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Introduction to the Interaction Between Gonadal Steroids and the Central Nervous System

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Biological Basis of Sex Differences in Psychopharmacology

Part of the book series: Current Topics in Behavioral Neurosciences ((CTBN,volume 8))

Abstract

The sex steroids are frequently referred to as the gonadal steroids and are erroneously assumed to be exclusively linked to the ovaries in women or the testes in men and the functions of the reproductive tract. This chapter will provide an overview of some of the extragonadal effects of these hormones, focusing on the central nervous system, and the mechanisms of hormone action. Hormone synthesis and metabolism within the CNS will be discussed with particular focus on the role of aromatase. Sex steroids exert many of their effects via intracellular receptors and these genomic responses tend to be slow in onset, however, some responses to steroids occur more quickly and are mediated via membrane receptors and involve interactions with many different transduction pathways to produce a diverse array of responses. These complexities do pose challenges but also offer opportunity for novel approaches for therapeutic exploitation as the pharmacological tools with which to modulate systems become increasingly available.

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References

  • Aguirre C, Jayaraman A, Pike C, Baudry M (2010) Progesterone inhibits estrogen-mediated neuroprotection against excitotoxicity by down-regulating estrogen receptor-β. J Neurochem 115:1277–1287

    Article  PubMed  CAS  PubMed Central  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Amantea D, Russo R, Bagetta G, Corasaniti MT (2005) From clinical evidence to molecular mechanisms underlying neuroprotection afforded by estrogens. Pharmacol Res 52:119–132

    Article  PubMed  CAS  Google Scholar 

  • Arevalo MA, Santos-Galindo M, Lagunas N, Azcoitia I, Garcia-Segura LM (2011) Selective estrogen receptor modulators as brain therapeutic agents. J Mol Endocrinol 46:R1–R9

    Article  PubMed  CAS  Google Scholar 

  • Balthazart J, Ball GF (2006) Is brain estradiol a hormone or a neurotransmitter? Trends Neurosci 29:241–249

    Article  PubMed  CAS  Google Scholar 

  • Balthazart J, Baillien M, Charlier TD, Cornil CA, Ball GF (2003) Multiple mechanisms control brain aromatase activity at the genomic and non-genomic level. J Steroid Biochem Mol Biol 86:367–379

    Article  PubMed  CAS  Google Scholar 

  • Baulieu EE, Robel P (1996) Dehydroepiandrosterone and dehydroepiandrosterone sulfate as neuroactive neurosteroids. J Endocrinol (Suppl)150:S221–S239

    CAS  Google Scholar 

  • Beato M, Sanchez-Pacheco A (1996) Interaction of steroid hormone receptors with the transcription initiation complex. Endocr Rev 17:587–609

    Article  PubMed  CAS  Google Scholar 

  • Beery AK, Zucker I (2011) Sex bias in neuroscience and biomedical research. Neurosci Biobehav Rev 35:565–572

    Article  PubMed  PubMed Central  Google Scholar 

  • Beyenberg S, Watzka M, Clusmann H, Blumcke I, Bidlingmaier F, Elger CE, Stoffel-Wagner B (2000) Androgen receptor mRNA expression in the human hippocampus. Neurosci Lett 94:25–28

    Article  Google Scholar 

  • Bezdickova M, Molikova R, Bebarova L, Kolar Z (2007) Distribution of nuclear receptor for steroid hormones in the human brain: a preliminary study. Biomedical Papers of the Medical Faculty of The University Palacky, Olomouc 151:69–71

    Article  CAS  Google Scholar 

  • Bodo C, Rissman EF (2006) New roles for estrogen receptor beta in behaviour and neuroendocrinology. Front Neuroendocrinol 27:217–232

    Article  PubMed  CAS  Google Scholar 

  • Bowers JM, Waddell J, McCarthy MM (2010) A developmental sex difference in hippocampal neurogenesis is mediated by endogenous oestradiol. Biol Sex Differ 1:1–8

    Article  Google Scholar 

  • Brailoiu E, Dun SL, Brailoiu GC, Mizuo K, Sklar LA, Oprea TI, Prossnitz ER, Dun NJ (2007) Distribution and characterization of estrogen receptor G protein-coupled receptor 30 in the rat central nervous system. J Endocrinol 193:311–321

