Neuropsychobiological Correlates of Sex-steroid Hormone Manipulation in Healthy Women: a Risk Model for Depression
Condition: Postpartum Depression; Major Depressive Disorder; Postpartum Psychosis; Menopause; Neurodegeneration; Schizophrenia
MeSH terms: Depression, Postpartum; Nerve Degeneration; Depression; Depressive Disorder; Schizophrenia; Depressive Disorder, Major
Study type: Interventional

Summary: 
      The project aimed at identifying neuropsychobiological signatures of pharmacological
      sex-steroid hormone manipulations in healthy women as a risk model for depression.

      The study is a double-blind, randomized, placebo-controlled study. Investigators included 63
      healthy female volunteers with regular menstrual cycles between 23 and 35 days. Participants
      were randomized to active Gonadotrophin-Releasing-Hormone agonist (GnRHa) (goserelin 3.6 mg
      implant) or placebo (saline injection) intervention, which was initiated in the mid
      follicular phase (i.e. cycle day 22.6 ±2.5). Sixty women completed follow-up and entered the
      analyses, except for a few drop outs on some domains. The following domains were addressed at
      baseline and at follow-up (16±3 days post intervention), (which corresponded to the early
      ovarian suppression phase of the biphasic hormone response to GnRHa): 1) serotonin
      transporter binding as imaged by 11CDASB Positron Emission Tomography (PET), 2) functional
      Magnetic Resonance Imaging (fMRI) emotional processing, 3) fMRI reward processing, 3) rating
      state fMRI (rsfMRI), 4) structural MRI, 5) Neuropsychology, 6) Psychophysiology, 7)
      Hypothalamus-Pituitary-Adrenal cortex (HPA)-axis dynamics, 8) Peripheral markers of
      immunoactive cell responses, 9) Epigenetic factors.

      Psychometrics in terms of self reported mental distress and interview based ratings were
      monitored across the intervention period to monitor potential symptoms of mental distress and
      psychopathology. Also ovarian hormone responses, peripheral blood markers, and side effects
      scores were collected across the intervention period.
    

Detailed description: 
      Aims and hypotheses:

      Gender matters in normal brain function as well as in neuropsychiatric disorders. E.g. the
      vulnerability to mood and anxiety disorders is considerably greater in women. Among other
      factors, this possibly reflects gender differences in central serotonergic function since
      dysfunction of serotonergic neurotransmission is critically involved in the pathophysiology
      of mood and anxiety disorders, schizophrenia, and Alzheimer's disease. In particular, women
      going through phases in life where sex hormones decline rapidly from high levels or
      fluctuate, have a higher frequency of severe mood state changes and are more vulnerable to
      psychiatric disorders, e.g. across the pre to postpartum and menopausal transition.
      Interestingly, this risk is associated with increased variability of the plasma levels of the
      sex-hormone estradiol. Therefore, sex-hormone manipulation with a pharmacologically induced
      biphasic ovarian hormone response serve as a unique opportunity to study how sex-hormone
      fluctuations provoke mood state changes and increase vulnerability to neuropsychiatric
      disorders.

      In this project investigators aimed at investigating whether sex-hormone manipulation
      affects: 1. Molecular imaging markers of serotonergic neurotransmission in vivo, 2. Brain
      structure, architecture and functional connectivity, 3. Stress and inflammatory responses,
      and 4. Cognitive functions, emotional processing, and information filtering, of importance in
      the pathophysiology of neuropsychiatric disorders.

      Mentally healthy female volunteers were assessed at baseline (i.e cycle day 6.6 ±2.2) and at
      follow-up (i.e 16.2 ±2.6 days post intervention) in the early ovarian suppression phase af a
      Gonadotrophin-Releasing-Hormone agonist response in a placebo-controlled, double-blinded
      design (cohort size aim: N=30x2).

      Research in neurobiological correlates of vulnerability related to sex-hormone changes is
      pivotal to improve the etiological understanding of brain disorders with gender differences
      in their incidence and/or nature. Such research may contribute to ameliorate fertility
      treatment, to improve treatment of mood disorders and schizophrenia, and, ideally, shed light
      on possible preventive strategies in vulnerable phases of women's lives such as the pre- to
      post-partum and menopausal transition period.

      Hypotheses:

      Investigators hypothesised that sex-hormone manipulation is associated with the following: 1.
      Compromised serotonergic neurotransmission, 2. Changes in functional and structural
      connectivity and lower hippocampal brain volumes and/or markers of decreased neurogenesis, 3.
      Increased stress reactivity and inflammatory responses, and 4. Changes in neurocognitive
      functioning and negative bias in emotional processing and information filtering.
      Investigators further hypothesised that these changes occur in a manner dependent on the
      magnitude of the estradiol drop from baseline and dependent on symptoms of depressed and
      anxious mood.

      General study design:

      The study is a prospective, double-blinded, placebo-controlled, combined within-subject and
      between-group design of neuropsychobiological changes in response to hormonal
      down-regulation. The investigation program will be performed at baseline in the
      mid-follicular phase, at day 5-8 of the menstrual cycle, and in the down-regulated state,
      14-19 days after GnRHa intervention.

      Participants. Investigators aimed at including 60 healthy female volunteers, in the age range
      18-40 years. Group 1 (N=30) will receive sex-hormone manipulation with GnRHa, and group 2
      (N=30) will receive placebo (saline injection). The inclusion will be stratified according to
      a polymorphism in the serotonin transporter promoter region (5-HTLPR).

      The investigation program includes functional brain imaging of the serotonin transporter with
      [11C]DASB PET (6) and fMRI, structural brain imaging, blood measurements of sex-hormone
      levels, inflammatory and epigenetic biomarkers, characterization of the cortisol awakening
      response, and psychophysiological measures of information processing, and monitoring of
      symptoms of mental distress and psychopathology across the intervention period. An initial
      screening program will secure inclusion of healthy controls only and determine trait
      parameters such as genotypes, IQ and personality measures.

      The study was registered at and approved by the Danish Ethical Committee before participant
      inclusion under the protocol identification number: H-2-2010-108. All participants gave
      written informed consent.
    

Intervention name(s): Goserelin 3.6 mg implant; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Pharmacologically induced biphasic sex-steroid hormone fluctuation; Injection of saline
Other intervention name(s): Zoladex; Saline
Intervention MeSH terms: Goserelin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Basic Science
Keywords: Mental health; Brain Imaging; Steroid hormones; Serotonin; PET; MRI; fMRI; human; gender; risk model