RARE DISEASE
Acromegaly
Acromegaly
Acromegaly
Drug discovery
21
drugs
With orphan designations
Overview
Acromegaly is a rare hormonal disorder caused by chronic hypersecretion of growth hormone (GH), typically from a pituitary adenoma, leading to progressive somatic enlargement and multisystem complications such as cardiovascular disease, diabetes mellitus, and osteoarthritis. Diagnosis relies on elevated IGF-1 levels and lack of GH suppression during oral glucose tolerance testing, complemented by pituitary MRI. First-line therapy involves transsphenoidal adenoma resection, with adjunctive medical treatments (somatostatin analogs, dopamine agonists, GH receptor antagonists) or radiotherapy for persistent disease [1][5][16][17].
Burden
Physical: 75–90% report arthralgia, cardiovascular/metabolic comorbidities (hypertension, diabetes), and sleep apnea [5][9][17]
Psychosocial: Impaired QoL due to fatigue (92%), depression/anxiety (75%), and social stigma from disfigurement [9][14]
Mortality: Untreated cases face 10-year reduced life expectancy; managed patients approach normal lifespan [11][17]
Therapies
First-line: Endoscopic transsphenoidal surgery (90% cured in microadenomas, <50% in macroaddenomas) [1][6][13]
Medical therapy: Somatostatin analogs (octreotide, lanreotide), dopamine agonists (cabergoline), and GH receptor antagonists (pegvisomant) [3][8][18]
Adjuvant: Radiation therapy for refractory cases; combination therapies improve biochemical control [3][13]
Categories: rare endocrine diseases, rare infertility disorders, rare neoplastic diseases
Research Papers
3,166 drug discovery papers about Acromegaly, with 2 first-in-class and 8 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
3,166 drug discovery papers about Acromegaly, with 2 first-in-class and 8 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
gene therapies
2024-12-16 | Bioinformatic materials science reconsidered.
Bioinformatic materials science integrates medical science, materials science, informatics, and other disciplines, aiming to maintain the balance of tissues and organs in the human body. This paper explores the relationship between structural information and the structures synthesized through regulated gene expression. Specifically, it describes the transformation of information into substances via biological structural systems, using mathematical formulas to develop bioinformatic materials. These materials have applications in medical treatments, functional foods for preventive healthcare, and cosmetic products for health maintenance. Notably, bioinformatic materials have been applied in treating acromegaly, a rare and life-threatening disease of unknown etiology, and have improved the neurofilament light chain (NFL) index and typical symptoms of Amyotrophic Lateral Sclerosis (ALS). In summary, bioinformatic materials science holds potential for enhancing human health and contributing to advances in medicine.
2024-05-09 | Histopathology of growth hormone-secreting pituitary tumors: State of the art and new perspectives.
Somatotroph (GH) adenomas/PitNETs typically arise from adenohypophysis and are biochemically active, leading to acromegaly and gigantism. More rarely, they present with ectopic origin and do not present overt biochemical or clinical features (silent variants). Histopathological examination should consider the clinical and radiological background, and include multiple steps assessing tumor morphology, pituitary transcription factors (PTFs), hormone secretion, proliferation markers, granulation, and somatostatin receptors (STRs), aimed at depicting as better as possible tumor origin (in case of non-functioning and/or metastatic tumor), and clinical behavior, including response to treatment. GH-secreting tumors are part of the Pit-1 family tumors and can secrete GH only (pure somatotrophs) or co-secrete prolactin (mixed tumors; in this case, various histological subtypes have been identified). Each subtype presents unique radiological, biochemical, and clinical characteristic. Therefore, the integration of biochemical, clinical, radiological, and histopathological elements is fundamental for proper diagnosis and management of pituitary adenomas/PitNETs, to be performed in referral Centers. In more recent times, the importance of genetic and epigenetic evaluation in the characterization of pituitary tumors (i.e., early identification of aggressive variants) has been outlined by some large studies, with the intention of improving targeted treatments.
2023-07-03 | Germline loss-of-function PAM variants are enriched in subjects with pituitary hypersecretion.
Pituitary adenomas (PAs) are common, usually benign tumors of the anterior pituitary gland which, for the most part, have no known genetic cause. PAs are associated with major clinical effects due to hormonal dysregulation and tumoral impingement on vital brain structures. PAM encodes a multifunctional protein responsible for the essential C-terminal amidation of secreted peptides. Following the identification of a loss-of-function variant (p.Arg703Gln) in the peptidylglycine a-amidating monooxygenase (PAM) gene in a family with pituitary gigantism, we investigated 299 individuals with sporadic PAs and 17 familial isolated PA kindreds for PAM variants. Genetic screening was performed by germline and tumor sequencing and germline copy number variation (CNV) analysis. In germline DNA, we detected seven heterozygous, likely pathogenic missense, truncating, and regulatory SNVs. These SNVs were found in sporadic subjects with growth hormone excess (p.Gly552Arg and p.Phe759Ser), pediatric Cushing disease (c.-133T>C and p.His778fs), or different types of PAs (c.-361G>A, p.Ser539Trp, and p.Asp563Gly). The SNVs were functionally tested in vitro for protein expression and trafficking by Western blotting, splicing by minigene assays, and amidation activity in cell lysates and serum samples. These analyses confirmed a deleterious effect on protein expression and/or function. By interrogating 200,000 exomes from the UK Biobank, we confirmed a significant association of the PAM gene and rare PAM SNVs with diagnoses linked to pituitary gland hyperfunction. The identification of PAM as a candidate gene associated with pituitary hypersecretion opens the possibility of developing novel therapeutics based on altering PAM function.
2021-12-21 | Results of a 5-Year N-of-1 Growth Hormone Releasing Hormone Gene Therapy Experiment.
Here presented for the first time are results showing persistence over a 5+ year period in a human who had a hormone gene therapy administered to muscle. This growth hormone releasing hormone (GHRH) therapy was administered in two doses, a year apart, with a mean after the second dose of 195 ng/mL (13 × normal, σ = 143, σM = 34, max = 495, min = 53). This level of GHRH therapy appears to be safe for the subject, although there were some adverse events. Insulin-like growth factor 1 levels were little affected, nor were the growth hormone test results, showing no indications of acromegaly for the hormone homologue used. Heart rate declined 8 to 13 bpm, persistent over 5 years. Testosterone rose by 52% (σ = 22%, σM = 6%). The high-density lipoprotein/low-density lipoprotein ratio dropped from 3.61 to mean 2.81 (σ = 0.26, σM = 0.057, max = 3.3, min = 2.5), and triglycerides declined from 196 mg/dL to mean 94.4 mg/dL (σ = 21.9, σM = 5.0, min = 59, max = 133, min = 59). White blood cell counts increased, however, the baseline was not strong. CD4 and CD8 mean increased by11.7% (σ = 11.6%, σM = 3.3%, max = 30.7%, min = -9.6%) and 12.0% (σ = 10.5%, σM = 3.0%, max = 29.1%, min = -6.7%), respectively. Ancillary observations comprise an early period of euphoria, and a dramatic improvement in visual correction after the first dose, spherical correction from baseline (L/R) -2.25/-2.75 to -0.25/-0.5. Over the next 5 years, correction drifted back to -1.25/-1.75. Horvath PhenoAge was cut 44.1% post-treatment. At completion, epigenetic age was -6 years (-9.3%), and telomere age was +7 months (+0.9%).
2020-04-06 | The absence of PRDM2 involved the tumorigenesis of somatotroph adenomas through regulating c-Myc.
Somatotroph adenoma is the main cause of acromegaly which have peripheral signs with growth of soft tissues and multiple comorbidities. Surgery and adjuvant therapy with somatostatin analogs (SSA) fail in more than 25% of patients. PRDM2, a tumor suppressor, plays an important role in cancer and obesity, including pituitary adenomas. In this study, we analyze the correlation of PRDM2 and oncogene c-Myc in 70 somatotroph adenomas according immunohistochemical staining, furthermore, we probed that whether PRDM2 participates in c-Myc signaling pathway in vitro experiment. 70 somatotroph adenomas patients were divided into low patients and high patients according to median of H-score of PRDM2 or c-Myc. Low PRDM2 patients had higher risk of invasive behavior, larger tumor volume and recurrence chance than high PRDM2 group (P = 0.015, P = 0.031, P = 0.017). High c-Myc patients had higher risk of invasive behavior, larger tumor volume and recurrence chance than low c-Myc group (P = 0.012, P = 0.002, P = 0.015). It was a negative correlation between H-score of PRDM2 and c-Myc (PRDM2 = -0.163 × c-Myc + 67.11, r = -0.407). The ability of cell proliferation was declined in a time dependent manner after overexpression of PRDM2 (PRDM2 group) compared to that in control GH3 cells (P < 0.05). Through flow cytometry assay, PRDM2 could induce the apoptosis and G2/M arrest in GH3 cell (both p < 0.05). Transwell experiment proved less trans-membrane cells in PRDM2 group than those in control group (415 ± 76 vs 145 ± 37, P < 0.01). RT-PCR and western blot both proved PRDM2 could inhibit the level c-Myc and elevate the levels of CDKN1A and CDKN1B. Combined with c-Myc inhibitor 10058-F4, PRDM2 further inhibited cell proliferation and induced more apoptosis in GH3 cell. Taken together, we found that PRDM2 negatively regulated the expression of c-Myc in somatotroph adenomas, and testified the synergism between PRDM2 gene therapy and c-Myc inhibitor in vitro experiment.
small molecules
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.
