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Pituitary Feb 2024The 14th Acromegaly Consensus Conference was convened to consider biochemical criteria for acromegaly diagnosis and evaluation of therapeutic efficacy.
PURPOSE
The 14th Acromegaly Consensus Conference was convened to consider biochemical criteria for acromegaly diagnosis and evaluation of therapeutic efficacy.
METHODS
Fifty-six acromegaly experts from 16 countries reviewed and discussed current evidence focused on biochemical assays; criteria for diagnosis and the role of imaging, pathology, and clinical assessments; consequences of diagnostic delay; criteria for remission and recommendations for follow up; and the value of assessment and monitoring in defining disease progression, selecting appropriate treatments, and maximizing patient outcomes.
RESULTS
In a patient with typical acromegaly features, insulin-like growth factor (IGF)-I > 1.3 times the upper limit of normal for age confirms the diagnosis. Random growth hormone (GH) measured after overnight fasting may be useful for informing prognosis, but is not required for diagnosis. For patients with equivocal results, IGF-I measurements using the same validated assay can be repeated, and oral glucose tolerance testing might also be useful. Although biochemical remission is the primary assessment of treatment outcome, biochemical findings should be interpreted within the clinical context of acromegaly. Follow up assessments should consider biochemical evaluation of treatment effectiveness, imaging studies evaluating residual/recurrent adenoma mass, and clinical signs and symptoms of acromegaly, its complications, and comorbidities. Referral to a multidisciplinary pituitary center should be considered for patients with equivocal biochemical, pathology, or imaging findings at diagnosis, and for patients insufficiently responsive to standard treatment approaches.
CONCLUSION
Consensus recommendations highlight new understandings of disordered GH and IGF-I in patients with acromegaly and the importance of expert management for this rare disease.
Topics: Humans; Acromegaly; Insulin-Like Growth Factor I; Delayed Diagnosis; Human Growth Hormone; Growth Hormone
PubMed: 37923946
DOI: 10.1007/s11102-023-01360-1 -
Cell Metabolism Jul 2023Maternal-offspring interactions in mammals involve both cooperation and conflict. The fetus has evolved ways to manipulate maternal physiology to enhance placental...
Maternal-offspring interactions in mammals involve both cooperation and conflict. The fetus has evolved ways to manipulate maternal physiology to enhance placental nutrient transfer, but the mechanisms involved remain unclear. The imprinted Igf2 gene is highly expressed in murine placental endocrine cells. Here, we show that Igf2 deletion in these cells impairs placental endocrine signaling to the mother, without affecting placental morphology. Igf2 controls placental hormone production, including prolactins, and is crucial to establish pregnancy-related insulin resistance and to partition nutrients to the fetus. Consequently, fetuses lacking placental endocrine Igf2 are growth restricted and hypoglycemic. Mechanistically, Igf2 controls protein synthesis and cellular energy homeostasis, actions dependent on the placental endocrine cell type. Igf2 loss also has additional long-lasting effects on offspring metabolism in adulthood. Our study provides compelling evidence for an intrinsic fetal manipulation system operating in placenta that modifies maternal metabolism and fetal resource allocation, with long-term consequences for offspring metabolic health.
Topics: Animals; Female; Mice; Pregnancy; Cell Communication; Homeostasis; Hypoglycemic Agents; Insulin Resistance; Placenta; Insulin-Like Growth Factor II; Genomic Imprinting
PubMed: 37437545
DOI: 10.1016/j.cmet.2023.06.007 -
International Journal of Biological... 2023Androgenetic alopecia (AGA) affects more than half of the adult population worldwide and is primarily caused by the binding of dihydrotestosterone (DHT) to androgen...
