Hippocampal volume changes in a pharmacological sex-hormone manipulation risk model for depression in women

• Published in: Hormones and behavior 2022-09, Vol.145, p.105234-105234, Article 105234
• Main Authors: Borgsted, Camilla, Hoegsted, Emma, Henningsson, Susanne, Pinborg, Anja, Ganz, Melanie, Frokjaer, Vibe G.
• Format: Article
• Language: English
• Subjects: Brain; Depression; Estradiol; Gonadotropin-releasing-hormone agonist; Hippocampus; Hormones; MRI; PET; Serotonin transporter; Women
• ISSN: 0018-506X; 1095-6867
• DOI: 10.1016/j.yhbeh.2022.105234

Hormone transition phases may trigger depression in some women, yet the underlying mechanisms remain elusive. In a pharmacological sex-hormone manipulation model, we previously reported that estradiol reductions, induced with a gonadotropin-releasing hormone agonist (GnRHa), provoked subclinical depressive symptoms in healthy women, especially if neocortical serotonin transporter (SERT) binding also increased. Within this model, we here evaluated if GnRHa, compared to placebo, reduced hippocampal volume, in a manner that depended on the magnitude of the estradiol decrease and SERT binding, and if this decrease translated to the emergence of subclinical depressive symptoms. Sixty-three healthy, naturally cycling women were included in a randomized, double-blind, placebo-controlled GnRHa-intervention study. We quantified the change from baseline to follow-up (n = 60) in serum estradiol (ΔEstradiol), neocortical SERT binding ([11C] DASB positron emission tomography; ΔSERT), subclinical depressive symptoms (Hamilton depression rating scale; ΔHAMD-17), and hippocampal volume (magnetic resonance imaging data analyzed in Freesurfer 7.1, ΔHippocampus). Group differences in ΔHippocampus were evaluated in a t-test. Within the GnRHa group, associations between ΔEstradiol, ΔHippocampus, and ΔHAMD-17, in addition to ΔSERT-by-ΔEstradiol interaction effects on ΔHippocampus, were evaluated with linear regression models. Mean ΔHippocampus was not significantly different between the GnRHa and placebo group. Within the GnRHa group, hippocampal volume reductions were associated with the magnitude of estradiol decrease (p = 0.04, Cohen's f2 = 0.18), controlled for baseline SERT binding, but not subclinical depressive symptoms. There was no ΔSERT-by-ΔEstradiol interaction effects on ΔHippocampus. If replicated, our data highlight a possible association between estradiol fluctuations and hippocampal plasticity, adjusted for serotonergic contributions. •Placebo-controlled pharmaco-MRI sex-hormone manipulation study in healthy women•Changes in estradiol and depressive symptoms were mapped across intervention.•Hippocampal volume changes and brain serotonin transporter availability were mapped.•Abrupt estradiol withdrawal reduced hippocampal volume in a non-depressogenic way.•Serotonergic markers contributed to hippocampal volume changes.