Stopped enrolling subjects due to challenge of identifying eligible participants

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.

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

Due to the challenge of identifying eligible participants, we decided to stop enrolling subjects and not to analyze the 2 completed participants.