Reproductive Hormones in Epilepsy Therapy: From Old Promises to New Hopes

  • Alberto VerrottiEmail author
  • Giovanni Prezioso
  • Claudia D’Egidio
  • Vincenzo Belcastro
Part of the Contemporary Clinical Neuroscience book series (CCNE)


A significant mutual interaction between sex hormones and the central nervous system has been reported by several studies in the past years.

This paper aims to discuss the genomic and electrophysiological effects of androgens, estrogens and progestogens on neurons, their influence on seizure frequency and antiepileptic drugs metabolism, and, conversely, the hormonal changes and reproductive dysfunction in patients with epilepsy.

In conclusion, the correlations between Polycystic Ovary Syndrome (PCOS), reduced effectiveness of contraceptives and antiepileptic drugs have also been mentioned.


Sex hormones Epilepsy Androgen Estrogen Progesterone Neurosteroids Catamenial epilepsy Antiepileptic drugs Sex functions PCOS Contraceptive 


  1. Bartoli A, Gatti G, Cipolla G, Barzaghi N, Veliz G, Fattore C, Mumford J, Perucca E (1997) A double-blind, placebo-controlled study on the effect of vigabatrin on in vivo parameters of hepatic microsomal enzyme induction and on the kinetics of steroid oral contraceptives in healthy female volunteers. Epilepsia 38:702–707PubMedCrossRefGoogle Scholar
  2. Bauer J, Isojärvi JI, Herzo AG, Reuber M, Polson D, Taubøll E, Genton P, van der Ven H, Roesing B, Luef GJ, Galimberti CA, van Parys J, Flügel D, Bergmann A, Elger CE (2002) Reproductive dysfunction in women with epilepsy: recommendations for evaluation and management. J Neurol Neurosurg Psychiatry 73:121–125PubMedCentralPubMedCrossRefGoogle Scholar
  3. Belcastro V, D’Egidio C, Striano P, Verrotti A (2013) Metabolic and endocrine effects of valproic acid chronic treatment. Epilepsy Res 107:1–8PubMedCrossRefGoogle Scholar
  4. Betts T, Yarrow H, Dutton N, Greenhill L, Rolfe T (2003) A study of anticonvulsant medication on ovarian function in a group of women with epilepsy who have only ever taken one anticonvulsant compared with a group of women without epilepsy. Seizure 12:323–329PubMedCrossRefGoogle Scholar
  5. Chen SS, Shen MR, Chen TJ, Lai SL (1992) Effects of antiepileptic drugs on sperm motility of normal controls and epileptic patients with long-term therapy. Epilepsia 33:149–153PubMedCrossRefGoogle Scholar
  6. Ciampani M, Verrotti A, Chiarelli F (2005) Sex hormones in patients with epilepsy-hormonal changes in epileptic men and women taking antiepileptics. Horm Metab Res 37:184–188PubMedCrossRefGoogle Scholar
  7. Drislane FW, Coleman AE, Schomer DL, Ives J, Levesque LA, Seibel MM, Herzog AG (1994) Altered pulsatile secretion of luteinizing hormone in women with epilepsy. Neurology 44:306–310PubMedCrossRefGoogle Scholar
  8. Duncan S, Talbot A, Sheldrick R, Caswell H (2009) Erectile function, sexual desire, and psychological well-being in men with epilepsy. Epilepsy Behav 15:351–357PubMedCrossRefGoogle Scholar
  9. Erel T, Guralp O (2011) Epilepsy and menopause. Arch Gynecol Obstet 284:749–755PubMedCrossRefGoogle Scholar
  10. Evans JL, Goldfine ID, Maddux BA, Grodsky GM. (2003) Are oxidative stress-activated signaling pathways mediators ofinsulin resistance and beta-cell dysfunction? Diabetes 52:1–8PubMedCrossRefGoogle Scholar
  11. Fawley JA, Pouliot WA, Dudek FE (2006) Epilepsy and reproductive disorders: the role of the gonadotropin-releasing hormone network. Epilepsy Behav 8:477–482PubMedCrossRefGoogle Scholar
