Epilepsy, sex hormones and antiepileptic drugs in female patients

Expert Review of Neurotherapeutics

Volumn 9, Issue 12, 2009, Pages 1803-1814

  Verrotti, Alberto ^a   D'Egidio, Claudia ^a   Coppola, Giangennaro ^b   Parisi, Pasquale ^c   Chiarelli, Francesco ^a  

^a UNIVERSITY OF CHIETI   (Italy)

^b SECOND UNIVERSITY OF NAPLES   (Italy)

^c SAPIENZA UNIVERSITY OF ROME   (Italy)

Author keywords

Amenorrhea; Antiepileptic drug; Epilepsy; Hyperandrogenemia; Hyperprolactinemia; Polycystic ovary syndrome; Sex hormone dysfunction

Indexed keywords

ANTICONVULSIVE AGENT; CARBAMAZEPINE; FOLLITROPIN; LAMOTRIGINE; LUTEINIZING HORMONE; OXCARBAZEPINE; PHENOBARBITAL; PHENYTOIN; SEX HORMONE; VALPROIC ACID;

DISEASE DURATION; DRUG EFFECT; DRUG PROTEIN BINDING; EPILEPSY; HORMONE BLOOD LEVEL; HUMAN; PATHOGENESIS; POPULATION; PREGNANCY; REPRODUCTION; REVIEW;

ANTICONVULSANTS; EPILEPSY; FEMALE; GONADAL STEROID HORMONES; HUMANS; PREGNANCY; REPRODUCTION;

EID: 72049129400     PISSN: 14737175     EISSN: 17448360     Source Type: Journal    
DOI: 10.1586/ern.09.112     Document Type: Review

References (153)

