Comparison of Reproductive Effects of Levetiracetam and Valproate Studied in Prepubertal Porcine Ovarian Follicular Cells

Taubøll, Erik; Gregoraszczuk, Ewa Ł.; Tworzydø, Anna; Wójtowicz, Anna K.; Ropstad, Erik

doi:10.1111/j.1528-1167.2006.00668.x

Cited by 41 publications

(40 citation statements)

References 15 publications

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“…The authors suggested that VPA may act as an apoptotic agent in small and medium sized follicles, providing an potential mechanistic link between VPA and PCO [163,164]. More studies are needed to test this hypothesis and clarify whether a causal relationship between VPA use and gonadotropin dysregulation exists.…”

Section: Gonadotropinsmentioning

confidence: 87%

Valproate and Neuroendocrine Changes in Relation to Women Treated for Epilepsy and Bipolar Disorder: A Review

Reynolds¹,

Sisk²,

Rasgon³

2007

CMC

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Valproic acid (2-n-propylpentanoic acid, VPA) is well-established as a mood-stabilizer for bipolar disorder, in addition to its application as a treatment in neurological disorders such as epilepsy, migraine headaches, and chronic neuropathic pain. Its mechanisms of actions in any of the disorders have not yet been fully elucidated but currently include GABA-ergic inhibitory effects, the suppression of NMDA-mediated excitatory neurotransmission, and possibly effects on monoamines and cerebral glucose metabolism. Given the rising use of VPA by women of reproductive age for various conditions it is increasingly important to understand how VPA affects reproductive and metabolic function in women, yet a number of key issues regarding VPA use in women of reproductive age remain unclear. These include the question of whether VPA use is associated with the development of polycystic ovary syndrome (PCOS)-like features (such as elevated androgen concentrations and/or chronic anovulation). The metabolic effects of VPA use, particularly on insulin sensitivity and weight gain, are also important to understand. Lastly, questions of VPA use during pregnancy and lactation require continued attention. This article reviews the current understanding of VPA's mechanisms of action, effects on the reproductive and metabolic system, and teratogenic qualities, highlighting important future areas of study.

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Section: Gonadotropinsmentioning

confidence: 87%

Valproate and Neuroendocrine Changes in Relation to Women Treated for Epilepsy and Bipolar Disorder: A Review

Reynolds¹,

Sisk²,

Rasgon³

2007

CMC

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“…Whether this is secondary to disturbances in bone tissue maturation (e.g., suboptimal mineralization of cartilage), related to a direct negative influence of LEV on chondroclasts (Nordahl et al, 1998; Nordahl et al, 2000) or to other unidentified factors, remains to be established. Previous studies suggest that prepubertal rather than fertile animals are susceptible to the effects of LEV on endocrine function (Taubøll et al, 2004; Svalheim et al, 2005; Taubøll et al, 2006). Whether these influences of LEV on the endocrine system are responsible for alterations in the epiphyseal growth plate structure or function, with impairment of bone growth as a possible outcome (i.e., particularly in children and adolescents), requires further investigation.…”

Section: Discussionmentioning

confidence: 99%

Levetiracetam, Phenytoin, and Valproate Act Differently on Rat Bone Mass, Structure, and Metabolism

Svalheim²,

et al. 2007

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Summary:Purpose: Long-term treatment with antiepileptic drugs (AEDs) is associated with increased risk of fractures. Phenytoin (PHT) and valproate (VPA) have both been suggested to influence bone health, whereas levetiracetam (LEV) is scarcely studied. The present study compares the effect of these AEDs on bone mass, biomechanical strength, and bone turnover in rats.Methods: Female rats received PHT (50mg/kg), VPA (300mg/kg), or LEV (50 and 150mg/kg) for 90 days. Dissected femurs were analyzed using dual energy x-ray absorptiometry (DXA), three-point cantilever bending, and histomorphological evaluation. Serum levels of biochemical bone turnover markers were monitored using immunoassay quantification.Results: PHT and VPA reduced bone mineral density (BMD) and content (BMC) in one or more bone compartments, whereas LEV did not. VPA induced increased bone turnover, whereas modest changes were observed for PHT. Interestingly, low-dose LEV was associated with reduced biomechanical strength of the femoral neck (mainly trabecular bone). In addition, low-dose LEV treatment resulted in significantly reduced levels of serum osteocalcin, a marker of bone formation. Histomorphological analyses indicated increased retention of cartilage remnants at the growth plate metaphysis of rats treated with low-dose LEV vs. controls.Conclusions: PHT, VPA, and LEV exert differential effects on bone mass and strength, suggesting different mechanisms of action. The weakening effect of low-dose LEV on the femoral neck, despite a constant BMD, suggests a primary effect on bone quality. These findings warrant further human studies of possible adverse effects of LEV on bone development and growth, particularly in children and adolescents.

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“…These findings imply that VPA causes reproductive endocrine dysfunction independently of epileptic activity itself. Additionally, there are some reports on VPA regarding reproductive endocrine dysfunction using cultured theca cells from rat ovaries (Fisseha et al, 2010) and granulosa cells from human and porcine ovaries (Tauboll et al, 2003(Tauboll et al, , 2006. Although these in vitro experiments provide new insights to reproductive endocrine dysfunction induced by VPA, the results are not directly applicable to evaluation of the effects of VPA on the fol-licular organization and entire synthetic pathway of steroid hormones, because the culture systems of these isolated cells do not have complete components of ovarian follicles.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of ovarian toxicity of sodium valproate (VPA) using cultured rat ovarian follicles

et al. 2012

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-Sodium valproate (VPA) is a major antiepileptic drug that is widely used for the treatment of epilepsy as well as other neuropsychiatric diseases. The present study was conducted to evaluate the ovarian toxicity of VPA using cultured rat ovarian follicles. Secondary follicles were isolated from the ovaries of 14-day-old female rats and cultured for 48 hr with VPA (0, 0.2, 1.0, and 5.0 mM). At 0, 24, and 48 hr of VPA treatment, follicular diameters were measured. After the culture, viability of follicles and expression of aromatase in the follicles were assessed, and progesterone, androstenedione, testosterone, and estradiol levels in culture media were measured. At all concentrations of VPA, follicular development was suppressed, and androstenedione, testosterone, estradiol, and combined levels of all steroid hormones tended to decrease in association with suppression of aromatase expression in granulosa cells. Additionally, the suppression of follicular development was associated with decreased viability of follicles and an increased progesterone level at 5.0 mM of VPA. The decrease in the combined levels of all steroid hormones implies that VPA suppresses the synthetic pathway from cholesterol to estradiol including de novo synthesis of cholesterol. In conclusion, VPA induces ovarian toxicity via suppression of development and abnormal steroid hormone synthesis in cultured rat ovarian follicles.

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Comparison of Reproductive Effects of Levetiracetam and Valproate Studied in Prepubertal Porcine Ovarian Follicular Cells

Cited by 41 publications

References 15 publications

Valproate and Neuroendocrine Changes in Relation to Women Treated for Epilepsy and Bipolar Disorder: A Review

Valproate and Neuroendocrine Changes in Relation to Women Treated for Epilepsy and Bipolar Disorder: A Review

Levetiracetam, Phenytoin, and Valproate Act Differently on Rat Bone Mass, Structure, and Metabolism

Evaluation of ovarian toxicity of sodium valproate (VPA) using cultured rat ovarian follicles

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