[Endocrine effects of antiepileptic drugs].
Both seizures and antiepileptic drugs may induce disturbances in hormonal system. Regarding endocrine effects of anticonvulsants, an interaction of these drugs with gonadal, thyroid, and adrenal axis deserves attention. Since majority of antiepileptic drugs block voltage dependent sodium and calcium channels, enhance GABAergic transmission and/or antagonize glutamate receptors, one may expect that similar neurochemical mechanisms are engaged in the interaction of these drugs with synthesis of hypothalamic neurohormones such as gonadotropin-releasing hormone (GnRH), thyrotropin-releasing hormone (TRH), corticotropin-releasing hormone (CRH) and growth hormone releasing hormone (GHRH). Moreover some antiepileptic drugs may affect hormone metabolism via inhibiting or stimulating cytochrome P-450 iso-enzymes. An influence of antiepileptic drugs on hypothalamic-pituitary-gonadal axis appears to be sex-dependent. In males, valproate decreased follicle-stimulating hormone (FSH) and luteinizing hormone (LH) but elevated dehydroepiandrosterone sulfate (DHEAS) concentrations. Carbamazepine decreased testosterone/sex-hormone binding globulin (SHBG) ratio, whereas its active metabolite--oxcarbazepine--had no effect on androgens. In females, valproate decreased FSH-stimulated estradiol release and enhanced testosterone level. On the other hand, carbamazepine decreased testosterone level but enhanced SHBG concentration. It has been reported that carbamazepine, oxcarbazepine or joined administration of carbamazepine and valproate decrease thyroxine (T4) level in patients with no effect on thyrotropin (TSH). While valproate itself has no effect on T4, phenytoin, phenobarbital and primidone, as metabolic enzyme inducers, can decrease the level of free and bound thyroxine. On the other hand, new antiepileptics such as levetiracetam, tiagabine, vigabatrine or lamotrigine had no effect on thyroid hormones. With respect to hormonal regulation of metabolic processes, valproate was reported to enhance leptin and insulin blood level and increased body weight, whereas topiramate showed an opposite effect. In contrast to thyroid and gonadal hormones, only a few data concern antiepileptic drug action in HPA axis. To this end, no effect of antiepileptic drugs on adrenocorticotropic hormone (ACTH)/cortisol circadian rhytmicity was found. Valproate decreased CRH release in rats, whereas lamotrigine stabilized ACTH/cortisol secretion. Moreover, felbamate was found to inhibit stress-induced corticosterone release in mice. Interestingly, recent data suggest that felbamat and some other new antiepileptic drugs may inhibit transcriptional activity of glucocorticoid receptors. Summing up, the above data suggest that traditional antiepileptic drugs may cause endocrine disturbances, especially in gonadal hormones.
Leśkiewicz
Monika
M
Zakład Neuroendokrynologii Doświadczalnej Instytutu Farmakologii Polskiej Akademii Nauk w Krakowie. leskiew@if-pan.krakow.pl
Budziszewska
Bogusława
B
Lasoń
Władysław
W
D000927:Anticonvulsants / Q000009:adverse effects*; D002220:Carbamazepine / Q000031:analogs & derivatives / Q000494:pharmacology; D004700:Endocrine System Diseases / Q000209:etiology*; D004958:Estradiol / Q000378:metabolism; D005260:Female; D006728:Hormones / Q000378:metabolism*; D006801:Humans; D000077287:Levetiracetam; D008297:Male; D000078330:Oxcarbazepine; D010889:Piracetam / Q000031:analogs & derivatives / Q000494:pharmacology; D012640:Seizures / Q000150:complications / Q000188:drug therapy / Q000378:metabolism; D013739:Testosterone / Q000378:metabolism; D013963:Thyroid Hormones / Q000378:metabolism; D014635:Valproic Acid / Q000494:pharmacology
D000927:Anticonvulsants; D006728:Hormones; D013963:Thyroid Hormones; D002220:Carbamazepine; D013739:Testosterone; D000077287:Levetiracetam; D004958:Estradiol; D014635:Valproic Acid; D000078330:Oxcarbazepine; D010889:Piracetam