Estradiol Fluctuation, Sensitivity to Stress, and Depressive Symptoms in the Menopause Transition: A Pilot Study

Abstract

The menopause transition is associated with an increased risk of depressed mood. Preliminary evidence suggests that increased sensitivity to psychosocial stress, triggered by exaggerated perimenopausal estradiol fluctuation, may play a role. However, accurately quantifying estradiol fluctuation while minimizing participant burden has posed a methodological challenge in the field. The current pilot project aimed to test the feasibility of capturing perimenopausal estradiol fluctuation via 12 weekly measurements of estrone-3-glucuronide (E1G), a urinary metabolite of estradiol, using participant-collected urine samples in 15 euthymic perimenopausal women ages 45-55 years. Furthermore, it aimed to correlate E1G fluctuation (standard deviation across the 12 E1G measurements) with weekly mood and cardiovascular, salivary cortisol, and subjective emotional responses to the Trier Social Stress Test (TSST) at weeks 4, 8, and 12. Protocol acceptability and adherence was high; furthermore, E1G fluctuation was positively associated with anhedonic depressive symptoms and weekly negative affect. E1G fluctuation was also associated with increased heart rate throughout the TSST as well as higher levels of rejection, anger, and sadness. E1G fluctuation was not significantly associated with TSST blood pressure or cortisol levels. This study suggests a feasible method of assessing estradiol fluctuation in the menopause transition and provides support for the hypothesis that perimenopausal estradiol fluctuation increases sensitivity to psychosocial stress and vulnerability to depressed mood.

Keywords: estradiol; estrone-3-glucuronide; menopause transition; perimenopausal depression; trier social stress test.

FIGURE 1

Theoretical model of perimenopausal depression development.

FIGURE 2

Study design.

FIGURE 3

Cardiovascular, cortisol, subjective stress responses to stress testing, and administered at weeks 4, 8, and 12. Standard error bars shown.

FIGURE 4

Mean heart rate during stress testing among women in the bottom vs. top tertile for mean E1G fluctuation, illustrating a significant relationship between continuous E1G fluctuation and heart rate (p = 0.020). Standard error bars shown.

FIGURE 5

Mean diastolic blood pressure during stress testing among women in the bottom vs. top tertile for mean E1G fluctuation, illustrating a near-significant relationship between continuous E1G fluctuation and blood pressure (p = 0.056). Standard error bars shown.

FIGURE 6

Mean PANAS-X subscale scores among women in the bottom vs. top tertile for mean E1G fluctuation, illustrating a significant relationship between continuous E1G fluctuation, and weekly negative affect (p = 0.042) but not sadness (p = 0.691).

FIGURE 7

Mean CES-D subscale scores among women in the bottom vs. top tertile for mean E1G fluctuation, illustrating a significant relationship between continuous E1G fluctuation, and the anhedonia subscale of the CES-D (p = 0.016) as well as a weak trend between greater E1G fluctuation and a higher total CES-D score (p = 0.122). No effect of E1G fluctuation was seen on the somatic (p = 0.349) or the negative affect CES-D subscale (p = 0.548). Standard error bars shown.