DOI: https://doi.org/10.18370/2309-4117.2019.50.70-75

Sexual and reproductive dysfunction in women with epilepsy in the aspect of current anti-epileptic pharmacotherapy

В. В. Оржешковский, Н. Н. Невмержицкая, Е. В. Ткаченко, И. В. Дзевульская

Abstract


Based on current literature analysis this review provides information on various issues of a woman’s reproductive system functioning under altered conditions of a pathologically functioning brain during epilepsy, outlines possible pathogenetic mechanisms of hormonal imbalance and its effect on epileptogenesis. There are complex multidirectional interactions between female sex hormones and epileptic pathological process. Any changes in the concentrations of endogenous

or exogenous hormones can affect the occurrence of epileptic seizures directly or by pharmacokinetic interactions through the modification of antiepileptic drugs level in plasma. These effects are realized by acting on various links of the hypothalamic-pituitary-ovarian axis. Special catamenial epilepsy when hormonal imbalance determines the epileptic process, mechanisms of its formation and therapeutic approaches to treatment are also considered.

The questions of reproductive dysfunctions typical for women with epilepsy are described, such as hyperandrogenism, high luteinizing hormone levels, irregular menstruation, hyperprolactinemia, polycystic ovary syndrome, infertility, premature menopause. The result of these dysfunctions is that 30–60% of patients with epilepsy have a low pregnancy and childbirth rate. Worsening of life quality in women with epilepsy results in approximately five-fold increase in the risk of sexual dysfunction compared with the general population, which is manifested by a decrease of sexual contacts quantity, libido problems, decreased lubrication, dyspareunia, vaginismus, problems with arousal and orgasm dissatisfaction despite a normal attraction.

It needs consider the effects of epilepsy pharmacotherapy and drugs interaction with hormonal contraception, that reduces its effectiveness. The possibilities of this problem solution and hormone replacement therapy in menopausal patients with epilepsy are reviewed. Information is presented on the current pharmacotherapy of epilepsy in the aspect of antiepileptic drugs as the causes of sexual and reproductive dysfunctions, primarily valproate and anticonvulsant inducers of cytochrome P450, as well as other drugs of this group.


Keywords


catamenial epilepsy; contraception; antiepileptic drugs; reproductive dysfunction; sexual dysfunction; epilepsy

References


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Amini, L., et al. “Comparing the frequency of polycystic ovary syndrome in women with and without epilepsy.” Journal of Family Medicine and Primary Care 1.7 (2018): 16.

Bachmann, G.A., et al. “Effect of gabapentin on sexual function in vulvodynia: a randomized, placebo-controlled trial.” American Journal of Obstetrics and Gynecology 1.220 (2019): 89.e1–89.e8.

Bangar, S., et al. “Women with epilepsy: clinically relevant issues.” Functional Neurology 3.31 (2016): 127–34.

Billakota, S., et al. “Sleep-disordered breathing, neuroendocrine function, and clinical SUDEP risk in patients with epilepsy.” Epilepsy & Behavior 87 (2018): 78–82.

Brodie, M.J., et al. “Enzyme induction with antiepileptic drugs: Cause for concern?” Epilepsia 1.54 (2013): 11–27.

Calabrò, R.S. “Sexual dysfunction in patients with epilepsy: Disentangling the pathogenic mechanisms!” Epilepsy & Behavior 64 (2016): 294.

D’Amour, J., et al. “Interictal spike frequency varies with ovarian cycle stage in a rat model of epilepsy.” Experimental Neurology 269 (2015): 102–19.

Erel, T., Guralp, O. “Epilepsy and menopause.” Archives of Gynecology and Obstetrics 3.284 (2011): 749–55.

Gerard, E.E., Meador, K.J. “Managing Epilepsy in Women.” CONTINUUM: Lifelong Learning in Neurology 1.22 (2016): 204–26.

Gooneratne, I.K., Wimalaratna, S. “Update on management of epilepsy in women for the non- neurologist.” Postgraduate Medical Journal 1091.92 (2016): 554–9.

