癫痫及抗癫痫药物对育龄期女性患者生殖内分泌的影响_Journal of Epilepsy

Authors：

额日登娜希 ,  刘献增

北京大学人民医院神经内科癫痫中心（北京 100044）;

Corresponding author：

刘献增, Email: liuxianzeng2004@sina.com

Keywords：

癫痫; 抗癫痫药物; 女性患者; 生殖内分泌

DOI：

10.7507/2096-0247.20180011

Video：

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癫痫是神经系统最常见的慢性疾病之一。癫痫患者结婚率、生育率低。多囊卵巢、多囊卵巢综合症、高雄激素血症、性功能障碍等常见于女性癫痫患者（Women with epilepsy，WWE）。癫痫放电或抗癫痫药物（AEDs）影响下丘脑-垂体-卵巢轴系统调节，引起体内激素水平改变，因而 WWE 易患生殖内分泌疾病。文章就癫痫及 AEDs 对育龄期 WWE 生殖内分泌的影响进行综述。

Citation： 额日登娜希, 刘献增. 癫痫及抗癫痫药物对育龄期女性患者生殖内分泌的影响. Journal of Epilepsy, 2018, 4(1): 44-48. doi: 10.7507/2096-0247.20180011 Copy

1.	Thomas SV. Controversies in contraception for women with epilepsy. Ann Indian Acad Neurol, 2015, 18(3): 278-283.
2.	吴逊. 我国癫痫的诊断与治疗现状. 中国现代神经疾病杂志, 2007, 7(3): 201-203.
3.	Isojärvi JI. Reproductive dysfunction in women with epilepsy. Neurology, 2003, 61(6 uppl 2): 27-34.
4.	Hamed SA. The effect of epilepsy and antiepileptic drugs on sexual, reproductive and gonadal health of adults with epilepsy. Expert Rev Clin Pharmacol, 2016, 9(6): 807-819.
5.	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. The Lancet, 1998, 352(9145): 1970-1973.
6.	Farmen AH, Grundt JH, Tomson T, et al. Age-specific birth rates in women with epilepsy:a population-based study. Brain Behav, 2016, 6(8): e00492.
7.	Scharfman HE, Kim M, Hintz TM, et al. Seizures and reproductive function: insights from female rats with epilepsy. Ann Neurol, 2008, 64(6): 687-697.
8.	Edwards HE, Burnham WM, Ng MM, et al. Limbic seizures alter reproductive function in the female rat. Epilepsia, 1999, 40(10): 1370-1377.
9.	Edwards HE, MacLusky NJ, Burnham WM. The effect of seizures and kindling on reproductive hormones in the rat. Neurosci Biobehav Rev, 2000, 24(7): 753-762.
10.	Hum KM, Megna S, Burnham WM. The effects of right and left amygdala kindling on the female reproductive system in rats. Epilepsia, 2009, 50(4): 880-886.
11.	Alvarenga TA, Matos G, Scorza FA, et al. Sexual response in female rats with status epilepticus. Epilepsia, 2013, 54(4): 644-648.
12.	Li J, Kim JS, Abejuela VA, et al. Disrupted female estrous cyclicity in the intrahippocampal kainic acid mouse model of temporal lobe epilepsy. Epilepsia Open , 2017, 2(1): 1-9.
13.	Boro A, Haut S.Medical comorbidities in the treatment of epilepsy. Epilepsy Behav, 2003, 4(Suppl 2): 2-12.
14.	Morrell MJ, Guldner GT. Self-reported sexual function and sexual arousability in women with epilepsy. Epilepsia, 1996, 37(12): 1204-1210.
15.	Luef G, Madersbacher H. Sexual dysfunction in patients with epilepsy. Handb Clin Neurol, 2015, 130: 383-394.
16.	Morrell MJ, Sperling MR, Stecker M, et al. Sexual dysfunction in partial epilepsy A deficit in physiologic sexual arousal. Neurology, 1994, 44(2): 243-243.