Androgenetic alopecia (AGA) affects more than half of the adult population worldwide and is primarily caused by the binding of dihydrotestosterone (DHT) to androgen receptors (AR). However, the mechanisms by which AR affects hair follicles remain unclear. In our study, we found that miR-221 significantly suppressed hair growth and the proliferation of dermal papilla cells (DPCs) and dermal sheath cells (DSCs) in AGA patients. Interestingly, miR-221 and AR were mainly co-located in the same part of the hair follicle. Mechanistic analysis revealed that AR directly promoted the transcription of miR-221, which in turn suppressed IGF-1 expression, leading to the inactivation of the MAPK pathway in DPCs and the PI3K/AKT pathway in DSCs. In AGA patients, miR-221 expression was positively correlated with AR expression and negatively correlated with IGF-1 expression. Our findings indicate that miR-221, as a direct target of AR, plays a crucial role in the pathogenesis of AGA, making it a novel biomarker and potential therapeutic target for treating AGA.
Topics: Adult; Humans; Alopecia; Insulin-Like Growth Factor I; MicroRNAs; Phosphatidylinositol 3-Kinases; Receptors, Androgen
PubMed: 37496996
DOI: 10.7150/ijbs.80481 -
Science Advances Jul 2023The progression of noninvasive ductal carcinoma in situ to invasive ductal carcinoma for patients with breast cancer results in a significantly poorer prognosis and is...
The progression of noninvasive ductal carcinoma in situ to invasive ductal carcinoma for patients with breast cancer results in a significantly poorer prognosis and is the precursor to metastatic disease. In this work, we have identified insulin-like growth factor-binding protein 2 (IGFBP2) as a potent adipocrine factor secreted by healthy breast adipocytes that acts as a barrier against invasive progression. In line with this role, adipocytes differentiated from patient-derived stromal cells were found to secrete IGFBP2, which significantly inhibited breast cancer invasion. This occurred through binding and sequestration of cancer-derived IGF-II. Moreover, depletion of IGF-II in invading cancer cells using small interfering RNAs or an IGF-II-neutralizing antibody ablated breast cancer invasion, highlighting the importance of IGF-II autocrine signaling for breast cancer invasive progression. Given the abundance of adipocytes in the healthy breast, this work exposes the important role they play in suppressing cancer progression and may help expound upon the link between increased mammary density and poorer prognosis.
Topics: Female; Humans; Adipocytes; Antibodies, Neutralizing; Breast; Breast Neoplasms; Insulin-Like Growth Factor II
PubMed: 37436978
DOI: 10.1126/sciadv.adg1840 -
Hepatology (Baltimore, Md.) Jul 2023NAFLD is characterized by steatosis, hepatic inflammation, and fibrosis, which can develop into NASH. Patients with NAFLD/NASH have increased ductular reaction (DR) and...
BACKGROUND AND AIMS
NAFLD is characterized by steatosis, hepatic inflammation, and fibrosis, which can develop into NASH. Patients with NAFLD/NASH have increased ductular reaction (DR) and biliary senescence. High fat/high cholesterol diet feeding increases biliary senescence, DR, and biliary insulin-like growth factor-1 (IGF-1) expression in mice. p16/IGF-1 converges with fork-head box transcription factor O1 (FOXO1) through E2F1. We evaluated p16 inhibition on NAFLD phenotypes and biliary E2F1/FOXO1/IGF-1 signaling.
APPROACH AND RESULTS
4-week wild-type (C57BL/6J) male mice were fed a control diet (CD) or high fat/high cholesterol diet and received either p16 or control Vivo Morpholino (VM) by tail vein injection 2× during the 16th week of feeding. We confirmed p16 knockdown and examined: (i) NAFLD phenotypes; (ii) DR and biliary senescence; (iii) serum metabolites; and (iv) biliary E2F1/FOXO1/IGF-1 signaling. Human normal, NAFLD, and NASH liver samples and isolated cholangiocytes treated with control or p16 VM were evaluated for p16/E2F1/FOXO1/IGF-1 signaling. p16 VM treatment reduced cholangiocyte and hepatocyte p16. In wild-type high fat/high cholesterol diet mice with control VM, there were increased (i) NAFLD phenotypes; (ii) DR and biliary senescence; (iii) serum metabolites; and (iv) biliary E2F1/FOXO1/IGF-1 signaling; however, p16 VM treatment reduced these parameters. Biliary E2F1/FOX-O1/IGF-1 signaling increased in human NAFLD/NASH but was blocked by p16 VM. In vitro , p16 VM reduced biliary E2f1 and Foxo1 transcription by inhibiting RNA pol II binding and E2F1 binding at the Foxo1 locus, respectively. Inhibition of E2F1 reduced biliary FOXO1 in vitro.
