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Pasireotide is a somatostatin analogue for the treatment of acromegaly, a chronic condition caused by excess growth hormone. Despite the therapeutic benefits of pasireotide as a second-line treatment for inadequately controlled acromegaly, a major concern is its hyperglycemic side-effect. Here, we provide guidance on how to select appropriate patients with acromegaly for treatment with pasireotide. We summarize baseline characteristics of patients at high risk for pasireotide-associated hyperglycemia and recommend a monitoring strategy based on the risk profile. Self-monitoring of blood glucose levels (SMBG), measurements of fasting plasma glucose (FPG), postprandial plasma glucose (PPG) and regular HbA1c measurements are the foundation of our proposed monitoring approach. The pathophysiology of pasireotide-induced hyperglycemia involves decreased secretion of the incretin hormones GIP (glucose-dependent insulinotropic polypeptide) and GLP-1 (glucagon-like peptide-1). Our expert recommendations address the specific pathophysiology of pasireotide-induced hyperglycemia by recommending the incretin-based therapeutics dipeptidyl peptidase-4 inhibitors (DPP-4i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA) in all appropriate patients as an alternative to first-line monotherapy with metformin. Furthermore, we emphasize the importance of adequate control of acromegaly, excellent diabetes education, nutrition and lifestyle guidance and advise to consult expert diabetologists in case of uncertainty in the management of patients with hyperglycemia under pasireotide., Competing Interests: SS has received consulting fees from Crinetics and Recordati Rare Diseases RRD as well as honoraria for lectures and conference chairing from Novartis, Ipsen, Hexal/Sandoz, Pfizer, and RRD. He has served as advisory board member for Novartis and RRD. Furthermore, RRD has donated a drug for compassionate use in one of his patients. SM has received lecturing fees and/or consulting fees and/or grants from AstraZeneca, Bayer, Boehringer Ingelheim, Lilly, Novo Nordisk, RRD. JG and JF have received consulting fees from RRD. KS has received lecturing fees and/or consulting fees from Pfizer, RRD, Sandoz, and Novo Nordisk. JS has received honoraria for talks and/or consultancy and/or research funding from Apitope, AstraZeneca, Bayer, Berlin Chemie, Boehringer Ingelheim, Bristol-Meyers Squibb, Eli Lilly, GI-Dynamics, GlaxoSmithKline, Intarcia, Ipsen, Janssen, LifeScan, MedScape, MSD, Novartis, Novo Nordisk, Omniamed, Pfizer, RRD, Roche, Sanofi, Servier, Takeda, and Ypsomed. In the past 3 years BV has received honoraria from Amgen, AstraZeneca, Lilly, Novo Nordisk, Sanofi and RRD for conferences or advisory boards, and received funding for research from AstraZeneca and Novo Nordisk., (Copyright © 2024 Störmann, Meyhöfer, Groener, Faust, Schilbach, Seufert and Vergès.)

