Junia Ribeiro de Oliveira Longo Schweizer

Long-acting growth hormone (LAGH) preparations have moved from development to routine clinical use over the past decade. Several products are now approved for paediatric growth hormone deficiency (GHD), selected non-GHD short-stature indications, and, in some regions, for adult GHD. The Growth Hormone Research Society convened an international workshop in October 2025 to reappraise the evidence base and refine clinical recommendations. Currently, data are available for up to 7 years of LAGH treatment in over 8000 individuals. This remains substantially shorter and smaller than for daily GH. Across preparations, short- to mid-term efficacy appears comparable to daily somatropin, provided dosing is individualized and monitored appropriately. Approvals and pivotal trials include both treatment initiation and switching from daily GH, depending on product and regional label. No new major safety signals have been identified in trials and real-world reports, although data on BMI trajectories require further evaluation. Injection-site reactions remain the most frequent adverse event and vary by formulation. Anti-drug antibodies have been observed, yet evidence suggests they have limited clinical impact. Effects on glucose metabolism resemble those of daily therapy, but metabolically, high-risk groups are under-represented in studies. Among cancer survivors, data on tumour recurrence and second neoplasms with LAGH are not yet available. Recommendations and practice points emphasized careful patient selection and counselling, product-specific dosing, and insulin-like growth factor-I (IGF-I) monitoring. Urgent knowledge gaps include transition care, long-term efficacy, adherence, and safety in cancer survivors. Well-resourced registries are essential for addressing these gaps and supporting safe, effective, and patient-centred use of LAGH.

Purpose: Sleep disturbances are common in endogenous Cushing’s syndrome (CS), impair quality of life, and often persist despite remission. We evaluated the diagnostic value of actigraphy in suspected CS, characterised sleep and rest-activity patterns during remission, and examined associations between late-night salivary cortisol (LNSC) and objective sleep measures. Methods: Exploratory prospective single-centre cohort study at LMU Hospital Munich with two cohorts: (1) individuals evaluated for suspected CS and (2) patients in remission, stratified by recovered versus persistent adrenal insufficiency. Participants wore an ActTrust2 actigraph for 21 days, provided daily LNSC samples, and completed the Munich Chronotype Questionnaire. Results: Cohort 1 included 16 patients with confirmed CS and 13 with exclusion of CS. Actigraphy detected comparable sleep efficiency, fragmentation and circadian rest-activity rhythms in both groups, without distinct alterations attributable to active CS, except for a significantly earlier chronotype (p=0.022). Cohort 2 comprised 23 patients in remission (13 with persistent, 10 with recovered adrenal insufficiency) and showed similar sleep characteristics across subgroups. LNSC revealed high inter- and intraindividual variability without consistent associations with actigraphy-derived sleep parameters. Statistically significant effects were confined to patients with persistent adrenal insufficiency, in whom higher LNSC (likely reflecting non-physiological replacement therapy) was associated with earlier bedtime, longer time in bed, prolonged sleep-onset latency, and reduced sleep efficiency. Conclusion: Apart from chronotype, actigraphy showed limited discriminatory value between clinical groups. LNSC was highly variable and showed no consistent associations with sleep parameters, underscoring the need for improved biomarkers and monitoring strategies in CS.