17.	Morrell MJ, Flynn KL, Done S, et al. Sexual dysfunction, sex steroid hormone abnormalities, and depression in women with epilepsy treated with antiepileptic drugs. Epilepsy Behav, 2005, 6(3): 360-365.
18.	Herzog AG, Seibel MM, Schomer DL, et al. Reproductive endocrine disorders in women with partial seizures of temporal lobe origin. ArchNeurol, 1986, 43(4): 341-346.
19.	Hamed SA, Hamed EA, Shokry M, et al. The reproductive conditions and lipid profile in females with epilepsy. Acta Neurol Scand, 2007, 115(1): 12-22.
20.	Herzog AG, Friedman MN. Menstrual cycle interval and ovulation in women with localization-related epilepsy. Neurology, 2001, 57(11): 2133-2135.
21.	Morrell MJ, Giudice L, Flynn KL, et al. Predictors of ovulatory failure in women with epilepsy. Ann Neurol, 2002, 52(6): 704-711.
22.	Bui E, Harden CL, Sazgar M.Controversies in caring for women with epilepsy: sorting through the evidence.In SazgarM & Harden CL (Eds.). Cham: Springer International Publishing, 2016: 87-97.
23.	Bauer J, Cooper-Mahkorn D. Reproductive dysfunction in women with epilepsy: menstrual cycle abnormalities, fertility, and polycystic ovary syndrome. Int Rev Neurobiol, 2008, 83: 135-155.
24.	Herzog AG, Coleman AE, Jacobs AR, et al. Relationship of sexual dysfunction to epilepsy laterality and reproductive hormone levels in women. Epilepsy Behav, 2003, 4(4): 407-413.
25.	Verrotti A, D'Egidio C, Mohn A, et al. Antiepileptic drugs, sex hormones, and PCOS. Epilepsia, 2011, 52(2): 199-211.
26.	Koppel BS, Harden CL. Gender issues in the neurobiology of epilepsy: a clinical perspective. Neurobiol Dis, 2014, 72(Pt B): 193-197.
27.	Thomas SV, Sarma P, Nirmala C, et al. Women with epilepsy and infertility have different reproductive hormone profile than others.Ann Indian Acad Neurol, 2013, 16(4): 544-548.
28.	Zhou JQ, Zhou LM, Chen LJ, et al. Polycystic ovary syndrome in patients with epilepsy: a study in 102 Chinese women. Seizure, 2012, 21(9): 729-733.
29.	黄静, 任榕娜. 细胞色素 P450 酶系与抗癫痫药物的代谢. 国际儿科学杂志, 2006, 33(3): 167-169.
30.	Browne TR. Pharmacokinetics of antiepileptic drugs. Neurology, 1998, 51(5 Suppl 4): 2-7.
31.	穆惠荣, 迟兆富. 抗癫痫药物的体内代谢及相互间作用机制的研究. 国外医学: 神经病学. 神经外科学分册, 2003, 30(5): 476-479.
32.	Lofgren E, Mikkonen K, Tolonen U, et al. Reproductive endocrine function in women with epilepsy: the role of epilepsy type and medication. Epilepsy Behav, 2007, 10(1): 77-83.
33.	Isojärvi JI, Taubøll E, Herzog AG. Effect of antiepileptic drugs on reproductive endocrine function in individuals with epilepsy. CNS Drugs, 2005, 19(3): 207-223.
34.	Taubøll E, Gregoraszczuk EL, Kołodziej A, et al. Valproate inhibits the conversion of testosterone to estradiol and acts as an apoptotic agent in growing porcine ovarian follicular cells. Epilepsia, 2003, 44(8): 1014-1021.