CONCLUSION
Attenuating hepatic p16 expression may be a therapeutic approach for improving NAFLD/NASH phenotypes.
Topics: Animals; Humans; Male; Mice; Cholesterol; Diet, High-Fat; Disease Models, Animal; E2F1 Transcription Factor; Forkhead Box Protein O1; Insulin-Like Growth Factor I; Liver; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Phenotype; Cyclin-Dependent Kinase Inhibitor p16
PubMed: 36799449
DOI: 10.1097/HEP.0000000000000307 -
Annals of the Rheumatic Diseases Nov 2023Prior studies noted that chondrocyte SIRT6 activity is repressed in older chondrocytes rendering cells susceptible to catabolic signalling events implicated in...
OBJECTIVES
Prior studies noted that chondrocyte SIRT6 activity is repressed in older chondrocytes rendering cells susceptible to catabolic signalling events implicated in osteoarthritis (OA). This study aimed to define the effect of deficiency on the development of post-traumatic and age-associated OA in mice.
METHODS
Male cartilage-specific -deficient mice and intact controls underwent destabilisation of the medial meniscus (DMM) or sham surgery at 16 weeks of age and OA severity was analysed at 6 and 10 weeks postsurgery. Age-associated OA was assessed in mice aged 12 and 18 months of age. OA severity was analysed by micro-CT, histomorphometry and scoring of articular cartilage structure, toluidine blue staining and osteophyte formation. SIRT6-regulated pathways were analysed in human chondrocytes by RNA-sequencing, qRT-PCR and immunoblotting.
RESULTS
deficient mice displayed enhanced DMM-induced OA severity and accelerated age-associated OA when compared with controls, characterised by increased cartilage damage, osteophyte formation and subchondral bone sclerosis. In chondrocytes, RNA-sequencing revealed that depletion significantly repressed cartilage extracellular matrix (eg, ) and anabolic growth factor (eg, insulin-like growth factor-1 ()) gene expression. Gain-of-function and loss-of-function studies in chondrocytes demonstrated that SIRT6 depletion attenuated, whereas adenoviral overexpression or MDL-800-induced activation promoted IGF-1 signalling by increasing Akt phosphorylation.
CONCLUSIONS
SIRT6 deficiency increases post-traumatic and age-associated OA severity in vivo. SIRT6 profoundly regulated the pro-anabolic and pro-survival IGF-1/Akt signalling pathway and suggests that preserving the SIRT6/IGF-1/Akt axis may be necessary to protect cartilage from injury-associated or age-associated OA. Targeted therapies aimed at increasing SIRT6 function could represent a novel strategy to slow or stop OA.
Topics: Male; Animals; Mice; Humans; Aged; Insulin-Like Growth Factor I; Osteophyte; Proto-Oncogene Proteins c-akt; Osteoarthritis; Chondrocytes; Cartilage, Articular; RNA; Sirtuins; Disease Models, Animal
PubMed: 37550003
DOI: 10.1136/ard-2023-224385 -
The Journal of Clinical Endocrinology... Sep 2023Growth hormone deficiency (GHD) in children is currently treated with daily injections of GH, which can be burdensome for patients and their parents/guardians....
CONTEXT
Growth hormone deficiency (GHD) in children is currently treated with daily injections of GH, which can be burdensome for patients and their parents/guardians. Somapacitan is a GH derivative in development for once-weekly treatment of GHD.
OBJECTIVE
This work aimed to assess the efficacy and safety of somapacitan, and associated disease/treatment burden, after 4 years of treatment and 1 year after switching to somapacitan from daily GH.
