Glucose intolerance in acromegaly is driven by low insulin secretion; results from an intravenous glucose tolerance test.

PURPOSE: Insulin sensitivity (Si) and its role in glucose intolerance of acromegaly has been extensively evaluated. However, data on insulin secretion is limited. We aimed to assess stimulated insulin secretion using an intravenous glucose tolerance test (IVGTT) in active acromegaly. METHODS: We performed an IVGTT in 25 patients with active acromegaly (13 normal glucose tolerance [NGT], 6 impaired glucose tolerance [IGT] and 6 diabetes mellitus [DM]) and 23 controls (8 lean NGT, 8 obese NGT and 7 obese IGT). Serum glucose and insulin were measured at 20 time points along the test to calculate Si and acute insulin response (AIRg). Medical treatment for acromegaly or diabetes was not allowed. RESULTS: In acromegaly, patients with NGT had significantly (p for trend < 0.001) higher AIRg (3383 ± 1082 pmol*min/L) than IGT (1215 ± 1069) and DM (506 ± 600). AIRg was higher in NGT (4764 ± 1180 pmol*min/L) and IGT (3183 ± 3261) controls with obesity than NGT (p = 0.01) or IGT (p = 0.17) acromegaly. Si was not significantly lower in IGT (0.68 [0.37, 0.88] 106*L/pmol*min) and DM (0.60 [0.42, 0.84]) than in NGT (0.81 [0.58, 1.55]) patients with acromegaly. NGT (0.33 [0.30, 0.47] 106*L/pmol*min) and IGT (0.37 [0.21, 0.66]) controls with obesity had lower Si than NGT (p = 0.001) and IGT (p = 0.43) acromegaly. CONCLUSION: We demonstrated that low insulin secretion is the main driver behind glucose intolerance in acromegaly. Compared to NGT and IGT controls with obesity, patients with NGT or IGT acromegaly had higher Si. Together, these findings suggest that impaired insulin secretion might be a specific mechanism for glucose intolerance in acromegaly.

Plurihormonal Pituitary Neuroendocrine Tumors: Clinical Relevance of Immunohistochemical Analysis.

Plurihormonal pituitary neuroendocrine tumors (PitNETs) are rare forms of tumors that express more than one hormone. The most common association is between growth hormone (GH) and prolactin (PRL), but other unusual combinations have been reported, such as GH and ACTH. Usually, the clinical dominance in these cases is related to GH hypersecretion. In these cases, immunohistochemistry (IHC) of transcription factors (TFs) is very useful for an accurate diagnosis. We included 42 patients diagnosed with pituitary neuroendocrine tumors (PitNETs): 37 patients with a confirmed diagnosis of acromegaly, and 5 patients with prolactinomas. All patients underwent transsphenoidal surgical intervention. We correlated the immunohistochemical features of plurihormonal PitNETs with clinical, hormonal, and imaging data. Tumor specimens were histologically and immunohistochemically examined. Based on the 2022 WHO classification, using IHC, 13 patients exhibited positive staining for more than one hormone, while unusual combinations like GH + ACTH and PRL + ACTH were also identified in other cases. Unusual cell combinations that produce hormones unrelated histogenetically, biochemically, or through regulatory mechanisms can appear and may display aggressive behavior, persistent disease, and high recurrence. We have not identified a clear correlation with the prognosis of these rare PitNETs.

The Value of ER∝ in the Prognosis of GH- and PRL-Secreting PitNETs: Clinicopathological Correlations.

Pituitary neuroendocrine tumors (PitNETs) are divided into multiple histological subtypes, which determine their clinical and biological variable behavior. Despite their benign evolution, in some cases, prolactin (PRL) and growth hormone (GH)-secreting PitNETs may have aggressive behavior. In this study, we investigated the potential predictive role of ER∝, alongside the clinicopathological classification of PitNETs (tumor diameter, tumor type, and tumor grade). A retrospective study was conducted with 32 consecutive cases of PRL- and mixed GH- and PRL-secreting PitNETs (5 patients with prolactinomas and 27 with acromegaly, among them, 7 patients with GH- and PRL- co-secretion) who underwent transsphenoidal intervention. Tumor specimens were histologically and immunohistochemical examined: anterior pituitary hormones, ki-67 labeling index, CAM 5.2, and ER∝; ER∝ expression was correlated with basal PRL levels at diagnosis (rho = 0.60, p < 0.01) and postoperative PRL levels (rho = 0.58, p < 0.001). In our study, the ER∝ intensity score was lower in female patients. Postoperative maximal tumor diameter correlated with Knosp grade (p = 0.02); CAM 5.2 pattern (densely/sparsely granulated/mixed densely and sparsely granulated) was correlated with postoperative PRL level (p = 0.002), and with ki-67 (p < 0.001). The IGF1 level at diagnosis was correlated with the postoperative GH nadir value in the oral glucose tolerance test (OGTT) (rho = 0.52, p < 0.05). Also, basal PRL level at diagnosis was correlated with postoperative tumor diameter (p = 0.63, p < 0.001). At univariate logistic regression, GH nadir in OGTT test at diagnostic, IGF1, gender, and invasion were independent predictors of remission for mixed GH- and PRL-secreting Pit-NETs; ER∝ can be used as a prognostic marker and loss of ER∝ expression should be considered a sign of lower differentiation and a likely indicator of poor prognosis. A sex-related difference can be considered in the evolution and prognosis of these tumors, but further studies are needed to confirm this hypothesis.