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.
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.
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.
2026-08-06 | Can acromegaly be controlled in all cases?
Acromegaly is a rare disease, due in most of the cases to a growth hormone (GH)-secreting pituitary adenoma (PA), namely neuroendocrine tumour (PitNET). The treatment of patients with acromegaly is multimodal and multi-step, including surgery, medical therapies, and radiotherapy. In the last 30 years, the therapeutic armamentarium for the treatment of acromegaly has progressively increased, and the therapeutic algorithm has been significantly modified through the identification of clinical, biochemical, and molecular biomarkers of treatment outcome. The personalization of acromegaly treatment has shifted the paradigm from a 'trial-and-error' to a 'target-to-treat' treatment approach to achieve early disease control and to reduce the risk of disease-related comorbidities that may lead to an increased mortality. Nevertheless, despite the numerous improvements in the treatment of patients with acromegaly, disease control is not achieved in all patients, according to the results of randomized clinical trials, interventional studies, and prospective and retrospective observational studies. In parallel, the normalization of GH and IGF-I levels may not be sufficient to control acromegaly related symptoms and prevent disease-related comorbidities. In this review, we will report on the most recent aims of treatment and cure in patients with acromegaly, on the efficacy and predictors of response to conventional treatments (such as first- and second-generation somatostatin receptor ligands and growth hormone receptor antagonist). A specific section will focus on the rarer aggressive disease pictures and on the treatment with systemic therapies (such as temozolomide and capecitabine) and on target therapies (such as neo-angiogenesis and immune checkpoint inhibitors).
proteins
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.
2026-08-04 | Micromegaly: a distinct clinical entity? Insights from a monocentric cohort study.
The term "micromegaly" historically refers to patients with acromegalic features, elevated IGF-1, but normal growth hormone (GH) levels. The physiological mechanism, the appropriate clinical and treatment approaches, as well as its existence as a separate clinical entity are not well-defined. We retrospectively collected clinical and hormonal data from 30 patients with acromegaly and 30 with micromegaly (displaying high IGF-1 but GH < 0.4 µg/L after glucose load), matched for age and sex. Data about acromegaly related comorbidities were collected (goiter, colonic polyps, malignancies, hypertension, cardiopathy, obstructive-sleep-apnea, carpal tunnel, and hyperglycemia). We performed a laboratory analysis of pituitary tissue samples from both groups, examining GH isoform expression and proliferative rate. We compared data of the two groups and described follow-up and treatment response in micromegalic patients. Patients with acromegaly exhibited higher IGF-1 values at diagnosis (+8.3 vs. +3.2 SDS, p < 0.01) and higher GH nadir levels after glucose load (6 vs. 0.15 μg/L, p < 0.01). All patients with acromegaly had a detectable pituitary adenoma (70% macroadenomas), whereas 52% of patients with micromegaly showed no evidence of pituitary adenoma. Despite different GH/IGF-1 values, the prevalence of most comorbidities was similar in both groups, except for valve disease and diabetes mellitus, which were more frequent in acromegaly (valvopathy: 42.9% vs. 16.7%, p = 0.006; diabetes: 56.7% vs. 23.3%, p = 0.016, respectively). Laboratory analyses in patients with micromegaly indicated a lower proliferative profile in tumor cells (D3 cyclin expression). Patients with a clinical diagnosis of acromegaly and high IGF-1 levels but a GH nadir < 0.4 µg/L following glucose load exhibit a high burden of comorbidities and therefore require appropriate screening and follow-up. Therapeutic strategies in these cases should be individualized, considering the frequent absence of neuroradiological findings, which may reflect a lower proliferative profile.
2026-07-17 | High-yield soluble expression and affinity-tag-free purification of growth hormone receptor antagonist B2036 in Escherichia coli.
Acromegaly is a severe endocrine disease, and growth hormone receptor antagonist B2036 constitutes the core protein backbone of pegvisomant. Conventional B2036 production based on inclusion bodies or periplasmic expression suffers from low yield, complicated refolding, and multi-step purification. Herein, we developed a highly efficient, refolding-free bioprocess for soluble expression of B2036 in Escherichia coli using SUMO fusion technology. The entire fermentation cycle was controlled within 24 h, and fermentation optimization via response surface methodology enabled a high-yield soluble yield of 0.95 g/L. For downstream processing, an industrial-scalable, affinity-tag-free strategy using only two chromatography steps (anion-exchange and mixed-mode chromatography) was established, producing 498.47 mg/L B2036 with 97.12% purity, representing a 20-fold improvement over previous reports. The obtained B2036 showed correct sequence, precise disulfide pairing, and strong biological activity with an IC₅₀ of 0.67 nmol/L. By removing protein refolding and metal-affinity chromatography, this simplified and robust workflow remarkably improves productivity and product quality, offering a cost-effective and scalable technical platform for large-scale manufacturing of pegvisomant biosimilars. Collectively, these findings provide a valuable reference for developing efficient soluble expression and downstream purification processes of other intrachain disulfide-bonded proteins in E. coli.
2026-07-03 | Beyond biochemical control: headache resolution with pasireotide in a patient with acromegaly and residual tumor.
Acromegaly management is particularly challenging when pituitary adenomas invade the cavernous sinus, limiting the likelihood of complete surgical resection. We describe a case of a 40-year-old woman with acromegaly caused by a growth hormone and prolactin co-secreting pituitary macroadenoma with bilateral cavernous sinus invasion and severe, frequent headache. Despite transsphenoidal surgery, radiotherapy, and sequential medical therapy with octreotide, cabergoline, and pegvisomant over 3 years, insulin-like growth factor 1 (IGF-1) levels remained elevated and headache burden persisted. Initiation of pasireotide long-acting release was followed by rapid normalization of IGF-1 levels and complete resolution of headache, with improvement in other acromegaly related symptoms. This case supports the potential role of pasireotide in selected patients with biochemically and clinically treatment-resistant acromegaly and contributes to the growing real-world evidence regarding its use in patients with residual disease in surgically challenging locations.
2026-05-06 | [Efficacy of octreotide LAR and lanreotide autogel in acromegaly assessed by SAGIT].
Biochemical control has been the main objective in the treatment of acromegaly; however, GH and IGF-1 levels do not necessarily translate into clinical response, as they fail to account for the complexity of symptoms and patients' perceptions. The SAGIT instrument was developed to assist in assessing the status and evolution of the disease in patients with acromegaly and facilitate decision-making. To compare the efficacy of octreotide LAR and lanreotide autogel in managing patients with acromegaly using the SAGIT instrument. Observational, unicentric study, conducted in 2022 at a referral hospital in León, Guanajuato, Mexico. Of 37 patients evaluated, 26 were included. 13 (50%) received lanreotide autogel and 11 (42.3%) received octreotide LAR. Disease control, as measured by IGF-1 levels, was achieved in 10 patients (42.3%). When assessing control using the SAGIT instrument, 8 patients (30.7%) met control criteria. Octreotide LAR showed greater disease control as assessed by SAGIT compared to lanreotide autogel (p = 0.043). Based on the SAGIT instrument, octreotide LAR is more effective for disease control in patients with acromegaly than in those patients treated with lanreotide. The preferential use of octreotide LAR could be recommended in resource-limited settings.
antibodies
2026-01-19 | Long-term effect on bone mineral density of denosumab in the treatment of hyperpituitarism driven osteoporosis: an exploratory study.
Treatment of skeletal fragility in patients with pituitary diseases is challenging. Denosumab, an antiresorptive bone active drug, increased bone mineral density (BMD) and reduced incidence and risk of fractures in primary osteoporosis. This study aimed to evaluate the efficacy of denosumab in patients with pituitary disease-driven osteoporosis. This retrospective study investigated the frequency of fragility fractures (FF) and the percent BMD changes at 1-, 2-, 5-, and 10-years of treatment with denosumab, in patients with osteoporosis due to secreting pituitary adenoma. Seventeen patients were included: 5 patients (29.4%) were affected by hyperprolactinemia due to PRL-secreting pituitary adenoma (PAs), six patients (35.3%) were affected by acromegaly and six patients (35.3%) by Cushing's disease. Four patients carried prevalent-FF (23.5%). A single patient with acromegaly developed FF at 2 and at 5 years of treatment with denosumab. Femoral neck BMD increased in 11 patients (64.7%) at 1 year of treatment, in 9 patients (52.9%) at 2 years of treatment, in 8 patients (47.1%) at 5 years of treatment and in 2 patients (66.7%) at 10 years of treatment. Lumbar spine BMD improved in all patients at 1 year of treatment (100%), in 16 patients at 2 years of treatment (100%), in 11 patients at 5 years of treatment (100%), and in 2 patients at 10 years of treatment (66.7%). No drug related adverse events occurred. This study demonstrated for the first time that long-term treatment with denosumab is effective and safe in patients with osteoporosis due to secreting pituitary adenoma.
