Faculty Bibliography

Alexander von Humboldt's early nineteenth-century explorations of the Andes established foundational methods in biogeography and environmental science, emphasizing measurement, spatial integration, and the interdependence of natural systems. Nearly two centuries later, southern Ecuador became the site of a landmark discovery in endocrine genetics: a population with growth hormone receptor deficiency (Laron syndrome) characterized by severe insulin-like growth factor-1 (IGF-1) deficiency. This article examines the historical and scientific continuity of observation in the Ecuadorian Andes, linking Humboldt's integrative natural philosophy with modern approaches to human molecular physiology. While no direct historical connection exists between Humboldt's writings and the later identification of this endocrine condition, the shared geographic setting underscores the enduring scientific value of place-based investigation.

Prader-Willi syndrome (PWS) is a rare genetic disorder marked by metabolic, endocrine, and behavioral challenges, with hyperphagia as a central feature contributing to significant health risks. Diazoxide choline extended-release (DCCR; VYKAT™ XR) is a once-daily adenosine triphosphate (ATP)-sensitive potassium channel activator recently approved for the treatment of hyperphagia in individuals with genetically confirmed PWS aged 4 years and older. As this novel therapy enters clinical practice, clinicians require practical guidance on appropriate use. This manuscript provides actionable recommendations for patient selection, baseline assessments, and strategies for optimizing comorbid conditions prior to initiation. Structured, weight-based dosing and titration protocols are outlined, along with recommendations for monitoring glycemia and edema and managing common adverse events (AEs), including hyperglycemia, peripheral edema, and rash. Special considerations are discussed for patients with diabetes, cardiopulmonary risk factors, and those on concomitant medications with potential drug-drug interactions. The guidance is informed by data from the phase 3 DESTINY-PWS program, long-term extension studies, and real-world clinical experience. Emphasis is placed on early identification and management of AEs and the importance of a multidisciplinary approach to care. These recommendations aim to support clinicians in safely and effectively incorporating DCCR into the management of PWS, improving outcomes for affected individuals. Ongoing research and real-world evidence will continue to refine best practices and address remaining gaps in knowledge.

CONTEXT:The hallmark condition of Prader-Willi syndrome, a rare, genetic neurobehavioral/metabolic disorder is life-threatening hyperphagia. OBJECTIVE:We assessed the efficacy and safety of recently FDA-approved diazoxide choline extended-release (DCCR) tablets for the treatment of hyperphagia in adults and children four years of age and older with Prader-Willi syndrome. METHODS:We conducted a 16-week, randomized withdrawal study in children and adults with Prader-Willi syndrome and hyperphagia. Participants who previously completed randomized (13-week DCCR or placebo) and open-label (2.5-4.5 years DCCR) studies were randomized one:one to receive once-daily DCCR or placebo. The primary endpoint was Hyperphagia Questionnaire for Clinical Trials (HQ-CT) total score change from baseline to 16 weeks. Secondary endpoints included Clinical Global Impression of Severity (CGI-S) and Improvement (CGI-I); exploratory endpoints included weight and body mass index (BMI) z-score. RESULTS:Seventy-seven participants were randomized (DCCR:38; placebo:39). Statistically significant increases in HQ-CT from baseline to week 16 were observed with placebo versus DCCR (least square [LS] mean [standard error] change 7.6 [1.09] with placebo and 2.6 [1.12] with DCCR; P=0.0022). CGI scores favored DCCR but were not significantly changed. Consistent with the hyperphagia response, the placebo cohort gained more weight and increased their BMI z-score more than the DCCR cohort (LS mean weight difference (95% confidence interval) -1.6 kg (-3.1, -0.1); LS mean z-score difference -0.09 (-0.17, -0.01). Adverse events were similar with both treatments, with no serious adverse events in the DCCR arm. CONCLUSIONS:Continued DCCR treatment was superior to placebo for hyperphagia. DCCR appears to offer meaningful therapeutic benefits for people with Prader-Willi syndrome.

