Treatment of acromegaly with oral octreotide.

Acromegaly is a rare disease caused by a growth hormone excess, usually due to a secreting pituitary adenoma. Somatostatin receptor ligands (SRL) are the mainstay of medical therapy for patients with acromegaly who fail to achieve biochemical control post-operatively or are not eligible for surgical treatment. SRLs are typically administered as monthly injections and have shown to be effective in maintaining biochemical and radiological control of acromegaly. However, these injections may cause local adverse events and are associated with increased psychological burden in some patients. Oral octreotide provides a new alternative for patients responding to injectable SRLs. This new formulation has shown to have similar safety and efficacy profiles compared to injectable SRLs and may be a preferable option for some patients with acromegaly. The aim of this review is to provide an overview of the role of oral octreotide in the management of acromegaly.

Autoimmune Disorders Associated With Surgical Remission of Cushing's Disease : A Cohort Study.

BACKGROUND: Glucocorticoids suppress inflammation. Autoimmune disease may occur after remission of Cushing's disease (CD). However, the development of autoimmune disease in this context is not well described. OBJECTIVE: To determine 1) the incidence of autoimmune disease in patients with CD after surgical remission compared with patients with nonfunctioning pituitary adenomas (NFPAs) and 2) the clinical presentation of and risk factors for development of autoimmune disease in CD after remission. DESIGN: Retrospective matched cohort analysis. SETTING: Academic medical center/pituitary center. PATIENTS: Patients with CD with surgical remission and surgically treated NFPA. MEASUREMENTS: Cumulative incidence of new-onset autoimmune disease at 3 years after surgery. Assessment for hypercortisolemia included late-night salivary cortisol levels, 24-hour urine free cortisol (UFC) ratio (UFC value divided by the upper limit of the normal range for the assay), and dexamethasone suppression tests. RESULTS: Cumulative incidence of new-onset autoimmune disease at 3 years after surgery was higher in patients with CD (10.4% [95% CI, 5.7% to 15.1%]) than in those with NFPAs (1.6% [CI, 0% to 4.6%]) (hazard ratio, 7.80 [CI, 2.88 to 21.10]). Patients with CD showed higher prevalence of postoperative adrenal insufficiency (93.8% vs. 16.5%) and lower postoperative nadir serum cortisol levels (63.8 vs. 282.3 nmol/L) than patients with NFPAs. Compared with patients with CD without autoimmune disease, those who developed autoimmune disease had a lower preoperative 24-hour UFC ratio (2.7 vs. 6.3) and a higher prevalence of family history of autoimmune disease (41.2% vs. 20.9%). LIMITATION: The small sample of patients with autoimmune disease limited identification of independent risk factors. CONCLUSION: Patients achieving surgical remission of CD have higher incidence of autoimmune disease than age- and sex-matched patients with NFPAs. Family history of autoimmune disease is a potential risk factor. Adrenal insufficiency may be a trigger. PRIMARY FUNDING SOURCE: Recordati Rare Diseases Inc.

A novel approach to hypophysitis: outcomes using non-glucocorticoid immunosuppressive therapy.

OBJECTIVE: To determine pituitary function before and after nonglucocorticoid immunosuppressive therapy (NGIT) in subjects with hypophysitis and evaluate their clinical and radiologic outcomes. DESIGN: Retrospective, longitudinal study. METHODS: We reviewed a large database, selected subjects with hypophysitis treated with NGIT, and collected information on the duration of therapy, and clinical, hormonal, and radiologic outcomes. RESULTS: Twelve subjects met the inclusion criteria. Five subjects had primary hypophysitis (PH), while seven had secondary hypophysitis (SH) due to an underlying systemic inflammatory disease. Mean age ± SD was 48.0 ± 15.7 years and 40.9 ± 13.0 years, for PH and SH, respectively. The majority were female (PH 60% and SH 86%). BMI ± SD at presentation was 25.2 ± 2.5 kg/m2 and 26.8 ± 6.7 kg/m2 for PH and SH, respectively. The most common symptom at presentation was fatigue (75%). All PH subjects (100%) and 2 (28.6%) SH subjects had polyuria/polydipsia. There was a significant decrease in mean pituitary stalk thickness after NGIT (P = .0051) (mean duration 16.5 ± 4.8 months). New hormone loss or recovery occurred rarely. Mycophenolate mofetil was the most used NGIT: adverse effects prompted discontinuation in 2 out of 7 subjects. CONCLUSIONS: Subjects with hypophysitis receiving NGIT had stable or improved brain/pituitary magnetic resonance imaging findings with a significant decrease in pituitary stalk thickness. NGITs did not improve anterior pituitary function. Our findings suggest that NGIT may be considered as an alternative therapy for patients with hypophysitis who require immunosuppression.

