Estradiol and Stress Reactivity in Women

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.

In a double-blinded repeated-measures within-between placebo-controlled design, two groups of women (premenopausal / postmenopausal) will receive either a placebo or estradiol valerate to experimentally increase estradiol (E2) levels. They will further undergo a psychosocial stress task (Montreal Imaging Stress Task) in a neuroimaging environment (functional magnetic resonance imaging - fMRI). By applying a multilevel approach, the investigators will be able to look at stress reactivity from a subjective, sympathetic (heart rate, skin conductance), endocrine (cortisol) and neural perspective. The investigators will further assess how changes in stress reactivity due to E2 increase are associated with gonadal hormones, and changes in neural activity, anatomy and connectivity in pre- compared to postmenopausal women.

At an initial screening session (T0) the investigators will be assessing sociodemographic variables, hand dominance, verbal intelligence, trial making, personality traits, gender identity and roles, childhood trauma, coping styles, sleep, female sexual health, reproductive status, menopausal symptoms, eating behaviour and premenstrual symptoms. After this all women will be invited to the first experimental session (T1, day 1), where blood and hair cortisol samples will be taken, subjective mood will be measured and the first pill treatment administered (placebo or E2 valerate, double-blinded) approx. 24h before the stress induction. They receive a second pill that they should take-in during the next day (T1/day2) approx. 4h before the stress induction. On T1/day 2 in the afternoon, participants come to the laboratory where the experimental procedure takes place. Participants will again be screened for MRI-exclusion criteria and after ensuring that all requirements are met to go into the MR-scanner, participants will be prepared (application of sensor for pulsoxymetry and electrodes for skin conductance assessment) and moved into the scanner, where they will undergo the stress induction via the Montreal Imaging Stress Task (MIST), a resting state scan, an anatomical scan and a diffusion tensor imaging (DTI) measurement. Throughout the MR-session, pulsoxymetry and skin conductance will constantly be assessed. Mood, subjective affect and stress, and saliva samples for further cortisol analyses will be taken at six time points throughout the experimental session. Furthermore, subjective variables on stress, self-esteem, emotion regulation, positive and negative affect, emotional self-rating, resting state, mental health, depression and anxiety scores and side effects of E2 intake will be assessed. A blood sample will be drawn (30ml) by medically trained personnel during the experimental session. For seven days following the experimental session, participants will give daily information on subjective experiences via an ecological momentary assessment (EMA). Then, the second experimental session (T2) will be scheduled at least two menstrual cycles (naturally cycling women) or 2 months (postmenopausal women) after the first experimental session (T1). For naturally cycling women, both experimental sessions will be scheduled up to 5 days after onset of menses. Naturally cycling women are asked to report the onset of their next menses after the experimental session. The procedure of the second experimental session (T2) will be similar to that of T1.

Eligibility Criteria:
Inclusion Criteria:

* 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.

Exclusion Criteria:

* 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
  * Restricted vision