Perimenopausal Estrogen Replacement Therapy Study (PERT)

• Change in Depressive Symptoms as Indicated by The Center for Epidemiologic Studies Depression Scale (CES-D) [ Time Frame: Baseline, month 1, 2, 4, 6, 8, 10, 12 ] [ Designated as safety issue: No ]
• Change in Psychiatric Diagnosis as Assessed by the Structured Clinical Interview for DSM Disorders I/NP [ Time Frame: Baseline and when prompted by CES-D score ] [ Designated as safety issue: No ]
• Change in Stress Reactivity during Laboratory Session including Trier Social Stress Test [ Time Frame: Baseline, month 6 and 12 ] [ Designated as safety issue: No ]
  Primary measures reflecting stress reactivity will consist of mean arterial pressure (MAP), vascular resistance index (VRI), plasma cortisol, and plasma IL-6. For each of these four measures, a delta score (change from rest to stress) will be calculated and then standardized as Z scores. The individual Z scores will then be averaged to yield a single Stress Reactivity profile measure - a composite score reflecting magnitude of activation in the four primary stress-responsive pathways.

• Change in Functional Well-being as Assessed by the Medical Outcomes Study 36-item Short form (SF-36) [ Time Frame: Baseline, month 6 and 12 ] [ Designated as safety issue: No ]
• Change in Metabolic risk [ Time Frame: Baseline, month 6 and 12 ] [ Designated as safety issue: No ]
  Subjects will be classified as having metabolic risk if they either meet standard criteria for the metabolic syndrome (based on 3 of 5 risk factors: elevated blood pressure, fasting triglycerides, fasting glucose, waist circumference and low HDL-cholesterol) or they exhibit insulin resistance based on the derivation of an insulin sensitivity index (ISI0,120 < 61) following the standard oral glucose tolerance test
• Change in Flow Mediated Vasodilatation [ Time Frame: Baseline, month 6 and 12 ] [ Designated as safety issue: No ]
  Flow mediated vasodilatation of the brachial artery in response to reactive hyperemia using high resolution ultrasound, yielding a measure of endothelial-dependent vasodilatation.
• Change in Baroreceptor sensitivity [ Time Frame: Baseline, month 6 and 12 ] [ Designated as safety issue: No ]
  Cardiac autonomic control via EKG measurement of HR and beat-to-beat changes in BP to assess baroreceptor sensitivity

Study Background and Objectives: In the U.S. the majority of heart disease deaths are in women, not men. Much of the gender disparity in CVD rates relate to the burden of CV risk in women after the menopause. Depression has been associated with an increased risk for CVD morbidity and mortality. Even histories of recurrent depression in euthymic individuals are associated with elevated CV risk. Understanding the depression-CVD link may have particular relevance for women since women experience depression at a rate twice that of men. Substantial convergent evidence indicates that ovarian failure (estrogen deprivation) is one likely mechanism contributing to both CVD and depression in women. The perimenopause, a time associated with a two-fold increase in rates of depression, may provide an ideal opportunity for studying the pathophysiology of CV risk and depression in women.

The primary objective of this study is to examine the prophylactic role of estradiol in the development of depressive symptoms and the progression of cardiovascular risk in perimenopausal women with or without histories of depression. The investigators predict that women susceptible to depression will be particularly vulnerable to the acceleration of CVD in the context of the perimenopause and, consequently, will show differentially greater benefit of estradiol treatment during the menopause transition for both indices of CV risk (e.g. inflammation, endothelial function, stress reactivity), as well as depressive symptoms.

• Perimenopause
• Menopause
• Depression

• Drug: Estradiol
  Transdermal 17β-estradiol (100 ug/day) for 12 months, administered as patches to be worn continuously and replaced once a week. Also, every 2 months, oral micronized progesterone (200 mg/day x 12 days) will be administered.
  Other Name: Climara and Prometrium.
• Drug: Placebo
  Placebo patches for 12 months, to be worn continuously and replaced once a week. Also, placebo pills will be administered for 12 days every 2 months.

• Placebo Comparator: Placebo
  Placebo patches for 12 months and placebo pills for 12 days every 2 months.
  Intervention: Drug: Placebo
• Experimental: Estradiol
  Transdermal 17β-estradiol (100 ug/day) for 12 months and oral micronized progesterone (200 mg/day) for 12 days every two months.
  Intervention: Drug: Estradiol

Inclusion Criteria:

• must be between 45 and 55 years of age
• must be in the menopause transition (irregular/ absent menstrual cycles or hot flashes)
• must be are medically healthy

Exclusion Criteria:

- currently taking antidepressant medication