Objective: The precise and accurate quantification of human growth hormone (GH) in plasma/ serum is crucial for the diagnosis and treatment of diseases like GH deficiency or acromegaly. However, the ligand-binding assays (LBAs) currently used for routine testing show considerable methodological variability. Here, we present a complementary, combined top-down and bottom-up LC-MS-based method to quantify (intact) GH in plasma and serum, which concurrently provides a basis for a MS-based analysis of GH in doping controls., Design: Extraction of GH from plasma/ serum was accomplished by protein precipitation, followed by an immunocapture step using protein A-coupled magnetic beads and a polyclonal anti-GH antibody. The intact protein was subsequently analyzed top-down on a 2D-LC-HRMS/MS system. In addition, sample extracts were digested with trypsin and analyzed for signal peptides corresponding to 'total', 22 kDa and 20 kDa GH (bottom-up). Both assays were validated according to current guidelines and compared to the GH isoform differential immunoassay used in routine doping control analysis. GH concentrations in serum samples of healthy adults, patients with acromegaly, and in samples obtained after administration of recombinant GH were analyzed as proof-of-principle., Results: The intact monomeric 22 kDa isoform of GH was selectively quantified in a representative working range of 0.5 to 10 ng/ml by top-down LC-HRMS/MS. Subsequent bottom-up analysis provided additional data on 'total' and 20 kDa GH. Top-down and bottom-up assay results for the 22 kDa isoform correlated well with the corresponding immunoassay results (R 2  > 0.95). For a possible application of the method in an anti-doping context, the ratio between 22 kDa and 'total' GH was evaluated, indicating differences between the various donor groups, but only with limited significance., Conclusion: The top-down and bottom-up LC-HRMS/MS method developed here presents a valuable tool for the quantification of GH in plasma/ serum complementary to established LBAs used at present in clinical measurements. Albeit the examination of the GH isoform proportions by the LC-MS method does not yet allow for the assessment of GH abuse, the obtained findings provide an important basis to enable LC-MS-based GH analysis of doping control samples in the future., Competing Interests: Declaration of Competing Interest MB holds shares in CMZ assay GmbH, the distributor of the isoform assay kits used in this study. All other authors have no competing interests or personal relationships to declare., (Copyright © 2023. Published by Elsevier Ltd.)

Context: Soluble alpha klotho (sαKL) has been linked to growth hormone (GH) action, but systematic evaluation and comparisons with traditional biomarkers in acromegaly are lacking., Objective: To evaluate the potential of sαKL to aid classification of disease activity., Methods: This retrospective study at 2 academic centers included acromegaly patients before surgery (A, n = 29); after surgery (controlled, discordant, or uncontrolled) without (B1, B2, B3, n = 28, 11, 8); or with somatostatin analogue treatment (C1, C2, C3, n = 17, 11, 5); nonfunctioning pituitary adenomas (n = 20); and healthy controls (n = 31). sαKL was measured by immunoassay and compared with traditional biomarkers (random and nadir GH, insulin-like growth factor I [IGF-I], IGF binding protein 3). Associations with disease activity were assessed., Results: sαKL was correlated to traditional biomarkers, particularly IGF-I (rs=0.80, P <0.0001). High concentrations before treatment (A, median, interquartile range: 4.04 × upper limit of normal [2.26-8.08]) dropped to normal after treatment in controlled and in most discordant patients. A cutoff of 1548 pg/mL for sαKL discriminated controlled (B1, C1) and uncontrolled (B3, C3) patients with 97.8% (88.4%-99.9%) sensitivity and 100% (77.1%-100%) specificity. sαKL was below the cutoff in 84% of the discordant subjects. In the remaining 16%, elevated sαKL and IGF-I persisted, despite normal random GH. Sex, age, body mass index, and markers of bone and calcium metabolism did not significantly affect sαKL concentrations., Conclusion: Our data support sαKL as a biomarker to assess disease activity in acromegaly. sαKL exhibits close association with GH secretory status, large dynamic range, and robustness toward biological confounders. Its measurement could be helpful particularly when GH and IGF-I provide discrepant information., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)

Objective: Growth hormone (GH) nadir (GHnadir) during oral glucose tolerance test (OGTT) is an important tool in diagnosing acromegaly, but data evaluating the need to adjust cut-offs to biological variables utilizing today's assay methods are scarce. We therefore investigated large cohorts of healthy subjects of both sexes to define normal GHnadir concentrations for a modern, sensitive, 22 kD-GH-specific assay., Design: Multicenter study with prospective and retrospective cohorts (525 healthy adults: 405 females and 120 males)., Methods: GH concentrations were measured by the IDS-iSYS immunoassay after oral application of 75 g glucose., Results: GHnadir concentrations (µg/L) were significantly higher in lean and normal weight subjects (group A) compared to overweight and obese subjects (group B); (males (M): A vs B, mean: 0.124 vs 0.065, P = 0.0317; premenopausal females without estradiol-containing OC (OC-EE) (FPRE): A vs B, mean: 0.179 vs 0.092, P < 0.0001; postmenopausal women (FPOST): A vs B, mean: 0.173 vs 0.078, P < 0.0061). Age, glucose metabolism and menstrual cycle had no impact on GHnadir. However, premenopausal females on OC-EE (FPREOC) exhibited significantly higher GHnadir compared to all other groups (all P < 0.0001). BMI had no impact on GHnadir in FPREOC (A vs B, mean: 0.624 vs 0.274, P = 0.1228)., Conclusions: BMI, sex and OC-EE intake are the major determinants for the GHnadir during OGTT in healthy adults. Using a modern sensitive GH assay, GHnadir concentrations in healthy subjects are distinctly lower than cut-offs used in previous guidelines for diagnosis and monitoring of acromegaly.