1. Herzog AG, Seibel MM, Schomer DL, Vaitukaitis JL, Geschwind N. Reproductive endocrine disorders in women with partial seizures of temporal lobe origin. Arch. Neurol. 43, 341-346 (1986). • Shows the lack of a significant relationship between the occurrence of menstrual disorders and the use of antiepileptic drugs (AEDs) in female epileptic patients.
2. Isojärvi JI, Laatikainen TJ, Pakarinen AJ, Juntunen KT, Myllylä VV. Polycystic ovaries and hyperandrogenism in women taking valproate for epilepsy. N. Engl. J. Med. 329, 1383-1388 (1993). •• Excellent study reporting for the first time a high incidence of menstrual disorders linked to obesity, hyperandrogenism and polycystic ovaries in women taking valproate (VPA).
3. Klüver H, Bucy PC, Klüver H, Bucy PC. Preliminary analysis of functions of the temporal lobes in monkeys. J. Neuropsychiatry Clin. Neurosci. 9, 606-620 (1939).
4. Herzog AG, Fowler KM. Sexual hormones and epilepsy: threat and opportunities. Curr. Opin. Neurol. 18, 167-172 (2005).
5. Isojärvi JI, Taubøll E, Herzog AG. Effect of antiepileptic drugs on reproductive endocrine function in individuals with epilepsy. CNS Drugs 19, 207-223 (2005). (Pubitemid 40460661)
6. de Vries L, Karasik A, Landau Z, Phillip M, Kiviti S, Goldberg-Stern H. Endocrine effects of valproate in adolescent girls with epilepsy. Epilepsia 48, 470-477 (2007). • Long-term treatment with VPA in adolescent girls is associated with increased testosterone levels after menarche, without clinical hyperandrogenism or polycystic ovary syndrome (PCOS). (Pubitemid 46365184)
7. Wallace H, Shorvon S, Tallis R. Age-specific incidence and prevalence rates of treated epilepsy in an unselected population of 2,052,922 and age-specific fertility rates of women with epilepsy. Lancet 352, 1970-1973 (1998).
8. Dansky LV, Andermann E, Andermann F. Marriage and fertility in epileptic patients. Epilepsia 21, 261-271 (1980).
9. Webber MP, Hauser WA, Ottman R, Annegers JF. Fertility in persons with epilepsy: 1935-1974. Epilepsia 27, 746-752 (1986).
10. Hamed SA. Neuroendocrine hormonal conditions in epilepsy: relationship to reproductive and sexual functions. Neurologist 14, 157-169 (2008).
11. Morrell MJ, Giudice L, Flynn KL et al. Predictors of ovulatory failure in women with epilepsy. Ann. Neurol. 52, 704-711 (2002). (Pubitemid 35403179)
12. Morrell MJ. Reproductive and metabolic disorders in women with epilepsy. Epilepsia 44, 11-20 (2002).
13. Herzog AG, Friedman MN. Menstrual cycle interval and ovulation in women with localization-related epilepsy. Neurology 57, 2133-2135 (2002).
14. Herzog AG, Coleman AE, Jacobs AR et al. Interictal EEG discharges, reproductive hormones, and menstrual disorders in epilepsy. Ann. Neurol. 54, 625-637 (2003). • Shows that the laterality and focality of epilepsy may be important determinants of reproductive endocrine function.
15. Klein P, Serje A, Pezzullo JC. Premature ovarian failure in women with epilepsy. Epilepsia 42, 1584-1589 (2001). (Pubitemid 34020098)
16. Harden CL, Koppel BS, Herzog AG, Nikolov BG, Hauser WA. Seizure frequency is associated with age at menopause in women with epilepsy. Neurology 61, 451-455 (2003).
17. Hamed SA, Hamed EA, Shokry M, Omar H, Abdellah MM. The reproductive conditions and lipid profile in females with epilepsy. Acta Neurol. Scand. 115, 112-122 (2007).
18. Bauer J, Isojärvi JI, Herzog AG et al. Reproductive dysfunction in women with epilepsy: recommendations for evaluation and management. J. Neurol. Neurosurg. Psychiatr. 73, 121-125 (2002). (Pubitemid 41652889)
19. Stoffel-Wagner B, Bauer J, Flügel D, Brennemann W, Klingmüller D, Elger CE. Serum sex hormones are altered in patients with chronic temporal lobe epilepsy receiving anticonvulsant medication. Epilepsia 39, 1164-1173 (1998). (Pubitemid 28516028)
20. Morrell MJ. Epilepsy in women. Am. Fam. Physician 66, 1489-1494 (2002).
21. Bilo L, Meo R, Nappi C et al. Reproductive endocrine disorders in women with primary generalized epilepsy. Epilepsia 29, 612-619 (1988). (Pubitemid 18240146)
