EPILEPSY EFFECTS ON REPRODUCTIVE HORMONES Reproductive Dysfunction in Epilepsy

Reproductive dysfunction is unusually common among women and men who have epilepsy. It is generally associated with reproductive endocrine disorders that may be causally related. Both epilepsy and antiepileptic drug (AED) use have been implicated in the pathophysiology. Epilepsy effects may vary with the laterality and focality of epileptiform discharges. AED effects vary in relation to their particular properties, especially the presence or absence of enzyme induction. Reproductive steroids have neuroactive properties that can impact seizure occurrence and may provide another modality of treatment. Perhaps one-third of women with epilepsy show notable levels of catamenial exacerbation characterized by one or more of three identified patterns. Women with hormonally sensitive seizures may respond to hormonal treatment with cyclic progesterone supplement or with abolition of their menstrual cycles using parenteral depomedroxyprogesterone or gonadotrophinreleasing hormone analogue treatments. Hypogonadal men may respond to testosterone supplement with or without aromatase inhibitor with clinically important improvement in sexual function, mood, and, perhaps, seizure control. Changes in thyroid function tests are common in men and women with epilepsy, especially in association with enzyme-inducing AED use, but clinically significant thyroid disorders are rarely found to be the consequence of AED use. Epilepsy is associated with disruption of the normal diurnal rhythm and orderly pulsatile secretion in the hypothalamic-pituitary-adrenal axis. Cortisol levels are elevated transiently postictally and to a lesser amount interictally. Elevation of excitatory neuroactive adrenal steroids may contribute to stress-related seizures. Continuum Lifelong Learning Neurol 2009;15(2):37–66. EPILEPSY EFFECTS ON REPRODUCTIVE HORMONES Reproductive Dysfunction in Epilepsy Reproductive dysfunction is unusually common among women and men who have epilepsy (Herzog, 1989; Herzog et al, 1986a; Herzog et al, 1986b). It generally manifests as menstrual disorder, hirsutism, and infertility in women (Herzog et al, 1986a) and loss of libido, impotence, and infertility in men (Herzog et al, 1986b). Reproductive dysfunction is often associated with and is the consequence of reproductive endocrine disorders (Herzog, 1989; Herzog et al, 1986a; Herzog et al, 1986b). Both epilepsy and antiepileptic drugs (AEDs) have been causally implicated (Herzog, 1989; Herzog et al, 1986a; Herzog et al, 1986b; Herzog et al, 2005; Isojärvi et al, 1993b). Epilepsy and AEDs can target a number of substrates to affect hormone levels. These include the limbic system, hypothalamus, pituitary, peripheral endocrine glands, liver, and adipose tissue (Herzog, 2002; Herzog et al, 2003). Reproductive endocrine disorders can 37 Relationship Disclosure: Dr Herzog has received research support from Abbott Laboratories, AstraZeneca Pharmaceuticals, GlaxoSmithKline, Inc., and the NIH. Unlabeled Use of Products/Investigational Use Disclosure: Dr Herzog discusses the use of progesterone in the treatment of seizures in women with catamenial epilepsy. Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited. lead not only to reproductive dysfunction but also to exacerbation of epilepsy (Herzog, 2002; Herzog et al, 2003). An understanding of these relationships and their underlying neurologic and neuroendocrine mechanisms is important to the comprehensive management of women and men with epilepsy. Women with epilepsy. Hospitalbased (Hamed et al, 2007; Herzog et al, 1986a; Herzog et al, 2003) and community-based (Svalheim et al, 2003) studies have shown that menstrual disorders are more common among women with epilepsy than in the general population. Menstrual disorders can be categorized as amenorrhea (no menses for 6 months), oligomenorrhea (cycle intervals greater than 32 days), polymenorrhea (cycle intervals less than 26 days), abnormal variation in cycle intervals (greater than 4 days), and menometrorrhagia (heavy menses and bleeding between menses (Herzog and Friedman, 2001). Cycle intervals between 26 and 32 days, rather than the currently popular broader range of 21 to 35 days, should be considered normal in women with epilepsy because ovulatory rates drop substantially and statistically significantly, ie, from greater than 75% to less than 50%, outside of the 26-day to 32-day range (Herzog and Friedman, 2001). Ovulation is considered an important criterion in this population because anovulatory cycles are associated with greater seizure frequency (Bäckström, 1976; Herzog et al, 1997). Menstrual disorders, using the above definition, are currently estimated to occur in one-third of women with epilepsy as compared with 12% to 14% of women in the general population (Herzog, 2002; Herzog and Friedman, 2001). More than one-third of cycles in women with localizationrelated epilepsy are anovulatory, as compared with 8% to 10% in controls (Cummings et al, 1995; Herzog and Friedman, 2001; Lofgren et al, 2007; Morrell et al, 2002). Conflicting evidence exists as to whether anovulatory cycles are more common with localizationrelated epilepsy or primary generalized epilepsy (Cummings et al, 1995; Lofgren et al, 2007; Morrell et al, 2002). Women with idiopathic epilepsy are only 37% as likely as unaffected female siblings to become pregnant (Schupf and Ottman, 1994). This finding is not attributable to marital rate or to seizure type, age at onset, or family history of epilepsy (Schupf and Ottman, 1994). In comparison with the general female population, fertility is reduced to 69% to 85% of the expected number of offspring among married women with epilepsy, primarily temporolimbic epilepsy (TLE) (Dansky et al, 1980; Webber et al, 1986). Reproductive endocrine disorders. The most common reproductive endocrine disorder in women with epilepsy as well as women in the general population is polycystic ovary syndrome (PCOS) (Bilo et al, 1988; Herzog et al, 1986a; Herzog and Schachter, 2001). PCOS occurs in 10% to 20% of women with epilepsy compared with 5% to 6% of women in the general population (Herzog, 2002; Herzog et al, 2003; Herzog and Schachter, 2001; Webber et al, 1986). This increased rate of occurrence may be of considerable medical significance because PCOS is associated with a higher prevalence of migraine, emotional disorders, diabetes, cardiovascular disease, and female cancers in the general population (Herzog and Schachter, 2001). PCOS is probably not a single nosologic entity, but rather the common end point for a number of pathophysiologic mechanisms, some of which may be attributable to epilepsy itself (Bilo et al, 1988; Herzog et al, 1986a; Herzog et al, 2003; Herzog and Schachter, 2001) or to the use of AEDs, most notably valproate (Eagleson et al, 2000; Isojärvi et al, 1993b; Lofgren et al, 2007; Morrell et al, 2002). PCOS represents the failure Continuum Lifelong Learning Neurol 2009;15(2) 38 KEY POINTS