Neuropsychiatric Aspects in Men with Klinefelter Syndrome

Author(s): Vito Angelo Giagulli*, Beatrice Campone, Marco Castellana, Ciro Salzano, Alessandra Daphne Fisher, Cristina de Angelis, Rosario Pivonello, Annamaria Colao, Daniela Pasquali, Mario Maggi, Vincenzo Triggiani, On behalf of the Klinefelter ItaliaN Group (KING).

Journal Name: Endocrine, Metabolic & Immune Disorders - Drug Targets
(Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders)

Volume 19 , Issue 2 , 2019

Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

Background and objective: Klinefelter Syndrome (KS) is the most common sex chromosome aneuploidy (47, XXY) and cause of male hypergonadotropic hypogonadism. It is characterized by an extreme clinical heterogeneity in presentation, including infertility, hypogonadism, language delay, metabolic comorbidities, and neurocognitive and psychiatric disorders. Since testosterone is known to have organizational, neurotrophic and neuroprotective effects on brain, the condition of primary hypogonadism could play a role. Moreover, given that KS subjects have an additional X, genes on the extra-chromosome could also exert a significant impact. The aim of this narrative review is to analyze the available literature on the relationship between KS and neuropsychiatric disorders.

Methods: To extend to the best of published literature on the topic, appropriate keywords and MeSH terms were identified and searched in Pubmed. Finally, references of original articles and reviews were examined.

Results: Both morphological and functional studies focusing on the brain showed that there were important differences in brain structure of KS subjects. Different psychiatric disorders such as Schizophrenia, autism, attention deficit hyperactivity disorder, depression and anxiety were frequently reported in KS patients according to a broad spectrum of phenotypes. T supplementation (TRT) was not able to improve the psychotic disorders in KS men with or without overt hypogonadism.

Conclusion: Although the risk of psychosis, depression and autism is increased in subjects with KS, no definitive evidence has been found in studies aiming at identifying the relationship between aneuploidy, T deficit and the risk of psychiatric and cognitive disorders in subjects affected by KS.

Keywords: Klinefelter Syndrome, Hypergonadotropic hypogonadism, testosterone, autism, schizophrenia, attention deficit, hyperactivity disorder, depression; anxiety.

[1]
Crow, T.J. The XY gene hypothesis of psychosis: Origins and current status. Am. J. Med. Genet. B. Neuropsychiatr. Genet., 2013, 162B(8), 800-824.
[2]
Bao, A.M.; Swaab, D.F. Sex differences in the brain, behavior, and neuropsychiatric disorders. Neuroscientist, 2010, 16(5), 550-565.
[3]
Barrick, T.R.; Mackay, C.E.; Prima, S.; Maes, F.; Vandermeulen, D.; Crow, T.J.; Roberts, N. Automatic analysis of cerebral asymmetry: An exploratory study of the relationship between brain torque and planum temporale asymmetry. Neuroimage, 2005, 24(3), 678-691.
[4]
Zitzmann, M.; Depenbusch, M.; Gromoll, J.; Nieschlag, E. X-chromosome inactivation patterns and androgen receptor functionality influence phenotype and social characteristics as well as pharmacogenetics of testosterone therapy in Klinefelter patients. J. Clin. Endocrinol. Metab., 2004, 89(12), 6208-6217.
[5]
Wikström, A.M.; Painter, J.N.; Raivio, T.; Aittomäki, K.; Dunkel, L. Genetic features of the X chromosome affect pubertal development and testicular degeneration in adolescent boys with Klinefelter syndrome. Clin. Endocrinol. (Oxf.), 2006, 65(1), 92-97.
[6]
Giagulli, V.A.; Guastamacchia, E.; Licchelli, B.; Triggiani, V. Serum testosterone and cognitive function in ageing male: Updating the evidence. Recent Pat. Endocr. Metab. Immune Drug Discov., 2016, 10(1), 22-30.
[7]
Bojesen, A.; Juul, S.; Gravholt, C.H. Prenatal and postnatal prevalence of Klinefelter syndrome: A national registry study. J. Clin. Endocrinol. Metab., 2003, 88(2), 622-626.