35.	Glister C, Satchell L, Michael AE, et al. The anti-epileptic drug valproic acid (VPA) inhibits steroidogenesis in bovine theca and granulosa cells in vitro. PLoS ONE, 2012, 7(11): e49553.
36.	Isojarvi J, Laatikainen TJ, Pakarinen AJ, et al.Polycystic ovaries and hyperandrogenism in women taking valproate for epilepsy. N Eng J Med,1993,329(19): 1383-1388.
37.	Isojärvi JI, Laatikainen TJ, Knip M, et al. Obesity and endocrine disorders in women taking valproate for epilepsy. Ann Neurol, 1996, 39(5): 579-584.
38.	Isojärvi JI, Rättyä J, Myllylä VV, et al. Valproate, lamotrigine, and insulin-mediated risks in women with epilepsy. Ann Neurol, 1998, 43(4): 446-451.
39.	Morrell MJ, Hayes FJ, Sluss PM, et al. Hyperandrogenism, ovulatory dysfunction, and polycystic ovary syndrome with valproate versus lamotrigine. Ann Neurol, 2008, 64(2): 200-211.
40.	Hu X, Wang J, Dong W, et al. A meta-analysis of polycystic ovary syndrome in women taking valproate for epilepsy. Epilepsy Res, 2011, 97(1-2): 73-82.
41.	Minagawa K, Watanabe T, Oyanagi R. Characteristics of women with epilepsy who developed polycysticovary syndrome owing to the therapy with valproate sodium. No To Hattatsu, 2013, 45(4): 304-308.
42.	高静, 迟兆富, 单培彦. 女性癫痫患者生殖内分泌功能紊乱. 中国神经精神疾病杂志, 2005, 31(6): i0005-i0006.
43.	Goldberg-Stern H, Yaacobi E, Phillip M, et al. Endocrine effects of valproic acid therapy in girls with epilepsy: a prospective study. Eur J Paediatr Neurol, 2014, 18(6): 759-765.
44.	Ayyagari M, Chitela SR, Kolachana V. Obesity, polycystic ovarian syndrome and thyroid dysfunction in women with epilepsy. Ann Indian Acad Neurol, 2012, 15(2): 101-105.
45.	Kumar S, Kaur G. Second generation anti-epileptic drugs adversely affect reproductive functions in young non-epileptic female rats. Eur Neuropsychopharmacol, 2014, 24(10): 1709-1718.
46.	Lofgren E, Tapanainen JS, Koivunen R, et al. Effects of carbamazepine and oxcarbazepine on the reproductive endocrine function in women with epilepsy. Epilepsia, 2006, 47(9): 1441-1446.
47.	Ribacoba-Montero R, Martínez-Faedo C, Díaz-Díaz C, et al. Remission of polycystic ovary syndrome associated with valproic acid in an epileptic female. Rev Neurol, 2002, 36(7): 639-642.
48.	洪震. 抗癫痫药物应用专家共识. 中华神经科杂志, 2011, 44(1): 56-64.
49.	廖卫平. 妊娠期女性抗癫痫药物应用中国专家共识. 中国医师杂志, 2015, 17(7): 969-971.
50.	郝南亚, 吴梦倩, 慕洁, 等. 中国西部女性癫痫患者妊娠及用药数据库的建立与实施. 癫痫杂志, 2016, 2(2): 114-117.
51.	Svalheim S, Tauboll E, Surdova K, et al.Long-term levetiracetam treatment affects reproductive endocrine function in female Wistar rats. Seizure, 2008, 17(2): 203-209.
52.	Perloff MD, Thaler DE, Otis JA. Anorgasmia with gabapentin may be common in older patients. Am J Geriatr Pharmacother, 2011, 9(3): 199-203.
53.	Grant AC, Oh H. Gabapentin-induced anorgasmia in women. Am JPsychiatry, 2002, 159(7): 1247-1247.