Prognostic Models in Growth-Hormone- and Prolactin-Secreting Pituitary Neuroendocrine Tumors: A Systematic Review.

Growth-hormone (GH)- and prolactin (PRL)-secreting PitNETs (pituitary neuroendocrine tumors) are divided into multiple histological subtypes, which determine their clinical and biological variable behavior. Proliferation markers alone have a questionable degree of prediction, so we try to identify validated prognostic models as accurately as possible. (1) Background: The data available so far show that the use of staging and clinical-pathological classification of PitNETs, along with imaging, are useful in predicting the evolution of these tumors. So far, there is no consensus for certain markers that could predict tumor evolution. The application of the WHO (World Health Organisation) classification in practice needs to be further evaluated and validated. (2) Methods: We performed the CRD42023401959 protocol in Prospero with a systematic literature search in PubMed and Web of Science databases and included original full-text articles (randomized control trials and clinical trials) from the last 10 years, published in English, and the search used the following keywords: (i) pituitary adenoma AND (prognosis OR outcome OR prediction), (ii) growth hormone pituitary adenoma AND (prognosis OR outcome OR prediction), (iii) prolactin pituitary adenoma AND (prognosis OR outcome OR prediction); (iv) mammosomatotroph adenoma AND (prognosis OR outcome OR prediction). (3) Results: Two researchers extracted the articles of interest and if any disagreements occurred in the selection process, these were settled by a third reviewer. The articles were then assessed using the ROBIS bias assessment and 75 articles were included. (4) Conclusions: the clinical-pathological classification along with factors such as GH, IGF-1, prolactin levels both preoperatively and postoperatively offer valuable information.

Clinicopathological Features of Growth Hormone-producing Pituitary Adenomas and Correlation With Preoperative Laboratory Findings.

BACKGROUND/AIM: The histopathological variability of each type of pituitary adenoma (PA) that causes growth hormone (GH) excess influences the phenotype, radiological characteristics and therapy response of acromegaly patients. We correlated the immunohistochemical (IHC) features of GH-secreting PAs with their clinical, laboratory and imaging data. PATIENTS AND METHODS: We included 32 patients with documented acromegaly; tumour specimens were histologically and IHC examined: anterior pituitary hormones, pituitary-specific transcription factor-1 (PIT-1), Ki-67 labelling index were evaluated. RESULTS: Macroadenomas represented 93.75%. Post-surgery disease control negatively correlated with the maximum initial tumour diameter (p=0.04). Ki-67 did not predict remission. No correlation was found between GH serum levels and IHC expression (p=0.45). PIT-1 was positive in all specimens, two had a weak expression. Four were considered PIT-1 positive plurihormonal adenomas and several had unusual IHC combinations. CONCLUSION: PIT-1 accurately classifies GH-secreting PAs. The IHC classification as well as radiological dimensions and extent influence disease control, probably being the best prognosis factors.

Pituitary transcription factors in the immunohistochemical and molecular diagnosis of pituitary tumours - a systematic review.

INTRODUCTION: Although histopathology remains in the first line of the diagnosis of pituitary pathology, immunohistochemistry and molecular biology are currently in charge of providing a more accurate characterisation of tumours in this field. MATERIAL AND METHODS: A systematic review of the literature was performed, using the PubMed and SCOPUS databases, with terms that included transcription factors involved in the development of pituitary tumours: T-PIT, PIT-1, and SF-1. RESULTS: The results showed different perspectives, but the evidence is in favour of a multifold immunohistochemical analysis that must include pituitary transcription factors for a highly accurate diagnosis, prognosis, and guidance of (multimodal) therapy. CONCLUSIONS: By using transcription factors, the understanding of the structure and function of the recently defined pituitary neuroendocrine tumours has made significant progress. This approach brings the (sub)classification of pituitary tumours, using cell types and cell lineages, with clinical and molecular implications and therapeutic results.