[8]
Lanfranco, F.; Kamischke, A.; Zitzmann, M.; Nieschlag, E. Klinefelter’s syndrome. Lancet, 2004, 364(9430), 273-283.
[9]
Bonomi, M.; Rochira, V.; Pasquali, D.; Balercia, G.; Jannini, E.A.; Ferlin, A.; Klinefelter Italia, N. Group (KING). Klinefelter syndrome (KS): Genetics, clinical phenotype and hypogonadism. J. Endocrinol. Invest., 2017, 40(2), 123-134.
[10]
Stochholm, K.; Bojesen, A.; Jensen, A.S.; Juul, S.; Gravholt, C.H. Criminality in men with Klinefelter’s syndrome and XYY syndrome: A cohort study. BMJ Open, 2012, 2(1), e000650.
[11]
Bastida, M.G.; Rey, R.A.; Bergadá, I.; Bedecarrás, P.; Andreone, L.; del Rey, G.; Boywitt, A.; Ropelato, M.G.; Cassinelli, H.; Arcari, A.; Campo, S.; Gottlieb, S. Establishment of testicular endocrine function impairment during childhood and puberty in boys with Klinefelter syndrome. Clin. Endocrinol. (Oxf.), 2007, 67(6), 863-870.
[12]
Corona, G.; Petrone, L.; Paggi, F.; Lotti, F.; Boddi, V.; Fisher, A.; Vignozzi, L.; Balercia, G.; Sforza, A.; Forti, G.; Mannucci, E.; Maggi, M. Sexual dysfunction in subjects with Klinefelter’s syndrome. Int. J. Androl., 2010, 33(4), 574-580.
[13]
Corona, G.; Pizzocaro, A.; Lanfranco, F.; Garolla, A.; Pelliccione, F.; Vignozzi, L.; Ferlin, A.; Foresta, C.; Jannini, E.A.; Maggi, M.; Lenzi, A.; Pasquali, D.; Francavilla, S.; Klinefelter Italia, N. Group (KING). Sperm recovery and ICSI outcomes in Klinefelter syndrome: A systematic review and meta-analysis. Hum. Reprod. Update, 2017, 23(3), 265-275.
[14]
Calogero, A.E.; Giagulli, V.A.; Mongioì, L.M.; Triggiani, V.; Radicioni, A.F.; Jannini, E.A.; Pasquali, D.; Klinefelter Italia, N. Group (KING). Klinefelter syndrome: Cardiovascular abnormalities and metabolic disorders. J. Endocrinol. Invest., 2017, 40(7), 705-712.
[15]
Mehta, A.; Paduch, D.A. Klinefelter syndrome: An argument for early aggressive hormonal and fertility management. Fertil. Steril., 2012, 98(2), 274-283.
[16]
Ross, J.L.; Roeltgen, D.P.; Stefanatos, G.; Benecke, R.; Zeger, M.P.; Kushner, H.; Ramos, P.; Elder, F.F.; Zinn, A.R. Cognitive and motor development during childhood in boys with Klinefelter syndrome. Am. J. Med. Genet. A., 2008, 146A(6), 708-719.
[17]
Gies, I.; Unuane, D.; Velkeniers, B.; De Schepper, J. Management of Klinefelter syndrome during transition. Eur. J. Endocrinol., 2014, 171(2), R67-R77.
[18]
Skakkebæk, A.; Gravholt, C.H.; Rasmussen, P.M.; Bojesen, A.; Jensen, J.S.; Fedder, J.; Laurberg, P.; Hertz, J.M.; Ostergaard, J.R.; Pedersen, A.D.; Wallentin, M. Neuroanatomical correlates of Klinefelter syndrome studied in relation to the neuropsychological profile. Neuroimage Clin., 2013, 4, 1-9.
[19]
DeLisi, L.E.; Maurizio, A.M.; Svetina, C.; Ardekani, B.; Szulc, K.; Nierenberg, J.; Leonard, J.; Harvey, P.D. Klinefelter’s syndrome (XXY) as a genetic model for psychotic disorders. Am. J. Med. Genet. B. Neuropsychiatr. Genet., 2005, 135B(1), 15-23.
