Metabolic Brain Disease

, Volume 33, Issue 2, pp 491–505 | Cite as

Neuroanatomical and molecular correlates of cognitive and behavioural outcomes in hypogonadal males

  • O. B. Akinola
  • M. O. Gabriel
Original Article


Robust epidemiological, clinical and laboratory evidence supports emerging roles for the sex steroids in such domains as neurodevelopment, behaviour, learning and cognition. Regions of the mammalian brain that are involved in cognitive development and memory do not only express the classical nuclear androgen receptor, but also the non-genomic membrane receptor, which is a G protein-coupled receptor that mediates some rapid effects of the androgens on neurogenesis and synaptic plasticity. Under physiological conditions, hippocampal neurons do express the enzyme aromatase, and therefore actively aromatize testosterone to oestradiol. Although glial expression of the aromatase enzyme is minimal, increased expression following injury suggests a role for sex steroids in neuroprotection. It is therefore plausible to deduce that low levels of circulating androgens in males would perturb neuronal functions in relation to cognition and memory, as well as neural repair following injury. The present review is an overview of some roles of the sex steroids on cognitive function in males, and the neuroanatomical and molecular underpinnings of some behavioural and cognitive deficits characteristic of such genetic disorders noted for low androgen levels, including Klinefelter syndrome, Bardet-Biedl syndrome, Kallman syndrome and Prader-Willi syndrome. Recent literature in relation to some behavioural and cognitive changes secondary to surgical and pharmacological castration are also appraised.


Cognition and behaviour Male hypogonadism Klinefelter syndrome Prader-Willi syndrome Bardet-Biedl syndrome Kallman syndrome 



This work is supported by the Return Home Fellowship from the International Brain Research Organization to Dr. Oluwole Akinola.


  1. Agassandian K, Patel M, Agassandian M, Steren KE, Rahmouni K, Sheffield VC, Card JP (2014) Ciliopathy is differentially distributed in the brain of a Bardet-Biedl syndrome mouse model. PLoS One 9(4):e93484. PubMedPubMedCentralCrossRefGoogle Scholar
  2. Akinola OB (2016) Sweet old memories: a review of the experimental models of the association between diabetes, senility and dementia. Metab Brain Dis 31(5):1003–1010. PubMedCrossRefGoogle Scholar
  3. Akinola OB, Poluch S, Juliano SL (2013) Abnormal expression of cation-chloride cotransporters results in impaired migration during corticogenesis. In 43rd annual meeting of the Society for Neuroscience). San Diego, USA: Society for NeuroscienceGoogle Scholar
  4. Aksglaede L, Juul A (2013) Testicular function and fertility in men with Klinefelter syndrome: a review. Eur J Endocrinol 168(4):R67–R76. PubMedCrossRefGoogle Scholar
  5. Aksoy A, Karaguzel G, Akbulut U, Turk A (2011) Two sisters with Bardet-Biedl syndrome: brain abnormalities and unusual facial findings. Turk J Pediatr 53(4):460–463PubMedGoogle Scholar
  6. Amidi A, LM W, Agerbæk M et al (2015) Cognitive impairment and potential biological and psychological correlates of neuropsychological performance in recently orchiectomized testicular cancer patients. Psycho-Oncology 24(9):1174–1180. PubMedCrossRefGoogle Scholar
  7. Anthoni H, Sucheston LE, Lewis BA, Tapia-Páez I, Fan X, Zucchelli M, Taipale M, Stein CM, Hokkanen ME, Castrén E, Pennington BF, Smith SD, Olson RK, Tomblin JB, Schulte-Körne G, Nöthen M, Schumacher J, Müller-Myhsok B, Hoffmann P, Gilger JW, Hynd GW, Nopola-Hemmi J, Leppanen PHT, Lyytinen H, Schoumans J, Nordenskjöld M, Spencer J, Stanic D, Boon WC, Simpson E, Mäkelä S, Gustafsson JÅ, Peyrard-Janvid M, Iyengar S, Kere J (2012) The aromatase gene CYP19A1: several genetic and functional lines of evidence supporting a role in reading, speech and language. Behav Genet 42(4):509–527. PubMedPubMedCentralCrossRefGoogle Scholar
  8. Atwi S, McMahon D, Scharfman H, MacLusky NJ (2016) Androgen, dulation of hppocampal structure an function. Neuroscientists 22(1):46–60. CrossRefGoogle Scholar