2025-10-01 | OR12-06 Development of a Novel Growth Hormone Receptor Antagonist Antibody for the Treatment of Acromegaly
Abstract Disclosure: K. Kurylo: Marea Therapeutics, Inc. W. Huynh: Marea Therapeutics, Inc. P.R. Bouchard: Marea Therapeutics, Inc. M.N. Milton: Marea Therapeutics, Inc. P.F. Moesta: Marea Therapeutics, Inc. L.E. Dichtel: Marea Therapeutics, Inc., Recordati, Lumos Pharma, Perspectum, Novo Nordisk, Third Rock Ventures, Merida Biosciences, Flare Therapeutics. J. Gromada: Marea Therapeutics, Inc. V. Ramanan: Marea Therapeutics, Inc. M.P. Joing: Marea Therapeutics, Inc. B.B. Cummings: Marea Therapeutics, Inc. E.J. Weiss: Marea Therapeutics, Inc.. Acromegaly is a rare disease characterized by excessive growth hormone (GH) production from a benign anterior pituitary adenoma. Elevated GH levels lead to increased production of IGF-1 from the liver, and acromegaly is linked to increased morbidity and mortality. GH receptor antagonists (GHRA) are an attractive therapeutic option, as they directly block GH action, lower IGF-1, and improve insulin sensitivity. However, the only currently available GHRA, pegvisomant, requires daily administration, resulting in low patient compliance and reduced real-world efficacy. Here, we report the development and characterization of MAR002, a novel half-life extended GHRA monoclonal antibody with the potential to enhance ease of use, improve efficacy, and elevate the quality of life for patients with acromegaly. In vitro, MAR002 had a significantly stronger binding affinity to GHR and resulted in more potent dose-dependent inhibition of GH-induced GHR signaling (IC50: 1 nM) vs. pegvisomant (IC50: 122nM). The greater potency of MAR002 was maintained when GH was pre-bound to GHR. MAR002 maintained stable GHR signaling suppression with supraphysiological GH levels (≥90% suppression), whereas such levels of GH outcompeted pegvisomant (no suppression). Epitope mapping revealed that unlike pegvisomant, MAR002 does not bind known GH binding sites on GHR, and additional binding assays confirmed MAR002 and GH can bind simultaneously to GHR. Together, these data demonstrate that MAR002 binds allosterically to inhibit GHR signaling; a novel GH-binding independent mechanism distinct from pegvisomant, which is an orthosteric inhibitor known to occupy the same binding site as GH. In cynomolgus monkeys, administration of equimolar doses of MAR002 and pegvisomant was well tolerated and demonstrated similar peak IGF-1 suppression (80% reduction, n=3 per group). MAR002 demonstrated a more favorable PK/PD profile, as it was detected in serum concentrations that resulted in ≥50% IGF-1 suppression for 36 days vs.15 days for pegvisomant. Of note, half-life extending mutations in monoclonal antibodies are reported to be up to 3x more durable in humans than in monkeys. This, in addition to the more favorable serum residence time of MAR002 predicts a substantially longer duration of IGF-1 lowering in humans compared to pegvisomant. In summary, we developed and characterized a novel half-life extended, allosteric, inhibitory GHR antibody with a mechanism distinct from pegvisomant. Stronger inhibitory activity of MAR002 against GHR in vitro, combined with a superior PK/PD profile in cynomolgus monkeys, should provide a prolonged therapeutic effect in patients, requiring less-frequent dosing vs. pegvisomant (e.g. potentially biweekly, monthly, or less frequent). This work enables continued MAR002 development to assess its safety, efficacy, and potential to improve the care for patients with acromegaly. Presentation: Sunday, July 13, 2025
2025-08-29 | Adherence, duration and healthcare costs in a real-world population of patients with acromegaly.
Aim: The aim of this study was to describe treatment patterns among patients with acromegaly who are newly treated with acromegaly medical therapy. Materials & methods: Data from IQVIA Pharmetrics Plus® Database from 1 January 2013 to 30 June 2023 were used to identify patients with acromegaly who started a new acromegaly medical therapy and observe their treatment patterns. Patients were required to have at least 12 months of data without any acromegaly therapy (medication or surgery) prior to the index date and at least 6 months of follow-up. Comorbidities were measured during the baseline period. Adherence, persistence, medication and switching were measured during follow-up. Results: A total of 453 patients with acromegaly who were newly treated with acromegaly medical therapy and had no evidence of acromegaly therapy for at least 12 months were identified. Among these patients, 46.1% (n = 206) were treated with cabergoline as their index treatment, 24.5% (n = 111) with injectable octreotide, 15.0% (n = 68) with lanreotide, 5.5% (n = 25) with bromocriptine, 4.9% (n = 22) with pegvisomant, 2.2% (n = 10) with pasireotide, 1.1% (n = 5) with oral octreotide, 0.4% (n = 2) with cabergoline + octreotide, and 0.2% (n = 1) with cabergoline + lanreotide. By the end of the follow-up period, 54.3% (n = 246) were not on any treatment, 19.6% (n = 89) remained on the index treatment, and the remaining 26.0% (n = 118) switched to another treatment. Conclusion: This study contributed to the growing evidence that patients with acromegaly are not well-served by current therapeutic options, as indicated by high rates of treatment discontinuation, switching and add-on therapy. However, treatment switching and add-on therapy represent ongoing efforts to optimize patient care toward more effective and tolerable treatments. Expanded treatment options may serve an unmet need in this patient population.
2025-04-04 | Carotid femoral pulse wave velocity and serum galectin-3 level significantly increases in patients with acromegaly.
Insulin-like growth factor-1 (IGF-1) and growth hormone release is elevated in acromegaly, a chronic condition. Our objective was to study the correlation between carotid femoral pulse wave velocity (CF-PWV) and galectin-3 level in acromegaly patients. This protein is believed to alter in response to early inflammation and atherosclerosis. Our study was planned as a prospective, single-center cross-sectional study. Our study comprised 40 healthy controls and 40 newly diagnosed acromegaly patients ranging in age from 18 to 65 years old at Adana City Training and Research Hospital. The patients' IGF-1, growth hormone, hemogram, and biochemistry values were assessed. Human galectin-3 kits and the Enzyme-Linked Immunosorbent Assay were used to measure the amount of galectin-3. Patients underwent CF-PWV assessments with the use of Doppler ultrasonography and concurrent electrocardiography. Our investigation indicated that acromegaly patients had greater levels of the fibrosis and inflammation indicator galectin-3 as well as the gold standard indication of arterial stiffness, CF-PWV. We observed a link between blood galectin-3 level and both IGF-1 level and CF-PWV measures in the correlation analysis. Galectin-3 has the potential to be a novel biomarker for the diagnosis and prognosis of cardiovascular disease in acromegaly patients, as well as a therapeutic target for the development of this disease.
2025-03-21 | Case Report and Literature Review: Overexpression of HMGA in Concomitant Plurihormonal Tumor and Papillary Thyroid Carcinoma.
This study described a case of plurihormonal tumor associated with papillary thyroid carcinoma (PTC) and summarized the treatment approaches for similar cases, while also exploring the underlying pathogenesis. The patient exhibited symptoms indicative of acromegaly, central hyperthyroidism, and hyperprolactinemia. A glucose loading test demonstrated persistently elevated growth hormone (GH) levels, while thyroid function tests revealed inappropriate thyroid stimulating hormone (TSH) secretion. Imaging of the pituitary gland revealed a 26 × 19 mm lesion compressing the optic chiasm. Thyroid ultrasound reveals bilateral Thyroid Imaging Reporting and Data System 4B nodules, with the largest on the right measuring 27 × 20 mm. Fine-needle aspiration cytology (FNAC) revealed the presence of PTC. Three weeks later, the patient underwent pituitary adenomectomy. Immunohistochemistry revealed a plurihormonal tumor positive for TSH, GH, luteinizing hormone (LH), prolactin (PRL), pituitary-specific transcription factor 1 (Pit1), and steroidogenic factor 1 (SF1). A total thyroidectomy followed 10 weeks post-adenomectomy. Immunohistochemical evaluation showed higher nuclear positivity for the high-mobility group AT-hook 1 (HMGA1) and the high-mobility group AT-hook 2 (HMGA2) proteins in neoplastic cells compared to normal tissues. In our search results, only three similar cases were identified, and we summarized the relevant literature search results which raise the possibility that the HMGA2-the Retinoblastoma Protein (pRB)/E2F Transcription Factor 1 (E2F1)-HMGA1 signaling pathway may represent a common pathogenic pathway for PTC and plurihormonal tumor. If a patient simultaneously suffers from PTC and plurihormonal tumor, the determination of the surgical sequence is crucial. In cases of postoperative recurrence, where patients are reluctant to undergo additional surgeries, targeting HMGA is likely to offer a promising approach to prevent the progression of both the pituitary tumors and PTC.
other
2025-10-02 | Possibility of calcification of type I collagen matrix in growth hormone-secreting pituitary neuroendocrine tumor.
