Androgen-induced Time-dependent Metabolic and Inflammatory Changes in a Rat Model of Polycystic Ovary Syndrome

Background: Polycystic Ovary Syndrome (PCOS) is the most common endocrine disorder among reproductive-age women, characterized by androgen excess, irregular ovulation, and metabolic dysfunctions such as insulin resistance, dyslipidemia, obesity, and hypertension. PCOS is also associated with systemic low-grade inflammation that correlates with visceral adiposity. While the etiology of PCOS remains unclear, elevated proinflammatory cytokines have been reported in women with PCOS, suggesting that chronic inflammation may play a critical role in the pathophysiology of the disease. Despite the significant metabolic and inflammatory involvement in PCOS, the onset and progression of metabolic disturbances, particularly those mediated by white adipose tissue (WAT), and the associated inflammatory changes, remain underexplored. Aim: Using a well-characterized hyperandrogenemic PCOS rat model, this study aims to test the hypothesis that androgen-induced obesity and increased inflammatory cytokines, progress in a time-dependent manner. Methods: Four-week-old female Sprague Dawley rats were randomly assigned to receive either vehicle or dihydrotestosterone pellets (DHT, 8 mg, s.c.) for 2, 4, 8, and 12 weeks (n=8-10/group). Body composition was measured using EchoMRI, while mesenteric, subcutaneous, and retroperitoneal (WAT) depots were measured by gravimetry. Body mass index (BMI) was calculated from the measured weights and heights [(body mass (gm)/ height (cm 2 )]. Plasma adiponectin was measured by ELISA, while random blood glucose levels were measured using glucose assay colorimetric kit. Twenty-three cytokines were assessed in the plasma by multiplex immunoassay (Bio-Plex rat 23-Plex Panel). Correlation analysis was performed using Pearson correlation coefficient. Results: DHT-treated rats showed significant (p<0.05) increases in body weight (1.3-fold) by week 4 and in BMI (1.1-fold) by week 2 that remained elevated until the end of the experimental period. DHT induced a transient decrease in fat mass, followed by a significant increase by week 12 (1.2-fold). Longer exposure to DHT (12-weeks) showed significant increases in the weights of mesenteric, subcutaneous, and retroperitoneal WAT depots, which were associated with lower adiponectin levels (25%) and higher random blood glucose levels (1.3-folds). Additionally, all assessed cytokines exhibited an initial decrease by week 2 of DHT exposure, followed by a gradual increase over the treatment period. Notably, eighteen cytokines—IL-1α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-10, IL-12, IL-17, G-CSF, GM-CSF, GRO/KC, IFN-γ, M-CSF, MIP-3α, RANTES, and TNF-α—were significantly elevated in the 12-week DHT-treated rats compared to controls. Interestingly, the findings showed significant correlation (p<0.005) between sixteen cytokines and the fat mass, with GM-CSF, TNF-α and IL-17 showing the highest correlation (r=0.4, 0.39 and 0.38, respectively). Conclusion and significance: Our study shows that androgen excess has a time-dependent impact on WAT expansion which is correlated with inflammation in female rats. Our findings suggest that promoting weight loss could provide a promising therapeutic approach for managing the chronic inflammation associated with PCOS. Supported by NIH grants R01HL171494 (LLYC), P50MD017338 (LLYC), R01HL144847 (DGR), P20GM121334 (DGR, SR, LLYC), P20GM104357, P01HL51971, AHA fellowship 24PRE1198302 (AA) This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.