Gustavsen, M.W., et al. “Differential effects of antiepileptic drugs on steroidogenesis in a human in vitro cell model.” Acta Neurologica Scandinavica 120 (2009): 14–21.

Hamed, S.A. “Neuroendocrine Hormonal Conditions in Epilepsy: Relationship to Reproductive and Sexual Functions.” The Neurologist 3.14 (2008): 157–69.

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Joshi, S., et al. “A novel therapeutic approach for treatment of catamenial epilepsy.” Neurobiology of Disease 111 (2018): 127–37.

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Koppel, B.S., Harden, C.L. “Gender issues in the neurobiology of epilepsy: A clinical perspective.” Neurobiology of Disease 72 (2014): 193–7.

Kumar, S., Kaur, G. “Second generation anti-epileptic drugs adversely affect reproductive functions in young non-epileptic female rats.” European Neuropsychopharmacology 10.24 (2014): 1709–18.

Leśkiewicz, M., Budziszewska, B., Lasoń, W. “Endocrine effects of antiepileptic drugs.” Przeglad Lekarski 11.65 (2008): 795–8.

Luef, G., Madersbacher, H. “Sexual dysfunction in patients with epilepsy.” Handb Clin Neurol 130 (2015): 383–94.

Marmura, M.J., Kumpinsky, A.S. “Refining the Benefit/Risk Profile of Anti-Epileptic Drugs in Headache Disorders.” CNS Drugs 8.32 (2018): 735–46.

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Reddy, D.S. “Neurosteroids and their role in sex-specific epilepsies.” Neurobiology of Disease 72 (2014): 198–209.

Reddy, D.S. “Do oral contraceptives increase epileptic seizures?” Expert Review of Neurotherapeutics 2.17 (2017): 129–34.

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Sidhu, H.S., Srinivasa, R., Sadhotra, A. “Evaluate the effects of long-term valproic acid treatment on metabolic profiles in newly diagnosed or untreated female epileptic patients: A prospective study.” Seizure 48 (2017): 15–21.

Sidhu, H.S., Srinivasa, R., Sadhotra, A. “Evaluate the effects of antiepileptic drugs on reproductive endocrine system in newly diagnosed female epileptic patients receiving either Valproate or Lamotrigine monotherapy: A prospective study.” Epilepsy Research 139 (2018): 20–7.

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Tao, L., et al. “Sexual dysfunction and associated factors in Chinese Han women with epilepsy.” Epilepsy & Behavior 85 (2018): 150–6.

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Voinescu, P., Pennell, P. “Delivery of a Personalized Treatment Approach to Women with Epilepsy.” Seminars in Neurology 06.37 (2017): 611–23.

Yang, Y., Wang, X. “Sexual dysfunction related to antiepileptic drugs in patients with epilepsy.” Expert Opinion on Drug Safety 1.15 (2016): 31–42.

Younus, I., Reddy, D.S. “Seizure facilitating activity of the oral contraceptive ethinyl estradiol.” Epilepsy Research 121 (2016): 29–32.

Zheleznova, E.V., et al. “Monotherapy of Epilepsy in Women: Psychiatric and Neuroendocrine Aspects.” Neuroscience and Behavioral Physiology 2.40 (2010): 157–62.


GOST Style Citations


1.         Abou-Khalil, B.W. “Update on Antiepileptic Drugs.” CONTINUUM: Lifelong Learning in Neurology 2.25 (2019): 508–36.

2.         Amini, L., et al. “Comparing the frequency of polycystic ovary syndrome in women with and without epilepsy.” Journal of Family Medicine and Primary Care 1.7 (2018): 16.

3.         Bachmann, G.A., et al. “Effect of gabapentin on sexual function in vulvodynia: a randomized, placebo-controlled trial.” American Journal of Obstetrics and Gynecology 1.220 (2019): 89.e1–89.e8.

4.         Bangar, S., et al. “Women with epilepsy: clinically relevant issues.” Functional Neurology 3.31 (2016): 127–34.