  12. Finocchi C, Ferrari M (2011) Female reproductive steroids and neuronal excitability. Neurol Sci 32(Suppl 1):S31–35CrossRefGoogle Scholar
  13. Foldvary-Schaefer N, Harden C, Herzog A, Falcone T (2004) Hormones and seizures. Cleve Clin J Med 71(Suppl 2):S11–18CrossRefGoogle Scholar
  14. Greco R, Latini G, Chiarelli F, Iannetti P, Verrotti A (2005) Leptin, ghrelin, and adiponectin in epileptic patients treatedwith valproic acid. Neurology 65:1808–1809PubMedCrossRefGoogle Scholar
  15. Guberman A (1999) Hormonal contraception and epilepsy. Neurology 53:S38–40CrossRefGoogle Scholar
  16. 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 13:12–24PubMedCentralPubMedCrossRefGoogle Scholar
  17. Gungor S, Yücel G, Akinci A, Tabel Y, Ozerol IH, Yologlu S (2007) The role of ghrelin in weight gain and growth in epileptic children using valproate. J Child Neurol 22:1384–1388PubMedCrossRefGoogle Scholar
  18. Hamed SA (2008) Neuroendocrine hormonal conditions in epilepsy: relationship to reproductive and sexual functions. Neurologist 14:157–169PubMedCrossRefGoogle Scholar
  19. Harden CL (2003) Menopause and bone density issues for women with epilepsy. Neurology 61:S16–S22CrossRefGoogle Scholar
  20. Harden CL (2008) Sexual dysfunction in women with epilepsy. Seizure 17:131–135PubMedCrossRefGoogle Scholar
  21. Herzog AG (1986) Intermittent progesterone therapy of partial complex seizures in women with menstrual disorders. Neurology 36:1607–1610PubMedCrossRefGoogle Scholar
  22. Herzog AG (1995) Progesterone therapy in women with complex partial and secondary generalized seizures. Neurology 45:1660–1662PubMedCrossRefGoogle Scholar
  23. Herzog AG (1999) Progesterone therapy in women with epilepsy: a 3-year follow-up. Neurology 52:1917–1918PubMedCrossRefGoogle Scholar
  24. Herzog AG (2008) Disorders of reproduction in patients with epilepsy: primary neurological mechanisms. Seizure 17:101–110PubMedCrossRefGoogle Scholar
  25. Herzog AG, Seibel MM, Schomer DL Vaitukaitis JL, Geschwind N (1986) Reproductive endocrine disorders in women with partial seizures of temporal lobe origin. Arch Neurol 43:341–346PubMedCrossRefGoogle Scholar
  26. Herzog AG, Klein P, Ransil BJ (1997) Three patterns of catamenial. Epilepsia 38:1082–1088PubMedCrossRefGoogle Scholar
  27. Herzog AG, Coleman AE, Jacobs AR, Klein P, Friedman MN, Drislane FW, Ransil BJ, Schomer DL (2003) Interictal EEG discharges, reproductive hormones, and menstrual disorders in epilepsy. Ann Neurol 54:625–637PubMedCrossRefGoogle Scholar
  28. Isojärvi JI, Laatikainen TJ, Pakarinen AJ, Juntunen KT, Myllylä VV (1993) Polycystic ovaries and hyperandrogenism in women taking valproate for epilepsy. N Engl J Med 329:1383–1388PubMedCrossRefGoogle Scholar
  29. Isojärvi JI, Laatikainen TJ, Pakarinen AJ, Juntunen KT, Myllylä VV (1995) Menstrual disorders in women with epilepsy receiving carbamazepine. Epilepsia 36:676–681PubMedCrossRefGoogle Scholar
  30. Isojärvi JI, Laatikainen TJ, Knip M, Pakarinen AJ, Juntunen KT, Myllylä VV (1996) Obesity and endocrine disorders in women taking valproate for epilepsy. Ann Neurol 39:579–584PubMedCrossRefGoogle Scholar
  31. Isojärvi JI, Rättyä J, Myllylä VV, Knip M, Koivunen R, Pakarinen AJ, Tekay A, Tapanainen JS (1998) Valproate, lamotrigine, and insulinmediated risks in women with epilepsy. Ann Neurol 43:446–451PubMedCrossRefGoogle Scholar
