癲癇及抗癲癇藥物對育齡期女性患者生殖內分泌的影響_Journal of Epilepsy

Authors：

額日登娜希 ,  劉獻增

北京大學人民醫院神經內科癲癇中心（北京 100044）;

Corresponding?author：

劉獻增, Email: liuxianzeng2004@sina.com

Keywords：

癲癇; 抗癲癇藥物; 女性患者; 生殖內分泌

DOI：

10.7507/2096-0247.20180011

Video：

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癲癇是神經系統最常見的慢性疾病之一。癲癇患者結婚率、生育率低。多囊卵巢、多囊卵巢綜合癥、高雄激素血癥、性功能障礙等常見于女性癲癇患者（Women with epilepsy，WWE）。癲癇放電或抗癲癇藥物（AEDs）影響下丘腦-垂體-卵巢軸系統調節，引起體內激素水平改變，因而 WWE 易患生殖內分泌疾病。文章就癲癇及 AEDs 對育齡期 WWE 生殖內分泌的影響進行綜述。

Citation： 額日登娜希, 劉獻增. 癲癇及抗癲癇藥物對育齡期女性患者生殖內分泌的影響. 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.	吳遜. 我國癲癇的診斷與治療現狀. 中國現代神經疾病雜志, 2007, 7(3): 201-203.
3.	Isoj?rvi 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.	黃靜, 任榕娜. 細胞色素 P450 酶系與抗癲癇藥物的代謝. 國際兒科學雜志, 2006, 33(3): 167-169.
30.	Browne TR. Pharmacokinetics of antiepileptic drugs. Neurology, 1998, 51(5 Suppl 4): 2-7.
31.	穆惠榮, 遲兆富. 抗癲癇藥物的體內代謝及相互間作用機制的研究. 國外醫學: 神經病學. 神經外科學分冊, 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.	Isoj?rvi JI, Taub?ll E, Herzog AG. Effect of antiepileptic drugs on reproductive endocrine function in individuals with epilepsy. CNS Drugs, 2005, 19(3): 207-223.
34.	Taub?ll E, Gregoraszczuk EL, Ko?odziej 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.	Isoj?rvi 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.	Isoj?rvi JI, R?tty? J, Myllyl? 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.	高靜, 遲兆富, 單培彥. 女性癲癇患者生殖內分泌功能紊亂. 中國神經精神疾病雜志, 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. 抗癲癇藥物應用專家共識. 中華神經科雜志, 2011, 44(1): 56-64.
49.	廖衛平. 妊娠期女性抗癲癇藥物應用中國專家共識. 中國醫師雜志, 2015, 17(7): 969-971.
50.	郝南亞, 吳夢倩, 慕潔, 等. 中國西部女性癲癇患者妊娠及用藥數據庫的建立與實施. 癲癇雜志, 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. 吳遜. 我國癲癇的診斷與治療現狀. 中國現代神經疾病雜志, 2007, 7(3): 201-203.
3. Isoj?rvi 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. 黃靜, 任榕娜. 細胞色素 P450 酶系與抗癲癇藥物的代謝. 國際兒科學雜志, 2006, 33(3): 167-169.
30. Browne TR. Pharmacokinetics of antiepileptic drugs. Neurology, 1998, 51(5 Suppl 4): 2-7.
31. 穆惠榮, 遲兆富. 抗癲癇藥物的體內代謝及相互間作用機制的研究. 國外醫學: 神經病學. 神經外科學分冊, 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. Isoj?rvi JI, Taub?ll E, Herzog AG. Effect of antiepileptic drugs on reproductive endocrine function in individuals with epilepsy. CNS Drugs, 2005, 19(3): 207-223.
34. Taub?ll E, Gregoraszczuk EL, Ko?odziej 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. Isoj?rvi 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. Isoj?rvi JI, R?tty? J, Myllyl? 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. 高靜, 遲兆富, 單培彥. 女性癲癇患者生殖內分泌功能紊亂. 中國神經精神疾病雜志, 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. 抗癲癇藥物應用專家共識. 中華神經科雜志, 2011, 44(1): 56-64.
49. 廖衛平. 妊娠期女性抗癲癇藥物應用中國專家共識. 中國醫師雜志, 2015, 17(7): 969-971.
50. 郝南亞, 吳夢倩, 慕潔, 等. 中國西部女性癲癇患者妊娠及用藥數據庫的建立與實施. 癲癇雜志, 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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