[20]
Bryant, D.M.; Hoeft, F.; Lai, S.; Lackey, J.; Roeltgen, D.; Ross, J.; Reiss, A.L. Neuroanatomical phenotype of Klinefelter syndrome in childhood: A voxel-based morphometry study. J. Neurosci., 2011, 31(18), 6654-6660.
[21]
Giedd, J.N.; Clasen, L.S.; Wallace, G.L.; Lenroot, R.K.; Lerch, J.P.; Wells, E.M.; Blumenthal, J.D.; Nelson, J.E.; Tossell, J.W.; Stayer, C.; Evans, A.C.; Samango-Sprouse, C.A. XXY (Klinefelter syndrome): A pediatric quantitative brain magnetic resonance imaging case-control study. Pediatrics, 2007, 119(1), e232-e240.
[22]
Patwardhan, A.J.; Brown, W.E.; Bender, B.G.; Linden, M.G.; Eliez, S.; Reiss, A.L. Reduced size of the amygdala in individuals with 47,XXY and 47,XXX karyotypes. Am. J. Med. Genet., 2002, 114(1), 93-98.
[23]
Shen, D.; Liu, D.; Liu, H.; Clasen, L.; Giedd, J.; Davatzikos, C. Automated morphometric study of brain variation in XXY males. Neuroimage, 2004, 23(2), 648-653.
[24]
Itti, E.; Gaw Gonzalo, I.T.; Pawlikowska-Haddal, A.; Boone, K.B.; Mlikotic, A.; Itti, L.; Mishkin, F.S.; Swerdloff, R.S. The structural brain correlates of cognitive deficits in adults with Klinefelter’s syndrome. J. Clin. Endocrinol. Metab., 2006, 91(4), 1423-1427.
[25]
Warwick, M.M.; Doody, G.A.; Lawrie, S.M.; Kestelman, J.N.; Best, J.J.; Johnstone, E.C. Volumetric magnetic resonance imaging study of the brain in subjects with sex chromosome aneuploidies. J. Neurol. Neurosurg. Psychiatry, 1999, 66(5), 628-632.
[26]
Kasahara, M. Abstracts of 17th Annual Meeting of the Organization for Human Brain Mapping, Quebec City, Canada2011.
[27]
Parent, A. Cerebral cortex. In: Carpenter’s Human Neuroanatomy. 9th edition; Williams Wilkins; United Stated of America, 1996; pp 890;
[28]
Itti, E.; Gaw Gonzalo, I.T.; Boone, K.B.; Geschwind, D.H.; Berman, N.; Pawlikowska-Haddal, A.; Itti, L.; Mishkin, F.S.; Swerdloff, R.S. Functional neuroimaging provides evidence of anomalous cerebral laterality in adults with Klinefelter’s syndrome. Ann. Neurol., 2003, 54(5), 669-673.
[29]
van Rijn, S.; Swaab, H.; Baas, D.; de Haan, E.; Kahn, R.S.; Aleman, A. Neural systems for social cognition in Klinefelter syndrome (47,XXY): Evidence from fMRI. Soc. Cogn. Affect. Neurosci., 2012, 7(6), 689-697.
[30]
van Rijn, S.; Aleman, A.; Swaab, H.; Vink, M.; Sommer, I.; Kahn, R.S. Effects of an extra X chromosome on language lateralization: An fMRI study with Klinefelter men(47,XXY). Schizophr. Res., 2008, 101(1-3), 17-25.
[31]
Patwardhan, A.J.; Eliez, S.; Bender, B.; Linden, M.G.; Reiss, A.L. Brain morphology in Klinefelter syndrome: Extra X chromosome and testosterone supplementation. Neurology, 2000, 54(12), 2218-2223.
[32]
Bojesen, A.; Juul, S.; Birkebaek, N.H.; Gravholt, C.H. Morbidity in Klinefelter syndrome: A Danish register study based on hospital discharge diagnoses. J. Clin. Endocrinol. Metab., 2006, 91(4), 1254-1260.
