scholarly journals MECHANISMS IN ENDOCRINOLOGY: Clinical and pharmacogenetic aspects of the growth hormone receptor polymorphism

2017 ◽  
Vol 177 (6) ◽  
pp. R309-R321 ◽  
Author(s):  
Cesar L Boguszewski ◽  
Edna J L Barbosa ◽  
Per-Arne Svensson ◽  
Gudmundur Johannsson ◽  
Camilla A M Glad
Keyword(s):  
Growth Hormone ◽  
Growth Hormone Receptor ◽  
Genetic Variant ◽  
Clinical Status ◽  
Age At Onset ◽  
Individual Response ◽  
Growth Disorders ◽  
Rhgh Therapy ◽  
Beneficial Effects ◽  
The Impact

Pharmacogenetics aims to maximize the beneficial effects of a medical therapy by identifying genetic finger prints from responders and non-responders and, thereby improving safety and efficacy profile of the drug. Most subjects who are deficient in growth hormone (GHD) are candidates for recombinant human GH (rhGH) therapy. To date, it is well established that even after adjustments for several clinical variables, such as age, gender, body composition and the age at onset of the GHD, response to rhGH treatment is highly variable among individuals, part of which is believed to be due to genetic factors within the GH system. As the first genetic variant to potentially influence the individual response to rhGH therapy in children with growth disorders, polymorphism in the GH receptor (GHR) has attracted a great interest as a target for pharmacogenetics. Studies have been conducted to compare the functional and molecular effects of the full-length GHR (fl-GHR) isoform with the exon 3 deleted (d3-GHR) isoform in children and adults treated with rhGH therapy. Additionally, the impact of the GHR polymorphism has been investigated in relation to the clinical status and response to medical treatment in acromegaly, especially to the GHR antagonist drug pegvisomant. We have performed a narrative review of the studies performed to date on the association of GHR polymorphism with rhGH response in children and adults, and its potential influence in the medical management of acromegaly. In addition, data from studies on the general population and in other chronic diseases examining a role of this genetic variant in the regulation of growth and metabolism are summarized.

scholarly journals Curcumin: Could This Compound Be Useful in Pregnancy and Pregnancy-Related Complications?

Nutrients ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 3179 ◽  
Author(s):  
Tiziana Filardi ◽  
Rosaria Varì ◽  
Elisabetta Ferretti ◽  
Alessandra Zicari ◽  
Susanna Morano ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Curcuma Longa ◽  
Growth Disorders ◽  
Beneficial Effects ◽  
Toxic Agents ◽  
Health Promoting ◽  
Short And Long Term ◽  
The Impact ◽  
In Pregnancy

Curcumin, the main polyphenol contained in turmeric root (Curcuma longa), has played a significant role in medicine for centuries. The growing interest in plant-derived substances has led to increased consumption of them also in pregnancy. The pleiotropic and multi-targeting actions of curcumin have made it very attractive as a health-promoting compound. In spite of the beneficial effects observed in various chronic diseases in humans, limited and fragmentary information is currently available about curcumin’s effects on pregnancy and pregnancy-related complications. It is known that immune-metabolic alterations occurring during pregnancy have consequences on both maternal and fetal tissues, leading to short- and long-term complications. The reported anti-inflammatory, antioxidant, antitoxicant, neuroprotective, immunomodulatory, antiapoptotic, antiangiogenic, anti-hypertensive, and antidiabetic properties of curcumin appear to be encouraging, not only for the management of pregnancy-related disorders, including gestational diabetes mellitus (GDM), preeclampsia (PE), depression, preterm birth, and fetal growth disorders but also to contrast damage induced by natural and chemical toxic agents. The current review summarizes the latest data, mostly obtained from animal models and in vitro studies, on the impact of curcumin on the molecular mechanisms involved in pregnancy pathophysiology, with the aim to shed light on the possible beneficial and/or adverse effects of curcumin on pregnancy outcomes.

scholarly journals Glucose homeostasis and insulin sensitivity in growth hormone-transgenic mice: a cross-sectional analysis

2010 ◽  
Vol 391 (10) ◽  
Author(s):  
Ravneet K. Boparai ◽  
Oge Arum ◽  
Romesh Khardori ◽  
Andrzej Bartke
Keyword(s):  
Growth Hormone ◽  
Insulin Sensitivity ◽  
Transgenic Mice ◽  
Glucose Homeostasis ◽  
Endocrine Control ◽  
Cross Sectional ◽  
Systematic Assessment ◽  
Beneficial Effects ◽  
Glucose Stimulated Insulin Secretion ◽  
The Impact

