Faculty Bibliography

Long-acting growth hormone (LAGH) preparations have moved from development to routine clinical use over the past decade. Several products are now approved for paediatric growth hormone deficiency (GHD), selected non-GHD short-stature indications, and, in some regions, for adult GHD. The Growth Hormone Research Society convened an international workshop in October 2025 to reappraise the evidence base and refine clinical recommendations. Currently, data are available for up to 7 years of LAGH treatment in over 8,000 individuals. This remains substantially shorter and smaller than for daily GH. Across preparations, short- to mid-term efficacy appears comparable to daily somatropin, provided dosing is individualised and monitored appropriately. Approvals and pivotal trials include both, treatment initiation and switching from daily GH, depending on product and regional label. No new major safety signals have been identified in trials and real-world reports, although data on BMI trajectories require further evaluation. Injection-site reactions remain the most frequent adverse event and vary by formulation. Anti-drug-antibodies have been observed, yet evidence suggests they have limited clinical impact. Effects on glucose metabolism resemble those of daily therapy, but metabolically high-risk groups are under-represented in studies. Among cancer survivors, data on tumour recurrence and second neoplasms with LAGH are not yet available. Recommendations and practice points emphasised careful patient selection and counselling, product-specific dosing, and insulin-like growth factor-I (IGF-I) monitoring. Urgent knowledge gaps include transition care, long-term efficacy, adherence and safety in cancer survivors. Well-resourced registries are essential for addressing these gaps and supporting safe, effective, and patient-centred use of LAGH.

BACKGROUND:Patients with Cushing's syndrome (CS) have a high prevalence of cardiovascular disease, and other recognized risk factors for atrial fibrillation/flutter (AF/AFL); however, the prevalence of AF/AFL has not been well characterized in this population. METHODS:We conducted a retrospective matched-cohort study using the Clalit Health Services database, including patients with CS and 1:5 matched controls. We assessed the risk of new-onset AF/AFL overall and according to disease etiology and remission status. Pre-existing AF/AFL was defined as >30 days before CS, and new-onset as within 30 days or thereafter. RESULTS:The cohort included 609 patients with CS and 3018 controls. Pre-existing AF/AFL was more common among patients with CS than controls (3.6% vs. 2.1%; OR 1.70, 95% CI 1.04-2.78). During a mean follow-up of 15 years, patients with CS had a significantly higher risk of developing new-onset AF/AFL compared with controls (HR 1.55, 95% CI 1.19-2.03). This increased risk was observed in both Cushing's disease (CD) (HR 1.53, 95% CI 1.01-2.32) and adrenal CS (HR 1.70, 95% CI 1.06-2.74). AF/AFL risk did not significantly differ according to remission status, although a trend toward lower risk was observed. Multivariate analysis identified older age at diagnosis, male sex, hypertension, vascular disease, and higher BMI as predictors for new-onset AF/AFL. CONCLUSION/CONCLUSIONS:CS is associated with an increased risk of AF/AFL. This elevated risk is observed across both CD and adrenal CS and persists despite disease remission, underscoring the need for heightened awareness and close cardiovascular surveillance in this population. The increased risk of AF/AFL appears to be primarily driven by coexisting cardiovascular comorbidities rather than cortisol excess or other CS-specific features.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Perioperative protocols facilitate earlier discharge without compromising safety in nonfunctioning pituitary adenomas, but no large multicenter studies in the United States have investigated protocols regarding Cushing disease (CD). We sought to characterize perioperative protocols and how their implementation influences clinical outcomes in patients with CD. METHODS:A retrospective analysis was conducted using data from the Registry of Adenomas of the Pituitary and Related Disorders consortium comprising 13 US academic pituitary centers. Institutions were surveyed regarding perioperative procedures for patients undergoing transsphenoidal tumor resection for CD. The impacts of institutional procedures and approaches to implementation on length of stay (LOS) and unplanned 90-day readmission were evaluated. RESULTS:Thirteen institutions contributed survey responses and clinical data for a total of 832 patients meeting inclusion criteria. Ten (76.9%) institutions reported having a postoperative protocol, 9 (69.2%) used a formal document to outline their protocol, and 3 (23.1%) had protocols implemented into hospital policy. Mean LOS was significantly reduced in centers with an established protocol (3.14 vs 3.42 days, P = .032), and more so with a formal document (3.10 vs 3.48 days, P = .001) or hospital policy (2.72 vs 3.36 days, P < .001). Patients treated after protocol implementation experienced shorter LOS (P < .001). Other factors associated with reduced LOS were presence of a separate CD pathway, intraoperative checklist specific to pituitary surgery, non-narcotic pain regimen, Foley removal order, dedicated outpatient advanced practice provider follow-up, and target discharge date ≤2 days. Intraoperative checklist (P = .045), non-narcotic pain regimen (P = .048), nasal packing (P = .005), and 1-day target discharge date (P = .032) were important factors against readmission. Compared with microscopic surgery, endoscopic surgery was associated with shorter LOS but increased readmission odds. CONCLUSION/CONCLUSIONS:This is the first multicenter study to illustrate that implementation of perioperative protocols is associated with a reduction in LOS and readmission risk in patients with CD.

