Endocrine Abstracts

Background: Androgen excess and metabolic abnormality largely contribute to the pathogenesis of PCOS, which primarily precipitates ovarian dysfunction and infertility in reproductive-age women. Impaired mitochondrial function and epigenetic alteration have been linked to the development of PCOS. However, the therapeutic potential of histone deacetylase (HDAC) inhibition on ovarian mitochondrial dysfunction is unclear, especially in PCOS is unclear. Herein, the present study hypothesized that HDAC2i reverses ovarian mitochondrial dysfunction in experimental PCOS rat model, possibly through modulation of mitofusin-2 (Mfn2).

Methods: Eight-week-old female Wistar rats were randomized into four groups (n=5). PCOS was induced by 1 mg/kg letrozole (p.o.), administered for 21 days. Thereafter, the rats were treated with acetate (200 mg/kg; p.o.) for six weeks.

Results: The PCOS rats demonstrated excess body weight gain and ovarian mass, abnormal metabolic indices, androgen excess, multiple ovarian cysts, elevated anti-mullerian hormone and leptin and decreased SHBG, adiponectin and 17-β estradiol with corresponding increase in plasma and ovarian triglyceride as well as TGFβ-1. Additionally, mitochondrial abnormality, including lipid peroxidation, depleted NrF2, inflammation (TNF-α and NF-kB), elevated caspase-6 and ATP synthase, decreased HIF-1α and Mfn2 as well as elevated level of ovarian HDAC2 were observed rats with PCOS. Treatment with acetate reversed the alterations.

Conclusion: The present results collectively suggest that HDAC inhibition by acetate ameliorate ovarian mitochondrial abnormality, a beneficial effect that is accompanied by mitofusin-2 with consequent normalization of reproductive/metabolic endocrine profile and ovarian function. Perhaps, the present data provide hope for PCOS individuals that suffer infertility.