Effects of Estrogen and Hot Flashes on Mood in Postmenopausal Women
Condition: Menopausal Depression
MeSH terms: Hot Flashes
Intervention: Estradiol; Placebo control
Intervention description: Oral estradiol 1.0 mg/day for four weeks.; Placebo control matched to estradiol tablets. Daily dosing for one month.
Intervention MeSH terms: Estradiol
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 2.0
Sex: Female
Minimum age: 40 Years
Healthy volunteers: Accepts Healthy Volunteers

Summary:

      This protocol is a controlled study of estradiol therapy in early postmenopausal women with
      and without frequent hot flashes that will be used to determine whether hot flashes are an
      important intermediary in the generation of menopause-associated depression.
    

Eligibility criteria:

        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