22. Nappi C, Meo R, Di Carlo C, Estraneo A, Bilo L. Reuced fertility and neuroendocrine dysfunction in women with epilepsy. Gynecol. Endocrinol. 8, 133-145 (1994). (Pubitemid 24194263)
23. Scharfman HE, Kim M, Hintz TM, MacLusky NJ. Seizures and reproductive function: insights from female rats with epilepsy. Ann. Neurol. 64, 687-697 (2008).
24. Edwards HE, Burnham WM, Ng MM, Asa S, MacLusky NJ. Limbic seizures alter reproductive function in the female rat. Epilepsia 40, 1370-1377 (1999). (Pubitemid 29471335)
25. Feeney DM, Gullotta FP, Gilmore W. Hyposexuality produced by temporal lobe epilepsy in the cat. Epilepsia 39, 140-149 (1998). (Pubitemid 28074349)
26. Sperling MR, Pritchard PB, Engel J, Daniel C, Sagel J. Prolactin in partial epilepsy: an indicator of limbic seizures. Ann. Neurol. 20, 716-722 (1986). (Pubitemid 17207647)
27. Hum KM, Megna S, Burnham WM. The effects of right and left amygdala kindling on the female reproductive system in rats. Epilepsia 50, 880-886 (2009).
28. Herzog AG. A relationship between particular reproductive endocrine disorders and the laterality of epileptiform discharges in women with epilepsy. Neurology 43, 1907-1910 (1993).
29. Löfgren E, Mikkonen K, Tolonen U et al. Reproductive endocrine function in women with epilepsy: the role of epilepsy type and medication. Epilepsy Behav. 10, 77-83 (2007). •• Excellent study that demonstrated the relationship between epilepsy treatment, medication and reproductive disorders. (Pubitemid 46132167)
30. Meo R, Bilo L, Nappi C et al. Derangement of the hypothalamic GnRH pulse generator in women with epilepsy. Seizure 2, 241-252 (1993).
31. Drislane FW, Coleman AE, Schomer DL et al. Altered pulsatile secretion of luteinizing hormone in women with epilepsy. Neurology 44, 306-310 (1994).
32. Cummings LN, Giudice L, Morrell MJ. Ovulatory function in epilepsy. Epilepsia 36, 355-359 (1995).
33. Herzog AG. Menstrual disorders in women with epilepsy. Neurology 66, S23-S28 (2006).
34. Bazán AC, Montenegro MA, Cendes F, Min LL, Guerreiro CA. Menstrual cycle worsening of epileptic seizures in women with symptomatic focal epilepsy. Arq. Neuropsiquiatr. 63, 751-756 (2005). (Pubitemid 41494493)
35. Bilo L, Meo R, Valentino R, Di Carlo C, Striano S, Nappi C. Characterization of reproductive endocrine disorders in women with epilepsy. J. Clin. Endocrinol. Metab. 86, 2950-2956 (2001). • The presence of increased luteinizing hormone pulse frequency in untreated or drug-free epileptic women with regular menstrual cycles supports the notion that epilepsy itself may contribute to reproductive abnormalities.
36. Bilo L, Meo, R, Valentino R, Buscaino GA, Striano S, Nappi C. Abnormal pattern of luteinizing hormone pulsatility in women with epilepsy. Fertil. Steril. 55, 705-711 (1991).
37. Murialdo G, Magri F, Tamagno G et al. Seizure frequency and sex steroids in women with partila epilepsy on antiepileptic therapy. Epilepsia 50, 1920-1926 (2009). •• Excellent cross-sectional study reporting more relevant changes in sex hormone levels in patients with more frequent seizures.
38. Svalheim S, Taubøll E, Bjørnenak T et al. Do women with epilepsy have increased frequency of menstrual disturbances? Seizure 12, 529-533 (2003). (Pubitemid 37509044)
39. Spratt DI, Finkelstein JS, Butler JP, Badger TM, Crowley WF. Effects of increasing the frequency of low doses of gonadotropin-releasing hormone (GnRH) on gonadotropin secretion in GnRH-deficient men. J. Clin. Endocrinol. Metab. 64, 1179-1186 (1987).
40. Herzog AG. A hypothesis to integrate partial seizures of temporal lobe origin and reproductive endocrine disorders. Epilepsy Res. 3, 151-159 (1989).
41. Klüver H, Bucy PC, Klüver H, Bucy PC. Preliminary analysis of functions of the temporal lobes in monkeys. 1939. J. Neuropsychiatry Clin. Neurosci. 9, 606-620 (1997).
42. Rao ML, Stefen H, Bauer J. Epileptic but not psychogenic seizures are accompained by simultaneous elevation of serum pituitary hormones and cortisol levels. Neuroendocrinology 49, 33-39 (1989). (Pubitemid 19048651)
43. Herzog AG. Polycystic ovarian syndrome in women with epilepsy: epileptic or iatrogenic? Ann. Neurol. 39, 559-560 (1996).