    Article  PubMed  CAS  Google Scholar 

  • Brinton RD, Thompson RF, Foy MR, Baudry M, Wang J, Finch CE, Morgan TE, Pike CJ, Mack WJ, Stanczyk FZ, Nilsen J (2008) Progesterone receptors: form and function in brain. Front Neuroendocrinol 29:313–339

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Brunton PJ, Russell JA (2010) Endocrine induced changes in brain function during pregnancy. Brain Res 1364:198–215

    Article  PubMed  CAS  Google Scholar 

  • Caruso D, Pesaresi M, Maschi O, Garcia-Segura LM, Melcangi RC (2010) Effect of short- and long-term gonadectomy on neuroactive steroid levels in the central and peripheral nervous system of male and female rats. J Neuroendocrinol 22:1137–1147

    Article  PubMed  CAS  Google Scholar 

  • Chabbert Buffet N, Djakoure C, Maitre SC, Bouchard P (1998) Regulation of the human menstrual cycle. Front Neuroendocrinol 19:151–186

    Article  PubMed  CAS  Google Scholar 

  • Coughlan T, Gibson C, Murphy S (2009) Progesterone, BDNF and neuroprotection in the injured CNS. Int J Neurosci 119:1718–1740

    Article  PubMed  CAS  Google Scholar 

  • Damdimopoulos AE, Spyrou G, Gustafsson JA (2000) Ligands differentially modify the nuclear ability of estrogen receptors alpha and beta. Endocrinology 149:339–345

    Article  Google Scholar 

  • Delaunay F, Pettersson K, Tujague M, Gustafsson JA (2000) Functional differences between thye amino-terminals of estrogen receptors alpha and beta. Mol Pharmacol 58:584–590

    PubMed  CAS  Google Scholar 

  • Dressing GE, Goldberg JE, Charles NJ, Schwertfeger KL, Lange CA (2011) Membrane progesterone receptor expression in mammalian tissues: A review of regulation and physiological implications. Steroids 76:11–17

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Fargo KN, Foecking EM, Jones KJ, Sengelaub DR (2009) Neuroprotective actions of androgens on motoneurons. Front Neuroendocrinol 30:130–141

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Freedman LP (1999) Multimeric coactivator complexes for steroid/nuclear receptors. Trends Endocrinol Metab 10:403–407

    Article  PubMed  CAS  Google Scholar 

  • Furr BJA (2006) Aromatase inhibitors. Birkhäuser Verlag, Basel-Boston-Berlin

    Book  Google Scholar 

  • Gao W, Dalton JT (2007) Expanding the therapeutic use of androgens via selective androgen receptor modulators (SARMs). Drug Discov Today 12:241–248

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Garcia-Segura LM, Melcangi RC (2006) Steroids and glial cell function. Glia 54:485–498

    Article  PubMed  Google Scholar 

  • Garcia-Segura LM, Veiga S, Sierra A, Melcangi RC, Azcoitia I (2003) Aromatase: a neuroprotective enzyme. Prog Neurobiol 71:31–41

    Article  PubMed  CAS  Google Scholar 

  • Genazzani AR, Monteleone P, Gambacciani M (2002) Hormonal influence on the central nervous system. Maturitas 43:S11–S17

    Article  PubMed  CAS  Google Scholar 

  • Giangrande PH, McDonnell DP (1999) The A and B isoforms of the human progesterone receptor: two functionally different transcription factors encodes by a single gene. Recent Prog Horm Res 54:291–313

    PubMed  CAS  Google Scholar 

  • Gilep AA, Sushko TA, Usanov SA (2011) At the cross-roads of steroid hormone biosynthesis: the role, substrate specificity and evolutionary development of CYP17. Biochim Biophys Acta 1814:200–209

    Article  PubMed  CAS  Google Scholar 

  • Gillies GE, McArthur S (2010) Estrogen actions in the brain and the basis for differential action in men and women: a case for sex-specific medicines. Pharmacol Rev 62:155–198

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Goren LJG, Kruijver FPM (2002) Androgens and male behavior. Mol Cell Endocrinol 198:31–40

    Article  Google Scholar 

  • Green S, Walter P, Kumar V, Krust A, Bornert JM, Argos P, Chambon P (1986) Human oestrogen receptor cDNA: sequence, expression and homology to v-erb-A. Nature 320:134–139

    Article  PubMed  CAS  Google Scholar 

  • Gustafson DR, Karlsson C, Skoog I, Rosengren L, Lissner L, Blennow K (2007) Mid-life adiposity factors relate to blood-brain barrier integrity in late life. J Intern Med 262:643–650