[33]
DeLisi, L.E.; Friedrich, U.; Wahlstrom, J.; Boccio-Smith, A.; Forsman, A.; Eklund, K.; Crow, T.J. Schizophrenia and sex chromosome anomalies. Schizophr. Bull., 1994, 20(3), 495-505.
[34]
van Rijn. S.; Aleman, A.; Swaab, H.; Kahn, R. Klinefelter’s syndrome (karyotype 47,XXY) and schizophrenia-spectrum pathology. Br. J. Psychiatry, 2006, 189, 459-460.
[35]
van Rijn, S.; Swaab, H.; Aleman, A.; Kahn, R.S. Social behavior and autism traits in a sex chromosomal disorder: Klinefelter (47XXY) syndrome. J. Autism Dev. Disord., 2008, 38(9), 1634-1641.
[36]
Bruining, H.; Swaab, H.; Kas, M.; van Engeland, H. Psychiatric characteristics in a self-selected sample of boys with Klinefelter syndrome. Pediatrics, 2009, 123(5), e865-e870.
[37]
Kumra, S.; Wiggs, E.; Krasnewich, D.; Meck, J.; Smith, A.C.; Bedwell, J.; Fernandez, T.; Jacobsen, L.K.; Lenane, M.; Rapoport, J.L. Brief report: Association of sex chromosome anomalies with childhood-onset psychotic disorders. J. Am. Acad. Child Adolesc. Psychiatry, 1998, 37(3), 292-296.
[38]
Bishop, D.V.; Jacobs, P.A.; Lachlan, K.; Wellesley, D.; Barnicoat, A.; Boyd, P.A.; Fryer, A.; Middlemiss, P.; Smithson, S.; Metcalfe, K.; Shears, D.; Leggett, V.; Nation, K.; Scerif, G. Autism, language and communication in children with sex chromosome trisomies. Arch. Dis. Child., 2011, 96(10), 954-959.
[39]
Nielsen, J.; Wohlert, M. Chromosome abnormalities found among 34,910 newborn children: Results from a 13-year incidence study in Arhus, Denmark. Hum. Genet., 1991, 87(1), 81-83.
[40]
Kumra, S.; Jacobsen, L.K.; Lenane, M.; Zahn, T.P.; Wiggs, E.; Alaghband-Rad, J.; Castellanos, F.X.; Frazier, J.A.; McKenna, K.; Gordon, C.T.; Smith, A.; Hamburger, S.; Rapoport, J.L. “Multidimensionally impaired disorder”: Is it a variant of very early-onset schizophrenia? J. Am. Acad. Child Adolesc. Psychiatry, 1998, 37(1), 91-99.
[41]
Boks, M.P.; de Vette, M.H.; Sommer, I.E.; van Rijn, S.; Giltay, J.C.; Swaab, H.; Kahn, R.S. Psychiatric morbidity and X-chromosomal origin in a Klinefelter sample. Schizophr. Res., 2007, 93(1-3), 399-402.
[42]
Gottesman, I.I.; Gould, T.D. The endophenotype concept in psychiatry: Etymology and strategic intentions. Am. J. Psychiatry, 2003, 160(4), 636-645.
[43]
Mandoki, M.W.; Sumner, G.S.; Hoffman, R.P.; Riconda, D.L. A review of Klinefelter’s syndrome in children and adolescents. J. Am. Acad. Child Adolesc. Psychiatry, 1991, 30(2), 167-172.
[44]
Bender, B.G.; Harmon, R.J.; Linden, M.G.; Robinson, A. Psychosocial adaptation of 39 adolescents with sex chromosome abnormalities. Pediatrics, 1995, 96(2 Pt 1), 302-308.
[45]
Walzer, S.; Wolff, P.H.; Bowen, D.; Silbert, A.R.; Bashir, A.S.; Gerald, P.S.; Richmond, J.B. A method for the longitudinal study of behavioral development in infants and children: The early development of XXY children. J. Child Psychol. Psychiatry, 1978, 19(3), 213-229.
