There is a complex, bidirectional interdependence between sex steroid hormones and epilepsy; hormones affect seizures, while seizures affect hormones thereby disturbing reproductive endocrine function. Both female and male sex steroid hormones influence brain excitability. For the female sex steroid hormones, progesterone and its metabolites are anticonvulsant, while estrogens are mainly proconvulsant. The monthly fluctuations in hormone levels of estrogen and progesterone are the basis for catamenial epilepsy described elsewhere in this issue. Androgens are mainly anticonvulsant, but the effects are more varied, probably because of its metabolism to, among others, estradiol. The mechanisms for the effects of sex steroid hormones on brain excitability are related to both classical, intracellularly mediated effects, and non-classical membrane effects due to binding to membrane receptors. The latter are considered the most important in relation to epilepsy. The different sex steroids can also be further metabolized within the brain to different neurosteroids, which are even more potent with regard to their effect on excitability. Estrogens potentiate glutamate responses, primarily by potentiating NMDA receptor activity, but also by affecting GABA-ergic mechanisms and altering brain morphology by increasing dendritic spine density. Progesterone and its main metabolite 5α-pregnan-3α-ol-20-one (3α-5α-THP) act mainly to enhance postsynaptic GABA-ergic activity, while androgens enhance GABA-activated currents. Seizures and epileptic discharges also affect sex steroid hormones. There are close anatomical connections between the temporolimbic system and the hypothalamus controlling the endocrine system. Several studies have shown that epileptic activity, especially mediated through the amygdala, alters reproductive function, including reduced ovarian cyclicity in females and altered sex steroid hormone levels in both genders. Furthermore, there is an asymmetric activation of the hypothalamus with unilateral amygdala seizures. This may, again, be the basis for the occurrence of different reproductive endocrine disorders described for patients with left-sided or right-sided temporal lobe epilepsy.

Antiepileptic drugs (AEDs) are known to have endocrine side effects in both men and women. These can affect fertility, sexuality, thyroid function, and bone health, all functions of major importance for well-being and quality of life. The liver enzyme inducing antiepileptic drugs (EIAEDs), like phenobarbital, phenytoin, and carbamazepine, and also valproate (VPA), a non-EIAED, are most likely to cause such side effects. AED treatment can alter the levels of different sex hormones. EIAEDs increase sex hormone binding globulin (SHBG) concentrations in both men and women. Over time, this elevation can lead to lower levels of bioactive testosterone and estradiol, which may cause menstrual disturbances, sexual problems, and eventually reduced fertility. VPA can cause weight gain in both men and women. In women, VPA can also lead to androgenization with increased serum testosterone concentrations, menstrual disturbances, and polycystic ovaries. Lamotrigine has not been shown to result in endocrine side effects. The newer AEDs have not yet been thoroughly studied, but case reports indicate that some of these drugs could also be suspected to cause such effects if endocrine changes commence after treatment initiation. It is important to be aware of possible endocrine side effects of AEDs as they can have a major impact on quality of life, and are, at least partly, reversible after AED discontinuation.

Summary:Purpose: Long-term treatment with antiepileptic drugs (AEDs) is associated with increased risk of fractures. Phenytoin (PHT) and valproate (VPA) have both been suggested to influence bone health, whereas levetiracetam (LEV) is scarcely studied. The present study compares the effect of these AEDs on bone mass, biomechanical strength, and bone turnover in rats.Methods: Female rats received PHT (50mg/kg), VPA (300mg/kg), or LEV (50 and 150mg/kg) for 90 days. Dissected femurs were analyzed using dual energy x-ray absorptiometry (DXA), three-point cantilever bending, and histomorphological evaluation. Serum levels of biochemical bone turnover markers were monitored using immunoassay quantification.Results: PHT and VPA reduced bone mineral density (BMD) and content (BMC) in one or more bone compartments, whereas LEV did not. VPA induced increased bone turnover, whereas modest changes were observed for PHT. Interestingly, low-dose LEV was associated with reduced biomechanical strength of the femoral neck (mainly trabecular bone). In addition, low-dose LEV treatment resulted in significantly reduced levels of serum osteocalcin, a marker of bone formation. Histomorphological analyses indicated increased retention of cartilage remnants at the growth plate metaphysis of rats treated with low-dose LEV vs. controls.Conclusions: PHT, VPA, and LEV exert differential effects on bone mass and strength, suggesting different mechanisms of action. The weakening effect of low-dose LEV on the femoral neck, despite a constant BMD, suggests a primary effect on bone quality. These findings warrant further human studies of possible adverse effects of LEV on bone development and growth, particularly in children and adolescents.

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Seizures before pregnancy are a predictor for seizures during pregnancy, and catamenial epilepsy may also predict the course of seizures during pregnancy. A first epileptic seizure may also have implications for the pregnancy, depending on the seizure aetiology. Seizures affecting maternal awareness and responsiveness may have cardiac effects on the foetus and may impact on the weight of the newborn. Status epilepticus in pregnancy is rare, but isolated cases of perinatal death and malformations after status epilepticus have been reported in women on antiepileptic drugs. Seizures during delivery occur in about 2% of pregnancies of women with epilepsy, and case studies indicate that the foetal heart may be affected. However, a diagnosis of epilepsy is not an indication per se for caesarean delivery. A well-planned pregnancy can reduce the likelihood of seizures occurring.

Svalheim S, Luef G, Rauchenzauner M, Mørkrid L, Gjerstad L, Taubøll E. Cardiovascular risk factors in epilepsy patients taking levetiracetam, carbamazepine or lamotrigine. Acta Neurol Scand: 2010: 122 (Suppl. 190): 30–33. © 2010 John Wiley & Sons A/S. Objectives –  The aim of the study was to investigate risk factors for cardiovascular disease in patients with epilepsy using the new antiepileptic drug levetiracetam (LEV), compared with patients taking carbamazepine (CBZ) or lamotrigine (LTG). Methods –  Two hundred and twelve patients and 80 controls (age: 18–45 years) of both genders were included. The patients had been treated with either LEV (n = 52), CBZ (n = 87) or LTG (n = 73) monotherapy for at least 6 months. Total cholesterol (TC), low‐density lipoprotein (LDL) and high‐density lipoprotein (HDL) were measured. Smoking, drinking habits and physical activity were recorded and body mass index (BMI) was calculated. Results –  Neither LEV nor LTG altered TC, LDL or HDL. Both men and women using CBZ had higher TC, HDL and LDL than controls. LDL/HDL and TC/HDL ratios were unchanged. Women on CBZ and LTG had a greater BMI when compared with the control group. Patients with epilepsy recorded less physical activity and lower alcohol use than the controls. Conclusions –  Neither LEV nor LTG affected blood lipid levels, while patients treated with CBZ have higher cholesterol, HDL and LDL than controls. The patients were less physically active, and women on CBZ and LTG had higher BMI.

This investigation confirms that women with epilepsy have an increased frequency of menstrual disturbances compared to women without epilepsy. In women with high seizure frequency and in those on polytherapy, the frequency of menstrual disturbances are further increased. The highest frequency of menstrual disturbances occurred in women using valproate.

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