In acromegaly caused by growth hormone (GH)-secreting pituitary neuroendocrine tumor (PitNET), excessive secretion of GH and insulin-like growth factor 1 (IGF-1) enhances bone anabolic effects while inducing the production of type I collagen, leading to increased bone mass and bone mineral density. We investigated the possibility of calcification of type I collagen matrix used in endoscopic transsphenoidal surgery (ETSS) for GH-secreting PitNET. Twelve patients with GH-secreting PitNET who underwent ETSS and were followed up for more than 1 year after surgery were divided into two groups: The "DuraGen group," in which DuraGen, a type I collagen matrix, was used as the overlay graft to cover the closed sella turcica for sellar floor reconstruction after tumor resection and the "fat group," in which fat was used. Clinical characteristics associated with surgery for GH-secreting PitNET were compared between the groups. Seven patients were assigned to the DuraGen group and five to the fat group. One year after surgery, the reconstructed sellar floor was thickly calcified in all cases in the DuraGen group, but not calcified in all cases in the fat group. Patient characteristics, tumor-related factors including image findings, tumor size, histopathology and extent of tumor resection, and the pre- and postoperative course of GH and IGF-1 demonstrated no significant differences between the groups. In ETSS for acromegaly due to GH-secreting PitNET, the possibility of calcification of type I collagen matrix used as the overlay graft for sellar floor reconstruction should be considered.
2022-03-14 | Downregulation of miR-216a-5p and miR-652-3p is associated with growth and invasion by targeting JAK2 and PRRX1 in GH-producing pituitary tumours.
Expression of aberrant microRNA (miRNA) is associated with tumour formation, migration, and invasion. However, there is limited information about the epigenetics of pituitary tumorigenesis. This study investigated the role of miRNA expression during the tumorigenesis of growth hormone (GH)-secreting pituitary tumours. miRNA profiling and real-time PCR were used to analyse the mRNA expression profile in sequential pituitary tissues of a unique animal model with a GH-producing pituitary tumour. Selected miRNAs were further validated in GH-producing cell lines and human pituitary tumour samples. The expression of significantly altered miRNAs and their predicted targets, as detected by microarray, was evaluated by real-time PCR, Western blotting, and immunohistochemistry using samples from mouse models and human pituitary tumours. The effect of miRNAs on tumour proliferation and invasion was examined in GH3 cells using the MTS and Matrigel invasion assays. Among the 14 miRNAs whose expression was significantly changed, miR-216a-5p (fold change = -5.638, P -value = 0.014) and miR-652-3p (fold change = -3.482, P -value = 0.010) were constantly and significantly downregulated. Transfection with mimics of miR-216a-5p and miR-652-3p inhibited GH3 proliferation and invasion, whereas inhibitors promoted them. The direct target genes of miR-216a-5p and miR-652-3p were Jak2 and Prrx1, respectively, which were downregulated in GH3 cells transfected with mimics and in serial pituitary gland tissues, including hyperplasic tissues and tumours of acromegalic animal models and pituitary tumour tissues of acromegalic patients. Downregulated miR-216a-5p and miR-652-3p expression may contribute to tumour progression by targeting JAK2 and PRRX1 on GH-producing pituitary tumours.
2021-06-21 | GPR64 promotes cAMP pathway in tumor aggressiveness in sparsely granulated growth hormone cell adenomas.
There is an increasing agreement that acromegaly caused by growth hormone (GH) cell adenoma has two distinct subtypes: densely granulated (DG) and sparsely granulated (SG). We hypothesized that differential molecular signatures may explain their behavior. Total transcriptome sequencing was performed on ten DG and seven SG adenomas. The differentially expressed RNAs were identified by bioinformatic analyses, and a candidate RNA was verified by quantitative real-time PCR. Immunohistochemical staining was also performed to detect the protein expression of the candidate. Clinical parameters were correlated with protein expression. Subsequently, cell proliferation, colony formation, and cell cycle progression were analyzed after knockdown of the candidate in pituitary GH3 cells. Activation of the cAMP pathway was assessed by ELISA and Western blot. We confirmed that there were obvious differentially expressed genes between the subtypes. Through gene profiling, we discovered that an orphan adhesion G protein-coupled receptor, GPR64, was overexpressed in more aggressive SG adenomas. Noticeably, GPR64 knockdown significantly inhibited the proliferation of GH3 tumor cells and decreased colony formation. The knockdown also induced cell cycle arrest in GH3 tumor cells. Further studies revealed that GPR64 knockdown decreased cAMP levels and the ratios of p-CREB/CREB, indicating that it suppressed the cAMP/CREB pathway. Our results indicated that GPR64 may promote aggressiveness in SG-type GH cell adenomas and that it is a key factor regulating the cAMP pathway to promote aggressiveness of GH cell adenomas.
2020-09-24 | Exosomal hsa-miR-21-5p derived from growth hormone-secreting pituitary adenoma promotes abnormal bone formation in acromegaly.
Growth hormone-secreting pituitary adenoma (GHPA), a benign endocrine tumor located in the base of the skull, results in acromegaly. In addition to the mass effect of the tumor itself in the sellar region, GHPA can lead to the overgrowth of almost every organ. Previous findings indicated that the processes underlying acromegaly were partly attributable to hyperactivity of the growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis. However, the mechanisms driving this syndrome remains largely unknown. Additionally, the roles of GHPA-derived exosomes, which contain functional microRNAs and proteins that manipulate target cell proliferation and differentiation in distal extremities, are also unknown. In this study, we demonstrated that GHPA exosomes promote bone formation in vitro and trabecula number in vivo. The mechanism of increased trabecula formation may be attributable to GHPA exosome-induced osteoblast proliferation via increased cell viability and DNA replication. We further discovered that exosomal hsa-miR-21-5p plays a distinct role from the GH/IGF-1 axis in these processes. Accordingly, the results of this study provide a novel mechanism whereby GHPA influences distal extremities and a new perspective for treating GHPA.
2020-09-10 | miR ‐34a is upregulated in AIP ‐ mutated somatotropinomas and promotes octreotide resistance
Abstract Pituitary adenomas (PAs) are intracranial tumors associated with significant morbidity due to hormonal dysregulation, mass effects and have a heavy treatment burden. Growth hormone (GH)‐secreting PAs (somatotropinomas) cause acromegaly‐gigantism. Genetic forms of somatotropinomas due to germline AIP mutations ( AIP mut+) have an early onset and are aggressive and resistant to treatment with somatostatin analogs (SSAs), including octreotide. The molecular underpinnings of these clinical features remain unclear. We investigated the role of miRNA dysregulation in AIP mut+ vs AIP mut− PA samples by array analysis. miR‐34a and miR‐145 were highly expressed in AIP mut+ vs AIP mut− somatotropinomas. Ectopic expression of AIP mut (p.R271W) in Aip −/− mouse embryonic fibroblasts (MEFs) upregulated miR‐34a and miR‐145, establishing a causal link between AIP mut and miRNA expression. In PA cells (GH3), miR‐34a overexpression promoted proliferation, clonogenicity, migration and suppressed apoptosis, whereas miR‐145 moderately affected proliferation and apoptosis. Moreover, high miR‐34a expression increased intracellular cAMP, a critical mitogenic factor in PAs. Crucially, high miR‐34a expression significantly blunted octreotide‐mediated GH inhibition and antiproliferative effects. miR‐34a directly targets Gnai2 encoding Gαi2, a G protein subunit inhibiting cAMP production. Accordingly, Gαi2 levels were significantly lower in AIP mut+ vs AIP mut− PA. Taken together, somatotropinomas with AIP mutations overexpress miR‐34a, which in turn downregulates Gαi2 expression, increases cAMP concentration and ultimately promotes cell growth. Upregulation of miR‐34a also impairs the hormonal and antiproliferative response of PA cells to octreotide. Thus, miR‐34a is a novel downstream target of mutant AIP that promotes a cellular phenotype mirroring the aggressive clinical features of AIP mut+ acromegaly.
gene therapies
2024-12-16 | Bioinformatic materials science reconsidered.
Bioinformatic materials science integrates medical science, materials science, informatics, and other disciplines, aiming to maintain the balance of tissues and organs in the human body. This paper explores the relationship between structural information and the structures synthesized through regulated gene expression. Specifically, it describes the transformation of information into substances via biological structural systems, using mathematical formulas to develop bioinformatic materials. These materials have applications in medical treatments, functional foods for preventive healthcare, and cosmetic products for health maintenance. Notably, bioinformatic materials have been applied in treating acromegaly, a rare and life-threatening disease of unknown etiology, and have improved the neurofilament light chain (NFL) index and typical symptoms of Amyotrophic Lateral Sclerosis (ALS). In summary, bioinformatic materials science holds potential for enhancing human health and contributing to advances in medicine.
