small molecules

2026-09-29 | Phosphoproteomic dysregulation promotes tumor proliferation in Cushing's disease.

Pituitary adenomas constitute up to 20% of primary brain tumors, yet somatic mutations are only found in 15% of pituitary adenomas. Epigenomic dysregulation has been proposed as a tumorigenic mechanism in pituitary adenomas causing Cushing's disease (CD). We created paired datasets of human CD adenomas and en-route margin adult human pituitary glands, and assayed their chromatin accessibility, DNA methylation, transcriptomic, proteomic, and phospho-proteomic landscapes. In CD adenomas, we found epigenetic reactivation of a neurodevelopmental phosphoprotein program typically lost in the postnatal pituitary gland. CD cells overexpressed PPP1R17, an endogenous inhibitor of the protein phosphatase PP2A. Mechanistically, PPP1R17 overexpression in normal murine pituitary cells recapitulated the adenoma phenotype, and the resulting hyperproliferation was reversed in a PP2A-dependent manner by fingolimod, an FDA-approved small molecule, both in vitro and in vivo. Our findings highlight kinase-phosphatase imbalance as a targetable mechanism in CD.

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2026-08-03 | A case report of osilodrostat treatment in primary bilateral macronodular adrenal hyperplasia associated with bilateral adrenal mass reduction

Abstract Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a rare cause of Cushing syndrome (CS), characterized by bilateral adrenal nodules larger than 1 cm. Cortisol hypersecretion in PBMAH is driven by intra-adrenal rather than pituitary adrenocorticotropic hormone (ACTH), with its pathogenesis mediated by aberrant hormone receptor expression in the adrenal cortex. This article reports a case of a 60-year-old woman with PBMAH in whom a marked reduction in bilateral adrenal masses was observed following treatment with osilodrostat. The patient presented with typical Cushingoid features, accompanied by hypertension, diabetes mellitus, osteoporosis, and severe restrictive lung disease. Genetic testing identified a pathogenic mutation in the ARMC5 gene, confirming the diagnosis. Because she was intolerant of surgical treatment, left adrenal artery embolization (AAE) was performed but failed to control hypercortisolism. Osilodrostat therapy was subsequently initiated—this potent 11β-hydroxylase inhibitor was recently approved in China for the treatment of Cushing syndrome. Notably, after 23 weeks of treatment, the patient's 24-hour urinary free cortisol (24 hours-UFC, CLIA) level returned to normal. Treatment was then discontinued, and during 11 months of follow-up the patient’s 24 hours-UFC remained within the normal range. Moreover, imaging performed during the period of osilodrostat therapy demonstrated significant shrinkage of both adrenal glands. To our knowledge, this is the first reported case of bilateral adrenal mass reduction observed in temporal association with osilodrostat treatment in a PBMAH patient. However, prior AAE confounds the attribution of tumor shrinkage to osilodrostat alone. These findings highlight an observed association between the drug and mass reduction, warranting further investigation to clarify its potential role beyond symptomatic control.

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2026-08-01 | EP994 - ECE_3299 - Molecular imaging in Cushing's disease: localization of an ACTH-secreting PitNET with [18F]FET PET-MRI after inconclusive MRI and negative inferior petrosal sinus sampling—a case report

Abstract Background Cushing's disease is a rare disorder caused by an adrenocorticotropic hormone (ACTH)-secreting pituitary neuroendocrine tumor (PitNET) resulting in hypercortisolism. Establishing a central source of ACTH hypersecretion can be challenging, as pituitary MRI is inconclusive in up to 40% of patients with ACTH-dependent hypercortisolism. In these cases, bilateral inferior petrosal sinus sampling (IPSS) is commonly used to differentiate between pituitary and ectopic ACTH secretion. While IPSS is considered the reference standard for confirming a pituitary origin, its ability to localize a PitNET—based on ACTH gradient lateralization—remains limited. Together with the procedure's invasiveness, dependence on venous anatomy, and restricted availability to specialized centers, this highlights the need for complementary diagnostic tools. Molecular imaging techniques, including [18F]FET PET-MRI, have shown promising results for localizing small or MRI-negative PitNETs in patients with Cushing's disease. Case A 42-year-old man presented with severe Cushingoid features. ACTH-dependent hypercortisolism was biochemically confirmed. Pituitary MRI revealed a small right-sided pituitary lesion (5.5 mm). Guideline-based IPSS demonstrated no significant central-to-peripheral ACTH gradient (ratio 1.21), suggesting an ectopic ACTH source. In parallel, [18F]FET PET-MRI showed focal increased uptake in the right-sided pituitary lesion, consistent with a functional PitNET. Given the IPSS result, additional imaging including whole-body [18F]FDG PET-MRI, [68Ga]Ga-DOTA-TATE PET-MRI, and CT were performed, without evidence of an ectopic ACTH source. Repeated IPSS with prolactin assessment remained inconclusive (prolactin-adjusted ACTH ratio 1.20), with correct catheter positioning confirmed by an experienced interventional radiologist. After multidisciplinary discussion, the patient underwent transsphenoidal adenomectomy directed at the PET-positive lesion. Postoperatively, cortisol levels became undetectable, and histopathological examination confirmed a corticotroph PitNET. Conclusions This case highlights a diagnostic dilemma in which a pituitary source of ACTH hypersecretion could not be confirmed using MRI and technically adequate IPSS, whereas [18F]FET PET-MRI successfully localized the culprit lesion. These findings support the potential added value of molecular imaging in patients with small functional PitNETs and may suggest a future role for [18F]FET PET in reducing reliance on invasive IPSS, improving localization, and shortening the time to diagnosis and definitive treatment in Cushing's disease.

