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Pituitary Feb 2021Guidelines and consensus statements ensure that physicians managing acromegaly patients have access to current information on evidence-based treatments to optimize... (Review)
Review
Guidelines and consensus statements ensure that physicians managing acromegaly patients have access to current information on evidence-based treatments to optimize outcomes. Given significant novel recent advances in understanding acromegaly natural history and individualized therapies, the Pituitary Society invited acromegaly experts to critically review the current literature in the context of Endocrine Society guidelines and Acromegaly Consensus Group statements. This update focuses on how recent key advances affect treatment decision-making and outcomes, and also highlights the likely role of recently FDA-approved therapies as well as novel combination therapies within the treatment armamentarium.
Topics: Acromegaly; Animals; Female; Human Growth Hormone; Humans; Insulin-Like Growth Factor I; Male; Octreotide; Pituitary Neoplasms; Receptors, Somatostatin
PubMed: 33079318
DOI: 10.1007/s11102-020-01091-7 -
Cells Jun 2021Growth hormone (GH) and insulin-like growth factor-1 (IGF-I) are pleiotropic hormones with important roles in lifespan. They promote growth, anabolic actions, and body... (Review)
Review
Growth hormone (GH) and insulin-like growth factor-1 (IGF-I) are pleiotropic hormones with important roles in lifespan. They promote growth, anabolic actions, and body maintenance, and in conditions of energy deprivation, favor catabolic feedback mechanisms switching from carbohydrate oxidation to lipolysis, with the aim to preserve protein storages and survival. IGF-I/insulin signaling was also the first one identified in the regulation of lifespan in relation to the nutrient-sensing. Indeed, nutrients are crucial modifiers of the GH/IGF-I axis, and these hormones also regulate the complex orchestration of utilization of nutrients in cell and tissues. The aim of this review is to summarize current knowledge on the reciprocal feedback among the GH/IGF-I axis, macro and micronutrients, and dietary regimens, including caloric restriction. Expanding the depth of information on this topic could open perspectives in nutrition management, prevention, and treatment of GH/IGF-I deficiency or excess during life.
Topics: Caloric Restriction; Carbohydrate Metabolism; Human Growth Hormone; Humans; Insulin-Like Growth Factor I; Lipolysis; Micronutrients; Signal Transduction
PubMed: 34199514
DOI: 10.3390/cells10061376 -
The Journal of Clinical Endocrinology... Jun 2022Somatrogon is a long-acting recombinant human growth hormone (rhGH) in development for once-weekly treatment of children with growth hormone deficiency (GHD). (Randomized Controlled Trial)
Randomized Controlled Trial
CONTEXT
Somatrogon is a long-acting recombinant human growth hormone (rhGH) in development for once-weekly treatment of children with growth hormone deficiency (GHD).
OBJECTIVE
We aimed to compare the efficacy and safety of once-weekly somatrogon with once-daily somatropin in prepubertal children with GHD.
METHODS
In this 12-month, open-label, randomized, active-controlled, parallel-group, phase 3 study, participants were randomized 1:1 to receive once-weekly somatrogon (0.66 mg/kg/week) or once-daily somatropin (0.24 mg/kg/week) for 12 months. A total of 228 prepubertal children (boys aged 3-11 years, girls aged 3-10 years) with GHD, impaired height and height velocity (HV), and no prior rhGH treatment were randomized and 224 received ≥1 dose of study treatment (somatrogon: 109; somatropin: 115). The primary endpoint was annualized HV at month 12.
RESULTS
HV at month 12 was 10.10 cm/year for somatrogon-treated subjects and 9.78 cm/year for somatropin-treated subjects, with a treatment difference (somatrogon-somatropin) of 0.33 (95% CI: -0.24, 0.89). The lower bound of the 2-sided 95% CI was higher than the prespecified noninferiority margin (-1.8 cm/year), demonstrating noninferiority of once-weekly somatrogon vs daily somatropin. HV at month 6 and change in height standard deviation score at months 6 and 12 were similar between both treatment groups. Both treatments were well tolerated, with a similar percentage of subjects experiencing mild to moderate treatment-emergent adverse events in both groups (somatrogon: 78.9%, somatropin: 79.1%).
CONCLUSION
The efficacy of once-weekly somatrogon was noninferior to once-daily somatropin, with similar safety and tolerability profiles. (ClinicalTrials.gov no. NCT02968004).
Topics: Body Height; Child; Child, Preschool; Dwarfism, Pituitary; Female; Growth Disorders; Growth Hormone; Human Growth Hormone; Humans; Male; Recombinant Proteins
PubMed: 35405011
DOI: 10.1210/clinem/dgac220 -
Endocrine Reviews May 2023This International Consensus Guideline was developed by experts in the field of small for gestational age (SGA) of 10 pediatric endocrine societies worldwide. A...