METHODS
This long-term safety extension of a multicenter, controlled phase 2 trial (NCT02616562) took place at 29 sites in 11 countries. Patients were prepubertal, GH-naive children with GHD. Fifty patients completed 4 years of treatment. Patients in the pooled group received somapacitan (0.04, 0.08, 0.16 mg/kg/week) for 1 year, followed by the highest dose (0.16 mg/kg/week) for 3 years. Patients in the switched group received daily GH 0.034 mg/kg/day for 3 years, then somapacitan 0.16 mg/kg/week for 1 year. Main outcome measures were height velocity (HV), change from baseline in HV SD score (SDS), change from baseline in height SDS, disease burden, and treatment burden for patients and parents/guardians.
RESULTS
Changes from baseline in HV and HV SDS were similar and as expected in both groups. Observer-reported outcomes showed that patients and parents/guardians seem to have experienced a reduced treatment burden when switching from daily GH to somapacitan. Most parents/guardians (81.8%) strongly/very strongly preferred somapacitan over daily GH.
CONCLUSIONS
Somapacitan showed similar efficacy and safety in patients who continued somapacitan treatment and those who switched from daily GH to somapacitan. Once-weekly injections may lead to a reduced treatment burden relative to once-daily injections. A plain-language summary of this work is available.
Topics: Child; Humans; Body Height; Drug Administration Schedule; Dwarfism, Pituitary; Human Growth Hormone; Insulin-Like Growth Factor I; Treatment Outcome
PubMed: 36995872
DOI: 10.1210/clinem/dgad183 -
The Journal of Clinical Endocrinology... Jul 2023The evidence of long-term polyethylene glycol recombinant human GH (PEG-rhGH) in pediatric GH deficiency (GHD) is limited.
CONTEXT
The evidence of long-term polyethylene glycol recombinant human GH (PEG-rhGH) in pediatric GH deficiency (GHD) is limited.
OBJECTIVE
This study aimed to examine the effectiveness and safety of long-term PEG-rhGH in children with GHD in the real world, as well as to examine the effects of dose on patient outcomes.
DESIGN
A prospective, observational, posttrial study (NCT03290235).
SETTING, PARTICIPANTS AND INTERVENTION
Children with GHD were enrolled from 81 centers in China in 4 individual clinical trials and received weekly 0.2 mg/kg/wk (high-dose) or 0.1 to <0.2 mg/kg/wk (low-dose) PEG-rhGH for 30 months.
MAIN OUTCOMES MEASURES
Height SD score (Ht SDS) at 12, 24, and 36 months.
RESULTS
A total of 1170 children were enrolled in this posttrial study, with 642 patients in the high-dose subgroup and 528 in the low-dose subgroup. The Ht SDS improved significantly after treatment in the total population (P < 0.0001), with a mean change of 0.53 ± 0.30, 0.89 ± 0.48, 1.35 ± 0.63, 1.63 ± 0.75 at 6 months, 12 months, 24 months, and 36 months, respectively. In addition, the changes in Ht SDS from baseline were significantly improved in the high-dose subgroup compared with the low-dose subgroup at 6, 12, 24, and 36 months after treatment (all P < 0.05). A total of 12 (1.03%) patients developed serious adverse events. There was no serious adverse event related to the treatment, and no AEs leading to treatment discontinuation or death occurred.
CONCLUSIONS
PEG-rhGH showed long-term effectiveness and safety in treating children with GHD. Both dose subgroups showed promising outcomes, whereas PEG-rhGH 0.2 mg/kg/wk might show additional benefit.
