DHEA model of PCOS selectively alters reproductive but not metabolic or behavioral phenotypes in female Long-Evans...

Polycystic Ovary Syndrome (PCOS) is the most common reproductive-metabolic disorder in women of reproductive age, yet preclinical models show considerable variability in their ability to capture its multiple diagnostic phenotypes and various non-diagnostic features. Androgen-based rodent models are widely used to mimic clinical hyperandrogenism; however, studies using dehydroepiandrosterone (DHEA), the most abundant circulating androgen in humans, have produced inconsistent findings across metabolic and behavioral domains. Here, we systematically evaluated a DHEA-based model of PCOS in female Long-Evans rats (N = 25), assessing reproductive, metabolic, and behavioral outcomes. To model a moderate metabolic challenge, relevant to the high comorbidity of PCOS and obesity, animals were given access to either a 10% fructose solution or water. We hypothesized that DHEA would induce PCOS-relevant phenotypes and that fructose consumption would exacerbate these effects. DHEA treatment increased ovarian testosterone levels and disrupted estrous cyclicity, consistent with key reproductive features of PCOS; however, no significant differences were observed in ovarian cyst count. In contrast, DHEA produced no robust effects across metabolic measures (including glucose tolerance, insulin resistance, and adiposity), anxiety-like behavior, or spatial working memory, and fructose exposure did not meaningfully exacerbate these outcomes. Together, these findings indicate that while DHEA reliably reproduces reproductive features of PCOS, it is insufficient to model broader metabolic and behavioral phenotypes under modest dietary challenge. These results highlight important limitations of this commonly used model and underscore the need for more robust metabolic manipulations when aiming to produce multi-system features of PCOS.