5.         Billakota, S., et al. “Sleep-disordered breathing, neuroendocrine function, and clinical SUDEP risk in patients with epilepsy.” Epilepsy & Behavior 87 (2018): 78–82.

6.         Brodie, M.J., et al. “Enzyme induction with antiepileptic drugs: Cause for concern?” Epilepsia 1.54 (2013): 11–27.

7.         Calabrò, R.S. “Sexual dysfunction in patients with epilepsy: Disentangling the pathogenic mechanisms!” Epilepsy & Behavior 64 (2016): 294.

8.         D’Amour, J., et al. “Interictal spike frequency varies with ovarian cycle stage in a rat model of epilepsy.” Experimental Neurology 269 (2015): 102–19.

9.         Erel, T., Guralp, O. “Epilepsy and menopause.” Archives of Gynecology and Obstetrics 3.284 (2011): 749–55.

10.       Gerard, E.E., Meador, K.J. “Managing Epilepsy in Women.” CONTINUUM: Lifelong Learning in Neurology 1.22 (2016): 204–26.

11.       Gooneratne, I.K., Wimalaratna, S. “Update on management of epilepsy in women for the non- neurologist.” Postgraduate Medical Journal 1091.92 (2016): 554–9.

12.       Gustavsen, M.W., et al. “Differential effects of antiepileptic drugs on steroidogenesis in a human in vitro cell model.” Acta Neurologica Scandinavica 120 (2009): 14–21.

13.       Hamed, S.A. “Neuroendocrine Hormonal Conditions in Epilepsy: Relationship to Reproductive and Sexual Functions.” The Neurologist 3.14 (2008): 157–69.

14.       Hamed, S.A. “The effect of epilepsy and antiepileptic drugs on sexual, reproductive and gonadal health of adults with epilepsy.” Expert Review of Clinical Pharmacology 6.9 (2016): 807–19.

15.       Harden, C.L., et al. “Anti-mullerian hormone is higher in seizure-free women with epilepsy compared to those with ongoing seizures.” Epilepsy Research 127 (2016): 66–71.

16.       Henning, O.J., et al. “Sexual problems in people with refractory epilepsy.” Epilepsy & Behavior 61 (2016): 174–9.

17.       Herzog, A.G. “Catamenial epilepsy: Update on prevalence, pathophysiology and treatment from the findings of the NIH Progesterone Treatment Trial.” Seizure 28 (2015): 18–25.

18.       Hill, M., et al. “The steroid metabolome in lamotrigine-treated women with epilepsy.” Steroids 12 (2011): 1351–7.

19.       Joshi, S., et al. “A novel therapeutic approach for treatment of catamenial epilepsy.” Neurobiology of Disease 111 (2018): 127–37.

20.       Kim, J.Y., Lee, H.W. “Metabolic and Hormonal Disturbances in Women with Epilepsy on Antiepileptic Drug Monotherapy.” Epilepsia 7.48 (2007): 1366–70.

21.       Koppel, B.S., Harden, C.L. “Gender issues in the neurobiology of epilepsy: A clinical perspective.” Neurobiology of Disease 72 (2014): 193–7.

22.       Kumar, S., Kaur, G. “Second generation anti-epileptic drugs adversely affect reproductive functions in young non-epileptic female rats.” European Neuropsychopharmacology 10.24 (2014): 1709–18.

23.       Leśkiewicz, M., Budziszewska, B., Lasoń, W. “Endocrine effects of antiepileptic drugs.” Przeglad Lekarski 11.65 (2008): 795–8.

24.       Luef, G., Madersbacher, H. “Sexual dysfunction in patients with epilepsy.” Handb Clin Neurol 130 (2015): 383–94.

25.       Marmura, M.J., Kumpinsky, A.S. “Refining the Benefit/Risk Profile of Anti-Epileptic Drugs in Headache Disorders.” CNS Drugs 8.32 (2018): 735–46.

