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There are five subtypes of somatostatin receptors (SST1‐5), which are expressed in several types of solid neoplasms, neuroendocrine tumors, and pituitary adenomas. Most commonly, SST2 and SST5, are of interest regarding diagnostic, treatment, and prognostic purposes. In this article the basic biological characteristics of SST are briefly reviewed, and focus given to the immunohistochemical evaluation of SST2 and SST5 in growth hormone (GH)‐secreting pituitary tumors, and their quantification as predictors of response to treatment with somatostatin receptor ligands (SRL), the mainstay of the pharmacological therapy available for these tumors. Although many different scoring systems for SST2 immunohistochemistry showing correlation with SRL response have been reported, among which the immunoreactivity score (IRS) has been the most consistently used, a universally validated immunohistochemical technique and scoring scheme is lacking. Efforts should be made on collaborative multicenter studies aiming at validating homogeneous immunostaining protocols and a scoring system for SST2 and SST5 expression, to help clinicians to define the optimal therapeutic strategy for the patients with somatotroph tumors. This article reviews the major biological characteristics of somatostatin receptors (SST2 and SST5) in anterior pituitary tumors, and the immunohistochemical evaluation of their expression as predictors of response to pharmacological therapy with SST ligands.

Abstract Context Paltusotine is a once-daily, oral, nonpeptide small-molecule somatostatin receptor type 2 (SST2) agonist in clinical development for treatment of acromegaly. Objective This work aimed to evaluate change in insulin-like growth factor I (IGF-I) levels in patients switched from octreotide long-acting release or lanreotide depot monotherapy to paltusotine. Methods A phase 2, open-label, prospective, multicenter, multinational, nonrandomized, single-arm exploratory study was conducted in which dosage uptitrations were performed in a double-blinded manner. At 26 global sites, patients with acromegaly switched to paltusotine from injected somatostatin receptor ligand (SRL)-based therapy. Patients received 13-week treatment with once-daily oral paltusotine (10-40 mg/d). The primary end point was change from baseline to week 13 in IGF-I for patients who switched from long-acting octreotide or lanreotide depot monotherapy to paltusotine (group 1). All patients underwent a 4-week paltusotine washout at end of treatment period (wk 13-17). IGF-I, growth hormone (GH), patient-reported outcome, and safety data were collected. Results Forty-seven patients enrolled. In group 1 (n = 25), IGF-I and GH showed no significant change between SRL baseline and end of paltusotine treatment at week 13 (median change in IGF-I = −0.03×upper limit of normal [ULN]; P = .6285; GH = −0.05 ng/mL; P = .6285). IGF-I and GH rose significantly in the 4 weeks after withdrawing paltusotine (median change in IGF-I = 0.55×ULN; P < .0001 [median increase 39%]; GH = 0.72 ng/mL; P < .0001 [109.1% increase]). No patients discontinued because of adverse events (AE); no treatment-related serious AEs were reported. Conclusion These results suggest once-daily oral paltusotine was effective in maintaining IGF-I values in patients with acromegaly who switched from injected SRLs. Paltusotine was well tolerated with a safety profile consistent with other SRLs.

Abstract Context Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene are responsible for a subset of familial isolated pituitary adenoma (FIPA) cases and sporadic pituitary neuroendocrine tumors (PitNETs). Objective To compare prospectively diagnosed AIP mutation-positive (AIPmut) PitNET patients with clinically presenting patients and to compare the clinical characteristics of AIPmut and AIPneg PitNET patients. Design 12-year prospective, observational study. Participants & Setting We studied probands and family members of FIPA kindreds and sporadic patients with disease onset ≤18 years or macroadenomas with onset ≤30 years (n = 1477). This was a collaborative study conducted at referral centers for pituitary diseases. Interventions & Outcome AIP testing and clinical screening for pituitary disease. Comparison of characteristics of prospectively diagnosed (n = 22) vs clinically presenting AIPmut PitNET patients (n = 145), and AIPmut (n = 167) vs AIPneg PitNET patients (n = 1310). Results Prospectively diagnosed AIPmut PitNET patients had smaller lesions with less suprasellar extension or cavernous sinus invasion and required fewer treatments with fewer operations and no radiotherapy compared with clinically presenting cases; there were fewer cases with active disease and hypopituitarism at last follow-up. When comparing AIPmut and AIPneg cases, AIPmut patients were more often males, younger, more often had GH excess, pituitary apoplexy, suprasellar extension, and more patients required multimodal therapy, including radiotherapy. AIPmut patients (n = 136) with GH excess were taller than AIPneg counterparts (n = 650). Conclusions Prospectively diagnosed AIPmut patients show better outcomes than clinically presenting cases, demonstrating the benefits of genetic and clinical screening. AIP-related pituitary disease has a wide spectrum ranging from aggressively growing lesions to stable or indolent disease course.

