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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 -
Endocrine Reviews Nov 2023Pregnancy-associated plasma protein-A (PAPP-A) was first identified in the early 1970s as a placental protein of unknown function, present at high concentrations in the... (Review)
Review
Pregnancy-associated plasma protein-A (PAPP-A) was first identified in the early 1970s as a placental protein of unknown function, present at high concentrations in the circulation of pregnant women. In the mid-to-late 1990s, PAPP-A was discovered to be a metzincin metalloproteinase, expressed by many nonplacental cells, that regulates local insulin-like growth factor (IGF) activity through cleavage of high-affinity IGF binding proteins (IGFBPs), in particular IGFBP-4. With PAPP-A as a cell surface-associated enzyme, the reduced affinity of the cleavage fragments results in increased IGF available to bind and activate IGF receptors in the pericellular environment. This proteolytic regulation of IGF activity is important, since the IGFs promote proliferation, differentiation, migration, and survival in various normal and cancer cells. Thus, there has been a steady growth in investigation of PAPP-A structure and function outside of pregnancy. This review provides historical perspective on the discovery of PAPP-A and its structure and cellular function, highlights key studies of the first 50 years in PAPP-A research, and introduces new findings from recent years.
Topics: Pregnancy; Humans; Female; Pregnancy-Associated Plasma Protein-A; Placenta; Metalloproteases; Cell Differentiation; Insulin-Like Growth Factor I
PubMed: 37267421
DOI: 10.1210/endrev/bnad017 -
International Journal of Molecular... Oct 2023Insulin-like growth factor 1 (IGF1) is a peptide growth factor with important functions in multiple aspects of growth, development and metabolism. The biological actions... (Review)
Review
Insulin-like growth factor 1 (IGF1) is a peptide growth factor with important functions in multiple aspects of growth, development and metabolism. The biological actions of IGF1 are mediated by the IGF1 receptor (IGF1R), a cell-surface protein that is evolutionarily related to the insulin receptor (InsR). The effects of IGF1 are moderated by a group of binding proteins (IGFBPs) that bind and transport the ligand in the circulation and extracellular fluids. In mechanistic terms, IGF1R function is linked to the MAPK and PI3K signaling pathways. Furthermore, IGF1R has been shown to migrate to cell nucleus, where it functions as a transcriptional activator. The co-localization of IGF1R and MAPK in the nucleus is of major interest as it suggests novel mechanistic paradigms for the IGF1R-MAPK network. Given its potent anti-apoptotic and pro-survival roles, and in view of its almost universal pattern of expression in most types of cancer, IGF1R has emerged as a promising molecular target in oncology. The present review article provides a concise overview of key scientific developments in the research area of IGF and highlights a number of more recent findings, including its nuclear migration and its interaction with oncogenes and tumor suppressors.
Topics: Phosphatidylinositol 3-Kinases; Receptor, IGF Type 1; Insulin-Like Growth Factor I; Signal Transduction
PubMed: 37834331
DOI: 10.3390/ijms241914882 -
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 -
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 -
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 -
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 -
Archives of Medical Research Dec 2023Acromegaly is a chronic and rare disease. The diagnosis usually takes several years. Multiple comorbidities are associated with acromegaly. Long-term exposure to growth... (Review)
Review
Acromegaly is a chronic and rare disease. The diagnosis usually takes several years. Multiple comorbidities are associated with acromegaly. Long-term exposure to growth factors may lead to complications such as the development of benign or malignant tumors. However, the association between acromegaly and cancer remains a matter of debate due to multiple limitations in epidemiological data. There is controversy between acromegaly and mortality, but evidence shows a significant improvement in mortality rates with disease control and careful management of comorbidities. Older age, increased growth hormone levels (GH) at last follow-up, higher insulin-like growth factor-1 (IGF-1) levels at diagnosis, malignancy and radiotherapy were proposed as independent predictors of mortality. In this review we summarize the current state of knowledge in this field. Incidence of different cancer types is described. Rigorous surveillance of endocrine diseases may contribute to increased tumor detection. Personalized screening should probably be recommended.
Topics: Humans; Acromegaly; Neoplasms; Comorbidity; Insulin-Like Growth Factor I; Incidence
PubMed: 38007382
DOI: 10.1016/j.arcmed.2023.102914 -
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 -
Archives of Medical Research Dec 2023Pegvisomant, the first and currently only clinically available growth hormone receptor antagonist, is an effective therapeutic option for the medical treatment of... (Review)
Review
Pegvisomant, the first and currently only clinically available growth hormone receptor antagonist, is an effective therapeutic option for the medical treatment of acromegaly, a rare disorder characterized by excessive growth hormone secretion. With now over 20 years of real world experience, its safety and efficacy is well-established. However, several aspects of its clinical use are still controversially discussed. The high cost of pegvisomant has limited its use in several countries, and recent studies have reported a lower efficacy than the initial clinical trials. A reported increase in tumor volume under therapy varies between studies and has been attributed to either actual growth or re-expansion after cessation of somatostatin receptor ligand therapy. Furthermore, different combinations of pegvisomant and other therapeutic agents aiming at reduction of acromegaly disease activity have been proposed to increase or retain effectiveness while lowering side effects and cost. This review aims to assess current clinical data on the safety and efficacy of pegvisomant while also addressing controversies surrounding its use.
Topics: Humans; Acromegaly; Receptors, Somatotropin; Human Growth Hormone; Hormone Antagonists; Insulin-Like Growth Factor I
PubMed: 37659952
DOI: 10.1016/j.arcmed.2023.102884