Skip to main content

Advertisement

Log in

Involvement of Luteinizing Hormone in Alzheimer Disease Development in Elderly Women

  • Review
  • Published:
Reproductive Sciences Aims and scope Submit manuscript

Abstract

Alzheimer disease (AD) is a slow progressive neurodegenerative disease that affects more elderly women than elderly men. It impairs memory, typically progresses into multidomain cognitive decline that destroys the quality of life, and ultimately leads to death. About 5.3 million older Americans are now living with this disease, and this number is projected to rise to 14 million by 2050. Annual health-care costs in the United States alone are projected to increase to about US$1.1 trillion by 2050. The initial theory that decreasing estrogen levels leads to AD development in postmenopausal women has been proven inconclusive. For example, Women’s Health Research Initiative Memory Study and the population-based nested case-control study have failed to demonstrate that estrogen/progesterone (hormone replacement therapy [HRT]) or estrogen replacement therapy could prevent the cognitive decline or reduce the risk of AD. This led to the realization that AD development could be due to a progressive increase in luteinizing hormone (LH) levels in postmenopausal women. Accordingly, a large number of studies have demonstrated that an increase in LH levels is positively correlated with neuropathological, behavioral, and cognitive changes in AD. In addition, LH has been shown to promote amyloidogenic pathway of precursor protein metabolism and deposition of amyloid β plaques in the hippocampus, a region involved in AD. Cognate receptors that mediate LH effects are abundantly expressed in the hippocampus. Reducing the LH levels by treatment with gonadotropin-releasing hormone agonists could provide therapeutic benefits. Despite these advances, many questions remain and require further research.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Alzheimer’s Society. What is Alzheimer’s disease? 2014. Web site. www.alzheimers.org.uk/site/scripts/documents_info.php?documentID=100. Accessed October 3, 2015.

    Google Scholar 

  2. Center for Disease Control and Prevention. Alzheimer’s disease. 2015. Web site. http://www.cdc.gov/aging/aginginfo/alzheimers.htm. Updated March 5, 2015. Accessed October 3, 2015.

    Google Scholar 

  3. Alzheimer’s Organization. 2015 Alzheimer’s Disease Facts and Figures. 2016. Web site. http://www.alz.org/facts/downloads/facts_figures_2015.pdf. Updated January 2016. Accessed March 7, 2016.

    Google Scholar 

  4. Gao S, Hendrie HC, Hall KS, Hui S. The relationships between age, sex, and the incidence of dementia and Alzheimer disease: a meta-analysis. Arch Gen Psychiatry. 1998;55(9):809–815.

    CAS  PubMed  Google Scholar 

  5. Wang YC, Pamplin J, Long MW, Ward ZJ, Gortmaker SL, Andreyeva T. Severe obesity in adults cost state medicaid programs nearly $8 billion in 2013. Health Aff. 2015;34(11):1923–1931.

    Google Scholar 

  6. Biessels GJ, Reijmer YD. Brain changes underlying cognitive dysfunction in diabetes: what can we learn from MRI? Diabetes. 2014;63(7):2244–2252.

    PubMed  Google Scholar 

  7. Suzuki N, Cheung TT, Cai XD, et al. An increased percentage of long amyloid beta protein secreted by familial amyloid beta protein precursor (beta APP717) mutants. Science. 1994;264(5463):1336–1340.

    CAS  PubMed  Google Scholar 

  8. Scheuner D, Eckman C, Jensen M, et al. Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer’s disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer’s disease. Nat Med. 1996;2(8):864–870.

    CAS  PubMed  Google Scholar 

  9. Burnham SC, Faux NG, Wilson W, et al. A blood-based predictor for neocortical Aβ burden in Alzheimer’s disease: results from the AIBL study. Mol Psych. 2014;19(4):519–526.

    CAS  Google Scholar 

  10. Herbert LE, Scherr PA, Bienias HL, Bennett DA, Evans DA. Alzheimers disease in the US population: prevalence estimates using the 2000 census. Arch Neurol. 2003;60(8):1119–1122.

    Google Scholar 

  11. Stefanacci RG. The costs of Alzheimer’s disease and the value of effective therapies. Am J Manage Care. 2011;17(suppl 13):S356–S362.

    Google Scholar 

  12. Bates KA, Verdile G, Li QX, et al. Clearance mechanisms of Alzheimer’s amyloid-beta peptide: implications for therapeutic design and diagnostic tests. Mol Psychiatry. 2009;14(5):469–486.

    CAS  PubMed  Google Scholar 

  13. Walsh DM, Teplow DB. Alzheimer’s disease and the amyloid beta-protein. Prog Mol Biol Transl Sci. 2012;107:101–124.

    CAS  PubMed  Google Scholar 

  14. Goedert M, Jakes R, Crowther RA, et al. The abnormal phosphorylation of tau protein at Ser-202 in Alzheimer disease recapitulates phosphorylation during development. Proc Natl Acad Sci U S A. 1993;90(11):5066–5070.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Ittner A, Yazi DK, van Eersel J, Gladbach A, Gotz J, Ittner LM. Brief update on different roles of tau in neurodegeneration. IUBMB Life. 2011;63(7):495–502.

    CAS  PubMed  Google Scholar 

  16. Hyman B. Untangling tau. Translational Sci. 2016;1:20–21.

    Google Scholar 

  17. Goldgaber D, Lerman MI, McBride WO, Saffiotti Y, Gajdusek DC. Isolation, characterization, and chromosomal localization of human brain cDNA clones coding for the precursor of the amyloid of brain in Alzheimer’s disease, Down’s syndrome and aging. J Neural Transm Suppl. 1987;24:23–28.

    CAS  PubMed  Google Scholar 

  18. Verdile G, Asih PR, Barron AM, Wahjoepramono EJ, Ittner LM, Martins RN. The impact of luteinizing hormone and testosterone on beta amyloid (Aβ) accumulation: animal and human clinical studies. Horm Behav. 2015;76:81–90.

    CAS  PubMed  Google Scholar 

  19. Xu H, Gouras GK, Greenfield JP, et al. Estrogen reduces neuronal generation of Alzheimer beta-amyloid peptides. Nat Med. 1998;4(4):447–451.

    CAS  PubMed  Google Scholar 

  20. Gouras GK, Xu H, Gross RS, et al. Testosterone reduces neuronal secretion of Alzheimer’s beta-amyloid peptides. Proc Natl Acad Sci U S A. 2000;97(3):1202–1205.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Bowen RL, Verdile G, Liu T, et al. Luteinizing hormone, a reproductive regulator that modulates the processing of amyloid-β precursor protein and amyloid-β deposition. J Biol Chem. 2004;279(19):20539–20545.