44. Daniele A, Azzoni A, Bizzi A, Rossi A, Gainotti G, Mazza S. Sexual behavior and hemispheric laterality of the focus in patients with temporal lobe epilepsy. Biol. Psychiatry 42, 617-624 (1997). (Pubitemid 27425480)
45. Baird AD, Wilson SJ, Bladin PF, Saling MM, Reutens DC. Sexual outcome after epilepsy surgery. Epilepsy Behav. 4268-4278 (2003). • Suggests that right temporal resection could improve sexual functioning.
46. Herzog AG, Coleman AE, Jacobs AR et al. Relationship of sexual dysfunction to epilepsy laterality and reproductive hormone levels in women. Epilepsy Behav. 4, 407-413 (2003).
47. Herzog AG, Schachter SC. On the association between valproate and polycystic ovary syndrome Epilepsia 42, 311-315 (2001).
48. Kalinin VV, Zheleznova EV. Chronology and evolution of temporal lobe epilepsy and endocrine reproductive dysfunction in women: relationships to side of focus and catameniality. Epilepsy Behav. 11, 185-191 (2007).
49. Harden CL. Sexual dysfunction in women with epilepsy. Seizure 17, 131-135 (2008).
50. Crawford P, Appleton R, Betts T, Duncan J, Guthrie E, Morrow J. Best practice guidelines for the management of women with epilepsy. The Women with Epilepsy Guidelines Development group. Seizure 8, 201-217 (1999).
51. Bauer J, Burr W, Elger CE. Seizure occurrence during ovulatory and anovulatory cycles in patients with temporal lobe epilepsy: a prospective study. Eur. J. Neurol. 5, 83-88 (1998). (Pubitemid 28059609)
52. Morrell MJ, Sperling MR, Stecker M, Dichter MA. Sexual dysfunction in partial epilepsy: a deficit in physiologic sexual arousal. Neurology 44, 243-247 (1994). (Pubitemid 24070959)
53. Bauer J, Cooper-Mahkorn D. Reproductive dysfunction in women with epilepsy: menstrual cycle abnormalities, fertility, and polycystic ovary syndrome. Int. Rev. Neurobiol. 83, 135-155 (2008).
54. Manna I, Labate A, Gambardella A et al. Serotonin transporter gene (5-Htt): association analysis with temporal lobe epilepsy. Neurosci. Lett. 421, 52-56 (2007). (Pubitemid 46908862)
55. Dana-Haeri J, Oxley J, Richen A. Reduction of free testosterone by antiepileptic drugs. Br. Med. J. 284, 85-86 (1982).
56. Beastall GH, Cowan RA, Gray JM, Fogelman I. Hormone binding globulins and anticonvulsant therapy. Scott. Med. J. 30, 101-105 (1985). (Pubitemid 15056517)
57. Victor A, Lundberg PO, Johansson ED. Induction of sex hormone binding globulin by phenytoin. Br. Med. J. 2, 934-935 (1977).
58. Levesque LA, Herzog AG, Seibe MM. The effect of phenytoin and carbamazepine on serum dehydroepiandrosterone sulfate in men and women who have partial seizures with temporal lobe involvement. J. Clin. Endocrinol. Metab. 63, 243-245 (1986).
59. Galimberti CA, Magri F, Copello F et al. Changes in sex steroid levels in women with epilepsy on treatment: relationship with antiepileptic therapies and seizure frequency. Epilepsia 50, 28-32 (2009). •• Excellent observational study that showed decreased sex steroid levels correlated with AED treatments, mainly when enzyme-inducing AED polytherapies were given.
60. Murialdo G, Galimberti CA, Gianelli MV et al. Effects of valproate, phenobarbital, and carbamazepine on sex steroid setup in women with epilepsy. Clin. Neuropharmacol. 21, 52-58 (1998). (Pubitemid 28078336)
61. Herzog AG. Disorders of reproduction in patients with epilepsy: primary neurological mechanisms. Seizure 17, 101-110 (2008).
62. Isojärvi JI. Serum steroid hormones and pituitary function in female epileptic patients during carbamazepine therapy. Epilepsia 31(4), 438-445 (1990).
63. Galimberti CA, Magri F, Copello F et al. Seizure frequency and cortisol and dehydroepiandrosterone sulfate (DHEAS) levels in women with epilepsy receiving antiepileptic drug treatment. Epilepsia 46, 517-523 (2005). (Pubitemid 40470673)
64. Mejias-Aponte CA, Jimenz-Rivera CA, Segarra AC. Sex differences in models of temporal lobe epilepsy: role of testosterone. Brain Res. 944, 210-218 (2002).
65. Jacobsen NW, Halling-Sorensen B, Birkved K. Inhibition of human aromatase complex (CYP19) by antiepileptic drugs. Toxicol. In Vitro 22, 146-1143 (2008).
