Cognition, mood, and physiological concentrations of sex hormones in the early and late postmenopause

Significance Hormone variations after menopause may influence brain processes concerned with cognition and mood. Effects may differ for exposures near menopause compared with much later. We addressed this prediction using serum concentrations of endogenous estradiol, estrone, progesterone, and testosterone in 643 healthy women not using hormone therapy (early group, <6 y after menopause; late group, 10+ y). In combined analyses, hormone levels were unrelated to verbal memory, executive functions, global cognition, or mood. For serum estradiol (our primary focus), the relation did not differ between postmenopause groups. In early group women, progesterone levels were associated with better memory and global cognition; this finding merits additional study. Results help clarify cognitive effects of physiological concentrations of sex steroids after menopause. Variations in the hormonal milieu after menopause may influence neural processes concerned with cognition, cognitive aging, and mood, but findings are inconsistent. In particular, cognitive effects of estradiol may vary with time since menopause, but this prediction has not been assessed directly using serum hormone concentrations. We studied 643 healthy postmenopausal women not using hormone therapy who were recruited into early (<6 y after menopause) and late (10+ y after menopause) groups. Women were administered a comprehensive neuropsychological battery and assessed with the Center for Epidemiologic Studies Depression Scale. They provided serum for free estradiol, estrone, progesterone, free testosterone, and sex hormone binding globulin measurements. Cognitive outcomes were standardized composite measures of verbal episodic memory, executive functions, and global cognition. Covariate-adjusted linear regression analyses were conducted for each hormone separately and after adjustment for other hormone levels. Endogenous sex steroid levels were unassociated with cognitive composites, but sex hormone binding globulin was positively associated with verbal memory. Results for early and late groups did not differ significantly, although progesterone concentrations were significantly positively associated with verbal memory and global cognition in early group women. Hormone concentrations were not significantly related to mood. Results fail to support the hypothesis that temporal proximity to menopause modifies the relation between endogenous serum levels of estradiol and verbal memory, executive functions, or global cognition. Physiological variations in endogenous postmenopausal levels of sex steroid hormones are not substantially related to these aspects of cognition or mood; positive associations for progesterone and sex hormone binding globulin merit additional study.

[1]  D. Wright,et al.  Progesterone's role in neuroprotection, a review of the evidence , 2013, Brain Research.

[2]  M. Baudry,et al.  Progesterone–estrogen interactions in synaptic plasticity and neuroprotection , 2013, Neuroscience.

[3]  C. Pike,et al.  Gender, sex steroid hormones, and Alzheimer's disease , 2013, Hormones and Behavior.

[4]  J. M. Daniel,et al.  Estrogens, estrogen receptors, and female cognitive aging: The impact of timing , 2013, Hormones and Behavior.

[5]  Nick C Fox,et al.  Clinical and biomarker changes in dominantly inherited Alzheimer's disease. , 2012, The New England journal of medicine.

[6]  L. Dennerstein,et al.  Hormone levels and cognitive function in postmenopausal midlife women , 2012, Neurobiology of Aging.

[7]  V. Henderson,et al.  Long-term soy isoflavone supplementation and cognition in women , 2012, Neurology.

[8]  T. Foster.  Role of estrogen receptor alpha and beta expression and signaling on cognitive function during aging , 2012, Hippocampus.

[9]  V. Henderson,et al.  Effects of endogenous and exogenous estrogen exposures in midlife and late-life women on episodic memory and executive functions , 2011, Neuroscience.

[10]  J. Morrison,et al.  Interactive effects of age and estrogen on cortical neurons: implications for cognitive aging , 2011, Neuroscience.

[11]  Dong-Sun Han,et al.  C terminus of Hsc70-interacting protein (CHIP)-mediated degradation of hippocampal estrogen receptor-α and the critical period hypothesis of estrogen neuroprotection , 2011, Proceedings of the National Academy of Sciences.

[12]  E. Levin.  Minireview: Extranuclear steroid receptors: roles in modulation of cell functions. , 2011, Molecular endocrinology.