    CAS  PubMed  Google Scholar 

  22. Saberi S, Du YP, Christie M, Goldsburry C. Human chorionic gonadotropin increases β-cleavage of amyloid precursor protein in SH-SY5Y cells. Cell Mol Neurobiol. 2013;33(6):747–751.

    CAS  PubMed  Google Scholar 

  23. Pierce JG, Parsons TF. Glycoprotein hormones: structure and function. Ann Rev Biochem. 1981;50:465–495.

    CAS  PubMed  Google Scholar 

  24. Lapthorn AJ, Harris DC, Littlejohn A, et al. Crystal structure of human chorionic gonadotropin. Nature. 1994;369(6480):455–461.

    CAS  PubMed  Google Scholar 

  25. Loosfelt H, Misrahi M, Atger M, et al. Cloning and sequencing of porcine LH-hCG receptor cDNA: variants lacking transmembrane domain. Science. 1989;245(4917):525–528.

    CAS  PubMed  Google Scholar 

  26. McFarland KC, Sprengel R, Phillips HS, et al. Lutropin-choriogonadotropin receptor: an unusual member of the G protein-coupled receptor family. Science. 1989;245(4917):494–499.

    CAS  PubMed  Google Scholar 

  27. Rao CV. There is no turning back on the paradigm shift on the actions of human chorionic gonadotropin and luteinizing hormone. J Reprod Health and Med. 2016;2:4–10.

    Google Scholar 

  28. Lei ZM, Rao ChV, Kornyei JL, Licht P, Hiatt ES. Novel expression of human chorionic gonadotropin/luteinizing hormone receptor gene in brain. Endocrinology. 1993;132(5):2262–2270.

    CAS  PubMed  Google Scholar 

  29. Rao SC, Li X, Rao ChV, Magnuson DSK. Human chorionic gonadotropin/luteinizing hormone receptor expression in the adult rat spinal cord. Neuroscience Lett. 2003;336(3):135–138.

    CAS  Google Scholar 

  30. Meng X-L, Rennert OM, Chan W-Y. Human chorionic gonadotropin induces neuronal differentiation of PC12 cells through activation of stably expressed lutropin/choriogonadotropin receptor. Endocrinology. 2007;148(12):5865–5873.

    CAS  PubMed  Google Scholar 

  31. AL-Hader AA, Tao YX, Lei ZM, Rao ChV. Fetal rat brains contain luteinizing hormone/human chorionic gonadotropin receptors. Early pregnancy. Biol Med. 1997;3(4):323–329.

    CAS  Google Scholar 

  32. Apaja PM, Harju KT, Aatsinki JT, Petaja-Repo UE, Rajaniemi HJ. Identification and structural characterization of the neuronal luteinizing hormone receptor associated with sensory systems. J Biol Chem. 2004;279(3):1899–1906.

    CAS  PubMed  Google Scholar 

  33. AL-Hader AA, Lei ZM, Rao ChV. Neurons from fetal brains contain functional luteinizing hormone/chorionic gonadotropin receptors. Biol Reprod. 1997;56(5):1071–1076.

    CAS  PubMed  Google Scholar 

  34. Al-Hader AA, Lei ZM, Rao ChV. Novel expression of functional luteinizing hormone/chorionic gonadotropin receptors in cultured glial cells from neonatal rat brains. Biol Reprod. 1997;56(2):501–507.

    CAS  PubMed  Google Scholar 

  35. Bhatnagar KP, Li X, Lei ZM, Rao CV. Human pineal luteinizing hormone receptors. Biotech Histochem. 2002;77(4):223–228.

    CAS  PubMed  Google Scholar 

  36. Lei ZM, Rao ChV. Novel presence of luteinizing hormone/human chorionic gonadotropin (hCG) receptors and the down-regulating action of hCG on gonadotropin-releasing hormone gene expression in immortalized hypothalamic GT1-7 neurons. Mol Endocrinol. 1994;8(8):1111–1121.

    CAS  PubMed  Google Scholar 

  37. Huang ZH, Lei ZM, Rao ChV. Immortalized anterior pituitary αT3 gonadotropes contain functional luteinizing hormone/human chorionic gonadotropin receptors. Mol Cell Endocrinol. 1995;114(1-2):217–222.

    CAS  PubMed  Google Scholar 

  38. Mores N, Krsmanovic LZ, Catt KJ. Activation of LH receptors expressed in GnRH neurons stimulates cyclic AMP production and inhibits pulsatile neuropeptide release. Endocrinology. 1996;137(12):5731–5734.

    CAS  PubMed  Google Scholar 

  39. Li X, Lei ZM, Rao ChV. Human chorionic gonadotropin down-regulates the expression of gonadotropin-releasing hormone receptor gene in GT1-7 neurons. Endocrinology. 1996;137(12):899–904.

    CAS  PubMed  Google Scholar 

  40. Zhang W, Lei ZM, Rao ChV. Immortalized hippocampal cells contain functional luteinizing hormone/human chorionic gonadotropin receptors. Life Sci. 1999;65(20):2083–2098.

    CAS  PubMed  Google Scholar 

  41. Hu YL, Lei ZM, Rao ChV. Analysis of the promoter of the luteinizing hormone/human chorionic gonadotropin receptor gene in neuroendocrine cells. Life Sci. 1998;63(24):2157–2165.

    CAS  PubMed  Google Scholar 

  42. Lei ZM, Rao ChV. Cis-Acting elements and trans-acting proteins in the transcriptional inhibition of gonadotropin-releasing hormone gene by human chorionic gonadotropin in immortalized hypothalamic GT1-7 neurons. J Biol Chem. 1997;272(22):14365–14371.

    CAS  PubMed  Google Scholar 

  43. Lei ZM, Rao ChV. Signaling and transacting factors in the transcriptional inhibition of gonadotropin releasing hormone gene by human chorionic gonadotropin in immortalized hypothalamic GT1-7 neurons. Mol Cell Endocrinol. 1995;109(2):151–157.

    CAS  PubMed  Google Scholar 

  44. David MA, Fraschini F, Martini L. Control of LH secretion: role of a “short” feedback mechanisms. Endocrinology. 1966;78(1):55–60.

    CAS  PubMed  Google Scholar 

  45. Molitch M, Edmonds M, Jones EE, Odell WD. Short-loop feedback control of luteinizing hormone in the rabbit. Am J Physiol. 1976;230(4):907–910.

    CAS  PubMed  Google Scholar 

  46. Patritti-Laborde N, Wolfsen AR, Heber D, Odell WD. Site of short-loop feedback for luteinizing hormone. J Clin Invest. 1979;64(4):1066–1069.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Melrose PA. In vitro evidence for short-loop gonadotropin feedback on gonadotropin-releasing hormone neurons harvested from adult male rats. Endocrinology. 1987;121(1):200–204.

