Estradiol's Effect on Brain Volume and Connectivity

NCT06312033 | Completed

• 1 other identifier: MRTG_P01
• Study Type: interventional
• Target: 32
• Locations: 1 country
• Sites: 1

Brief Summary

Ovarian hormones are not only modulators of cognitive function, emotion regulation and mental health, but also seem to affect brain plasticity and functional connectivity, During the menstrual cycle, women experience cyclic fluctuation of the ovarian hormone estradiol, which is closely associated with neuroplasticity/changes in brain structure in regions with high estradiol receptor density, such as the amygdala, hippocampus/parahippocampus, anterior cingulate cortex (ACC), striatum, and prefrontal cortex (PFC). Further functional connectivity between these areas seems to be associated with hormonal changes dependent on the menstrual cycle phase. But next to estradiol, also other hormones like progesterone fluctuate across the menstrual cycle. In the past, effects of ovarian hormone levels were often investigated in combination. However, one way to disentangle the impact of estradiol from that of other hormones on neuroplasticity, emotion regulation and mood states, can be the experimental increase of estradiol via estradiol administration. In this double-blinded within-subject study, women were administered either estradiol valerate or placebo during the early follicular phase (thus when ovarian hormone concentrations are low) before undergoing neuroimaging. Parts of the study are already described in Rehbein et al., 2021 and 2022.

Conditions

Emotion Regulation; Estradiol

Keywords

brain structure; functional connectivity; sex hormones; women's mental health

Outcome Measures

Primary Outcomes (7)

• Impact of E2 concentration on brain structure

  Brain structure (assessed via anatomical MRI scans, MPRAGE) will be compared between E2 and placebo conditions in regions of interest (ROI) (including amygdala, hippocampus/parahippocampus, ACC, striatum, and PFC).

  From first measurement up to 6 months, with at least two months apart; each time: approx. 6 minutes during neuroimaging

• Impact of E2 concentration and state emotion regulation on brain structure

  Brain structure (assessed via anatomical MRI scans, MPRAGE, in cm³) will be compared between E2 and placebo conditions in dependence of state emotion regulation ratings in ROIs (as above). State emotion regulation ratings obtained via the emotion regulation task (subjective rating ranging from -200 to 200).

  From first measurement up to 6 months, with at least two months apart; each time: approx. 6 minutes during neuroimaging (structure) and 20 minutes (emotion regulation task)

• Impact of E2 concentration and emotion regulation traits on brain structure

  Brain structure (assessed via anatomical MRI scans) will be compared between E2 and placebo conditions in dependence of emotion regulation traits in ROIs (as above). Emotion regulation traits assessed via the Heidelberg Form of Emotion Regulation (HFERST, ranging from 1 to 5) and the Emotion Regulation Questionnaire (ERQ, likert scale 1-7).

  From first measurement up to 6 months, with at least two months apart; each time: approx. 6 minutes during neuroimaging

• Impact of E2 concentration on resting state functional connectivity

  Resting state functional connectivity (assessed via resting state fMRI) will be compared between E2 and placebo condition in the whole brain and ROIs (as above).

  From first measurement up to 6 months, with at least two months apart; each time: approx. 7 minutes during neuroimaging

• Impact of E2 concentration and state emotion regulation on connectivity

  Resting state functional connectivity (assessed via resting state fMRI) will be compared between E2 and placebo conditions in dependence of emotion regulation ratings in ROIs (as above). State emotion regulation ratings obtained via the emotion regulation task (subjective rating ranging from -200 to 200).

  From first measurement up to 6 months, with at least two months apart; each time: approx. 7 minutes (connectivity) and 20 minutes (emotion regulation task)

• Impact of E2 concentration and emotion regulation traits on functional connectivity

  Resting state functional connectivity (assessed via resting state fMRI) will be compared between E2 and placebo conditions in dependence of emotion regulation traits in ROIs (as above). Emotion regulation traits assessed via the Heidelberg Form of Emotion Regulation (HFERST, ranging from 1 to 5) and the Emotion Regulation Questionnaire (ERQ, likert scale 1-7).