[46]
Cannon, T.D. The inheritance of intermediate phenotypes for schizophrenia. Curr. Opin. Psychiatry, 2005, 18(2), 135-140.
[47]
O’Driscoll, G.A.; Callahan, B.L. Smooth pursuit in schizophrenia: A meta-analytic review of research since 1993. Brain Cogn., 2008, 68(3), 359-370.
[48]
Levy, D.L.; Holzman, P.S.; Matthysse, S.; Mendell, N.R. Eye tracking dysfunction and schizophrenia: A critical perspective. Schizophr. Bull., 1993, 19(3), 461-536.
[49]
Calkins, M.E.; Iacono, W.G. Eye movement dysfunction in schizophrenia: A heritable characteristic for enhancing phenotype definition. Am. J. Med. Genet., 2000, 97(1), 72-76.
[50]
Adler, L.E.; Olincy, A.; Waldo, M.; Harris, J.G.; Griffith, J.; Stevens, K.; Flach, K.; Nagamoto, H.; Bickford, P.; Leonard, S.; Freedman, R. Schizophrenia, sensory gating, and nicotinic receptors. Schizophr. Bull., 1998, 24(2), 189-202.
[51]
Aukes, M.F.; Alizadeh, B.Z.; Sitskoorn, M.M.; Selten, J.P.; Sinke, R.J.; Kemner, C.; Ophoff, R.A.; Kahn, R.S. Finding suitable phenotypes for genetic studies of schizophrenia: Hheritability and segregation analysis. Biol. Psychiatry, 2008, 64(2), 128-136.
[52]
Cadenhead, K.S.; Swerdlow, N.R.; Braff, D.L. Relative risk of prepulse inhibition deficits in schizophrenia patients and their siblings. Biol. Psychiatry, 2001, 49(8), 126S-126S.
[53]
Ettinger, U.; Kumari, V.; Crawford, T.J.; Corr, P.J.; Das, M.; Zachariah, E.; Hughes, C.; Sumich, A.L.; Rabe-Hesketh, S.; Sharma, T. Smooth pursuit and antisaccade eye movements in siblings discordant for schizophrenia. J. Psychiatr. Res., 2004, 38(2), 177-184.
[54]
Karoumi, B.; Saoud, M.; d’Amato, T.; Rosenfeld, F.; Denise, P.; Gutknecht, C.; Gaveau, V.; Beaulieu, F.E.; Daléry, J.; Rochet, T. Poor performance in smooth pursuit and antisaccadic eye-movement tasks in healthy siblings of patients with schizophrenia. Psychiatry Res., 2001, 101(3), 209-219.
[55]
Wynn, J.K.; Dawson, M.E.; Schell, A.M.; McGee, M.; Salveson, D.; Green, M.F. Prepulse facilitation and prepulse inhibition in schizophrenia patients and their unaffected siblings. Biol. Psychiatry, 2004, 55(5), 518-523.
[56]
Oranje, B.; Geyer, M.A.; Bocker, K.B.; Leon Kenemans, J.; Verbaten, M.N. Prepulse inhibition and P50 suppression: Commonalities and dissociations. Psychiatry Res., 2006, 143(2-3), 147-158.
[57]
Boada, R.; Janusz, J.; Hutaff-Lee, C.; Tartaglia, N. The cognitive phenotype in Klinefelter syndrome: A review of the literature including genetic and hormonal factors. Dev. Disabil. Res. Rev., 2009, 15(4), 284-294.
[58]
Boone, K.B.; Swerdloff, R.S.; Miller, B.L.; Geschwind, D.H.; Razani, J.; Lee, A.; Gonzalo, I.G.; Haddal, A.; Rankin, K.; Lu, P.; Paul, L. Neuropsychological profiles of adults with Klinefelter syndrome. J. Int. Neuropsychol. Soc., 2001, 7(4), 446-456.
[59]
van Rijn, S.; Swaab, H. Vulnerability for psychopathology in Klinefelter syndrome: Age-specific and cognitive-specific risk profiles. Acta Paediatr., 2011, 100(6), 908-916.
