Abstract

Purpose: Valproic acid (VPA) treatment in female patients is suggested to be associated with the occurrence of a variety of endocrine side effects that include many characteristic symptoms of polycystic ovary syndrome (PCOS). The aim of our study was to prospectively measure whether VPA treatment was associated with the presentation of PCOS symptoms in rats, as well as determine whether this model could be used to examine the underlying mechanism by which these effects are induced. Methods: Normal estrus-cycling female rats (n=22) were treated perorally three times daily with VPA (300 mg/kg/day), divalproex sodium (DVS) (330 mg/kg/day), or phosphate-buffered saline for a minimum of 30 days. PCOS-associated symptoms (estrus cycle, weight, estradiol and testosterone levels, aromatase activity, and ovarian morphology) were assessed at baseline, mid-, and endpoint. Results: There was no significant difference in the mean number of days animals were in proestrus–estrus or metestrus–diestrus between the three groups. All groups of animals gained weight during the study and there were no appreciable differences in mean weight gain or leptin between groups. Total serum estradiol or testosterone levels and ovarian aromatase activity were not significantly different between the groups. The number of corpora lutea was not significantly different between the groups; however, cystic follicles were present in 50% of the drug-treated animals compared to 25% of saline-treated animals. Conclusions: VPA and DVS treatment were associated with a higher proportion of animals developing cystic follicles but did not mimic the VPA-induced PCOS that is observed in women. Thus, it appears that the rat has limited usefulness for modeling VPA-induced symptoms associated with PCOS.

Author Keywords: Bipolar disorder; Epilepsy; Polycystic ovary syndrome (PCOS); Rat; Valproic acid

Abbreviations: ANOVA, one-way analysis of variance; DVS, divalproex sodium; NADPH, nicotinamide adenine dinucleotide phosphate; PO, peroral; PBS, phosphate-buffered saline; PCOS, polycystic ovary syndrome; VPA, valproic acid

Article Outline

1. Introduction

2. Materials and methods

2.1. Animals

2.2. Drugs

2.3. Handling and study entry criteria

2.4. Baseline assessment

2.5. Treatment initiation

2.6. Midpoint and endpoint assessment

2.7. Vaginal smears

2.8. Blood collection

2.9. Serum hormone and VPA levels

2.10. Aromatase activity

2.11. Histology

2.12. Statistical analysis

3. Results

4. Discussion

4.1. VPA induction of PCOS

4.2. VPA-induced weight gain

4.3. Future directions and limitations of the model

5. Conclusion

Acknowledgements

References