Context Discordant GH and IGF-1 values are frequent in acromegaly. Objective To evaluate the impact of different GH cut-offs on discordance rate. To investigate whether the mean of consecutive GH measurements impact discordance rate when matched to the last available IGF-1 value. Design Retrospective study. Setting Referral centre for pituitary diseases. Patients Ninety acromegaly patients with at least three consecutive evaluations for GH and IGF-1 using the same assay in the same laboratory (median follow-up 13 years). Interventions Multimodal treatment of acromegaly. Main outcome measures Single fasting GH (GH_f) and IGF-1 (IGF-1_f). Mean of three GH measurements (GH_m), collected during consecutive routine patients’ evaluations. Results At last evaluation GH_f values were 1.99 ± 2.79 µg/L and age-adjusted IGF-1_f 0.86 ± 0.44 xULN (mean ± SD). Discordance rate using GH_f was 52.2% (cut-off 1 µg/L) and 35.6% (cut-off 2.5 µg/L) (p=0.025). “High GH” discordance was more common for GH_f <1.0 µg/L, while “high IGF-1” was predominant for GH_f <2.5 µg/L (p<0.0001). Using GH_m mitigated the impact of GH cut-offs on discordance (GH_m <1.0 µg/L: 43.3%; GH_m <2.5 µg/L: 38.9%; p=0.265). At ROC curve analysis, both GH_f and GH_m were poor predictors of IGF-1_f normalization (AUC=0.611 and AUC=0.645, respectively). The prevalence of disease-related comorbidities did not significantly differ between controlled, discordant, and active disease patients. Discussion GH/IGF-1 discordance strongly depends on GH cut-offs. The use of GH_m lessen the impact of GH cut-offs. Measurement of fasting GH levels (both GH_f and GH_m) is a poor predictor of IGF-1_f normalization in our cohort.

Objective: The aim of this study was to develop an open-source and reproducible digital quantitative analysis (DIA) of somatostatin receptor subtype 2a (SST₂) staining in formalin-fixed paraffin-embedded tissues of pancreatic neuroendocrine tumors (panNETs) and growth hormone (GH)-secreting pituitary adenomas (GHomas). Design: SST₂ immunostaining of 18 panNETs and 39 GHomas was assessed using a novel DIA protocol and compared with a widely used semi-quantitative immunoreactivity score (IRS). Methods: The DIA software calculates the staining intensity/area and the percentage of positive cells (%PC). Four representative images were selected for each sample by two independent selectors (S₁ and S₂), with the analysis performed by two independent analyzers (A₁ and A₂). Agreement between observers was calculated using the concordance correlation coefficient (CCC). Results: In panNETs, the CCC ranged 0.935–0.977 for intensity/area and 0.942–0.983 for %PC. In GHomas, the CCC ranged 0.963–0.997 for intensity/area and 0.979–0.990 for %PC. In both panNETs and GHomas, the DIA staining intensity was strongly correlated with the IRS (Spearman rho: 0.916–0.969, P < 0.001), as well as the DIA %PC with the IRS %PC (Spearman rh: 0.826–0.881, P < 0.001). In GHomas, the biochemical response to somatostatin receptor ligands correlated with SST₂ expression, evaluated both as DIA intensity/area (Spearman rho: −0.448 to −0.527, P = 0.007–0.004) and DIA %PC (Spearman rho: −0.558 to −0.644, P ≤ 0.001). Conclusions: The DIA has an excellent inter-observer agreement and showed a strong correlation with the widely used semi-quantitative IRS. The DIA protocol is an open-source, highly reproducible tool and provides a reliable quantitative evaluation of SST₂ immunohistochemistry.

Acromegaly is a rare endocrine disorder caused by excessive growth hormone (GH) production, due, in the vast majority of cases, to the presence of a GH-secreting pituitary tumour. The chronic elevation of GH and the resulting high circulating levels of insulin-like growth factor-1 (IGF-1) cause the characteristic tissue overgrowth and a number of associated comorbidities, including several metabolic changes, such as glucose intolerance and overt diabetes mellitus (DM). Elevated GH concentrations directly attenuate insulin signalling and stimulate lipolysis, decreasing glucose uptake in peripheral tissues, thus leading to the development of impaired glucose tolerance and DM. Acromegaly treatment aims to normalize plasma GH and IGF-1 levels using surgery, medical treatment, or radiotherapy. The effect of the different medical therapies on glucose homeostasis varies. This literature review explores the impact of the currently available pharmacological therapies for acromegaly (first- and second-generation somatostatin receptor ligands, a GH receptor antagonist, and dopamine agonists) on glucose homeostasis. We also discuss the underlying biological mechanisms through which they impact glucose metabolism.

First-generation somatostatin receptor ligands (fg-SRLs), such as octreotide (OCT), represent the first-line medical therapy in acromegaly. Fg-SRLs show a preferential binding affinity for somatostatin receptor subtype-2 (SST₂), while the second-generation ligand, pasireotide (PAS), has high affinity for multiple SSTs (SST₅ > SST₂ > SST₃ > SST₁). Whether PAS acts via SST₂ in somatotroph tumors, or through other SSTs (e.g., SST₅), is a matter of debate. In this light, the combined treatment OCT+PAS could result in additive/synergistic effects. We evaluated the efficacy of OCT and PAS (alone and in combination) on growth hormone (GH) secretion in primary cultures from human somatotroph tumors, as well as on cell proliferation, intracellular signaling and receptor trafficking in the rat GH4C1 cell line. The results confirmed the superimposable efficacy of OCT and PAS in reducing GH secretion (primary cultures), cell proliferation, cAMP accumulation and intracellular [Ca²⁺] increase (GH4C1 cells), without any additive effect observed for OCT+PAS. In GH4C1 cells, co-incubation with a SST₂-selective antagonist reversed the inhibitory effect of OCT and PAS on cell proliferation and cAMP accumulation, while both compounds resulted in a robust internalization of SST₂ (but not SST₅). In conclusion, OCT and PAS seem to act mainly through SST₂ in somatotroph tumor cells in vitro, without inducing any additive/synergistic effect when tested in combination.

Immunohistochemistry (IHC) of somatostatin receptor subtype 2 can predict response to first-generation somatostatin receptor ligands (fg-SRLs) in acromegaly. Recently, we validated an open-source digital image analysis (DIA) to quantify somatostatin receptor subtype 2 (SSTR2) expression. We aimed to validate the DIA also on somatostatin receptor subtype 5 (SSTR5) in a new cohort of growth hormone (GH)-secreting pituitary tumors, with IHC performed in a different laboratory, and to correlate fg-SRL response with SSTs expression. Somatostatin receptor subtype 2 and SSTR5 were assessed in 42 GH-secreting pituitary tumors, using a semiquantitative immunoreactivity score (IRS) and the DIA by use of the open-access software CellProfiler. The DIA calculates the staining intensity and the percentage of positive cells (%PC). We found a good correlation between IRS and DIA for both SSTR2 and SSTR5 (P < .001), demonstrating the reliability of the DIA in this setting. Response to fg-SRL treatment correlated with SSTR2, but not SSTR5, expression. Somatostatin receptor subtype 2 expression predicted response to fg-SRL. In particular, the identified cut-offs were IRS ≥ 5 (area under the curve [AUC] 0.763; sensitivity 77%; specificity 83%); intensity/area ≥0.106 (AUC 0.833; sensitivity 92%; specificity 83%); and %PC-DIA ≥63.7% (AUC 0.917; sensitivity 92%; specificity 83%). The SSTR2 %PC correlated with treatment response only when evaluated using the DIA, showing a better performance of this method.