Prader-Willi Syndrome (PWS) is a complex genetic disorder with distinct developmental stages. In the first stage, PWS manifests as failure to thrive, hypotonia and feeding diffculty in infants. This is followed by hyperphagia, hypogonadism, and behavioral challenges which characterize the later stage of this disease. Hypothalamic-pituitary dysregulation is believed to be responsible for many aspects of the PWS phenotype, potentially contributing to several of the hallmark characteristics of this disorder. Changes in the ability of the central nervous system to respond to stressors by integrating and responding to insults to the homeostatic state are well documented in PWS, and adrenal insuffciency may further complicate endocrine dysfunction in PWS. The inability of PWS patients to respond to stress may be due to alterations at any or all three levels of the hypothalamo-pituitary-adrenal (HPA) axis. In this study, we sought to investigate the hypothesis that adrenal insuffciency in Magel2-deficient rats, a model of PWS, is at least in part due to loss of pituitary secretory capacity, since disruption of Magel2 expression, as is observed in PWS patients, is known to affect vesicular traffcking and secretion. To address this hypothesis, anterior pituitaries collected from Magel2-deficient and wild type rats were dispersed and aliquoted. The following day, cells were treated with either 0.1, 1.0, 10, 100, or 1000 nM of corticotrophin-releasing hormone (CRH). Following a 60 minute incubation, media were collected for the assessment of adrenocorticotropin (ACTH) by radioimmunoassay. We also collected pituitary cells for measurement of intracellular content of ACTH. Our results showed that cells from Magel2-deficient rats had decreased basal ACTH secretion, but remained responsive to CRH stimulation, albeit to a lesser degree than cells isolated from wild type animals. This suggests a pituitary deficiency in the response to hypothalamic factors (e.g. CRH) that normally control ACTH release. It is also possible that the other two levels of the HPA axis are altered in PWS. We now are investigating potential alterations in CRH prohormone processing or release (i.e. hypothalmic deficiencies) and responsiveness of the adrenal gland itself to ACTH administration. Furthermore, we have investigated circulating levels of cortisol in stressed and non-stressed animals to determine if the Magel2 rat model recapitulates the the aberrant stress response observed in PWS patients. Through this investigation of Magel2’s potential contributions to adrenal insuffciency, we hope to advance the understanding of PWS pathophysiology and lay the groundwork for developing new treatment strategies. This work has been paid for through a grant from the Foundation for Prader-Willi Research. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.