66. Taubøll E, Gregoraszczuk LE, Wojtowicz AK, Milewicz T. Effects of levetiracetam and valproate on reproductive endocrine function studied in human ovarian follicular cells. Epilepsia 50, 1868-1874 (2009).
67. Murialdo G, Galimberti CA, Magri F et al. Menstrual cycle and ovary alterations in women with epilepsy on antiepileptic therapy. J. Endocrinol. Invest. 20, 519-526 (1997). • Good study that did not show an increased frequency of menstrual disorders or hyperandrogenism and polycystic ovaries in women taking carbamazepine (CBZ).
68. Rättyä J, Pakarinen AJ, Knip M et al. Early hormonal changes during valproate or carbamazepine treatment: a 3-month study. Neurology 57, 440-444 (2001). (Pubitemid 32757590)
69. Isojärvi JI, Laatikainen TJ, Pakarinen AJ, Juntunen KT, Myllylä VV. Menstrual disorders in women with epilepsy receiving carbamazepine. Epilepsia 36, 676-681 (1995). • Longitudinal study reporting that menstrual disorders in female patients on CBZ treatment with normal ovaries are associated with increased serum sex hormone-binding globulin (SHBG) levels and low estradiol/SHBG ratio.
70. Isojärvi JI, Laatikainen TJ, Knip M, Pakarinen AJ, Juntunen KT, Myllylä VV. Obesity and endocrine disorders in women taking valproate for epilepsy. Ann. Neurol. 39, 579-584 (1996).
71. Lossius MI, Taubøll E, Mowinckel P, Mørkrid L, Gjerstad L. Reversible effects of antiepileptic drugs on reproductive endocrine function in men and women with epilepsy - a prospective randomized double-blind withdrawal study. Epilepsia 48, 1875-1882 (2007).
72. Dana-Haeri J, Oxley J, Richens A. Pituitary responsiveness to gonadotrophin-releasing and thyrotrophin-releasing hormones in epileptic patients receiving carbamazepine or phenytoin. Clin. Endocrinol. (Oxf.) 20, 163-168 (1984). (Pubitemid 14177188)
73. Isojärvi JI, Myllylä VV, Pakarinen AJ. Effects of carbamazepine on pituitary responsiveness to luteinizing hormone-releasing hormone, thyrotropin-releasing hormone, and metoclopramide in epileptic patients. Epilepsia 30, 50-56 (1989).
74. Bonuccelli U, Murialdo G, Martino E et al. Effects of carbamazepine on prolactin secretion in normal subjects and in epileptic subjects. Clin. Neuropharmacol. 8, 165-174 (1985). (Pubitemid 15055813)
75. Isojärvi JI, Taubøll E, Pakarinen AJ et al. Altered ovarian function and cardiovascular risk factors in valproate-treated women. Am. J. Med. 111, 290-296 (2001). (Pubitemid 32885625)
76. Bauer J, Jarre A, Klingmüller D, Elger CE. Polycystic ovary syndrome in patients with focal epilepsy: a study in 93 women. Epilepsy Res. 41, 163-167 (2000). (Pubitemid 30625029)
77. Stephen LJ, Kwan P, Shapiro D, Dominiczak M, Brodie MJ. Hormone profiles in young adults with epilepsy treated with sodium valproate or lamotrigine monotherapy. Epilepsia 42, 1002-1006 (2001). (Pubitemid 32802064)
78. Betts T, Yarrow H, Dutton N, Greenhill L, Rolfe T. 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, 323-329 (2003). (Pubitemid 37062760)
79. Prabhakar S, Sahota P, Kharbanda PS et al. Sodium valproate, hyperandrogenism and altered ovarian function in Indian women with epilepsy: a prospective study. Epilepsia 48, 1371-1377 (2007). (Pubitemid 47063088)
80. Morrel M, Bhatt M, Ozkara C et al. Higher incidence of symptoms of polycystic ovary syndrome in women with epilepsy treated with valproate versus lamotrigine. Neurology 64, 428 (2005).
81. Kwan P, Yip FP, Hui AC et al. Effects of valproate or lamotrigine monotherapy on the reproductive endocrine and insulin-related metabolic profile in Chinese adults with epilepsy: a prospective randomized study. Epilepsy Behav. 14, 610-616 (2009).
82. Stephen LJ, Sills GJ, Leach JP et al. Sodium valproate versus lamotrigine: a randomised comparison of efficacy, tolerability and effects on circulating androgenic hormones in newly diagnosed epilepsy. Epilepsy Res. 75, 122-129 (2007).
83. Vainionpää LK, Rättyä J, Knip M et al. Valproate-induced hyperandrogenism during pubertal maturation in girls with epilepsy. Ann. Neurol. 45, 444-450 (1999). •• Demonstrates an increasing frequency of hyperandrogenism with pubertal development, suggesting that the sensitivity to VPA-induced hyperandrogenism is a function of sexual maturation. (Pubitemid 29165810)