Acromegaly-related sub/infertility, tidily related to suboptimal disease control (1/2 of cases), correlates with hyperprolactinemia (1/3 of patients), hypogonadotropic hypogonadism—mostly affecting the pituitary axis in hypopituitarism (10–80%), and negative effects of glucose profile (GP) anomalies (10–70%); thus, pregnancy is an exceptional event. Placental GH (Growth Hormone) increases from weeks 5–15 with a peak at week 37, stimulating liver IGF1 and inhibiting pituitary GH secreted by normal hypophysis, not by somatotropinoma. However, estrogens induce a GH resistance status, protecting the fetus form GH excess; thus a full-term, healthy pregnancy may be possible. This is a narrative review of acromegaly that approaches cardio-metabolic features (CMFs), somatotropinoma expansion (STE), management adjustment (MNA) and maternal-fetal outcomes (MFOs) during pregnancy. Based on our method (original, in extenso, English—published articles on PubMed, between January 2012 and September 2022), we identified 24 original papers—13 studies (3 to 141 acromegalic pregnancies per study), and 11 single cases reports (a total of 344 pregnancies and an additional prior unpublished report). With respect to maternal acromegaly, pregnancies are spontaneous or due to therapy for infertility (clomiphene, gonadotropins or GnRH) and, lately, assisted reproduction techniques (ARTs); there are no consistent data on pregnancies with paternal acromegaly. CMFs are the most important complications (7.7–50%), especially concerning worsening of HBP (including pre/eclampsia) and GP anomalies, including gestational diabetes mellitus (DM); the best predictor is the level of disease control at conception (IGF1), and, probably, family history of 2DM, and body mass index. STE occurs rarely (a rate of 0 to 9%); some of it symptoms are headache and visual field anomalies; it is treated with somatostatin analogues (SSAs) or alternatively dopamine agonists (DAs); lately, second trimester selective hypophysectomy has been used less, since pharmaco-therapy (PT) has proven safe. MNA: PT that, theoretically, needs to be stopped before conception—continued if there was STE or an inoperable tumor (no clear period of exposure, preferably, only first trimester). Most data are on octreotide > lanreotide, followed by DAs and pegvisomant, and there are none on pasireotide. Further follow-up is required: a prompt postpartum re-assessment of the mother’s disease; we only have a few data confirming the safety of SSAs during lactation and long-term normal growth and developmental of the newborn (a maximum of 15 years). MFO seem similar between PT + ve and PT − ve, regardless of PT duration; the additional risk is actually due to CMF. One study showed a 2-year median between hypophysectomy and pregnancy. Conclusion: Close surveillance of disease burden is required, particularly, concerning CMF; a personalized approach is useful; the level of statistical evidence is expected to expand due to recent progress in MNA and ART.

Aim To investigate the impact of pituitary surgery on glucose metabolism and to identify predictors of remission of diabetes after pituitary surgery in patients with acromegaly. Methods A national multicenter retrospective study of patients with acromegaly undergoing transsphenoidal surgery for the first time at 33 tertiary Spanish hospitals (ACRO-SPAIN study) was performed. Surgical remission of acromegaly was evaluated according to the 2000 and 2010 criteria. Results A total of 604 acromegaly patients were included in the study with a total median follow up of 91 months (interquartile range [IQR] 45–163). At the acromegaly diagnosis, 23.8% of the patients had diabetes mellitus (DM) with a median glycated hemoglobin (HbA1c) of 6.9% (IQR 6.4–7.9) [51.9 mmol/mol (IQR 46.4–62.8)]. In the multivariate analysis, older age (odds ratio [OR] 1.02, 95% CI 1.00-1.05), dyslipidemia (OR 5.25, 95% CI 2.81 to 9.79), arthropathy (OR 1.39, 95% CI 2.82 to 9.79), and higher IGF-I levels (OR 1.30, 95% CI 1.05 to 1.60) were associated with a greater prevalence of DM. At the last follow-up visit after surgery, 21.1% of the DM patients (56.7% of them with surgical remission of acromegaly) experienced diabetes remission. The cure rate of DM was more common in older patients (hazard ratio [HR] 1.77, 95% CI 1.31 to 2.43), when surgical cure was achieved (HR 2.10, 95% CI 1.01 to 4.37) and when anterior pituitary function was not affected after surgery (HR 3.38, 95% CI 1.17 to 9.75). Conclusion Glucose metabolism improved in patients with acromegaly after surgery and 21% of the diabetic patients experienced diabetes remission; being more frequent in patients of older age, and those who experienced surgical cure and those with preserved anterior pituitary function after surgery.

