Estradiol's Effect on Brain Volume and Connectivity

Emotion Regulation Clinical Trial

Official title:

Estradiol's Effect on Brain Volume and Connectivity in Naturally Cycling Women

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT06312033
• Other study ID #: MRTG_P01
• Status: Completed
• Phase: N/A
• Start date: August 1, 2018
• Est. completion date: December 31, 2021

Study information

• Verified date: March 2024
• Source: International Research Training Group 2804
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Description:

In this project the investigators wanted to assess women with/without experimentally elevated estradiol (E2) levels in order to understand E2's effect on volume and resting state functional connectivity. Thus, women underwent fMRI (functional magnetic resonance imaging) scanning twice (with/without elevated E2) to deduce underlying neuronal activation. All participants underwent a structured assessment including demographical data, psychological/clinical data, e.g., structured clinical interview, anxiety traits, depression, emotion regulation traits, self-esteem as well as cognitive abilities, e.g., verbal intelligence, cognitive flexibility) and two (f)MRI measurements (T1/T2, separated by at least 2-3 months), including resting-state and anatomical scans as well as a behavioural emotion regulation task. At T1/T2 either E2 valerate or placebo was administered in a double-blinded, counterbalanced, randomized order.

E2 valerate administration: To experimentally elevate E2 concentrations each woman has received 6mg on two consecutive days (total 12mg) of E2 valerate (Progynova21©) Administration of E2 has been randomly distributed, so that women either received placebo (i.e. leading to an early follicular phase with low ovarian hormone levels) or E2 (i.e. leading to an early follicular phase with high E2 levels) first. Functional resting-state and anatomical data, emotion regulation performance, state anxiety, mood and depression scores have been acquired after the second pill intake. During the emotion regulation task women were asked to either (a) passively view aversive pictures or (b) down regulate their emotional response by e.g. changing their perspective on the picture and then rate their emotional state.

To assess changes in hormone concentrations (E2, progesterone, testosterone) blood samples were obtained before the first and after the second pill intake.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 32
• Est. completion date: December 31, 2021
• Est. primary completion date: July 31, 2019
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Female
• Age group: 19 Years to 35 Years

Eligibility

Inclusion Criteria:

• Women, biologically female (assigned sex at birth)

• regular menstrual cycle lasting between 26 and 32 days

• right handedness

Exclusion Criteria:

• 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

Related Conditions & MeSH terms

• Emotion Regulation

Intervention

Drug:
• Estradiol Valerate
To elevate estradiol levels each woman has received 6mg on two consecutive days (total 12mg) of estradiol valerate (Progynova21©)
• Placebo
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)

Locations

Country	Name	City	State
Germany	University of Tuebingen; Department of Psychiatry & Psychotherapy	Tuebingen	BW

Sponsors (4)

Lead Sponsor	Collaborator
International Research Training Group 2804	German Research Foundation, University Hospital Tübingen, Werner Reichardt Centrum für Integrative Neurowissenschaften (CIN)

Country where clinical trial is conducted

Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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)
Primary	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
Primary	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
Primary	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)
Primary	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
Primary	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	Impact of E2 concentration and self-esteem on brain structure	Brain structure (assessed via anatomical MRI scans, MPRAGE) will be compared between E2 and placebo condition on dependence of self-esteem ratings in ROIs (as above). Self-esteem self-ratings assessed via the Rosenberg Self-Esteem Questionnaire (RSQ).	From first measurement up to 6 months, with at least two months apart; each time: approx. 6 minutes during neuroimaging
Secondary	Impact of E2 concentration and self-esteem on functional connectivity	Resting state functional connectivity (assessed via resting state fMRI) will be compared between E2 and placebo condition on dependence of self-esteem ratings in ROIs (as above). Self-esteem self-ratings assessed via the Rosenberg Self-Esteem Questionnaire (RSQ).	From first measurement up to 6 months, with at least two months apart; each time: approx. 7 minutes during neuroimaging
Secondary	Impact of E2 concentration and subjective mood on brain structure	Brain Structure (assessed via anatomical MRI scans, MPRAGE) will be compared between E2 and placebo condition in dependence of subjective mood in ROIs (as above). Ratings of subjective mood/affect obtained on the neuroimaging day.	From first measurement up to 6 months, with at least two months apart; each time: approx. 6 minutes during neuroimaging
Secondary	Impact of E2 concentration and state anxiety on brain structure	Brain Structure (assessed via anatomical MRI scans, MPRAGE) will be compared between E2 and placebo condition in dependence of state anxiety in ROIs (as above). Ratings of state anxiety (State Anxiety Inventory) obtained on the neuroimaging day	From first measurement up to 6 months, with at least two months apart; each time: approx. 6 minutes during neuroimaging
Secondary	Impact of E2 concentration and subjective mood on functional connectivity	Resting state functional connectivity (assessed via resting state MRI) will be compared between E2 and placebo condition in dependence of subjective mood in ROIs (as above). Ratings of subjective mood/affect obtained on the neuroimaging day.	From first measurement up to 6 months, with at least two months apart; each time: approx. 7 minutes during neuroimaging
Secondary	Impact of E2 concentration and state anxiety on functional connectivity	Resting state functional connectivity (assessed via resting state MRI) will be compared between E2 and placebo condition in dependence of state anxiety in ROIs (as above). Ratings of state anxiety (State Anxiety Inventory) obtained on the neuroimaging day.	From first measurement up to 6 months, with at least two months apart; each time: approx. 7 minutes during neuroimaging
Secondary	Impact of E2 administration on E2 concentrations	Changes in E2 concentrations(pmol/L), will be assessed from blood samples before and after pill intake.	From first measurement up to 6 months, with at least two months apart; each time before and after pill intake
Secondary	Impact of E2 administration on E2-progesterone ratio	Changes in E2-progesterone ratio will be assessed from blood samples before and after pill intake.	From first measurement up to 6 months, with at least two months apart; each time before and after pill intake
Secondary	Impact of E2 administration on testosterone and progesterone concentration	Changes in testosterone and progesterone concentrations (nmol/L) will be assessed from blood samples before and after pill intake.	From first measurement up to 6 months, with at least two months apart; each time before and after pill intake