    CAS  PubMed  Google Scholar 

  48. Huang ZH, Lei ZM, Rao ChV. Novel independent and synergistic regulation of gonadotropin-α subunit gene by luteinizing hormone/human choriogonadotropin and gonadotropin releasing hormone in the αT3-1 gonadotrope cells. Mol Cell Endocrinol. 1997;130(1-2):23–31.

    CAS  PubMed  Google Scholar 

  49. Licht P, Cao H, Lei ZM, Rao CV, Merz WE. Novel self-regulation of human chorionic gonadotropin biosynthesis in term pregnancy human placenta. Endocrinol. 1993;133(6):3014–3025.

    CAS  Google Scholar 

  50. Webber KM, Stocco DM, Casadesus G, et al. Steroidogenic acute regulatory protein (StAR): evidence of gonadotropin-induced steroidogenesis in Alzheimer disease. Mol Neurodegener. 2006;1:14.

    PubMed  PubMed Central  Google Scholar 

  51. Liu T, Wimalasena J, Bowen RL, Atwood CS. Luteinizing hormone receptor mediates neuronal pregnenolone production via up-regulation of steroidogenic acute regulatory protein expression. J Neurochem. 2007;100(5):1329–1339.

    CAS  PubMed  Google Scholar 

  52. Kim HM, Moon YH. Human chorionic gonadotropin induces nitric oxide synthase mRNA in mouse peritoneal macrophages. Biochem Biophys Res Commun. 1996;229(2):548–552.

    CAS  PubMed  Google Scholar 

  53. Zhang YM, Rao CV, Lei ZM. Functional importance of human monocyte luteinizing hormone and chorionic gonadotropin receptors. J Soc Gynecol Investig. 1999;6. Abstract #6.

  54. Zhang YM, Rao CV, Lei ZM. Macrophages in human reproductive tissues contain luteinizing hormone/chorionic gonadotropin receptors. Am J Reprod Immunol. 2003;49(2):93–100.

    CAS  PubMed  Google Scholar 

  55. Kim HM, Rim HK, Shin T, et al. Human chorionic gonadotropin induces nitric oxide synthesis by murine microglia. Int J Immunopharmacol. 2000;22(6):453–461.

    CAS  PubMed  Google Scholar 

  56. Kawakami M, Sawyer CH. Induction of behavioral and electroencephalographic changes in the rabbit by hormone administration or brain stimulation. Endocrinology. 1959;65:631–643.

    CAS  PubMed  Google Scholar 

  57. Telegdy G, Rozsahegyi. Effect of gonadotropins on extinction of an avoidance conditioned reflex and exploratory behaviors in the rat. Acta Physiol Acad Sci Hung. 1971;40(2):209–214.

    CAS  Google Scholar 

  58. Telegdy G, Rozsahegyi Lissak K. Further data on the effect of human chorionic gonadotrophin on avoidance and exploratory behavior in the rat. Acta Physiol Acad Sci Hung. 1971;40(2):215–220.

    CAS  PubMed  Google Scholar 

  59. Emanuele NV, Tentler J, Metcalfe L, et al. Intracerebroventricular luteinizing hormone (LH) depresses feeding in male rats. Neuroendocrinol Lett. 1991;13(6):413–418.

    CAS  Google Scholar 

  60. Toth P, Lukacs H, Hiatt ES, Reid KH, Iyer V, Rao ChV. Administration of human chorionic gonadotropin affects sleep-wake phases and other associated behaviors in cycling female rats. Brain Res. 1994;654(2):181–190.

    CAS  PubMed  Google Scholar 

  61. Lukacs H, Hiatt ES, Lei ZM, Rao ChV. Peripheral and intracerebroventricular administration of human chorionic gonadotropin alters several hippocampus-associated behaviors in cycling female rats. Horm Behav. 1995;29(1):42–58.

    CAS  PubMed  Google Scholar 

  62. Thompson DA, Othman MI, lei ZM, et al. Localization of receptors for luteinizing hormone/chorionic gonadotropin in neural retina. Life Sci. 1998;63(12):1057–1064.

    CAS  PubMed  Google Scholar 

  63. Dukic-Stefanovic S, Walther J, Wosch S, et al. Chorionic gonadotropin and its receptor are both expressed in human retina, possible implications in normal and pathological conditions. PloS One. 2012;7(12):e52567–e52567.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Elman J, Capriolo J, Sears M, Mead A, Rubin P. Chorionic gonadotropin decreases intraocular pressure and aqueous humor flow in rabbit eyes. Invest Ophthalmol Vis Sci. 1987;28(1):197–200.

    CAS  PubMed  Google Scholar 

  65. Carmichael DN, Morgan NG, Scarpello JHB. Human chorionic-gonadotropin stimulates the growth of retinal vascular cells. Diabetologia. 1994;38:A275.

    Google Scholar 

  66. Patil A, Fillmore K, Valentine J, Hill D. The study of the effect of human chorionic gonadotrophic (hCG) hormone on the survival of adrenal medulla transplant in brain. Preliminary study. Acta Neurochir. 1987;87(1-2):76–78.

    CAS  PubMed  Google Scholar 

  67. Patil AA, Nagaraj MP. The effect of human chorionic gonadotropin (hCG) on functional recovery of spinal cord sectioned rats. Acta Neurochir. 1983;69(3-4):205–218.

    CAS  PubMed  Google Scholar 

  68. Garcia-Segura LM, Azcoitia L, DonCarlos LL. Neuroprotection by estradiol. Prog Neurobiol. 2001;63(1):29–60.

    CAS  PubMed  Google Scholar 

  69. Norbury R, Cutter WJ, Compton J, et al. The neuroprotective effects of estrogen on the aging brain. Exp Gerontol. 2003;38(1-2):109–117.

    CAS  PubMed  Google Scholar 

  70. Pike CJ, Carroll JC, Rosario ER, Barron AM. Protective actions of sex steroid hormones in Alzheimer’s disease. Front Neuroendocrinol. 2009;30(2):239–258.

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Jaffe AB, Toran-Allerand CD, Greengard P, Gandy SE. Estrogen regulates metabolism of Alzheimer amyloid beta precursor protein. J Biol Chem. 1994;269(18):13065–13068.

    CAS  PubMed  Google Scholar 

  72. Chang D, Kwan J, Timiras PS. Estrogens influence growth, maturation, and amyloid beta-peptide production in neuroblastoma cells and in beta-APP transfected kidney 293 cell line. Adv Exp Med Biol. 1997;429:261–271.

    CAS  PubMed  Google Scholar 

  73. Zhang Y, Champagne N, Beitel LJ, Goodyer CG, Trifiro M, LeBlanc A. Estrogen and androgen protection of human neurons against intracellular amyloid beta1-42 toxicity through heat shock protein 70. J Neurosci. 2004;24(23):5315–5321.

