Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Estrogen therapy: is time of initiation critical for neuroprotection?

Nature Reviews Endocrinology volume 5, pages 620–627 (2009)Cite this article

Abstract

According to the 'critical period' hypothesis, which attempts to explain the observed discrepancies in the studies on estrogen and cognition, estrogen therapy effectively decreases cognitive decline in aging women when it is initiated around the time of menopause but not when it is started decades later. Here, I review studies in which the timing of the initiation of estrogen therapy was provided, to determine whether their findings support the 'critical period' hypothesis. The vast majority of the reviewed studies support the idea that early but not late initiation of estrogen therapy might prevent or delay cognitive decline in aging women. Nevertheless, numerous design issues, such as the specific drugs and doses that were used, the possible effects of progestins on cognition, and the failure to administer neuropsychological tests of specific cognitive domains that are sensitive to estrogen therapy confound the extant literature. In view of the reanalyzes of the Women's Health Initiative's data that show a beneficial effect of estrogen therapy on cardiac and breast diseases in women aged 50−59 years, more definitive evidence is needed to confirm that the early initiation of estrogen therapy that is continued for a few years provides enduring protection against cognitive aging 15−20 years later.

Key Points

  • Estrogen has numerous beneficial effects on the structure and function of the brain

  • Findings of previous studies are inconsistent with regard to the protective role of estrogen therapy against cognitive aging in postmenopausal women

  • According to the 'critical period' hypothesis, estrogen therapy effectively delays cognitive aging when it is initiated shortly after the menopause but not when it is initiated decades after the menopause

  • Some, but not all, previous findings support the 'critical period' hypothesis

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. United Nations: Bulletin on Aging No. 2, Division for Social Policy and Development. United Nations Secretariat: New York (2001).

  2. Wilson, R. S. et al. Individual differences in rates of change in cognitive abilities of older persons. Psychol. Aging 17, 179–193 (2002).

    Article  Google Scholar 

  3. Small, S. A., Stern, Y. M., Tang, Y. M. & Mayeux, R. Selective decline in memory function among healthy elderly. Neurology 52, 1392–1396 (1999).

    Article  CAS  Google Scholar 

  4. Salthouse, T. A. Mediation of adult age differences in cognition by reductions in working memory and speed of processing. Psychol. Sci. 2, 179–183 (1991).

    Article  Google Scholar 

  5. Zelinski, E. M., Gilewski, M. J. & Schaie, K. W. Individual differences in cross-sectional and 3-year longitudinal memory performance across the adult life span. Psychol. Aging 8, 176–186 (1993).

    Article  CAS  Google Scholar 

  6. Grady, C. L. & Craik, F. I. Changes in memory processing with age. Curr. Opin. Neurobiol. 10, 224–231 (2000).

    Article  CAS  Google Scholar 

  7. Gregoire, J. M. & Van der Linden, M. Effects of age on forward and backward digit span. Aging, Neuropsychology, and Cognition 4, 140–149 (1997).

    Article  Google Scholar 

  8. Esiri, M. M. Ageing and the brain. J. Pathol. 211, 181–187 (2007).

    Article  CAS  Google Scholar 

  9. H. Morrison, J. H. & Hof, P. R. Life and death of neurons in the aging brain. Science 278, 412–419 (1997).

    Article  Google Scholar 

  10. McEwen, B. Estrogen actions throughout the brain. Recent Prog. Horm. Res. 57, 357–384 (2002).

    Article  CAS  Google Scholar 

  11. Gould, E., Woolley, C. S., Frankfurt, M. & McEwen, B. S. Gonadal steroids regulate dendritic spine density in hippocampal pyramidal cells in adulthood. J. Neurosci. 10, 1286–1291 (1990).

    Article  CAS  Google Scholar 

  12. Woolley, C. S., Gould, E., Frankfurt, M. & McEwen, B. S. Naturally occurring fluctuation in dendritic spine density on adult hippocampal pyramidal neurons. J. Neurosci. 10, 4035–4039 (1990).