2024-05-09 | Histopathology of growth hormone-secreting pituitary tumors: State of the art and new perspectives.
Somatotroph (GH) adenomas/PitNETs typically arise from adenohypophysis and are biochemically active, leading to acromegaly and gigantism. More rarely, they present with ectopic origin and do not present overt biochemical or clinical features (silent variants). Histopathological examination should consider the clinical and radiological background, and include multiple steps assessing tumor morphology, pituitary transcription factors (PTFs), hormone secretion, proliferation markers, granulation, and somatostatin receptors (STRs), aimed at depicting as better as possible tumor origin (in case of non-functioning and/or metastatic tumor), and clinical behavior, including response to treatment. GH-secreting tumors are part of the Pit-1 family tumors and can secrete GH only (pure somatotrophs) or co-secrete prolactin (mixed tumors; in this case, various histological subtypes have been identified). Each subtype presents unique radiological, biochemical, and clinical characteristic. Therefore, the integration of biochemical, clinical, radiological, and histopathological elements is fundamental for proper diagnosis and management of pituitary adenomas/PitNETs, to be performed in referral Centers. In more recent times, the importance of genetic and epigenetic evaluation in the characterization of pituitary tumors (i.e., early identification of aggressive variants) has been outlined by some large studies, with the intention of improving targeted treatments.
2023-07-03 | Germline loss-of-function PAM variants are enriched in subjects with pituitary hypersecretion.
Pituitary adenomas (PAs) are common, usually benign tumors of the anterior pituitary gland which, for the most part, have no known genetic cause. PAs are associated with major clinical effects due to hormonal dysregulation and tumoral impingement on vital brain structures. PAM encodes a multifunctional protein responsible for the essential C-terminal amidation of secreted peptides. Following the identification of a loss-of-function variant (p.Arg703Gln) in the peptidylglycine a-amidating monooxygenase (PAM) gene in a family with pituitary gigantism, we investigated 299 individuals with sporadic PAs and 17 familial isolated PA kindreds for PAM variants. Genetic screening was performed by germline and tumor sequencing and germline copy number variation (CNV) analysis. In germline DNA, we detected seven heterozygous, likely pathogenic missense, truncating, and regulatory SNVs. These SNVs were found in sporadic subjects with growth hormone excess (p.Gly552Arg and p.Phe759Ser), pediatric Cushing disease (c.-133T>C and p.His778fs), or different types of PAs (c.-361G>A, p.Ser539Trp, and p.Asp563Gly). The SNVs were functionally tested in vitro for protein expression and trafficking by Western blotting, splicing by minigene assays, and amidation activity in cell lysates and serum samples. These analyses confirmed a deleterious effect on protein expression and/or function. By interrogating 200,000 exomes from the UK Biobank, we confirmed a significant association of the PAM gene and rare PAM SNVs with diagnoses linked to pituitary gland hyperfunction. The identification of PAM as a candidate gene associated with pituitary hypersecretion opens the possibility of developing novel therapeutics based on altering PAM function.
2021-12-21 | Results of a 5-Year N-of-1 Growth Hormone Releasing Hormone Gene Therapy Experiment.
Here presented for the first time are results showing persistence over a 5+ year period in a human who had a hormone gene therapy administered to muscle. This growth hormone releasing hormone (GHRH) therapy was administered in two doses, a year apart, with a mean after the second dose of 195 ng/mL (13 × normal, σ = 143, σM = 34, max = 495, min = 53). This level of GHRH therapy appears to be safe for the subject, although there were some adverse events. Insulin-like growth factor 1 levels were little affected, nor were the growth hormone test results, showing no indications of acromegaly for the hormone homologue used. Heart rate declined 8 to 13 bpm, persistent over 5 years. Testosterone rose by 52% (σ = 22%, σM = 6%). The high-density lipoprotein/low-density lipoprotein ratio dropped from 3.61 to mean 2.81 (σ = 0.26, σM = 0.057, max = 3.3, min = 2.5), and triglycerides declined from 196 mg/dL to mean 94.4 mg/dL (σ = 21.9, σM = 5.0, min = 59, max = 133, min = 59). White blood cell counts increased, however, the baseline was not strong. CD4 and CD8 mean increased by11.7% (σ = 11.6%, σM = 3.3%, max = 30.7%, min = -9.6%) and 12.0% (σ = 10.5%, σM = 3.0%, max = 29.1%, min = -6.7%), respectively. Ancillary observations comprise an early period of euphoria, and a dramatic improvement in visual correction after the first dose, spherical correction from baseline (L/R) -2.25/-2.75 to -0.25/-0.5. Over the next 5 years, correction drifted back to -1.25/-1.75. Horvath PhenoAge was cut 44.1% post-treatment. At completion, epigenetic age was -6 years (-9.3%), and telomere age was +7 months (+0.9%).
2020-04-06 | The absence of PRDM2 involved the tumorigenesis of somatotroph adenomas through regulating c-Myc.
Somatotroph adenoma is the main cause of acromegaly which have peripheral signs with growth of soft tissues and multiple comorbidities. Surgery and adjuvant therapy with somatostatin analogs (SSA) fail in more than 25% of patients. PRDM2, a tumor suppressor, plays an important role in cancer and obesity, including pituitary adenomas. In this study, we analyze the correlation of PRDM2 and oncogene c-Myc in 70 somatotroph adenomas according immunohistochemical staining, furthermore, we probed that whether PRDM2 participates in c-Myc signaling pathway in vitro experiment. 70 somatotroph adenomas patients were divided into low patients and high patients according to median of H-score of PRDM2 or c-Myc. Low PRDM2 patients had higher risk of invasive behavior, larger tumor volume and recurrence chance than high PRDM2 group (P = 0.015, P = 0.031, P = 0.017). High c-Myc patients had higher risk of invasive behavior, larger tumor volume and recurrence chance than low c-Myc group (P = 0.012, P = 0.002, P = 0.015). It was a negative correlation between H-score of PRDM2 and c-Myc (PRDM2 = -0.163 × c-Myc + 67.11, r = -0.407). The ability of cell proliferation was declined in a time dependent manner after overexpression of PRDM2 (PRDM2 group) compared to that in control GH3 cells (P < 0.05). Through flow cytometry assay, PRDM2 could induce the apoptosis and G2/M arrest in GH3 cell (both p < 0.05). Transwell experiment proved less trans-membrane cells in PRDM2 group than those in control group (415 ± 76 vs 145 ± 37, P < 0.01). RT-PCR and western blot both proved PRDM2 could inhibit the level c-Myc and elevate the levels of CDKN1A and CDKN1B. Combined with c-Myc inhibitor 10058-F4, PRDM2 further inhibited cell proliferation and induced more apoptosis in GH3 cell. Taken together, we found that PRDM2 negatively regulated the expression of c-Myc in somatotroph adenomas, and testified the synergism between PRDM2 gene therapy and c-Myc inhibitor in vitro experiment.
small molecules
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.
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.
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.
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.
2026-08-06 | Can acromegaly be controlled in all cases?
Acromegaly is a rare disease, due in most of the cases to a growth hormone (GH)-secreting pituitary adenoma (PA), namely neuroendocrine tumour (PitNET). The treatment of patients with acromegaly is multimodal and multi-step, including surgery, medical therapies, and radiotherapy. In the last 30 years, the therapeutic armamentarium for the treatment of acromegaly has progressively increased, and the therapeutic algorithm has been significantly modified through the identification of clinical, biochemical, and molecular biomarkers of treatment outcome. The personalization of acromegaly treatment has shifted the paradigm from a 'trial-and-error' to a 'target-to-treat' treatment approach to achieve early disease control and to reduce the risk of disease-related comorbidities that may lead to an increased mortality. Nevertheless, despite the numerous improvements in the treatment of patients with acromegaly, disease control is not achieved in all patients, according to the results of randomized clinical trials, interventional studies, and prospective and retrospective observational studies. In parallel, the normalization of GH and IGF-I levels may not be sufficient to control acromegaly related symptoms and prevent disease-related comorbidities. In this review, we will report on the most recent aims of treatment and cure in patients with acromegaly, on the efficacy and predictors of response to conventional treatments (such as first- and second-generation somatostatin receptor ligands and growth hormone receptor antagonist). A specific section will focus on the rarer aggressive disease pictures and on the treatment with systemic therapies (such as temozolomide and capecitabine) and on target therapies (such as neo-angiogenesis and immune checkpoint inhibitors).
proteins
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.
2026-08-04 | Micromegaly: a distinct clinical entity? Insights from a monocentric cohort study.