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2026-08-01 | EP1247 - ECE_3606 - ACTH-dependent Cushing's syndrome: diagnostic pitfalls and personalised treatment strategies: a case series

Abstract Introduction Cushing's syndrome (CS) is caused by increased cortisol production from the adrenals or by ACTH secretion from a pituitary tumour (Cushing disease – CD) or non-pituitary tumour (ectopic secretion), leading to increased morbidity and mortality. The first line of treatment is surgery, but medical treatment, radiation or bilateral adrenalectomy are needed for recurrences or inoperable lesions. Objective and Methods To present the therapeutic challenges and individualised treatment options in 3 patients with ACTH-dependent CS, treated in a tertiary centre. Results The first patient is a 61-year-old female with a microprolactinoma (responsive to low-dose cabergoline), who developed CD due to a second pituitary microadenoma 10 years later, complicated with obesity, hypertension, diabetes mellitus, dyslipidaemia. Inferior petrosal sinus sampling was not available for the lateralisation of the ACTH secretion – she underwent selective neurosurgery on the biggest lesion followed by a second surgery due to persistent hypercortisolism, with a resolution of the CD and the metabolic syndrome. Three years later, CD relapsed, without identifiable pituitary or ectopic lesions on imaging. Low-dose pasireotide was initiated, with biochemical control and favourable metabolic evolution. The second patient is a 51-year-old woman with an invasive non-functioning pituitary macrodenoma, who underwent 2 partial adenomectomies and radiotherapy. Thirteen years later tumour progression was accompanied by the development of CD and metabolic complications – she underwent a third surgery, with persistent hypercortisolism. Pasireotide achieved cortisol control, but the diabetes worsened, therefore she was switched to ketoconazole, with a good biochemical and metabolic response. The third patient is a 67-year-old woman with a florid Cushing phenotype, weight loss, hypokalaemia, markedly elevated cortisol, ACTH and DHEAS levels. Extensive imagery (pituitary, chest and abdomen) came back negative, with the exception of a small indeterminate renal lesion. The somatostatin receptor scintigraphy and the inferior petrosal sinus sampling also failed to localise the ACTH source. She was initially started on ketoconazole, with a partial biochemical response, therefore she was switched to osilodrostat with a good clinical and hormonal evolution. She was referred to Nephrology for a renal biopsy, given the severe initial clinical and biochemical profile, suggesting a possible ectopic ACTH secretion (even though the scintigraphy was negative). Conclusion ACTH-dependent CS remains a complex condition with significant challenges, particularly in recurrent disease, aggressive pituitary tumours or occult ectopic ACTH secretion. These cases underscore the importance of a personalised approach and demonstrate the expanding role of medical therapies when surgical cure is not attainable.

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2026-08-01 | EP1292 - ECE_3773 - Occult ectopic ACTH secretion in cyclic Cushing syndrome: a prolonged diagnostic and therapeutic challenge

Abstract Introduction ACTH-dependent Cushing syndrome represents a major diagnostic and therapeutic challenge when the source of ACTH secretion remains elusive despite extensive investigations. Identifying ectopic ACTH-secreting tumors is particularly difficult in cyclic forms, where fluctuating biochemical activity may delay or preclude tumor localization. Severe hypercortisolism with intermittent remission further complicates diagnostic assessment, treatment monitoring, and long-term management. Case Presentation We report the case of a 61-year-old woman with a history of papillary thyroid microcarcinoma treated surgically in 2005. In 2016, she presented with progressive neuro-ophthalmic symptoms. Pituitary magnetic resonance imaging revealed a large sellar mass (23 × 35 × 29 mm) with optic chiasm compression. Incomplete transsphenoidal resection was performed. Histopathology confirmed a pituitary adenoma (Ki-67 index 4%), initially immunonegative for ACTH. At that time, pituitary hormonal work-up, including assessment of cortisol secretion, came back normal. Later the same year, the patient developed severe ACTH-dependent hypercortisolism with hypokalemia. While patient history data from that period are scarce, abdominal imaging studies were performed, showing two left sided adrenal adenomas and bilateral adrenal hyperplasia, which led to the surgical removal of the left adrenal gland. Due to persistent diagnostic uncertainty, a second transsphenoidal surgery was subsequently undertaken, with immunohistochemistry demonstrating ACTH positivity. Follow-up pituitary MRI showed an empty sella. Despite these interventions, the disease course was characterized by recurrent episodes of ACTH-dependent hypercortisolism with hypokalemia, profound muscle weakness, and diabetes mellitus, alternating with periods of biochemical remission, consistent with cyclic Cushing syndrome. Further evaluation identified a large cephalo-isthmic pancreatic lesion, which was surgically resected; however, histopathological examination and subsequent clinical evolution excluded the pancreas as the source of ACTH secretion. During follow-up, a pulmonary nodule with progressive dimensional increase was detected, raising suspicion for an ectopic ACTH-secreting tumor. Functional imaging with 99mTc-tektrotyd SPECT/CT didn't show pathological tracer uptake. Because of severe complications related to prolonged hypercortisolism—including recurrent infections, respiratory failure, and major metabolic disturbances—definitive surgical or invasive diagnostic procedures were repeatedly deferred. Medical treatment with steroidogenesis inhibitors was initiated. Given the cyclic disease pattern, a block-and-replace strategy combining ketoconazole with glucocorticoid replacement was adopted, allowing partial biochemical control. The condition was ultimately classified as occult ectopic ACTH secretion with cyclic activity. Conclusions This case underscores the complexity of ACTH-dependent Cushing syndrome when the source of ACTH secretion cannot be localized. Cyclic hypercortisolism, intermittent spontaneous remission, and limited interventional options substantially hinder diagnostic confirmation and disease monitoring, emphasizing the need for prolonged, individualized, multidisciplinary management.

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cell therapies

2025-07-18 | Rare Collision Tumors: ACTH-Secreting Pituitary Adenoma and Pituicytoma: Histopathological and Ultrastructural Analyses- case report

Background Collision tumors are rare conditions characterized by the coexistence of two histologically distinct neoplasms in the same region without histological admixture or an intermediate cell population zone. Case presentation Our report represents one of the few studies on a collision tumor composed of an ACTH-secreting pituitary adenoma and a sellar pituicytoma. Here, we describe the clinical presentation, radiological findings, immunohistochemical/histopathological analysis and ultrastructural examination of a 21-year-old woman with two different intracranial primary tumors at adjacent sites. Magnetic resonance imaging (MRI) of the sellar region revealed a focal nodular, 4 mm lesion located in the left lateral recess that was hypointense at T2 and compatible with a pituitary microadenoma. Transnasal transsphenoidal resection was performed. Histopathological analysis revealed patterns consistent with a corticotroph PitNET, with diffuse, cytoplasmic ACTH positivity by immunostaining and a Ki-67 index of 4%. Furthermore, the specimens included scattered adenohypophyseal and neural tissue. The latter was characterized by increased neoplastic proliferation consistent with a pituicytoma, confirmed by nuclear positivity for TTF-1 and a Ki-67 index of 3%. Ultrastructural analysis confirmed the coexistence of two morphologically distinct lesions. Postoperatively, the patient developed diabetes insipidus and remained in clinical and biochemical remission with no remaining tumor at nine months postsurgery. Conclusions Pituitary collision tumors are sporadically reported and rare. Specifically, pituicytomas associated with pituitary hyperfunction are notably infrequent, and those linked to Cushing’s disease are extremely uncommon. Pituicytomas exhibit unique histological and ultrastructural characteristics that distinguish them from other pituitary tumors. A deeper understanding of pituicytomas will enable the development of more specific and effective treatments tailored to the molecular characteristics of individual patients in the future.

