WorldLink Medical

Estrogen's Impact on Cognitive Function

Estrogen's Impact on Cognitive Function:

Brain lapses, memory loss, blank stares, confusion. Do you feel like you are losing your mind as you get older? What you may classify as old age and impaired brain function may truly be related to a decrease in estrogen.

Cognitive Decline as a Disease of Aging

Cognitive decline is a common concern for an aging population, in which the growing rate of Alzheimer’s disease and dementia has led researchers to look for ways to prevent cognitive degeneration. By the year 2050, it is estimated that 13 million Americans will have Alzheimer’s disease.1 While hormone replacement therapy is not considered a treatment for cognitive degeneration, it has been considered a benefit for female patients to delay age-related cognitive decline and sustain healthy cognition.2

Estrogen and Cognition

A large concentration of estrogen receptors are found in the hippocampus – an area in the brain that regulates memory and learning.4,5 Estrogen’s role in cognitive function is to support communication between neurons, aid the development of neuronal processes, and sustain the synthesis of neurotransmitters.6,7

Overall, estrogen benefits cognition to:

• Support regulation of the neurotransmitters, acteylcholine and glutamate8

• Improve communication between neurons in the hippocampus2

• Protect nerve cells from free radical and excitotoxin damage9,10

Summary of Estrogen Studies

Several studies have observed the effects of estrogen on cognitive function in older women. Researchers have found that among women who are over 65 years old, those that take estrogen replacement therapy (ERT) perform better on cognitive tests and show less cognitive deterioration over time.11,12,13,14 One study recruited 288 postmenopausal women that were either taking or not taking estrogen replacement therapy.15 Researchers found that women taking ERT had better visual memory when compared to those not taking the treatment. A similar study followed 788 older women for over two years to find that those taking ERT had better cognition than those who were not taking ERT.16 A series of studies found that women had higher scores on verbal and fine motor skills tests when estrogen levels were at their peak in their menstrual cycle. Additionally, these women performed better on speed and accuracy tests.17

The Impact of a Healthy Lifestyle

Estrogen therapy may not be a main treatment for cognitive function, but it can help inhibit memory loss and cognitive impairment in women who already take HRT to treat their menopausal symptoms. It is important for the female patient to recognize that healthy cognitive function comes by living a healthy lifestyle. Along with balancing hormone levels, diet, nutrient supplementation, exercise, staying socially active, and a fascination to continue learning can help prevent age-related cognitive decline.18


  1. Shumaker SA, et al. Conjugated equine estrogens and incidence of probably dementia and mild cognitive impairment in postmenopausal women: women’s health initiative memory study. JAMA. 2004;291(24):2947-58.
  2. 1 Shumaker SA, et al. Conjugated equine estrogens and incidence of probably dementia and mild cognitive impairment in postmenopausal women: women’s health initiative memory study. JAMA. 2004;291(24):2947-58.
  3. 2 Sherwin BB. Estrogen and cognitive functioning in women. Endocrine Reviews. 2003;24(2):133-151.
  4. 3 Jaffe AB, Toron-Allerand CD, Greengard P, Gandy SE. Estrogen regulates metabolism of Alzheimer amyloid B-precursor protein. J Biol Chem. 1994;269:13065-13068.
  5. 4 Gazzaley AH, Weiland NG, McEwen BS, Morrison JH. Differential regulation of NMDAR1 mRNA and protein by estradiol in the rat hippocampus. J Neurosci. 1996;16:6830.
  6. 5 Luine VN. Estradiol increases choline acetyltransferase activity in specific basal forebrain nuclei and projection areas of femail rats. Exp Neurol. 1985;89:484.
  7. 6 Sherwin BB. Can estrogen keep you smart? Evidence from clinical studies. J Psychiatry Neuroscience. 1999;24(4):315-321.
  8. 7 Morley BJ, Rodriguez-Sierra JF, Clough RW. Increase in hypothalamic nicotinic acetylcholine receptors in prepubertal female rats administered estrogen. Brain Res. 1983;278:262.
  9. 8 Luine VN, Khylchevskaya RI, McEwen BS. Effect of gonadal steroids on activities of monoamine oxidase and choline acetylase in rat brain. Brain Res. 1975;86:293–306.
  10. 9 McEwen BS. Clinical review 108: The molecular and neuroanatomical basis for estrogen effects in the central nervous system. J Clin Endocrinol Metab. 1999;84:1790.
  11. 10 McEwen BS. Estrogen action throughout the brain. Recent Prog Horm Res. 2002;57:357–384.
  12. 11 Yaffe K, Lui L, Grady D, Cauley J, et al. Cognitive decline in women in relation to non-protein-bound oestradiol concentrations. Lancet. 2000;356:708-712.
  13. 12 Matthews K, Cauley J, Yaffe K, Zmuda JM. Estrogen replacement therapy and cognitive decline in older community women. J Am Geriatr Soc. 1999;47:518-523.
  14. 13 Grodstein F, Chen J, Pollen DA, Albert MS, et al. Postmenopausal hormone therapy and cognitive function in healthy older women. J Am Geriatr Soc. 2000;49:746-752.
  15. 14 Rice MM, Graves AB, McCurry SM, Gibbons LE, 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. 2000;160:1641-1649.
  16. 15 Resnick SM, Metter EJ, Zonderman AB. Estrogen replacement therapy and longitudinal decline in visual memory. A possible protective effect? Neurology. 1997 Dec;49(6):1491-1497.
  17. 16 Jacobs DM, Tang MX, Stern Y, Sano M, et al. Cognitive function in nondemented older women who took estrogen after menopause. Neurology. 1008 Feb;50(2):368-373.
  18. 17 Hampson E, Kimura D. Cognitive pattern in men and women is influenced by fluctuations in sex hormones. Curr Dir in Psychol Sci. 1994;3:57-61.
  19. 18 Fillit HM, Butler RN, OConnell AW, et al. Achieving and maintaining cognitive vitality with aging. Mayo Clin Proc. 2002;77:681-696.

