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Estrogen, Gender and Aging effects on Central Nervous System Physiology

by Timothy Bilash MD, MS
September 2003

based on
Neuroimaging of aging and estrogen effects on central nervous system physiology
Yolanda R. Smith, M.D. and Jon-Kar Zubieta, M.D., Ph.D.
Fertility and Sterility Vol76, No4, October 2001:651-659

  3. REGIONAL BLOOD FLOW AND METABOLISM (Language, Visual-spatial with Age and Gender)


    1. Estrogen appears to modulate nerve growth factor, to have effects on neuronal survival and repair, and to induce neuronal plasticity.
      1. Cholinergic neurons, thought to be of importance in memory consolidation among other functions, coexpress E and nerve growth factor receptors, which are modulated by E.
      2. Exposing neurons to E in culture appears to increase their branching and synaptic microspikes.

    2. Estrogen receptors
      1. Estrogen ER-alpha subtype shows highest level of expression in the amygdala, hypothalamus, and subfields of the hippocampal formation.
      2. Estrogen ER-beta subtype is most abundant in the hippocampal formation, claustrum, and the cerebral cortex.

    3. Improved cognition: A number of reports have demonstrated improved cognitive status with E therapy in healthy postmenopausal women.
      1. Clinical trials have suggested that estrogen may reduce the rate of cognitive decline in memory-impaired postmenopausal women and improve the effectiveness of tacrine, a cholinesterase enzyme inhibitor used in the treatment of Alzheimer's disease.
      2. Mild-to-moderate Alzheimer's disease did respond to estrogen in a multicenter trial.
      3. Estrogen favors soluble forms of amyloid that are less likely to precipitate and cause placques in the brain.
      4. E has antioxidant and anti-inflammatory properties.


    1. MRI studies show overall brain volume and cerebrospinal fluid volume are greater in men than in women.
      1. Mainly due to white matter volume, which appears larger in men.
      2. Women have higher proportions of gray matter to whole brain volume.

    2. Women have a larger splenium of the corpus callosum, which may indicate greater interhemispheric connectivity.

    3. Men have show greater age-related loss of volume than women, particularly in the frontal and temporal lobes, in gray matter and more in left hemisphere. Women have more symmetrical age-related atrophy.

    4. In the Austrian Stroke Prevention Study (1996), there was an association between ERT and better cognitive functioning in postmenopausal women taking estrogen, although there was no association between the actual duration of E therapy and cognitive functioning, just whether they were on it.
      1. However, MRI scans revealed a lower rate, size and extent of white matter hyperintensities in women treated with E which was less with longer duration of E therapy. This is thought to reflect less ischemic brain damage in E users.

  3. REGIONAL BLOOD FLOW AND METABOLISM (Language, Visual-spatial with Age and Gender)

    1. Functional MRI uses labeled markers to measure magnetic field changes associated with the deoxygenation of hemoglobin. A more active brain area is indicated by less deoxyhemoglobin due to increased local blood flow and increased oxyhemoglobin. These techniques is thought to reflect synaptic activity, mapping activated or inactivated neuronal groups.

    2. Age

      1. Age is associated with a reduction in regional cerebral blood flow and glucose metabolism, affecting the frontal and temporal lobes, with differences in the activation patterns of younger versus older adults. Age was associated with a decrease in glucose metabolism of the whole brain, frontal, temporal and parietal areas.

        1. These decreases were asymmetric in the frontal lobes (more asymmetric in men) and in language areas. Women showed greater age declines in the thalamus and hippocampus. The first areas are critical to cognitive functioning and second to memory processing. [Murphy et al 1996]

        2. Brain cytosolic choline uptake was decreased after oral injection of choline was demonstrated in older individuals (16%) compared with younger (60%) using proton magnetic resonance spectroscopy. Choline is primarily provided by the diet, and is essential for the production of acetylcholine, cellular membrane components and second messenger systems.

        3. N-acetyl aspartate levels decrease with age in the hippocampus using proton magnetic resonance spectroscopy.

    3. Gender

      1. Women show a higher resting global cerebral blood flow, as well as higher regional cerebral blood flow in response to tasks that activate prefrontal cortical regions, depending on the specific task
        1. Women primarily activate the right parietal and right prefrontal cortex and men activate the left hippocampus on visual-spatial tasks.
        2. The data suggests that sex differences in the function of the temporal lobes could underlie the variations seen in verbal memory measures. [Ragland et al 2000 PET]

          1. Women showed higher scores in the immediate recall of verbal material, with higher blood flow in the mid-temporal regions bilaterally.

          2. Womens immediate and delayed recall in verbal tests correlated with greater cerebral blood flow in the left relative to right temporal lobe, where as mens did not.

        3. Women showed bilateral and symmetrical activation of the premotor cortex during performance of a tactile discrimination task compared to men.

      2. Men regionally show higher metabolism in the temporal limbic areas and in the cerebellum, and lower metabolism in the cingulate cortex. There are hemispheric (left/right) differences seen as well. [Gur et al 1995 PET]

      3. No gender differences in brain activation were found during a language comprehension task.


    1. Women activate a larger number of regions, especially the anterior cingulate and prefrontal cortical areas, in response to the experience of transient sadness.

    2. In women, the Cingulate gyrus, an association cortical area involved in the regulation of emotion and cognitive functions, demonstrates higher N-acetyl aspartate values in women by proton magnetic resonance spectroscopy.
      1. N-acetyl aspartate, choline and other metabolites are also higher in cortical areas of healthy young women compared to men. [Grachev et al 1999]

    3. Men but not in women show increases in signal from the amygdala region during performance of a transient sadness task. [Schneider et al 2000]


    1. Animal studies in rodents show that Estradiol (E2) has direct effects on brain glucose metabolsm, increasing it diffusely in cortical and subcortical areas.