  9. Aubele T, Kritzer MF (2012) Androgen influence on prefrontal dopamine systems in adult male rats: localization of cognate intracellular receptors in medial prefrontal projections to the ventral tegmental area and effects of gonadectomy and hormone replacement on glutamate-stimulated extracellular dopamine level. Cereb Cortex 22(8):1799–1812. PubMedCrossRefGoogle Scholar
  10. Ayub M, Levell MJ (1990) Suppression of plasma androgens by the antiandrogen flutamide in prostatic cancer patients treated with zoladex, a gonadotropin releasing hormone analogue. Clin Endocrinol 32(3):329–340. CrossRefGoogle Scholar
  11. Azcoitia I, Sierra A, Veiga S, Honda S, Harada N, Garcia-Segura LM (2001) Brain aromatase is neuroprotective. J Neurobiol 47(4):318–329. PubMedCrossRefGoogle Scholar
  12. Azcoitia I, Sierra A, Veiga S, Garcia-Segura LM (2003) Aromatase expression by reactive astroglia is neuroprotective. Ann N Y Acad Sci 1007(1):298–305. PubMedCrossRefGoogle Scholar
  13. Azcoitia I, Yague JG, Garcia-Segura LM (2011) Estradiol synthesis within the human brain. Neuroscience 191:139–147. PubMedCrossRefGoogle Scholar
  14. Baker K, Northam GB, Chong WK, Banks T, Beales P, Baldeweg T (2011) Neocortical and hippocampal volume loss in a human ciliopathy: a quantitative MRI study in Bardet-Biedl syndrome. Am J Med Genet A 1:1–8CrossRefGoogle Scholar
  15. Baskin E, Kayiran SM, Oto S, Alehan F, Agildere AM, Saatci U (2002) Cerebellar vermis hypoplasia in a patient with Bardet-Biedl syndrome. J Child Neurol 17(5):385–387. PubMedCrossRefGoogle Scholar
  16. Beattie MC, Adekola L, Papadopoulos V, Chen H, Zirkin BR (2015) Leydig cell aging and hypogonadism. Exp Gerontol 68:87–91. PubMedPubMedCentralCrossRefGoogle Scholar
  17. Bennouna-Greene V, Kremer S, Stoetzel C, Christmann D, Schuster C, Durand M, Verloes A, Sigaudy S, Holder-Espinasse M, Godet J, Brandt C, Marion V, Danion A, Dietemann JL, Dollfus H (2011) Hippocampal dysgenesis and variable neuropsychiatric phenotypes in patients with Bardet-Biedl syndrome underline complex CNS impact of primary cilia. Clin Genet 80(6):523–531. PubMedCrossRefGoogle Scholar
  18. Beyer C (1999) Estrogen and the developing mammalian brain. Anat Embryol 199(5):379–390. PubMedCrossRefGoogle Scholar
  19. Bian C, Zhang K, Zhao Y, Guo Q, Cai W, Zhang J (2014a) Regional specific regulation of steroid receptor coactivator-1 immunoreactivity by orchidectomy in the brain of adult male mice. Steroids 88:7–14. PubMedCrossRefGoogle Scholar
  20. Bian C, Zhu H, Zhao Y, Cai W, Zhang J (2014b) Intriguing roles of hippocampus-synthesized 17beta-estradiol in the modulation of hippocampal synaptic plasticity. J Mol Neurosci 54(2):271–281. PubMedCrossRefGoogle Scholar
  21. Bittel DC, Butler MG (2005) Prader-Willi syndrome: clinical genetics, cytogenetics and molecular biology. Expert Rev Mol Med 7(14):1–20. PubMedCrossRefGoogle Scholar
  22. Bojesen A, Juul S, Gravholt CH (2003) Prenatal and postnatal prevalence of Klinefelter syndrome: a national registry study. J Clin Endocrinol Metab 88(2):622–626. PubMedCrossRefGoogle Scholar
  23. Boone KB, Swerdloff RS, Miller BL et al (2001) Neuropsychological profiles of adults with Klinefelter syndrome. J Int Neuropsychol Soc 7(4):446–456. PubMedCrossRefGoogle Scholar
  24. Bortone D, Polleux F (2009) KCC2 expression promotes the termination of cortical interneuron migration in a voltage-sensitive calcium-dependent manner. Neuron 62(1):53–71. PubMedPubMedCentralCrossRefGoogle Scholar
  25. Braun JJ, Noblet V, Durand M, Scheidecker S, Zinetti-Bertschy A, Foucher J, Marion V, Muller J, Riehm S, Dollfus H, Kremer S (2014) Olfaction evaluation and correlation with brain atrophy in Bardet-Biedl syndrome. Clin Genet 86(6):521–529. PubMedCrossRefGoogle Scholar
  26. Braun JJ, Noblet V, Kremer S, Molière S, Dollfus H, Marion V, Goetz N, Muller J, Riehm S (2016) Value of MRI olfactory bulb evaluation in the assessment of olfactory dysfunction in Bardet-Biedl syndrome. Clin Genet 90(1):79–83. PubMedCrossRefGoogle Scholar
  27. Buiting K (2010) Prader-Willi syndrome and Angelman syndrome. Am J Med Genet C Semin Med Genet 15:365–376CrossRefGoogle Scholar