Topics: Humans; Child; Prospective Studies; Human Growth Hormone; Growth Disorders; Dwarfism, Pituitary; Insulin-Like Growth Factor I; Polyethylene Glycols; Recombinant Proteins
PubMed: 36669772
DOI: 10.1210/clinem/dgad039 -
Endocrine Jul 2023Secondary diabetes mellitus (DM) is a common complication of acromegaly, encountered in up to 55% of cases. Vice versa, the prevalence of acromegaly is markedly higher... (Review)
Review
Secondary diabetes mellitus (DM) is a common complication of acromegaly, encountered in up to 55% of cases. Vice versa, the prevalence of acromegaly is markedly higher in cohorts of patients with type 2 DM (T2DM). The presence of secondary DM depends primarily on acromegaly status and is associated with increased cardiovascular morbidity, malignancy rate and overall mortality. The principal pathophysiologic mechanism is increased insulin resistance due to excessive lipolysis and altered fat distribution, reflected at the presence of intermuscular fat and attenuated, dysfunctional adipose tissue. Insulin resistance is ascribed to the direct, diabetogenic effects of growth hormone (GH), which prevail over the insulin-sensitizing effects of insulin-like growth factor 1 (IGF-1), probably due to higher glucometabolic potency of GH, IGF-1 resistance, or both. Inversely, GH and IGF-1 act synergistically in increasing insulin secretion. Hyperinsulinemia in portal vein leads to enhanced responsiveness of liver GH receptors and IGF-1 production, pointing towards a mutually amplifying loop between GH-IGF-1 axis and insulin. Secondary DM occurs upon beta cell exhaustion, principally due to gluco-lipo-toxicity. Somatostatin analogues inhibit insulin secretion; especially pasireotide (PASI) impairs glycaemic profile in up to 75% of cases, establishing a separate pathophysiologic entity, PASI-induced DM. In contrast, pegvisomant and dopamine agonizts improve insulin sensitivity. In turn, metformin, pioglitazone and sodium-glucose transporters 2 inhibitors might be disease-modifying by counteracting hyperinsulinemia or acting pleiotropically. Large, prospective cohort studies are needed to validate the above notions and define optimal DM management in acromegaly.
Topics: Humans; Acromegaly; Insulin-Like Growth Factor I; Insulin Resistance; Prospective Studies; Human Growth Hormone; Growth Hormone; Insulin; Diabetes Mellitus
PubMed: 36882643
DOI: 10.1007/s12020-023-03339-1 -
The Journal of Clinical Endocrinology... Nov 2023Somapacitan is a long-acting GH derivative for treatment of GH deficiency (GHD). (Randomized Controlled Trial)
Randomized Controlled Trial
CONTEXT
Somapacitan is a long-acting GH derivative for treatment of GH deficiency (GHD).
OBJECTIVE
Evaluate the efficacy and tolerability of somapacitan in children with GHD after 2 years of treatment and after the switch from daily GH.
DESIGN
A randomized, multinational, open-labelled, controlled parallel group phase 3 trial, comprising a 52-week main phase and 3-year safety extension (NCT03811535).
SETTING
Eighty-five sites across 20 countries.
PATIENTS
A total of 200 treatment-naïve prepubertal patients were randomized and exposed; 194 completed the 2-year period.
INTERVENTIONS
Patients were randomized 2:1 to somapacitan (0.16 mg/kg/wk) or daily GH (0.034 mg/kg/d) during the first year, after which all patients received somapacitan 0.16 mg/kg/wk.
MAIN OUTCOME MEASURES
Height velocity (HV; cm/year) at week 104. Additional assessments included HV SD score (SDS), height SDS, IGF-I SDS, and observer-reported outcomes.
RESULTS
HV was sustained in both groups between 52 and 104 weeks. At week 104, mean (SD) for HV between weeks 52 and 104 was 8.4 (1.5) cm/year after continuous somapacitan treatment and 8.7 (1.8) cm/year after 1 year of somapacitan treatment following switch from daily GH. Secondary height-related endpoints also supported sustained growth. Mean IGF-I SDS during year 2 was similar between groups and within normal range (-2 to +2). Somapacitan was well tolerated, with no safety or tolerability issues identified. GH patient preference questionnaire results show that most patients and their caregivers (90%) who switched treatment at year 2 preferred once-weekly somapacitan over daily GH treatment.
CONCLUSIONS
Somapacitan in children with GHD showed sustained efficacy and tolerability for 2 years, and after switching from daily GH. Patients/caregivers switching from daily GH expressed a preference for somapacitan.
CLINICAL TRIAL REGISTRATION
NCT03811535.
Topics: Humans; Child; Insulin-Like Growth Factor I; Human Growth Hormone; Growth Hormone; Growth Disorders; Dwarfism, Pituitary; Body Height
PubMed: 37406251
DOI: 10.1210/clinem/dgad394