Measurements of human growth hormone (GH) and insulin-like growth-factor I (IGF-I) are cornerstones in the diagnosis of acromegaly. Both hormones are also used as biochemical markers in the evaluation of disease activity during treatment. Management of acromegaly is particularly challenging in cases where discordant information is obtained from measurement of GH concentrations following oral glucose load and from measurement of IGF-I. While in some patients biological factors can explain the discrepancy, in many cases issues with the analytical methods seem to be responsible. Assays used by endocrine laboratories to determine concentrations of GH and IGF-I underwent significant changes during the last decades. While generally leading to more sensitive and reproducible methods, these changes also had considerable impact on absolute concentrations measured. This must be reflected by updated decision limits, cut-offs and reference intervals. Since different commercially available assays do not agree very well, method specific interpretation of GH and IGF-I concentrations is required. This complexity in the interpretation of hormone concentrations is not always appropriately reflected in laboratory reports, but also not in clinical guidelines reporting decision limits not related to a specific analytical method. The present review provides an overview about methodological and biological variables affecting the biochemical assessment of acromegaly in diagnosis and follow up.

A significant proportion of total circulating growth hormone (GH) is bound to a high affinity growth hormone binding protein (GHBP). Several low affinity binding proteins have also been described. Significant differences between species exist with respect to origin and regulation of GHBP, but generally it resembles the extracellular domain of the GH receptor. Concentrations are associated with GH status, body composition and other factors. Although the clinical relevance of GHBP is not fully understood it is suggested that concentrations indirectly reflect GH receptor status. This is supported by cases of Laron's syndrome where a molecular defect in the extracellular domain of the GH receptor is associated with low or unmeasurable GHBP concentrations. Methods to measure GHBP have evolved from chromatographic, activity based procedures to direct immunoassays. In clinical practice, measurement of GHBP can be helpful to differentiate between GH deficiency and GH insensitivity, particularly if GHBP is absent., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

In a comprehensive review, Sahakian et al. recapitulate the medical treatment of pituitary tumors and summarize the fundamental aspects of approved and emerging drugs in the treatment of growth-hormone-secreting tumors [[16]]. The principal substance class used in the medical treatment of acromegaly are somatostatin analogs (SSA; sometimes also referred to as somatostatin receptor ligands: SRL), chemically resembling endogenous somatostatin and effectively inhibiting growth hormone secretion in a significant proportion of patients. Acromegaly is a rare and disabling disease with some distinct and striking clinical features that have fascinated (and frightened) laypeople and medical experts alike throughout history [[1]]. In another review, Akirov et al. lay down the fundamental aspects of biochemical diagnosis of acromegaly, peering into the role of GH and IGF-I in establishing the diagnosis as well as their function as follow-up biomarkers of disease activity [[9]]. [Extracted from the article]