84. Verrotti A, Ciampani M, Pomilio M, Latini G, Chiarelli F. Endocrine abormalities induced by antiepileptic drugs. Curr. Pediatr. Rev. 2, 85-92 (2006). (Pubitemid 44043340)
85. Death AK, McGrath KC, Handelsman DJ. Valproate is an anti-androgen and anti-progestin. Steroids 70, 946-953 (2005).
86. Lydon JP, DeMayo FJ, Conneely OM, O'Malley BW. Reproductive phenotpes of the progesterone receptor null mutant mouse. J. Steroid Biochem. Mol. Biol. 56, 67-77 (1996).
87. Rättya J, Vainionpää L, Knip M, Lanning P, Isojärvi JI. The effects of valproate, carbamazepine, and oxcarbazepine on growth and sexual maturation in girls with epilepsy. Pediatrics 103, 588-593 (1999).
88. Löfgren E, Tapanainen JS, Koivunen R, Pakarinen A, Isojärvi JI. Effects of carbamazepine and oxcarbazepine on the reproductive endocrine function in women with epilepsy. Epilepsia 47, 1441-1446 (2006).
89. Isojärvi JI, Rättyä J, Myllylä VV et al. Valproate, lamotrigine, and insulinmediated risks in women with epilepsy. Ann. Neurol. 43, 446-451 (1998).
90. Morrell MJ, Isojärvi J, Taylor AE et al. Higher androgens and weight gain with valproate compared with lamotrigine for epilepsy. Epilepsy Res. 54, 189-199 (2003). (Pubitemid 36776737)
91. Opaleke A, Helmers SL. Hormonal consequences of epilepsy. Semin. Pediatr. Neurol. 14, 189-195 (2007).
92. Sahota P, Prabhakar S, Kharbanda PS et al. Seizure type, antiepileptic drugs, and reproductive endocrine dysfunction in Indian women with epilepsy: a cross-sectional study. Epilepsia 49, 2069-2077 (2008).
93. Gorkemli H, Genc BO, Dogan E, Genc E, Ozdemir S. Long-term effects of valproic acid on reproductive endocrine functions in Turkish women with epilepsy. Gynecol. Obstet. Invest. 67, 223-227 (2009).
94. Luef G, Abraham I, Trinka E et al. Hyperandrogenism, postprandial hyperinsulinism and the risk of PCOS in a cross sectional study of women with epilepsy treated with valproate. Epilepsy Res. 48, 91-102 (2002). (Pubitemid 34127720)
95. Genton P, Bauer J, Duncan S et al. On the association between valproate and polycystic ovary syndrome. Epilepsia 42, 295-304 (2001). (Pubitemid 32275905)
96. Luef G, Abraham I, Haslinger M et al. Polycystic ovaries, obesity and insulin resistance in women with epilepsy. A comparative study of carbamazepine and valproic acid in 105 women. J. Neurol. 249, 835-841 (2002). (Pubitemid 34754219)
97. Azziz R, Woods KS, Reyna R, Key TJ, Knochenhauer ES, Yildiz BO. The prevalence and features of the polycystic ovary syndrome in an unselected population. J. Clin. Endocrinol. Metab. 89, 2745-2749 (2004). (Pubitemid 38766360)
98. Polson DW. Polycystic ovary syndrome and epilepsy - a gynaecological perspective. Seizure 12, 397-402 (2003).
99. Rasgon N. The relationship between polycystic ovary syndrome and antiepileptic drugs: a review of the evidence. J. Clin. Psychopharmacol. 24, 322-334 (2004). (Pubitemid 38658041)
100. Duncan S. Polycystic ovarian syndrome in women with epilepsy: a review. Epilepsia 42, 60-65 (2001). (Pubitemid 32781385)
101. Betts T, Dutton N, Yarrow H. Epilepsy and the ovary (cutting out the hysteria). Seizure 10, 220-328 (2001). (Pubitemid 32624514)
102. Verrotti A, Basciani F, Morresi S, de Martino M, Morgese G, Chiarelli F. Serum leptin changes in epileptic patients who gain weight after therapy with valproic acid. Neurology 53, 230-232 (1999). (Pubitemid 29329682)
103. Verrotti A, la Torre R, Trotta D, Mohn A, Chiarelli F. Valproate-induced insulin resistance and obesity in children. Horm. Res. 71, 125-131 (2009).
104. Jallon P, Picard F. Bodyweight gain and anticonvulsants: a comparative review. Drug Saf. 24, 969-978 (2001). (Pubitemid 33097097)
105. Biton V, Mirza W, Montouris G, Vuong A, Hammer AE, Barrett PS. Weight change associated with valproate and lamotrigine monotherapy in patients with epilepsy. Neurology 56, 172-177 (2001). (Pubitemid 32095356)
106. Wirrell EC. Valproic acid-associated weight gain in older children and teens with epilepsy. Pediatr. Neurol. 28, 126-129 (2003).
