Human Reproduction Update Advance Access originally published online on March 2, 2007
Human Reproduction Update 2007 13(3):329-330; doi:10.1093/humupd/dmm003
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Reply: Cognitive function and menopausal hormone therapy
Department of Reproductive Medicine and Child Development
Division of Gynecology and Obstetrics, University of Pisa
Via Roma 35, 56100 Pisa, Italy
E-mail: a.genazzani{at}obgynmed.unipi.it
The review published in Human Reproduction Update was aimed at reviewing the available data on the central effects of endogenous and exogenous estrogens with significance to female ageing and cognition. Results from basic science studies and from the most relevant clinical trials were cited, their discrepant findings discussed and suggestions made for new research directions (Genazzani et al., 2006
).
The evaluation of strategies to analyse the spectrum of cognitive function throughout the menopause transition and during post-menopause is becoming a highly relevant matter in women's health, since the neuropathological cascade of events contributing to the clinical diagnosis of cognitive impairment and dementia begin many years before the onset of overt memory dysfunction. At the same time, this dichotomy represents one of the most interesting challenges in women's health in terms of study of midlife therapeutic interventions aimed at modifying later clinical effects.
In this regard, the observation in the letter to the editor of Martina Dören appears, at least in part, conflicting and misleading, especially in terms of analysis of the ‘critical window hypothesis’ for neuroprotection. The Cochrane review published in 2002, by Hogervost et al. and cited by Dören, investigates the estrogen effect on measures of cognitive function, throughout the analyses of 15 randomized controlled trials (RCT) published from 1976 to 2002 (Hogervorst et al., 2002). This Cochrane review encompass clinical studies based on different design protocols and outcome measures, testing women of wide age range (from 29 to 91 years) and differing menopausal status, receiving different types of treatment (oral conjugated equine estrogen, transdermal or intramuscular estradiol and estrone and estriol) for diverse duration time (from 2 weeks to 9 months). In addition, only nine studies have sufficient outcome data for the overall analysis. In their meta-analysis, Hogervost et al. recognized a significant effect of estrogen treatment on verbal memory in relatively young surgical menopausal women demonstrated in two elegant studies of Phillips and Sherwin (Sherwin, 1988; Phillips and Sherwin, 1992). In addition, an advantage for estrogen treatment on at least one cognitive test was found in nine RCT studies mentioned in this meta-analysis, and other studies, all involving women younger than age 65 Hackman and Galbraith, 1976; Linzmayer et al., 2001).
These studies are cited and commented in the review published in Human Reproduction Update and they are recently reanalysed by P. Maki to demonstrate the ‘critical period hypothesis’(Maki, 2005, 2006).
In conclusion, Hogervost et al. in 2002, commented that the lack of estrogen effects on other measures of cognitive function could be explained also by the several methodological differences (patient selection, cognition test and treatment) in the studies available and the authors postponed any additional comments until after the results of large RCT designed to answer these questions more properly.
Actually, after the results of WHIMS study, the impact of estrogen and estrogen plus progestin treatment on cognitive vitality and for prevention of dementia has become a major priority in European population and worldwide and results from the ongoing KEEPS and REMEMBER studies will be critically important in providing new answers.
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Genazzani AR, Pluchino N, Luisi S., et al. (2006) Human Reprod Update. (Advance Access doi: 10.1093/Humupd/dml042).
Hackman BW and Galbraith D. (1976) Replacement therapy with piperazine oestrone sulfate ("Harmogen") and its effect on memory. Curr Med Res Opin 4:303–6.[Medline]
Hogervorst E, Yaffe K, Richards M., et al. (2002) Hormone replacement therapy for cognitive function in postmenopausal women. Cochrane Database Sys Rev 1–30 (Art. No.: CD003122. DOI: 10.1002/14651858.CD003122).
Linzmayer L, Semlitsch HV, Saletu B., et al. (2001) Double-blind, placebo-controlled psychometric studies on the effects of a combined estrogen-progestin regimen versus estrogen alone on performance, mood and personalityof menopausal syndrome patients. Arzneimittelforschung 51:238.[Medline]
Maki PM. (2005) A systematic review of clinical trials of hormone therapy on cognitive function effects of age at initiation and progestin use. Ann NY Acad Sci 1052:182–97.
Maki PM. (2006) Hormone therapy and cognitive function: is there a critical period for benefit? Neuroscience 138:1027–30.[CrossRef][ISI][Medline]
Phillips SM and Sherwin BB. (1992) Effects of estrogen on memory function in surgically menopausal women. Psychoneuroendocrinology 17:485–95.[CrossRef][ISI][Medline]
Sherwin BB. (1988) Estrogen and/or androgen replacement therapy and cognitive functioning in surgically menopausal women. Psychoneuroendocrinology 13:345–57.[CrossRef][ISI][Medline]
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