This International Consensus Guideline was developed by experts in the field of small for gestational age (SGA) of 10 pediatric endocrine societies worldwide. A consensus meeting was held and 1300 articles formed the basis for discussions. All experts voted about the strengths of the recommendations. The guideline gives new and clinically relevant insights into the etiology of short stature after SGA birth, including novel knowledge about (epi)genetic causes. Further, it presents long-term consequences of SGA birth and also reviews new treatment options, including treatment with gonadotropin-releasing hormone agonist (GnRHa) in addition to growth hormone (GH) treatment, as well as the metabolic and cardiovascular health of young adults born SGA after cessation of childhood GH treatment in comparison with appropriate control groups. To diagnose SGA, accurate anthropometry and use of national growth charts are recommended. Follow-up in early life is warranted and neurodevelopment evaluation in those at risk. Excessive postnatal weight gain should be avoided, as this is associated with an unfavorable cardiometabolic health profile in adulthood. Children born SGA with persistent short stature < -2.5 SDS at age 2 years or < -2 SDS at 3 to 4 years of age, should be referred for diagnostic workup. In case of dysmorphic features, major malformations, microcephaly, developmental delay, intellectual disability, and/or signs of skeletal dysplasia, genetic testing should be considered. Treatment with 0.033 to 0.067 mg GH/kg/day is recommended in case of persistent short stature at age of 3 to 4 years. Adding GnRHa treatment could be considered when short adult height is expected at pubertal onset. All young adults born SGA require counseling to adopt a healthy lifestyle.
Topics: Infant, Newborn; Young Adult; Humans; Child; Infant; Child, Preschool; Gestational Age; Body Height; Infant, Small for Gestational Age; Human Growth Hormone; Growth Hormone
PubMed: 36635911
DOI: 10.1210/endrev/bnad002 -
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 -
International Journal of Molecular... Dec 2021Ever since the discoveries that human hair follicles (HFs) display the functional peripheral equivalent of the hypothalamic-pituitary-adrenal axis, exhibit elements of... (Review)
Review
Ever since the discoveries that human hair follicles (HFs) display the functional peripheral equivalent of the hypothalamic-pituitary-adrenal axis, exhibit elements of the hypothalamic-pituitary-thyroid axis, and even generate melatonin and prolactin, human hair research has proven to be a treasure chest for the exploration of neurohormone functions. However, growth hormone (GH), one of the dominant neurohormones of human neuroendocrine physiology, remains to be fully explored in this context. This is interesting since it has long been appreciated clinically that excessive GH serum levels induce distinct human skin pathology. Acromegaly, or GH excess, is associated with hypertrichosis, excessive androgen-independent growth of body hair, and hirsutism in females, while dysfunctional GH receptor-mediated signaling (Laron syndrome) is associated with alopecia and prominent HF defects. The outer root sheath keratinocytes have recently been shown to express functional GH receptors. Furthermore, and contrary to its name, recombinant human GH is known to inhibit female human scalp HFs' growth ex vivo, likely via stimulating the expression of the catagen-inducing growth factor, TGF-β2. These limited available data encourage one to systematically explore the largely uncharted role of GH in human HF biology to uncover nonclassical functions of this core neurohormone in human skin physiology.
Topics: Female; Hair Follicle; Human Growth Hormone; Humans; Receptors, Somatotropin; Skin
PubMed: 34948002
DOI: 10.3390/ijms222413205 -
The Journal of Clinical Endocrinology... Nov 2022Somapacitan, a once-weekly reversible albumin-binding GH derivative, is evaluated in children with GH deficiency (GHD). (Randomized Controlled Trial)
Randomized Controlled Trial
CONTEXT
Somapacitan, a once-weekly reversible albumin-binding GH derivative, is evaluated in children with GH deficiency (GHD).
OBJECTIVE
To demonstrate efficacy and safety of somapacitan vs daily GH.
METHODS
REAL4 is a randomised, multinational, open-labeled, active-controlled parallel group phase 3 trial, comprising a 52-week main trial and 3-year extension (NCT03811535).
SETTING
Eighty-six sites across 20 countries.
PATIENTS
200 treatment-naïve patients were randomized and exposed.
INTERVENTIONS
Patients were randomized 2:1 to somapacitan (0.16 mg/kg/wk) or daily GH (Norditropin; 0.034 mg/kg/d), administered subcutaneously.
MAIN OUTCOME MEASURES
The primary endpoint was annualized height velocity (HV; cm/y) at week 52. Additional assessments included HV SD score (SDS), height SDS, bone age, IGF-I SDS, patient-reported outcomes, and safety measures.
RESULTS
Estimated mean HV at week 52 was 11.2 and 11.7 cm/y for somapacitan and daily GH, respectively. Noninferiority was confirmed. Changes in HV SDS, height SDS, bone age, and IGF-I SDS from baseline to week 52 were similar between treatment groups. At week 52, mean IGF-I SDS values were similar between treatment groups and within normal range (-2 to +2). Safety of somapacitan was consistent with the well-known daily GH profile. Low proportions of injection-site reactions were reported for somapacitan (5.3%) and daily GH (5.9%). Both treatments similarly reduced disease burden from baseline to week 52, whereas a greater treatment burden reduction was observed for somapacitan.
CONCLUSIONS
Similar efficacy for somapacitan compared to daily GH was demonstrated over 52 weeks of treatment with comparable safety and mean IGF-I SDS levels in treatment-naïve children with GHD.