PurposePredicting resistance to first-generation Somatostatin Receptor Ligands (fg-SRL) in Acromegaly patients remains an ongong challenge. Tumor-associated immune components participate in various pathological processes, including drug-resistance. We aimed to identify the immune components involved in resistance of fg-SRL, and to investigate biomarkers that can be targeted to treat those drug-resistant Acromegaly.MethodsWe conducted a retrospective study involving 35 Acromegaly patients with somatotropinomas treated postoperatively with fg-SRL. Gathering clinicopathological data, SSTR2 expression, and immunological profiles, we utilized univariate, binary logistic regression, and ROC analyses to assess their predictive roles in fg-SRL resistance. Spearman correlation analysis further examined interactions among interested characteristics.Results19 patients (54.29%) exhibited resistance to postoperative fg-SRL. GH level at diagnosis, preoperative tumor volume, T2WI-MRI intensity, granularity, PD-L1, SSTR2, and CD8 + T cell infiltration showed association with clinical outcomes of fg-SRL. Notably, T2WI-MRI hyperintensity, PD-L1-IRS > 7, CD8 + T cell infiltration < 14.8/HPF, and SSTR2-IRS < 5.4 emerged as reliable predictors for fg-SRL resistance. Correlation analysis highlighted a negative relationship between PD-L1 expression and CD8 + T cell infiltration, while showcasing a positive correlation with preoperative tumor volume of somatotropinomas. Additionally, 5 patients with fg-SRL resistance underwent re-operation were involved. Following fg-SRL treatment, significant increases in PD-L1 and SSTR5 expression were observed, while SSTR2 expression decreased in somatotropinoma.ConclusionPD-L1 expression and CD8 + T cell infiltration, either independently or combined with SSTR2 expression and T2WI-MRI intensity, could form a predictive model guiding clinical decisions on fg-SRL employment. Furthermore, targeting PD-L1 through immunotherapy and embracing second-generations of SRL with higher affinity to SSTR5 represent promising strategies to tackle fg-SRL resistance in somatotropinomas.

ABSTRACT A 12‐year‐old, male Labrador Retriever was presented because of polyuria, polydipsia, polyphagia, joint pain, and physical features consistent with acromegaly. Circulating insulin‐like growth factor‐1 (IGF‐1) concentration was increased (> 1000 ng/mL; reference interval [RI], 42–449), suggestive of hypersomatotropism. An abnormal low‐dose dexamethasone suppression test and increased circulating adrenocorticotropic (ACTH) concentration indicated pituitary‐dependent hypercortisolism. Computed tomography identified an enlarged pituitary gland. Treatment with cabergoline initially decreased circulating IGF‐1 and ACTH concentrations and urinary cortisol‐to‐creatinine ratio (UCCR), with a notable reduction in acromegalic physical features. However, 7 months after the start of cabergoline treatment, IGF‐1, ACTH, and UCCR had increased again, although pituitary gland size remained stable. Because of worsening joint pain, euthanasia was performed. On necropsy, double immunohistochemistry identified pituitary tumor cells with cytoplasmic co‐expression of both growth hormone (GH) and ACTH, consistent with a monomorphic plurihormonal macroadenoma. This case shows that concurrent hypersomatotropism and hypercortisolism can occur in dogs caused by a plurihormonal pituitary adenoma.

Sirtuins 1–7 (SIRT) are a highly conserved family of histone deacetylases involved in the regulation of longevity that have a considerable impact in transcription, DNA repair regulation, telomeric stability, cell senescence and apoptosis. In the present study, SIRT1–7 mRNA levels were evaluated in 37 somatotropinomas and 31 nonfunctioning pituitary adenomas (NFPAs) using qPCR and relation to tumor size, invasiveness and Ki-67 proliferative index was made. Overexpression of SIRT1 was observed in 86.5% of somatotropinomas versus 41.9% of NFPAs (P < 0.01). SIRT3 was more underexpressed in NFPAs than somatotropinomas (77.4 and 40.5%, respectively, P < 0.01) as well as SIRT4 and SIRT7. Despite the lack of association between sirtuins and invasiveness or Ki-67 index, SIRT1 and SIRT3 expressions were related to tumor size. Mean of the largest diameter was smaller in adenomas with SIRT1 overexpression than with normal expression (P < 0.01) and SIRT3 underexpression was associated with larger tumors (P < 0.01). In conclusion, a pronounced difference in sirtuins expression was identified between pituitary adenomas, suggesting that these genes are potential markers of pituitary adenomas and could be employed in the characterization of somatotropinomas and NFPAs. The role of sirtuins in pathogenesis of pituitary tumors merits further investigation and possibly will provide new molecular insight about their progression.

Background: It is still controversial if activating mutations in the stimulatory G-protein α subunit (gsp mutation) are a biomarker of response to first generation somatostatin receptor ligands (fg-SRL) treatment in acromegaly. Thus, we aimed to evaluate whether gsp mutation predicts long-term response to fg-SRL treatment and to characterize the phenotype of patients harboring gsp mutations. Methods: GNAS1 sequencing was performed by Sanger. SST2 and SST5 were analyzed by immunohistochemistry (IHC) and real-time RT-PCR. The cytokeratin granulation pattern was evaluated by IHC. Biochemical control was defined as GH < 1.0 ng/mL and normal age-adjusted IGF-I levels. Results: gsp mutation was found in 54 out of 136 patients evaluated. Biochemical control with fg-SRL treatment was similar in gsp+ and gsp- patients (37% vs. 25%, p = 0.219). Tumors harboring gsp mutation were smaller (p = 0.035) and had a lower chance of invading cavernous sinuses (p = 0.001). SST5 protein (p = 0.047) and mRNA (p = 0.013) expression levels were higher in wild-type tumors. Conclusions: In this largest series available in the literature, we concluded that gsp is not a molecular biomarker of response to fg-SRL treatment in acromegaly. However, the importance of its negative association with cavernous sinus invasion and SST5 expression needs to be further investigated.