
==== Front
Epilepsy Curr
Epilepsy Curr
EPI
spepi
Epilepsy Currents
1535-7597
1535-7511
SAGE Publications Sage CA: Los Angeles, CA

10.1177/15357597231213248
10.1177_15357597231213248
Current Review in Clinical Research
Epilepsy and Anti-Seizure Medications: Secret Agents for Endocrine Disruption
Sazgar Mona MD 1
Mnatsakanyan Lilit MD 1
Pack Alison M. MD 2
Harden Cynthia L. MD 3
1 Department of Neurology, University of California, Irvine CA, USA
2 Department of Neurology, Columbia University, New York, NY, USA
3 Xenon Pharmaceuticals Inc, Burnaby, British Columbia, Canada
Mona Sazgar, Department of Neurology, University of California, Irvine, CA 92868, USA. Email: msazgar@uci.edu
6 12 2023
Mar-Apr 2024
24 2 7983
© The Author(s) 2023
2023
SAGE Publications
https://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).
There is a reciprocal relationship between epilepsy and reproductive endocrine disorders. Seizures and anti-seizure medications (ASMs) can contribute to reproductive and endocrine dysfunction and reproductive dysfunction may exacerbate seizures. Epilepsy via neuroendocrine mechanisms affects the hypothalamic–pituitary-ovarian (HPO) axis, disrupting the regulation of gonadotropin secretion, and resulting in dystrophic effects on the ovaries and early menopause. Anti-seizure medications have endocrine-related side effects on sexual function and bone health. Long-term use of ASMs may result in menstrual irregularities, sexual dysfunction, anovulatory cycles, polycystic ovaries, and reduced fertility. Some ASMs also interfere with bone metabolism. Epilepsy patients treated with ASMs are at risk for bone loss and fractures. This article explores the endocrine and hormonal effects of seizures and ASMs.

endocrine disruption
bone health
ASM
epilepsy
reproductive disorder
sexual dysfunction
PCOS
menstrual irregularities
menopause
catamenial epilepsy
cover-dateMarch–April 2024
typesetterts3
==== Body
pmcThere is a higher rate of menstrual disorders, polycystic ovary syndrome (PCOS), and sexual dysfunction in women with epilepsy. Menstrual disorders occur in a third of women with epilepsy compared with 12% to 14% in general population. 1 Polycystic ovary syndrome is characterized by enlarged ovaries, multiple cysts, androgen-secreting ovarian stroma causing symptoms of androgen excess including hirsutism, alopecia, acne, obesity, and menstrual disturbances. 2 It is seen in 4% to 7% of women of reproductive age but 10% to 25% of women with epilepsy. 3,4 In a study of 50 consecutive patients with temporal lobe epilepsy, Herzog and colleagues found that 56% reported amenorrhea, oligomenorrhea, and abnormal menstrual cycle intervals. 5

Brain regulates sex hormones via the hypothalamic–pituitary–ovarian (HPO) axis. Gonadotropin-releasing hormone (GnRH) produced by hypothalamus stimulates the production of follicle stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary gland and eventually affects the production of estrogen and progesterone by the ovaries. The temporo-limbic system, implicated in the pathophysiology of more common adult-onset epilepsies, plays an integral role in endocrine regulation. There are direct projections from amygdala to hypothalamus and its neurosecretory cells. Seizures originating from the amygdala and temporo-limbic system can affect the pulsatile GnRH secretion, and therefore result in disruption of hypothalamic regulation of pituitary gonadotropin secretion and subsequent reproductive-endocrine disorders. The temporo-limbic system is in turn affected by the feedback of neuroactive reproductive steroids. 6 -8

In their study of women with temporo-limbic epilepsy and normal control subjects, Herzog and colleagues demonstrated that there was a relationship among abnormal interictal epileptiform discharges, reproductive endocrine dysfunction, and menstrual disorders. 9 Furthermore, there is evidence that the laterality and focality of epilepsy is associated with specific types of endocrine disorders. There is increasing evidence that PCOS is associated with left temporal as well as right extra-temporal lobe epilepsies, whereas hypothalamic amenorrhea is seen more commonly in women with right temporal epileptogenic focus. Left temporal lobe epilepsy is associated with higher pulse GnRH secretion, resulting in higher LH/FSH ratio. This in turn causes failure of follicular ovarian maturation, chronic anovulation, and cyst formation. Right temporal lobe epilepsy is associated with lower pulse GnRH secretion, decreased LH and estradiol levels, characteristic for hypothalamic anovulation. The association of laterality of epilepsy with specific endocrine disorders further supports the important role of epilepsy as an endocrine disruptor.