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2025-04-05 | Genetic models of Cushing's disease : From cells, in vivo transgenic models to human pituitary organoids.

Cushing's disease (CD) is caused by pituitary tumors that overproduce adrenocorticotropic hormone (ACTH); however, effective medical treatments remain limited, significantly impairing patients' quality of life and prognosis. Despite extensive molecular analyses, the pathogenesis of CD remains unclear. Although previous molecular studies have relied heavily on rodent-derived cells and rodent transgenic models, significant species differences exist in the tumorigenesis of CD between humans and rodents. To date, an established human CD cell model is lacking, as human CD cells are limited in availability and sustainability over time. Additionally, the gene modifications used in transgenic models do not necessarily reflect the causative genes in CD. CD tumors exhibit wide phenotypic heterogeneity, which further complicates the development of an ideal genetic model. In this review, we provide an analysis of 11 genetic models used to study CD, outlining their historical development, strengths, and limitations. Additionally, we discuss the ongoing development of human induced pluripotent stem cell (iPSC)-derived pituitary organoids and further describe various models of pituitary organoids as an emerging novel approach to studying CD. By comparing all these models, we highlight the necessity of advancing genetic models to improve our understanding and treatment of CD.

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2024-11-01 | TMOD-06. ESTABLISHMENT OF PITUITARY NEUROENDOCRINE TUMOR (PITNET) ORGANOID MODELS

Abstract Pituitary neuroendocrine tumors (PitNETs) are tumors that originate from the anterior pituitary gland. While they are mostly benign, they can cause various clinical symptoms due to hormonal secretion abnormalities. PitNET can be broadly categorized into three lineages, each of which has its differentiation controlled by specific transcription factors. Treatment options for PitNET include surgical resection and pharmacotherapy, but available drugs are limited, and their efficacy markers remain unclear. To develop novel drugs for PitNET and identify their efficacy markers, it is necessary to develop new research models. In recent years, organoid models have garnered attention as novel research models for various cancer types. In this study, we established novel organoid models derived from PitNET patients and analyzed their histological and endocrinological characteristics. Surgical specimens from 4 cases of somatotroph adenoma, 1 case of double adenoma, 1 case of gonadotroph adenoma, and 1 case of corticotroph adenoma were minced in dissection medium and embedded in Matrigel basement membrane matrix respectively. The organoids were cultured under 5% CO2 at 37°C using media supplemented with various growth factors. After 28 days of culture, formalin-fixed paraffin-embedded sections were prepared to examine histological homology with patient tumors. Hematoxylin and eosin staining results showed that all organoids maintained cell morphology and tissue structure similar to the original tumors. Immunohistochemical staining for markers specific to each PitNET revealed similar staining patterns between the organoids and the original tumors. Furthermore, analysis of hormone levels in the culture medium showed that hormone production capabilities, such as growth hormone and follicle stimulating hormone, were maintained even after long-term culture. In this study, we successfully established PitNET organoid models that retain histological and endocrinological characteristics. These models are expected to serve as useful research tools for elucidating the molecular mechanisms of PitNET and developing novel therapies targeting critical molecular abnormalities.

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2023-12-29 | Cushing Syndrome Is Associated With Gut Microbial Dysbiosis and Cortisol-Degrading Bacteria

Abstract Context Cushing syndrome (CS) is a severe endocrine disease characterized by excessive secretion of cortisol with multiple metabolic disorders. While gut microbial dysbiosis plays a vital role in metabolic disorders, the role of gut microbiota in CS remains unclear. Objective The objective of this work is to examine the alteration of gut microbiota in patients with CS. Methods We performed shotgun metagenomic sequencing of fecal samples from 78 patients with CS and 78 healthy controls matched for age and body mass index. Furthermore, we verify the cortisol degradation capacity of Ruminococcus gnavus in vitro and identify the potential metabolite by LC-MC/MS. Results We observed significant differences in microbial composition between CS and controls in both sexes, with CS showing reduced Bacteroidetes (Bacteroides vulgatus) and elevated Firmicutes (Erysipelotrichaceae_bacterium_6_1_45) and Proteobacteria (Enterobacter cloacae). Despite distinct causes of hypercortisolism in ACTH-dependent and ACTH-independent CS, we found no significant differences in metabolic profiles or gut microbiota between the 2 subgroups. Furthermore, we identified a group of gut species, including R. gnavus, that were positively correlated with cortisol levels in CS. These bacteria were found to harbor cortisol-degrading desAB genes and were consistently enriched in CS. Moreover, we demonstrated the efficient capacity of R. gnavus to degrade cortisol to 11-oxygenated androgens in vitro. Conclusion This study provides evidence of gut microbial dysbiosis in patients with CS and identifies a group of CS-enriched bacteria capable of degrading cortisol. These findings highlight the potential role of gut microbiota in regulating host steroid hormone levels, and consequently host health.