INTRODUCTION/UNASSIGNED:are common in these tumors, yet their diagnostic, prognostic, and therapeutic implications are less clear. METHODS/UNASSIGNED:mutations versus those without at our affiliated institution, NYU Langone Health. RESULTS/UNASSIGNED:+ tumors were older at the time of surgery and most classified as mammosomatotroph adenomas on pathology. CONCLUSIONS/UNASSIGNED:+ tumors. SYSTEMATIC REVIEW REGISTRATION/UNASSIGNED:https://www.crd.york.ac.uk/prospero/, identifier CRD420251107763.

Cushing's disease (CD) is an endogenous hypercortisolism state caused by an adrenocorticotropic hormone (ACTH) secreting pituitary adenoma. Medical therapy is an important second-line treatment for CD. New pharmacologic agents for the treatment of patients with CD are under development. New possible intervention targets include various receptors and pathways in the corticotroph tumor, the hormone ACTH, and its receptor and enzymes involved in cortisone metabolism. This part of the article will focus on tailoring pharmacologic therapy according to patient specific characteristics, long-term medical therapy and development of new drugs for CD.

Cushing's disease (CD) is an endogenous hypercortisolism state caused by an adrenocorticotropic hormone secreting pituitary adenoma. CD is associated with vast comorbidities and has a significant detrimental effect on quality of life as well as longevity. First line treatment for CD is transsphenoidal surgery (TSS) while medical therapy is an important second line treatment in cases of TSS failure or infeasibility. Current existing medications for CD target different processes related to CD including the corticotroph adenoma, cortisol adrenal manufacturing mechanisms, and glucocorticoid receptor blockage and widely differ in advantages as well as adverse effects. In depth acquaintance with the specific characteristics of each drug is needed in order to provide patients with the appropriate therapy according to their specific needs.

The majority of prolactinomas are treated with dopamine agonists (DA) with excellent response, however DA-resistance occurs in 10% of prolactinomas. Somatostatin (SST) receptors have been increasingly studied in prolactinomas. There are five SST receptor subtypes and a significant number of prolactinomas show expression of SST₅ and SST₁ mRNA. The somatostatin analog (SSA) pasireotide, which has 40-fold greater binding affinity to SST₅ compared to first-generation SSAs, shows promising results in case reports of DA-resistant prolactinomas. This two-center retrospective cohort study investigated the expression patterns of dopamine 2 (D2R), SST₂ and SST₅ receptors in surgical specimen of 34 patients with prolactinomas, 22 of which were DA-resistant. In vitro effects of cabergoline, octreotide and pasireotide on prolactin production was also examined in cultured prolactinoma cells. Receptor expression was scored using the immunoreactivity score (IRS). 31/34(91%) patients used DA preoperatively; 22/34(64.7%) were DA-resistant. Receptor expression in the cases was 97.1% for D2R, 70.6% for SST₅ and 41.2% for SST₂. In the majority of SST₂ positive cases SST₂ expression was very low. In in vitro studies comparing the effects of octreotide, pasireotide, and cabergoline on prolactin secretion, octreotide was the least potent drug and cabergoline was the most potent. SST₅ and D2R expression was highest in prolactinomas showing the highest response to pasireotide and cabergoline in vitro (median D2R IRS 1.0 vs 8.0 for < 50% vs. > 50% inhibition by cabergoline and median SST₅ IRS 3.5 avs. 12.0 for < 50% vs. > 50% inhibition by pasireotide). In a subgroup, pasireotide inhibited prolactin secretion with comparable potency to cabergoline. Targeting SST₅ with pasireotide may be a potential treatment modality for further clinical investigation in the treatment of a subset of DA resistant or intolerant prolactinomas.

