Differential Effects of Antiepileptic Drugs on Neuroactive Steroids in Men with Epilepsy

Abstract

Summary:Purpose: To compare serum levels of neuroactive steroids among men with epilepsy who take various antiepileptic drugs, untreated men with epilepsy and normal controls (NC).Methods: Subjects were 85 men with localization-related epilepsy [unmedicated >6 months (No Rx)-10, carbamazepine (CBZ)-25, phenytoin (PHT)-25, lamotrigine (LTG)-25] and 25 NC. Sexual function scores (S-Score), hormone levels [dehydroepiandrosterone sulfate (DHEAS), bioactive (BA) testosterone (T), estradiol (BAE), and androstanediol (BAL)] and the ratios of inhibitory to excitatory neuroactive metabolites of T, i.e., BAL/BAE, were compared among groups.Results: S-scores, DHEAS, and bioactive testosterone (BAT) were significantly (p < 0.05) lower and BAL and BAL/BAE were significantly higher among CBZ and PHT groups than among NC and LTG groups. LTG did not differ from NC in any of these measures. BAT correlated significantly with BAL/BAE for PHT (r = 0.44, p = 0.02) and CBZ (r = 0.42, p = 0.03) but not for NC (r = 0.03, p = NS) and LTG (r = 0.06, p = NS) groups.Conclusions: In comparison to LTG, enzyme inducing AEDs (CBZ, PHT) are associated with a more favorable neuroactive steroid balance (lower DHEAS and higher BAL/BAE) for seizure management, but at the expense of reduced serum bioavailable testosterone levels and sexual function. Key Words: Epilepsy-Reproductive-NeurosteroidsEndocrine-Men.Sexual dysfunction is unusually common among men with epilepsy and has been related to hypogonadism (Herzog et al., 2005). Androgens play an important role in sexual function (Herzog et al. 2005). Androgens also have precursors and metabolites that can influence neuronal excitability and seizures (Paul and Purdy, 1992;Rhodes and Frye, 2004;Smith, 1989;Wong and Moss, 1992). Dehydroepiandrosterone, a weak androgen, becomes highly neuroexcitatory when it is metabolized to a sulfated ester dehydroepiandrosterone sulfate (DHEAS) (Paul and Purdy, 1992). Aromatization of testosterone (T) produces estradiol (E), a highly neuroexcitatory steroid (Smith, 1989;Wong and Moss, 1992). Reduction of testosterone produces androstanediol (AL), a potent inhibitory GABAergic steroid (Rhodes and Frye, 2004).Some antiepileptic drugs (AEDs) alter the synthesis, binding, and metabolism of androgens (Herzog et al., ). This may result in different levels and ratios of excitatory and inhibitory neuroactive steroids. A systematic comparison of the effects of various AEDs on neuroactive steroids could help identify the mechanisms by which AEDs might act to suppress seizures. This investigation compared the effects of various AEDs on sexual function, reproductive steroids and some neuroactive precursors and metabolites of androgens in men with localization-related epilepsy (LRE) and normal controls (NC). Effects on sexual function and bioactive testosterone (BAT) were published previously (Herzog et al., 2005) and will be reviewed solely to place the current neuroactive steroid findings in context. METHODS Study design and subjectsThe study design was an unrandomized, observ...

The Testosterone-Derived Neurosteroid Androstanediol Is a Positive Allosteric Modulator of GABAA Receptors

“…Studies in animals have shown that decreased testosterone is associated with higher incidences of seizures and replacement with testosterone attenuates seizures (Thomas and McLean, 1991;Reddy, 2008). Because testosterone elevates seizure threshold via androstanediol (Reddy, 2004b), a decrease in testosterone levels, such as occur in hypogonadism and enzyme-inducing drug therapy (Herzog et al, 2006), may therefore contribute to seizure exacerbation. The introduction of finasteride, a 5␣-reductase inhibitor that blocks androstanediol synthesis, for the treatment of male pattern baldness led to recurrent seizures.…”

Mass spectrometric assay and physiological–pharmacological activity of androgenic neurosteroids

“…Enzyme inducing AEDs (carbamazepine and phenytoin) are associated with a more favorable neurosteroid balance (lower DHEAS and higher androstanediol/estradiol ratio) for seizure management. Moreover, a markedly reduced serum bioavailable testosterone levels and sexual function was reported (Herzog et al, 2006). Two-week phenytoin treatment has been shown to affect the hippocampal levels of testosterone, CYP isoforms, and AR expression in a mouse model (Meyer et al, 2006).…”

“…Recently, Herzog et al(2006) compared serum levels of neurosteroids among men with epilepsy who take various AEDs. Enzyme inducing AEDs (carbamazepine and phenytoin) are associated with a more favorable neurosteroid balance (lower DHEAS and higher androstanediol/estradiol ratio) for seizure management.…”

Ghrelin Regulation in Epilepsy

“…These alterations are likely related to a liver enzyme induction, which leads to an increase of the sex hormone-binding globulin and a reduction of the bioavailability of serum-free sex hormone levels in both genders (Opaleke & Helmers, 2007). In contrast, testosterone and androgens are elevated in association with valproate treatments (Herzog et al, 2006;Isojarvi et al, 2004). Clinical data on gonads dysfunctions led to investigate the role of sex hormones on epilepsy mechanisms.…”