    2. Cerebral and Cerebellar blood flow in postmenopausal women increased when ERT was resumed after halting it for 4 weeks. Three of five control patients who did not restart ERT actually had a decrease in cerebral blood flow. [Okura et al 1995 SPECT, small sample size restricted to global measures]

    3. Premenopausal women with induced menopause by GNRH agonist who received either E2 or P for 4-5 weeks in a double-blind crossover design, studied with PET. [Berman et al 1997]

      1. Without estrogen, regional cerebral blood flow was attenuated in prefrontal cortical structures during the Wisconsin Card Sort Test. This task is known to activate dorsilateral prefrontal, parietal, and temporal cortices.

      2. Replacement with either Estrogen or Progesterone restored the typical pattern of cortical activation during the task.

    4. Regional cerebral blood flow activation patterns were significantly different with or without ERT (independent of progestin) during memory tasks. [Baltimore Longitudinal Study of Aging 1998, PET & MRI]

      1. MRI scans showed no differences in regional brain volumes or ventricular size to account for differences.

      2. Users
        1. ERT users showed better performance on figural and verbal memory neurophysiologcal tests.

        2. ERT users had greater regional activation of the right inferior parietal region and deactivation of the right parahippocampal gyrus.

        3. ERT users had greater deactivation in the right hippocampal gyrus, precuneus, and dorsal frontal gyrus.

      3. Nonusers
        1. Nonusers had greater activation of the right inferior frontal cortex and deactivation of the left hypotahlamus.

        2. Nonusers had greater activation of the left anterior thalamus and a region proximal to the right mammilary body.

    5. Estrogen effects on working memory tasks were studied with functional MRI [Shaywitz et al 1999]

      1. Estrogen did not affect the performance of memory tasks.

      2. However, menopausal brain activation patterns were modified by Estrogen.

        1. E sharpened the hemispheric encoding/retrieval asymmetry effect for both verbal and nonverbal tasks.
          1. The left hemisphere showed greater activation during encoding, and the right hemisphere showed greater activation during retrieval.
        2. E increased activation in the inferior parietal lobe and the superior frontal gyrus (phonetic coding).
        3. These are similar to patterns observed in younger women.


    1. Decreased brain mass with aging may reflect general brain atrophy,but the cholinergic system seems especially vulnerable. There are decreases in size, number and function of cholinergic neurons.

    2. This may be related to the uses of choline as a precursor for multiple brain substrates (acetylcholine, phosphatidylcholine, sphingomyelin. and phosphoholipids), resulting in competition for choline which is obtained primarily through the diet.

    3. In Alzheimer's disease, this cholinergic loss is greater than in other neurons.

      1. Cortical losses were related to the severity of the disease. In mild Alzheimer's, presynaptic terminal tracer binding was reduced 30% in the temporal cortex and hippocampus after 65 years of age, and in the entire cortex and hippocampus with onset before 65 years of age. [Kuhl et al 1996 SPECT]

      2. Sex-related differences were seen using nonselective muscarinic cholinergic radiotracers, suggesting women experience faster rates of decline than men with age.

      3. PET studies did not show large changes in acetylcholinesterase activity with normal aging. [Kuhl et al 1999, Namba et al 1999]

      4. Regional binding of radiotracer to cholinergic synapses did not differ in a study of women given HRT versus none since menopause, but localized binding in a number of cortical regions increased with the length of HRT treatment. [Smith et al 2001]

        1. Hormone treatment was associated with higher radiotracer binding in the anterior and posterior cingulate cortex, while no hormone was associated with lower binding in the posterior cingulate cortex (a region associated with the very early stages of Alzheimer's disease).

        2. The younger the age that hormone replacement was initiated, or the longer it was maintained, the higher was the binding.

        3. Women treated with E alone showed higher binding in the posterior cingulate cortex compared to E and P.


    1. Dopamine involved with a number of disorders (psychotic, substance abuse) and in neurogenreative disorders (Parkinson's disease). Dopamine appears to influence motor and cognitive performance, and dopamine function may be inluenced by gonadal steroids.

    2. Caudate/cerebellar dopamine and frontal/cerebellar dopamine receptor ratios declined with age in men and women. There were some sex-related differences and changes with menstrual phase. [Wong et al 1984, 1988]


    1. Dysfunction in the seratonin system has been implicated in mood disorders, reaction to stress, and the effect of antidepressants.

    2. Gender differences have been seen in brain uptake of tryptophan, but with both increase and decrease in different studies. Data suggests that this reflects tryptophan transport across the blood-brain barrier rather than seratonin synthesis.

    3. Higher seratonin agonist binding was found in men compared to women in most cortical areas except for the occipital cortex, and especially in the frontal and cingulate cortices. Another study did not replicate this.

    4. In human subjects, 2-6 weeks of E2 + P was associated with increases in seratonin 2A receptor-binding estimates in neocortical regions. 8-14 weeks of E2 alone was not.


    1. Brain metabolic response to alpha2 antagonist was more pronounced in women than in men, involving numerous cortical and subcortical regions. [Schmidt et al 1997]


    1. Mu-opioid receptor binding increases with age in neocortical areas and the putamen of humans.

    2. There are sex differences in these age-associated changes: [Zubieta et al 1999]

      1. Higher binding is seen in the amygdala, thalamus, and cerebellum in women as opposed to men.

      2. Binding declines after the menopause in the amygdala and thalamus.

      3. E2 Levels and LH pulsatility are correlated with mu-opioid receptor binding in some brain regions (amygdala, thalamus).

      4. Opioid system in animals is sexually dimorphic in regions of the hypothalamus.

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