[13]  Wendy W. Wu,et al.  Ovarian Hormone Deficiency Reduces Intrinsic Excitability and Abolishes Acute Estrogen Sensitivity in Hippocampal CA1 Pyramidal Neurons , 2011, The Journal of Neuroscience.

[14]  L. McMahon,et al.  Duration of estrogen deprivation, not chronological age, prevents estrogen's ability to enhance hippocampal synaptic physiology , 2010, Proceedings of the National Academy of Sciences.

[15]  R. Mayeux,et al.  Sex hormone binding globulin and incident Alzheimer’s disease in elderly men and women , 2010, Neurobiology of Aging.

[16]  J. Morrison,et al.  Estrogen and the aging brain: an elixir for the weary cortical network , 2010, Annals of the New York Academy of Sciences.

[17]  J. Janowsky,et al.  Association between sex steroids and cognition in elderly men , 2010, Clinical endocrinology.

[18]  J. Bohacek,et al.  Transient estradiol exposure during middle age in ovariectomized rats exerts lasting effects on cognitive function and the hippocampus. , 2010, Endocrinology.

[19]  E. Barrett-Connor,et al.  Endogenous oestrogens predict 4‐year decline in verbal fluency in postmenopausal women: the Rancho Bernardo Study , 2010, Clinical endocrinology.

[20]  B. Sherwin.  Estrogen therapy: is time of initiation critical for neuroprotection? , 2009, Nature Reviews Endocrinology.

[21]  C. Frye.  Progestogens influence cognitive processes in aging. , 2009, Future medicinal chemistry.

[22]  Larry R Squire,et al.  Memory and Brain Systems: 1969–2009 , 2009, The Journal of Neuroscience.

[23]  H. Burger,et al.  A prospective study of the association between endogenous hormones and depressive symptoms in postmenopausal women , 2009, Menopause.

[24]  Robert Detrano,et al.  Subclinical atherosclerosis is weakly associated with lower cognitive function in healthy hyperhomocysteinemic adults without clinical cardiovascular disease , 2009, International journal of geriatric psychiatry.

[25]  G. Guerriero.  Vertebrate Sex Steroid Receptors: Evolution, Ligands, and Neurodistribution , 2009, Annals of the New York Academy of Sciences.

[26]  G. Jirikowski,et al.  Sex Hormone Binding Globulin and Aging , 2008, Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme.

[27]  M. Ogiue-Ikeda,et al.  Estrogen synthesis in the brain—Role in synaptic plasticity and memory , 2008, Molecular and Cellular Endocrinology.

[28]  Richard F. Thompson,et al.  Progesterone receptors: Form and function in brain , 2008, Frontiers in Neuroendocrinology.

[29]  B. McEwen,et al.  Uncovering the mechanisms of estrogen effects on hippocampal function , 2008, Frontiers in Neuroendocrinology.

[30]  K. Matthews,et al.  Depressive symptoms during the menopausal transition: the Study of Women's Health Across the Nation (SWAN). , 2007, Journal of affective disorders.

[31]  Anne B. Newman,et al.  Associations between sex steroid hormone levels and depressive symptoms in elderly men and women: Results from the Health ABC study , 2007, Psychoneuroendocrinology.

[32]  G. Meyer,et al.  Distribution patterns of estrogen receptor α and β in the human cortex and hippocampus during development and adulthood , 2007 .

[33]  J. Bohacek,et al.  Increased daily handling of ovariectomized rats enhances performance on a radial-maze task and obscures effects of estradiol replacement , 2007, Hormones and Behavior.

[34]  J. Morrison,et al.  Interactive effects of age and estrogen on cognition and pyramidal neurons in monkey prefrontal cortex , 2007, Proceedings of the National Academy of Sciences.

[35]  M. Schumacher,et al.  Novel perspectives for progesterone in hormone replacement therapy, with special reference to the nervous system. , 2007, Endocrine reviews.

[36]  A. Herlitz,et al.  Endogenous estrogen is not associated with cognitive performance before, during, or after menopause , 2007, Menopause.