    Article  CAS  Google Scholar 

  13. Sandstrom, N. J. & Williams, C. L. Memory retention is modulated by acute estradiol and progesterone replacement. Behav. Neurosci. 115, 384–393 (2001).

    Article  CAS  Google Scholar 

  14. Luine, V. N. Estradiol increases choline acetyltransferase activity in specific basal forebrain nuclei and projection areas of female rats. Exp. Neurol. 89, 484–490 (1985).

    Article  CAS  Google Scholar 

  15. Pike, C. J. Estrogen modulates neuronal Bel-xl expression and β-amyloid-induced apoptosis: relevance to Alzheimer's disease. J. Neurochem. 72, 1552–1563 (1999).

    Article  CAS  Google Scholar 

  16. Greene R. A. Estrogen and cerebral blood flow: a mechanism to explain the impact of estrogen on the incidence and treatment of Alzheimer's disease. Int. J. Fertil. Womens Med. 45, 253–257 (2000).

    CAS  PubMed  Google Scholar 

  17. Lee, S. J. & McEwen, B. S. Neurotrophic and neuroprotective actions of estrogens and their therapeutic implications. Annu. Rev. Pharmacol. Toxicol. 41, 569–591 (2001).

    Article  CAS  Google Scholar 

  18. Sherwin, B. B. Estrogen and/or androgen replacement therapy and cognitive functioning in surgically menopausal women. Psychoneuroendocrinology 13, 345–357 (1988).

    Article  CAS  Google Scholar 

  19. Phillips, S. M. & Sherwin, B. B. Effects of estrogen on memory function in surgically menopausal women. Psychoneuroendocrinology 17, 485–495 (1992).

    Article  CAS  Google Scholar 

  20. Shaywitz, S. E. et al. Better oral reading and short-term memory in midlife, postmenopausal women taking estrogen. Menopause 10, 420–426 (2003).

    Article  Google Scholar 

  21. Espeland, M. A. et al. Conjugated equine estrogens and global cognitive function in postmenopausal women: Women's Health Initiative Memory Study. JAMA 291, 2959–2968 (2004).

    Article  CAS  Google Scholar 

  22. Shumaker, S. A. et al. Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women's Health Initiative Memory Study. JAMA 291, 2947–2958 (2004).

    Article  CAS  Google Scholar 

  23. Gibbs, R. B. & Gabor, R. Estrogen and cognition: applying preclinical findings to clinical perspectives. J. Neurosci. Res. 74, 637–643 (2003).

    Article  CAS  Google Scholar 

  24. Resnick, S. M. & Henderson, V. W. Hormone therapy and risk of Alzheimer disease: a critical time. JAMA 288, 2170–2172 (2002).

    Article  Google Scholar 

  25. Jezierski, M. K. & Sohrabji, F. Neurotrophin expression in the reproductively senescent forebrain is refractory to estrogen stimulation. Neurobiol. Aging 22, 309–319 (2001).

    Article  CAS  Google Scholar 

  26. Gibbs, R. B. Effects of gonadal hormone replacement on measures of basal forebrain cholinergic function. Neuroscience 101, 931–938 (2000).

    Article  CAS  Google Scholar 

  27. Verghese, J. et al. Cognitive performance on surgically menopausal women on estrogen. Neurology 55, 872–874 (2000).

    Article  CAS  Google Scholar 

  28. MacLennan, A. H. et al. Hormone therapy, timing of initiation, and cognition in women aged older than 60 years: the REMEMBER pilot study. Menopause 13, 28–36 (2006).

    Article  Google Scholar 

  29. Jacobs, D. M. et al. Cognitive function in nondemented older women who took estrogen after the menopause. Neurology 50, 368–373 (1998).

