Estradiol and Stress Reactivity in Women

NCT06204016 | Recruiting

• 1 other identifier: IRTG_P02
• Study Type: observational
• Target: 74
• Locations: 1 country
• Sites: 1

Brief Summary

Stress reactivity and prevalence of stress related diseases differ between pre- and postmenopausal women. Thus, hormonal fluctuations may present a general vulnerability factor for stress-related diseases. Especially, the gonadal hormone estradiol (E2) seems to modulate the activity of stress related brain areas. The hippocampus and prefrontal areas control the amygdala's response to stress, and E2 may directly modulate the activity, connectivity and structure of these areas. In premenopausal women E2 seems to reduce stress reactivity. However, in postmenopausal women, who no longer produce E2 from the ovaries, E2 seem to increase stress reactivity. With the proposed study the investigators want to directly test E2's modulating effects (disentangled from other gonadal hormones) on stress reactivity of premenopausal women during their early follicular phase, and postmenopausal women by subjecting both groups of women to a psychosocial stress task in a neuroimaging environment.

Conditions

Stress vs. Control; Estradiol vs. Placebo

Keywords

stress reactivity; mood homeostasis; neuroimaging (fMRI); menopause; menstrual cycle; sex hormones; women's mental health; estradiol

Outcome Measures

Primary Outcomes (7)

• Associations between elevated E2 concentration and acute stress effects on subjective experience

  Ratings of positive and negative affect as well as stress, before and after stress induction. Comparing E2 against placebo in pre- and postmenopausal women.

  Measured twice two-three months apart; each time: approx. 45 minutes before stress onset, just before stress onset, immediately after stress, approx. 40 minutes, 60 minutes and 120 minutes after stress onset

• Associations of E2 and acute stress effects on Hypothalamic-Pituitary-Adrenal-axis (HPA) response

  Cortisol saliva samples before and after the stress task as indicator of stress/HPA-axis activation. Comparing E2 against placebo in pre- and postmenopausal women.

  Measured twice two-three months apart; each time: approx. 45 minutes before stress onset, just before stress onset, immediately after stress, approx. 40 minutes, 60 minutes and 120 minutes after stress onset

• Association between E2 concentration and acute stress induced effects on neural level.

  Variability in activity of the brains stress network will be quantified using fMRI to assess differences between stress vs. control conditions during the stress task. Changes in activity will be assessed within regions associated with stress reactivity and regulation (amygdala, hippocampus, prefrontal cortex, anterior cingulate cortex (ACC), middle frontal gyrus (MFG), right superior temporal gyrus (STG), insula, striatum and praecuneus). Comparing E2 against placebo in pre- and postmenopausal women.

  Measured twice three months apart; each time: approx. 5 minutes during neuroimaging

• Association between E2 concentration and brain volume changes

  Via structural MRI scans changes in brain volume following E2 administration compared to placebo will be assessed, especially for the following brain regions: amygdala, hippocampus, prefrontal cortex (including orbito frontal cortex), anterior cingulate cortex (ACC), insula, middle frontal gyrus (MFG), right superior temporal gyrus (STG), fusiform gyrus, thalamus, cerebellum and inferior parietal lobule (IPL). Comparing E2 against placebo in pre- and postmenopausal women.

  Measured twice two- three months apart; each time: approx. 10 minutes during neuroimaging

• Association between E2 concentration and connectivity (resting state) changes

  Via a resting state scan, effects of estradiol concentration compared to placebo administration on connectivity changes will be assessed by applying whole brain network (especially Default Mode, Dorsal Attention, Frontoparietal, and Limbic networks) and region of interest analysis (especially of the amygdala, middle temporal gyrus (MTG), inferior frontal gyrus (IFG), postcentral gyrus, striatum, insula and ventrolateral, dorsolateral and medial prefrontal cortex (PFC), fusiform gyrus and anterior cingulate gyrus (ACC)). Comparing E2 against placebo in pre- and postmenopausal women.

  Measured twice two-three months apart; each time: approx. 10 minutes during neuroimaging

• Changes in hormonal levels induced by increased E2 concentration.

  Changes in E2 levels (pmol/L) will be assessed from blood samples before and after pill intake (placebo or estradiol valerate) and stress induction. Comparing E2 against placebo in pre- and postmenopausal women.