The hallmarks of cancer in pituitary tumors?

Over 20 years ago, Hanahan and Weinberg published a seminal review that addressed the biological processes that underly malignant transformation. This classical review, along with two revisions published in 2011 and 2022, has remain a classic of the oncology literature. Since many of the addressed biological processes may apply to non-malignant tumorigenesis, we evaluated to what extent these hallmarks pertain to the development of pituitary adenomas.Some of the biological processes analyzed in this review include genome instability generated by somatic USP8 and GNAS mutations in Cushing's diseases and acromegaly respectively; non-mutational epigenetic reprograming through changes in methylation; induction of angiogenesis through alterations of VEGF gene expression; promotion of proliferative signals mediated by EGFR; evasion of growth suppression by disrupting cyclin dependent kinase inhibitors; avoidance of immune destruction; and the promotion of inflammation mediated by alteration of gene expression of immune check points. We also elaborate further on the existence of oncogene induced senescence in pituitary tumors. We conclude that a better understanding of these processes can help us dilucidated why pituitary tumors are so resistant to malignant transformation and can potentially contribute to the development of novel anticancer treatments.

Reply to Scarpati, G.; Piazza, O. Comment on "Guerrero-Romero et al. Magnesium-to-Calcium Ratio and Mortality from COVID-19. Nutrients 2022, 14, 1686".

We thank Dr. Scarpati and Dr. Piazza for their interest and comments [...].

Magnesium-to-Calcium Ratio and Mortality from COVID-19.

Obesity, type 2 diabetes, arterial hypertension, decrease in immune response, cytokine storm, endothelial dysfunction, and arrhythmias, which are frequent in COVID-19 patients, are associated with hypomagnesemia. Given that cellular influx and efflux of magnesium and calcium involve the same transporters, we aimed to evaluate the association of serum magnesium-to-calcium ratio with mortality from severe COVID-19. The clinical and laboratory data of 1064 patients, aged 60.3 ± 15.7 years, and hospitalized by COVID-19 from March 2020 to July 2021 were analyzed. The data of 554 (52%) patients discharged per death were compared with the data of 510 (48%) patients discharged per recovery. The ROC curve showed that the best cut-off point of the magnesium-to-calcium ratio for identifying individuals at high risk of mortality from COVID-19 was 0.20. The sensitivity and specificity were 83% and 24%. The adjusted multivariate regression model showed that the odds ratio between the magnesium-to-calcium ratio ≤0.20 and discharge per death from COVID-19 was 6.93 (95%CI 1.6-29.1) in the whole population, 4.93 (95%CI 1.4-19.1, p = 0.003) in men, and 3.93 (95%CI 1.6-9.3) in women. In conclusion, our results show that a magnesium-to-calcium ratio ≤0.20 is strongly associated with mortality in patients with severe COVID-19.

The Genomic Landscape of Corticotroph Tumors: From Silent Adenomas to ACTH-Secreting Carcinomas.