    Article  CAS  Google Scholar 

  30. Matthews, K., Cauley, J., Yaffe, K. & Zmuda, J. M. Estrogen replacement therapy and cognitive decline in older community women. J. Am. Geriatr. Soc. 47, 518–523 (1999).

    Article  CAS  Google Scholar 

  31. Bagger, Y. Z. et al. Early postmenopausal hormone therapy may prevent cognitive impairment in later life. Menopause 12, 12–17 (2005).

    Article  Google Scholar 

  32. Viscoli, C. M. et al. Estrogen therapy and risk of cognitive decline: results from the Women's Estrogen for Stroke Trial (WEST). Am. J. Obstet. Gynecol. 192, 387–393 (2005).

    Article  CAS  Google Scholar 

  33. Duka, T., Tasker, R. & McGowan, J. F. The effects of 3-week estrogen hormone replacement on cognition in elderly healthy females. Psychopharmacology (Berl.) 149, 129–139 (2000).

    Article  CAS  Google Scholar 

  34. Schiff, R., Bulpitt, C. J., Wesnes, K. A. & Rajkumar, C. Short-term transdermal estrogen therapy, cognition and depressive symptoms in healthy older women. A randomized placebo-controlled pilot cross-over study. Psychoneuroendocrinology 30, 309–315 (2005).

    Article  CAS  Google Scholar 

  35. Pefanco, M. A. et al. The effect of 3-year treatment with 0.25 mg/day of micronized 17 beta-estradiol on cognitive function in older postmenopausal women. J. Am. Geriatr. Soc. 55, 426–431 (2007).

    Article  Google Scholar 

  36. Yaffe, K. et al. Effects of ultra-low dose transdermal estradiol on cognition and health related quality of life. Arch. Neurol. 63, 945–950 (2006).

    Article  Google Scholar 

  37. Janowsky, S. J., Chavez, B. & Orwoll, F. Sex steroids modify working memory. J. Cogn. Neurosci. 12, 407–414 (2000).

    Article  CAS  Google Scholar 

  38. Binder, E. F., Schectman, K. B., Birge, S. J., Williams, D. B. & Kohrt, W. M. Effects of hormone replacement therapy on cognitive performance in elderly women. Maturitas 38, 137–146 (2001).

    Article  CAS  Google Scholar 

  39. Wolf, O. T. et al. Two weeks of transdermal estradiol treatment in postmenopausal elderly women and its effect on memory and mood. Psychoneuroendocrinology 24, 727–741 (1999).

    Article  CAS  Google Scholar 

  40. Resnick, S. M., Pham, D. L., Kraut, M. A., Zonderman, A. M. & Davatzikos, C. Longitudinal magnetic resonance imaging studies of older adults: a shrinking brain. J. Neurosci. 23, 3295–3301 (2003).

    Article  CAS  Google Scholar 

  41. Gleason, C. E., Carlsson, C. M., Johnson, S., Atwood, C. & Asthana, S. Clinical pharmacology and differential cognitive efficacy of estrogen preparations. Ann. NY Acad. Sci. 1052, 93–115 (2005).

    Article  CAS  Google Scholar 

  42. Bhavnani, B. R. Pharmacokinetics and pharmacodynamics of conjugated equine estrogens: chemistry and metabolism. Proc. Soc. Exp. Biol. Med. 217, 6–16 (1998).

    Article  CAS  Google Scholar 

  43. Kuiper, G. G. et al. Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta. Endocrinology 138, 863–870 (1997).

    Article  CAS  Google Scholar 

  44. Bassuk, S. S. & Murphy, J. M. Characteristics of the Modified Mini-Mental State Exam among elderly persons. J. Clin. Epidemiol. 56, 622–628 (2003).

    Article  Google Scholar 

  45. LeBlanc, E. S., Janowsky, J., Chan, B. K. & Nelson, H. D. Hormone replacement therapy and cognition: systematic review and meta-analysis. JAMA 285, 1489–1499 (2001).

