Women in the menopause transition (perimenopause) experience substantial day-to-day variability in estradiol and have a 2-4-fold increase in major depression risk. About 40% of perimenopausal women are susceptible to the emergence of affective symptoms tied to changes in estradiol. Among the perimenopausal women with affective impairment, most report irritability, not "depression," is their primary source of impairment and distress. The purpose of this research is to determine the neurophysiologic basis of susceptibility to estradiol fluctuations and irritability symptoms in perimenopausal women.

Using a within-subjects, cross-over design and transdermal estradiol to stabilize estradiol fluctuations (and increase levels) the investigators will test if neural dynamics (oscillatory activity in the theta and beta frequencies assessed via EEG) associated with key constructs of irritability (attentional bias to threat and frustration to non-reward) represent a biomarker target of irritability symptom response to transdermal estradiol.

Inclusion Criteria:

• Healthy women 45 - 59 years of age
• In the early menopause transition (defined by variable menstrual cycle length that is 7+ days longer or shorter than usual)
• Increase in irritability since the onset of menstrual cycle changes
• Moderate to severe irritability symptoms, as defined by IDAS ill-temper scale score >10
• Have experienced 1+ very stressful life event (e.g. divorce, death of family member) within the past 6 months
• Negative mammogram within the past two years
• BMI between 18 - 45 kg/m^2

Exclusion Criteria:

• Use of psychotropic agents or hormonal preparations, or herbal supplements (other than multivitamins) believed to affect mood or menopausal symptoms
• History of psychosis, bipolar disorder, or substance dependence
• Active psychological symptoms severe enough to require treatment
• Current suicidal intent or recent history of suicide attempts (within past 10 years)
• Personal or family history of cancer indicative of more than average risk for breast, ovarian or endometrial cancers
• Personal history of any cardiovascular disease including coronary artery disease, arteriosclerosis, heart attack, stroke
• Personal history of thromboembolic disorders
• History of E2-dependent neoplasia
• History of gallbladder disease
• Recent history of migraine with aura
• Blood pressure classified as higher than stage 2 hypertension (≥160 mmHg systolic or ≥100 mmHg diastolic)
• Liver dysfunction or disease
• Undiagnosed abnormal genital bleeding
• Type I diabetes
• Known sensitivities to the matrix patch system in Climara® or allergy to peanut oil used in Prometrium®

After the study is completed, the de-identified, archived data will be transmitted to and stored at the National Institute of Mental Health Data Archive (NDA) for use by other researchers including those outside of the study.

Raw experimental data will not be released or shared until publication or after the project end date, whichever comes first.

Refer to National Institute of Mental Health Data Archive (NDA) for details.

From the time of the first laboratory visit through final follow up visit, up to approximately 3 months.

There will be one unblinded Research Assistant administering interventions to preserve masking of research personnel and participants involved. Care provider may be unmasked for specific participants if there are adverse events requiring referral.