2026-08-13 | Acromegaly and colorectal cancer risk: emerging roles of the gut microbiota
Acromegaly is a rare endocrine disorder characterized by chronic growth hormone (GH) hypersecretion, usually due to a pituitary neuroendocrine tumor, leading to persistently elevated insulin-like growth factor 1 (IGF-1) levels. Although improved biochemical control reduces complications, cancer-related mortality remains a growing concern. Patients with acromegaly exhibit an increased prevalence of colorectal neoplasia, likely driven by sustained GH/IGF-1–mediated epithelial proliferation, reduced apoptosis, and activation of pro-tumorigenic signaling pathways. Concurrently, gut microbiota has emerged as a key modulator of intestinal homeostasis and carcinogenesis. Dysbiosis contributes to colorectal cancer development through chronic inflammation, production of genotoxins, disruption of epithelial barrier, and altered microbial metabolite profiles, including reduced short-chain fatty acids (SCFAs). Increasing evidence supports a bidirectional relationship between the gut microbiota and the GH/IGF-1 axis: microbial composition and SCFAs production can influence systemic and local IGF-1 levels, while GH and IGF-1 modulate microbial diversity, intestinal barrier function, and immune responses. Recent studies suggest that acromegalic patients display distinct oral and fecal microbial signatures, characterized by reduced alpha diversity, altered Firmicutes/Bacteroidetes ratio, and increased abundance of taxa potentially associated with colorectal carcinogenesis. Although causality has not been established, these alterations may interact with hormonal excess, insulin resistance, and systemic inflammation to create a permissive microenvironment for neoplastic transformation. This review provides an integrated clinical and pathophysiological synthesis of current evidence linking acromegaly, gut microbiota alterations, and colorectal cancer risk. Understanding this complex interplay may refine colorectal cancer risk stratification and open avenues for microbiota-targeted preventive or therapeutic strategies alongside endocrine disease control.
Open article ↗
2026-08-13 | Postural Stability, Fall Risk, and Effects of Balance-Based Exercise in Acromegaly.
Acromegaly may impair balance and increase fall risk. We aimed to evaluate postural stability, fall risk, and vestibulo-ocular reflex function in patients with acromegaly and to assess the effects of a balance-oriented exercise program. Single-center, prospective case-control study with an exercise intervention. Thirty-two patients with acromegaly (15 active, 17 inactive) and 32 age-, sex-, and body mass index-matched sedentary healthy controls were enrolled. Balance was assessed using computerized dynamic posturography along the anterior-posterior (AP) and medial-lateral (ML) axes. Vestibulo-ocular reflex function was evaluated with the video head impulse test. Clinical assessments included the Berg Balance Scale, International Falls Efficacy Scale, and Dizziness Handicap Inventory-Short Form. Fifteen patients with balance impairment completed an 8-week home-based exercise program, with outcomes reassessed afterward. Patients had lower preference AP, visual ML, vestibular ML, and global AP/ML scores than controls (P < .01). Berg Balance Scale scores were lower, whereas fall risk, fear-of-falling, and dizziness scores were higher in patients (P < .05). Fourier analysis demonstrated increased sway amplitudes with low-frequency dominance under static and dynamic conditions (P < .05). Global AP/ML scores were lower in active than inactive patients (P < .05). Vestibulo-ocular reflex gains were similar between groups (P > .05). Exercise significantly improved balance and clinical scale scores (P < .05). Balance impairment and increased fall risk may occur in acromegaly, likely due to deficits in central sensory integration. Balance-oriented rehabilitation may improve postural control and reduce fall risk in this population.
Open article ↗
2026-08-11 | Quality of Life in Acromegaly. Results from the ACROFAST Study.
Quality of life (QoL) is impaired in acromegaly, particularly in patients with active disease. Improvement of symptoms following hormonal normalization is expected to positively affect QoL. To assess whether earlier and more effective disease control, achieved in the ACROFAST study, is associated with improvements in AcroQoL scores and symptom burden evaluated by the PASQ questionnaire. AcroQoL and PASQ outcomes were analysed within the ACROFAST study timeframe, comparing controlled and uncontrolled patients. Assessments were performed at baseline, 6 months, and 12 months. No differences in global AcroQoL scores were observed between treatment arms. However, hormonally controlled patients presented better results in the appearance sub-dimension of the AcroQoL (59 ± 19 vs 45 ± 20 points; p = 0.04) and in PASQ score (15 ± 12 vs 23 ± 10 points; p = 0.01) at the end of the study. Paired analyses confirmed improvement in PASQ among controlled patients, and linear mixed-effects modelling further demonstrated a reduction over time (estimated marginal means: 19, 14, 14), while scores remained stable in uncontrolled patients. Sub-group analysis revealed that women had worse scores for both QoL and symptoms tests. Severity of symptoms correlated with QoL. Biochemical control is associated with improved symptoms and appearance-related QoL. A personalized approach, which is more effective achieving biochemical control than the standard one, may provide additional patient centred benefits, even if this study only provides indirect evidence. Women exhibited poorer QoL despite similar control rates, suggesting unmet supportive care needs in this subgroup.