1. Thomas SV. Controversies in contraception for women with epilepsy. Ann Indian Acad Neurol, 2015, 18(3): 278-283.
2. 吴逊. 我国癫痫的诊断与治疗现状. 中国现代神经疾病杂志, 2007, 7(3): 201-203.
3. Isojärvi JI. Reproductive dysfunction in women with epilepsy. Neurology, 2003, 61(6 uppl 2): 27-34.
4. Hamed SA. The effect of epilepsy and antiepileptic drugs on sexual, reproductive and gonadal health of adults with epilepsy. Expert Rev Clin Pharmacol, 2016, 9(6): 807-819.
5. 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. The Lancet, 1998, 352(9145): 1970-1973.
6. Farmen AH, Grundt JH, Tomson T, et al. Age-specific birth rates in women with epilepsy:a population-based study. Brain Behav, 2016, 6(8): e00492.
7. Scharfman HE, Kim M, Hintz TM, et al. Seizures and reproductive function: insights from female rats with epilepsy. Ann Neurol, 2008, 64(6): 687-697.
8. Edwards HE, Burnham WM, Ng MM, et al. Limbic seizures alter reproductive function in the female rat. Epilepsia, 1999, 40(10): 1370-1377.
9. Edwards HE, MacLusky NJ, Burnham WM. The effect of seizures and kindling on reproductive hormones in the rat. Neurosci Biobehav Rev, 2000, 24(7): 753-762.
10. Hum KM, Megna S, Burnham WM. The effects of right and left amygdala kindling on the female reproductive system in rats. Epilepsia, 2009, 50(4): 880-886.
11. Alvarenga TA, Matos G, Scorza FA, et al. Sexual response in female rats with status epilepticus. Epilepsia, 2013, 54(4): 644-648.
12. Li J, Kim JS, Abejuela VA, et al. Disrupted female estrous cyclicity in the intrahippocampal kainic acid mouse model of temporal lobe epilepsy. Epilepsia Open , 2017, 2(1): 1-9.
13. Boro A, Haut S.Medical comorbidities in the treatment of epilepsy. Epilepsy Behav, 2003, 4(Suppl 2): 2-12.
14. Morrell MJ, Guldner GT. Self-reported sexual function and sexual arousability in women with epilepsy. Epilepsia, 1996, 37(12): 1204-1210.
15. Luef G, Madersbacher H. Sexual dysfunction in patients with epilepsy. Handb Clin Neurol, 2015, 130: 383-394.
16. Morrell MJ, Sperling MR, Stecker M, et al. Sexual dysfunction in partial epilepsy A deficit in physiologic sexual arousal. Neurology, 1994, 44(2): 243-243.
17. Morrell MJ, Flynn KL, Done S, et al. Sexual dysfunction, sex steroid hormone abnormalities, and depression in women with epilepsy treated with antiepileptic drugs. Epilepsy Behav, 2005, 6(3): 360-365.
18. Herzog AG, Seibel MM, Schomer DL, et al. Reproductive endocrine disorders in women with partial seizures of temporal lobe origin. ArchNeurol, 1986, 43(4): 341-346.
19. Hamed SA, Hamed EA, Shokry M, et al. The reproductive conditions and lipid profile in females with epilepsy. Acta Neurol Scand, 2007, 115(1): 12-22.
20. Herzog AG, Friedman MN. Menstrual cycle interval and ovulation in women with localization-related epilepsy. Neurology, 2001, 57(11): 2133-2135.
21. Morrell MJ, Giudice L, Flynn KL, et al. Predictors of ovulatory failure in women with epilepsy. Ann Neurol, 2002, 52(6): 704-711.
22. Bui E, Harden CL, Sazgar M.Controversies in caring for women with epilepsy: sorting through the evidence.In SazgarM & Harden CL (Eds.). Cham: Springer International Publishing, 2016: 87-97.
23. Bauer J, Cooper-Mahkorn D. Reproductive dysfunction in women with epilepsy: menstrual cycle abnormalities, fertility, and polycystic ovary syndrome. Int Rev Neurobiol, 2008, 83: 135-155.
24. Herzog AG, Coleman AE, Jacobs AR, et al. Relationship of sexual dysfunction to epilepsy laterality and reproductive hormone levels in women. Epilepsy Behav, 2003, 4(4): 407-413.
25. Verrotti A, D'Egidio C, Mohn A, et al. Antiepileptic drugs, sex hormones, and PCOS. Epilepsia, 2011, 52(2): 199-211.
26. Koppel BS, Harden CL. Gender issues in the neurobiology of epilepsy: a clinical perspective. Neurobiol Dis, 2014, 72(Pt B): 193-197.
27. Thomas SV, Sarma P, Nirmala C, et al. Women with epilepsy and infertility have different reproductive hormone profile than others.Ann Indian Acad Neurol, 2013, 16(4): 544-548.