Topics: Child; Humans; Insulin-Like Growth Factor I; Dwarfism, Pituitary; Human Growth Hormone; Growth Hormone
PubMed: 36062966
DOI: 10.1210/clinem/dgac513 -
The Lancet. Diabetes & Endocrinology Apr 2023Tackling the mechanisms underlying ageing is desirable to help to extend the duration and improve the quality of life. Life extension has been achieved in animal models... (Review)
Review
Tackling the mechanisms underlying ageing is desirable to help to extend the duration and improve the quality of life. Life extension has been achieved in animal models by suppressing the growth hormone-insulin-like growth factor 1 (IGF-1) axis and also via dietary restriction. Metformin has become the focus of increased interest as a possible anti-ageing drug. There is some overlap in the postulated mechanisms of how these three approaches could produce anti-ageing effects, with convergence on common downstream pathways. In this Review, we draw on evidence from both animal models and human studies to assess the effects of suppression of the growth hormone-IGF-1 axis, dietary restriction, and metformin on ageing.
Topics: Animals; Humans; Growth Hormone; Insulin-Like Growth Factor I; Metformin; Quality of Life; Aging; Human Growth Hormone
PubMed: 36848915
DOI: 10.1016/S2213-8587(23)00001-3 -
Advances in Therapy Sep 2023Achondroplasia is the most common form of skeletal dysplasia. Recent advances in therapeutic options have highlighted the need for understanding the burden and treatment... (Review)
Review
BACKGROUND
Achondroplasia is the most common form of skeletal dysplasia. Recent advances in therapeutic options have highlighted the need for understanding the burden and treatment landscape of the condition. This systematic literature review (SLR) aimed to identify health-related quality of life (HRQoL)/utilities, healthcare resource use (HCRU), costs, efficacy, safety and economic evaluation data in achondroplasia and to identify gaps in the research.
METHODS
Searches of MEDLINE, Embase, the University of York Centre for Reviews and Dissemination (CRD), the Cochrane Library and grey literature were performed. Articles were screened against pre-specified eligibility criteria by two individuals and study quality was assessed using published checklists. Additional targeted searches were conducted to identify management guidelines.
RESULTS
Fifty-nine unique studies were included. Results demonstrated a substantial HRQoL and HCRU/cost-related burden of achondroplasia on affected individuals and their families throughout their lifetimes, particularly in emotional wellbeing and hospitalisation costs and resource use. Vosoritide, growth hormone (GH) and limb lengthening all conferred benefits for height or growth velocity; however, the long-term effects of GH therapy were unclear, data for vosoritide were from a limited number of studies, and limb lengthening was associated with complications. Included management guidelines varied widely in their scope, with the first global effort to standardise achondroplasia management represented by the International Achondroplasia Consensus Statement published at the end of 2021. Current evidence gaps include a lack of utility and cost-effectiveness data for achondroplasia and its treatments.
CONCLUSIONS
This SLR provides a comprehensive overview of the current burden and treatment landscape for achondroplasia, along with areas where evidence is lacking. This review should be updated as new evidence becomes available on emerging therapies.
Topics: Humans; Quality of Life; Achondroplasia; Human Growth Hormone; Cost-Benefit Analysis
PubMed: 37382866
DOI: 10.1007/s12325-023-02549-3 -
The Journal of Clinical Endocrinology... Jun 2020Long-acting GH (LAGH) preparations are currently being developed in an attempt to improve adherence. The profile of GH action following administration of LAGH raises... (Review)
Review
CONTEXT
Long-acting GH (LAGH) preparations are currently being developed in an attempt to improve adherence. The profile of GH action following administration of LAGH raises practical questions about clinical monitoring and long-term safety and efficacy of these new therapeutic agents.
METHODS
Recent literature and meeting proceedings regarding LAGH preparations are reviewed.
RESULTS
Multiple LAGH preparations are currently at various stages of development, allowing for decreased GH injection frequency from daily to weekly, biweekly, or monthly. Following administration of LAGH, the serum peak and trough GH and IGF-I levels vary depending upon the mechanism used to prolong GH action. Randomized, controlled clinical trials of some LAGH preparations have reported non-inferiority compared with daily recombinant human GH (rhGH) for improved growth velocity and body composition in children and adults with GH deficiency (GHD), respectively. No significant LAGH-related adverse events have been reported during short-term therapy.
CONCLUSION
Multiple LAGH preparations are proceeding through clinical development with some showing promising evidence of short-term clinical efficacy and safety in children and adults with GHD. The relationship of transient elevations of GH and IGF-I following administration of LAGH to efficacy and safety remain to be elucidated. For LAGH to replace daily rhGH in the treatment of individuals with GHD, a number of practical questions need to be addressed including methods of dose adjustment, timing of monitoring of IGF-I, safety, efficacy, and cost-effectiveness. Long-term surveillance of efficacy and safety of LAGH preparations will be needed to answer these clinically relevant questions.
Topics: Delayed-Action Preparations; Growth Disorders; Human Growth Hormone; Humans; Treatment Outcome
PubMed: 31676901
DOI: 10.1210/clinem/dgz149