A 20-week randomized controlled trial of estradiol replacement therapy for women aged 70 years and older: effect on mood, cognition and quality of life

Neurobiol Aging. 2006 Jan;27(1):141-9. doi: 10.1016/j.neurobiolaging.2004.12.012. Epub 2005 Mar 16.


The results of several observational studies suggest that the use of estrogen replacement is associated with better mood, cognitive function and quality of life. Such findings are consistent with those of laboratory-based research showing that estrogen promotes neuronal sprouting, enhances cholinergic activity in the brain, decreases brain and plasma levels of beta-amyloid, increases serotonin postsynaptic responsivity and the turnover of noradrenaline, and inhibits monoamine oxidase activity. However, the findings from the Women's Health Initiative controlled trial showed that hormone replacement (estrogen plus progestin) not only failed to improve mood, cognition and quality of life but also increased the risk of dementia. At present, there is limited information about the effect of unopposed estradiol replacement therapy (ERT) on the mental health outcomes of women at increased risk of cognitive decline (aged 70 years and over). We designed the present randomized, double-blind, placebo-controlled trial to clarify this issue. One hundred and fifteen women were randomized to treatment with estradiol (n=58; 2mg per day) or placebo for a total period of 20 weeks. The outcomes of interest in this study included changes in the Beck Depression Inventory (BDI) scores between baseline and week 20, as well as changes in quality of life scores (as measured by the SF-36) and cognitive function (CAMCOG, Block Design, Memory for Faces, California Verbal Learning Test (CVLT) and verbal fluency (VF)). Nineteen women treated with estradiol and 10 of those treated with placebo discontinued the use of the medication during trial, most frequently due to adverse reactions (OR=4.11, 95% CI=1.29-15.37). Intention-to-treat analysis showed that the active and placebo groups did not differ in their response to treatment in any of the outcome measures (p>0.05). A separate analysis restricted to women who completed the 20-week-trial produced similar negative results. The results of this trial indicate that the use of a relatively high dosage of unopposed estrogen replacement for 20 weeks is not associated with significant changes in cognitive function, mood and quality of life. Other more efficacious and safer interventions need to be devised with the aim of improving the mental state and quality of life of older women.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Affect / drug effects*
  • Aged
  • Aged, 80 and over
  • Anxiety Disorders / epidemiology
  • Anxiety Disorders / prevention & control*
  • Australia / epidemiology
  • Cognition / drug effects*
  • Depressive Disorder / epidemiology
  • Depressive Disorder / prevention & control*
  • Double-Blind Method
  • Estradiol / administration & dosage*
  • Female
  • Hormone Replacement Therapy / statistics & numerical data*
  • Humans
  • Placebo Effect
  • Prognosis
  • Quality of Life*
  • Treatment Outcome
  • Women's Health


  • Estradiol