  32. Isojärvi JI, Taubøll E, Pakarinen AJ, van Parys J, Rättyä J, Harbo HF, Dale PO, Fauser BC, Gjerstad L, Koivunen R, Knip M, Tapanainen JS (2001) Altered ovarian function and cardiovascular risk factors in valproate-treated women. Am J Med 111:290–296PubMedCrossRefGoogle Scholar
  33. Isojärvi JI, Taubøll E, Herzog AG (2005) Effect of antiepileptic drugs on eproductive endocrine function in individuals with epilepsy. CNS Drugs 19:207–223PubMedCrossRefGoogle Scholar
  34. Keefe DL (2002) Sex hormones and neural mechanisms. Arch Sex Behav 31:401–403PubMedCrossRefGoogle Scholar
  35. Klein P, Serje A, Pezzullo JC (2001) Premature ovarian failure in women with epilepsy. Epilepsia 42:1584–1589PubMedCrossRefGoogle Scholar
  36. Lim LL, Foldvary N, Mascha E, Lee J (2001) Acetazolamide in women with catamenial epilepsy. Epilepsia 42:746–749PubMedCrossRefGoogle Scholar
  37. Luef G, Abraham I, Trinka E, Alge A, Windisch J, Daxenbichler G, Unterberger I, Seppi K, Lechleitner M, Krämer G, Bauer G. (2002) Hyperandrogenism, postprandial hyperinsulinism and the risk of PCOS in a cross sectional study of women with epilepsy treated with valproate. Epilepsy Res 48:91–102PubMedCrossRefGoogle Scholar
  38. Luef G, Lechleitner M, Bauer G, Trinka E, Hengster P (2003) Valproic acid modulates islet cell insulin secretion: a possible mechanism of weight gain in epilepsy patients. Epilepsy Res 55:53–58PubMedCrossRefGoogle Scholar
  39. Luef G, Rauchenzauner M, Waldmann M, Sturm W, Sandhofer A, Seppi K, Trinka E, Unterberger I, Ebenbichler CF, Joannidis M, Walser G, Bauer G, Hoppichler F, Lechleitner M (2009) Non-alcoholic fatty liver disease (NAFLD), insulin resistance and lipid profile in antiepileptic drugtreatment. Epilepsy Res 86:42–47PubMedCrossRefGoogle Scholar
  40. Mattson RH, Cramer JA, Caldwell BV, Siconolfi BC (1984) Treatment of seizures with medroxyprogesterone acetate: preliminary report. Neurology 34:1255–1258PubMedCrossRefGoogle Scholar
  41. McAuley JW, Moore JL, Reeves AL, Flyak J, Monaghan EP, Data J (2001) A pilot study of the neurosteroid ganaxolone in catamenial epilepsy: clinical experience in two patients. Epilepsia 42:85–85Google Scholar
  42. Morell MJ (2003) Reproductive and metabolic disorders in women with epilepsy. Epilepsia 44:11–20CrossRefGoogle Scholar
  43. Morrell MJ, Giudice L, Flynn KL, Seale CG, Paulson AJ, Doñe S, Flaster E, Ferin M, Sauer MV (2002) Predictors of ovulatory failure in women with epilepsy. Ann Neurol 52:704–711PubMedCrossRefGoogle Scholar
  44. Morrell MJ, Flynn KL, Doñe S, Flaster E, Kalayjian L, Pack AM (2005) Sexual dysfunction, sex steroid hormone abnormalities, and depression in women with epilepsy treated with antiepileptic drugs. Epilepsy Behav 6:360–365PubMedCrossRefGoogle Scholar
  45. Morrell MJ, Hayes FJ, Sluss PM, Adams JM, Bhatt M, Ozkara C, Warnock CR, Isojärvi J (2008) Hyperandrogenism, ovulatory dysfunction, and polycystic ovary syndrome with valproate versus lamotrigine. Ann Neurol 64:200–211PubMedCrossRefGoogle Scholar
  46. Pack AM (2010) Implications of hormonal and neuroendocrine changes associated with seizures and antiepileptic drugs: a clinical perspective. Epilepsia 51(Suppl 3):150–153PubMedCrossRefGoogle Scholar
  47. Pennell PB (2009) Hormonal aspects of epilepsy. Neurol Clin 27:941–965PubMedCentralPubMedCrossRefGoogle Scholar