The term "micromegaly" historically refers to patients with acromegalic features, elevated IGF-1, but normal growth hormone (GH) levels. The physiological mechanism, the appropriate clinical and treatment approaches, as well as its existence as a separate clinical entity are not well-defined. We retrospectively collected clinical and hormonal data from 30 patients with acromegaly and 30 with micromegaly (displaying high IGF-1 but GH < 0.4 µg/L after glucose load), matched for age and sex. Data about acromegaly related comorbidities were collected (goiter, colonic polyps, malignancies, hypertension, cardiopathy, obstructive-sleep-apnea, carpal tunnel, and hyperglycemia). We performed a laboratory analysis of pituitary tissue samples from both groups, examining GH isoform expression and proliferative rate. We compared data of the two groups and described follow-up and treatment response in micromegalic patients. Patients with acromegaly exhibited higher IGF-1 values at diagnosis (+8.3 vs. +3.2 SDS, p < 0.01) and higher GH nadir levels after glucose load (6 vs. 0.15 μg/L, p < 0.01). All patients with acromegaly had a detectable pituitary adenoma (70% macroadenomas), whereas 52% of patients with micromegaly showed no evidence of pituitary adenoma. Despite different GH/IGF-1 values, the prevalence of most comorbidities was similar in both groups, except for valve disease and diabetes mellitus, which were more frequent in acromegaly (valvopathy: 42.9% vs. 16.7%, p = 0.006; diabetes: 56.7% vs. 23.3%, p = 0.016, respectively). Laboratory analyses in patients with micromegaly indicated a lower proliferative profile in tumor cells (D3 cyclin expression). Patients with a clinical diagnosis of acromegaly and high IGF-1 levels but a GH nadir < 0.4 µg/L following glucose load exhibit a high burden of comorbidities and therefore require appropriate screening and follow-up. Therapeutic strategies in these cases should be individualized, considering the frequent absence of neuroradiological findings, which may reflect a lower proliferative profile.
2026-07-17 | High-yield soluble expression and affinity-tag-free purification of growth hormone receptor antagonist B2036 in Escherichia coli.
Acromegaly is a severe endocrine disease, and growth hormone receptor antagonist B2036 constitutes the core protein backbone of pegvisomant. Conventional B2036 production based on inclusion bodies or periplasmic expression suffers from low yield, complicated refolding, and multi-step purification. Herein, we developed a highly efficient, refolding-free bioprocess for soluble expression of B2036 in Escherichia coli using SUMO fusion technology. The entire fermentation cycle was controlled within 24 h, and fermentation optimization via response surface methodology enabled a high-yield soluble yield of 0.95 g/L. For downstream processing, an industrial-scalable, affinity-tag-free strategy using only two chromatography steps (anion-exchange and mixed-mode chromatography) was established, producing 498.47 mg/L B2036 with 97.12% purity, representing a 20-fold improvement over previous reports. The obtained B2036 showed correct sequence, precise disulfide pairing, and strong biological activity with an IC₅₀ of 0.67 nmol/L. By removing protein refolding and metal-affinity chromatography, this simplified and robust workflow remarkably improves productivity and product quality, offering a cost-effective and scalable technical platform for large-scale manufacturing of pegvisomant biosimilars. Collectively, these findings provide a valuable reference for developing efficient soluble expression and downstream purification processes of other intrachain disulfide-bonded proteins in E. coli.
2026-07-03 | Beyond biochemical control: headache resolution with pasireotide in a patient with acromegaly and residual tumor.
Acromegaly management is particularly challenging when pituitary adenomas invade the cavernous sinus, limiting the likelihood of complete surgical resection. We describe a case of a 40-year-old woman with acromegaly caused by a growth hormone and prolactin co-secreting pituitary macroadenoma with bilateral cavernous sinus invasion and severe, frequent headache. Despite transsphenoidal surgery, radiotherapy, and sequential medical therapy with octreotide, cabergoline, and pegvisomant over 3 years, insulin-like growth factor 1 (IGF-1) levels remained elevated and headache burden persisted. Initiation of pasireotide long-acting release was followed by rapid normalization of IGF-1 levels and complete resolution of headache, with improvement in other acromegaly related symptoms. This case supports the potential role of pasireotide in selected patients with biochemically and clinically treatment-resistant acromegaly and contributes to the growing real-world evidence regarding its use in patients with residual disease in surgically challenging locations.
2026-05-06 | [Efficacy of octreotide LAR and lanreotide autogel in acromegaly assessed by SAGIT].
Biochemical control has been the main objective in the treatment of acromegaly; however, GH and IGF-1 levels do not necessarily translate into clinical response, as they fail to account for the complexity of symptoms and patients' perceptions. The SAGIT instrument was developed to assist in assessing the status and evolution of the disease in patients with acromegaly and facilitate decision-making. To compare the efficacy of octreotide LAR and lanreotide autogel in managing patients with acromegaly using the SAGIT instrument. Observational, unicentric study, conducted in 2022 at a referral hospital in León, Guanajuato, Mexico. Of 37 patients evaluated, 26 were included. 13 (50%) received lanreotide autogel and 11 (42.3%) received octreotide LAR. Disease control, as measured by IGF-1 levels, was achieved in 10 patients (42.3%). When assessing control using the SAGIT instrument, 8 patients (30.7%) met control criteria. Octreotide LAR showed greater disease control as assessed by SAGIT compared to lanreotide autogel (p = 0.043). Based on the SAGIT instrument, octreotide LAR is more effective for disease control in patients with acromegaly than in those patients treated with lanreotide. The preferential use of octreotide LAR could be recommended in resource-limited settings.
antibodies
2026-01-19 | Long-term effect on bone mineral density of denosumab in the treatment of hyperpituitarism driven osteoporosis: an exploratory study.
Treatment of skeletal fragility in patients with pituitary diseases is challenging. Denosumab, an antiresorptive bone active drug, increased bone mineral density (BMD) and reduced incidence and risk of fractures in primary osteoporosis. This study aimed to evaluate the efficacy of denosumab in patients with pituitary disease-driven osteoporosis. This retrospective study investigated the frequency of fragility fractures (FF) and the percent BMD changes at 1-, 2-, 5-, and 10-years of treatment with denosumab, in patients with osteoporosis due to secreting pituitary adenoma. Seventeen patients were included: 5 patients (29.4%) were affected by hyperprolactinemia due to PRL-secreting pituitary adenoma (PAs), six patients (35.3%) were affected by acromegaly and six patients (35.3%) by Cushing's disease. Four patients carried prevalent-FF (23.5%). A single patient with acromegaly developed FF at 2 and at 5 years of treatment with denosumab. Femoral neck BMD increased in 11 patients (64.7%) at 1 year of treatment, in 9 patients (52.9%) at 2 years of treatment, in 8 patients (47.1%) at 5 years of treatment and in 2 patients (66.7%) at 10 years of treatment. Lumbar spine BMD improved in all patients at 1 year of treatment (100%), in 16 patients at 2 years of treatment (100%), in 11 patients at 5 years of treatment (100%), and in 2 patients at 10 years of treatment (66.7%). No drug related adverse events occurred. This study demonstrated for the first time that long-term treatment with denosumab is effective and safe in patients with osteoporosis due to secreting pituitary adenoma.
2025-10-01 | OR12-06 Development of a Novel Growth Hormone Receptor Antagonist Antibody for the Treatment of Acromegaly
Abstract Disclosure: K. Kurylo: Marea Therapeutics, Inc. W. Huynh: Marea Therapeutics, Inc. P.R. Bouchard: Marea Therapeutics, Inc. M.N. Milton: Marea Therapeutics, Inc. P.F. Moesta: Marea Therapeutics, Inc. L.E. Dichtel: Marea Therapeutics, Inc., Recordati, Lumos Pharma, Perspectum, Novo Nordisk, Third Rock Ventures, Merida Biosciences, Flare Therapeutics. J. Gromada: Marea Therapeutics, Inc. V. Ramanan: Marea Therapeutics, Inc. M.P. Joing: Marea Therapeutics, Inc. B.B. Cummings: Marea Therapeutics, Inc. E.J. Weiss: Marea Therapeutics, Inc.. Acromegaly is a rare disease characterized by excessive growth hormone (GH) production from a benign anterior pituitary adenoma. Elevated GH levels lead to increased production of IGF-1 from the liver, and acromegaly is linked to increased morbidity and mortality. GH receptor antagonists (GHRA) are an attractive therapeutic option, as they directly block GH action, lower IGF-1, and improve insulin sensitivity. However, the only currently available GHRA, pegvisomant, requires daily administration, resulting in low patient compliance and reduced real-world efficacy. Here, we report the development and characterization of MAR002, a novel half-life extended GHRA monoclonal antibody with the potential to enhance ease of use, improve efficacy, and elevate the quality of life for patients with acromegaly. In vitro, MAR002 had a significantly stronger binding affinity to GHR and resulted in more potent dose-dependent inhibition of GH-induced GHR signaling (IC50: 1 nM) vs. pegvisomant (IC50: 122nM). The greater potency of MAR002 was maintained when GH was pre-bound to GHR. MAR002 maintained stable GHR signaling suppression with supraphysiological GH levels (≥90% suppression), whereas such levels of GH outcompeted pegvisomant (no suppression). Epitope mapping revealed that unlike pegvisomant, MAR002 does not bind known GH binding sites on GHR, and additional binding assays confirmed MAR002 and GH can bind simultaneously to GHR. Together, these data demonstrate that MAR002 binds allosterically to inhibit GHR signaling; a novel GH-binding independent mechanism distinct from pegvisomant, which is an orthosteric inhibitor known to occupy the same binding site as GH. In cynomolgus monkeys, administration of equimolar doses of MAR002 and pegvisomant was well tolerated and demonstrated similar peak IGF-1 suppression (80% reduction, n=3 per group). MAR002 demonstrated a more favorable PK/PD profile, as it was detected in serum concentrations that resulted in ≥50% IGF-1 suppression for 36 days vs.15 days for pegvisomant. Of note, half-life extending mutations in monoclonal antibodies are reported to be up to 3x more durable in humans than in monkeys. This, in addition to the more favorable serum residence time of MAR002 predicts a substantially longer duration of IGF-1 lowering in humans compared to pegvisomant. In summary, we developed and characterized a novel half-life extended, allosteric, inhibitory GHR antibody with a mechanism distinct from pegvisomant. Stronger inhibitory activity of MAR002 against GHR in vitro, combined with a superior PK/PD profile in cynomolgus monkeys, should provide a prolonged therapeutic effect in patients, requiring less-frequent dosing vs. pegvisomant (e.g. potentially biweekly, monthly, or less frequent). This work enables continued MAR002 development to assess its safety, efficacy, and potential to improve the care for patients with acromegaly. Presentation: Sunday, July 13, 2025
2025-08-29 | Adherence, duration and healthcare costs in a real-world population of patients with acromegaly.