PURPOSE/OBJECTIVE:Data on mortality risk in patients with hyperprolactinemia is limited. This study aimed to evaluate all-cause mortality in a cohort of dopamine agonist (DA)-treated patients with hyperprolactinemia. METHODS:A nationwide retrospective study (2000-2023) using the Clalit Health Services database evaluated all-cause mortality in patients with DA-treated hyperprolactinemia, matched 1:5 with controls by age, sex, socioeconomic status, and BMI. The primary outcome was all-cause mortality. Secondary outcomes included the impact of hyperprolactinemia severity, prolactin (PRL) normalization, and other mortality risk factors. RESULTS:The study included 2,492 patients with hyperprolactinemia (mean age ± SD:38.7 ± 14.8 years, 59.6% women) and 12,456 controls (38.7 ± 14.8 years, 59.6% women). Over > 17 years of follow-up, 182 patients (7.3%) and 936 controls (7.5%) died (HR = 0.972, 95% CI 0.829-1.139), with similar mean age at death. Causes of death in both groups were mainly infectious, cardiovascular, and malignancies. Compared to controls, patients achieving PRL normalization within 1 year had lower mortality (HR = 0.730), while those without normalization had similar risk. Patients with baseline PRL < 5×ULN had lower mortality (6.9% vs. 7.9%, HR = 0.725) than those with ≥ 5×ULN. Mortality was higher in men than in women with hyperprolactinemia but not versus controls. Independent predictors for all-cause mortality included older age, higher BMI, male sex, heart failure, malignancy, hypertension, diabetes, and ischemic heart disease. CONCLUSION/CONCLUSIONS:All-cause mortality in patients with DA-treated hyperprolactinemia is not increased compared to matched controls, however is higher in men vs. women. Mortality is primarily influenced by age, sex, BMI, and comorbidities. Achieving PRL normalization within a year decreases mortality compared with controls.

BACKGROUND:Pituitary neuroendocrine tumors (PitNETs) are the most common intracranial neuroendocrine tumors. PitNETs can be challenging to classify, and current recommendations include a large immunohistochemical panel to differentiate among 14 WHO-recognized categories. METHODS:In this study, we analyzed clinical, immunohistochemical and DNA methylation data of 118 PitNETs to develop a clinico-molecular approach to classifying PitNETs and identify epigenetic classes. RESULTS:CNS DNA methylation classifier has an excellent performance in recognizing PitNETs and distinguishing the three lineages when the calibrated score is ≥0.3. Unsupervised DNA methylation analysis separated PitNETs into two major clusters. The first was composed of silent gonadotrophs, which form a biologically distinct group of PitNETs characterized by clinical silencing, weak hormonal expression on immunohistochemistry, and simple copy number profile. The second major cluster was composed of corticotrophs and Pit1 lineage PitNETs, which could be further classified using DNA methylation into distinct subclusters that corresponded to clinically functioning and silent tumors and are consistent with transcription factor expression. Analysis of promoter methylation patterns correlated with lineage for corticotrophs and Pit1 lineage subtypes. However, the gonadotrophic genes did not show a distinct promoter methylation pattern in gonadotroph tumors compared to other lineages. Promoter of the NR5A1 gene, which encodes SF1, was hypermethylated across all PitNETs clinical and molecular subtypes including gonadotrophs with strong SF1 protein expression indicating alternative epigenetic regulation. CONCLUSION/CONCLUSIONS:Our findings suggest that classification of PitNETs may benefit from DNA methylation for clinicopathological stratification.