Genome architecture in endocrine diseases: X-Linked Acrogigantism (X-LAG) syndrome.

Genotype-phenotype correlation and challenges in mutation detection in McCune-Albright syndrome: A retrospective study of a French cohort.

Exploring impact of the phosphoinositide-3 kinase on excess growth hormone in acromegaly patients.

Endothelial cells maintain vascular homeostasis through the regulation of permeability and coagulation. Interferon-gamma (IFN-γ), a proinflammatory cytokine released by activated T lymphocytes and natural killer cells, disrupts endothelial junctional integrity, leading to barrier dysfunction. Octreotide (OCT), a synthetic somatostatin analog (SSA), is used to suppress excessive growth hormone secretion and inhibits tumor growth. The present study investigates the potential anti-inflammatory and cytoprotective properties of OCT in IFN-γ-induced endothelial injury. Our observations suggest that OCT suppresses IFN-γ-induced activation of cofilin, MLC2, JAK2, STAT1, STAT3, and P38; as well as endothelial hyperpermeability and ROS generation. Hence, the study supports ongoing efforts aiming to substantiate the protective role of somatostatin analogs in endothelium-dependent disorders, including lung injury and sepsis.

Treatment of acromegaly includes surgery followed by chronic medical therapy for persistent growth hormone (GH) excess, and, in some patients, radiation. Treatment is aimed at biochemical normalization, which improves survival and comorbidities. However, many patients experience lifelong burden related to persistent acromegaly manifestations and adverse treatment effects. Long-acting somatostatin receptor ligand (SRL) therapy with octreotide or lanreotide has been the cornerstone of management. Pasireotide long-acting release, a somatostatin receptor multiligand, achieves more favorable biochemical control rates but is associated with an increased risk of hyperglycemia. Pegvisomant, a GH receptor antagonist, can be used as monotherapy or in combination with SRLs. The spectrum of medical therapy has expanded with the advent of oral octreotide capsules; the oral selective somatostatin receptor subtype 2 agonist, paltusotine; and monthly self-administered subcutaneous octreotide. This review outlines the updates to current acromegaly treatment options and their impact on patient outcomes.

Growth hormone (GH) excess and elevated insulin-like growth factor-1 (IGF-1) in acromegaly are considered to promote cancer development. To investigate cancer incidence and outcome in patients with acromegaly in relation to biochemical control. Matched cohort study in patients with acromegaly diagnosed from 1991 to 2018 and ten controls per case from the Swedish population. Cancer diagnoses and fatalities were obtained from the Swedish Pituitary and National Patient Registers. Adjusted hazard ratio (HR) and 95% confidence intervals (CIs) for cancer incidence and death were estimated using a Cox proportional hazard regression model adjusted for age, sex, and comorbidity. We included 1035 patients with acromegaly (49.5% female; median age 52.0 years) and 10,261 matched controls. Patients had higher adjusted HR (95% CI) for all cancer (1.28, 1.11-1.49), colorectal cancer (1.84, 1.28-2.64), lung cancer (1.95, 1.22-3.11), hematologic cancer (1.68, 1.03-2.73), and breast cancer in women (1.46, 1.02-2.11) from 5 years before acromegaly diagnosis. Second cancers after diagnosis tended to be increased (1.54, 0.98-2.44). Death from cancer was only significantly elevated in patients 40-60 years of age (1.48, 1.19-1.85). Patients with persistently elevated IGF-1 had a higher overall mortality rate (1.50, 1.10-2.01) but no increase in cancer incidence nor cancer-related mortality compared to biochemically controlled patients. This nationwide, matched cohort study showed an increased risk of cancer in patients with acromegaly, underscoring the importance of vigilance for early signs of cancer after acromegaly diagnosis. Biochemical control had minor effects on increased cancer development, indicating an effect beyond GH hypersecretion.