107. Mikkonen K, Vainionpää LK, Pakarinen AJ et al. Long-term reproductive endocrine health in young women with epilepsy during puberty. Neurology 62, 445-450 (2004). •• Demonstrates the reversibility of the reproductive endocrine effects of VPA after discontinuation of the treatment. (Pubitemid 38200858)
108. Egger J, Brett EM. Effects of sodium valproate in 100 children with special reference to weight. Br. Med. J. 283, 577-581 (1981). (Pubitemid 11052923)
109. Dinesen H, Gram L, Andersen T, Dam M. Weight gain during treatment with valproate. Acta Neurol. Scand. 70, 65-69 (1984).
110. Breum L, Astrup A, Gram L et al. Metabolic changes during treatment with valproate in humans: implication for untoward weight gain. Metab. Clin. Exp. 41, 666-670 (1992).
111. Gidal BE, Anderson GD, Spencer NW et al. Valproate-associated weight gain: potential relation to energy expenditure and metabolism in patients with epilepsy. J. Epilepsy 9, 234-241 (1996).
112. Demir E, Aysun S. Weight gain associated with valproate in childhood. Pediatr. Neurol. 22, 361-364 (2000). (Pubitemid 30410787)
113. Covanis A, Gupta AK, Jeavons PM. Sodium valproate: monotherapy and polytherapy. Epilepsia 23, 693-720 (1982).
114. Pylvänen V, Knip M, Pakarinen A, Kotila M, Turkka J, Isojärvi JI. Serum insulin and leptin levels in valproate-associated obesity. Epilepsia, 43, 514-517 (2002).
115. Dunaif A. Insulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis. Endocr. Rev. 18, 774-800 (1997). (Pubitemid 28009567)
116. Luef GJ, Lechleitner M, Bauer G, Trinka E, Hengster P. Valproic acid modulates islet cell insulin secretion: a possible mechanism of weight gain in epilepsy patients. Epilepsy Res. 55, 53-58 (2003). (Pubitemid 37011372)
117. Wong HY, Chu TS, Lai JC et al. Sodium valproate inhibits glucose transport and exacerbates Glut-1 deficiency in vitro. J. Cell. Biochem. 96, 775-785 (2005).
118. Gregoraszczuk E, Wójtowicz AK, Taubøll E, Ropstad E. Valproate-induced alterations in testosterone, estradiol and progesterone secretion from porcine follicular cells isolated from small- and medium-sized ovarian follicles. Seizure 9, 480-485 (2000). (Pubitemid 30806710)
119. Taubøll E, Isojärvi JI, Flinstad Harbo H, et al. Long-term valproate treatment induces changes in ovarian morphology and serum sex steroid hormone levels in female Wistar rats. Seizure 8, 490-493 (1999).
120. Røste LS, Taubøll E, Berner A, Isojärvi JI, Gjerstad L. Valproate, but not lamotrigine, induces ovarian morphological changes in Wistar rats. Exp. Toxicol. Pathol. 52, 545-552 (2001). (Pubitemid 33791865)
121. Isojärvi J. Disorders of reproduction in patients with epilepsy: antiepileptic drug related mechanisms. Seizure 17, 111-119 (2008).
122. Adab N, Kini U, Vinten J et al. The long term outcome of children born to mothers with epilepsy. J. Neurol. Neurosurg. Psychiatry 75, 1575-1583 (2004). (Pubitemid 39430610)
123. Teramo K, Hiilesmaa V, Bardy A, Saarikoski S. Fetal heart rate during a maternal grand mal epileptic seizure. J. Perinat. Med. 7, 3-6 (1979). (Pubitemid 9100233)
124. Tomson T, Battino D. Pharmacokinetics and therapeutic drug monitoring of newer antiepileptic drugs during pregnancy and puerperium. Clin. Pharmacokinet. 46, 209-219 (2007). (Pubitemid 46425647)
125. Teramo K, Hiilesmaa V. Pregnancy and fetal complications in epileptic pregnancies. In: Epilepsy, Pregnancy, and the Child. Janz D, Dam M, Bossi L, Helge H, Richens A, Schmidt D (Eds). Raven, NY, USA 53-59 (1982).
126. The EURAP study group. Seizure control and treatment in pregnancy: observations from the EURAP Epilepsy Pregnancy Registry. Neurology 66, 354-360 (2006).
127. Katz O, Levy A, Wizniter A et al. Pregnancy and perinatal outcome in epileptic women: a population-based study. J. Matern. Fetal Neonatal Med. 19, 21-25 (2006). (Pubitemid 43308163)
128. Richmond JR, Krishnamoorthy P, Andermann E, Benjamin A. (2004) Epilepsy and pregnancy: an obstetric perspective. Am. J. Obstet. Gynecol. 190, 371-379 (2004).
129. Olafsson E, Hallgrimsson JT, Hauser WA. Pregnancies of women with epilepsy: a population-based study in Iceland. Epilepsia 39, 887-892 (1998). (Pubitemid 128721656)