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Paganini-Hill A, Henderson VW. Estrogen deficiency and risk of Alzheimer disease in women. Am J Epidemiol. 1994;140(3):256–261.

    CAS  PubMed  Google Scholar 

  75. Fillit H. Estrogens in the pathogenesis and treatment of Alzheimer’s disease in postmenopausal women. Ann N Y Acad Sci. 1994;743:233–239.

    CAS  PubMed  Google Scholar 

  76. Tang MX, Jacobs D, Stern Y, et al. Effects of oestrogen during menopause on risk and age at onset of Alzheimer’s disease. Lancet. 1996;348(9025):429–432.

    CAS  PubMed  Google Scholar 

  77. Birge SJ. The role of estrogen in the treatment and prevention of dementia: introduction. Am J Med. 1997;103(3A):1S–2S.

    CAS  PubMed  Google Scholar 

  78. Kawas C, Resnick S, Morrison A, et al. A prospective study of estrogen replacement therapy and the risk of developing Alzheimer’s disease: the Baltimore longitudinal study of aging. Neurology. 1997;48(6):1517–1521.

    CAS  PubMed  Google Scholar 

  79. Polo-Kantola P, Portin R, Polo O, Helenius H, Irjala K, Erkkola R. The effect of short-term estrogen replacement therapy on cognition: a randomized, double blind, cross-over trial in postmenopausal women. Obstet Gynecol. 1998;91(3):449–466.

    Google Scholar 

  80. Jacobs DM, Tang MX, Stern Y, et al. Cognitive function in nondemented older women who took estrogen after menopause. Neurology. 1998;50(2):368–373.

    CAS  PubMed  Google Scholar 

  81. Rissanen A, Puolivali J, van Groen T, Riekkinen P. In mice tonic estrogen replacement therapy improves non-spatial and spatial memory in a water maze task. Neuroreport. 1999;10(6):1369–1372.

    CAS  PubMed  Google Scholar 

  82. Bimonte HA, Denenberg VH. Estradiol facilitates performance as working memory load increases. Psychoneuroendocrinology. 1999;24(2):161–173.

    CAS  PubMed  Google Scholar 

  83. Petanceska SS, Nagy V, Frail D, Gandy S. Ovariectomy and 17beta-estradiol modulate the levels of Alzheimer’s amyloid beta peptides in brain. Exp Gerontol. 2000;35(9-10):1317–1325.

    CAS  PubMed  Google Scholar 

  84. Monk D, Brodaty H. Use of estrogens for the prevention and treatment of Alzheimer’s disease. Dement Geriatr Cogn Disord. 2000;11(1):1–10.

    CAS  PubMed  Google Scholar 

  85. Green PS, Simpkins JW. Estrogens and estrogen-like non-feminizing compounds. Their role in the prevention and treatment of Alzheimer’s disease. Ann N Y Acad Sci. 2000;924:93–98.

    CAS  PubMed  Google Scholar 

  86. Manly JJ, Merchant CA, Jacobs DM, et al. Endogenous estrogen levels and Alzheimer’s disease among postmenopausal women. Neurology. 2000;54(4):833–837.

    CAS  PubMed  Google Scholar 

  87. Henderson VW, Paganini-Hill A, Miller BL, et al. Estrogen for Alzheimer’s disease in women: randomized, double-blind, placebo-controlled trial. Neurology. 2000;54(2):295–301.

    CAS  PubMed  Google Scholar 

  88. Mulnard RA. Estrogen as a treatment for Alzheimer disease. J Am Med Assoc. 2000;284(20):307–308.

    CAS  Google Scholar 

  89. Mulnard RA, Cotman CW, Kawas C, et al. Estrogen replacement therapy for treatment of mild to moderate Alzheimer disease: a randomized controlled trial. Alzheimer’s Disease Cooperative Study. JAMA. 2000;283(8):1007–1015.

    CAS  PubMed  Google Scholar 

  90. Birge SK, McEwen BS, Wise PM. Effects of estrogen deficiency on brain function. Implications for the treatment of postmenopausal women. Postgrad Med Spec. 2001;(spec no):11–16.

    Google Scholar 

  91. Zandi PP, Carlson MC, Plassman BL, et al. Hormone replacement therapy and incidence of Alzheimer disease in older women. JAMA. 2002;288(17):2123–2129.

    CAS  PubMed  Google Scholar 

  92. Sherwin BB. Estrogen and cognitive functioning in women. Endocr Rev. 2003;24(2):133–151.

    CAS  PubMed  Google Scholar 

  93. Henderson VW, Guthrie JR, Dudley EC, Burger HG, Dennerstein L. Estrogen exposures and memory at midlife: a population-based study of women. Neurology. 2003;60(8):1369–1371.

    CAS  PubMed  Google Scholar 

  94. Sherwin BB. Surgical menopause, estrogen and cognitive function in women: what do the findings tell us? Ann N Y Acad Sci. 2005;1052:133–151.

    Google Scholar 

  95. Yue X, Lu M, Lancaster T, et al. Brain estrogen deficiency accelerates Abeta plaque formation in an Alzheimer’s disease animal model. Proc Natl Acad Sci U S A. 2005;102(52):19198–19203.

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Simpkins JW, Yang SH, Wen Y, Singh M. Estrogens, progestins, menopause and neurodegeneration: basic and clinical studies. Cell Mol Life Sci. 2005;62(3):271–280.

    CAS  PubMed  Google Scholar 

  97. Almeida OP, Lautenschlager NT, Vasikaran S, Leedman P, Gelavis A, Flicker L. A 20-week randomized controlled trial of estradiol replacement therapy for women aged 70 years and older: effect on mood, cognition and quality of life. Neurobiol Aging. 2006;27(1):141–149.

    CAS  PubMed  Google Scholar 

  98. Henderson VW., Cognitive changes after menopause: influence of estrogen. Clin Obstet Gynecol. 2008;51(3):618–626.

    PubMed  PubMed Central  Google Scholar 

  99. Hogervorst E. Effects of gonadal hormones on cognitive behavior in elderly men and women. J Neuroendocrinol. 2013;25(11):1182–1195.

    CAS  PubMed  Google Scholar 

  100. Casadesus G, Garrett MR, Webber KM, et al. The estrogen myth: potential use of gonadotropin-releasing hormone agonists for the treatment of Alzheimer’s disease. Drugs R D. 2006;7(3):187–193.

    CAS  PubMed  Google Scholar 

  101. Simpkins JW, Green BS, Gridley KE, Singh M, de Fiebre NC, Rajakumar G. Role of estrogen replacement therapy in memory enhancement and the prevention of neuronal loss associated with Alzheimer disease. Am J Med. 1997;103(3A):19s–25s.

    CAS  PubMed  Google Scholar 

  102. Sansdstrom NJ, Williams CL. Memory retention is modulated by acute estradiol and progesterone replacement. Behav Neurosci. 2001;115(2):384–393.