Background/Objectives: Acromegaly is a systemic connective tissue disease driven by chronic growth hormone (GH) and insulin-like growth factor-1 (IGF-1) excess; yet, the female reproductive tract-especially the extracellular matrix (ECM)-rich cervix-has been poorly studied. We aimed to compare uterine and cervical morphology in women with acromegaly versus healthy controls and a gynecologic disease comparator, testing the hypothesis of selective cervical hypertrophy. Methods: We performed a retrospective case-control study of reproductive-age women who underwent pelvic ultrasound: acromegaly (n = 33), healthy controls (n = 45), and adenomyosis without acromegaly (n = 44). Uterine body measurements were obtained by TAUS/TVUS; cervical biometry was performed transvaginally in all cases. Volumes were estimated using the ellipsoid formula, and a uterus-to-cervix (U:C) volume ratio was calculated. Group differences were analyzed with Mann-Whitney tests and Bonferroni correction. Results: A total of 122 women were included. Uterine body length, width, AP size, and volume did not differ between acromegaly and either comparison group (all p-values non-significant). In contrast, cervical length, width, AP thickness, and volume were significantly higher in acromegaly than in healthy controls, with a corresponding reduction in the U:C volume ratio, indicating disproportionate cervical enlargement. Compared with adenomyosis, women with acromegaly again showed larger cervical width, AP thickness, and volume, together with altered U:C indices, whereas cervical length did not differ, suggesting a pattern not explained by nonspecific pelvic pathology. Conclusions: Women with acromegaly demonstrate a distinct uterine phenotype characterized by selective cervical hypertrophy with preserved uterine corpus size-an ECM-centric "acromegalic uteropathy." This noninvasive morphometric signature may have diagnostic and procedural relevance and warrants confirmation in prospective studies.

A 62-year-old Iraqi woman exhibited progressive enlargement of her hands, feet, and facial features over several years, accompanied by poorly controlled type 2 diabetes mellitus, hypertension, and dyslipidemia—metabolic disorders that had become increasingly challenging to manage despite conventional treatment. These gradual physical changes, which are often very small in middle-aged and older people, eventually made doctors think that the person might have acromegaly. Biochemical testing confirmed the diagnosis by showing consistently high levels of growth hormone, no suppression on oral glucose tolerance testing, and insulin-like growth factor-1 concentrations that were much higher than normal for someone of the same age and sex. A macroadenoma measuring 14 × 12 × 9 mm was found on a pituitary magnetic resonance imaging scan. There was no suprasellar extension, optic chiasm compression, or visual field problems on formal testing. After a thorough discussion of treatment options, the patient opted against transsphenoidal surgery, citing personal preference and apprehensions about surgical risks, and instead chose to initiate primary medical treatment. She began taking Sandostatin LAR (octreotide), a long-acting somatostatin receptor ligand, at a low dose that was gradually increased over the next few months based on how well she tolerated it and how her biochemical response changed. Regular follow-up lab tests showed that insulin-like growth factor-1 levels were steadily dropping toward the normal range. This showed that the excess growth hormone was being successfully suppressed. A follow-up MRI about a year into treatment showed a good response, with the adenoma getting smaller and cystic degeneration appearing in the tumor, which is what you would expect from somatostatin analog–mediated regression. This hormonal enhancement was accompanied by improved management of her metabolic comorbidities, including enhanced glycemic control, lowered blood pressure, and optimized lipid profiles, highlighting the close association between acromegaly and cardiometabolic complications. This case underscores the necessity of early recognition of acromegaly in patients primarily exhibiting metabolic disturbances and subtle physical manifestations, particularly when surgical intervention is not feasible. It also shows how effective somatostatin analogs can be as a powerful nonsurgical treatment that can help with biochemical control, tumor reduction, and overall metabolic health. In these cases, successful management depends on a personalized, multidisciplinary framework that includes regular endocrinological evaluations, hormonal monitoring, and periodic imaging. This is done to get the best disease control, reduce long-term complications, and improve quality of life.