Corticotroph cells give rise to aggressive and rare pituitary neoplasms comprising ACTH-producing adenomas resulting in Cushing disease (CD), clinically silent ACTH adenomas (SCA), Crooke cell adenomas (CCA) and ACTH-producing carcinomas (CA). The molecular pathogenesis of these tumors is still poorly understood. To better understand the genomic landscape of all the lesions of the corticotroph lineage, we sequenced the whole exome of three SCA, one CCA, four ACTH-secreting PA causing CD, one corticotrophinoma occurring in a CD patient who developed Nelson syndrome after adrenalectomy and one patient with an ACTH-producing CA. The ACTH-producing CA was the lesion with the highest number of single nucleotide variants (SNV) in genes such as USP8, TP53, AURKA, EGFR, HSD3B1 and CDKN1A. The USP8 variant was found only in the ACTH-CA and in the corticotrophinoma occurring in a patient with Nelson syndrome. In CCA, SNV in TP53, EGFR, HSD3B1 and CDKN1A SNV were present. HSD3B1 and CDKN1A SNVs were present in all three SCA, whereas in two of these tumors SNV in TP53, AURKA and EGFR were found. None of the analyzed tumors showed SNV in USP48, BRAF, BRG1 or CABLES1. The amplification of 17q12 was found in all tumors, except for the ACTH-producing carcinoma. The four clinically functioning ACTH adenomas and the ACTH-CA shared the amplification of 10q11.22 and showed more copy-number variation (CNV) gains and single-nucleotide variations than the nonfunctioning tumors.

Neuroendocrine-immune Interface: Interactions of Two Complex Systems in Health and Disease.

The relationship between the neuroendocrine and the immune systems is essential to maintain homeostasis. Their complex interactions are present in many physiological or pathological states whereby hormones exert different actions in immune system cells and vice versa. Hormones such as prolactin, growth hormone, cortisol and sex hormones are known to regulate the differentiation and function of immune system cells and the production of cytokines. Many of these cells express hormone receptors leading to the tempering of several autoimmune and neoplastic diseases. The pituitary gland is susceptible to autoimmune damage, be it because of primary lymphocytic hypophysitis, as part of IgG4-related disease or as an adverse event of treatment with immune checkpoint inhibitors (ICi). Finally, pituitary adenomas, like many other neoplasms, are frequently infiltrated by different cells of the immune system, a phenomenon that can be related to the degree of invasiveness of these lesions. The purpose of the present work is to critically analyze the neuroendocrine-immune interphase, from both a biological and a clinical perspective.

[Acromegaly and it's cardiovascular implications]. / Acromegalia y sus implicaciones cardiovasculares.

Acromegaly is a chronic and slowly progressive disease that results from the hypersecretion of growth hormone (GH) and consequently insulin-like growth factor type 1 (IGF-1), due to a GH-secreting pituitary adenoma in 95-98% of cases. There are several complications or co-morbidities associated with acromegaly, the most frequent being cardiovascular, metabolic and neoplastic. The cardiovascular complications of acromegaly go from arterial hypertension to a peculiar form of cardiomyopathy and are the result of the long-standing exposure to high GH and IGF-1 levels. The pathophysiology of these complications is complex and includes an increased tubular reabsorption of sodium and the direct effects of GH and IGF-1 on the endothelium and the cardiac tissue itself. Frequently, the cardiovascular comorbidities of acromegaly occur concomitantly with metabolic complications such as diabetes and respiratory abnormalities such as the sleep apnea syndrome. In this brief review we analyze the pathophysiology, the clinical manifestations and the management of the cardiovascular complications of acromegaly.

La acromegalia es una enfermedad crónica lentamente progresiva causada por la hipersecreción de hormona de crecimiento (GH) y consecuentemente de factor de crecimiento insulinoide tipo 1 (IGF-1), originada en el 95-98% de las ocasiones por un adenoma hipofisario secretor de GH. Existen diversas complicaciones o comorbilidad asociadas a la acromegalia, de las cuales destacan las enfermedades cardiovasculares, metabólicas y neoplásicas. Las complicaciones cardiovasculares van desde la hipertensión arterial hasta la cardiomiopatía acromegálica, y resultan de la exposición crónica a valores elevados de GH y de IGF-1. La fisiopatología de estas complicaciones es compleja e incluye tanto un aumento en la reabsorción tubular de sodio como efectos directos de la GH y del IGF-1 sobre el endotelio vascular y las células cardiacas. Con frecuencia estas alteraciones cardiovasculares ocurren simultáneamente con trastornos metabólicos como la diabetes y trastornos respiratorios como la apnea del sueño, y son agravadas por ellos. En esta breve revisión se analizan la fisiopatología, las manifestaciones clínicas y el manejo de las complicaciones cardiovasculares de la acromegalia.