the early or late menopause transition. Baseline E2-sensitivity strength was calculated from eight weekly individual correlations between week-to-week E2 change and index week anxiety (State-Trait Anxiety Inventory) and anhedonia (Snaith-Hamilton Pleasure Scale). Women then received eight weeks of TE2 or transdermal placebo.

Results: Analyses included 73 women (active TE2 n = 35). Greater baseline E2 fluctuations predicted greater anhedonia (p = .002), particularly in women with more SLEs. Greater E2 fluctuations also predicted higher cortisol (p = .012) and blunted interleukin-6 (p = .02) stress-responses. Controlling for baseline symptoms, TE2 was associated with lower post-treatment anxiety (p < .001) and anhedonia (p < .001) versus placebo. However, the efficacy of TE2 for anxiety (p = .007) and also for somatic complaints (p = .05) was strongest in women with greater baseline E2 sensitivity strength.

Conclusions: TE2 treatment reduced perimenopausal anxiety and anhedonia. The ability of baseline mood-sensitivity to E2 fluctuations to predict greater TE2 efficacy has implications for individualized treatment of perimenopausal anxiety disorders.

Trial registration: ClinicalTrials.gov NCT03003949.

Keywords: Anhedonia; Anxiety; Differential sensitivity; Estradiol fluctuations; Perimenopause; Transdermal estradiol.

Figure 1.

Stylistic figure depicting the calculation of the correlations between the change in E2 from the past week based on two methods: 1) including the direction of change and 2) using the absolute change in E2 from the past week (directionless) with mood (anxiety and anhedonia) at the index week. In the figure, there is a 50pg/ml decrease in E2 from week 1 to week 2. In one calculation: , the value −50 (with direction) is correlated with the anxiety value at week 2. In the other calculation, the value 50 (without direction) is correlated with the anxiety value at week 2. Both calculations were used for every index week, resulting in two overall correlation coefficients for anxiety for every participant (one including the direction and one without the direction). The same procedure was employed for calculating the correlations between changes in E2 and changes in anhedonia symptoms.

Figure 2.

Model-based estimates of the relationship between baseline E2 variability (mean absolute squared difference, MASD) and cortisol Area Under the curve (AUC) in response to the Trier Social Stress Test.

Figure 3.

Model-based estimates of the relationship between baseline E2 variability (mean absolute difference, MASD) and Interleukin 6 (IL-6) Area Under the curve (AUC) in response to the Trier Social Stress Test.

Figure 4.

Model-based estimates of the relationship between baseline E2-anxiety sensitivity strength and post-randomization anxiety scores (State-Trait-Anxiety Inventory) among each treatment group.

Figure 5.

Model-based estimates of the relationship between baseline E2-anxiety sensitivity strength and post-randomization somatic symptoms scores (Greene Climacteric Scale) among each treatment group.