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2023-10-01 | THU213 Posterior Reversible Encephalopathy Syndrome As A Rare Presentation Of ACTH-dependent Cushing Syndrome In A Pediatric Patient

Abstract Disclosure: E.E. Bell-Sambataro: None. C. Tatsi: None. P. Chittiboina: None. S.A. Bowden: None. Background: Cushing disease (CD), caused by ACTH-secreting pituitary adenoma, is the most common cause of Cushing Syndrome (CS) in children > 5 years of age. Hypertension is reported in up to 50% of pediatric cases with CS. We report a challenging pediatric case with a rare presentation of hypertensive emergency associated with CD. Clinical Case: A 6-year-old female with 3 month-history of rapid weight gain (8 kg), round face, and hypertrichosis presented to emergency department for abdominal pain from nephrolithiasis and was noted to have severe hypertension. While in ED, she developed status epilepticus and altered mental status. Brain MRI findings were consistent with posterior reversible encephalopathy syndrome (PRES). Her hypertensive encephalopathy gradually improved with aggressive anti-hypertensive and anti-epileptic therapy. Further studies confirmed hypercortisolism with markedly elevated urine free cortisol of 1288 ug/day (<18 ug/day) and lack of diurnal variation of serum cortisol (8 AM cortisol of 47.9 ug/dL, midnight cortisol of 20.3 ug/dL). ACTH level of 23 pg/mL suggested ACTH-dependent CS. Low dose (1 mg) dexamethasone suppression test (DST) failed to suppress 8 am cortisol (31.4 ug/dL). High dose DST (120 mcg/kg) suppressed serum cortisol to 67%- borderline threshold for CD, likely due to increased dexamethasone clearance by anticonvulsant. Pituitary MRI did not reveal a visible lesion. Desmopressin stimulation test showed stimulation of ACTH by 700% and cortisol by 160% suggesting pituitary source. Inferior petrosal sinus sampling showed a mildly increased gradient in central to peripheral plasma ACTH of 1.7 at baseline (>2) and post-stimulation of 2.5 (>3). ACTH gradient did not reach cutoffs for pituitary source, likely due to insufficient catheterization of petrosal sinus from anatomically small blood vessels. Given her severity, she underwent surgical pituitary exploration. Postoperative morning cortisol was <5 mcg/dL, with decreased midnight salivary cortisol level obtained 2 months after surgery. She developed post-operative central hypothyroidism but did not have diabetes insipidus. She had a 4 kg weight loss with increased height percentile 5 months after surgery and remains under close monitoring. Conclusion: PRES is a clinical-radiographic disorder characterized by seizures, encephalopathy with neuroimaging findings of reversible cortical and subcortical vasogenic edema. Hypertension induced by marked hypercortisolism precipitated by pain is likely the etiologic factor. Prompt recognition and treatment of PRES are crucial to prevent further life-threatening complications and permanent neurological damage. Early diagnosis and treatment of CD are critical to prevent associated morbidities. Pituitary exploration by expert neurosurgery team should be considered in patients with MRI-negative CD. Presentation: Thursday, June 15, 2023

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proteins

2026-07-31 | Evaluation of desmopressin stimulation test specificity in healthy volunteers.

The desmopressin stimulation test (DesST) is used to identify Cushing disease (CD). Reportedly, most healthy people and patients with non-neoplastic hypercortisolism lack a significant response. We aimed to evaluate and improve DesST specificity (Sp). Prospective evaluation of four DesST protocols in healthy volunteers. Twenty healthy volunteers underwent four DesST protocols in a randomized order. Protocols involved fluid restriction with desmopressin 10 µg (10NPO; 'standard'), 4 µg (4NPO), and 10 µg preceded by dexamethasone 1 mg (10+DexNPO); and desmopressin 10 µg without fluid restriction (10H2O). We evaluated Sp for each protocol, using established response criteria. Previous criteria of relative increases of 35% and/or 20% for ACTH and cortisol, respectively, had low Sp: 50% (95% CI: 28-72%; 10NPO) to 85% (95% CI: 69-100%; 10+DexNPO). Using absolute ACTH increase >8.1 pmol/L (37 pg/mL) improved Sp to 100% across all protocols. Compared with 10NPO, median ACTH and cortisol were lower throughout during 10+DexNPO and also at +15 min during 4NPO (ACTH: 4.4 vs 4.9 pmol/L (19.9 vs 22.1 pg/mL), P = 0.06; cortisol: 248 vs 284 nmol/L (9.0 vs 10.3 µg/dL), P = 0.01). 10H2O and 10NPO results were similar. Adverse events were mild; hyponatremia occurred after 5/80 tests. After desmopressin, healthy volunteers have small absolute increases in ACTH and cortisol that equate to large relative changes from baseline. Optimized response criteria should likely incorporate absolute values. Fluid restriction did not impact Sp, but using a lower desmopressin dose and dexamethasone pre-treatment are promising ways to improve diagnostic accuracy, if sensitivity is maintained in CD. Half of healthy volunteers had a response consistent with Cushing disease (CD) during a commonly used 10 µg desmopressin stimulation test, interpreted using relative ACTH and/or cortisol increases. This puts the test's reliability for excluding CD in question, particularly in settings of mild hypercortisolism. These situations include differentiating CD from non-neoplastic hypercortisolism, identifying cyclic ectopic ACTH-producing tumors during nadir phases, and establishing early CD recurrence. Optimized response criteria likely require absolute ACTH and/or cortisol cutoffs. Using a reduced 4 µg dose of desmopressin or pre-treatment with 1 mg dexamethasone improved test specificity, offering promising ways to improve test performance if sensitivity is maintained in CD. NCT06635629.

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2026-06-16 | Structure-based rational design of high-affinity JAZF1 variants peptides to target the testicular orphan nuclear receptor 4 and pro-opiomelanocortin axis in Cushing's disease.

The regulation of pro-opiomelanocortin (Pomc) expression by the testicular orphan receptor 4 (TR4) constitutes a critical mechanism underlying the pathogenesis of Cushing's disease (CD). Although the endogenous repressor juxtaposed with another zinc finger gene 1 (JAZF1) inhibits TR4 activity, its relatively low binding affinity (KD = 2246 nM) limits its therapeutic potential. In this study, we employed an iterative structure-based lead optimization strategy to enhance the JAZF1 scaffold. Utilizing Discovery Studio for virtual screening, we conducted successive rounds of in silico saturation mutagenesis, ranging from single point to multi-site combinatorial substitutions, which were subsequently validated through incremental experimental binding assays. This recursive optimization process led to the identification of two triple-mutant JAZF1 peptides (V56L/A68Y/A69R and D67L/A68Y/A69R) exhibiting more than a 2,200-fold enhancement in TR4 binding affinity. These engineered peptides, along with high-affinity small molecules such as nilotinib (KD = 4.83 nM), effectively downregulated Pomc expression and inhibited proliferation of AtT-20 tumor cells. Taken together, these findings suggest that the JAZF1-TR4-Pomc axis may serve as a potential therapeutic target for modulating adrenocorticotropic hormone (ACTH) hypersecretion in CD.