[60]
Amminger, G.P.; Schlögelhofer, M.; Lehner, T.; Looser Ott, S.; Friedrich, M.H.; Aschauer, H.N. Premorbid performance IQ deficit in schizophrenia. Acta Psychiatr. Scand., 2000, 102(6), 414-422.
[61]
Ott, S.L.; Spinelli, S.; Rock, D.; Roberts, S.; Amminger, G.P.; Erlenmeyer-Kimling, L. The New York High-Risk Project: Social and general intelligence in children at risk for schizophrenia. Schizophr. Res., 1998, 31(1), 1-11.
[62]
Lawrie, S.M.; Abukmeil, S.S. Brain abnormality in schizophrenia. A systematic and quantitative review of volumetric magnetic resonance imaging studies. Br. J. Psychiatry, 1998, 172, 110-120.
[63]
McCarley, R.W.; Wible, C.G.; Frumin, M.; Hirayasu, Y.; Levitt, J.J.; Fischer, I.A.; Shenton, M.E. MRI anatomy of schizophrenia. Biol. Psychiatry, 1999, 45(9), 1099-1119.
[64]
Wright, I.C.; Rabe-Hesketh, S.; Woodruff, P.W.; David, A.S.; Murray, R.M.; Bullmore, E.T. Meta-analysis of regional brain volumes in schizophrenia. Am. J. Psychiatry, 2000, 157(1), 16-25.
[65]
Bogerts, B.; Ashtari, M.; Degreef, G.; Alvir, J.M.; Bilder, R.M.; Lieberman, J.A. Reduced temporal limbic structure volumes on magnetic resonance images in first episode schizophrenia. Psychiatry Res., 1990, 35(1), 1-13.
[66]
Breier, A.; Buchanan, R.W.; Elkashef, A.; Munson, R.C.; Kirkpatrick, B.; Gellad, F. Brain morphology and schizophrenia. A magnetic resonance imaging study of limbic, prefrontal cortex, and caudate structures. Arch. Gen. Psychiatry, 1992, 49(12), 921-926.
[67]
Shenton, M.E.; Kikinis, R.; Jolesz, F.A.; Pollak, S.D.; LeMay, M.; Wible, C.G.; Hokama, H.; Martin, J.; Metcalf, D.; Coleman, M.; McCarley, R.W. Abnormalities of the left temporal lobe and thought disorder in schizophrenia. A quantitative magnetic resonance imaging study. N. Engl. J. Med., 1992, 327(9), 604-612.
[68]
Pearlson, G.D.; Barta, P.E.; Powers, R.E.; Menon, R.R.; Richards, S.S.; Aylward, E.H.; Federman, E.B.; Chase, G.A.; Petty, R.G.; Tien, A.Y. Ziskind-Somerfeld Research Award 1996. Medial and superior temporal gyral volumes and cerebral asymmetry in schizophrenia versus bipolar disorder. Biol. Psychiatry, 1997, 41(1), 1-14.
[69]
Bryant, N.L.; Buchanan, R.W.; Vladar, K.; Breier, A.; Rothman, M. Gender differences in temporal lobe structures of patients with schizophrenia: A volumetric MRI study. Am. J. Psychiatry, 1999, 156(4), 603-609.
[70]
Sanderson, T.L.; Best, J.J.; Doody, G.A.; Owens, D.G.; Johnstone, E.C. Neuroanatomy of comorbid schizophrenia and learning disability: A controlled study. Lancet, 1999, 354(9193), 1867-1871.
[71]
Ratcliffe, S.G.; Butler, G.E.; Jones, M. Edinburgh study of growth and development of children with sex chromosome abnormalities. IV. Birth Defects Orig. Artic. Ser., 1990, 26(4), 1-44.
[72]
Bender, B.G.; Harmon, R.J.; Linden, M.G.; Bucher-Bartelson, B.; Robinson, A. Psychosocial competence of unselected young adults with sex chromosome abnormalities. Am. J. Med. Genet., 1999, 88(2), 200-206.
