Pharmacologically Induced Sex Hormone Fluctuation Effects on Resting-State Functional Connectivity in a Risk Model for Depression: A Randomized Trial

Abstract

Women are at relatively greater lifetime risk for depression than men. This elevated risk in women is partly due to heightened risk during time periods characterized by marked fluctuations in sex hormones, including postpartum and perimenopausal periods. How sex hormone fluctuations contribute to heightened risk is not fully understood but may involve intrinsic functional connectivity. We induced a biphasic ovarian sex hormone fluctuation using the gonadotropin-releasing hormone agonist (GnRHa) goserelin to determine, with a randomized placebo-controlled design, intervention effects on or GnRHa-provoked depressive symptoms associations with change in resting-state functional connectivity (rs-FC) in 58 healthy women for six seeds (amygdala, hippocampus, anterior cingulate cortex, dorsal raphe, median raphe, and posterior cingulate cortex). GnRHa intervention did not significantly affect rs-FC in any seeds. Considering the GnRHa group only, the emergence of depressive symptoms following intervention was positively associated with amygdala-right temporal cortex and negatively associated with hippocampus-cingulate rs-FC. A test for mediation suggested that rs-FC changes in these networks marginally mediated the association between decrease in estradiol and increase in depressive symptoms in the GnRHa group (p=0.07). Our findings provide novel evidence-linking changes in rs-FC networks, the emergence of depressive symptoms and sex hormone fluctuations. Notably, we observed evidence that changes in rs-FC may represent a key neurobiological intermediary between molecular changes induced by hormone fluctuations and the emergence of depressive symptoms. Taken together, our findings indicate that sex hormone fluctuations may contribute to heightened risk for developing depressive symptoms by affecting intrinsic functional connectivity of key limbic brain structures.

Trial registration: ClinicalTrials.gov NCT02661789.

Figures

Figure 1

Resting-state functional connectivity maps across participants at baseline. (a–d) Statistical parametric maps showing areas significantly correlated with (a) anterior cingulate cortex, (b) amygdala, (c), hippocampus, (d) posterior cingulate cortex. Color bars represent t-scores. Sagittal slice is X=0. (e and f) Surface maps showing medial wall areas significantly correlated with (e) dorsal raphe and (f) median raphe seeds as reported previously (Beliveau et al, 2015). Color bars represent negative log10p-values. Warm colors denote a positive correlation whereas cool colors denote a negative correlation. Outline of respective seed inset.

Figure 2

Emergence of depressive symptoms associated with change in rs-FC. Top, statistical parametric map showing (a) right temporal cortex, (b) cingulate gyrus/pre-SMA where change in rs-FC with respective seed (inset) was significantly associated with change in depressive symptoms. Red and blue denote a positive and negative correlation, respectively. Bottom, plot of mean change in respective functional connectivity estimates against change in depressive symptoms (change scores: rescan—baseline, adjusted for baseline depressive symptoms). Orange points represent individual mean functional connectivity estimates. Blue line and shading represents fit line and 95% confidence limits on fit line, respectively. Amy, amygdala; Hip, hippocampus; ΔHAM-D, change in Hamilton 17-item depression score.

Figure 3

Schematic of mediation model to evaluate indirect effect of change in estradiol on change in depressive symptoms via change in rs-FC. Direct and mediation effects are described in Table 2. The mediation effect is the product of the two top arrows. The Δestradiol →ΔHAM-D connection is the direct effect. The total effect is the sum of the mediation and direct effects.