  28. Butler MG, Manzardo AM (2015) Androgen receptor (AR) gene CAG trinucleotide repeat length associated with body composition measures in non-syndromic obese, non-obese and Prader-Willi syndrome individuals. J Assist Reprod Genet 32(6):909–915. PubMedPubMedCentralCrossRefGoogle Scholar
  29. Cadman SM, Kim SH, Hu Y, Gonzalez-Martinez D, Bouloux PM (2007) Molecular pathogenesis of Kallmann's syndrome. Horm Res 67(5):231–242. PubMedGoogle Scholar
  30. Cappuccio F, Abate V, Bolognini I et al (2016) Impact of testicular cancer on survivors’ quality of life: systematic review. World Cancer Res J 3:e738Google Scholar
  31. Cariboni A, Maggi R (2006) Kallmann's syndrome, a neuronal migration defect. Cell Mol Life Sci 63(21):2512–2526. PubMedCrossRefGoogle Scholar
  32. Cariboni A, Andre V, Chauvet S et al (2015) Dysfunctional SEMA3E signaling underlies gonadotropin-releasing hormone neuron deficiency in Kallmann syndrome. J Clin Invest 125(6):2413–2428. PubMedPubMedCentralCrossRefGoogle Scholar
  33. Cassidy SB (1997) Prader-Willi syndrome. J Med Genet 34(11):917–923. PubMedPubMedCentralCrossRefGoogle Scholar
  34. Celotti F, Melcangi RC, Negri-Cesi P, Poletti A (1991) Testosterone metabolism in brain cells and membranes. J Steroid Biochem Mol Biol 40(4-6):673–678. PubMedCrossRefGoogle Scholar
  35. Chen JR, Tseng GF, Wang YJ, Wang TJ (2014) Exogenous dehydroepiandrosterone sulphate reverses the dendritic changes of the central neurons in aging male rats. Exp Gerontol 57:191–202. PubMedCrossRefGoogle Scholar
  36. Cherrier MM, Aubin S, Higano CS (2009) Cognitive and mood changes in men undergoing intermittent combined androgen blockade for non-metastatic prostate cancer. Psycho-Oncology 18(3):237–247. PubMedCrossRefGoogle Scholar
  37. Chu J, Anderson SA (2015) Development of cortical interneurons. Neuropsychopharmacology 40(1):16–23. PubMedCrossRefGoogle Scholar
  38. Cleland WH, Mendelson CR, Simpson ER (1983) Aromatase activity of membrane fractions of human adipose tissue stromal cells and adipocytes. Endocrinology 113(6):2155–2160. PubMedCrossRefGoogle Scholar
  39. Copet P, Jauregi J, Laurier V, Ehlinger V, Arnaud C, Cobo AM, Molinas C, Tauber M, Thuilleaux D (2010) Cognitive profile in a large French cohort of adults with Prader-Willi syndrome: differences between genotypes. J Intellect Disabil Res 54(3):204–215. PubMedCrossRefGoogle Scholar
  40. Danos P, Baumann B, Bernstein HG, Franz M, Stauch R, Northoff G, Krell D, Falkai P, Bogerts B (1998) Schizophrenia and anteroventral thalamic nucleus: selective decrease of parvalbumin-immunoreactive thalamocortical projection neurons. Psychiatry Res 82(1):1–10. PubMedCrossRefGoogle Scholar
  41. Djankpa FT, Akinola OB, Juliano SL (2016) Regional distribution and cellular localization of KCC2 in ferret cortex. Proceedings of the, published by the in USU research days 2016). Bethesda: Uniformed Services University of the Health SciencesGoogle Scholar
  42. Emmelot-Vonk MH, Verhaar HJ, Nakhai Pour HR, Aleman A, Lock TM, Bosch JL, Grobbee DE, van der Schouw YT (2008) Effect of testosterone supplementation on functional mobility, cognition, and other parameters in older men: a randomized controlled trial. JAMA 299(1):39–52. PubMedCrossRefGoogle Scholar
  43. Farag TI, Teebi AS (1988) Bardet-Biedl and Laurence-moon syndromes in a mixed Arab population. Clin Genet 33(2):78–82Google Scholar
  44. Farag TI, Teebi AS (1989) High incidence of Bardet Biedl syndrome among the Bedouin. Clin Genet 36(6):463–464PubMedCrossRefGoogle Scholar
  45. Feldman HA, Longcope C, Derby CA, Johannes CB, Araujo AB, Coviello AD, Bremner WJ, McKinlay JB (2002) Age trends in the level of serum testosterone and other hormones in middle-aged men: longitudinal results from the Massachusetts male aging study. J Clin Endocrinol Metab 87(2):589–598. PubMedCrossRefGoogle Scholar
  46. Ferrini RL, Barrett-Connor E (1998) Sex hormones and age: a cross-sectional study of testosterone and estradiol and their bioavailable fractions in community-dwelling men. Am J Epidemiol 147(8):750–754. PubMedCrossRefGoogle Scholar