Open article ↗
2026-08-10 | A Randomized First-in-human Study of a Novel Growth Hormone Receptor Peptide Antagonist ALXN2420 in Healthy Subjects.
Acromegaly is a rare disease typically caused by a growth hormone (GH) secreting pituitary adenoma. Somatostatin receptor ligand (SRL) monotherapy does not provide optimal control of circulating insulin-like growth factor-1 (IGF-1) levels in all patients with acromegaly. ALXN2420, a 16-amino acid peptide growth hormone receptor antagonist (GHRA), is being developed in combination therapy in patients with acromegaly insufficiently controlled with SRLs. To evaluate the safety and tolerability (primary), pharmacokinetics and pharmacodynamics of ALXN2420 in healthy subjects. Phase 1, randomized, double-blind, placebo-controlled single- (SAD) and 2-week multiple ascending dose (MAD) studies. : Single centre. : Overall, 101 eligible and evaluable healthy subjects. : ALXN2420 or placebo. Safety assessments, pharmacokinetic parameters, serum IGF-1 levels. Subcutaneous injections of ALXN2420 up to 120 mg/day were well tolerated, with no safety concerns. Pharmacokinetic parameters increased dose proportionally. The terminal half-life was approximately 22 hours. ALXN2420 induced dose-related decreases in IGF-1 levels at doses ≥20 mg, with a more prolonged reduction at higher doses for up to 72 hours (SAD) and up to the end of treatment (MAD). Repeated daily ALXN2420 administration for 2 weeks suggested a cumulative effect compared to single administration. For ALXN2420 doses ≥40 mg, maximal mean changes from baseline versus placebo in IGF-1 levels ranged from approximately 20% to 30% (SAD) and 40% to 50% (MAD). ALXN2420 doses of up to 120 mg/day appeared to be safe and substantially decreased IGF-1 levels in healthy subjects, thereby supporting further testing in patients with acromegaly.
Open article ↗
2026-08-07 | Development and Characterization of a Long-Acting Allosteric Growth Hormone Receptor Antagonist for Acromegaly.
Acromegaly is a rare disease caused by growth hormone (GH) hypersecretion from a pituitary adenoma. Pegvisomant is the only approved GH receptor antagonist (GHRA) and is administered via daily subcutaneous injections, which limits real-world effectiveness. Here, we report the discovery and characterization of MAR002, a novel, half-life extended monoclonal antibody GHRA. MAR002 was identified by immunizing transgenic mice with the extracellular domain (ECD) of human and cynomolgus monkey GH receptor (GHR) and engineered with Fc modifications to limit effector function and extend serum half-life. MAR002 was benchmarked against pegvisomant in biophysical assays, cellular signaling inhibition studies, and a head-to-head pharmacokinetic/pharmacodynamic (PK/PD) study in cynomolgus monkeys. MAR002 exhibited higher binding affinity to GHR and >100-fold more potent inhibition of GH-induced GHR signaling than pegvisomant (human half-maximal inhibitory concentration [IC50] 1.05 nM vs 122 nM). Epitope binning demonstrated simultaneous binding of MAR002 and GH to GHR, consistent with an allosteric, non-competitive mechanism; notably, MAR002 inhibitory activity was maintained at supraphysiological GH concentrations, whereas pegvisomant activity was competitively reduced. In cynomolgus monkeys, a single 10 mg/kg intravenous (IV) dose of MAR002 sustained ≥50% IGF-1 suppression for 36 days compared with 15 days for an equimolar pegvisomant dose, with comparable maximal lowering (∼80%). These findings support clinical evaluation of MAR002 as a next-generation long-acting GHRA for acromegaly, with potential for reduced dosing frequency and more consistent suppression of the GH-IGF-1 axis.
Open article ↗