Aim: The aim of this study was to describe treatment patterns among patients with acromegaly who are newly treated with acromegaly medical therapy. Materials & methods: Data from IQVIA Pharmetrics Plus® Database from 1 January 2013 to 30 June 2023 were used to identify patients with acromegaly who started a new acromegaly medical therapy and observe their treatment patterns. Patients were required to have at least 12 months of data without any acromegaly therapy (medication or surgery) prior to the index date and at least 6 months of follow-up. Comorbidities were measured during the baseline period. Adherence, persistence, medication and switching were measured during follow-up. Results: A total of 453 patients with acromegaly who were newly treated with acromegaly medical therapy and had no evidence of acromegaly therapy for at least 12 months were identified. Among these patients, 46.1% (n = 206) were treated with cabergoline as their index treatment, 24.5% (n = 111) with injectable octreotide, 15.0% (n = 68) with lanreotide, 5.5% (n = 25) with bromocriptine, 4.9% (n = 22) with pegvisomant, 2.2% (n = 10) with pasireotide, 1.1% (n = 5) with oral octreotide, 0.4% (n = 2) with cabergoline + octreotide, and 0.2% (n = 1) with cabergoline + lanreotide. By the end of the follow-up period, 54.3% (n = 246) were not on any treatment, 19.6% (n = 89) remained on the index treatment, and the remaining 26.0% (n = 118) switched to another treatment. Conclusion: This study contributed to the growing evidence that patients with acromegaly are not well-served by current therapeutic options, as indicated by high rates of treatment discontinuation, switching and add-on therapy. However, treatment switching and add-on therapy represent ongoing efforts to optimize patient care toward more effective and tolerable treatments. Expanded treatment options may serve an unmet need in this patient population.
2025-04-04 | Carotid femoral pulse wave velocity and serum galectin-3 level significantly increases in patients with acromegaly.
Insulin-like growth factor-1 (IGF-1) and growth hormone release is elevated in acromegaly, a chronic condition. Our objective was to study the correlation between carotid femoral pulse wave velocity (CF-PWV) and galectin-3 level in acromegaly patients. This protein is believed to alter in response to early inflammation and atherosclerosis. Our study was planned as a prospective, single-center cross-sectional study. Our study comprised 40 healthy controls and 40 newly diagnosed acromegaly patients ranging in age from 18 to 65 years old at Adana City Training and Research Hospital. The patients' IGF-1, growth hormone, hemogram, and biochemistry values were assessed. Human galectin-3 kits and the Enzyme-Linked Immunosorbent Assay were used to measure the amount of galectin-3. Patients underwent CF-PWV assessments with the use of Doppler ultrasonography and concurrent electrocardiography. Our investigation indicated that acromegaly patients had greater levels of the fibrosis and inflammation indicator galectin-3 as well as the gold standard indication of arterial stiffness, CF-PWV. We observed a link between blood galectin-3 level and both IGF-1 level and CF-PWV measures in the correlation analysis. Galectin-3 has the potential to be a novel biomarker for the diagnosis and prognosis of cardiovascular disease in acromegaly patients, as well as a therapeutic target for the development of this disease.
2025-03-21 | Case Report and Literature Review: Overexpression of HMGA in Concomitant Plurihormonal Tumor and Papillary Thyroid Carcinoma.
This study described a case of plurihormonal tumor associated with papillary thyroid carcinoma (PTC) and summarized the treatment approaches for similar cases, while also exploring the underlying pathogenesis. The patient exhibited symptoms indicative of acromegaly, central hyperthyroidism, and hyperprolactinemia. A glucose loading test demonstrated persistently elevated growth hormone (GH) levels, while thyroid function tests revealed inappropriate thyroid stimulating hormone (TSH) secretion. Imaging of the pituitary gland revealed a 26 × 19 mm lesion compressing the optic chiasm. Thyroid ultrasound reveals bilateral Thyroid Imaging Reporting and Data System 4B nodules, with the largest on the right measuring 27 × 20 mm. Fine-needle aspiration cytology (FNAC) revealed the presence of PTC. Three weeks later, the patient underwent pituitary adenomectomy. Immunohistochemistry revealed a plurihormonal tumor positive for TSH, GH, luteinizing hormone (LH), prolactin (PRL), pituitary-specific transcription factor 1 (Pit1), and steroidogenic factor 1 (SF1). A total thyroidectomy followed 10 weeks post-adenomectomy. Immunohistochemical evaluation showed higher nuclear positivity for the high-mobility group AT-hook 1 (HMGA1) and the high-mobility group AT-hook 2 (HMGA2) proteins in neoplastic cells compared to normal tissues. In our search results, only three similar cases were identified, and we summarized the relevant literature search results which raise the possibility that the HMGA2-the Retinoblastoma Protein (pRB)/E2F Transcription Factor 1 (E2F1)-HMGA1 signaling pathway may represent a common pathogenic pathway for PTC and plurihormonal tumor. If a patient simultaneously suffers from PTC and plurihormonal tumor, the determination of the surgical sequence is crucial. In cases of postoperative recurrence, where patients are reluctant to undergo additional surgeries, targeting HMGA is likely to offer a promising approach to prevent the progression of both the pituitary tumors and PTC.
other
2025-10-02 | Possibility of calcification of type I collagen matrix in growth hormone-secreting pituitary neuroendocrine tumor.
In acromegaly caused by growth hormone (GH)-secreting pituitary neuroendocrine tumor (PitNET), excessive secretion of GH and insulin-like growth factor 1 (IGF-1) enhances bone anabolic effects while inducing the production of type I collagen, leading to increased bone mass and bone mineral density. We investigated the possibility of calcification of type I collagen matrix used in endoscopic transsphenoidal surgery (ETSS) for GH-secreting PitNET. Twelve patients with GH-secreting PitNET who underwent ETSS and were followed up for more than 1 year after surgery were divided into two groups: The "DuraGen group," in which DuraGen, a type I collagen matrix, was used as the overlay graft to cover the closed sella turcica for sellar floor reconstruction after tumor resection and the "fat group," in which fat was used. Clinical characteristics associated with surgery for GH-secreting PitNET were compared between the groups. Seven patients were assigned to the DuraGen group and five to the fat group. One year after surgery, the reconstructed sellar floor was thickly calcified in all cases in the DuraGen group, but not calcified in all cases in the fat group. Patient characteristics, tumor-related factors including image findings, tumor size, histopathology and extent of tumor resection, and the pre- and postoperative course of GH and IGF-1 demonstrated no significant differences between the groups. In ETSS for acromegaly due to GH-secreting PitNET, the possibility of calcification of type I collagen matrix used as the overlay graft for sellar floor reconstruction should be considered.
2022-03-14 | Downregulation of miR-216a-5p and miR-652-3p is associated with growth and invasion by targeting JAK2 and PRRX1 in GH-producing pituitary tumours.
Expression of aberrant microRNA (miRNA) is associated with tumour formation, migration, and invasion. However, there is limited information about the epigenetics of pituitary tumorigenesis. This study investigated the role of miRNA expression during the tumorigenesis of growth hormone (GH)-secreting pituitary tumours. miRNA profiling and real-time PCR were used to analyse the mRNA expression profile in sequential pituitary tissues of a unique animal model with a GH-producing pituitary tumour. Selected miRNAs were further validated in GH-producing cell lines and human pituitary tumour samples. The expression of significantly altered miRNAs and their predicted targets, as detected by microarray, was evaluated by real-time PCR, Western blotting, and immunohistochemistry using samples from mouse models and human pituitary tumours. The effect of miRNAs on tumour proliferation and invasion was examined in GH3 cells using the MTS and Matrigel invasion assays. Among the 14 miRNAs whose expression was significantly changed, miR-216a-5p (fold change = -5.638, P -value = 0.014) and miR-652-3p (fold change = -3.482, P -value = 0.010) were constantly and significantly downregulated. Transfection with mimics of miR-216a-5p and miR-652-3p inhibited GH3 proliferation and invasion, whereas inhibitors promoted them. The direct target genes of miR-216a-5p and miR-652-3p were Jak2 and Prrx1, respectively, which were downregulated in GH3 cells transfected with mimics and in serial pituitary gland tissues, including hyperplasic tissues and tumours of acromegalic animal models and pituitary tumour tissues of acromegalic patients. Downregulated miR-216a-5p and miR-652-3p expression may contribute to tumour progression by targeting JAK2 and PRRX1 on GH-producing pituitary tumours.