[73]
Turriff, A.; Levy, H.P.; Biesecker, B. Klinefelter syndrome. Prevalence and psychosocial correlates of depressive symptoms among adolescents and adults with Klinefelter syndrome. Genet. Med., 2011, 13(11), 966-972.
[74]
Miyagawa, Y.; Tsujimura, A.; Fujita, K.; Matsuoka, Y.; Takahashi, T.; Takao, T.; Takada, S.; Matsumiya, K.; Osaki, Y.; Takasawa, M.; Oku, N.; Hatazawa, J.; Kaneko, S.; Okuyama, A. Differential brain processing of audiovisual sexual stimuli in men: Comparative positron emission tomography study of the initiation and maintenance of penile erection during sexual arousal. Neuroimage, 2007, 36(3), 830-842.
[75]
Drevets, W.C.; Videen, T.O.; Price, J.L.; Preskorn, S.H.; Carmichael, S.T.; Raichle, M.E. A functional anatomical study of unipolar depression. J. Neurosci., 1992, 12(9), 3628-3641.
[76]
LeDoux, J.E. Emotion: Clues from the brain. Annu. Rev. Psychol., 1995, 46, 209-235.
[77]
Amen, D.G.; Stubblefield, M.; Carmicheal, B.; Thisted, R. Brain SPECT findings and aggressiveness. Ann. Clin. Psychiatry, 1996, 8(3), 129-137.
[78]
Gould, E.; Woolley, C.S.; Frankfurt, M.; McEwen, B.S. Gonadal steroids regulate dendritic spine density in hippocampal pyramidal cells in adulthood. J. Neurosci., 1990, 10(4), 1286-1291.
[79]
Simerly, R.B.; Chang, C.; Muramatsu, M.; Swanson, L.W. Distribution of androgen and estrogen receptor mRNA-containing cells in the rat brain: An in situ hybridization study. J. Comp. Neurol., 1990, 294(1), 76-95.
[80]
Yokosuka, M.; Okamura, H.; Hayashi, S. Postnatal development and sex difference in neurons containing estrogen receptor-alpha immunoreactivity in the preoptic brain, the diencephalon, and the amygdala in the rat. J. Comp. Neurol., 1997, 389(1), 81-93.
[81]
Sarrieau, A.; Mitchell, J.B.; Lal, S.; Olivier, A.; Quirion, R.; Meaney, M.J. Androgen binding sites in human temporal cortex. Neuroendocrinology, 1990, 51(6), 713-716.
[82]
Axelson, D.A.; Doraiswamy, P.M.; McDonald, W.M.; Boyko, O.B.; Tupler, L.A.; Patterson, L.J.; Nemeroff, C.B.; Ellinwood, E.H., Jr; Krishnan, K.R. Hypercortisolemia and hippocampal changes in depression. Psychiatry Res., 1993, 47(2), 163-173.
[83]
Drevets, W.C. Prefrontal cortical-amygdalar metabolism in major depression. Ann. N. Y. Acad. Sci., 1999, 877, 614-637.
[84]
Shores, M.M.; Sloan, K.L.; Matsumoto, A.M.; Moceri, V.M.; Felker, B.; Kivlahan, D.R. Increased incidence of diagnosed depressive illness in hypogonadal older men. Arch. Gen. Psychiatry, 2004, 61(2), 162-167.
[85]
Almeida, O.P.; Yeap, B.B.; Hankey, G.J.; Jamrozik, K.; Flicker, L. Low free testosterone concentration as a potentially treatable cause of depressive symptoms in older men. Arch. Gen. Psychiatry, 2008, 65(3), 283-289.
[86]
Wang, C.; Swerdloff, R.S.; Iranmanesh, A.; Dobs, A.; Snyder, P.J.; Cunningham, G.; Matsumoto, A.M.; Weber, T.; Berman, N. Testosterone Gel Study Group. Transdermal testosterone gel improves sexual function, mood, muscle strength, and body composition parameters in hypogonadal men. J. Clin. Endocrinol. Metab., 2000, 85(8), 2839-2853.
[87]
Wang, C.; Cunningham, G.; Dobs, A.; Iranmanesh, A.; Matsumoto, A.M.; Snyder, P.J.; Weber, T.; Berman, N.; Hull, L.; Swerdloff, R.S. Long-term testosterone gel (AndroGel) treatment maintains beneficial effects on sexual function and mood, lean and fat mass, and bone mineral density in hypogonadal men. J. Clin. Endocrinol. Metab., 2004, 89(5), 2085-2098.
[88]
Steidle, C.; Schwartz, S.; Jacoby, K.; Sebree, T.; Smith, T.; Bachand, R. North American AA2500 T Gel Study Group. AA2500 testosterone gel normalizes androgen levels in aging males with improvements in body composition and sexual function. J. Clin. Endocrinol. Metab., 2003, 88(6), 2673-2681.
[89]
Tartaglia, N.; Cordeiro, L.; Howell, S.; Wilson, R.; Janusz, J. The spectrum of the behavioral phenotype in boys and adolescents 47,XXY (Klinefelter syndrome). Pediatr. Endocrinol. Rev., 2010, 8(Suppl. 1), 151-159.
[90]
Ratcliffe, S. Long-term outcome in children of sex chromosome abnormalities. Arch. Dis. Child., 1999, 80(2), 192-195.
[91]
Geschwind, D.H.; Dykens, E. Neurobehavioral and Psychosocial Issues in Klinefelter Syndrome. Learn. Disabil. Res. Pract., 2014, 19(3), 166-173.
[92]
Visootsak, J.; Graham, J.M., Jr Social function in multiple X and Y chromosome disorders: XXY, XYY, XXYY, XXXY. Dev. Disabil. Res. Rev., 2009, 15(4), 328-332.
[93]
Robinson, A.; Bender, B.G.; Linden, M.G.; Salbenblatt, J.A. Sex chromosome aneuploidy: The denver prospective study. Birth Defects Orig. Artic. Ser., 1990, 26(4), 59-115.
[94]
Stewart, D.A.; Bailey, J.D.; Netley, C.T.; Rovet, J.; Park, E.; Cripps, M.; Curtis, J.A. Growth and development of children with X and Y chromosome aneuploidy from infancy to pubertal age: The Toronto study. Birth Defects Orig. Artic. Ser., 1982, 18(4), 99-154.
[95]
Bak, C.W.; Byun, J.S.; Lee, J.H.; Park, J.H.; Lee, K.A.; Shim, S.H. Clinical and social characteristics of Korean men with Klinefelter syndrome. Int. J. Urol., 2012, 19(5), 443-449.
[96]
Bender, B.G.; Linden, M.G.; Robinson, A. Verbal and spatial processing efficiency in 32 children with sex chromosome abnormalities. Pediatr. Res., 1989, 25(6), 577-579.
[97]
Bender, B.G.; Linden, M.G.; Robinson, A. Neuropsychological impairment in 42 adolescents with sex chromosome abnormalities. Am. J. Med. Genet., 1993, 48(3), 169-173.
[98]
Graham, J.M., Jr; Bashir, A.S.; Stark, R.E.; Silbert, A.; Walzer, S. Oral and written language abilities of XXY boys: Implications for anticipatory guidance. Pediatrics, 1988, 81(6), 795-806.
[99]
Netley, C.; Rovet, J. Verbal deficits in children with 47,XXY and 47,XXX karyotypes: A descriptive and experimental study. Brain Lang., 1982, 17(1), 58-72.
[100]
Heaton-Ward, A. Psychosis in mental handicap. The tenth blake marsh lecture delivered before the royal college of psychiatrists, February 2, 1976. Br. J. Psychiatry, 1977, 130, 525-533.
[101]
Doody, G.A.; Johnstone, E.C.; Sanderson, T.L.; Owens, D.G.; Muir, W.J. ‘Pfropfschizophrenie’ revisited. Schizophrenia in people with mild learning disability. Br. J. Psychiatry, 1998, 173, 145-153.


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 19
ISSUE: 2
Year: 2019
Page: [109 - 115]
Pages: 7
DOI: 10.2174/1871530318666180703160250
Price: $58

Article Metrics

PDF: 48
HTML: 2