[37]  T. Seeman,et al.  Menopause transition stage and endogenous estradiol and follicle-stimulating hormone levels are not related to cognitive performance: cross-sectional results from the study of women's health across the nation (SWAN). , 2007, Journal of women's health.

[38]  S. Cummings,et al.  Endogenous sex hormone levels and risk of cognitive decline in an older biracial cohort , 2007, Neurobiology of Aging.

[39]  S. MacDonald,et al.  The association between endogenous free testosterone and cognitive performance: A population-based study in 35 to 90 year-oldmen and women , 2006, Psychoneuroendocrinology.

[40]  M. Sammel,et al.  Associations of hormones and menopausal status with depressed mood in women with no history of depression. , 2006, Archives of general psychiatry.

[41]  V. W. Henderson,et al.  Estrogen-containing hormone therapy and Alzheimer’s disease risk: Understanding discrepant inferences from observational and experimental research , 2006, Neuroscience.

[42]  H. Bernstein,et al.  Identification of Sex Hormone-Binding Globulin in the Human Hypothalamus , 2005, Neuroendocrinology.

[43]  D. Grobbee,et al.  Endogenous oestrogens are related to cognition in healthy elderly women , 2005, Clinical endocrinology.

[44]  P. Leedman,et al.  Association between physiological serum concentration of estrogen and the mental health of community-dwelling postmenopausal women age 70 years and over. , 2005, The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry.

[45]  K. Frick,et al.  Environmental enrichment reduces the mnemonic and neural benefits of estrogen , 2004, Neuroscience.

[46]  D. Korol.  Role of estrogen in balancing contributions from multiple memory systems , 2004, Neurobiology of Learning and Memory.

[47]  B. Shaywitz,et al.  Better oral reading and short-term memory in midlife, postmenopausal women taking estrogen , 2003, Menopause.

[48]  E. Dudley,et al.  Estrogen exposures and memory at midlife , 2003, Neurology.

[49]  Albert Hofman,et al.  Higher estrogen levels are not associated with larger hippocampi and better memory performance. , 2003, Archives of neurology.

[50]  J. Buckwalter,et al.  Associations between circulating sex steroid hormones and cognition in normal elderly women , 2000, Neurology.

[51]  E. Barrett-Connor,et al.  Cognitive Function and Endogenous Sex Hormones in Older Women , 1999, Journal of the American Geriatrics Society.

[52]  E. Barrett-Connor,et al.  Endogenous Levels of Dehydroepiandrosterone Sulfate, but Not Other Sex Hormones, Are Associated with Depressed Mood in Older Women: The Rancho Bernardo Study , 1999, Journal of the American Geriatrics Society.

[53]  K. Yaffe,et al.  Serum Estrogen Levels, Cognitive Performance, and Risk of Cognitive Decline in Older Community Women , 1998, Journal of the American Geriatrics Society.

[54]  B. Sherwin,et al.  "Add-back" estrogen reverses cognitive deficits induced by a gonadotropin-releasing hormone agonist in women with leiomyomata uteri. , 1997, The Journal of clinical endocrinology and metabolism.

[55]  V. Henderson,et al.  The Effects of Hormone Replacement Therapy, Lipoprotein Cholesterol Levels, and Other Factors on a Clock Drawing Task in Older Women , 1996, Journal of the American Geriatrics Society.

[56]  D L Patrick,et al.  Screening for depression in well older adults: evaluation of a short form of the CES-D (Center for Epidemiologic Studies Depression Scale). , 1994, American journal of preventive medicine.

[57]  D. Bayliss,et al.  The androgen-binding protein gene is expressed in male and female rat brain. , 1990, Endocrinology.

[58]  R. Brinton,et al.  Estrogen regulation of mitochondrial bioenergetics: implications for prevention of Alzheimer's disease. , 2012, Advances in pharmacology.

[59]  Richard F. Thompson,et al.  Regulation of hippocampal synaptic plasticity by estrogen and progesterone. , 2010, Vitamins and hormones.

[60]  Francisco J. López,et al.  Distribution patterns of estrogen receptor alpha and beta in the human cortex and hippocampus during development and adulthood. , 2007, The Journal of comparative neurology.