Excess growth hormone (GH) production leading to acromegaly most commonly emanates from an adenomatous pituitary somatotroph. Understanding the pathogenesis of these adenomas will elucidate how biologic behavior affects acromegaly treatment outcomes. We searched PubMed for relevant English-language original research and review articles on signaling pathways and molecular drivers implicated in the pathogenesis of non-familial somatotroph adenomas in patients with acromegaly. Somatotroph cells express cognate G-protein coupled receptors for both hypothalamic stimulatory GH-releasing hormone (GHRH) and inhibitory somatostatin. Somatotroph GH transcription and secretion, as well as somatotroph cell lineage development, proliferation, and differentiation, are mediated by GHRH signaling through its cognate receptor (GHRHR), driving increased intracellular cyclic adenosine monophosphate (cAMP) levels. Point mutations in GNAS and other genomic and non-genomic aberrations in the tightly regulated GHRH-GHRHR signaling pathway result in persistent cAMP signaling, inducing GH production and somatotroph proliferation, and potentially favoring the development of sporadic somatotroph adenomas. Enhanced cAMP signaling also increases DNA damage markers and activates DNA damage response pathways, leading to a senescent adenomatous phenotype tightly linked to GH overproduction. The cAMP pathway appears to be a dominant molecular driver of somatotroph adenoma pathogenesis. Elevated cAMP drives GH hypersecretion and somatotroph proliferation and also induces DNA damage, as evidenced by increased genomic instability and a senescent signature. Collectively, these findings elucidate a molecular framework for the biological behavior of these adenomas and their responsiveness to therapies targeting cAMP-dependent pathways, including somatostatin receptor ligands.

Genome architecture in endocrine diseases: X-linked acrogigantism (X-LAG) syndrome.

McCune-Albright syndrome MAS is a rare mosaic disorder caused by post-zygotic GNAS activating mutations. MAS is characterized by fibrous dysplasia (FD) of the skeleton, café-au-lait skin macules, and hyperfunctioning endocrinopathies such as precocious puberty, thyroid disease, growth hormone excess, and FGF23-mediated phosphate wasting. Mosaicism leads to marked clinical heterogeneity and complicates molecular diagnosis. We retrospectively analyzed clinical and genotyping data of patients referred for suspected or clinically diagnosed MAS in a single French center (2014-2025). GNAS R201C and R201H mutations were detected by digital droplet PCR using peripheral blood as first-line samples, with additional testing of circulating cell-free, saliva, or tissue when indicated. We included 405 patients, from which 89 (22%) carried a GNAS mutation (52 R201C, 37 R201H). No significant clinical differences were observed between R201C and R201H. Among 578 analyzed samples, mutation detection varied by sample type, with the highest rates in tissue. Mutant allele frequency (MAF) in blood DNA was higher in patients with polyostotic than in monostotic FD (P=0.0055), but was not associated with the overall MAS-related lesion number. No correlation was found between MAF and age at diagnosis. MAS shows substantial clinical and molecular heterogeneity without clear genotype-phenotype differences between R201 variants. Mutation detection strongly depends on sample type, reflecting disease mosaicism. A multimodal diagnostic strategy and larger collaborative cohorts are needed to optimize molecular diagnosis and refine genotype-phenotype correlations in MAS patients.

The cross-talk between prolactin and growth hormone in pituitary adenomas.

Remission Rates in Repeat Endoscopic Transsphenoidal Surgery for Recurrent Growth Hormone Secreting Pituitary Adenoma

Adipose tissue (AT) fibrosis impairs tissue function and is linked to obesity and insulin resistance. Acromegaly, caused by growth hormone excess, promotes lipolysis-driven insulin resistance and profound stimulation of collagen synthesis. It is unknown if this translates into excessive tissue fibrosis. Quantification of collagen turnover and fibrosis in fat and muscle in patients with acromegaly before and after treatment. Two patient cohorts were examined before and after treatment. In cohort 1 (n = 17), AT collagen content and fibrosis- and inflammation-related gene expression were analyzed. In cohort 2 (n = 15), skeletal muscle collagen content, and serum fibroblast activation protein (FAPα) activity and levels were analyzed. Collagen turnover serum biomarkers were analyzed in both cohorts. AT collagen content (%) decreased from 4.6 ± 2.9 before to 2.1 ± 1.2 after disease control (P < .05). AT type I and III collagen gene expression decreased by 53% and 39%, respectively, and correlated closely with disease activity. Muscle collagen content (relative units) decreased from 0.020 ± 0.004 to 0.012 ± 0.008 after disease control (P = .0460). FAPα activity (RFU/min) and levels (µg/L) decreased following disease control (373 ± 111 [before] vs 248 ± 62 [after]; P < .0001, and 102 ± 35 [before] vs 63 ± 23 [after]; P < .001, respectively). In both cohorts, collagen turnover biomarkers declined after disease control. Inflammatory markers were unaffected. Our study reports for the first time that prolonged growth hormone excess induces reversible fibrosis in human adipose and muscle tissue. We hypothesize that fibrosis in acromegaly is mainly driven by a direct effect on collagen formation and likely not secondary to inflammation, which contrasts with obesity-driven AT fibrosis. NCT00647179; NCT03431727.

