Neurologist-induced sexual dysfunction: Enzyme-inducing antiepileptic drugs.

Sex remains an awkward area for most patients and physicians to discuss, not routinely covered during clinical visits despite its importance to the individual and the frequency of disorders. Central and peripheral nervous system diseases often compromise libido and sexual function, either directly or by psychological reactions. Further, medications prescribed by neurologists and other physicians can be the culprits.



Depression and sexual dysfunction are underdiagnosed and undertreated. Neurologists focus on sensorimotor and cognitive problems but may not discern limbic disorders that affect emotional well-being. For example, in one study of patients with refractory epilepsy, depression was common (54%), severe (19% with suicidal thoughts), underdiagnosed (37%), and largely untreated (17% taking antidepressants). Mood, not seizure frequency, was a powerful predictor of quality of life. The modest strides in diagnosing and treating depression in neurologic disorders are not paralleled for sexual function. Indeed, we may do more harm than good for our patients’ sexual function. Many medicines we prescribe, such as enzyme-inducing antiepileptic drugs (AEDs), propranolol, and selective serotonin reuptake inhibitors (SSRIs) can reduce sexual interest and impair the quality of sexual experiences.



The study of health issues for women with epilepsy has increased dramatically during the past decade. There are now large registries and studies tracking birth defect rates among mothers taking AEDs during pregnancy as well as the development of their children. Others focus on bone health, contraceptive efficacy, pregnancy, and sexual function. The Epilepsy Foundation has an initiative on Women and Epilepsy, and there are numerous academic symposia and journal supplements on the health of women with epilepsy. No registries track the effect of paternal use of AEDs on the fetus, and no academic symposia focus on health issues for men with epilepsy. Health issues for men with epilepsy is a neglected area of study.



Herzog et al. report in this issue of Neurology that carbamazepine and phenytoin decreased testosterone bioactivity in men and that this correlated with, and likely caused, diminished libido and sexual function. Lamotrigine, by contrast, had no effect on testosterone and sexual function. AEDs that induce hepatic enzymes enhance synthesis of sex hormone binding globulin and thereby reduce free (bioactive) testosterone levels. Free testosterone levels were thus strongly correlated with sexual function scores (i.e., lower free testosterone, lower sexual function scores). This result and its proposed mechanism are supported by other studies.



Other AEDs can affect testosterone levels and sexual function. Primidone use was associated with higher rates of decreased libido and impotence than carbamazepine or phenytoin. Valproate can increase testosterone as well as estrogen levels. Unlike carbamazepine, oxcarbazepine does not decrease free testosterone levels or increase sex hormone binding globulin.



Notably, Herzog et al. found that 20% of men with localization-related epilepsy taking no AEDs have abnormally low sexual function. This supports the idea that epilepsy has biologic or psychological effects on sexual function. The lamotrigine-treated group had only a 4% frequency of abnormally low sexual function. Could lamotrigine improve sexual function? Other reports suggest that it might. Additional data are needed to explore this possibility—is it an effect of mood stabilization, of seizure control in addition to the absence of an effect on hormone levels?
The findings of this multicenter study are strengthened by its sample size compared with many previous studies, as well as the assessment of multiple endocrine and behavioral parameters. However, subgroups were relatively small (e.g., only 10 subjects taking no AEDs), and many other potential physiologic and behavioral parameters (e.g., mood) were not assessed. Despite these limitations, their data provide strong support for the hypothesis that enzyme-inducing AEDs can impair sexual function. The study did not address why sexual function is often impaired in men with epilepsy who do not take medications. This important topic deserves further study because it may help us to identify subjects at risk and suggest treatment strategies.



The study of Herzog et al. has implications for neurologists: ask about sexual function in men and women with epilepsy, consider medication-induced problems (e.g., carbamazepine, phenytoin, primidone, propranolol, SSRIs), and make referrals for or treat sexual dysfunction. The physician should routinely ask about sexual function; many patients do not report problems.



For patients with epilepsy, the scales are further tipping away from the use of enzyme-inducing AEDs: they impair bone health; are likely to have drug interactions, including oral contraceptive failure; and reduce sexual function. Herzog et al. remind us: do no harm, especially if alternatives are available. For example, it may be relatively simple to convert the patient’s treatment to an AED that does not induce hepatic enzymes. Patients with epilepsy and depression are at additional risk, because between 30% and 60% of SSRI-treated patients experience sexual dysfunction.



Although this adverse effect may resolve within 4 to 6 weeks, if it persists, dose reduction, altering the timing of the daily dose, or not taking the drug for 2 days (for sertraline and paroxetine) may be helpful. Conversion to other antidepressant agents should be considered: bupropion and nefazodone cause sexual dysfunction in 10% or less of patients. Bupropion may promote seizures, however, so should be used with caution. Counseling should always be considered, especially if psychological or marital issues are suspected. Medical therapies for erectile dysfunction (sildenafil and vardenafil) seem safe for men with epilepsy and other neurologic disorders. If no contraindications are present, patients should be allowed to use them. Finally, patients may benefit from referral to specialists such as urologists, gynecologists, psychiatrists, or sex therapists.



Although efficacy remains the basis of AED therapy, there are other important issues that require attention. The quality of life for persons with epilepsy is enhanced by attending to mood and adverse effects of AEDs, especially related to sexual function. During the past decade, the advances in research on health issues for women with epilepsy have not been paralleled for men with epilepsy. We need to define and study the problems that afflict men with epilepsy. Many problems, such as bone health and sexual function, are not limited to women.