Effects of Estrogen and Hot Flashes on Mood in Postmenopausal Women

Inclusion Criteria: * Healthy women ≥40 years-old * Early postmenopausal, defined as: * No menstrual bleeding for 12-60 months secondary to natural menopause, according to STRAW criteria48 * Hysterectomy without bilateral oophorectomy if surgery was completed after 6+ months of amenorrhea (no maximum duration of amenorrhea required) * Bilateral oophorectomy (no minimum or maximum duration of amenorrhea required) * Serum follicle-stimulating hormone (FSH) \>25 IU/L and estradiol \<20 pg/ml * Diagnosis of major depression on the MINI * Mild-to-moderate depressive symptoms, as indicated by MADRS score 15-31 and BDI score \>15 * Normal mammogram within the past 2 years * Good general health Exclusion Criteria: * Severe depression, defined as a MADRS score \>31, psychotic symptoms, or suicidal or homicidal ideation * Psychiatric illness, as defined by clinical interview and the Mini-International Neuropsychiatric Interview (MINI), as: * A lifetime history of bipolar disorder * A lifetime history of severe depression, as characterized by current or prior psychotic symptoms, inpatient psychiatric hospitalization or a suicide attempt in the previous 5 years, or * Current panic disorder or obsessive compulsive disorder * A lifetime history of psychotic symptoms * Current anorexia nervosa * An alcohol or substance-use disorder active within the past year * Current suicidal or homicidal ideation * Previous diagnosis of a sleep disorder (sleep apnea, PLMS, etc) or diagnosed on a screening PSG study * Pregnant, confirmed with serum ß-HCG at baseline (Visit 1) * Breastfeeding * Contraindication, hypersensitivity, or previous adverse reaction to E2 therapy * Current or recent (1 month) use of centrally active medications (antidepressants, anxiolytics, hypnotics, anticonvulsants, stimulants) * Current or recent (2 months) use of systemic hormone medications * History of breast cancer, premalignant breast lesions, or undiagnosed breast mass * Vaginal spotting or bleeding * History of thrombo-embolism, cardiovascular disease, congestive heart failure or other contraindication to estradiol therapy. * Liver dysfunction or disease * Renal insufficiency * Contraindications to progestin therapy * Asthma, diabetes mellitus, epilepsy, and migraine disorders that are not stable and under medical management * Other medical contraindications to estradiol and progestin therapy including porphyria, systemic lupus erythematosus, hepatic hemangiomas, deep vein thrombosis, hereditary angioedema, hypertriglyceridemia, severe Hypocalcemia. * Clinically significant abnormalities in screening blood tests including: * Thyroid-stimulating hormone \<0.50 or \>5.0 uU/mL) * Shift workers