MON-191 In Vivo Overexposure to Non-esterified Fatty Acids Increases Circulating Androgen Levels in Normal Mongrel Dogs

Abstract Disclosure: C. Richer dit Laflèche: None. J. Faubert: None. F. Naimi: None. S. Bellanger: None. M. Battista: None. O. Benrezzak: None. A. Carpentier: None. J. Baillargeon: None. Background. The exact etiology of polycystic ovary syndrome is poorly understood, but studies suggest that lipotoxicity may be an important contributor. The aim of this study was to evaluate the effects of an in vivo overexposure to non-esterified fatty acids (NEFA) on changes in circulating androgen levels in a dog model, which was selected for its similarities with humans in steroidogenesis and energy metabolism. Methods. Female mongrel dogs (27.6 ± 2.9 kg) underwent a 17.5-hour metabolic protocol. During the first 8 hours (night period), dogs (n=6/group) received either a Intralipid-heparin 20% (IH; 0.02 ml/kg/min+0.5 U/kg/min) or a saline infusion (control group), followed by a standard meal at 8:30. Blood samples were drawn every 60 minutes during the night period (8h) and for 9 hrs post-meal (day period). Only 2 dogs (1/group) were in estrus. Changes from baseline were calculated as the ratio of mean levels during the period to the level measured at baseline (before IH infusion initiation) and compared between groups using Wilcoxon tests. Associations of androgen (testosterone, androstenedione, 17-hydroxyprogesterone (17-OHP), and DHEA) ratios with insulin and NEFA ratios during each test phase were tested using Spearman’s correlations. In addition, NEFA or insulin ratios were correlated with 17-OHP ratios corrected for potential confounders (individually, by dividing 17-OHP ratios by either cortisol, ACTH, insulin or NEFA ratios). Results. Baseline androgen levels were comparable between experimental groups. NEFA levels nearly doubled during the nocturnal IH infusion compared with the saline group (1.77 vs. 0.93-fold increase, p=0.015) and rapidly returned to normal after discontinuation. 17-OHP level ratios were significantly increased 1.5-fold in the IH group compared to the saline group both at night (0.86 vs. 0.56, p=0.026) and more than doubled during the day (0.90 vs. 0.42, p=0.009), without significant changes in other androgens. Nocturnal NEFA ratios correlated with both the nocturnal and diurnal 17-OHP ratios (rho=0.783, p=0.003; and rho=0.755, p=0.005); and diurnal insulin ratios correlated with 17-OHP ratios (rho=0.615, p=0.03). Correcting for nocturnal insulin ratios weakened the correlation between nocturnal 17-OHP ratios and NEFA ratios (rho=0.434, p=0.159), indicating a confounding effect. Moreover, adjusting for diurnal insulin ratios decreased the correlation between diurnal 17-OHP ratios and nocturnal NEFA ratios (rho=0.378, p=0.226). The association between diurnal 17-OHP ratios and diurnal insulin ratios was partly confounded by both night and day NEFA ratios (rho=0.336; and rho=0.224). Associations were mostly independent of ACTH and cortisol ratios. Conclusion. An acute in vivo elevation of NEFA using an IH protocol induces a significant increase in androgen production through a mechanism that is partially dependent on insulin. Presentation: Monday, July 14, 2025