Share this post

Comments (2)

  • Dr. Sean Breen Reply

    Great post. Did the effect on cognition depend on the route of administration? Or are oral and trans-dermal equally effective? Thanks! Dr. Breen

    October 10, 2012 at 11:35 pm
    • Neal Rouzier Reply

      That is an excellent question. The average reader might ask why that question was asked. However only someone that had insight and understanding into the complexity of HRT would ask that type of question. And Sean does. The answer to the question is that we don’t know which had the better effect, oral or transdermal, because that was not studied. There are few head to head comparison studies of oral vs transdermal and therefore this question cannot be answered directly as this was a summation of many different studies. However if you were to look at the studies referenced, most of the studies evaluated Premarin in the oral form. Very few studies use the transdermal for studies.

      In the upcoming Part III course next weekend we will look at all the comparison studies to help decide which estrogen might be the better choice for cognitive protection. There are 2 major disease processes that affect memory and cognition: Alzheimer’s disease, which is plaque deposition on the nerves, and vascular dementia which affects plaque deposition in the arteries of the brain. Seeing that vascular dementia is more common than Alzheimer’s dementia, then we would have to look at which estrogen is better in protecting against CAD, CVD, and atherosclerosis. As we will see in Part III, the oral form is much better at protecting against plaque deposition than is transdermal. Oral estrogen is worse at causing thrombus in the arteries of the brain in older women greater than 63 years of age. So excluding women from this group that could get worse from oral estrogen, then oral estrogen would be the preferred form to prevent vascular dementia. In head to head studies, oral by far and above is better for long term vascular protection due to an increase in HDL cholesterol, a decrease in LDL cholesterol, an increase in the good lipoproteins like apolipoprotein A, and a decrease in the bad apolipoprotein B. Oral estrogen causes an increase in SHBG which protects against CAD and CVD. Most importantly, oral increases production of fatty acid esthers which prevent plaque formation at the blood vessel. Transdermal estrogen does none of the above. The recent results of the KRONOS study just released showed the same benefit of oral over transdermal estrogen. In part III next weekend we will look at all the studies showing better cardiovascular and therefore better cerebrovascular protection than transdermal.
      In conclusion oral provides much better protection against atherosclerosis than does transdermal and therefore would probably provide better cognitive benefits and protection. I have not seen any comparative studies on Alzheimer’s protection between types of estrogen, although the classic Cache County Study utilized Premarin, or oral estrogen, and found a 75% decrease in Alzheimer’s disease with oral estrogen. If you follow scientific reasoning and copy what the scientific studies show, then oral is the way to go unless there is some contraindication due to clotting, etc. Hope that helps provide insight as to which is better. Sean, see you in Part III.
      Best, Neal

      October 12, 2012 at 12:51 am

Leave a comment

Your email address will not be published.