In the quest to understand the endocrine disruptive effects of epilepsy, the name of a neuroactive peptide, Anti-Müllerian hormone (AMH) comes up in the literature. Anti-Müllerian hormone is a ligand of the transforming growth factor beta family (TGF-β), that is known to regulate sexual differentiation and gonadal function and have seizure protection properties. In females, granulosa cells of the ovary begin to produce AMH upon the initiation of follicular development to support ovarian function. Anti-Müllerian hormone receptors are also expressed in brain regions known to be involved in epileptic network including hippocampus, hypothalamus, and cortex. Women with epilepsy who have active seizures have a lower concentration of AMH compared with those without seizures and healthy controls. Anti-Müllerian hormone is hypothesized to protect neurons against N-Methyl-D-Aspartate mediated neurotoxicity both in vitro and in vivo. 10 -12

Women with epilepsy have a higher rate of premature ovarian failure and early menopause. In fact, there is a correlation between uncontrolled epilepsy and earlier age of menopause. This is attributed to endocrine effects of seizures on disruption of function of the HPO axis, leading to poor maturation and early loss of follicles discussed earlier. 13 There is increased risk for seizures during perimenopause period, when estradiol predominates with a net neuroexcitatory effect. Epilepsy is likely to improve after menopause is established and estradiol levels drop. 14

Reproductive and Endocrine Effects of Anti-Seizure Medications

Anti-seizure medications (ASMs) can result in endocrine related side effects including polycystic ovaries, decreased libido, erectile dysfunction, and bone loss. Microsomal hepatic enzyme inducing anti-seizure medications (EIASM) may impact sex hormones and result in lower levels of bioavailable testosterone and estradiol and subsequently contribute to sexual dysfunction, menstrual irregularities, and problems with fertility. Some non-enzyme inducing ASMs such as valproic acid (VPA) are also associated with endocrine disturbances such as polycystic ovary and weight gain. Certain ASMs may contribute to sexual dysfunction by a variety of mechanisms. Anti-seizure medications have influence on the metabolism of the central and peripheral endocrine hormones and their binding proteins. 15 Some hepatic cytochrome P450 enzyme inducing ASMs increase the breakdown of biologically active testosterone resulting in hyposexuality in men and women with epilepsy. They also decrease bioavailability of estradiol, resulting in menstrual disorders, anovulatory cycles, and polycystic ovaries. 15 Most of the non-enzyme inducing ASMs such as gabapentin, pregabalin, benzodiazepines (BZDs), and VPA enhance GABAergic transmission, which in turn has specific effects on sexual function. 15

Hepatic Enzyme Inducing ASMs

Carbamazepine (CBZ), phenobarbital (PB), and phenytoin (PHT) are all hepatic microsomal enzyme inducing ASMs (EIASMs). Oxcarbazepine (OXC) and topiramate (TPM) are weak hepatic enzyme inducers. Long-term treatment with these medications results in low levels of free testosterone and estradiol and therefore high levels of sex-hormone binding globulin concentrations in people with epilepsy. 16 -19 This in turn may lead to menstrual irregularities, sexual dysfunction, and reduced fertility.