  48. Prabhakar S, Sahota P, Kharbanda PS, Siali R, Jain V, Lal V, Khurana D (2007) Sodium valproate, hyperandrogenism and altered ovarian function in Indian women with epilepsy: a prospective study. Epilepsia 48:1371–1377PubMedCrossRefGoogle Scholar
  49. Quigg M, Smithson SD, Fowler KM, Sursal T, Herzog AG (2009) Laterality and location influence catamenial seizure expression in women with partial epilepsy. Neurology 73:223–227PubMedCentralPubMedCrossRefGoogle Scholar
  50. Rauchenzauner M, Haberlandt E, Scholl-Bürgi S, Karall D, Schoenherr E, Tatarczyk T, Engl J, Laimer M, Luef G, Ebenbichler CF (2008) Effect of valproic acid treatment on body composition, leptin and the soluble leptin receptor in epileptic children. Epilepsy Res 80:142–149PubMedCrossRefGoogle Scholar
  51. Rauchenzauner M, Bitsche G, Svalheim S, Tauboll E, Haberlandt E, Wildt L, Rostasy K, Luef G (2010) Effects of levetiracetam and valproic acid monotherapy on sex-steroid hormones in prepubertal children—results from a pilot study. Epilepsy Res 88:264–268PubMedCrossRefGoogle Scholar
  52. Reddy DS (2009) The role of neurosteroids in the pathophysiology and treatment of catamenial epilepsy. Epilepsy Res 85:1–30PubMedCentralPubMedCrossRefGoogle Scholar
  53. Reddy DS, Rogawski MA (2009) Neurosteroid replacement therapy for catamenial epilepsy. Neurotherapeutics 6:392–401PubMedCentralPubMedCrossRefGoogle Scholar
  54. Ross IP (1958) Acetazolamide therapy in epilepsy. Lancet 2:1308–1309PubMedCrossRefGoogle Scholar
  55. Røste LS, Taubøll E, Svalheim S, Gjerstad L (2008) Does menopause affect the epilepsy? Seizure 17:172–175PubMedCrossRefGoogle Scholar
  56. Scharfman HE, Kim MK, Hintz TM, MacLusky NJ (2008) Seizures and reproductive function: insights from female rats with epilepsy. Ann Neurol 64:687–697PubMedCentralPubMedCrossRefGoogle Scholar
  57. Verrotti A, Basciani F, Morresi S, de Martino M, Morgese G, Chiarelli F (1999) Serum leptin changes in epileptic patients who gain weight after therapy with valproic acid. Neurology 53:230–232PubMedCrossRefGoogle Scholar
  58. Verrotti A, Manco R, Agostinelli S, Coppola G, Chiarelli F (2010) The metabolic syndrome in overweight epileptic patients treated with valproic acid. Epilepsia 51:268–273PubMedCrossRefGoogle Scholar
  59. Verrotti A, D’Egidio C, Mohn A, Coppola G, Parisi P, Chiarelli F (2011) Antiepileptic drugs, sex hormones, and PCOS. Epilepsia 52:199–211PubMedCrossRefGoogle Scholar
  60. Wong HY, Chu TS, Lai JC, Fung KP, Fok TF, Fujii T (2005) Sodium valproate inhibits glucose transport and exacerbates Glut1-deficiency in vitro. J Cell Biochem 96:775–785PubMedCrossRefGoogle Scholar
  61. Xiaotian X, Hengzhong Z, Yao X, Zhipan Z, Daoliang X, Yumei W (2013) Effects of antiepileptic drugs on reproductive endocrine function, sexual function and sperm parameters in Chinese Han men with epilepsy. J Clin Neurosci 20:1492–1497PubMedCrossRefGoogle Scholar
  62. Zimmerman AW, Holder DT, Reiter EO, Dekaban AS (1973) Medroxyprogesterone acetate in the treatment of seizures associated with menstruation. J Pediatr 83:959–963PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  • Alberto Verrotti
    • 1
    Email author
  • Giovanni Prezioso
    • 2
  • Claudia D’Egidio
    • 2
  • Vincenzo Belcastro
    • 3
  1. 1.Department of PediatricsUniversity of PerugiaPerugiaItaly
  2. 2.Department of PediatricsUniversity of ChietiChietiItaly
  3. 3.Neurology Unit, Department of MedicineS. Anna HospitalComoItaly

Personalised recommendations