The Anti-Epileptic Drugs Phenytoin and Valproate Produce Reproductive Endocrine Dysfunction among Reproductive Endocrine Dysfunction among Female Rats through its Effects on Progesterone and its 5 Alpha-Reduced Metabolites
Date of Award
Bachelor of Science
Background: Many people with seizure disorder experience reproductive endocrine dysfunction (RED). The extent to which RED is due to intrinsic aspects of seizure disorder, and/or therapies used to manage epilepsy, is not well understood. Many anti-epileptic drugs (AEDs), such as phenytoin or valproate, can have effects that alter endocrine status. Phenytoin is a cytochrome p450 enzyme-inducing drug. Valproate is a cytochrome p450 enzyme-reducing AED. Objective: To evaluate the effects and mechanism of some AEDs on RED in a rodent model. Hypothesis: If AEDs produce RED in part by altering the activities of cytochrome p450 enzymes, then AEDs that disrupt estrous cyclicity and/or sexual behavior will alter levels of steroids, that are products of p450 enzymes, in brain areas mediating such responses. Methods: Phenytoin (50 mg/kg, IP), valproate (165 mg/kg, IP), or placebo (40% propylene glycol and 10% ethanol in distilled water, IP) was administered to gonadally-intact, female Long-Evans rats, twice daily for four weeks. Estrous cyclicity was monitored daily. After 4 weeks, when rats were in proestrous, they were tested for sexual receptivity. Immediately after completion of sex testing, brain and trunk blood were collected for later radioimmunoassay. Ovaries and uterus were collected and weighed as a measure of trophic effects. Results: Phenytoin and valproate disrupted the estrous cycle and increased aggressive behavior of rats. The levels of 5-pregnan-3-ol-20-one (3,5-THP) in the hippocampus and hypothalamus of phenytoin-treated rats were significantly lower than in controls. Levels of progesterone (P4) in plasma were lower among rats administered valproate compared to the controls. Conclusion: AEDs, such as phenytoin and valproate, disrupted estrous cylicity and sexual behavior of female rats, and reduced levels of hypothalamic, hippocampal, and circulating progestogens, which are products of p450 enzymes.
Haddad, Fareed, "The Anti-Epileptic Drugs Phenytoin and Valproate Produce Reproductive Endocrine Dysfunction among Reproductive Endocrine Dysfunction among Female Rats through its Effects on Progesterone and its 5 Alpha-Reduced Metabolites" (2010). Biological Sciences. 7.