    Article  PubMed  CAS  Google Scholar 

  • Hapgood JP, Koubovec D, Louw A, Africander D (2004) Not all progestins are the same: implications for usage. Trends Pharmacol Sci 25:554–557

    Article  PubMed  CAS  Google Scholar 

  • Harrison PJ, Tunbridge EM (2008) Catechol-O-Methyltransferase (COMT): a gene contributing to sex differences in brain function, and to sexual dimorphism in the predisposition to psychiatric disorders. Neuropsychopharmacology 33:3037–3045

    Article  PubMed  CAS  Google Scholar 

  • Ishrat T, Sayeed I, Atif F, Hua F, Stein DG (2010) Progesterone and allopregnanolone attenuate blood-brain barrier dysfunction following permanent focal ischemia by regulating the expression of matrix metalloproteinases. Exp Neurol 226:183–190

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Keenan DM, Veldhuis JD (2009) Age-dependent regression analysis of male gonadal axis. Am J Physiol Regul Integr Comp Physiol 297:R1215–R1227

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Kuiper GG, Enmark E, Pelto-Huikko M, Nilsson S, Gustafsson JA (1996) Cloning of a novel receptor expressed in rat prostate and ovary. Proc Natl Acad Sci USA 93:5925–5930

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Kumar RC, Thakur MK (2004) Androgen receptor mRNA is inversely regulated by testosterone and estradiol in adult mouse brain. Neurobiol Aging 25:925–933

    Article  PubMed  CAS  Google Scholar 

  • Lappano R, Rosano C, De Marco P, De Francesco EM, Pezzi V, Maggiolini M (2010) Estriol acts as a GPR30 antagonist in estrogen receptor-negative breast cancer cells. Mol Cell Endocrinol 320:162–170

    Article  PubMed  CAS  Google Scholar 

  • Lephart E (1996) A review of brain aromatase cytochrome P450. Brain Res Rev 22:1–26

    Article  PubMed  CAS  Google Scholar 

  • Leranth C, Hajszan T, MacLusky NJ (2004) Androgens increase spine synapse density in the CA1 hippocampal subfield of ovariectomized female rats. J Neurosci 24:485–499

    Article  Google Scholar 

  • Levin-Allerhand JA, Lominska CE, Wang J, Smith JD (2002) 17Alpha-estradiol and 17beta-estradiol treatment are effective in lowering cerebral amyloid-beta levels in AbetaPPSWE transgenic mice. J Alzheimers Dis 4:449–457

    PubMed  CAS  Google Scholar 

  • Liehr JG, Roy D (1990) Free radical generation by redox cycling of estrogens. Free Radic Biol Med 8:415–423

    Article  PubMed  CAS  Google Scholar 

  • Lonard DM, Lanz RB, O’Malley BW (2007) Nuclear receptor coregulators and human disease. Endocr Rev 28:575–587

    Article  PubMed  CAS  Google Scholar 

  • Lubbers LS, Zafian PT, Gautreaux C, Gordon M, Alves SE, Correa L, Lorrain DS, Hickey GJ, Luine V (2010) Estrogen receptor (ER) subtype agonists alter monoamine levels in the female rat brain. J Steroid Biochem Mol Biol 122:310–317

    Article  PubMed  CAS  Google Scholar 

  • Maggiolini M, Picard D (2010) The unfolding stories of GPR30, a new membrane-bound estrogen receptor. J Endocrinol 204:105–114

    Article  PubMed  CAS  Google Scholar 

  • Mangelsdorf DJ, Thummel C, Beato M, Herrlich P, Schutz G, Umesono K, Blumberg B, Mark M, Chambon P, Evans RM (1995) The nuclear receptor superfamily: the second decade. Cell 83:835–839

    Article  PubMed  CAS  Google Scholar 

  • Mannella P, Sanchez AM, Giretti MS, Genazzani AR, Simoncini T (2009) Oestrogen and progestins differently prevent glutamate toxicity in cortical neurons depending on prior hormonal exposure via the induction of neural nitric oxide synthase. Steroids 74:650–656

    Article  PubMed  CAS  Google Scholar 

  • Matsumoto A, Prins G (2002) Androgenic regulation of expression of androgen receptor protein in peripheral motoneurons of aged male rats. J Comp Neurol 443:383–387

    Article  PubMed  CAS  Google Scholar 

  • Mesiano S (2001) Roles of estrogen and progesterone in human parturition. Front Horm Res 27:86–104

    Article  PubMed  CAS  Google Scholar 

  • Million Women Study Collaborators (2003) Breast cancer and hormone replacement therapy in the Million Women Study. Lancet 362:419–427

    Google Scholar 

  • Mooradian AD, Morley JE, Korenman SG (1987) Biological actions of androgens. Endocr Rev 8:1–28

    Article  PubMed  CAS  Google Scholar 

  • Murphy DD, Segal M (2000) Progesterone prevents estradiol-induced dendritic spine density formation in hippocamp0la neurons. Neuroendocrinology 72:133–143

    Article  PubMed  CAS  Google Scholar 

  • Nakhla AM, Hryb DJ, Hryb DJ, Rosner W, Romas NA, Xiang Z, Kahn SM (2009) Human sex hormone-binding globulin gene expression- multiple promoters and complex alternative splicing. BMC Mol Biol 10:37–55

    Article  PubMed  PubMed Central  Google Scholar 

  • Nguyen T-V, Yao M, Pike CJ (2005) Androgens activate mitogen-activated protein kinase signaling: Role in neuroprotection. J Neurochem 94:1639–1651

    Article  PubMed  CAS  Google Scholar 

  • Nguyen HP, Li L, Gatson JW, Maass D, Wigginton JG, Simpkins JW, Schug KA (2011) Simultaneous quantification of four native estrogen hormones at trace levels in human cerebrospinal fluid using liquid chromatography–tandem mass spectrometry. J Pharm Biomed Anal 54:830–837

    Article  PubMed  CAS  Google Scholar 

  • Nilsen J, Brinton RD (2002) Impact of progestins on estrogen-induced neuroprotection: synergy by progesterone and 19-norprogesterone and antagonism by medroxyprogesterone acetate. Endocrinology 143:205–212

    Article  PubMed  CAS  Google Scholar 

  • O’Malley BW (2006) Little molecules with big goals. Science 313:1749–1750

    Article  PubMed  Google Scholar 

  • Österlund MK, Hurd YL (2001) Estrogen receptors in the human forebrain and the relation to neuropsychiatric disorders. Prog Neurobiol 64(3):251–267

    Article  PubMed  Google Scholar 

  • Patchev VK, Schroeder J, Goetz F, Rohde W, Patchev AV (2004) Neurotropic action of androgens: principles, mechanisms and novel targets. Exp Gerontol 39:1651–1660

    Article  PubMed  CAS  Google Scholar 

  • Paul SM, Purdy RH (1992) Neuroactive steroids. FASEB J 6:2311–2322

    PubMed  CAS  Google Scholar 

  • Pettersson H, Lundqvist J, Oliw E, Norlin M (2009) CYP7B1-mediated metabolism of 5α-androstane-3α,17β-diol (3α-Adiol):A novel pathway for potential regulation of the cellular levels of androgensand neurosteroids. Biochim Biophys Acta 1791:1206–1215

    Article  PubMed  CAS  Google Scholar 

  • Picazo O, Azcoitia I, Garcia-Segura LM (2003) Neuroprotective and neurotoxic effect of estrogens. Brain Res 990:220–227

    Google Scholar 

  • Pike CJ (2001) Testosterone attenuates β-amyloid toxicity in cultured hippocampal neurons. Brain Res 919:160–165

    Article  PubMed  CAS  Google Scholar 

  • Pilgrim C, Hutchison JB (1994) Developmental Regulation of Sex Differences in the Brain: Can the role of the gonadal steroids be redefined. Neuroscience 604:843–855

    Article  Google Scholar 

  • Powell SM, Christiaens V, Voulgaraki D, Waxman J, Claessens F, Bevan CL (2004) Mechanisms of androgen receptor signalling via steroid receptor coactivator-1 in prostate. Endocr RelatCancer 11:117–130

    CAS  Google Scholar 

  • Prokal L, Simpkins JW (2007) Structure-non-genomic neuroprotection relationship of estrogens and estrogen-derived compounds. Pharmacol Ther 114:1–12

    Article  Google Scholar 

  • Reddy DS (2004) Testosterone modulation of seizure susceptibility is mediated by neurosteroids 3α androstanediol and 17β-estradiol. Neuroscience 129:195

    Article  PubMed  CAS  Google Scholar 

  • Reyes-Romero MA (2001) The physiological role of estriol during human fetal development is to act as antioxidant at lipophilic milieus of the central nervous system. Med Hypotheses 56:107–109

    Article  PubMed  CAS  Google Scholar 

  • Rohr UW (2002) The impact of testosterone imbalance on depression and women’s health. Maturitas 41:S25–S46

    Article  PubMed  CAS  Google Scholar 

  • Roselli CE, Resko JA (1993) Aromatase activity in the brain:hormonal regulation and sex differences. J Steroid Biochem Mol Biol 61:365–374

    Article  Google Scholar 

  • Simpkins JW, Rajakumar G, Zhang YQ, Simpkins CE, Grenwald D, Yu CJ, Bodor N, Day LJ (1997) Estrogens may reduce mortality and ischemic damage caused by middle cerebral artery occlusion in the female rat. Neurosurgery 87:724–730

    Article  CAS  Google Scholar 

  • Steckelbroeck S, Watzka M, Reichelt R, Hans VHJ, Stoffel-Wagner B, Heidrich DD, Schramm J, Bidlingmaier F, Klingmüller D (2001) Characterization of the 5α-reductase-3α-hydroxysteroid dehydrogenase complex in the human brain. J Clin Endocrinol Metab 86:1324–1331

    PubMed  CAS  Google Scholar 

  • Swaab DF (2007) Sexual differentiation of the brain and behavior. Best Practice & Research Clinical Endocrinology and Metabolism 21:431–444

    Article  Google Scholar 

  • Thomas P (2008) Characteristics of membrane progestin receptor alpha (mPRalpha) and progesterone membrane receptor component 1 (PGMRC1) and their roles in mediating rapid progestin actions. Front Neuroendocrinol 29:292–312

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Toran-Allerand CD (2004) Estrogen and the brain: beyond ER-alpha and ER-beta. Exp Gerontol 39:1579–1586

    Article  PubMed  CAS  Google Scholar 

  • Tsai MJ, O'Malley BW (1994) Molecular mechanisms of action of steroid/thyroid receptor superfamily members. Annu Rev Biochem 63:451–486

    Article  PubMed  CAS  Google Scholar 

  • Tunbridge EM, Harrison PJ (2011) Importance of the COMT gene for sex differences in brain function and predisposition to psychiatric disorders. Curr Topics Behav Neurosci DOI: 10.1007/7854_2010_97.

    Google Scholar 

  • Wallis CJ, Luttge WG (1980) Influence of estrogen and progesterone on gluatamic acid decarboxylase activity in discrete regions of rat brain. J Neurochem 34:609–613

    Article  PubMed  CAS  Google Scholar 

  • Weiser MJ, Foradori CD, Handa RJ (2008) Estrogen receptor beta in the brain: from form to function. Brain Res Rev 57:309–320

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • WHI Investigators (2003) Influence of Estrogen Plus Progestin on Breast Cancer and Mammography in Healthy Postmenopausal Women. JAMA 289(24):3243–3253

    Google Scholar 

  • Wright DW, Kellermann AL, Hertzberg VS, Clark PL, Frankel M, Goldstein FC, Salomone JP, Dent LL, Harris OA, Ander DS, Lowery DW, Patel MM, Denson DD, Gordon AB, Wald MM, Gupta S, Hoffman SW, Stein DG (2007) ProTECT: a randomized clinical trial of progesterone for acute traumatic brain injury. Ann Emerg Med 49:391–402

    Article  PubMed  Google Scholar 

  • Yore MA, Im D, Webb LK, Zhao Y, Chadwick JG, Molenda-Figueira HA, Haidacher SJ, Denner L, Tetel MJ (2010) Steroid receptor coactivator-2 expression in brain and physical associations with steroid receptors. Neuroscience 169:1017–1028

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Zwain IH, Yen SSC (1999) Dehydroepiandrosterone: biosynthesis and metabolism in the brain. Endocrinology 140:880–887

    Article  PubMed  CAS  Google Scholar 

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Marshall, K.M. (2011). Introduction to the Interaction Between Gonadal Steroids and the Central Nervous System. In: Neill, J., Kulkarni, J. (eds) Biological Basis of Sex Differences in Psychopharmacology. Current Topics in Behavioral Neurosciences, vol 8. Springer, Berlin, Heidelberg. https://doi.org/10.1007/7854_2011_136

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