Background: The Itabaianinha cohort in Brazil carries a homozygous growth hormone-releasing hormone (GHRH) receptor (GHRH-R) gene mutation, causing congenital isolated GH deficiency (GHD). Affected individuals present with severe short stature, central obesity, hypercholesterolemia, and marked reductions in serum GH, IGF-I, and IGFBP 3 concentrations yet show no premature atherosclerosis and maintain a normal lifespan. IGF-I mostly circulates bound to IGFBPs and requires proteolytic cleavage for IGF-I receptor activation. Pregnancy-associated plasma protein A (PAPP-A) is an important IGF-dependent cleavage enzyme, binding to IGFBP 4 and releasing IGF-I. PAPP-A activity is inhibited by stanniocalcin-2 (STC2). The IGFBP 4-STC2-PAPP-A axis (ISPa) has emerged as a key regulator of IGF-I bioactivity. Methods: We evaluated the ISPa in: (1) GHD subjects with homozygous GHRH-R c.57 + 1G→A mutation, (2) heterozygotes (HTZ), and (3) homozygous wild-type controls (HMZ). Parameters from the ISPa were measured at LMU Klinikum, Munich. Additional biochemical parameters were analyzed at the Federal University of Sergipe, Brazil. Results: As expected, GHD subjects had markedly low GH, IGF-I, IGF-II, free IGF-I, and IGFBP 3 (P < .001), while HTZ resembled HMZ subjects. STC2, PAPP-A, and PAPP-A-STC2 complex concentrations did not differ between groups. However, PAPP-A2 and intact IGFBP 4 were higher in the GHD subjects (P < .05 and P < .01). Notably, IGF-I and IGFBP 3 positively correlated with IGF-II, whereas intact IGFBP 4 and PAPP-A2 showed inverse correlations with IGF-I and IGF-II. Conclusion: Our findings suggest altered IGF-I bioavailability regulation via the ISPa in congenital lifetime GHD, leading to increased PAPP-A2 proteolytic activity, reduced PAPP-A enzymatic activity, and reduced sequestration of PAPP-A2 by STC2.

Cushing'sdisease (CD), caused by an adrenocorticotropin-secreting pituitary adenoma, is a rare but severe endocrine disorder associated with high cardiometabolic morbidity and mortality. Diagnosis is challenging as many symptoms are nonspecific, and biochemical or imaging results may be inconclusive, contributing to substantial diagnostic delay. Although the core features of CD are consistent across the lifespan, certain clinical manifestations of chronic hypercortisolism vary from childhood through older age, reflecting differences in growth, puberty, metabolism, and comorbidity burden. In children, impaired growth coupled with weight gain is most prominent, whereas adolescents often present with pubertal disturbances and psychological or academic difficulties. Adults typically exhibit the classic Cushingoid features such as round face, plethora, and central obesity, along with metabolic and reproductive complications. Older individuals typically present with frailty, sarcopenia, fractures, and cognitive decline. Age also influences the interpretation of endocrine tests, the accuracy of pituitary magnetic resonance imaging, the role of inferior petrosal sinus sampling, perioperative risks, and the long-term impact of remission or persistent disease. Given this context, this narrative review used five representative clinical vignettes (pediatric, adolescent, adult female, adult male, and elderly) to illustrate how the presentation, diagnostic evaluation, and management of CD vary across the lifespan. Each case was paired with a structured synthesis of current evidence, highlighting both shared principles and age-specific nuances essential for timely diagnosis, appropriate treatment selection, and effective long-term multidisciplinary care. Understanding age-related differences is crucial to improving outcomes and reducing the substantial morbidity and mortality associated with CD throughout the lifespan.

Background: Secondary hypogonadism (SH) is common in men with Cushing's syndrome (CS), but its impact on comorbidities is largely unknown and longitudinal data are scarce. If SH also affects men with mild autonomous cortisol secretion (MACS) is unknown. Methods: We included 30 treatment-naïve adult men with CS and 17 men with MACS diagnosed since 2012. Hypogonadism was diagnosed based on total testosterone (TT) concentrations < 10.4 nmol/L and age-specific cut-offs. Outcomes were compared to age- and BMI-matched controls. In 20 men in remission of CS, a longitudinal analysis was conducted at 6, 12, and 24 months. Results: Men with CS had significantly lower concentrations of TT, bioavailable T, and free T compared to controls (P < .0001) with lowest concentrations in ectopic CS. Likewise, TT was lower in men with MACS compared to controls. At baseline, 93% of men with CS and 59% of men with MACS had SH. Testosterone correlated negatively with late night salivary cortisol and serum cortisol pre- and post-1 mg dexamethasone suppression test. Following successful surgery, TT increased significantly (P = .001), normalising within 6 months. Despite normalisation, several RBC parameters remained lower in men with CS even 2 years after successful surgery. Conclusions: Secondary hypogonadism is common in men with CS and MACS but usually reversible after successful surgery. The persisting changes observed in RBC parameters need to be further investigated in larger cohorts and longer follow-up durations.