Acromegaly and gigantism are rare neuroendocrine diseases caused by excessive secretion of growth hormone (GH) and/ or high levels of insulin-like growth factor (IGF-1). Gigantism develops when excess GH or IGF-1 leads to accelerated linear growth before the completion of puberty and the closure of the epiphyses, most commonly caused by a somatotropic pituitary adenoma. The diagnosis of somatotropinoma in childhood is particularly challenging due to its subtle and nonspecific clinical presentation. Somatotropinomas at a young age are more often caused by genetic abnormalities and have a more aggressive course. The article presents a clinical case of acrogigantism in a patient with two identified heterozygous variants in the PRKAR1A and SDHB genes. The scientific interest of the described observation is due to the debut of gigantism in childhood, complex pathogenetic treatment, as well as the experience of using the growth hormone receptor antagonist pegvisomant in a teenager in Russia.

Acromegaly is a chronic endocrine disorder characterized by prolonged exposure to excess growth hormone (GH) and insulin-like growth factor-1 (IGF-1), leading to systemic connective tissue remodeling. Although corneal and choroidal structural changes have been extensively reported, scleral alterations remain poorly understood. This prospective case–control study aimed to quantitatively assess anterior scleral thickness (ST) across multiple meridians in patients with acromegaly compared with healthy controls using anterior segment optical coherence tomography (AS-OCT). Fifty-five eyes were examined 22 from patients with confirmed acromegaly and 33 from age- and sex-matched healthy controls. Baseline ocular characteristics, including axial length (optical biometry) and refractive status (manifest refraction; spherical equivalent = sphere + ½ cylinder), were recorded for all participants.Scleral thickness was measured at eight meridians (inferior, superior, temporal, nasal, inferotemporal, inferonasal, superotemporal, superonasal) using standardized AS-OCT imaging. Between-group differences were analyzed using the Mann–Whitney U test, and effect sizes were expressed as Cohen’s d. Across all meridians, acromegaly patients demonstrated significantly thicker sclera compared with controls: inferior (673.2 ± 51.6 μm vs. 636.9 ± 33.1 μm, p = 0.024, d = 0.87), superior (650.7 ± 31.3 μm vs. 613.0 ± 31.3 μm, p = 5.6 × 10⁻⁵, d = 1.20), temporal (674.2 ± 35.8 μm vs. 620.6 ± 42.4 μm, p = 5.0 × 10⁻⁶, d = 1.34), and nasal (694.1 ± 53.5 μm vs. 637.2 ± 59.5 μm, p = 0.0016, d = 0.99). Oblique meridians showed parallel trends. Axial length was higher in the acromegaly group, while spherical equivalent did not differ significantly between groups. Anterior sclera is significantly thickened in acromegaly, consistent with GH/IGF-1–driven extracellular matrix expansion. These findings extend the ocular phenotype of acromegaly beyond corneal and choroidal changes, highlighting the need to consider scleral biomechanics in ocular and systemic disease evaluation.

The management of acromegaly, a chronic hormone disorder characterized by excessive growth hormone (GH) secretion, remains a subject of debate. This systematic review and meta-analysis aim to evaluate the impact of preoperative somatostatin analog (SA) treatment on surgical outcomes in acromegaly patients. A comprehensive search of medical databases was conducted following PRISMA guidelines, resulting in the inclusion of 15 studies published between 2013 and 2024, encompassing 4,387 patients with an average age of 46-47 years. The primary outcomes analyzed were surgical remission rates, postoperative GH levels, tumor volume reduction, and complication rates. Studies indicate that preoperative SA treatment significantly improves remission rates and reduces postoperative GH levels compared to surgery alone. For instance, one study reported a biochemical control rate of 59.5% in the SA group versus 46.5% in the non-SA group. Another study showed that preoperative SA treatment led to a higher rate of tumor volume reduction (62.5% vs. 53.7%). Additionally, patients treated with SAs experienced fewer surgical complications and higher rates of biochemical control. Despite the higher initial costs associated with SA treatment, long-term benefits such as reduced complications and enhanced surgical outcomes suggest it is a cost-effective approach. However, the analysis also highlights the need for further research on long-term outcomes, recurrence rates, patient quality of life, and the overall costeffectiveness of preoperative SA treatment. This study provides evidence supporting the integration of medical management into the preoperative care plan for acromegaly patients, emphasizing the potential benefits of SA treatment in improving surgical outcomes.

