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

Horm Behav. 2022 Sep;145:105234. doi: 10.1016/j.yhbeh.2022.105234. Epub 2022 Jul 27.


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.

Keywords: Brain; Depression; Estradiol; Gonadotropin-releasing-hormone agonist; Hippocampus; Hormones; MRI; PET; Serotonin transporter; Women.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Depression* / metabolism
  • Estradiol / metabolism
  • Female
  • Gonadal Steroid Hormones / metabolism
  • Gonadotropin-Releasing Hormone / metabolism
  • Hippocampus / diagnostic imaging
  • Hippocampus / metabolism
  • Humans
  • Serotonin Plasma Membrane Transport Proteins*


  • Gonadal Steroid Hormones
  • Serotonin Plasma Membrane Transport Proteins
  • Gonadotropin-Releasing Hormone
  • Estradiol