title: Role of Serotonin Transporter Changes in Depressive Responses to Sex-Steroid Hormone Manipulation: A Positron Emission Tomography Study.
abstract: BACKGROUND
  An adverse response to acute and pronounced changes in sex-hormone levels during, for example, the perimenopausal or postpartum period appears to heighten risk for major depression in women. The underlying risk mechanisms remain elusive but may include transiently compromised serotonergic brain signaling. Here, we modeled a biphasic ovarian sex hormone fluctuation using a gonadotropin-releasing hormone agonist (GnRHa) and evaluated if emergence of depressive symptoms was associated with change in cerebral serotonin transporter (SERT) binding following intervention.
  
  
  METHODS
  A double-blind, randomized, placebo-controlled study included 63 healthy female volunteers (mean age 24.3 ± 4.9 years) with regular menstrual cycles between 23 and 35 days. Participants were randomized to active (goserelin [GnRHa] 3.6 mg implant) or placebo intervention. Sixty women completed follow-up and entered the analyses. Primary outcome measures were changes from baseline in depressive symptoms assessed on the 17-item Hamilton Depression Rating Scale and SERT binding as imaged by [(11)C]DASB positron emission tomography. Outcome measures were acquired at baseline in the follicular phase (cycle day 6.6 ± 2.2) and at follow-up (16.2 ± 2.6 days after intervention start).
  
  
  RESULTS
  Sex hormone manipulation with GnRHa significantly triggered subclinical depressive symptoms within-group (p = .003) and relative to placebo (p = .02), which were positively associated with net decreases in estradiol levels (p = .02) from baseline within the GnRHa group. Depressive symptoms were associated with increases in neocortical SERT binding in the GnRHa group relative to placebo (p = .003).
  
  
  CONCLUSIONS
  Our data imply both serotonergic signaling and estradiol in the mechanisms by which sex-steroid hormone fluctuations provoke depressive symptoms and thus provide a rationale for future preventive strategies in high-risk groups.
authors.affiliation: Center for Integrated Molecular Brain Imaging, Copenhagen; Neurobiology Research Unit, Copenhagen. Electronic address: vibe@nru.dk.
authors.forename: Vibe Gedsoe
authors.initials: VG
authors.lastname: Frokjaer
authors.affiliation: The Fertility Clinic, PET, Copenhagen; University of Copenhagen, Copenhagen.
authors.forename: Anja
authors.initials: A
authors.lastname: Pinborg
authors.affiliation: Department of Biostatistics, Copenhagen.
authors.forename: Klaus Kähler
authors.initials: KK
authors.lastname: Holst
authors.affiliation: Neurobiology Research Unit, Copenhagen.
authors.forename: Agnete
authors.initials: A
authors.lastname: Overgaard
authors.affiliation: University of Copenhagen, Copenhagen.
authors.forename: Susanne
authors.initials: S
authors.lastname: Henningsson
authors.affiliation: Center for Integrated Molecular Brain Imaging, Copenhagen; Neurobiology Research Unit, Copenhagen.
authors.forename: Maria
authors.initials: M
authors.lastname: Heede
authors.affiliation: The Fertility Clinic, PET, Copenhagen.
authors.forename: Elisabeth Clare
authors.initials: EC
authors.lastname: Larsen
authors.affiliation: Center for Integrated Molecular Brain Imaging, Copenhagen; Neurobiology Research Unit, Copenhagen.
authors.forename: Peter Steen
authors.initials: PS
authors.lastname: Jensen
authors.affiliation: Center for Integrated Molecular Brain Imaging, Copenhagen; Neurobiology Research Unit, Copenhagen.
authors.forename: Mikael
authors.initials: M
authors.lastname: Agn
authors.affiliation: Center for Integrated Molecular Brain Imaging, Copenhagen; Neurobiology Research Unit, Copenhagen.
authors.forename: Anna Pors
authors.initials: AP
authors.lastname: Nielsen
authors.affiliation: Center for Integrated Molecular Brain Imaging, Copenhagen; Neurobiology Research Unit, Copenhagen.
authors.forename: Dea Siggaard
authors.initials: DS
authors.lastname: Stenbæk
authors.affiliation: Center for Integrated Molecular Brain Imaging, Copenhagen; Neurobiology Research Unit, Copenhagen.
authors.forename: Sophie
authors.initials: S
authors.lastname: da Cunha-Bang
authors.affiliation: Cyclotron Unit (SL), Rigshospitalet, Copenhagen.
authors.forename: Szabolcs
authors.initials: S
authors.lastname: Lehel
authors.affiliation: Danish Research Centre for Magnetic Resonance, Centre for Functional and Diagnostic Imaging and Research, Hvidovre Hospital, Hvidovre; University of Copenhagen, Copenhagen; Department of Neurology, Bispebjerg, Copenhagen, Denmark.
authors.forename: Hartwig Roman
authors.initials: HR
authors.lastname: Siebner
authors.affiliation: Center for Integrated Molecular Brain Imaging, Copenhagen; University of Copenhagen, Copenhagen.
authors.forename: Jens Damsgaard
authors.initials: JD
authors.lastname: Mikkelsen
authors.affiliation: Center for Integrated Molecular Brain Imaging, Copenhagen; Neurobiology Research Unit, Copenhagen.
authors.forename: Claus
authors.initials: C
authors.lastname: Svarer
authors.affiliation: Center for Integrated Molecular Brain Imaging, Copenhagen; Neurobiology Research Unit, Copenhagen; University of Copenhagen, Copenhagen.
authors.forename: Gitte Moos
authors.initials: GM
authors.lastname: Knudsen
mesh_terms: D000328:Adult; D001921:Brain / Q000187:drug effects; D003865:Major Depressive Disorder / Q000175:diagnosis*; D004311:Double-Blind Method; D005260:Female; D012739:Gonadal Steroid Hormones / Q000008:administration & dosage* / Q000009:adverse effects*; D006801:Humans; D008597:Menstrual Cycle / Q000187:drug effects; D017063:Outcome Assessment, Health Care; D049268:Positron-Emission Tomography; D049590:Postpartum Period / Q000523:psychology*; D011569:Psychiatric Status Rating Scales; D050486:Serotonin Plasma Membrane Transport Proteins / Q000187:drug effects* / Q000235:genetics*; D055815:Young Adult
chemical_list: D012739:Gonadal Steroid Hormones; D050486:Serotonin Plasma Membrane Transport Proteins
keywords: 5-HT; 5-HTT; Estradiol; Gonadotropin-releasing-hormone agonist; Mood disorder; [(11)C]DASB-PET