28. Zhou JQ, Zhou LM, Chen LJ, et al. Polycystic ovary syndrome in patients with epilepsy: a study in 102 Chinese women. Seizure, 2012, 21(9): 729-733.
29. 黄静, 任榕娜. 细胞色素 P450 酶系与抗癫痫药物的代谢. 国际儿科学杂志, 2006, 33(3): 167-169.
30. Browne TR. Pharmacokinetics of antiepileptic drugs. Neurology, 1998, 51(5 Suppl 4): 2-7.
31. 穆惠荣, 迟兆富. 抗癫痫药物的体内代谢及相互间作用机制的研究. 国外医学: 神经病学. 神经外科学分册, 2003, 30(5): 476-479.
32. Lofgren E, Mikkonen K, Tolonen U, et al. Reproductive endocrine function in women with epilepsy: the role of epilepsy type and medication. Epilepsy Behav, 2007, 10(1): 77-83.
33. Isojärvi JI, Taubøll E, Herzog AG. Effect of antiepileptic drugs on reproductive endocrine function in individuals with epilepsy. CNS Drugs, 2005, 19(3): 207-223.
34. Taubøll E, Gregoraszczuk EL, Kołodziej A, et al. Valproate inhibits the conversion of testosterone to estradiol and acts as an apoptotic agent in growing porcine ovarian follicular cells. Epilepsia, 2003, 44(8): 1014-1021.
35. Glister C, Satchell L, Michael AE, et al. The anti-epileptic drug valproic acid (VPA) inhibits steroidogenesis in bovine theca and granulosa cells in vitro. PLoS ONE, 2012, 7(11): e49553.
36. Isojarvi J, Laatikainen TJ, Pakarinen AJ, et al.Polycystic ovaries and hyperandrogenism in women taking valproate for epilepsy. N Eng J Med,1993,329(19): 1383-1388.
37. Isojärvi JI, Laatikainen TJ, Knip M, et al. Obesity and endocrine disorders in women taking valproate for epilepsy. Ann Neurol, 1996, 39(5): 579-584.
38. Isojärvi JI, Rättyä J, Myllylä VV, et al. Valproate, lamotrigine, and insulin-mediated risks in women with epilepsy. Ann Neurol, 1998, 43(4): 446-451.
39. Morrell MJ, Hayes FJ, Sluss PM, et al. Hyperandrogenism, ovulatory dysfunction, and polycystic ovary syndrome with valproate versus lamotrigine. Ann Neurol, 2008, 64(2): 200-211.
40. Hu X, Wang J, Dong W, et al. A meta-analysis of polycystic ovary syndrome in women taking valproate for epilepsy. Epilepsy Res, 2011, 97(1-2): 73-82.
41. Minagawa K, Watanabe T, Oyanagi R. Characteristics of women with epilepsy who developed polycysticovary syndrome owing to the therapy with valproate sodium. No To Hattatsu, 2013, 45(4): 304-308.
42. 高静, 迟兆富, 单培彦. 女性癫痫患者生殖内分泌功能紊乱. 中国神经精神疾病杂志, 2005, 31(6): i0005-i0006.
43. Goldberg-Stern H, Yaacobi E, Phillip M, et al. Endocrine effects of valproic acid therapy in girls with epilepsy: a prospective study. Eur J Paediatr Neurol, 2014, 18(6): 759-765.
44. Ayyagari M, Chitela SR, Kolachana V. Obesity, polycystic ovarian syndrome and thyroid dysfunction in women with epilepsy. Ann Indian Acad Neurol, 2012, 15(2): 101-105.
45. Kumar S, Kaur G. Second generation anti-epileptic drugs adversely affect reproductive functions in young non-epileptic female rats. Eur Neuropsychopharmacol, 2014, 24(10): 1709-1718.
46. Lofgren E, Tapanainen JS, Koivunen R, et al. Effects of carbamazepine and oxcarbazepine on the reproductive endocrine function in women with epilepsy. Epilepsia, 2006, 47(9): 1441-1446.
47. Ribacoba-Montero R, Martínez-Faedo C, Díaz-Díaz C, et al. Remission of polycystic ovary syndrome associated with valproic acid in an epileptic female. Rev Neurol, 2002, 36(7): 639-642.
48. 洪震. 抗癫痫药物应用专家共识. 中华神经科杂志, 2011, 44(1): 56-64.
49. 廖卫平. 妊娠期女性抗癫痫药物应用中国专家共识. 中国医师杂志, 2015, 17(7): 969-971.
50. 郝南亚, 吴梦倩, 慕洁, 等. 中国西部女性癫痫患者妊娠及用药数据库的建立与实施. 癫痫杂志, 2016, 2(2): 114-117.
51. Svalheim S, Tauboll E, Surdova K, et al.Long-term levetiracetam treatment affects reproductive endocrine function in female Wistar rats. Seizure, 2008, 17(2): 203-209.
52. Perloff MD, Thaler DE, Otis JA. Anorgasmia with gabapentin may be common in older patients. Am J Geriatr Pharmacother, 2011, 9(3): 199-203.
53. Grant AC, Oh H. Gabapentin-induced anorgasmia in women. Am JPsychiatry, 2002, 159(7): 1247-1247.

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