Improving the Dehydroepiandrosterone Induced PCOS Rat Model: Interplay of Age, High Fat Diet, and Treatment Regimen on Reproductive and Metabolic Phenotypes

Polycystic ovary syndrome (PCOS) is a ubiquitous reproductive condition with triggering hallmarks such as glucose intolerance, hyperandrogenism, and dyslipidemia. Despite the existence of various PCOS animal models, an ideal model which could encompass all PCOS-specific phenotype is of dire need. Dehydroepiandrosterone (DHEA) induced PCOS rats are frequently employed; though, determining the superior model among pubertal and prepubertal rats, incorporation of high fat diet (HFD), and their sustainability remains uncertain. This study aims to examine the age factor, impact of HFD, and DHEA regimen in model development. Prepubertal and pubertal Sprague-Dawley rats were subcutaneously injected with DHEA (6 mg/kg and 60 mg/kg/day, respectively) with and without HFD up to 21 days. Serum testosterone, glucose, lipid profile, ovary morphology, and estrous cycle were evaluated. Following 21 days of treatment with DHEA, pubertal PCOS rats exhibited better reproductive phenotype than prepubertal rats. However, there was no significant difference in the lipid profile. Accordingly, both the age-group rats were concomitantly treated with DHEA and HFD for additional 3 weeks on alternate day basis after model development. The persistence of reproductive and metabolic features on treatment withdrawal were also simultaneously investigated by alienating the rats into continuous and stop dosing groups. The DHEA + HFD and DHEA treated pubertal rats in continuous dosing group showed significant PCOS features (p < 0.05) compared to stop dosing, prepubertal, and control groups. To conclude, continual dosing with DHEA on alternate days for 3 weeks is necessary to sustain metabolic and reproductive phenotypes of PCOS.