The effect of TPM on sexual function can be either central and related to interference at the limbic and cortico-striatal loop or through affecting peripheral spinal and autonomic neurons. Substitution or reduction in dose resulted in recovery of symptoms. 20

Non-Enzyme Inducing ASMs

In women with epilepsy, valproate (VPA) is associated with increased risk of developing PCOS, hyperandrogenism, anovulatory cycles, and menstrual irregularities. 21 -25 A cross-sectional study in 1993 of 238 women with epilepsy showed that menstrual disorders were common in women taking VPA monotherapy (45%). Polycystic ovary syndrome and hyperandrogenism were seen in 90% of women on VPA monotherapy especially if VPA was started before age 20. 26

Lamotrigine (LTG) does not have hepatic enzyme inducing properties and LTG monotherapy is reported to cause minimal sexual effects in men and even improvement in sexual function in women. 19,27 Levetiracetam (LEV) was studied as monotherapy and was found not associated with drug-specific endocrine or sexual side effects in men and women. In a study by Svalheim and Colleagues women treated with LTG and LEV were found to be more satisfied with their sexual function than patients treated with CBZ and healthy control. 28 There are case reports of LEV associated hypersexuality 29 as well as loss of libido and anhedonia. 30 The effect is postulated to be due to changing in the balance of dopamine/serotonin ratio. There is lack of large population-based studies to provide conclusive guidance regarding the potential adverse sexual effects of lacosamide, zonisamide (ZNS), and some other newer ASMs.

Endocrine Effects of Epilepsy and ASMs on Bone Health

Osteoporosis is the most common bone disease. The WHO diagnostic classification defines osteoporosis as a bone mineral density (BMD) at the hip or spine that is less than or equal to 2.5 standard deviations below the young normal mean reference population. Osteoporosis is characterized by low bone mass or deterioration of bone tissue, disruption of bone architecture, compromised bone strength, with an increase in risk of fracture. Reduction in skeletal mass is caused by an imbalance between bone resorption and bone formation. Osteoporosis can be caused both by a failure to build bone and reach peak bone mass as a young adult and by bone loss later in life.

The peak bone mass is an important determinant of osteoporotic fracture risk. The peak bone mass is determined by the amount of bony tissue present at the end of the skeletal maturation. Factors influencing peak bone mass include sex hormones, insulin growth factor system, physical activity, calcium and protein intake, illness, and medications. Estrogen deficiency can accelerate bone loss and lead to excessive bone resorption accompanied by inadequate bone formation in post-menopausal women.

In people with epilepsy there is a 2-6-fold increased risk of fractures when compared to general population due to altered bone metabolism, decreased bone density, and a propensity to fall as a result of ASM-induced loss of balance. 31,32 Non traumatic fracture incidence is increased in younger age among ASM taking population peaking at 11 to 13 years, decreasing with the older age groups. 33 Other risk factors for bone loss include duration and severity of epilepsy, certain ASMs and prolonged duration of exposure, female sex, menopause, polytherapy, sedentary lifestyle, smoking, excessive alcoholic beverage intake, inadequate sun exposure, and certain endocrine conditions. 31

Certain ASMs are independent risk factors for bone loss and Hepatic CYP450 enzyme inducing ASMs such as CBZ, PHT, PB, primidone, and BZDs have long been associated with decreased BMD and abnormal bone metabolism. There are several mechanisms suggested for ASM-induced bone disease. Enzyme inducing ASMs and VPA may affect specific isoenzymes involved in vitamin D metabolism and result in accelerated vitamin D metabolism, therefore lowering vitamin D levels and interfering with normal absorption of calcium. Secondary hyperparathyroidism has been reported in patients taking ASMs. 34 Anti-seizure medications may also affect the proliferation of chondrocytes in the growth plate, resulting in bone loss. 35 Enzyme inducing ASMs can reduce the capacity of thyroid chief cells to secrete calcitonin. Some ASMs can increase serum homocysteine by lowering the folate levels. Folate is thought to have a role in preserving nitric oxide synthase activity in bone cells, stimulating osteoblasts and inhibiting bone catabolism and loss. It has been found that (independent of age and sex) for each standard deviation increase in the homocysteine level, the risk of fracture increased by 30%. 36