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2025-10-01 | SUN-075 Efficacy of Glucagon-Like Peptide-1 Receptor Agonists (GLP-1 RAs) for Diabetes Management in Patients with Cushing’s Disease

Abstract Disclosure: Z. Nasrallah: None. E. Montaser: None. V. Shah: None. Management of type 2 diabetes (T2D) and obesity is challenging in patients with Cushing’s Disease (CD). While once-weekly Glucagon-Like Peptide-1 Receptor Agonists (GLP-1 RAs) are established treatments for T2D and obesity, their efficacy in the setting of CD remains unexplored. In this study, we investigated the efficacy of GLP-1 RAs for weight and diabetes management in patients with CD. We conducted a retrospective chart review of adult patients at Indiana University Healthcare System (January 2021-October 2024) with confirmed CD and T2D who received weekly GLP-1 RAs for ≥3 months. Eligible patients were identified using ICD codes for T2D, CD and GLP-1 RAs. Patients with non-pituitary Cushing's syndrome or exogenous steroid use were excluded. Primary outcomes included changes in glycated hemoglobin (HbA1c) and Body Mass Index (BMI) at 3-, 6-, and 12-month intervals. Fifteen patients (93.3% female, median age 47 years) were identified. Prescribed GLP-1 RAs included Semaglutide (60%), Dulaglutide (26.7%), and Tirzepatide (13.3%). Median baseline HbA1c and BMI were 8.2% (IQR 7.2 - 8.6%) and 37.2 kg/m² (IQR 32.4 - 44.2 kg/m2), respectively. Non-significant reductions in mean HbA1c from baseline were observed at 3, 6, and 12 months, with changes of 1.21%, 0.72%, and 1.35%, respectively (unadjusted). No reduction of BMI was observed - on the contrary, patients experienced a non-significant mean increase in BMI over the treatment period. Our findings suggest that GLP-1 RAs may retain their glucose-lowering effects in CD patients while failing to achieve weight reduction. We hypothesize that the presence of a corticotroph adenoma may interfere with central GLP-1 receptor signaling in the hypothalamus, potentially disrupting the weight-loss response while preserving peripheral glucose regulation. These findings align with our previous observations of reduced efficacy of GLP-1 RAs in patients with genetic forms of obesity1. Further research is needed to distinguish between the centrally vs peripherally-mediated effects of GLP-1 RAs. This understanding can provide insight into individualized medical therapy for obesity and/or diabetes management. 1.Klein MP, Akturk HK, Snell-Bergeon JK, Shah VN. Reduced Efficacy of Glucagon-Like Peptide-1 Receptor Agonists Therapy in People With Type 1 Diabetes and Genetic Forms of Obesity. J Diabetes Sci Technol. 2024 Apr 17:19322968241245680. Presentation: Sunday, July 13, 2025

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2025-09-13 | Growth hormone deficiency in Cushing's syndrome: an update on diagnosis and management.

Endogenous Cushing's syndrome (CS) is associated with substantial morbidity and mortality. Patients in remission may experience many comorbidities, including growth hormone deficiency (GHD). Electronic searches (PubMed) were conducted through July 2025. The published data largely pertain to patients with Cushing's disease (CS caused by a pituitary tumor). This article reviews the epidemiology of GHD in patients with CS in remission, underlying mechanisms, and clinical manifestations. The diagnosis of GHD is discussed along with data on the effectiveness and safety of growth hormone replacement. GHD is common in patients with active CS and may persist among patients in remission. In children, decreased linear growth is prevalent. In adults in remission, GHD has been associated with a higher prevalence of cardiometabolic burden (hypertension, diabetes mellitus, cardiovascular and cerebrovascular disease), decreased muscle strength, lower bone mineral density and increased prevalence of fractures. The diagnosis of GHD generally requires stimulation testing and should only be undertaken in patients in remission. In children with CS in remission, growth hormone replacement improves adult height. In adults, growth hormone replacement may improve quality of life, bone mineral density, muscle strength and dyslipidemia but requires careful monitoring for the possible development of hyperglycemia.

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2024-12-16 | Lateralization outcomes of bilateral inferior petrosal sinus sampling: desmopressin vs CRH.

Bilateral inferior petrosal sinus sampling (BIPSS) is the gold standard for localizing ACTH-dependent Cushing's syndrome (CS). While corticotropin-releasing hormone (CRH) was initially used for stimulation, desmopressin has become a common alternative. This research evaluates desmopressin's effectiveness in lateralizing Cushing's disease (CD) during BIPSS compared to CRH stimulation. The study included 33 individuals with ACTH-dependent CS who underwent BIPSS and had diagnoses confirmed by endoscopic endonasal transsphenoidal pituitary surgery (EETPS). Fourteen participants underwent BIPSS with CRH and 19 with desmopressin. A comparative analysis was conducted. BIPSS accurately lateralized 76% of cases, specifically, 71% with CRH and 79% with desmopressin (p = 0.2). For tumors < 6 mm on MRI, overall accuracy was 82%, namely, 75% with CRH and 90% with desmopressin (p = 0.4). IPSS achieved 100% accuracy in the four cases with no lesion on preoperative MRI. This study demonstrates no significant difference in lateralization accuracy between desmopressin and CRH for IPSS. In challenging cases, especially those with microadenomas or non-lesional CD, desmopressin with IPSS aids in preoperative lateralization.

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antibodies

2026-03-04 | Neutralization of acyl-CoA-binding protein attenuates glucocorticoid-mediated suppression of cancer immunosurveillance.

