Hormone replacement therapy for cognitive function in postmenopausal women

As estrogens have been found in animal models to be associated with the maintenance and protection of brain structures, it is biologically plausible that maintaining high levels of estrogens in postmenopausal women by medication could be protective against cognitive decline.

To investigate the effect of ERT (estrogens only) or HRT (estrogens combined with a progestagen) in comparison with placebo in RCTs on cognitive function in postmenopausal women.

The CDCIG Specialized Register was searched 7 March 2006. Additional searches were made of MEDLINE (1966-2006/02); EMBASE (1985-2006/02); PsycINFO (1967-2006/02) and CINAHL (1982-2006/01).

All double-blind RCTs trials of the effect of ERT or HRT on cognitive function over a treatment period of at least two weeks in postmenopausal women.

Selection of studies, assessment of quality and extraction of data were undertaken independently by three reviewers with disagreements resolved by discussion.

In total, 24 trials were included, but only 16 (10,114 women) had analysable data. Meta-analyses showed no effects of either ERT or HRT on prevention of cognitive impairment after five and four years of treatment, respectively (odds ratio 1.34, 95% CI 0.95 to 1.9; odds ratio 1.05, 95% CI 0.72 to 1.54 respectively) (trend favouring control in both instances). Analyses assessing the effects of treatment over time found that both ERT and HRT did not maintain or improve cognitive function and may even adversely affect this outcome (WMD = -0.45, 95% CI -0.99 to 0.09; WMD = -0.16, 95% CI -0.58 to 0.26, respectively at maximum follow up). Negative effects were found for ERT after one year and HRT after three and four years of therapy. Results from smaller trials assessing effects on individual cognitive domains mostly reported no evidence of benefit.

There is good evidence that both ERT and HRT do not prevent cognitive decline in older postmenopausal women when given as short term or longer term (up to five years) therapy. It is not known whether either specific types of ERT or HRT have specific effects in subgroups of women, although there was evidence that combined hormone therapy in similarly aged women was associated with a decrement in a number of verbal memory tests and a small improvement in a test of figural memory. There is insufficient evidence to determine whether subgroups of women using specific types of hormone therapy could benefit from treatment. It remains to be determined whether factors such as younger age (< 60 years of age), type of menopause (surgical or natural) and type of treatment (type of estrogen with or without a progestagen), mode of delivery (transdermal, oral or intramuscular) and dosage have positive effects at a clinically relevant level. In addition, whether the absence or presence of menopausal symptoms can modify treatment effects should be investigated in more detail. Large RCTs currently underway in the USA may be able to provide answers to these uncertainties by the year 2010. In the meantime, based on the available evidence, ERT or HRT cannot be recommended for overall cognitive improvement or maintenance in older postmenopausal women without cognitive impairment.