BACKGROUND/UNASSIGNED:Endocrine findings in premature adrenarche have been characterized by elevated DHEAS levels in the past. METHODS/UNASSIGNED:We reviewed 44 female patients, aged 4 to 8 years, with premature adrenarche who were seen at our center between 2019 and 2023. Data were collected on the traditional androgens (DHEA and DHEAS) and novel 11-oxo-androgens. 11-oxo-androgens, DHEAS, and DHEA levels were measured using Liquid chromatography/tandem mass spectrometry (LC/MS-MS) assays in commercial laboratories (Lab Corp). RESULTS/UNASSIGNED:The majority, 89% of patients from the youngest group (4-5year olds), presented with apocrine odor as the only symptom of premature adrenarche. We have demonstrated that DHEA and DHEAS levels were within the normal range in many girls with premature adrenarche, whereas 11-oxo-androgens, particularly 11-hydroxyandrostenedione and 11β-hydroxytestosterone, were elevated. Out of those with normal DHEAS, 75 % had elevated 11-hydroxyandrostenedione, and 77.8% of those patients with normal DHEA had the same elevated oxo-adrogen. Additionally, advanced bone age greater than 1 year compared to chronological age was positively associated with 11-ketotestosterone (Spearman correlation coefficient = 0.32, 95% CI: 0.01-0.57, p=0.0429) and 11β-hydroxy testosterone (Spearman correlation coefficient=0.32, 95% CI: 0.01-0.58, p=0.0395). CONCLUSION/UNASSIGNED:We propose that 11-oxoandrogens are a more sensitive steroid to be measured in premature adrenarche.

Hyperglycemia, one of the major risk factors for atherosclerosis, leads to the accumulation of Advanced glycation end products (AGEs), contributing to cardiovascular complications. Such accumulation may accelerate the progression of vascular disease in patients with diabetes. Reverse cholesterol transport (RCT) protein, ATP-binding membrane cassette transporters A1 and G1 (ABCA1 and ABCG1) and cholesterol 27-hydroxylase facilitate cholesterol removal from macrophages. AGE inhibits reverse cholesterol transport by reducing the expression of ABCA1 and ABCG1. This study aimed to evaluate whether plasma from poorly controlled adolescents with type 1 diabetes (T1D) disrupts cholesterol homeostasis in human monocytes/macrophages. Twenty healthy controls (HC) and 20 patients with T1DM, 10 to 19 years old, were enrolled. Naïve THP-1 macrophages were exposed to plasma from each HC and patient with T1D. Following incubation, mRNA for cholesterol efflux (ABCA1, ABCG1, 27-hydroxylase) and cholesterol uptake (CD36, ScR-A1, lectin oxidized low-density lipoprotein (LOX)-1, CXCL16) were isolated. Foam cell formation was quantified to confirm the pro-atherogenic effects of T1D plasma on macrophages. Results showed that T1D plasma had an elevated level of CML-modified proteins and upregulated CXCL16 and, to a lesser degree, ScR-A1. This change in gene expression in the presence of T1D plasma is associated with increased lipid accumulation and foam cell formation by THP-1 macrophages. In our study, these cells' uptake of an AGE product occurred mainly through the SR-A1 and CXCL16 receptors, leading to increased intracellular oxidized LDL. We conclude that AGEs may contribute to accelerated atherosclerosis in diabetes through effects on both forward and reverse cholesterol movement.

BACKGROUND:Prader-Willi syndrome (PWS) is a complex genetic disorder with severe hypotonia, failure to thrive, childhood obesity, hypogonadism/hypogenitalism and learning/behavioral problems with endocrine-related growth and other hormone deficiencies. The prevalence of central adrenal insufficiency (CAI) using dynamic testing ranges from rare to 60%. We compared routine morning plasma cortisol (MPC) and ACTH levels in large cohorts of PWS and control children to address CAI. METHODS:Retrospective analysis of MPC and ACTH levels was undertaken in 128 PWS growth hormone (GH)-treated children under medical care before considering dynamic testing for CAI and 128 non-syndromic control children with short stature evaluated for GH deficiency. RESULTS: 8.0 pg/mL with one individual having an initial low plasma ACTH level (8 pg/mL), but normal upon repeat. CONCLUSIONS:

After the introduction of recombinant human growth hormone (rhGH) in 1985, a myriad of children and adults have benefited from its growth-promoting and metabolic effects. Nowadays, current therapeutic regimens rely on daily subcutaneous GH injections that could be burdensome and inconvenient to pediatric patients. As expected with any long-term parenteral pharmacological treatment, these daily regimens may promote nonadherence, poor compliance, treatment abandonment and/or suboptimal clinical outcomes. In order to improve patient and caregiver acceptance of proposed regimens, simplified dosing schedules could potentially aid in reducing poor compliance and maximize the therapeutic end results. Long-acting GH formulations have been designed and perfected over the last two decades, and currently there are several formulations in advanced stages of research as a reasonable attempt to improve patient's adherence to GH treatment. A long-acting GH preparation allowing for reduced injection frequency is likely to improve treatment adherence and to decrease the distress and inconvenience associated with daily injections. This review presents an update about the status of current and recent efforts that have enabled the formulation of sustained-release, long-acting rhGH as it has been longed for many years in the pediatric endocrinology field.