Although the prognosis in Guillain-Barré syndrome (GBS) is generally good, protracted and incomplete courses of recovery can be a heavy burden. Animal studies suggest growth hormone (GH) treatment could stimulate myelin repair and thus accelerate functional recovery in acute polyneuropathy. We report on the first use of GH in GBS. Our objective was to monitor safety and tolerability as well as to evaluate the effect of an off-label GH therapy during recovery from GBS in 1 patient. A 28-year-old male with flaccid tetraparesis caused by pure motor GBS was treated off-label with GH (1 mg/day) for 10 weeks. Muscle strength was measured regularly before, during, and after the treatment over a total span of 330 days. Serum levels of IGF-I were assessed before, during, and after GH treatment. Changes in strength gain were used as the main parameter of efficacy. No side effects of GH treatment were observed. Serum IGF-I increased from 177 ng/mL at baseline to an average of 342 ng/mL (normal range 78–270 ng/mL) during treatment. Prior to GH administration, strength (R2 = 0.99, p < 0.01) was associated with time, representing the natural course of recovery. During GH treatment, the slope of strength gain increased (Glass' ∆ = 1.08, p < 0.01). The association between alterations of strength gain and IGF-I serum levels reached trend level (R2 = 0.36, p = 0.09). In this single case, GH treatment seemed to be associated with faster muscular strength gain. Controlled studies are needed in order to establish GH as a potential therapeutic approach in motor GBS. [ABSTRACT FROM AUTHOR]

Context Method-specific reference intervals (RIs) determine utility of IGF-I as a biomarker in GH-related diseases. Differences between populations might affect applicability of RIs. Objective To compare population-specific RIs derived from IGF-I routine testing in laboratories in the United States and Europe using the same assay. Design and setting Uncensored routine IGF-I testing results generated over 5 years in 4 accredited laboratories (US, n = 778 173 males/710 752 females; Europe, n = 23 220 males/40 183 females). Main outcome measures Construction of RIs by indirect statistical methods designed to use routine testing data (modified Hoffmann approach). Comparison to published RIs, between the US and Europe, and between regions in the United States with lower and higher mean body mass indexes (BMIs). Results Lower limits (LLs) of RIs calculated from all routine data sets do not differ from the published LLs. The same is true for upper limits (ULs) calculated from European routine data. ULs derived from US routine data are significantly higher (children, 10-18 years [mean, %]: boys + 149.3 ng/mL [+34.6%]; girls + 94.9 ng/mL [+19.8%]); adults (19-95 years: males + 45 ng/mL [+20.3%]; and females + 29.7 ng/mL [+13.8%]). Average IGF-I is higher in samples from Colorado (lower mean BMI) compared with Alabama (P  < 0.0001), although the difference is smaller than between each of them and Europe. Conclusions We provide evidence that in large datasets from the same population, direct sampling and the indirect Hoffmann approach provide comparable RIs. Although LLs are comparable between Europe and the United States, the UL is significantly higher in the United States. We suggest use of adapted RIs for the United States. [ABSTRACT FROM AUTHOR]

Growth hormone (GH) and IGF-I levels in serum are used as biomarkers in the diagnosis and management of GH-related disorders but have not been subject to structured validation. Auxological parameters in children and changes in body composition in adults, as well as metabolic parameters and patient related outcomes are used as clinical and surrogate endpoints. New treatment options, such as long acting GH and GH antagonists, require reevaluation of the currently used biochemical biomarkers. This article will review biomarkers, surrogate endpoints and clinical endpoints related to GH treatment in children and adults as well as in acromegaly. [ABSTRACT FROM AUTHOR]

Introduction: Somatostatin analogs are most commonly used in pharmacological treatment of acromegaly. Pegvisomant and dopamine agonists are alternatives, which are used to a lesser extent. Dopamine agonists are the only orally applicable medication but are less effective than the other options. For a large number of patients, life-long pharmacotherapy has to be applied and frequent injections represent a reduction of quality of life for many of them. Areas covered: Recently published evidence for the use of oral octreotide therapy for acromegaly. Expert commentary: Oral octreotide is a novel and effective treatment for acromegaly and the side effects have been shown to be comparable to the injectable SSAs. The combination with a transient permeability enhancer allows intestinal permeation but also enables molecules with a size <70 kDa to pass transiently. This does not seem to have an acute or subacute consequence, but the long-term effect is still elusive. Therefore, more long-term trials are desirable. [ABSTRACT FROM AUTHOR]