Glucocorticoids (GCs) are potent immunosuppressive agents that compromise anticancer immune responses, yet the molecular mediators of this effect remain incompletely understood. Here, we identify the acyl-CoA-binding protein/diazepam-binding inhibitor (ACBP/DBI) as a critical effector of the GC-induced suppression of tumor immunosurveillance and immunotherapy efficacy. Using orthotopic murine models of breast cancer, non-small cell lung cancer, and cutaneous fibrosarcoma, we show that corticosterone (CORT) accelerates tumor progression and abrogates therapeutic responses to immunogenic chemotherapy and PD-1 blockade. Genetic ablation or monoclonal antibody (mAb)-mediated neutralization of ACBP/DBI prevents immunosuppression by CORT, restoring both natural and therapy-enhanced antitumor immunity in a T cell-dependent manner. Mechanistically, CORT induces Tsc22d3 expression in dendritic cells, impairs type I interferon signaling, and reduces antigen presentation capacity, which all can be reversed by ACBP/DBI neutralization. The immunosuppressive activity of GCs and the immunostimulatory function of anti-ACBP/DBI mAb converge on Tsc22d3 expression in myeloid cells, as shown by loss-of-function experiments in myeloid-specific Tsc22d3-deficient mice. These findings reveal ACBP/DBI as a central mediator of GC-induced immune evasion and suggest its neutralization as a therapeutic strategy to restore anticancer immunity during endogenous or iatrogenic GC exposure.

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2026-01-19 | Long-term effect on bone mineral density of denosumab in the treatment of hyperpituitarism driven osteoporosis: an exploratory study.

Treatment of skeletal fragility in patients with pituitary diseases is challenging. Denosumab, an antiresorptive bone active drug, increased bone mineral density (BMD) and reduced incidence and risk of fractures in primary osteoporosis. This study aimed to evaluate the efficacy of denosumab in patients with pituitary disease-driven osteoporosis. This retrospective study investigated the frequency of fragility fractures (FF) and the percent BMD changes at 1-, 2-, 5-, and 10-years of treatment with denosumab, in patients with osteoporosis due to secreting pituitary adenoma. Seventeen patients were included: 5 patients (29.4%) were affected by hyperprolactinemia due to PRL-secreting pituitary adenoma (PAs), six patients (35.3%) were affected by acromegaly and six patients (35.3%) by Cushing's disease. Four patients carried prevalent-FF (23.5%). A single patient with acromegaly developed FF at 2 and at 5 years of treatment with denosumab. Femoral neck BMD increased in 11 patients (64.7%) at 1 year of treatment, in 9 patients (52.9%) at 2 years of treatment, in 8 patients (47.1%) at 5 years of treatment and in 2 patients (66.7%) at 10 years of treatment. Lumbar spine BMD improved in all patients at 1 year of treatment (100%), in 16 patients at 2 years of treatment (100%), in 11 patients at 5 years of treatment (100%), and in 2 patients at 10 years of treatment (66.7%). No drug related adverse events occurred. This study demonstrated for the first time that long-term treatment with denosumab is effective and safe in patients with osteoporosis due to secreting pituitary adenoma.

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2025-01-23 | Hormone circuit explains why most HPA drugs fail for mood disorders and predicts the few that work

Elevated cortisol in chronic stress and mood disorders causes morbidity including metabolic and cardiovascular diseases. There is therefore interest in developing drugs that lower cortisol by targeting its endocrine pathway, the hypothalamic-pituitary-adrenal (HPA) axis. However, several promising HPA-modulating drugs have failed to reduce long-term cortisol in mood disorders, despite effectiveness in other hypercortisolism conditions such as Cushing's syndrome. The reasons for these failures remain unclear. Here, we use a mathematical model of the HPA axis to demonstrate that the pituitary and adrenal glands compensate for drug effects by adjusting their functional mass, a feedback mechanism absent in Cushing tumors. Our systematic in silico analysis identifies two interventions targeting corticotropin-releasing hormone (CRH) as effective for lowering long-term cortisol. Other targets either fail due to gland mass compensation or harm other aspects of the HPA axis. We propose CRH-neutralizing antibodies and CRH-synthesis inhibitors as potential targets for reducing long-term cortisol in mood disorders and chronic stress. More generally, this study indicates that understanding the slow compensatory mechanisms in endocrine axes can be crucial to prioritize drug targets.

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2024-10-01 | 12484 Safety And Pharmacokinetics Of Anti-ACTH Antibody Lu AG13909 In Patients With Classic Congenital Adrenal Hyperplasia: Phase 1 Open-label, Multiple-Ascending-Dose Trial Protocol

Abstract Disclosure: U. Srirangalingam: Advisory Board Member; Self; Lundbeck. Consulting Fee; Self; Diurnal. Research Investigator; Self; Neurocrine. A. Velusamy: Consulting Fee; Self; Novo Nordisk. M. Binderup: Employee; Self; H. Lundbeck A/S. B. Baker: Employee; Self; H. Lundbeck A/S. M. Folden Flensburg: Employee; Self; H. Lundbeck A/S. L. Pickering Boserup: Employee; Self; H. Lundbeck A/S. J. Luthman: Employee; Self; H. Lundbeck A/S. H. Benecke: Employee; Self; H. Lundbeck A/S. R.J. Auchus: Consulting Fee; Self; Neurocrine Biosciences, Diurnal, Corcept Therapeutics, Recordati Rare Diseases, Crinetics Pharmaceuticals, Quest Diagnostics, Xeris Pharmaceuticals, Novo Nordisk, H. Lundbeck A/S, Sparrow Pharmaceuticals. Research Investigator; Self; Adrenas Therapeutics, Spruce Biosciences, Neurocrine Biosciences, Diurnal, Corcept Therapeutics, Recordati Rare Diseases, Crinetics Pharmaceuticals. Introduction: Classic congenital adrenal hyperplasia (CAH) is a rare, autosomal recessive disorder characterized by cortisol and aldosterone deficiency, elevated adrenocorticotropic hormone (ACTH) and subsequent hyperandrogenemia, most commonly due to 21-hydroxylase deficiency. Balancing physiological glucocorticoid replacement and control of hyperandrogenism remains a challenge with the risk of long-term consequences of glucocorticoid overtreatment. Lu AG13909 is a novel, high-affinity, anti-ACTH monoclonal antibody that neutralizes ACTH-induced signaling. In preclinical models, Lu AG13909 dose-dependently and persistently reduced plasma corticosterone and cortisol concentrations. No adverse effects were observed after 6 months of intravenous dosing every 2 weeks in cynomolgus monkeys. Here, we describe the ongoing first-in-human trial of Lu AG13909, investigating the safety, tolerability, pharmacokinetic (PK) properties, and pharmacodynamic (PD) effects of Lu AG13909 in adults with classic CAH. Methods: This is a Phase 1, open-label, multiple-ascending-dose trial with intra-participant dose escalation (EUCT #2023-503711-15-00). The trial enrolls men and women with classic CAH aged between ≥18 and ≤70 years under stable glucocorticoid and mineralocorticoid dosing, with morning 17-hydroxyprogesterone &gt;4 times the upper limit of normal. Each participant receives up to 6 doses of Lu AG13909 every 28-35 days at increasing dose levels. The trial consists of 2 parts: Part A has a 3+3 design, in which 3 participants are given a certain dose, and escalation to the next dose is based on a 28-day safety observation period. Part B explores the pharmacologically relevant Lu AG13909 doses identified in Part A in a larger number of participants. The aim is for a total of 12 participants to receive each of the dose levels identified as relevant. Outcomes The primary safety and tolerability endpoints include adverse events and clinical safety tests. PK endpoints include maximum observed exposure and area under the Lu AG13909 concentration-time curve in a dosing interval. The PD endpoints are the relative reductions in morning 17-hydroxyprogesterone, androstenedione, and unbound ACTH, from baseline to the day after each Lu AG13909 dose. Conclusions This innovative, multi-dose, intra-participant dose escalation trial design was developed specifically for the rare classic CAH population, who have a high unmet medical need due to the challenges with current glucocorticoid treatment. The aim of the trial is to gather safety, PK, and PD data while minimizing participant risk and burden. Data from this trial will reinforce the development of Lu AG13909 as a novel treatment strategy in conditions characterized by increased levels of ACTH, such as classic CAH and Cushing disease. Presentation: 6/3/2024