Several studies have reported decreased BMD, osteopenia and osteoporosis of hip and lumbar spine with CBZ, 15,37 -39 PHT, 40 -42 VPA, 15,40,41,43 TPM, 44,45 and OXC. 39,46 A recent study of adult patients newly diagnosed with epilepsy treated with VPA, LTG, and LEV monotherapy found that VPA altered bone turn over, while LTG and LEV did not exert harmful effects on bone health. 47 Koo and colleagues did not find any harmful effect of LEV on bone density. 48 However, at least one study has reported reduced BMD in adults treated with LEV. 49 One study of the effects of ZNS after 13 months of monotherapy in epilepsy patients concluded that long-term ZNS monotherapy does not negatively affect bone health in drug-naive patients with epilepsy. 50

Epilepsy patients treated with ASMs are at risk for bone loss and fractures. Most ASMs irrespective of hepatic enzyme inducing or non-enzyme inducing may result in low BMD, hypocalcemia, and vitamin D deficiency, which may occur early during treatment and initially remain asymptomatic. Neurologists caring for patients with epilepsy should consider monitoring for calcium and vitamin D levels and periodic BMD examinations in their patients for early detection of upcoming bone loss.

In summary, this article explored the complex and reciprocal relationship among epilepsy, ASMs, and reproductive endocrine disorders. Epilepsy and its treatment can act as silent agents disrupting the endocrine pathways and contributing to reproductive and endocrine consequences. Physicians treating patients with epilepsy should be aware of these long-term endocrine disruptions including menstrual irregularities, sexual dysfunction, anovulatory cycles, polycystic ovaries, reduced fertility, and bone health issues and try to identify and address them as they care for their epilepsy patients.

