Estradiol's Effect on Reward-Related Functional Connectivity in Perimenopause-Onset Major Depressive Disorder

Background: Hormone replacement therapy with estradiol (E2), the most common form of estrogen, is an effective intervention for affective symptoms associated with perimenopause–onset major depressive disorder (PO–MDD). However, the precise neural mechanisms by which E2 influences these symptoms remain unclear. This study aimed to investigate changes in reward-related frontostriatal connectivity following E2 administration for PO-MDD using fMRI with a monetary incentive delay task. Methods: Fifteen participants with PO–MDD and 16 control participants underwent three weeks of transdermal E2 administration to evaluate its impact on mood symptoms and frontostriatal connectivity. Functional MRI scans were conducted before and after the administration of E2. Changes in functional brain connectivity related to reward anticipation were examined using the CONN toolbox. Depression symptoms were assessed with the IDAS Dysphoria and the MASQ–AD scales. Results: The PO–MDD group exhibited altered connectivity compared with controls during reward anticipation prior to E2 administration. During reward anticipation, they exhibited decreased connectivity from striatal and cortical seed regions, including the caudate, putamen, nucleus accumbens, and insula seeds. E2 administration increased connectivity during reward anticipation across many of these seed regions in the PO–MDD group but not in the control group. Within the PO-MDD group, changes in functional connectivity following E2 administration predicted reduced dysphoria, with increased connectivity between the insula–angular gyrus linked to greater symptom reduction over three weeks. In contrast, decreased insula–inferior temporal gyrus connectivity was associated with greater symptom reduction over three weeks. Conclusion: The PO–MDD group exhibited reduced functional connectivity during reward anticipation compared with controls, with distinct patterns of connectivity with striatal and limbic seeds, including the caudate nucleus, putamen, nucleus accumbens, and insula. E2 administration generally increased connectivity between striatal and limbic seed regions and the cortex. Additionally, changes in connectivity during reward anticipation predicted greater reductions in dysphoria following E2 administration. These findings highlight the potential significance of reward–related functional connectivity for explaining the triggering of PO–MDD and potential mechanisms underlying the antidepressant effects of E2.