    Google Scholar 

  103. Rapp SR, Espeland MA, Shumaker SA, et al. Effect of estrogen plus progestin on global cognitive function in postmenopausal women. JAMA. 2003;289(20):2663–2672.

    CAS  PubMed  Google Scholar 

  104. Shumaker SA, Legault C, Rapp SR, et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women’s Health Initiative Memory Study: a randomized controlled trial. JAMA. 2003;289(20):2651–2662.

    CAS  PubMed  Google Scholar 

  105. Seshadri S, Zornberg GL, Derby LE, Myers MW, Jick H, Drachman DA. Postmenopausal estrogen replacement therapy and the risk of Alzheimer disease. Arch Neurol. 2001;58(3):435–440.

    CAS  PubMed  Google Scholar 

  106. Daniel JM, Hulst JL, Berbling JL. Estradiol replacement enhances working memory in middle-aged rats when initiated immediately after ovariectomy but not after a long-term period of ovarian hormone deprivation. Endocrinology. 2006;147(1):607–614.

    CAS  PubMed  Google Scholar 

  107. Bohacek J, Daniel JM. The beneficial effects of estradiol on attentional processes are dependent on timing of treatment initiation following ovariectomy in middle-aged rats. Psychoneuroendocrinology. 2010;35(5):694–705.

    CAS  PubMed  Google Scholar 

  108. Chakravarti S, Collins WP, Forecast JD, Newton JR, Oram DH, Studd JW. Hormonal profiles after the menopause. Br Med J. 1976;2(6039):784–787.

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Rossmanith WG, Reichelt C, Scherbaum WA. Neuroendocrinology of aging in humans: attenuated sensitivity to sex steroid feedback in elderly postmenopausal women. Neuroendocrinology. 1994;59(4):355–362.

    CAS  PubMed  Google Scholar 

  110. Chu C, Gao G, Huang W. A study on co-localization of FSH and its receptor in rat hippocampus. J Mol Hist. 2008;39(1):49–55.

    CAS  Google Scholar 

  111. Payami H, Montee K, Grimslid H, Shattuc S, Kaye J. Increased risk of familial late-onset Alzheimer’s disease in women. Neurology. 1996;46(1):126–129.

    CAS  PubMed  Google Scholar 

  112. Bowen RL, Isley JP, Atkinson RL. An association of elevated serum gonadotropin concentrations and Alzheimer disease? J Neuroendocrinol. 2000;12(4):351–354.

    CAS  PubMed  Google Scholar 

  113. Short RA, O’Brien PC, Graff-Radford NR, Bowen RL. Elevated gonadotropin levels in patients with Alzheimer disease. Mayo Clin Proc. 2001;76(9):906–909.

    CAS  PubMed  Google Scholar 

  114. Barron AM, Cake M, Verdile RN. Ovariectomy and 17beta-estradiol replacement do not alter beta-amyloid levels in sheep brain. Endocrinology. 2009;150(7):3228–3236.

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Bryan KJ, Mudd JC, Richardson SL, et al. Down-regulation of serum gonadotropins is as effective as estrogen replacement at improving menopause-associated cognitive deficits. J Neurochem. 2010;112(4):870–881.

    CAS  PubMed  Google Scholar 

  116. Casadesus G, Webber KM, Atwood CS, et al. Luteinizing hormone modulates cognition and amyloid-β deposition in Alzheimer APP transgenic mice. Biochem Biophys Acta. 2006;1762(4):447–452.

    CAS  PubMed  Google Scholar 

  117. Ziegler SG, Thornton JW. Low luteinizing hormone enhances spatial memory and has protective effects on memory loss in rats. Horm Behav. 2010;58(5):705–713.

    CAS  PubMed  Google Scholar 

  118. Blair JA, Bjatta S, McGee H, Casadesus G. Luteinizing hormone: evidence for direct action in the CNS. Horm Behav. 2015;76:57–62.

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Palm R, Chang J, Blair J, et al. Down-regulation of serum gonadotropins but not estrogen replacement improves cognition in aged-ovariectomized 3xTg AD female mice. J Neurochem. 2014;130(1):115–125.

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Casadesus G, Milliken EL, Webber KM, et al. Increases in luteinizing hormone are associated with declines in cognitive performance. Mol Cell Endocrinol. 2007;269(1-2):107–111.

    CAS  PubMed  Google Scholar 

  121. Bowen RL, Smith MA, Harris PLR, et al. Elevated luteinizing hormone expression colocalizes with neurons vulnerable to Alzheimer’s disease pathology. J Neurosci Res. 2002;70(3):514–518.

    CAS  PubMed  Google Scholar 

  122. Barron A, Verdile G, Martins RN. The role of gonadotropins in Alzheimer’s disease: potential neurodegenerative mechanisms. Endocrine. 2006;29(2):257–270.

    CAS  PubMed  Google Scholar 

  123. Rodrigues MA, Verdile G, Foster JK, et al. Gonadotropins and cognition in older women. J Alzheimers Dis. 2008;13(3):267–274.

    CAS  PubMed  Google Scholar 

  124. Burnham VL, Thornton JE. Luteinizing hormone as a key player in the cognitive decline of Alzheimer’s disease. Horm Behav. 2015;76:48–56.

    CAS  PubMed  Google Scholar 

  125. Wahjoepramono EJ, Wijaya LK, Taddei K, et al. Direct exposure of guinea pig CNS to human luteinizing hormone increases cerebrospinal fluid and cerebral beta amyloid levels. Neuroendocrinol. 2011;94(4):313–322.

    CAS  Google Scholar 

  126. Berry A, Tomidokoro Y, Ghiso J, Thornton J. Human chorionic gonadotropin (a luteinizing hormone homologue) decreases spatial memory and increases brain amyloid-β levels in male rats. Horm Behav. 2008;54(1):143–152.

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Barron AM, Verdile G, Taddei K, Bates KA, Martins RN. Effect of chronic hCG administration on Alzheimer’s-related cognition and Aβ accumulation in PS1KI mice. Endocrinology. 2010;151(11):5380–5388.

    CAS  PubMed  Google Scholar 

  128. Lin J, Li X, Yuan F, et al. Genetic ablation of luteinizing hormone receptor improves the amyloid pathology in a mouse model of Alzheimer disease. J Neuropathol Exp Neurol. 2010;69(3):253–261.

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Masters CL, Simms G, Weinman NA, Multhaup G, McDonald BL, Beyreuther K. Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc Natl Acad Sci U S A. 1985;82(12):4245–4249.

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Takashima S, Kuruta H, Mito T, Nishizawa M, Kunishita T, Tabira T. Developmental and aging changes in the expression patterns of beta-amyloid in the brains of normal and Down syndrome cases. Brain. 1990;12(4):367–371.

    CAS  Google Scholar 

  131. Schupf N, Kapell D, Nightingale B, Rodriguez A, Tycko B, Mayeux R. Earlier onset of Alzheimer’s disease in men with Down syndrome. Neurology. 1998;50(4):991–995.

    CAS  PubMed  Google Scholar 

  132. Nakano R, Shina K, Yarnoto M, Kobayashi M, Nishimori K, Hiraoka JI. Binding sites for gonadotropins in human postmenopausal ovaries. Obstet Gynecol. 1989;73:196–200.

    CAS  PubMed  Google Scholar 

  133. Pabon J, Li X, Lei Z, Sanfilippo J, Yussman M, Rao CV. Novel presence of luteinizing hormone/chorionic gonadotropin receptors in human adrenal glands. J Clin Endocrinol Metab. 1996;81(2):2397–2400.

    CAS  PubMed  Google Scholar 

  134. Dos Santo E, Dieudonne M-N, Leneveu M-C, Pacquery R, Serazin V, Giudicelli Y. In vitro effects of chorionic gonadotropin hormone on human adipose development. J Endocrinol. 2007;194(2):313–325.

    Google Scholar 

  135. Parkash J, Lei ZM, Rao CV. The presence of human chorionic gonadotropin/luteinizing hormone receptors in pacreatic beta-cells. Reprod Sci. 2015;22(8):1000–1007.

    CAS  PubMed  Google Scholar 

  136. Lasley BL, Conley AJ, Morrison JH, Gee NA, Rao CV. Identification of immunoreactive luteinizing hormone receptors in the adrenal cortex of the female rhesus macaque. Reprod Sci. 2016;23(4):524–530.

    CAS  PubMed  Google Scholar 

  137. Poliak A, Jones GES, Goldberg B, Soloman D, Woodruff ID. Effect of human chorionic gonadotropin on postmenopausal women. Am J Obstet Gynecol. 1968;101:731–739.

    CAS  Google Scholar 

  138. Dennefors BL, Janson PO, Knutson F, Hamberger L. Steroid production and responsiveness to gonadotropin in isolated stromal tissue of human postmenopausal ovaries. Am J Obstet Gynecol. 1980;136(4):997–1002.

    CAS  PubMed  Google Scholar 

  139. Rao CV, Zhou XL, Lei ZM. Functional luteinizing hormone/chorionic gonadotropin receptors in human adrenal cortical H295R cells. Biol Reprod. 2004;71(2):579–587.

    CAS  PubMed  Google Scholar 

  140. Moran F, Chen J, Lohstroh PN, Gee NA, Lasley BL. Dehydroepiandrosterone sulfate (DHEAS) levels reflect endogenous LH production and response to human chorionic gonadotropin (hCG) challenge in the older female macaque (Macaca fascicularis). Menopause. 2013;20(3):329–335.

    PubMed  PubMed Central  Google Scholar 

  141. Saxena AR, Seely. Luteinizing hormone correlates with adrenal function in postmenopausal women. Menopause. 2012;19(11):1280–1283.

    PubMed  PubMed Central  Google Scholar 

  142. Cuatrecasas P. Insulin-receptor interactions in adipose tissue cells: direct measurement and properties. Proc Natl Acad Sci U S A. 1971;68(6):1264–1268.

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Schindler AE, Ebert A, Friedrich E. Conversion of androstenedione to estrone by human fat tissue. J Clin Endocr Metab. 1972;35(4):627–630.

    CAS  PubMed  Google Scholar 

  144. Ackerman GE, Smoth ME, Mendelson CR, MacDonald PC, Simpson ER. Aromatization of androstenedione by human adipose tissue stromal cells in monolayer culture. J Clin Endocrinol Metab. 1981;53(2):412–417.

    CAS  PubMed  Google Scholar 

  145. Nagamani M, Hannigan EV, Dinh VT, Stuart CA. Hyperinsulinemia and stromal luteinizing of the ovaries in postmenopausal women with endometrial cancer. J Clin Endocrinol Metab. 1988;67(1):144–148.

    CAS  PubMed  Google Scholar 

  146. Urban RJ, Veldhuis JD, Dufau LM. Estrogen regulates the gonadotropin-releasing hormone-stimulated secretion of biologically active luteinizing hormone. J Clin Endocrinol Metab. 1991;72(3):660–668.

    CAS  PubMed  Google Scholar 

  147. McTernan PG, Anderson LA, Anwar AJ, et al. Glucocorticoid regulation of P450 aromatase activity in human adipose tissue: gender and site differences. J Clin Endocrinol Metab. 2002;87(3):1327–1336.

    CAS  PubMed  Google Scholar 

  148. Barnard L, Balen AH, Ferriday D, Tiplady B, Dye L. Cognitive functioning in polycystic ovary syndrome. Psychoneuroendocrinology. 2007;32(8-10):906–914.

    CAS  PubMed  Google Scholar 

  149. Hart R, Doherty DA. The potential implications of a PCOS diagnosis on a woman’s long-term health using data linkage. J Clin Endocrinol Metab. 2015;100(3):911–919.

    CAS  PubMed  Google Scholar 

  150. Rees DA, Udiawar M, Berlot R, Jones DK, O’Sullivan MJ. White matter microstructure and cognitive function in young women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2016;101(1):314–323.

    CAS  PubMed  Google Scholar 

  151. The Translational Scientist. Navigating the complexities of Alzheimer’s. 2016. https://thetranslationalscientist.com/issues/0116/navigating-alzheimers/. Accessed March 2016.

    Google Scholar 

  152. Croxatto H, Arrau J, Croxatto H. Luteinizing hormone-like activity in human median eminence extracts. Nature. 1964;204:584–585.

    CAS  PubMed  Google Scholar 

  153. Antunes JL, Carmel PW, Zimmerman EA, Ferin M. The pars tuberalis of the rhesus monkey secretes luteinizing hormone. Brain Res. 1979;166(1):49–55.

    CAS  PubMed  Google Scholar 

  154. Gross DS, Page RB. Luteinizing hormone and follicle-stimulating hormone production in the pars tuberalis of hypophysectomized rats. Am J Anat. 1979;156(2):285–291.

    CAS  PubMed  Google Scholar 

  155. Hostetter G, Gallo RV, Brownfield MS. Presence of immunoreactive luteinizing hormone in the rat forebrain. Neuroendocrinology. 1981;33(4):241–245.

    CAS  PubMed  Google Scholar 

  156. Emanuele N, Connick E, Howell T, et al. Hypothalamic luteinizing hormone (LH): characteristics and response to hypophysectomy. Biol Reprod. 1981;25(2):321–326.

    CAS  PubMed  Google Scholar 

  157. Emanuele N, Oslapas R, Connick E, Kirsteins L, Lawrence AM. Hypothalamic LH may play a role in control of pituitary LH release. Neuroendocrinology. 1981;33(1):12–17.

    PubMed  Google Scholar 

  158. Emanuele N, Anderson J, Andersen E, et al. Extrahypothalamic brain luteinizing hormone: characterization by radioimmunoassay, chromatography, radioligand assay and bioassay. Neuroendocrinology. 1983;36(4):254–260.

    CAS  PubMed  Google Scholar 

  159. Weill-Engerer S, David JP, Sazdovitch V, et al. Neurosteroid quantification in human brain regions: comparison between Alzheimer’s and nondemented patients. J Clin Endocrinol Metab. 2002;87(11):5138–5143.

    CAS  PubMed  Google Scholar 

  160. Murakami G, Tanabe N, Ishii HT, et al. Role of cytochrome p450 in synaptocrinology: endogenous estrogen synthesis in the brain hippocampus. Drug Metab Rev. 2006;38(3):353–369.

    CAS  PubMed  Google Scholar 

  161. Neaves WB, Johnson L, Porter JC, Parker CR, Petty CS. Leydig cell numbers, daily sperm production, and serum gonadotropin levels in aging men. J Clin Endocrinol Metab. 1984;59(4):756–763.

    CAS  PubMed  Google Scholar 

  162. Butchart J, birch B, basil R, Wolfe L, Holmes C. Male sex hormones and systematic inflammation in Alzheimer disease. Alzheimer Dis Assoc Disord. 2013;27(2):153–156.

    CAS  PubMed  Google Scholar 

  163. Tenover JS, Matsumoto AM, Plymate SR, Bremmer WJ. The effects of aging in normal men on bioavailable testosterone and luteinizing hormone secretion: response to clomiphene citrate. J Clin Endocrinol Metab. 1987;65(6):1118–1126.

    CAS  PubMed  Google Scholar 

  164. Morley JE, Kaiser FE, Perry HM, et al. Longitudinal changes in testosterone, luteinizing hormone, and follicle-stimulating hormone in healthy older men. Metab Clin Exp. 1997;46(4):410–413.

    CAS  PubMed  Google Scholar 

  165. Morley JE. Androgens and aging. Maturitas. 2001;38(1):61–71; discussion 71-73.

    CAS  PubMed  Google Scholar 

  166. Kaufman JM, Vermeulen A. The decline of androgen levels in elderly men and its clinical and therapeutic implications. Endocr Rev. 2005;26(6):833–876.

    CAS  PubMed  Google Scholar 

  167. Yeap BB, Almeida OP, Hyde Z, et al. In men older than 70 years, total testosterone remains stable while free testosterone declines with age. The Health in Men Study. Eur J Endocrinol. 2007;156(5):585–594.

    CAS  PubMed  Google Scholar 

  168. Veldhuis JD, Keenan DM, Liu PY, Iranmanesh A, Takahashi PY, Nehra AX. The aging male hypothalamic-pituitary-gonadal axis: pulsatility and feedback. Mol Cell Endocrinol. 2009;299(1):14–22.

    CAS  PubMed  Google Scholar 

  169. Wang J, Tanila H, Puolivali J, Kadish I, van Groen T. Gender differences in the amount and deposition of amyloid beta in APPswe and PS1 double transgenic mice. Neurobiol Dis. 2003;14(3):318–327.

    CAS  PubMed  Google Scholar 

  170. Barrett-Connor E, Goodman-Gruen D, Patay B. Endogenous sex hormones and cognitive function in older men. J Clin Endocrinol Metab. 1999;84(10):3681–3685.

    CAS  PubMed  Google Scholar 

  171. Gillet MJ, Martins RN, Clarnette RM, Chubb SA, Bruce DG, Yeap BB. Relationship between testosterone, sex hormone binding globulin and plasma amyloid beta peptide 40 in older men with subjective memory loss or dementia. J Alzheimers Dis. 2003;5(4):267–269.

    Google Scholar 

  172. Hogervorst E, Combrinck M, Smith AD. Testosterone and gonadotropin levels in men with dementia. Neuro Endocrinol Lett. 2003;24(3-4):203–208.

    CAS  PubMed  Google Scholar 

  173. Janowsky JS. The role of androgens in cognition and brain aging in men. Neuroscience. 2006;138(3):1015–1020.

    CAS  PubMed  Google Scholar 

  174. Rosario ER, Pike CJ. Androgen regulation of beta-amyloid protein and the risk of Alzheimer’s disease. Brain Res. 2008;57(2);444–453.

    CAS  Google Scholar 

  175. McConnell SEA, Alla J, Wheat E, Romeo RD, McEwen B, Thornton JE. The role of testicular hormones and luteinizing hormone in spatial memory in adult male rats. Horm Behav. 2012;61(4):479–486.

    CAS  PubMed  Google Scholar 

  176. Rosario ER, Carrol JC, Pike CJ. Evaluation of the effects of testosterone and luteinizing hormone on regulation of β-amyloid in male 3xTg-AD mice. Brain Res. 2012;1466:137–145.

    CAS  PubMed  PubMed Central  Google Scholar 

  177. Verdile G, Laws SM, Henley D, et al. Associations between gonadotropins, testosterone and β amyloid in men at risk of Alzheimer’s Disease. Mol Psych. 2014;19(1):69–75.

    CAS  Google Scholar 

  178. Verdile G, Yeap BB, Clamette RM, et al. Luteinizing hormone levels are positively correlated with plasma amyloid-β protein levels in elderly men. J Alzheimers Dis. 2008;14(2):201–208.

    CAS  PubMed  Google Scholar 

  179. Haasl RJ, Ahmadi MR, Meethal SV, et al. A luteinizing hormone receptor intronic variant is significantly associated with decreased risk of Alzheimer’s disease in males carrying on apolipoprotein E epsilon 4 allele. BMC Med Genet. 2008;9:37.

    PubMed  PubMed Central  Google Scholar 

  180. D’Amico AV, Braccioforte MH, Moran BJ, Chen MH. Luteinizing-hormone releasing hormone therapy and the risk of death from Alzheimer disease. Alzheimer Dis Assoc Disord. 2010;24(1):85–89.

    PubMed  Google Scholar 

  181. Leranth C, Petnehazy O, MaclUsky NJ. Gonadal hormones affect spine synaptic density in the CA1 hippocampal subfield of male rats. J Neurosci. 2003;23(5):1588–1592.

    CAS  PubMed  PubMed Central  Google Scholar 

  182. Hogervorst E, Williams J, Budge M, Barnetson L, Combrinck M, Smith AD. Serum total testosterone is lower in men with Alzheimer’s disease. Neuro Endocrinol Lett. 2001;22(3):163–168.

    CAS  PubMed  Google Scholar 

  183. Hogervorst E, Bandelow S, Combrinck M, Smith AD. Low free testosterone is an independent risk factor for Alzheimers disease. Exp Gerontol. 2004;39(11-12):1633–1639.

    CAS  PubMed  Google Scholar 

  184. Rosario ER, Chang L, Stanczyk FZ, Pike CJ. Age related testosterone depletion and the development of Alzheimer disease. J Am Med Assoc. 2004;292(12):1431–1432.

    CAS  Google Scholar 

  185. Tan RS, Pu SJ. A pilot study on the effects of testosterone in hypogonadal aging male patients with Alzheimer’s disease. Aging Male. 2003;6(1):13–17.

    CAS  PubMed  Google Scholar 

  186. Gandy S, Almeida OP, Fonte J, et al. Chemical andropause and amyloid-beta peptide. JAMA. 2001;285(17):2195–2196.

    CAS  PubMed  Google Scholar 

  187. Almeida OP, Waterreus A, Spry N, Flicker L, Martins RN. One year follow-up study of the association between chemical castration, sex hormones, beta-amyloid, memory and depression in men. Psychoneuroendocrinology. 2003;29(8):1071–1081.

    Google Scholar 

  188. Nead KT, Gaskin G, Chester C, Swisher-McClure S, Leeper NJ, Shah NH. Androgen deprivation therapy and future Alzheimer’s disease risk. J Clin Oncol. 2016;34(6):533–571.

    Google Scholar 

  189. Ahlbom E, Prins GS, Ceccatelli S. Testosterone protects cerebellar granule cells from oxidative stress-induced cell death through a receptor mediated mechanism. Brain Res. 2001;892(2):255–262.

    CAS  PubMed  Google Scholar 

  190. Wahjoepramono EJ, Wijaya LK, Taddei K, et al. Distinct effects of testosterone on plasma and cerebrospinal fluid amyloid-beta levels. J Alzheimers Dis. 2008;15(1):129–137.

    CAS  PubMed  Google Scholar 

  191. Moffat SD, Zonderman AB, Metter EJ, et al. Free testosterone and risk of Alzheimer disease in older men. Neurology. 2004;62(2):188–193.

    CAS  PubMed  Google Scholar 

  192. Pike CJ. Testosterone attenuates beta-amyloid toxicity in cultured hippocampal neurons. Brain Res. 2001;919(1):160–165.

    CAS  PubMed  Google Scholar 

  193. Hammond J, Le Q, Goodyer C, Gelfand M, Trifiro M, LeBlanc A. Testosterone-mediated neuroprotection through the androgen receptor in human primary neurons. J Neurochem. 2001;77(5):1319–1326.

    CAS  PubMed  Google Scholar 

  194. Rosario ER, Carroll JC, Oddo S, LaFerla FM, Pike CJ. Androgens regulate the development of neuropathology in a triple transgenic mouse model of Alzheimer’s disease. J Neurosci. 2006;26(51):13384–13389.

    CAS  PubMed  PubMed Central  Google Scholar 

  195. Rosario ER, Carroll J, Pike CJ. Testosterone regulation of Alzheimer-like neuropathology in male 3xTg-AS mice involves both estrogen and androgen pathways. Brain Res. 2010;1359:281–290.

    CAS  PubMed  PubMed Central  Google Scholar 

  196. McAllilster C, Long J, Bowers A, et al. Genetic targeting aromatase in male amyloid precursor protein transgenic mice down-regulates beta-secretase (BACE1) and prevents Alzheimer-like pathology and cognitive impairment. J Neurosci. 2010;30(21):7326–7334.

    Google Scholar 

  197. Walsch JP, Kitchens AC. Testosterone therapy and cardiovascular risk. Trends Cardiovasc Med. 2015;25(3):250–257.

    Google Scholar 

  198. Alzheimer’s Association. FDA-approved treatments for Alzheimer’s. Web site. http://www.alz.org/dementia/downloads/topicsheet_treatments.pdf. Accessed March 2016. Updated February 2016.

  199. Gallagher M. The overactive brain. Translational Sci. 2016;1:23.

    Google Scholar 

  200. Bakker A, Krauss GL, Albert MS, et al. Reduction of hippocampal hyperactivity improves cognition in amnestic mild cognitive impairment. Neuron. 2016;74(3):467–474.

    Google Scholar 

  201. Defelice FG, Ferreira ST. Physiopathological modulators of amyloid aggregation and novel pharmacological approaches in Alzheimer’s disease. Anais da Academia Brasileira de Ciencias. 2002;74(2):265–284.

    CAS  PubMed  Google Scholar 

  202. Verdile G, Fuller SJ, Martins RN. The role of type 2 diabetes in neurodegeneration. Neurobiol Dis. 2015;84:22–38.

    CAS  PubMed  Google Scholar 

  203. McNay E. Food for thought. Translational Sci. 2016;1:24–25.

    Google Scholar 

  204. Havrankova J, Roth J, Brownstein MJ. Concentrations of insulin and insulin receptors in the brain are independent of peripheral insulin levels. Studies of obese and streptozotocin-treated rodents. J Clin Invest. 1979;64(2):636–642.

    CAS  PubMed  PubMed Central  Google Scholar 

  205. Blazquez E, Velazquez E, Hurtado-Carneiro V, Ruiz-Albusac JM. Insulin in the brain: its pathophysiological implications for states related with central insulin resistance, type 2 diabetes and Alzheimer’s disease. Front Endocrinol. 2014;5:161.

    Google Scholar 

  206. Havrankova J, Schmechel D, Roth J, Brownstein M. Identification of insulin in rat brain. Proc Natl Acad Sci U S A. 1978;75(11):5737–5741.

    CAS  PubMed  PubMed Central  Google Scholar 

  207. Havrankova J, Roth J, Brownstein M. Insulin receptors are widely distributed in the central nervous system of the rat. Nature. 1978;272(5656):827–829.

    CAS  PubMed  Google Scholar 

  208. Antigonadotropin-Leuprolide in Alzheimer’s Disease Drug Investigation (ALADDIN) VP 104 Study. Web site. http://www.clinicaltrials.gov/ct/show/NTC00076440. Accessed February 22, 2016.

  209. Bowen RL, Perry G, Xiong C, Smith MA, Atwood CS. A clinical study of Lupron depot in the treatment of women with Alzheimer’s disease: preservation of cognitive function in patients taking an acetylcholinesterase inhibitor and treated with high dose Lupron over 48 weeks. J Alzheimers Dis. 2015;44(2):549–560. Updated December 2009.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to C. V. Rao PhD.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rao, C.V. Involvement of Luteinizing Hormone in Alzheimer Disease Development in Elderly Women. Reprod. Sci. 24, 355–368 (2017). https://doi.org/10.1177/1933719116658705

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1177/1933719116658705

Keywords

Navigation