  47. Fester L, Prange-Kiel J, Jarry H, Rune GM (2011) Estrogen synthesis in the hippocampus. Cell Tissue Res 345(3):285–294. PubMedCrossRefGoogle Scholar
  48. Forsythe E, Beales PL (2013) Bardet-Biedl syndrome. Eur J Hum Genet 21(1):8–13. PubMedCrossRefGoogle Scholar
  49. Funakoshi T, Yanai A, Shinoda K, Kawano MM, Mizukami Y (2006) G protein-coupled receptor 30 is an estrogen receptor in the plasma membrane. Biochem Biophys Res Commun 346(3):904–910. PubMedCrossRefGoogle Scholar
  50. Garcia-Segura LM (2008) Aromatase in the brain: not just for reproduction anymore. J Neuroendocrinol 20(6):705–712. PubMedCrossRefGoogle Scholar
  51. Giagulli VA, Guastamacchia E, Licchelli B, Triggiani V (2016) Serum testosterone and cognitive function in ageing male: updating the evidence. Recent Pat Endocr Metab Immune Drug Discov 10(1):22–30. PubMedCrossRefGoogle Scholar
  52. Giedd JN, Clasen LS, Lenroot R et al (2006) Puberty-related influences on brain development. Mol Cell Endocrinol 255:154–162CrossRefGoogle Scholar
  53. Green HJ, Pakenham KI, Headley BC, Yaxley J, Nicol DL, Mactaggart PN, Swanson C, Watson RB, Gardiner RA (2002) Altered cognitive function in men treated for prostate cancer with luteinizing hormen-releasing hormone analogues and cyproterone acetate: a randomized controlled trial. BJUI 90(4):427–432. CrossRefGoogle Scholar
  54. Guo J, Higginbotham H, Li J, Nichols J, Hirt J, Ghukasyan V, Anton ES (2015) Developmental disruptions underlying brain abnormalities in ciliopathies. Nat Commun 6:7857. PubMedPubMedCentralCrossRefGoogle Scholar
  55. Guran T, Ekinci G, Atay Z, Turan S, Akcay T, Bereket A (2011) Radiologic and hormonal evaluation of pituitary abnormalities in patients with Bardet-Biedl syndrome. Clin Dysmorphol 20(1):26–31. PubMedCrossRefGoogle Scholar
  56. Han JC, Muehlbauer MJ, Cui HN, Newgard CB, Haqq AM (2010) Lower brain-derived neurotrophic factor in patients with prader-willi syndrome compared to obese and lean control subjects. J Clin Endocrinol Metab 95(7):3532–3536. PubMedPubMedCentralCrossRefGoogle Scholar
  57. Hardelin JP (2001) Kallmann syndrome: towards molecular pathogenesis. Mol Cell Endocrinol 179(1-2):75–81. PubMedCrossRefGoogle Scholar
  58. Harman SM, Metter EJ, Tobin JD, Pearson J, Blackman MR (2001) Longitudinal effects of aging on serum total and free testosterone levels in healthy men. J Clin Endocrinol Metab 86(2):724–731. PubMedCrossRefGoogle Scholar
  59. Hayashi M, Miyata R, Tanuma N (2011) Decrease in acetylcholinergic neurons in the pedunculopontine tegmental nucleus in a patient with Prader-Willi syndrome. Neuropathology 31(3):280–285. PubMedCrossRefGoogle Scholar
  60. Hernando-Quintana N, Playan-Uson J, Crespo-Burillo JA, Marin-Cardenas MA, Gazulla J (2015) Ataxia and focal dystonia in Kallmann syndrome. Clin Case Rep 4:182–185PubMedPubMedCentralCrossRefGoogle Scholar
  61. Hogervorst E, Williams J, Budge M, Barnetson L, Combrinck M, Smith D (2001) Serum total testosterone is lower in men with Alzheimer’s disease. Neuroendocrinol Lett 22(3):163–168PubMedGoogle Scholar
  62. Hogervorst E, Lehmann DJ, Warden DR, McBroom J, Smith AD (2002) Apolipoprotein E ε4 and testosterone interact in the risk of Alzheimer’s disease in men. Geriatr Psychiatry 17(10):938–940. CrossRefGoogle Scholar
  63. Hogervorst E, Bandelow S, Combrinck S, Smith AD (2004) Low free testosterone is an independent risk factor for Alzheimer’s dosease. Exp Gerontol 39(11-12):1633–1639. PubMedCrossRefGoogle Scholar
  64. Honea RA, Holsen LM, Lepping RJ et al (2012) The neuroanatomy of genetic subtype differences in Prader-Willi syndrome. Am J Med Genet B Neuropsychiatr Genet 2:243–253CrossRefGoogle Scholar
  65. Host C, Skakkebaek A, Groth KA, Bojesen A (2014) The role of hypogonadism in Klinefelter syndrome. Asian J Androl 16(2):185–191. PubMedPubMedCentralCrossRefGoogle Scholar
  66. Itti E, Gaw Gonzalo IT, Pawlikowska-Haddal A, Boone KB, Mlikotic A, Itti L, Mishkin FS, Swerdloff RS (2006) The structural brain correlates of cognitive deficits in adults with Klinefelter's syndrome. J Clin Endocrinol Metab 91(4):1423–1427. PubMedCrossRefGoogle Scholar
  67. Iwuala S, Olamoyegun M, Fasanmade O, Ohwovoriole A (2013) Bardet-Biedel syndrome: a case report and a review of literature. Nigerian. Endocr Pract 7:33–38Google Scholar
  68. Jacome LF, Barateli K, Buitrago D, Lema F, Frankfurt M, Luine VN (2016) Gonadal hormones rapidly enhance spatial memory and increase hippocampal spine density in male rats. Endocrinology 157(4):1357–1362. PubMedPubMedCentralCrossRefGoogle Scholar
  69. Jung HJ, Shin HS (2016) Effect of testosterone replacement therapy on cognitive performance and depression in men with testosterone deficiency syndrome. World J Mens Health 34(3):194–199. PubMedCrossRefGoogle Scholar
  70. Kerr JE, Allore RJ, Beck SG, Handa RJ (1995) Distribution and hormonal regulation of androgen receptor (AR) and AR messenger ribonucleic acid in the rat hippocampus. Endocrinology 136(8):3213–3221. PubMedCrossRefGoogle Scholar
  71. Kertesz A, Geschwind N (1971) Patterns of pyramidal decussation and their relationship to handedness. Arch Neurol 24(4):326–332. PubMedCrossRefGoogle Scholar
  72. Kim HJ, Casadesus G (2010) Estrogen-mediated effects on cognition and synaptic plasticity: what do estrogen receptor knockout models tell us? Biochim Biophys Acta 10:12Google Scholar
  73. Knorr JR, Ragland RL, Brown RS, Gelber N (1993) Kallmann syndrome: MR findings. AJNR Am J Neuroradiol 14(4):845–851PubMedGoogle Scholar
  74. Kompus K, Westerhausen R, Nilsson LG, Hugdahl K, Jongstra S, Berglund A, Arver S, Savic I (2011) Deficits in inhibitory executive functions in Klinefelter (47, XXY) syndrome. Psychiatry Res 189(1):135–140. PubMedCrossRefGoogle Scholar
  75. Krams M, Quinton R, Mayston MJ et al (1997) Mirror movements in X-linked Kallmann's syndrome. II. A PET study. Brain 120(7):1217–1228. PubMedCrossRefGoogle Scholar
  76. Krams M, Quinton R, Ashburner J, Friston KJ, Frackowiak RSJ, Bouloux PMG, Passingham RE (1999) Kallmann's syndrome: mirror movements associated with bilateral corticospinal tract hypertrophy. Neurology 52(4):816–822. PubMedCrossRefGoogle Scholar
  77. Labrie F, Dupout A, Belanger A, St-Arnaud R, Giguere M, Lacourciere Y, Emond J, Monfette G (1986) Treatment of prostate cancer with gonadotropin-releasing hormone agonists. Endocr Rev 7(1):67–74. PubMedCrossRefGoogle Scholar
  78. Laitinen EM, Vaaralahti K, Tommiska J et al (2011) Incidence, phenotypic features and molecular genetics of Kallmann syndrome in Finland. Orphanet J Rare Dis 6:1750–1172CrossRefGoogle Scholar
  79. Lasaite L, Ceponis J, Preiksa RT, Zilaitiene B (2014) Impaired emotional state, quality of life and cognitive functions in young hypogonadal men. Andrologia 46(10):1107–1112. PubMedCrossRefGoogle Scholar
  80. Lasaite L, Ceponis J, Preiksa RT, Zilaitiene B (2017) Effects of two-years testosterone replacement therapy on cognition, emotions and quality of life in young and middle-aged hypogonadal men. Andrologia 49:22CrossRefGoogle Scholar
  81. Ledbetter DH, Riccardi VM, Airhart SD, Strobel RJ, Keenan BS, Crawford JD (1981) Deletions of chromosome 15 as a cause of the Prader–Willi syndrome. N Engl J Med 304(6):325–329. PubMedCrossRefGoogle Scholar
  82. Leranth C, Szigeti-Buck K, Maclusky NJ, Hajszan T (2008) Bisphenol a prevents the synaptogenic response to testosterone in the brain of adult male rats. Endocrinology 149(3):988–994. PubMedCrossRefGoogle Scholar
  83. Lettieri A, Oleari R, Gimmelli J, ANDRé V, Cariboni A (2016) The role of semaphorin signaling in the etiology of hypogonadotropic hypogonadism. Minerva Endocrinol 41(2):266–278Google Scholar
  84. Li J, Siegel M, Yuan M, Zeng Z, Finnucan L, Persky R, Hurn PD, McCullough LD (2011) Estrogen enhances neurogenesis and behavioural recovery after stroke. J Cereb Blood Flow Metab 31(2):413–425. PubMedCrossRefGoogle Scholar
  85. Li S, Kang L, Zhang Y, Feng B, Du J, Cui H (2015) Detecting the presence of hippocampus membrane androgen receptors in male SAMP8 mice and their induced synaptic plasticity. Mol Cell Endocrinol 414:82–90. PubMedCrossRefGoogle Scholar
  86. Liu PY, Erkkila K, Lue Y et al (2010) Genetic, hormonal, and metabolomic influences on social behaviour and sex preference of XXY mice. Am J Physiol Endocrinol Metab 299:22Google Scholar
  87. Locklear MN, Bhamidipaty S, Kritzer MF (2015) Local N-methyl-d-aspartate receptor antagonism in the prefrontal cortex attenuates spatial cognitive deficits induced by gonadectomy in adult male rats. Neuroscience 288:73–85. PubMedCrossRefGoogle Scholar
  88. Lue Y, Jentsch JD, Wang C, Rao PN, Sinha Hikim AP, Salameh W, Swerdloff RS (2005) XXY mice exhibit gonadal and behavioural phenotypes similar to Klinefelter syndrome. Endocrinology 146(9):4148–4154. PubMedCrossRefGoogle Scholar
  89. Lukoshe A, White T, Schmidt MN, van der Lugt A, Hokken-Koelega AC (2013) Divergent structural brain abnormalities between different genetic subtypes of children with Prader-Willi syndrome. J Neurodev Disord 5:1866–1955CrossRefGoogle Scholar
  90. Lukoshe A, Hokken-Koelega AC, van der Lugt A, White T (2014) Reduced cortical complexity in children with Prader-Willi syndrome and its association with cognitive impairment and developmental delay. PLoS One 9(9):e107320. PubMedPubMedCentralCrossRefGoogle Scholar
  91. Mainwaring WI, Irving R (1970) The partial purification of a soluble androgen receptor. Biochem J 118(2):12P–13PPubMedPubMedCentralCrossRefGoogle Scholar
  92. Manara R, Salvalaggio A, Favaro A, Palumbo V, Citton V, Elefante A, Brunetti A, di Salle F, Bonanni G, Sinisi AA, for the Kallmann Syndrome Neuroradiological Study Group (2014) Brain changes in Kallmann syndrome. AJNR Am J Neuroradiol 35(9):1700–1706. PubMedCrossRefGoogle Scholar
  93. Manara R, Salvalaggio A, Citton V, Palumbo V, D'Errico A, Elefante A, Briani C, Cantone E, Ottaviano G, Pellecchia MT, Greggio NA, Weis L, D'Agosto G, Rossato M, de Carlo E, Napoli E, Coppola G, di Salle F, Brunetti A, Bonanni G, Sinisi AA, Favaro A (2015) Brain anatomical substrates of mirror movements in Kallmann syndrome. NeuroImage 104:52–58. PubMedCrossRefGoogle Scholar
  94. Matousek RH, Sherwin BB (2010) Sex steroid hormones and cognitive functioning in healthy, older men. Horm Behav 57(3):352–359. PubMedPubMedCentralCrossRefGoogle Scholar
  95. McAbee MD, DonCarlos LL (1998) Ontogeny of region-specific sex differences in androgen receptor messenger ribonucleic acid expression in the rat forebrain. Endocrinology 139(4):1738–1745. PubMedCrossRefGoogle Scholar
  96. Messina MF, Sgro DL, Aversa T, Pecoraro M, Valenzise M, De Luca F (2012) A characteristic cognitive and behavioural pattern as a clue to suspect Klinefelter syndrome in prepubertal age. J Am Board Fam Med 25(5):745–749. PubMedCrossRefGoogle Scholar
  97. Mori F, Okada KI, Nomura T, Kobayashi Y (2016) The Pedunculopontine tegmental nucleus as a motor and cognitive Interface between the cerebellum and basal ganglia. Front Neuroanat 10:109. PubMedPubMedCentralCrossRefGoogle Scholar
  98. Mott NN, Pak TR (2012) Characterisation of human oestrogen receptor beta (ERbeta) splice variants in neuronal cells. J Neuroendocrinol 24(10):1311–1321. PubMedPubMedCentralCrossRefGoogle Scholar
  99. Nakamura N, Fujita H, Kawata M (2002) Effects of gonadectomy on immunoreactivity of choline acetyltransferase in the cortex, hippocampus and basal forebrain of adult male rats. Neuroscience 109(3):473–485. PubMedCrossRefGoogle Scholar
  100. Nand N, Mittal R, Yadav M, Venu S, Deshmukh AR (2016) Kallman Syndrome. J Assoc Physicians India 64(10):106–107PubMedGoogle Scholar
  101. Nelson CJ, Lee JS, Gamboa MC, Roth AJ (2008) Cognitive effects of hormone therapy in men with prostate cancer. Cancer 113(5):1097–1106. PubMedPubMedCentralCrossRefGoogle Scholar
  102. Nguyen TV, Yao M, Pike CJ (2005) Androgens activate mitogen-activated protein kinase signaling: role in neuroprotection. J Neurochem 94(6):1639–1651. PubMedCrossRefGoogle Scholar
  103. Obaydi H, Izmeth MGA, Rigby JC (1992) Kallmann's syndrome and mental handicap. J Intellect Disabil Res 36:457–460PubMedCrossRefGoogle Scholar
  104. Ogura K, Fujii T, Abe N, Hosokai Y, Shinohara M, Takahashi S, Mori E (2011) Small gray matter volume in orbitofrontal cortex in Prader-Willi syndrome: a voxel-based MRI study. Hum Brain Mapp 32(7):1059–1066. PubMedCrossRefGoogle Scholar
  105. Okoronkwo NC (2016) A rare classical presentation of Bardet-Biedl syndrome in a three-year-old male from south East Nigeria: a case report. Case Rep Clin Med 5:243CrossRefGoogle Scholar
  106. Pan J, Wang Q, Snell WJ (2005) Cilium-generated signaling and cilia-related disorders. Lab Investig 85(4):452–463. PubMedCrossRefGoogle Scholar
  107. Patchev VK, Schroeder J, Goetz F, Rohde W, Patchev AV (2004) Neurotropic action of androgens: principles, mechanisms and novel targets. Exp Gerontol 39(11-12):1651–1660. PubMedCrossRefGoogle Scholar
  108. Pike CJ (2001) Testosterone attenuates β-amyloid toxicity in cultured hippocampal neurons. Brain Res 919(1):160–165. PubMedCrossRefGoogle Scholar
  109. Pintana H, Pongkan W, Pratchayasakul W, Chattipakorn N, Chattipakorn SC (2015) Testosterone replacement attenuates cognitive decline in testosterone-deprived lean rats, but not in obese rats, by mitigating brain oxidative stress. Age 37(5):84. PubMedPubMedCentralCrossRefGoogle Scholar
  110. Poluch S, Juliano SL (2015) Fine-tuning of neurogenesis is essential for the evolutionary expansion of the cerebral cortex. Cereb Cortex 25(2):346–364. PubMedCrossRefGoogle Scholar
  111. Poluch S, Akinola OB, Juliano SL (2012) The contribution of proliferative zones to gyral formation in a ferret model of lissencephaly in 42nd annual meeting of the Society for Neuroscience. Society for Neuroscience, New OrleansGoogle Scholar
  112. Prossnitz ER, Arterburn JB, Sklar LA (2007) GPR30: a G protein-coupled receptor for estrogen. Mol Cell Endocrinol 265-266:138–142. PubMedPubMedCentralCrossRefGoogle Scholar
  113. Randy J (2011) An introduction to Behavioural endocrinology. Sinauer associates, Inc. Publishers, OhioGoogle Scholar
  114. Resnick SM, Matsumoto AM, Stephens-Shields AJ, Ellenberg SS, Gill TM, Shumaker SA, Pleasants DD, Barrett-Connor E, Bhasin S, Cauley JA, Cella D, Crandall JP, Cunningham GR, Ensrud KE, Farrar JT, Lewis CE, Molitch ME, Pahor M, Swerdloff RS, Cifelli D, Anton S, Basaria S, Diem SJ, Wang C, Hou X, Snyder PJ (2017) Testosterone treatment and cognitive function in older men with low testosterone and age-associated memory impairment. JAMA 317(7):717–727. PubMedPubMedCentralCrossRefGoogle Scholar
  115. Rice LJ, Einfeld SL (2015) Cognitive and behavioural aspects of Prader-Willi syndrome. Curr Opin Psychiatry 28(2):102–106. PubMedGoogle Scholar
  116. Rice LJ, Lagopoulos J, Brammer M, Einfeld SL (2016) Reduced gamma-aminobutyric acid is associated with emotional and behavioural problems in Prader-Willi syndrome. Am J Med Genet B Neuropsychiatr Genet 171(8):1041–1048. PubMedCrossRefGoogle Scholar
  117. Rooryck C, Pelras S, Chateil JF, Cances C, Arveiler B, Verloes A, Lacombe D, Goizet C (2007) Bardet-biedl syndrome and brain abnormalities. Neuropediatrics 38(1):5–9. PubMedCrossRefGoogle Scholar
  118. Salminen EK, Portin RI, Koskinen A, Helenins H, Nurmi M (2004) Association between serum testosterone fall and cognitive function in prostate cancer patients. Clin Cancer Res 10(22):7575–7582. PubMedCrossRefGoogle Scholar
  119. Sar M, Lubahn DB, French FS, Wilson EM (1990) Immunohistochemical localization of the androgen receptor in rat and human tissues. Endocrinology 127(6):3180–3186. PubMedCrossRefGoogle Scholar
  120. Shughrue PJ, Merchenthaler I (2000) Evidence for novel estrogen binding sites in the rat hippocampus. Neuroscience 99(4):605–612. PubMedCrossRefGoogle Scholar
  121. Shughrue PJ, Lane MV, Merchenthaler I (1997) Comparative distribution of estrogen receptor-alpha and -beta mRNA in the rat central nervous system. J Comp Neurol 388(4):507–525.<507::AID-CNE1>3.0.CO;2-6 PubMedCrossRefGoogle Scholar
  122. Simerly RB, Chang C, Muramatsu M, Swanson LW (1990) Distribution of androgen and estrogen receptor mRNA-containing cells in the rat brain: an in situ hybridization study. J Comp Neurol 294(1):76–95. PubMedCrossRefGoogle Scholar
  123. Simm PJ, Zacharin MR (2006) The psychosocial impact of Klinefelter syndrome--a 10 years review. J Pediatr Endocrinol Metab 19(4):499–505PubMedGoogle Scholar
  124. Singh K, Kumar R, Prakash J, Krishna A (2015) Bardet-Biedl syndrome presenting with steroid sensitive nephrotic syndrome. Indian J Nephrol 25:300PubMedPubMedCentralCrossRefGoogle Scholar
  125. Soni S, Whittington J, Holland A et al (2008) The phenomenology and diagnosis of psychiatric illness in people with Prader–Willi syndrome. Psychol Med 38(10):1505–1514. PubMedCrossRefGoogle Scholar
  126. Srivastava DP, Woolfrey KM, Liu F, Brandon NJ, Penzes P (2010) Estrogen receptor ss activity modulates synaptic signaling and structure. J Neurosci 30(40):13454–13460. PubMedPubMedCentralCrossRefGoogle Scholar
  127. Sultan KT, Brown KN, Shi SH (2013) Production and organization of neocortical interneurons. Front Cell Neurosci 7:00221CrossRefGoogle Scholar
  128. Tang H, Zhang Q, Yang L, Dong Y, Khan M, Yang F, Brann DW, Wang R (2014) GPR30 mediates estrogen rapid signaling and neuroprotection. Mol Cell Endocrinol 387(1-2):52–58. PubMedPubMedCentralCrossRefGoogle Scholar
  129. Trivino-Paredes J, Patten AR, Gil-Mohapel J, Christie BR (2016) The effects of hormones and physical exercise on hippocampal structural plasticity. Front Neuroendocrinol 41:23–43. PubMedCrossRefGoogle Scholar
  130. Tveter KJ (1969) Subcellular localization of androgen in the rat ventral prostate in vivo. Endocrinology 85(3):597–600. PubMedCrossRefGoogle Scholar
  131. Vagenakis GA, Hyphantis TN, Papageorgiou C, Protonatariou A, Sgourou A, Dimopoulos PA, Mavreas V, Vagenakis AG, Georgopoulos NA (2004) Kallmann's syndrome and schizophrenia. Int J Psychiatry Med 34(4):379–390. PubMedCrossRefGoogle Scholar
  132. Vale TC, Pedroso JL, Rivero RLM, Mandeli AS, Dias-da-Silva MR, Barsottini OG (2017) Lack of decussation of pyramids in Kallmann syndrome presenting with mirror movements. J Neurol Sci 372:220–222. PubMedCrossRefGoogle Scholar
  133. van den Berg MP, Verhoef JC, Romeijn SG, Merkus FW (2004) Uptake of estradiol or progesterone into the CSF following intranasal and intravenous delivery in rats. Eur J Pharm Biopharm 58(1):131–135. PubMedCrossRefGoogle Scholar
  134. Vicencio JM, Estrada M, Galvis D et al (2011) Anabolic androgenic steroids and intracellular calcium signaling: a mini review on mechanisms and physiological implications. Mini Rev Med Chem 11(5):390–398. PubMedPubMedCentralCrossRefGoogle Scholar
  135. Wahjoepramono EJ, Asih PR, Aniwiyanti V et al (2016) The effects of testosterone supplementation on cognitive functioning in older men. CNS Neurol Disord Drug Targets 15(3):337–343. PubMedPubMedCentralCrossRefGoogle Scholar
  136. Wang AY, Lohmann KM, Yang CK, Zimmerman EI, Pantazopoulos H, Herring N, Berretta S, Heckers S, Konradi C (2011) Bipolar disorder type 1 and schizophrenia are accompanied by decreased density of parvalbumin- and somatostatin-positive interneurons in the parahippocampal region. Acta Neuropathol 122(5):615–626. PubMedPubMedCentralCrossRefGoogle Scholar
  137. Wang C, Liu Y, Cao JM (2014) G protein-coupled receptors: extranuclear mediators for the non-genomic actions of steroids. Int J Mol Sci 15(9):15412–15425. PubMedPubMedCentralCrossRefGoogle Scholar
  138. Waters A, Beales P (1993) Bardet-Biedl syndrome. University of Washington, Seattle.
  139. Yague JG, Munoz A, de Monasterio-Schrader P, Defelipe J, Garcia-Segura LM, Azcoitia I (2006) Aromatase expression in the human temporal cortex. Neuroscience 138(2):389–401. PubMedCrossRefGoogle Scholar
  140. Yague JG, Wang AC, Janssen WG et al (2008) Aromatase distribution in the monkey temporal neocortex and hippocampus. Brain Res 13:115–127CrossRefGoogle Scholar
  141. Zaghloul NA, Katsanis N (2009) Mechanistic insights into Bardet-Biedl syndrome, a model ciliopathy. J Clin Invest 119(3):428–437. PubMedPubMedCentralCrossRefGoogle Scholar

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Authors and Affiliations

  1. 1.Division of Endocrinology, Department of Anatomy, Faculty of Basic Medical Sciences, College of Health SciencesUniversity of IlorinIlorinNigeria

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