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2024-08-30 | Therapeutical Usefulness of PD-1/PD-L1 Inhibitors in Aggressive or Metastatic Pituitary Tumours

Therapeutic options for pituitary neuroendocrine tumours (PitNETs) refractory to temozolomide are scarce. Immune checkpoint inhibitors (ICIs), particularly inhibitors of the programmed cell death-1 (PD-1) pathway and its ligand (PD-L1), have been experimentally used in aggressive or metastatic PitNETs. We aimed to study the therapeutic usefulness of anti-PD-1 drugs in patients with aggressive or metastatic PitNETs. Published cases and case series involving patients with PitNETs treated with PD-1/PD-L1 inhibitors were reviewed. Demographic data, clinical–pathological features, previous therapies, drug dosage and posology, and the best radiological and biochemical responses, as well as survival data, were evaluated. We identified 29 cases of aggressive (n = 13) or metastatic (n = 16) PitNETs treated with PD-1/PD-L1 inhibitors. The hypersecretion of adrenocorticotropic hormone (ACTH) was documented in eighteen cases (62.1%), seven were prolactinomas (24.1%), and four were non-functioning PitNETs. All patients underwent various therapies prior to using ICIs. Overall, a positive radiological response (i.e., partial/complete radiological response and stable disease) was observed in eighteen of twenty-nine cases (62.1%), of which ten and four were ACTH- and prolactin-secreting PitNETs, respectively. Hormonal levels reduced or stabilised after using ICIs in 11 of the 17 functioning PitNET cases with available data (64.7%). The median survival of patients treated with ICIs was 13 months, with a maximum of 42 months in two ACTH-secreting tumours. Among 29 patients with PitNETs treated with PD-1/PD-L1 inhibitors, the positive radiological and biochemical response rates were 62.1% and 64.7%, respectively. Altogether, these data suggest a promising role of ICIs in patients with aggressive or metastatic PitNETs refractory to other treatment modalities.

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2026-06-26 | Hydrogel-based lineage-specific gene therapy prevents recurrence of corticotroph tumors.

Pituitary corticotroph tumors are the primary cause of Cushing's disease. Even after transsphenoidal surgery, residual tumor cells frequently persist, leading to a recurrence rate of approximately 20%. However, safe and effective adjuvant treatments for these residual lesions are lacking. In this study, we analyzed single-cell RNA sequencing data to characterize the transcriptional profile of corticotroph tumors. On the basis of the high activity of the POMC promoter and its transcriptional regulators, we designed an adeno-associated virus vector carrying the pro-apoptotic gene Puma, with expression controlled by the Pomc promoter for lineage-specific targeting. We also developed an injectable, self-assembling peptide hydrogel for the sustained local delivery of the Puma gene and tested its therapeutic efficacy in subcutaneous and post-resection mouse models. Results showed the Pomc promoter drove selective Puma expression in corticotroph tumor cells, inducing mitochondrial membrane potential loss and apoptosis in vitro. In vivo, the virus suppressed tumor growth and lessened systemic tumor effects; when delivered via the hydrogel into surgical cavities, it completely eliminated residual tumors without detectable toxicity in major organs. This targeted, localized strategy, thus has translational potential as an adjuvant therapy for reducing the recurrence of Cushing's disease.

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2026-01-22 | Resistant Hypertension: Integration of Novel Agents and Interventional Approaches in Clinical Practice

Resistant hypertension (RH) is a high-risk phenotype characterized by blood pressure readings ≥130/80 mmHg despite maximally tolerated therapy with three antihypertensive agents, including a diuretic, or controlled blood pressure requiring four or more medications. The diagnosis of RH requires a structured evaluation that confirms accurate blood pressure measurement, excludes pseudoresistance-particularly nonadherence and white coat hypertension-and identifies secondary causes such as obstructive sleep apnea, primary aldosteronism, renovascular disease, pheochromocytoma, and Cushing syndrome. RH arises from overlapping mechanisms, including activation of the renin-angiotensin-aldosterone system (RAAS), sympathetic overactivity, arterial stiffness, volume expansion, and immune-mediated pathways. Management begins with lifestyle modification and optimized triple therapy, followed by mineralocorticoid receptor antagonists as the preferred fourth-line treatment. Emerging pharmacological options, such as sodium-glucose cotransporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, endothelin receptor antagonists, aldosterone synthase inhibitors, and angiotensin receptor and neprilysin inhibitors (ARNIs), offer additional therapeutic potential; meanwhile, device-based interventions, including renal denervation and baroreflex activation therapy, have shown sustained blood pressure reductions in selected patients. Future directions highlight precision medicine, digital health technologies, and artificial intelligence as methods to improve diagnosis, guide individualized therapy, and enhance long-term blood pressure control.

