Anne Lethaby, Eva Hogervorst, Marcus Richards, Amina Yesufu, Kristine Yaffe

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 randomized controlled trials (RCTs) on cognitive function in postmenopausal women. The CDCIG Specialized Register was searched using the terms ORT, PORT, ERT, HRT, estrogen*, oestrogen*, progesteron* on 16 May 2002. In addition MEDLINE (1966-2002/01); EMBASE (1985-2000/11); PsycINFO (1967-2002/01) and CINAHL (1982-2001/12) were searched as the CDCIG Register does not contain all trials with healthy volunteers. All double-blind randomized controlled trials of the effect of ERT or HRT on cognitive function over a treatment period of at least two weeks in postmenopausal women. Abstracts of the references retrieved by the searches were read by two reviewers in order to discard those that were clearly not eligible for inclusion. The two reviewers studied the full text of the remaining references and independently selected studies for inclusion. Any disparity in the resulting lists was resolved by discussion with all reviewers in order to arrive at the final list of included studies. The selection criteria ensured that the blinding and randomization of the included studies was adequate. Two reviewers (EH and KY) assessed the quality of other aspects including design and assessment of outcomes. One reviewer (EH) extracted the data from the studies. In total, 15 trials involving 566 postmenopausal women were included, but 6 studies did not have adequate data for analysis. Meta-analyses showed a positive effect of 10 mg of estradiol (E2) bolus injections intramuscularly monthly in relatively young surgically menopausal women on the Paired Associate learning test immediate recall (z=2.40, p<0.05, chi-square test=1.12, p=0.29, SMD=1.02, 95% C.I.=0.19-1.85), on a test of abstract reasoning (z=10.45, p<0.0001, WMD=6.80, 95% C.I.=5.52-8.08) and a test of speed and accuracy (z=9.16, p<0.0001 WMD=6.00, 95% C.I.=4.72-7.28). However, most studies showed no evidence of an effect on verbal or visuospatial memory, mental rotations, speed or accuracy measures. There was little evidence that Premarin, the most widely prescribed estrogen for postmenopausal use, had positive effects on cognitive function. The one effect of 9 months of treatment with Premarin (and a progestagen) on a measure of complex speed of information processing (the TMT-B) was probably explained by baseline differences, as it was not reported by the authors. There was little evidence regarding the effect HRT or ERT on overall cognitive function in healthy postmenopausal women. There was an effect on some verbal memory functions (immediate recall), on a test of abstract reasoning and a test of speed and accuracy in relatively young (47 years of age) surgically menopausal women who had been given a bolus intramuscular injection of 10 mg E2 every month for 3 months. These effects were from small studies from a single research group. It remains to be determined whether factors such as an older age (> 69 years of age), type of menopause (surgical or natural) and type of treatment (E2 with or without a progestagen), mode of delivery (transdermal, oral or intramuscular), dosage and duration (> 3 months) could alter the effect on memory functions to a clinically relevant level. In addition, whether the absence or presence of menopausal symptoms can modify treatment effects should be investigated in more detail. Longitudinal RCTs currently underway in the U.S.A., U.K. and Canada will be able to test these hypotheses by the year 2010.