Clinical trial NCT06312033: Estradiol's Effect on Brain Volume and Connectivity
Official title: Estradiol's Effect on Brain Volume and Connectivity in Naturally Cycling Women
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Emotion Regulation
Estradiol
Keywords: brain structure
functional connectivity
sex hormones
women's mental health
Lead sponsor: International Research Training Group 2804
Sponsor class: OTHER
Collaborators: name: University Hospital Tübingen
name: German Research Foundation
name: Werner Reichardt Centrum für Integrative Neurowissenschaften (CIN)
First posted: 2024-03-15
Enrollment: 32
Sex: FEMALE
Minimum age (years): 19
Maximum age (years): 35
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: The intervention assessed the effect of estradiol administration on stress reactivity using a double blind randomized within -between placebo-controled design with repeated measures.
Primary purpose: OTHER

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.

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: Impact of E2 concentration on brain structure
timeFrame: From first measurement up to 6 months, with at least two months apart; each time: approx. 6 minutes during neuroimaging
measure: Impact of E2 concentration and state emotion regulation on brain structure
timeFrame: 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)
measure: Impact of E2 concentration and emotion regulation traits on brain structure
timeFrame: From first measurement up to 6 months, with at least two months apart; each time: approx. 6 minutes during neuroimaging
measure: Impact of E2 concentration on resting state functional connectivity
timeFrame: From first measurement up to 6 months, with at least two months apart; each time: approx. 7 minutes during neuroimaging
measure: Impact of E2 concentration and state emotion regulation on connectivity
timeFrame: 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)
measure: Impact of E2 concentration and emotion regulation traits on functional connectivity
timeFrame: From first measurement up to 6 months, with at least two months apart; each time: approx. 7 minutes (connectivity) during neuroimaging
measure: Impact of E2 concentration and associated structural brain changes on connectivity
timeFrame: 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:
measure: Impact of E2 concentration and self-esteem on brain structure
timeFrame: From first measurement up to 6 months, with at least two months apart; each time: approx. 6 minutes during neuroimaging
measure: Impact of E2 concentration and self-esteem on functional connectivity
timeFrame: From first measurement up to 6 months, with at least two months apart; each time: approx. 7 minutes during neuroimaging
measure: Impact of E2 concentration and subjective mood on brain structure
timeFrame: From first measurement up to 6 months, with at least two months apart; each time: approx. 6 minutes during neuroimaging
measure: Impact of E2 concentration and state anxiety on brain structure
timeFrame: From first measurement up to 6 months, with at least two months apart; each time: approx. 6 minutes during neuroimaging
measure: Impact of E2 concentration and subjective mood on functional connectivity
timeFrame: From first measurement up to 6 months, with at least two months apart; each time: approx. 7 minutes during neuroimaging
measure: Impact of E2 concentration and state anxiety on functional connectivity
timeFrame: From first measurement up to 6 months, with at least two months apart; each time: approx. 7 minutes during neuroimaging
measure: Impact of E2 administration on E2 concentrations
timeFrame: From first measurement up to 6 months, with at least two months apart; each time before and after pill intake
measure: Impact of E2 administration on E2-progesterone ratio
timeFrame: From first measurement up to 6 months, with at least two months apart; each time before and after pill intake
measure: Impact of E2 administration on testosterone and progesterone concentration
timeFrame: From first measurement up to 6 months, with at least two months apart; each time before and after pill intake
Other outcomes:
Locations:
city: Tuebingen
country: Germany
facility: University of Tuebingen; Department of Psychiatry & Psychotherapy
state: BW
Study officials:
affiliation: Departement of Psychiatry & Psychotherapy
name: Birgit Derntl, Prof.
role: PRINCIPAL_INVESTIGATOR
References: