Neurological Sciences

, Volume 32, Supplement 1, pp 31–35 | Cite as

Female reproductive steroids and neuronal excitability

  • C. FinocchiEmail author
  • M. Ferrari
Migraine Pathophysiology


Oestrogen and progesterone have specific receptors in the central nervous system and are able to regulate neuronal development and plasticity, neuronal excitability, mitochondrial energy production, and neurotransmitter synthesis, release, and transport. On neuronal excitability, estradiol and progesterone seem to have an opposite effect, with estradiol being excitatory and progesterone and its derivative allopregnanolone being inhibitory. Estradiol augments N-methyl-d-aspartate-mediated glutamate receptor activity, while progesterone enhances gamma-aminobutyric acid-mediated chloride conductance. Sex steroid regulation of the balance of neuroexcitatory and neuroinhibitory activities may have a role in modulating clinical susceptibility to different neurological conditions such as migraine, catamenial epilepsy, premenstrual dysphoric disorder, and premenstrual syndrome.


Reproductive steroids Neuronal excitability Migraine 


Conflict of interest

The authors declare that there is no actual or potential conflict of interest in relation to this article.


  1. 1.
    McEwen BS (2001) Invited review: estrogens effects on the brain: multiple sites and molecular mechanisms. J Appl Physiol 91:2785–2801PubMedGoogle Scholar
  2. 2.
    Herzog AG (2007) Neuroactive properties of reproductive steroids. Headache 47(Suppl 2):S68–S78PubMedCrossRefGoogle Scholar
  3. 3.
    Guille C, Spencer S, Cavus I, Epperson CN (2008) The role of sex steroids in catamenial epilepsy and premenstrual dysphoric disorder: implications for diagnosis and treatment. Epilepsy Behav 13:12–24PubMedCrossRefGoogle Scholar
  4. 4.
    Aguggia M, D’Andrea G, Bussone G (2007) Neurophysiology and neuromodulators. Neurol Sci 28(Suppl 2):S97–S100PubMedCrossRefGoogle Scholar
  5. 5.
    Aurora SK, Barrodale P, Chronicle EP, Mulleners WM (2005) Cortical inhibition is reduced in chronic and episodic migraine and demonstrates a spectrum of illness. Headache 45:546–552PubMedCrossRefGoogle Scholar
  6. 6.
    Moskowitz MA, Bolay H, Dalkara T (2004) Deciphering migraine mechanisms: clues from familial hemiplegic migraine genotypes. Ann Neurol 55:276–280PubMedCrossRefGoogle Scholar
  7. 7.
    Rasmussen B, Jensen R, Schroll M, Olesen J (1991) Epidemiology of headache in a general population: a prevalence study. J Clin Epidemiol 44:1147–1157PubMedCrossRefGoogle Scholar
  8. 8.
    Silberstein SD (2001) Hormone-related headache. Med Clin North Am 285:1017–1035CrossRefGoogle Scholar
  9. 9.
    Lipton RB, Stewart WF, Diamond S, Diamond ML, Reed M (2001) Prevalence and burden of migraine in the United States: Results from the American Migraine Study II. Headache 41:646–657PubMedCrossRefGoogle Scholar
  10. 10.
    Herzog AG (2008) Catamenial epilepsy: definition, prevalence pathophysiology and treatment. Seizure 17:151–159PubMedCrossRefGoogle Scholar
  11. 11.
    Backstrom T, Andersson A, Andree L et al (2003) Pathogenesis of menstrual cycle-linked CNS disorders. Ann N Y Acad Sci 1007:42–53PubMedCrossRefGoogle Scholar
  12. 12.
    Mensah-Nyagan AG, Do-Rego JL, Beaujean D, Luu-The V, Pelletier G, Vaudry H (1999) Neurosteroids: expression of steroidogenic enzymes and regulation of steroid biosynthesis in the central nervous system. Pharmacol Rev 51:63–81PubMedGoogle Scholar
  13. 13.
    Woolley CS, McEwen BS (1993) Roles of estradiol and progesterone in regulation of hippocampal dendritic spine density during the estrous cycle in the rat. J Comp Neurol 336:293–306PubMedCrossRefGoogle Scholar
  14. 14.
    Gazzaley AH, Weiland NG, McEwen BS, Morrison JH (1996) Differential regulation of NMDAR1 mRNA and protein by estradiol in the rat hippocampus. J Neurosci 16:6830–6838PubMedGoogle Scholar
  15. 15.
    Woolley CS, McEwen BS (1994) Estradiol regulates hippocampal dendritic spine density via an N-methyl-d-aspartate receptor-dependent mechanism. J Neurosci 14:7680–7687PubMedGoogle Scholar
  16. 16.
    Rudick CN, Woolley CS (2001) Estrogen regulates functional inhibition of hippocampal CA1 pyramidal cells in the adult female rat. J Neurosci 21:6532–6543PubMedGoogle Scholar
  17. 17.
    Wallis CJ, Luttge WG (1980) Influence of estrogen and progesterone on glutamic acid decarboxylase activity in discrete regions of rat brain. J Neurochem 34:609–613PubMedCrossRefGoogle Scholar
  18. 18.
    Toran-Allerand CD, Guan X, MacLusky NJ et al (2002) ER-X: a novel, plasma membrane-associated, putative estrogen receptor that is regulated during development and after ischemic brain injury. J Neurosci 22:8391–8401PubMedGoogle Scholar
  19. 19.
    Smith SS (1989) Estrogen administration increases neuronal responses to excitatory amino acids as a long term effect. Brain Res 503:354–357PubMedCrossRefGoogle Scholar
  20. 20.
    Wong M, Moss RL (1992) Long-term and short-term electrophysiological effects of estrogen on the synaptic properties of hippocampal CA1 neurons. J Neurosci 12:3217–3225PubMedGoogle Scholar
  21. 21.
    Kokate TG, Svensson BE, Rogawski MA (1994) Anticonvulsant activity of neurosteroids: correlation with gamma-aminobutyric acid-evoked chloride current potentiation. J Pharmacol Exp Ther 270:1223–1229PubMedGoogle Scholar
  22. 22.
    Reddy DS, Castaneda DC, O’Malley BW, Rogawski MA (2004) Anticonvulsant activity of progesterone and neurosteroids in progesterone receptor knockout mice. J Pharmacol Exp Ther 310:230–239PubMedCrossRefGoogle Scholar
  23. 23.
    Smith SS (2002) Withdrawal properties of a neuroactive steroid: implications for GABA(A) receptor gene regulation in the brain and anxiety behavior. Steroids 67:519–528PubMedCrossRefGoogle Scholar
  24. 24.
    Gulinello M, Gong QH, Smith SS (2002) Progesterone withdrawal increases the alpha4 subunit of the GABA(A) receptor in male rats in association with anxiety and altered pharmacology: a comparison with female rats. Neuropharmacology 43:701–714PubMedCrossRefGoogle Scholar
  25. 25.
    Smith SS, Gong QH, Hsu FC, Markowitz RS, French-Mullen JM, Li X (1998) GABA(A) receptor alpha4 subunit suppression prevents withdrawal properties of an endogenous steroid. Nature 392:926–930PubMedCrossRefGoogle Scholar
  26. 26.
    Smith SS, Ruderman Y, Frye C, Homanics G, Yuan M (2006) Steroid withdrawal in the mouse results in anxiogenic effects of 3alpha, 5beta-THP: a possible model of premenstrual dysphoric disorder. Psychopharmacology 186:323–333PubMedCrossRefGoogle Scholar
  27. 27.
    Terasawa E, Timiras PS (1968) Electrical activity during the estrous cycle of the rat: cyclic changes in limbic structures. Endocrinology 83:207–216PubMedCrossRefGoogle Scholar
  28. 28.
    Marcus EM, Watson CW, Goldman PL (1966) Effects of steroids on cerebral electrical activity. Epileptogenic effects of conjugated estrogens and related compounds in the cat and rabbit. Arch Neurol 15:521–532PubMedGoogle Scholar
  29. 29.
    Landgren S, Backstrom T, Kalistratov G (1978) The effect of progesterone on the spontaneous interictal spike evoked by the application of penicillin to the cat’s cerebral cortex. J Neurol Sci 36:119–133PubMedCrossRefGoogle Scholar
  30. 30.
    van den Maagdenberg AM, Pietrobon D, Pizzorusso T et al (2004) A Cacna1a knockin migraine mouse model with increased susceptibility to cortical spreading depression. Neuron 41:701–710PubMedCrossRefGoogle Scholar
  31. 31.
    Eikermann-Haerter K, Kudo C, Moskowitz MA (2007) Cortical spreading depression and estrogen. Headache 47(Suppl 2):S79–S85PubMedCrossRefGoogle Scholar
  32. 32.
    Sachs M, Pape HC, Speckmann EJ, Gorji A (2007) The effect of estrogen and progesterone on spreading depression in rat neocortical tissues. Neurobiol Dis 25:27–34PubMedCrossRefGoogle Scholar
  33. 33.
    Smith MJ, Keel JC, Greenberg BD, Adams LF, Schmidt PJ, Rubinow DA, Wassermann EM (1999) Menstrual cycle effects on cortical excitability. Neurology 53:2069–2072PubMedGoogle Scholar
  34. 34.
    Smith MJ, Adams LF, Schmidt PJ, Rubinow DR, Wassermann EM (2002) Effects of ovarian hormones on human cortical excitability. Ann Neurol 51:599–603PubMedCrossRefGoogle Scholar
  35. 35.
    Inghilleri M, Conte A, Curra A, Frasca V, Lorenzano B, Berardellia A (2004) Ovarian hormones and cortical excitability. An rTMS study in humans. Clin Neurophysiol 115:1063–1068PubMedCrossRefGoogle Scholar
  36. 36.
    De Tommaso M, Valeriani M, Sardaro M, Serpino C, Fruscolo OD, Vecchio E, Cerbo R, Livrea P (2009) Pain perception and laser evoked potentials during menstrual cycle in migraine. J Headache Pain 10(6):423–429PubMedCrossRefGoogle Scholar
  37. 37.
    Herzog AG, Klein P, Ransil BJ (1997) Three patterns of catamenial epilepsy. Epilepsia 38:1082–1088PubMedCrossRefGoogle Scholar
  38. 38.
    Herzog AG (2008) Catamenial epilepsy: definition, prevalence pathophysiology and treatment. Seizure 17:151–159PubMedCrossRefGoogle Scholar
  39. 39.
    Sundstrom I, Backstrom T (1998) Citalopram increases pregnanolone sensitivity in patients with premenstrual syndrome: an open trial. Psychoneuroendocrinology 23:73–88PubMedCrossRefGoogle Scholar
  40. 40.
    Epperson CN, Haga K, Mason GF et al (2002) Cortical gammaaminobutyric acid levels across the menstrual cycle in healthy women and those with premenstrual dysphoric disorder: a proton magnetic resonance spectroscopy study. Arch Gen Psychiatry 59:851–858PubMedCrossRefGoogle Scholar
  41. 41.
    Somerville BW (1972) The role of estradiol withdrawal in the etiology of menstrual migraine. Neurology 22:355–365PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  1. 1.Department of Neurosciences, Ophthalmology and GeneticsUniversity of GenovaGenoaItaly

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