  Measured twice two-three months apart; pill intake a day before and on the day of neuroimaging

• Changes in hormonal levels induced by increased E2 concentration.

  Changes in progesterone, testosterone, and allopregnanolone levels (nmol/L) will be assessed from blood samples before and after pill intake (placebo or estradiol valerate) and stress induction. Comparing E2 against placebo in pre- and postmenopausal women.

  Measured twice two-three months apart; pill intake a day before and on the day of neuroimaging

Secondary Outcomes (5)

• Associations between E2 concentration and acute stress effects on physiological responses.

  Measured twice two-three months apart; each time: 20 minutes during the fMRI stress task

• Association between E2 concentration and chronic stress

  Measured twice two-three months apart

• Association between E2 concentration and effects on aftermath of stress.

  Measured twice two-three months apart; each time for 7days

• Associations between elevated E2 concentration and acute stress effects on subjective experience

  Measured twice two-three months apart; each time: approx. 45 minutes before stress onset and120 minutes after stress onset

• Associations between elevated E2 concentration and acute stress effects on subjective experience

  Measured twice two-three months apart; each time: approx. 45 minutes before stress onset and120 minutes after stress onset

Study Arms (2)

premenopausal women

naturally cycling women without hormonal contraception

Drug: Estradiol Valerate; Drug: Placebo

postmenopausal women

women after menopause (min. 12 months no menstrual bleeding)

Drug: Estradiol Valerate; Drug: Placebo

Interventions

Estradiol Valerate DRUG

To elevate estradiol levels each woman will receive 12mg on two consecutive days (total 24mg) of estradiol valerate (Progynova21©)

Also known as: Progynova21

postmenopausal women; premenopausal women

Placebo DRUG

Placebo tablets will be administered as placebo-controlled condition (P-Tabletten White 7mm, Lichtenstein)

Also known as: P-Tabletten

postmenopausal women; premenopausal women

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)
• Sampling Method: Non-Probability Sample

Study Population

The study population will mainly consist of residents of Tübingen and surrounding areas.

You may qualify if:

• Women, biologically female (assigned sex at birth)
• normal body mass index (18-28 kg/m2)
• Caucasian
• non-smoking
• German language fluency: at least advanced technical college entrance qualification
• Naturally cycling women, older than 18 years with a regular menstrual cycle (25-35 days) and postmenopausal women up to the age of 60 will be included.

You may not qualify if:

• Neurological or mental disease
• Medical problems such as hormonal, metabolic, or chronic diseases (e.g., severe hypertension, diabetes, dysfunctions of the thyroid, or congestive heart failure) as well as venous thromboembolism
• Pregnancy, delivery, and lactation (current and within the last year)
• Any kind of steroid hormonal, pharmacological treatment, or psychotropic treatment in the last three months
• Shift work
• Participants engaging in competitive/extreme sports
• 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
• Intake of antidepressants or neuroleptics

Sponsors & Collaborators

• International Research Training Group 2804: lead
• University Hospital Tuebingen: collaborator
• German Research Foundation: collaborator
• Uppsala University: collaborator

Study Sites (1)

University of Tuebingen; Department of Psychiatry & Psychotherapy

Tübingen, Baden-Wurttemberg, 72076, Germany

RECRUITING

Biospecimen

Retention: SAMPLES WITH DNA

blood

MeSH Terms

Interventions

Estradiol

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

Central Study Contacts

Birgit Derntl, Prof.

CONTACT

0049 07071 2985437; birgit.derntl@med.uni-tuebingen.de

Lydia Kogler, Mag. Dr.

CONTACT

0049 07071 2987030; lydia.kogler@med.uni-tuebingen.de

Study Design

• Study Type: observational
• Observational Model: CASE CROSSOVER
• Time Perspective: CROSS SECTIONAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 21, 2023
• First Posted: January 12, 2024
• Study Start: March 7, 2024
• Primary Completion: July 1, 2025
• Study Completion: December 1, 2025
• Last Updated: March 8, 2024

Record last verified: 2024-03

Data Sharing

• IPD Sharing: Will share
• Time Frame: Data can become available after an embargo period of 12 months after completion and publication of the study
• Access Criteria: Researchers may contact the lead PI to gain access

Locations

DE (1)