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
==== Refs
References

1 Herzog AG. Disorders of reproduction in patients with epilepsy: primary neurological mechanisms. Seizure. 2008;17 (2 ):101–110.18165118
2 Balen A . Pathogenesis of polycystic ovary syndrome—the enigma unravels? Lancet. 1999;354 (9183 ):966–967.10501353
3 Bauer J Cooper-Mahkorn D . Reproductive dysfunction in women with epilepsy: menstrual cycle abnormalities, fertility, and polycystic ovary syndrome. Int Rev Neurobiol. 2008;83 :135–155.18929079
4 Knochenhauer ES Key TJ Kahsar-Miller M Waggoner W Boots LR Azziz R . Prevalence of the polycystic ovary syndrome in unselected black and white women of the Southeastern United States: a prospective study. J Clin Endocrinol Metab. 1998;83 (9 ):3078–3082.9745406
5 Herzog AG . Reproductive endocrine considerations and hormonal therapy for men with epilepsy. Epilepsia. 1991;32 (Suppl 6 ):S34–S37.1959510
6 Herzog AG . A hypothesis to integrate partial seizures of temporal lobe origin and reproductive endocrine disorders. Epilepsy Res. 1989;3 (2 ):151–159.2651114
7 Kokate TG Cohen AL Karp E Rogawski MA . Neuroactive steroids protect against pilocarpine- and kainic acid-induced limbic seizures and status epilepticus in mice. Neuropharmacology. 1996;35 (8 ):1049–1056.9121607
8 Wong M Moss RL . Long-term and short-term electrophysiological effects of estrogen on the synaptic properties of hippocampal CA1 neurons. J Neurosci. 1992;12 (8 ):3217–3225.1353794
9 Herzog AG Coleman AE Jacobs AR , et al. Interictal EEG discharges, reproductive hormones, and menstrual disorders in epilepsy. Ann Neurol. 2003;54 (5 ):625–637.14595652
10 Harden CL Pennell PB French JA , et al. Anti-mullerian hormone is higher in seizure-free women with epilepsy compared to those with ongoing seizures. Epilepsy Res. 2016;127 :66–71.27565413
11 Lebeurrier N Launay S Macrez R , et al. Anti-Mullerian-hormone-dependent regulation of the brain serine-protease inhibitor neuroserpin. J Cell Sci. 2008;121 (Pt 20 ):3357–3365.18796535
12 Gazzaley AH Weiland NG McEwen BS Morrison JH . Differential regulation of NMDAR1 mRNA and protein by estradiol in the rat hippocampus. J Neurosci. 1996;16 (21 ):6830–6838.8824322
13 Harden CL Pennell PB . Neuroendocrine considerations in the treatment of men and women with epilepsy. Lancet Neurol. 2013;12 (1 ):72–83.23237902
14 Harden CL Pulver MC Ravdin L Jacobs AR . The effect of menopause and perimenopause on the course of epilepsy. Epilepsia. 1999;40 (10 ):1402–1407.10528936
15 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 ):807–819.26934627
16 Macphee GJ Larkin JG Butler E Beastall GH Brodie MJ . Circulating hormones and pituitary responsiveness in young epileptic men receiving long-term antiepileptic medication. Epilepsia. 1988;29 (4 ):468–475.3134193
17 Isojarvi JI . Serum steroid hormones and pituitary function in female epileptic patients during carbamazepine therapy. Epilepsia. 1990;31 (4 ):438–445.2142450
18 Murialdo G Galimberti CA Gianelli MV , et al. Effects of valproate, phenobarbital, and carbamazepine on sex steroid setup in women with epilepsy. Clin Neuropharmacol. 1998;21 (1 ):52–58.9579286
19 Herzog AG. Differential impact of antiepileptic drugs on the effects of contraceptive methods on seizures: interim findings of the epilepsy birth control registry. Seizure. 2015;28 :71–75.25770029
20 Chen LW Chen MY Chen KY Lin HS Chien CC Yin HL . Topiramate-associated sexual dysfunction: a systematic review. Epilepsy Behav. 2017;73 :10–17.28605628
21 Verrotti A Mencaroni E Cofini M , et al. Valproic acid metabolism and its consequences on sexual functions. Curr Drug Metab. 2016;17 (6 ):573–581.27000076
22 Prabhakar S Sahota P Kharbanda PS , et al. Sodium valproate, hyperandrogenism and altered ovarian function in Indian women with epilepsy: a prospective study. Epilepsia. 2007;48 (7 ):1371–1377.17441994
23 Meador K Reynolds MW Crean S Fahrbach K Probst C . Pregnancy outcomes in women with epilepsy: a systematic review and meta-analysis of published pregnancy registries and cohorts. Epilepsy Res. 2008;81 (1 ):1–13.18565732
24 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. 2008;49 (12 ):2069–2077.18503558
25 Pack AM . Implications of hormonal and neuroendocrine changes associated with seizures and antiepileptic drugs: a clinical perspective. Epilepsia. 2010;51 (Suppl 3 ):150–153.20618422
26 Isojarvi JI Laatikainen TJ Pakarinen AJ Juntunen KT Myllyla VV . Polycystic ovaries and hyperandrogenism in women taking valproate for epilepsy. N Engl J Med. 1993;329 (19 ):1383–1388.8413434