26.       Navis, A., Harden, C. “A Treatment Approach to Catamenial Epilepsy.” Current Treatment Options in Neurology 7.18 (2016): 30.

27.       Pack, A.M. “Implications of hormonal and neuroendocrine changes associated with seizures and antiepileptic drugs: A clinical perspective: Epilepsy and Neuroendocrine Effects.” Epilepsia 51 (2010): 150–3.

28.       Pack, A.M., et al. “Neuroendocrinological aspects of epilepsy: Important issues and trends in future research.” Epilepsy & Behavior 1.22 (2011): 94–102.

29.       Rathore, C., et al. “Sexual dysfunction in people with epilepsy.” Epilepsy & Behavior 100 (2019): 106495.

30.       Reddy, D.S. “Neurosteroids and their role in sex-specific epilepsies.” Neurobiology of Disease 72 (2014): 198–209.

31.       Reddy, D.S. “Do oral contraceptives increase epileptic seizures?” Expert Review of Neurotherapeutics 2.17 (2017): 129–34.

32.       Reimers, A. “New antiepileptic drugs and women.” Seizure 8.23 (2014): 585–91.

33.       Samba Reddy, D. “Sex differences in the anticonvulsant activity of neurosteroids: Sex Differences in Anticonvulsant Neurosteroids.” Journal of Neuroscience Research 1–2.95 (2017): 661–70.

34.       Sazgar, M. “Treatment of Women With Epilepsy.” CONTINUUM: Lifelong Learning in Neurology 2.25 (2019): 408–30.

35.       Sidhu, H.S., Srinivasa, R., Sadhotra, A. “Evaluate the effects of long-term valproic acid treatment on metabolic profiles in newly diagnosed or untreated female epileptic patients: A prospective study.” Seizure 48 (2017): 15–21.

36.       Sidhu, H.S., Srinivasa, R., Sadhotra, A. “Evaluate the effects of antiepileptic drugs on reproductive endocrine system in newly diagnosed female epileptic patients receiving either Valproate or Lamotrigine monotherapy: A prospective study.” Epilepsy Research 139 (2018): 20–7.

37.       Svalheim, S., et al. “Interactions between antiepileptic drugs and hormones.” Seizure 28 (2015): 12–7.

38.       Tao, L., et al. “Sexual dysfunction and associated factors in Chinese Han women with epilepsy.” Epilepsy & Behavior 85 (2018): 150–6.

39.       Thomas, S., et al. “Women with epilepsy and infertility have different reproductive hormone profile than others.” Annals of Indian Academy of Neurology 4.16 (2013): 544.

40.       Thomas, S. “Controversies in contraception for women with epilepsy.” Annals of Indian Academy of Neurology 3.18 (2015): 278.

41.       Vélez-Ruiz, N.J., Pennell, P.B. “Issues for Women with Epilepsy.” Neurologic Clinics 2.34 (2016): 411–25.

42.       Verrotti, A., et al. “Epilepsy, sex hormones and antiepileptic drugs in female patients.” Expert Review of Neurotherapeutics 12.9 (2009): 1803–14.

43.       Verrotti, A., et al. “Antiepileptic drugs, sex hormones, and PCOS: Epilepsy and Reproductive Dysfunction.” Epilepsia 52.2 (2011): 199–211.

44.       Voinescu, P., Pennell, P. “Delivery of a Personalized Treatment Approach to Women with Epilepsy.” Seminars in Neurology 06.37 (2017): 611–23.

45.       Yang, Y., Wang, X. “Sexual dysfunction related to antiepileptic drugs in patients with epilepsy.” Expert Opinion on Drug Safety 1.15 (2016): 31–42.

46.       Younus, I., Reddy, D.S. “Seizure facilitating activity of the oral contraceptive ethinyl estradiol.” Epilepsy Research 121 (2016): 29–32.

47.       Zheleznova, E.V., et al. “Monotherapy of Epilepsy in Women: Psychiatric and Neuroendocrine Aspects.” Neuroscience and Behavioral Physiology 2.40 (2010): 157–62.





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