title: 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.
authors.affiliation: Center for Integrated Molecular Brain Imaging, Copenhagen, Denmark.|Neurobiology Research Unit, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.
authors.forename: Patrick MacDonald
authors.identifier: 0000-0002-8115-0611
authors.initials: PM
authors.lastname: Fisher
authors.affiliation: Center for Integrated Molecular Brain Imaging, Copenhagen, Denmark.|Neurobiology Research Unit, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.
authors.forename: Camilla Borgsted
authors.initials: CB
authors.lastname: Larsen
authors.affiliation: Center for Integrated Molecular Brain Imaging, Copenhagen, Denmark.|Neurobiology Research Unit, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.|Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Vincent
authors.initials: V
authors.lastname: Beliveau
authors.affiliation: Center for Integrated Molecular Brain Imaging, Copenhagen, Denmark.|Danish Research Centre for Magnetic Resonance, Centre for Functional and Diagnostic Imaging and Research, Hvidovre Hospital, Hvidovre, Denmark.
authors.forename: Susanne
authors.initials: S
authors.lastname: Henningsson
authors.affiliation: Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.|The Fertility Clinic, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.
authors.forename: Anja
authors.initials: A
authors.lastname: Pinborg
authors.affiliation: Department of Biostatistics, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Klaus Kähler
authors.initials: KK
authors.lastname: Holst
authors.affiliation: Center for Integrated Molecular Brain Imaging, Copenhagen, Denmark.|Neurobiology Research Unit, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.
authors.forename: Peter Steen
authors.initials: PS
authors.lastname: Jensen
authors.affiliation: Center for Integrated Molecular Brain Imaging, Copenhagen, Denmark.|Neurobiology Research Unit, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.
authors.forename: Claus
authors.initials: C
authors.lastname: Svarer
authors.affiliation: Center for Integrated Molecular Brain Imaging, Copenhagen, Denmark.|Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.|Danish Research Centre for Magnetic Resonance, Centre for Functional and Diagnostic Imaging and Research, Hvidovre Hospital, Hvidovre, Denmark.|Department of Neurology, Bispebjerg Hospital, Copenhagen, Denmark.
authors.forename: Hartwig Roman
authors.initials: HR
authors.lastname: Siebner
authors.affiliation: Center for Integrated Molecular Brain Imaging, Copenhagen, Denmark.|Neurobiology Research Unit, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.|Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Gitte Moos
authors.initials: GM
authors.lastname: Knudsen
authors.affiliation: Center for Integrated Molecular Brain Imaging, Copenhagen, Denmark.|Neurobiology Research Unit, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.
authors.forename: Vibe Gedsoe
authors.initials: VG
authors.lastname: Frokjaer
mesh_terms: D000328:Adult; D001921:Brain / Q000187:drug effects / Q000503:physiopathology*; D001931:Brain Mapping; D003863:Depression / Q000139:chemically induced / Q000503:physiopathology*; D005260:Female; D012739:Gonadal Steroid Hormones / Q000502:physiology*; D007987:Gonadotropin-Releasing Hormone / Q000819:agonists; D017273:Goserelin / Q000819:agonists; D006801:Humans; D008279:Magnetic Resonance Imaging; D009434:Neural Pathways / Q000187:drug effects / Q000503:physiopathology; D012307:Risk Factors; D055815:Young Adult
chemical_list: D012739:Gonadal Steroid Hormones; D017273:Goserelin; D007987:Gonadotropin-Releasing Hormone