    Article  CAS  Google Scholar 

  46. Utian, W. H. et al. Estrogen and progestogen use in postmenopausal women: July 2008 position statement of the North American Menopause Society. Menopause 15, 584–602 (2008).

    Article  Google Scholar 

  47. Reid, R. L. et al. Menopause and Osteoporosis Update 2009. J. Soc. Obstet. Gynecol. Can. 31 (Suppl. 1), S1–S48 (2009).

    Google Scholar 

  48. Rocca, W. A. et al. Increased risk of cognitive impairment or dementia in women who underwent oophorectomy before menopause. Neurology 69, 1074–1083 (2007).

    Article  CAS  Google Scholar 

  49. Jezierski, M. K. & Sohrabji, F. Neurotrophin expression in the reproductively senescent forebrain is refractory to estrogen stimulation. Neurobiol. Aging 22, 309–319 (2001).

    Article  CAS  Google Scholar 

  50. Dumas, J., Hancur-Bucci, C., Naylor, M., Sites, C. & Newhouse, P. Estradiol interacts with the cholinergic system to affect verbal memory in postmenopausal women: evidence for the critical period hypothesis. Horm. Behav. 53, 159–169 (2008).

    Article  CAS  Google Scholar 

  51. Rossouw, J. E. et al. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA 297, 1465–1477 (2007).

    Article  CAS  Google Scholar 

  52. Stefanick, M. L. et al. Effects of conjugated equine estrogens on breast cancer and mammography screening in postmenopausal women with hysterectomy. JAMA 295, 1647–1657 (2006).

    Article  CAS  Google Scholar 

  53. Henderson, V. W. et al. Prior use of hormone therapy and incident Alzheimer's disease in the Women's Health Initiative Memory Study [abstract]. Neurology 68 (Suppl. 1), A205 (2007).

    Google Scholar 

  54. Chlebowski, R. T. et al. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women's Health Initiative Randomized Trial. JAMA 289, 3243–3253 (2003).

    Article  CAS  Google Scholar 

  55. Rice, M. M. et al. Postmenopausal estrogen and estrogen-progestin use and 2-year rate of cognitive change in a cohort of older Japanese American women: The Kame Project. Arch. Intern. Med. 160, 1641–1649 (2000).

    Article  CAS  Google Scholar 

  56. Smith, Y. R., Giordoni, B., Lajiness-O'Neill, R. & Zubieta, J. K. Long-term estrogen replacement is associated with improved nonverbal memory and attentional measures in postmenopausal women. Fertil. Steril. 76, 1101–1107 (2001).

    Article  CAS  Google Scholar 

  57. Grady, D. et al. Effect of postmenopausal hormone therapy on cognitive function: the Heart and Estrogen/Progestin Replacement Study. Am. J. Med. 113, 543–548 (2002).

    Article  CAS  Google Scholar 

  58. Resnick, S. M. et al. Effects of combination estrogen plus progestin hormone treatment on cognition and affect. J. Clin. Endocrinol. Metab. 91, 1802–1810 (2006).

    Article  CAS  Google Scholar 

  59. Rapp, S. R. et al. Effect of estrogen plus progestin on global cognitive function in postmenopausal women: the Women's Health Initiative Memory Study: a randomized controlled trial. JAMA 289, 2663–2672 (2003).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The preparation of this manuscript was supported by a grant from the Canadian Institutes of Health Research (No. MOP 89960) awarded to B. B. Sherwin.

Author information

Authors and Affiliations

  1. Department of Psychology, McGill University, Montreal, QC, Canada

    Barbara B. Sherwin

Authors
  1. Barbara B. Sherwin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Barbara B. Sherwin.

Ethics declarations

Competing interests

The author declares no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sherwin, B. Estrogen therapy: is time of initiation critical for neuroprotection?. Nat Rev Endocrinol 5, 620–627 (2009). https://doi.org/10.1038/nrendo.2009.193

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrendo.2009.193

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing