Nonestrogen-Based Hormonal Therapies for Alzheimer‘s Disease

• Hebert LE , ScherrPA, BieniasJL, Bennett DA, Evans DA: Alzheimer disease in the US population: prevalence estimates using the 2000 census. Arch. Neurol.60, 1119–1122 (2003).
   PubMed Web of Science ®Google Scholar
• Perry G , NunomuraA, RainaAK, Smith MA: Amyloid-β junkies. Lancet355, 757 (2000).
   PubMed Web of Science ®Google Scholar
• Anthony SG , SchipperHM, TavaresRet al.: Stress protein expression in the Alzheimer-diseased choroid plexus. J. Alzheimers Dis.5, 171–177 (2003).
   PubMed Web of Science ®Google Scholar
• Gold G , KovariE, CorteGet al.: Clinical validity of Aβ-protein deposition staging in brain aging and Alzheimer disease. J. Neuropathol. Exp. Neurol.60, 946–952 (2001).
   PubMed Web of Science ®Google Scholar
• Westermann MA , Cooper-BlacketerD, MariashAet al.: The relationship between Aβ and memory in the Tg2576 mouse model of Alzheimer‘s disease. J. Neurosci.22, 1858–1876, (2002).
   PubMed Web of Science ®Google Scholar
• Kobayashi D , ChenKS: Behavioral phenotypes of amyloid-based genetically modified mouse models of Alzheimer‘s disease.Genes Brain Behav.4, 173–196, (2005).
   PubMed Web of Science ®Google Scholar
• Nunomura A , PerryG, AlievGet al.: Oxidative damage is the earliest event in Alzheimer disease. J. Neuropathol. Exp. Neurol.60, 759–767 (2001).
   PubMed Web of Science ®Google Scholar
• Castellini RJ , LeeHG, ZhuX, Nunomura A, Perry G, Smith MA: Neuropathology of Alzheimer disease: pathognomonic but not pathogenic. Acta Neuropathol.111, 503–509 (2006).
   PubMed Web of Science ®Google Scholar
• Tang MX , JacobsD, SternYet al.: Effect of oestrogen during menopause on risk and age at onset of Alzheimer‘s disease. Lancet348, 429–432 (1996).
   PubMed Web of Science ®Google Scholar
• Barness LL , WilsonRS, BieniasJL, Schneider JA, Evans DA, Bennett DA: Sex differences in the clinical manifestations of Alzheimer disease pathology. Arch. Gen. Psychiatry62, 685–691 (2005).
   PubMed Web of Science ®Google Scholar
• Genazzani AR , GastaldiM, BidzinskaBet al.: The brain as a target organ of gonadal steroids. Psychoneuroendocrinology17, 385–390 (1992).
   PubMed Web of Science ®Google Scholar
• Lathe R : Hormones and the hippocampus.J. Endocrinol.169, 205–231 (2001).
   PubMed Web of Science ®Google Scholar
• Wu JM , ZelinskiMB, IngramDK, Ottinger MA: Ovarian aging and menopause: current theories, hypotheses, and research models. Exp. Biol. Med.230, 818–828 (2005).
   Web of Science ®Google Scholar
• Couzinet B , SchaisonG: The control of gonadotrophin secretion by ovarian steroids.Hum. Reprod.8(Suppl. 2), 97–101 (1993).
   PubMedGoogle Scholar
• Chakravarti S , CollinsWP, ForecastJD, NewtonJR, OramDH, StuddJW: Hormonal profiles after the menopause.Br. Med. J.2, 784–787 (1976).
   PubMed Web of Science ®Google Scholar
• Neaves WB , JohnsonL, PorterJC, Parker CR Jr, Petty CS: Leydig cell numbers, daily sperm production, and serum gonadotropin levels in aging men. J. Clin. Endocrinol. Metab.59, 756–763 (1984).
   PubMed Web of Science ®Google Scholar
• Magarinos AM , VerdugoJM, McEwenBS: Chronic stress alters synaptic terminal structure in hippocampus.Proc. Natl Acad. Sci. USA94, 14002–14008 (1997).
   PubMed Web of Science ®Google Scholar
• Birge SJ , McEwenBS, WisePM: Effects of estrogen deficiency on brain function. Implications for the treatment of postmenopausal women.Postgrad. Med.11–16 (2001).
   Google Scholar
• Manly JJ , MerchantCA, JacobsDMet al.: Endogenous estrogen levels and Alzheimer‘s disease among postmenopausal women.Neurology54(4), 833–837 (2000).
   PubMed Web of Science ®Google Scholar
• Brookmeyer R , GrayS, KawasC: Projections of Alzheimer‘s disease in the United States and the public health impact of delaying disease onset.Am. J. Public Health88(9), 1337–1342 (1998).
   PubMed Web of Science ®Google Scholar
• Paganini-Hill A , HendersonVW: Estrogen deficiency and risk of Alzheimer‘s disease in women.Am. J. Epidemiol.140, 256–261 (1994).
   PubMed Web of Science ®Google Scholar
• Petanceska SS , NagyV, FrailD, GandyS: Ovariectomy and 17β-estradiol modulate the levels of Alzheimer‘s amyloid β peptides in brain.Neurology54(12), 2212–2217 (2000).
   PubMed Web of Science ®Google Scholar
• Goodman Y , BruceAJ, ChengB, Mattson MP: Estrogens attenuate and corticosterone exacerbates excitotoxicity, oxidative injury, and amyloid β-peptide toxicity in hippocampal neurons. J. Neurochem.66(5), 1836–1844 (1996).
   PubMed Web of Science ®Google Scholar
• Bi R , FoyMR, VouimbaRM, Thompson RF, Baudry M: Cyclic changes in estradiol regulate synaptic plasticity through the MAP kinase pathway. Proc. Natl Acad. Sci. USA98(23), 13391–13395 (2001).
   PubMed Web of Science ®Google Scholar
• Gould E , WoolleyCS, FrankfurtM, McEwenBS: Gonadal steroids regulate dendritic spine density in hippocampal pyramidal cells in adulthood.J. Neurosci.10(4), 1286–1291 (1990).
   PubMed Web of Science ®Google Scholar
• Woolley CS , GouldE, FrankfurtM, McEwenBS: Naturally occurring fluctuation in dendritic spine density on adult hippocampal pyramidal neurons.J. Neurosci.10(12), 4035–4039 (1990).
   PubMed Web of Science ®Google Scholar
• Woolley CS , McEwenBS: Roles of estradiol and progesterone in regulation of hippocampal dendritic spine density during the estrous cycle in the rat.J. Comp. Neurol.336(2), 293–306 (1993).
   PubMed Web of Science ®Google Scholar
• Leranth C , ShanabroughM, Redmond DE Jr: Gonadal hormones are responsible for maintaining the integrity of spine synapses in the CA1 hippocampal subfield of female nonhuman primates. J. Comp. Neurol.447(1), 34–42 (2002).
   PubMed Web of Science ®Google Scholar
• Hao J , JanssenWG, TangYet al.: Estrogen increases the number of spinophilin-immunoreactive spines in the hippocampus of young and aged female rhesus monkeys. J. Comp. Neurol.465(4), 540–550 (2003).
   PubMed Web of Science ®Google Scholar
• McEwen B : Estrogen actions throughout the brain.Recent Prog. Horm. Res.57, 357–384 (2002).
   PubMedGoogle Scholar
• Yankova M , HartSA, WoolleyCS: Estrogen increases synaptic connectivity between single presynaptic inputs and multiple postsynaptic CA1 pyramidal cells: a serial electron-microscopic study.Proc. Natl Acad. Sci. USA98(6), 3525–3530 (2001).
   PubMed Web of Science ®Google Scholar
• Choi JM , RomeoRD, BrakeWG, Bethea CL, Rosenwaks Z, McEwen BS: Estradiol increases pre- and post-synaptic proteins in the CA1 region of the hippocampus in female rhesus macaques (Macaca mulatta). Endocrinology144(11), 4734–4738 (2003).
   PubMed Web of Science ®Google Scholar
• Yokomaku D , NumakawaT, NumakawaYet al.: Estrogen enhances depolarization-induced glutamate release through activation of phosphatidylinositol 3-kinase and mitogen-activated protein kinase in cultured hippocampal neurons. Mol. Endocrinol.17(5), 831–844 (2003).
   PubMedGoogle Scholar
• Rune GM , WehrenbergU, Prange-KielJ, ZhouL, AdelmannG, FrotscherM: Estrogen up-regulates estrogen receptor α and synaptophysin in slice cultures of rat hippocampus.Neuroscience113(1), 167–175 (2002).
   PubMed Web of Science ®Google Scholar
• Kretz O , FesterL, WehrenbergUet al.: Hippocampal synapses depend on hippocampal estrogen synthesis. J. Neurosci.24(26), 5913–5921 (2004).
   PubMed Web of Science ®Google Scholar
• Sudhof TC , JahnR: Proteins of synaptic vesicles involved in exocytosis and membrane recycling.Neuron6(5), 665–677 (1991).
   PubMed Web of Science ®Google Scholar
• Allen PB , OuimetCC, GreengardP: Spinophilin, a novel protein phosphatase 1 binding protein localized to dendritic spines.Proc. Natl Acad. Sci. USA94(18), 9956–9961 (1997).
   PubMed Web of Science ®Google Scholar
• Feng J , YanZ, FerreiraAet al.: Spinophilin regulates the formation and function of dendritic spines. Proc. Natl Acad. Sci. USA97(16), 9287–9292 (2000).
   PubMed Web of Science ®Google Scholar
• Kelly MJ , MossRL, DudleyCA: Differential sensitivity of preoptic-septal neurons to microelectrophoresed estrogen during the estrous cycle.Brain Res.114, 152–157 (1976).
   PubMed Web of Science ®Google Scholar
• Qui J , BoschMA, TobiasSCet al.: Rapid signaling of estrogen in hypothalamic neurons involves a novel G-protein-coupled estrogen receptor that activates protein kinase C. J. Neurosci.23, 9529–9540 (2003).
   PubMed Web of Science ®Google Scholar
• Naberkura J , OomuraY, MinamiT, Mizuno Y, Fukuda A: Mechanism of the rapid effect of 17β-estradiol on medial amygdale neurons. Science233, 226–228 (1986).
   PubMed Web of Science ®Google Scholar
• Mermelstein PG , BeckerJB, SurmeierDJ: Estradiol reduces calcium currents in rat neostriatal neurons via a membrane receptor.J. Neurosci.16, 595–604 (1996).
   PubMed Web of Science ®Google Scholar
• Teter B , Harris-WhiteME, FrautschySA, ColeGM: Role of apolipoprotein E and estrogen in mossy fiber sprouting in hippocampal slice cultures.Neuroscience91, 1009–1016 (1999).
   PubMed Web of Science ®Google Scholar
• Bales KR , VerinaT, CumminsDJet al.: Apolipoprotein E is essential for amyloid deposition in the APP(V717F) transgenic mouse model of Alzheimer‘s disease. Proc. Natl Acad. Sci. USA96(26), 15233–15238 (1999).
   PubMed Web of Science ®Google Scholar
• Garcia-Segura LM , WisePM: Introduction to the special issue on neuroprotection by steroids: new perspectives.J. Neurocytol.29, 305–306 (2000).
   PubMedGoogle Scholar
• Gibbs RB , AggarwalP: Estrogen and basal forebrain cholinergic neurons: implications for brain aging and Alzheimer‘s disease-related cognitive decline.Horm. Behav.34(2), 98–111 (1998).
   PubMed Web of Science ®Google Scholar
• Luine VN , KhylchevskayaRI, McEwenBS: Effect of gonadal steroids on activities of monoamine oxidase and choline acetylase in rat brain.Brain Res.86, 293–306 (1975).
   PubMed Web of Science ®Google Scholar
• Shumaker SA , LegaultC, RappSRet al.: WHIMS Investigators: 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. JAMA289, 2651–2662 (2003).
   PubMed Web of Science ®Google Scholar
• Rapp SR , EspelandMA, ShumakerSA: Effect of estrogen plus progestin on global cognitive function in postmenopausal women: the Women‘s Health Initiative Memory Study: a randomized controlled trial.JAMA289, 2663–2672 (2003).
   PubMed Web of Science ®Google Scholar
• Yaffe K : Hormone therapy and the brain: deja vu all over again?JAMA289(20), 2717–2719 (2003).
   PubMed Web of Science ®Google Scholar
• Baum LW : Sex, hormones, and Alzheimer‘s disease.J. Gerontol. A Biol. Sci. Med. Sci.60(6), 736–743 (2005).
   PubMed Web of Science ®Google Scholar
• Henderson VW : Hormone therapy and Alzheimer‘s disease: benefit or harm?Expert Opin. Pharmacother.5, 389–406 (2004).
   Google Scholar
• Morley JE : Testosterone and behavior.Clin. Geriatr. Med.19(3), 605–616 (2003).
   PubMed Web of Science ®Google Scholar
• Paoletti AM , CongiaS, LelloSet al.: Low androgenization index in elderly women and elderly men with Alzheimer‘s disease. Neurology62(2), 301–303 (2004).
   PubMed Web of Science ®Google Scholar
• Hogervorst E , BandelowS, CombrinckM, SmithAD: Low free testosterone is an independent risk factor for Alzheimer‘s disease.Exp. Gerontol.39(11–12), 1633–1639 (2004).
   PubMed Web of Science ®Google Scholar
• Hoskin EK , TangMX, ManlyJJ, Mayeux R: Elevated sex-hormone binding globulin in elderly women with Alzheimer‘s disease. Neurobiol. Aging25(2), 141–147 (2004).
   PubMed Web of Science ®Google Scholar
• Gillett MJ , MartinsRN, ClarnetteRM, ChubbSA, BruceDG, YeapBB: Relationship between testosterone, sex hormone binding globulin and plasma amyloid β peptide 40 in older men with subjective memory loss or dementia.J. Alzheimers Dis.5(4), 267–269 (2003).
   PubMed Web of Science ®Google Scholar
• MacLennan AH , HendersonVW, PaineBJet al.: Hormone therapy, timing of initiation, and cognition in women aged older than 60 years: the REMEMBER pilot study. Menopause13(1), 28–36 (2006).
   PubMed Web of Science ®Google Scholar
• Daniel JM , LeeCD: Estrogen replacement in ovariectomized rats affects strategy selection in the Morris water maze.Neurobiol. Learn Mem.82(2), 142–149 (2006).
   Web of Science ®Google Scholar
• Brinton RD : Requirements of a brain selective estrogen: advances and remaining challenges for developing a neuroSERM.J. Alzheimers Dis.6, S27–S35 (2004).
   PubMed Web of Science ®Google Scholar
• Ishii H , TsurugizawaT, Ogiue-IkedaMet al.: Local production of sex hormones and their modulation of hippocampal synaptic plasticity. Neuroscientist13(4), 323–334 (2007).
   PubMed Web of Science ®Google Scholar
• Lloyd JM , HoffmanGE, WisePM: Decline in immediate early gene expression in gonadotropin-releasing hormone neurons during proestrus in regularly cycling, middle-aged rats.Endocrinology134(4), 1800–1805 (1994).
   PubMed Web of Science ®Google Scholar
• Park OK , GugnejaS, MayoKE: Gonadotropin-releasing hormone gene expression during the rat estrous cycle: effects of pentobarbital and ovarian steroids.Endocrinology127(1), 365–372 (1990).
   PubMed Web of Science ®Google Scholar
• King JC , AnthonyEL, DamassaDA, Elkind-HirschKE: Morphological evidence that luteinizing hormone-releasing hormone neurons participate in the suppression by estradiol of pituitary luteinizing hormone secretion in ovariectomized rats.Neuroendocrinology45(1), 1–13 (1987).
   PubMed Web of Science ®Google Scholar
• Gibbs RB : Long-term treatment with estrogen and progesterone enhances acquisition of a spatial memory task by ovariectomized aged rats.Neurobiol. Aging21, 107–116 (2000).
   PubMed Web of Science ®Google Scholar
• Sherwin BB : Estrogen and memory in women: how can we reconcile the findings?Horm. Behav.47, 371–375 (2005).
   PubMed Web of Science ®Google Scholar
• Lei AM , RaoCV, KornyeiJL, LichtP, Hiatt ES: Novel expression of human chorionic gonadotropin/luteinizing hormone receptor gene in brain. Endocrinology132, 2262–2270 (1993).
   PubMed Web of Science ®Google Scholar
• Welt C , SidisY, KeutmannH, SchneyerA: Activins, inhibins, and follistatins: from endocrinology to signaling. A paradigm for the new millennium.Exp. Biol. Med.227, 724–752 (2002).
   PubMed Web of Science ®Google Scholar
• Bowen RL , IsleyJP, AtkinsonRL: An association of elevated serum gonadotropin concentrations and Alzheimer disease?J. Neuroendocrinol.12(4), 351–354 (2000).
   PubMed Web of Science ®Google Scholar
• Short RA , BowenRL, O‘BrienPC, Graff-RadfordNR: Elevated gonadotropin levels in patients with Alzheimer disease.Mayo Clin. Proc.76(9), 906–909 (2001).
   PubMed Web of Science ®Google Scholar
• Zandi PP , CarlsonMC, PlassmanBLet al.; Cache County Memory Study Investigators: Hormone replacement therapy and incidence of Alzheimer disease in older women: the Cache County Study.JAMA288, 2123–2129 (2002).
   PubMed Web of Science ®Google Scholar
• Markowska AL , SavonenkoAV: Effectiveness of estrogen replacement in restoration of cognitive function after long-term estrogen withdrawal in aging rats.J. Neurosci.22, 10985–10995 (2002).
   PubMed Web of Science ®Google Scholar
• Casadesus G , MillikenEL, WebberKMet al.: Increases in luteinizing hormone/human chorionic gonadotropin receptor gene. Mol. Endocrinol.15, 184–200 (2007).
   Google Scholar
• Casadesus G , WebberKM, AtwoodCSet al.: Luteinizing hormone modulates cognition and amyloid-β deposition in Alzheimer APP transgenic mice. Biochim. Biophys. Acta1762(4), 447–452 (2006).
   PubMed Web of Science ®Google Scholar
• Bowen RL , VerdileG, LiuTet al.: Luteinizing hormone, a reproductive regulator that modulates the processing of amyloid-β precursor protein and amyloid β deposition. J. Biol. Chem.279(19), 20539–20545 (2004).
   PubMed Web of Science ®Google Scholar
• Beer TM , BlandLB, BussiereJRet al.: Testosterone loss and estradiol administration modify memory in men. J. Urol.175(1), 130–135 (2006).
   PubMed Web of Science ®Google Scholar
• Cherrier M , RoseA, HiganoC: The effects of combined androgen blockade on cognitive function during the first cycle of intermittent androgen suppression in patients with prostate cancer.J. Urol.170(5), 1808–1811 (2003).
   PubMed Web of Science ®Google Scholar
• Gordon HW , CorbinED, LeePA: Changes in specialized cognitive function following changes in hormone levels.Cortex22, 399–415 (1986).
   PubMed Web of Science ®Google Scholar
• Green HJ , PakenhamKI, HeadleyBC, YaxleyJ, NicolDL, MactaggartPN: Altered cognitive function in men treated for prostate cancer with luteinizing hormone-releasing hormone analogues and cyproterone acetate: a randomized controlled trial.BJU Int.90(4), 427–432 (2002).
   PubMed Web of Science ®Google Scholar
• Berman KF , SchmidtPJ, RubinowJJet al.: Modulation of cognition-specific cortical activity by gonadal steroids: a positron-emission tomography study in women. Proc. Natl Acad. Sci. USA94, 8836–8841 (1997).
   PubMed Web of Science ®Google Scholar
• Grigorova M , SherwinBB, TulandiT: Effects of treatment with leuprolide acetate depot on working memory and executive functions in young premenopausal women.Psychoneuroendocrinology31(8), 935–947 (2006).
   PubMed Web of Science ®Google Scholar
• Varney NR , SyropC, KubuCS, Struchen M, Hahn S, Franzen K: Neuropsychological dysfunction in women following leuprolide acetate induction of hypoestrogenism. J. Assist. Reprod. Genet.10, 53–57 (1993).
   PubMed Web of Science ®Google Scholar
• Handelsman DJ : Male reproductive ageing: human fertility, androgens and hormone dependent disease.Novartis Found. Symp.242, 66–77 (2002).
   PubMedGoogle Scholar
• Pommerville PJ , ZakusP: Andropause: knowledge and awareness among primary care physicians in Victoria, BC, Canada.Aging Male9, 215–220 (2006).
   PubMed Web of Science ®Google Scholar
• Jannini EA , CarosaE, RossiS, Di Sante S, Sebastiani G, Lenzi A: Ageing and male sexuality. Minerva Ginecol.59, 35–41 (2007).
   PubMedGoogle Scholar
• Hogervorst E , BandelowS, MoffatSD: Increasing testosterone levels and effects on cognitive functions in elderly men and women: a review.Curr. Drug Targets CNS Neurol. Disord.4, 531–540 (2005).
   PubMedGoogle Scholar
• Bowen RL , SmithMA, HarrisPL: Elevated luteinizing hormone expression colocalizes with neurons vulnerable to Alzheimer‘s disease pathology.J. Neurosci. Res.70(3), 514–518 (2002).
   PubMed Web of Science ®Google Scholar

Website

• Clinical trials; ALADDIN Study: Antigonadotropin–Leuprolide in Alzheimer‘s Disease Drug Investigation http://clinicaltrials.gov/ct2/show/NCT00063310?term=leuprolide+acetate&rank=19
   Google Scholar