2021-06-21 | GPR64 promotes cAMP pathway in tumor aggressiveness in sparsely granulated growth hormone cell adenomas.
There is an increasing agreement that acromegaly caused by growth hormone (GH) cell adenoma has two distinct subtypes: densely granulated (DG) and sparsely granulated (SG). We hypothesized that differential molecular signatures may explain their behavior. Total transcriptome sequencing was performed on ten DG and seven SG adenomas. The differentially expressed RNAs were identified by bioinformatic analyses, and a candidate RNA was verified by quantitative real-time PCR. Immunohistochemical staining was also performed to detect the protein expression of the candidate. Clinical parameters were correlated with protein expression. Subsequently, cell proliferation, colony formation, and cell cycle progression were analyzed after knockdown of the candidate in pituitary GH3 cells. Activation of the cAMP pathway was assessed by ELISA and Western blot. We confirmed that there were obvious differentially expressed genes between the subtypes. Through gene profiling, we discovered that an orphan adhesion G protein-coupled receptor, GPR64, was overexpressed in more aggressive SG adenomas. Noticeably, GPR64 knockdown significantly inhibited the proliferation of GH3 tumor cells and decreased colony formation. The knockdown also induced cell cycle arrest in GH3 tumor cells. Further studies revealed that GPR64 knockdown decreased cAMP levels and the ratios of p-CREB/CREB, indicating that it suppressed the cAMP/CREB pathway. Our results indicated that GPR64 may promote aggressiveness in SG-type GH cell adenomas and that it is a key factor regulating the cAMP pathway to promote aggressiveness of GH cell adenomas.
2020-09-24 | Exosomal hsa-miR-21-5p derived from growth hormone-secreting pituitary adenoma promotes abnormal bone formation in acromegaly.
Growth hormone-secreting pituitary adenoma (GHPA), a benign endocrine tumor located in the base of the skull, results in acromegaly. In addition to the mass effect of the tumor itself in the sellar region, GHPA can lead to the overgrowth of almost every organ. Previous findings indicated that the processes underlying acromegaly were partly attributable to hyperactivity of the growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis. However, the mechanisms driving this syndrome remains largely unknown. Additionally, the roles of GHPA-derived exosomes, which contain functional microRNAs and proteins that manipulate target cell proliferation and differentiation in distal extremities, are also unknown. In this study, we demonstrated that GHPA exosomes promote bone formation in vitro and trabecula number in vivo. The mechanism of increased trabecula formation may be attributable to GHPA exosome-induced osteoblast proliferation via increased cell viability and DNA replication. We further discovered that exosomal hsa-miR-21-5p plays a distinct role from the GH/IGF-1 axis in these processes. Accordingly, the results of this study provide a novel mechanism whereby GHPA influences distal extremities and a new perspective for treating GHPA.
2020-09-10 | miR ‐34a is upregulated in AIP ‐ mutated somatotropinomas and promotes octreotide resistance
Abstract Pituitary adenomas (PAs) are intracranial tumors associated with significant morbidity due to hormonal dysregulation, mass effects and have a heavy treatment burden. Growth hormone (GH)‐secreting PAs (somatotropinomas) cause acromegaly‐gigantism. Genetic forms of somatotropinomas due to germline AIP mutations ( AIP mut+) have an early onset and are aggressive and resistant to treatment with somatostatin analogs (SSAs), including octreotide. The molecular underpinnings of these clinical features remain unclear. We investigated the role of miRNA dysregulation in AIP mut+ vs AIP mut− PA samples by array analysis. miR‐34a and miR‐145 were highly expressed in AIP mut+ vs AIP mut− somatotropinomas. Ectopic expression of AIP mut (p.R271W) in Aip −/− mouse embryonic fibroblasts (MEFs) upregulated miR‐34a and miR‐145, establishing a causal link between AIP mut and miRNA expression. In PA cells (GH3), miR‐34a overexpression promoted proliferation, clonogenicity, migration and suppressed apoptosis, whereas miR‐145 moderately affected proliferation and apoptosis. Moreover, high miR‐34a expression increased intracellular cAMP, a critical mitogenic factor in PAs. Crucially, high miR‐34a expression significantly blunted octreotide‐mediated GH inhibition and antiproliferative effects. miR‐34a directly targets Gnai2 encoding Gαi2, a G protein subunit inhibiting cAMP production. Accordingly, Gαi2 levels were significantly lower in AIP mut+ vs AIP mut− PA. Taken together, somatotropinomas with AIP mutations overexpress miR‐34a, which in turn downregulates Gαi2 expression, increases cAMP concentration and ultimately promotes cell growth. Upregulation of miR‐34a also impairs the hormonal and antiproliferative response of PA cells to octreotide. Thus, miR‐34a is a novel downstream target of mutant AIP that promotes a cellular phenotype mirroring the aggressive clinical features of AIP mut+ acromegaly.
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Drug Discovery Landscape
21 orphan drug designations for Acromegaly, including 9 approved therapies.
21 orphan drug designations for Acromegaly, including 9 approved therapies.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Paltusotine [Palsonify] | small molecules | EMA | 2025-02-26 | 2026-04-27 | Crinetics Pharmaceuticals Europe GmbH |
paltusotine [Palsonify] | small molecules | FDA | 2020-07-07 | 2025-09-25 | Crinetics Pharmaceuticals, Inc. |
octreotide acetate (intranasal) | peptides | FDA | 2018-01-23 | — | Dauntless Pharmaceuticals, Inc. |
H-(4-amino-3-iodo)-D-Phe-c[Cys-(3-iodo)-Tyr-D-Trp-Lys-Val-Cys]-Thr-NH2 | peptides | FDA | 2016-11-03 | — | Amryt Research Ltd. |
Cimdelirsen | oligonucleotides | EMA | 2016-06-27 | — | IQVIA RDS Ireland Limited |
2'-O-(2-methoxyethyl)phosphorothioate antisense oligonucleotide | oligonucleotides | FDA | 2016-05-10 | — | Percheron Therapeutics Limited |
Octreotide acetate [Mycapssa] | peptides | EMA | 2013-08-06 | 2022-12-05 | Amryt Pharmaceuticals Designated Activity Company |
veldoreotide | peptides | FDA | 2013-06-24 | — | Xeris Pharmaceuticals, lnc. |
Cyclo(-gamma-aminobutyryl-L-phenylalanyl-L-tryptophanyl-D-tryptophanyl-L-lysyl-L-threonyl-L phenylalanyl-N-3-carboxypropyl)-glycine amide, acetate salt | peptides | EMA | 2012-12-06 | — | S-cubed Pharmaceutical Services ApS |
Modified growth hormone releasing-hormone fused to the light chain endopeptidase and the N-terminal domain of the heavy chain of botulinum toxin serotype D | proteins | EMA | 2012-01-11 | — | Ipsen Bioinnovation Limited |
octreotide (oral) [MYCAPSSA (formerly Octreolin)] | peptides | FDA | 2010-06-17 | 2020-06-26 | Chiesi USA, Inc. |
octreotide acetate subcutaneous implant | peptides | FDA | 2009-12-07 | — | Endo Pharmaceuticals Solutions, Inc. |
Pasireotide [Signifor] | peptides | EMA | 2009-10-08 | 2014-11-21 | Novartis Europharm Limited |
pasireotide | peptides | FDA | 2009-08-25 | 2014-12-15 | Novartis Pharmaceuticals Corporation |
Octreotide hydrochloride [Oczyesa] | small molecules | EMA | 2009-06-12 | — | Camurus AB |
vapreotide | peptides | FDA | 2003-11-04 | — | H3 Pharma, Inc. |
Pegvisomant [Somavert] | proteins | EMA | 2001-02-14 | — | Pfizer Limited |
Lanreotide [Somatuline Depot] | peptides | FDA | 2000-09-11 | 2007-08-30 | IPSEN, Inc. |
Octreotide [Sandostatin LAR] | peptides | FDA | 1998-08-24 | 1998-11-25 | Novartis Pharmaceuticals Corporation |
Pegvisomant [Somavert] | proteins | FDA | 1997-06-24 | 2003-03-25 | Sensus Corporation |
Butyrylcholinesterase | — | FDA | 1992-09-30 | — | Shire Laboratories Inc. |
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