  From first measurement up to 6 months, with at least two months apart; each time: approx. 7 minutes (connectivity) during neuroimaging

• Impact of E2 concentration and associated structural brain changes on connectivity

  In order to investigate to which degree structural changes in association with E2 concentrations are related to changes in connectivity, both structure and connectivity were assessed via anatomical (MPRAGE) and resting state MRI scans.

  From first measurement up to 6 months, with at least two months apart; each time before and after pill intake (6 minutes structure and 7 minutes connectivity)

Secondary Outcomes (9)

• Impact of E2 concentration and self-esteem on brain structure

  From first measurement up to 6 months, with at least two months apart; each time: approx. 6 minutes during neuroimaging

• Impact of E2 concentration and self-esteem on functional connectivity

  From first measurement up to 6 months, with at least two months apart; each time: approx. 7 minutes during neuroimaging

• Impact of E2 concentration and subjective mood on brain structure

  From first measurement up to 6 months, with at least two months apart; each time: approx. 6 minutes during neuroimaging

• Impact of E2 concentration and state anxiety on brain structure

  From first measurement up to 6 months, with at least two months apart; each time: approx. 6 minutes during neuroimaging

• Impact of E2 concentration and subjective mood on functional connectivity

  From first measurement up to 6 months, with at least two months apart; each time: approx. 7 minutes during neuroimaging

Study Arms (2)

naturally cycling women starting with placebo

EXPERIMENTAL

naturally cycling women during early follicular phase starting with placebo (order was randomly selected)

Drug: Estradiol Valerate; Drug: Placebo

naturally cycling women starting with estradiol

EXPERIMENTAL

naturally cycling women during early follicular phase starting with estradiol (order was randomly selected)

Drug: Estradiol Valerate; Drug: Placebo

Interventions

Estradiol Valerate DRUG

To elevate estradiol levels each woman has received 6mg on two consecutive days (total 12mg) of estradiol valerate (Progynova21©)

Also known as: Progynova21

naturally cycling women starting with estradiol; naturally cycling women starting with placebo

Placebo DRUG

Placebo (blue-colored hard gelatine capsules completely filled with a mixture of 99.5% mannitol and 0.5% Aerosil (fumed silica)) has been administered (placebo-controlled condition)

naturally cycling women starting with estradiol; naturally cycling women starting with placebo

Eligibility Criteria

• Age: 19 Years - 35 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Women, biologically female (assigned sex at birth)
• regular menstrual cycle lasting between 26 and 32 days
• right handedness

You may not qualify if:

• present or past mental, neurological or endocrine disorders
• use of hormonal contraceptives during the last six months
• any other medication intake,
• or past and present pregnancies
• Intake of antidepressants or neuroleptics
• contraindication for MRI
• People with non-removable metal objects on or in the body
• Tattoos (if not MRI-incompatible according to expert guidelines)
• Pathological hearing or increased sensitivity to loud noises
• Claustrophobia
• Surgery less than three months ago
• Neurological disease or injury
• Moderate or severe head injury
• Restricted vision

Sponsors & Collaborators

• International Research Training Group 2804: lead
• University Hospital Tübingen: collaborator
• German Research Foundation: collaborator
• Werner Reichardt Centrum für Integrative Neurowissenschaften (CIN): collaborator

Study Sites (1)

University of Tuebingen; Department of Psychiatry & Psychotherapy

Tübingen, Baden-Wurttemberg, 72076, Germany

Location

MeSH Terms

Conditions

Emotional Regulation

Interventions

Estradiol

Condition Hierarchy (Ancestors)

Self-Control; Social Behavior; Behavior

Intervention Hierarchy (Ancestors)

Estrenes; Estranes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists

Study Officials

• Birgit Derntl, Prof.

  Departement of Psychiatry & Psychotherapy

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Neither participant or investigator knew the timepoint of drug or placebo administration. Pills were prepared by independent members of the university hospital.
• Purpose: OTHER
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: The intervention assessed the effect of estradiol administration on stress reactivity using a double blind randomized within -between placebo-controled design with repeated measures.

Study Record Dates

• First Submitted: February 6, 2024
• First Posted: March 15, 2024
• Study Start: August 1, 2018
• Primary Completion: July 31, 2019
• Study Completion: December 31, 2021
• Last Updated: March 15, 2024

Record last verified: 2024-03

Locations

DE (1)