Acromegaly is a rare endocrine disorder primarily caused by excessive Growth Hormone (GH) secretion, often due to an anterior pituitary macroadenoma. Patients frequently experience cardiovascular complications, including hypertension and Dilated Cardiomyopathy (DCM). A 32-year-old male presented with features suggestive of acromegaly, including headache and blurred vision. Hormonal tests revealed a growth hormone level of 21 ng/mL and an Insulin-like Growth Factor-1 (IGF-1) level of 778.7 ng/mL. Magnetic Resonance Imaging (MRI) identified a 2.4×2.8×3.1 cm GH-secreting pituitary macroadenoma. Two-dimensional echocardiography indicated severe DCM with a Left Ventricular Ejection Fraction (LVEF) of 15-20% and severe diastolic dysfunction. The patient had no prior history of diabetes or hypertension and underwent successful endonasal trans-sphenoidal excision of the tumour, despite challenges posed by impaired cardiac function. This case emphasises the importance of careful anaesthetic management in acromegaly patients with cardiomyopathy

Since its discovery almost 100 years ago, growth hormone (GH) has been extensively studied to elucidate its structural characteristics, receptor interactions and its physiologic and non-physiologic effects. These actions include but are not limited to its effects on somatic growth, substrate metabolism, body composition, bone mineral density, cardiovascular system, and cognitive function. Contextually, recombinant human GH was approved for growth promotion in children and to enhance metabolic health in adult patients with GH deficiency (GHD), along with other clinical indications. Studies involving individuals and animal models exhibiting dysregulated GH levels, ranging from complete or partial GHD to GH excess, have unveiled a spectrum of several less evident GH actions. In this review, we exclude discussing the classic GH therapeutic applications but instead focus on the interplay between GH and glucose metabolism, fibrosis, and carcinogenesis that is observed with varying GH levels and action. We also discuss clinical data derived from studies in acromegaly and GHD patients (including individuals with congenital GH and insulin-like growth factor I [IGF-I] deficiencies), and attempt to integrate findings from cellular, animal and human studies with the aim of highlighting novel characteristics and underlying molecular pathways through which both GH and IGF-I exert their more subtle actions.

Gender medicine focuses on disease differences between females and males regarding symptoms, treatment, prognosis, psychosocial effects and prevention. Acromegaly is a rare endocrine disorder caused by excessive growth hormone (GH) production, in the vast majority of cases due to the presence of a GH-secreting pituitary adenoma. Chronic GH elevation leads to increased insulin-like growth factor-1 (IGF-1), resulting in tissue overgrowth and a number of comorbidities. Among these, patients with acromegaly can experience various issues of the cardiovascular and metabolic system, including glucose metabolism unbalance, diabetes mellitus, arterial hypertension and cardiomyopathy. This narrative review discusses the impact of gender differences on glycometabolic and cardiovascular comorbidities in patients with acromegaly. We performed a detailed literature search, gathering scientific articles on this topic, including original research studies, case reports, reviews, systematic reviews, meta-analyses, guidelines, and consensus papers published in English from 1989 to early 2025. A diagnostic delay between females and males is reported, together with a gender-related impact of the disease on body composition, lipid and glucose metabolism; gender differences in the development and progression of acromegaly cardiomyopathy are also described. In detail, females with acromegaly exhibit greater insulin resistance, increased adiposity, and higher risk of developing overt diabetes mellitus compared to males, along with milder cardiac abnormalities, despite experiencing higher cardiovascular mortality. Gender differences in metabolic and cardiovascular comorbidities of acromegaly need to be considered. Future studies should clarify the biological bases of these differences, to optimize treatment protocols and monitoring for our patients.