The measurement of circulating concentrations of growth hormone (GH) is an indispensable tool in the diagnosis of both GH deficiency and GH excess. GH is a heterogeneous protein composed of several molecular isoforms, but the physiological role of these different isoforms has not yet been fully understood. The 22KD GH (22 K-GH) is the main isoform in circulation, followed by 20KD GH (20 K-GH) and other rare isoforms. Studies have been performed to better understand the biological actions of the different isoforms as well as their importance in pathological conditions. Generally, the non-22 K- and 20 K-GH isoforms are secreted in parallel to 22 K-GH, and only very moderate changes in the ratio between isoforms have been described in some pituitary tumors or during exercise. Therefore, in a diagnostic approach, concentrations of 22 K-GH accurately reflect total GH secretion. On the other hand, the differential recognition of GH isoforms by different GH immunoassays used in clinical routine contributes to the known discrepancy in results from different GH assays. This makes the application of uniform decision limits problematic. Therefore, the worldwide efforts to standardize GH assays include the recommendation to use 22 K-GH specific GH assays calibrated against the pure 22 K-GH reference preparation 98/574. Adoption of this recommendation might lead to improvement in diagnosis and follow-up of pathological conditions, and facilitate the comparison of results from different laboratories.

Pasireotide is a new-generation somatostatin analog that acts through binding to multiple somatostatin receptor subtypes. Studies have shown that pasireotide induces hyperglycemia, reduces glucocorticoid secretion, alters neurotransmission, and potentially affects stress responses typically manifested as hyperglycemia and increased corticosterone secretion. This study specifically aimed to evaluate whether pasireotide treatment modifies glucose and costicosterone secretion in response to acute restraint stress. Male Holtzman rats of 150–200 g were treated with pasireotide (10 µg/kg/day) twice-daily for two weeks or vehicle for the same period. Blood samples were collected at baseline and after 5, 10, 30, and 60 min of restraint stress. The three experimental groups comprised of vehicle + restraint (VEHR), pasireotide + restraint (PASR), and pasireotide + saline (PASNR). Following pasireotide treatment, no significant differences in baseline glucose and corticosterone levels were observed among the three groups. During restraint, hyperglycemia was observed at 10 min (p < .01 for both comparisons), peaked at 30 min (p < .01 for both comparisons) and showed higher 60 min areas under glucose curves in the VEHR and PASR stressed groups when compared to the non-stressed PASNR group (p < .05 for both comparisons). Restraint also increased corticosterone secretion in the VEHR and PASR stressed groups at 5 min (p < .01 for both comparisons), and peaked at 30 min (p < .01 for both comparisons) with corresponding higher 60 min areas under corticosterone curves when compared to the non-stressed PASNR group (p < .01 for both comparisons). In conclusion, pasireotide treatment does not modify hyperglycemic- and corticosterone-restraint stress responses, thus preserving acute stress regulation.

Background: Long-term remission of acromegaly after somatostatin analog withdrawal has been reported in 18-42% of patients in studies with a relatively small number of patients using different inclusion and remission criteria. The objectives of this study were to establish the probability and predictive factors for short- and long-term remission [normal IGF-1 for age/sex: IGF-1 ≤1.00 × upper limit of normal (ULN)] after octreotide long-acting release (LAR) withdrawal in a larger population of well-controlled patients with acromegaly (normal mean IGF-1 in the last 24 months). Methods: This is a prospective multicenter study in which 58 well-controlled patients with acromegaly receiving only octreotide LAR as a primary or postsurgical treatment were included in 14 university centers in Brazil. All patients had been on stable doses and dose intervals of octreotide LAR in the last year, and none had been submitted to radiotherapy. The main outcome measure was serum IGF-1 after 8 weeks (short-term) and 60 weeks (long-term) of octreotide LAR withdrawal. Results: Seventeen of 58 patients (29%) were in remission in the short term, and only 4 patients achieved long-term remission after treatment withdrawal. The Kaplan-Meier estimated remission probability at 60 weeks was 7% and decreased to 5% at 72 weeks. The short-term remission rate was significantly higher (44%; p = 0.017) in patients with pretreatment IGF-1 <2.4 × ULN. No other predictive factor for short- or long-term remission was found. Conclusion: Our results show that long-term remission of acromegaly after octreotide LAR withdrawal was an uncommon and frequently unsustainable event and do not support the recommendation of a systematic withdrawal of treatment in controlled patients.