27 Gil-Nagel A Lopez-Munoz F Serratosa JM Moncada I Garcia-Garcia P Alamo C . Effect of lamotrigine on sexual function in patients with epilepsy. Seizure. 2006;15 (3 ):142–149.16434217
28 Svalheim S Tauboll E Luef G , et al. Differential effects of levetiracetam, carbamazepine, and lamotrigine on reproductive endocrine function in adults. Epilepsy Behav. 2009;16 (2 ):281–287.19716343
29 Metin SZ Ozmen M Ozkara C Ozmen E . Hypersexuality in a patient with epilepsy during treatment of levetiracetam. Seizure. 2013;22 (2 ):151–152.23200413
30 Calabro RS Italiano D Militi D Bramanti P . Levetiracetam-associated loss of libido and anhedonia. Epilepsy Behav. 2012;24 (2 ):283–284.22560189
31 Pack AM . Treatment of epilepsy to optimize bone health. Curr Treat Options Neurol. 2011;13 (4 ):346–354.21557040
32 Souverein PC Webb DJ Petri H Weil J Van Staa TP Egberts T . Incidence of fractures among epilepsy patients: a population-based retrospective cohort study in the General Practice Research Database. Epilepsia. 2005;46 (2 ):304–310.15679512
33 Whitney DG Kalia V Rajapakse CS , et al. The effect of age when initiating anti-seizure medication therapy on fragility fracture risk for children with epilepsy. Bone. 2021;149 :115996.33962082
34 Telci A Cakatay U Kurt BB , et al. Changes in bone turnover and deoxypyridinoline levels in epileptic patients. Clin Chem Lab Med. 2000;38 (1 ):47–50.10774961
35 Lee HS Wang SY Salter DM Wang CC Chen SJ Fan HC . The impact of the use of antiepileptic drugs on the growth of children. BMC Pediatr. 2013;13 :211.24354857
36 Golbahar J Hamidi A Aminzadeh MA Omrani GR . Association of plasma folate, plasma total homocysteine, but not methylenetetrahydrofolate reductase C667 T polymorphism, with bone mineral density in postmenopausal Iranian women: a cross-sectional study. Bone. 2004;35 (3 ):760–765.15336613
37 Nilsson OS Lindholm TS Elmstedt E Lindback A Lindholm TC . Fracture incidence and bone disease in epileptics receiving long-term anticonvulsant drug treatment. Arch Orthop Trauma Surg. 1986;105 (3 ):146–149.3741066
38 Linde J Molholm Hansen J Siersbaek-Nielsen K Fuglsang-Fredriksen V . Bone density in patients receiving long-term anticonvulsant therapy. Acta Neurol Scand. 1971;47 (5 ):650–651.5139727
39 Mintzer S Boppana P Toguri J DeSantis A . Vitamin D levels and bone turnover in epilepsy patients taking carbamazepine or oxcarbazepine. Epilepsia. 2006;47 (3 ):510–515.16529614
40 Sato Y Kondo I Ishida S , et al. Decreased bone mass and increased bone turnover with valproate therapy in adults with epilepsy. Neurology. 2001;57 (3 ):445–449.11502911
41 Nissen-Meyer LS Svalheim S Tauboll E , et al. Levetiracetam, phenytoin, and valproate act differently on rat bone mass, structure, and metabolism. Epilepsia. 2007;48 (10 ):1850–1860.17634065
42 Moro-Alvarez MJ Diaz Curiel M de la Piedra C Marinoso ML Carrascal MT . Bone disease induced by phenytoin therapy: clinical and experimental study. Eur Neurol. 2009;62 (4 ):219–230.19628941
43 Boluk A Guzelipek M Savli H Temel I Ozisik HI Kaygusuz A . The effect of valproate on bone mineral density in adult epileptic patients. Pharmacol Res. 2004;50 (1 ):93–97.15082034
44 Heo K Rhee Y Lee HW , et al. The effect of topiramate monotherapy on bone mineral density and markers of bone and mineral metabolism in premenopausal women with epilepsy. Epilepsia. 2011;52 (10 ):1884–1889.21692779
45 Zhang J Wang KX Wei Y , et al. Effect of topiramate and carbamazepine on bone metabolism in children with epilepsy [in Chinese]. Zhongguo Dang Dai Er Ke Za Zhi. 2010;12 (2 ):96–98.20199720
46 Cansu A Yesilkaya E Serdaroglu A , et al. Evaluation of bone turnover in epileptic children using oxcarbazepine. Pediatr Neurol. 2008;39 (4 ):266–271.18805365
47 Guo Y Lin Z Huang Y Yu L . Effects of valproate, lamotrigine, and levetiracetam monotherapy on bone health in newly diagnosed adult patients with epilepsy. Epilepsy Behav. 2020;113 :107489.33220583
48 Koo DL Joo EY Kim D Hong SB . Effects of levetiracetam as a monotherapy on bone mineral density and biochemical markers of bone metabolism in patients with epilepsy. Epilepsy Res. 2013;104 (1-2 ):134–139.23032070
49 Beniczky SA Viken J Jensen LT Andersen NB . Bone mineral density in adult patients treated with various antiepileptic drugs. Seizure. 2012;21 (6 ):471–472.22541979
50 Koo DL Nam H . Effects of zonisamide monotherapy on bone health in drug-naive epileptic patients. Epilepsia. 2020;61 (10 ):2142–2149.32944954