130. Fairgrieve SD, Jackson M, jonas P et al. Population based, prospective study of the care of women with epilepsy in pregnancy. BMJ 321, 674-675 (2000).
131. Crawford P. Best practice guidelines for the management of women with epilepsy. Epilepsia 46, 117-124 (2005). (Pubitemid 44921989)
132. Viinikainen K, Heinonen S, Eriksson K, Kalviainen R. Community-based, prospective, controlled study of obstetric and neonatal outcome of 179 pregnancies in women with epilepsy. Epilepsia 47, 186-192 (2006).
133. Harden LH, Hopp J, Ting YT et al. Management issues for women with epilepsy - focus on pregnancy (an evidence-based review): I. Obstetrical complications and change in seizure frequency. Epilepsia 50, 1229-1236 (2009).
134. Fried S, Kozer E, Nulman I, Einarson TR, Koren G. Malformation rates in children of women with untreated epilepsy: a meta-analysis. Drug Saf. 27, 197-202 (2004). (Pubitemid 38315328)
135. Fonager K, Larsen H, Pedersen L, Sørensen HT. Birth outcomes in women exposed to anticonvulsant drugs. Acta Neurol. Scand. 101, 289-294 (2000). (Pubitemid 30249531)
136. Holmes LB, Harvey EA, Coull BA et al. The teratogenicity of anticonvulsant drugs. N. Engl. J. Med. 344, 1132-1138 (2001).
137. Kaaja E, Kaaja R, Matila R, Hiilesmaa V. Enzyme-inducing antiepileptic drugs in pregnancy and the risk of bleeding in the neonate. Neurology 58, 549-553 (2002). (Pubitemid 34164935)
138. Sabers A, Dam M, Rogvi-Hansen B, Boas J, Sidenius P, Laue FM. Epilepsy and pregnancy: lamotrigine as main drug used. Acta Neurol. Scand. 10, 9-13 (2004). (Pubitemid 38161121)
139. Aguglia U, Barboni G, Battino D et al. Italian Consensus Conference on Epilepsy and Pregnancy, Labor and Puerperium. Epilepsia 50, 7-23 (2009).
140. Tomson T. Gender aspects of pharmacokinetics of new and old AEDs: pregnancy and breast-feeding. Ther. Drug Monit. 27, 718-721 (2005). (Pubitemid 44391722)
141. Veiby G, Daltveit KA, Engelsen AB, Gilhus EN. Pregnancy, delivery, and outcome for the child in maternal epilepsy. Epilepsia 50, 2130-2139 (2009).
142. Artama M, Auvinen A, Raudaskoski T, Isojarvi I, Isojarvi J. Antiepileptic drug use of women with epilepsy and congenital malformations in offspring. Neurology 64, 1874-1878 (2005).
143. Vajda FJ, Eadie MJ. Maternal valproate dosage and foetal malformations. Acta Neurol. Scand. 112, 137-143 (2005).
144. Morrow J, Russell A, Guthrie E et al. Malformation risks of antiepileptic drugs in pregnancy: a prospective study from the UK Epilepsy and Pregnancy Register. J. Neurol. Neurosurg. Psychiatry 77, 193-198 (2006). (Pubitemid 43220841)
145. Wide K, Winbladh B, Kallen B. Major malformations in infants exposed to antiepileptic drugs in utero, with emphasis on carbamazepine and valproic acid: a nation-wide, population-based register study. Acta Paediatr. 9, 174-176 (2004). (Pubitemid 38230710)
146. Wyszynski DF, Nambisan M, Surve T, Alsdorf RM, Smith CR, Holmes LB. Increased rate of major malformations in offspring exposed to valproate during pregnancy. Neurology 64, 961-965 (2005). (Pubitemid 40388443)
147. Barrett C, Richens A. Epilepsy and pregnancy: report of an Epilepsy Research Foundation Workshop. Epilepsy Res. 52, 147-187 (2003). (Pubitemid 36109178)
148. Olafsson E, Hauser WA, Gudmundsson G. Fertility in patients with epilepsy: a population-based study. Neurology 51, 71-73 (1998). (Pubitemid 28345362)
149. Harden CL. Sexuality in women with epilepsy. Epilepsy Behav 7, S2-S6 (2005).
150. Bauer J, Stefan H, Schrell U, Sappke U, Uhlig B. Neurophysiologic principles and clinical value of post-convulsive serum prolactin determination in epileptic seizure. Fortschr. Neurol. Psychiatr. 57, 457-468 (1989).
151. Bauer J. Epilepsy and prolactin in adults: a clinical review. Epilepsy Res. 24, 1-7 (1996). (Pubitemid 26191607)
152. Duncan S, Blacklaw J, Beastall GH, Brodie MJ. Sexual function in women with epilepsy. Epilepsia 38, 1074-1081 (1997).
153. Morrell MJ, Guldner GT. Self-reported sexual function and sexual arousability in women with epilepsy. Epilepsia 37, 1204-1210 (1996).