Effects of Estrogen and Hot Flashes on Mood in Postmenopausal Women

SPECIFIC AIMS (Research Objectives)

To define the relative effects of hot flashes and changes in estradiol on mood in
postmenopausal women:

Hypotheses:

1. Estrogen treatment has a similar therapeutic effect on mood in women with and without
frequent hot flashes

2. Estradiol levels correlate with improvement in mood

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