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2024-10-01 | 6589 Antisense Oligonucleotides for Reducing ACTH Secretion in a Model of Cushing's Disease

Abstract Disclosure: M.S. Varughese: None. H. Eltumi: None. E.H. Kemp: None. J.D. Newell-Price: None. Antisense Oligonucleotides for Reducing ACTH Secretion in a Model of Cushing’s Disease Background: Cushing’s disease (CD) is a multi-system disorder with high morbidity and mortality characterised by pathologically raised serum cortisol due excess expression of proopiomelanocortin (Pomc) and overproduction of ACTH by a pituitary corticotroph adenoma. Trans-sphenoidal adenomectomy is the treatment of choice, but there is a 30% recurrence rate over time. Advances in medical therapy are needed. Antisense oligonucleotides (ASOs) can silence mRNA translation by specific base-pairing. Locked nucleic acid (LNA) and 2’-O-methyl (OMe) ribose terminals make ASOs more effective by improving affinity and resistance to nuclease degradation. Aims: To investigate the effectiveness of LNA- and OMe-modified anti-Pomc ASOs at reducing ACTH secretion from murine adrenotropic tumour (AtT20) cells. To analyse the nuclease resistance of Pomc ASOs and their ability to drive an immune response. Methods: Two ASOs (ASO2 and ASO3) were designed against Pomc with phosphorothioate backbones modified with either LNA or OMe ribose terminals. These were used in lipofectamine-mediated cell transfections of AtT20 cells and ACTH in the culture medium measured by immunoassay. ASO stability was assessed by nuclease degradation assays and immunogenicity by cytokine ELISAs. Results: When compared with untreated AtT20 cells, LNA- and OMe-modified Pomc ASOs at 1 nM significantly suppressed ACTH secretion for up to 120 h and 96 h, respectively (n = 4; Unpaired t tests, all P values &lt; 0.05). In contrast, control treatments, including scrambled and mismatched ASOs, did not cause a significant reduction. For comparison, 1 nM of ASO2-OMe, ASO2-LNA, ASO3-OMe and ASO3-LNA lowered ACTH at 24 h by 62%, 71%, 63% and 79%, respectively. Modified Pomc ASOs showed 14-31% degradation over a 120-min incubation period with 3’- and 5’-exonucleases, whilst equivalent unmodified Pomc ASOs were completely degraded. No secretion of IFN-α, IFN-β, TNF-α, IL-6 or IL-1β was detected following transfection of AtT20 cells with Pomc ASOs. Conclusions:Pomc ASOs caused significant reduction of ACTH secretion from AtT-20 cells. LNA-modified Pomc ASOs were more effective than those with OMe modifications, with neither stimulating a detectable immune response. These ASOs hold promise as a systemic therapy for Cushing’s disease. Presentation: 6/3/2024

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2023-01-20 | Germline loss-of-function PAM variants are enriched in subjects with pituitary hypersecretion.

Abstract Pituitary adenomas (PAs) are common, usually benign tumors of the anterior pituitary gland which, for the most part, have no known genetic cause. PAs are associated with major clinical effects due to hormonal dysregulation and tumoral impingement on vital brain structures. Following the identification of a loss-of-function variant (p.Arg703Gln) in the PAM gene in a family with pituitary gigantism, we investigated 299 individuals with sporadic PAs and 17 familial isolated pituitary adenomas kindreds for PAM variants. PAM encodes a multifunctional protein responsible for the essential C-terminal amidation of secreted peptides. Genetic screening was performed by germline and tumor sequencing and germline copy number variation (CNV) analysis. No germline CNVs or somatic single nucleotide variants (SNVs) were identified. We detected seven likely pathogenic heterozygous missense, truncating, and regulatory SNVs. These SNVs were found in sporadic subjects with GH excess (p.Gly552Arg and p.Phe759Ser), pediatric Cushing disease (c.-133T>C and p.His778fs), or with different types of PAs (c.-361G>A, p.Ser539Trp, and p.Asp563Gly). The SNVs were functionally tested in vitro for protein expression and trafficking by Western blotting, for splicing by minigene assays, and for amidation activity in cell lysates and serum samples. These analyses confirmed a deleterious effect on protein expression and/or function. By interrogating 200,000 exomes from the UK Biobank, we confirmed a significant association of the PAM gene and rare PAM SNVs to diagnoses linked to pituitary gland hyperfunction. Identification of PAM as a candidate gene associated with pituitary hypersecretion opens the possibility of developing novel therapeutics based on altering PAM function.

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2023-01-05 | Early post-natal life stress induces permanent adrenocorticotropin-dependent hypercortisolism in male mice.

It has been hypothesized that specific early-life stress (ES) procedures on CD-1 male mice produce diabetes-like alterations due to the failure of negative feedback of glucocorticoid hormone in the pituitary. The aim of this study is to investigate the possible mechanism that leads to this pathological model, framing it in a more specific clinical condition. Metabolic and hypothalamic-pituitary-adrenal-related hormones of stressed mice (SM) have been analyzed immediately after stress procedures (21 postnatal days, PND) and after 70 days of a peaceful (unstressed) period (90 PND). These data have been compared to parameters from age-matched controls (CTR), and mice treated during ES procedures with oligonucleotide antisense for pro-opiomelanocortin (AS-POMC). At 21 PND, SM presented an increased secretion of hypothalamic CRH and pituitary POMC-derived peptides, as well as higher plasmatic levels of ACTH and corticosterone vs. CTR. At 90 PND, SM showed hyperglycemia, with suppression of hypothalamic CRH, while pituitary and plasmatic ACTH levels, as well as plasma corticosterone, were constantly higher than in CTR. These values are accompanied by a progressive acceleration in gaining total body weight, which became significant vs. CTR at 90 PND together with a higher pituitary weight. Treatment with AS-POMC prevented all hormonal and metabolic alterations observed in SM, both at 21 and 90 PND. These findings show that these specific ES procedures affect the negative glucocorticoid feedback in the pituitary, but not in the hypothalamus, suggesting a novel model of ACTH-dependent hypercortisolism that can be prevented by silencing the POMC gene.

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