Abstract In contrast to its stimulatory effects on musculature, bone, and organ development, and its lipolytic effects, growth hormone (GH) opposes insulin effects on glucose metabolism. Chronic GH overexposure is thought to result in insulin insensitivity and decreased blood glucose homeostatic control. Yet, despite the importance of this concept for basic biology, as well as human conditions of GH excess or deficiency, no systematic assessment of the impact of GH over- expression on glucose homeostasis and insulin sensitivity has been conducted. We report that male and female adult GH transgenic mice have enhanced glucose tolerance compared to littermate controls and this effect is not dependent on age or on the particular heterologous GH transgene used. Furthermore, increased glucose-stimulated insulin secretion, augmented insulin sensitivity, and muted gluconeogenesis were also observed in bovine GH overexpressing mice. These results show that markedly increased systemic GH concentration in GH-transgenic mice exerts unexpected beneficial effects on glucose homeostasis, presumably via a compensatory increase in insulin release. The counterintuitive nature of these results challenges previously held presumptions of the physiology of these mice and other states of GH overexpression or suppression. In addition, they pose intriguing queries about the relationships between GH, endocrine control of metabolism, and aging.

scholarly journals Thyroid Hormone Changes Related to Growth Hormone Therapy in Growth Hormone Deficient Patients

2021 ◽  
Vol 10 (22) ◽  
pp. 5354
Author(s):  
Anna Małgorzata Kucharska ◽  
Ewelina Witkowska-Sędek ◽  
Małgorzata Rumińska ◽  
Beata Pyrżak
Keyword(s):  
Growth Hormone ◽  
Thyroid Hormone ◽  
Thyroid Function ◽  
Hormone Receptors ◽  
Recombinant Human Growth Hormone ◽  
Human Growth ◽  
Hormone Deficiency ◽  
Central Hypothyroidism ◽  
Rhgh Therapy ◽  
The Impact

The alterations in thyroid function during recombinant human growth hormone (rhGH) treatment have been reported by many authors since this therapy became widely available for patients with growth hormone deficiency (GHD). Decrease of thyroxine level is the most frequent observation in patients treated with rhGH. This paper presents literature data describing changes in thyroid function related to rhGH therapy and a current explanation of mechanisms involved in this phenomenon. The effect of GH on the hypothalamic-pituitary-thyroid (HPT) axis is dependent on a multilevel regulation beginning from influence on the central axis, thyroid, and extra-thyroidal deiodinases activity as well as the impact on thyroid hormone receptors on the end. Changes in central and peripheral regulation could overlap during rhGH therapy, resulting in central hypothyroidism or an isolated slight deficiency of thyroxine. The regular monitoring of thyroid function is recommended in patients treated with rhGH and the decision of levothyroxine (L-thyroxine) supplementation should be made in the clinical context, taking into account thyroid hormone levels, as well as the chance for satisfactory growth improvement.

scholarly journals Three years of growth hormone therapy in children born small for gestational age: results from the ANSWER Program

2018 ◽  
Vol 7 (10) ◽  
pp. 1096-1104 ◽  
Author(s):  
Robert Rapaport ◽  
Peter A Lee ◽  
Judith L Ross ◽  
Paul Saenger ◽  
Vlady Ostrow ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Short Stature ◽  
Gestational Age ◽  
Small For Gestational Age ◽  
Growth Failure ◽  
Hormone Deficiency ◽  
Birth Size ◽  
Growth Disorders ◽  
Gh Therapy ◽  
The Impact

Growth hormone (GH) is used to treat short stature and growth failure associated with growth disorders. Birth size and GH status variably modulate response to GH therapy. The aim of this study was to determine the effect of birth size on response to GH therapy, and to determine the impact of GH status in patients born small for gestational age (SGA) on response to GH therapy. Data from the prospective, non-interventional American Norditropin Studies: Web-Enabled Research (ANSWER) Program was analyzed for several growth outcomes in response to GH therapy over 3 years. GH-naïve children from the ANSWER Program were included in this analysis: SGA with peak GH ≥10 ng/mL (20 mIU/L), SGA with peak GH <10 ng/mL (20 mIU/L), isolated growth hormone deficiency (IGHD) born SGA, IGHD not born SGA and idiopathic short stature. For patients with IGHD, those who did not meet criteria for SGA at birth showed greater improvements in height SDS and BMI SDS than patients with IGHD who met criteria for SGA at birth. For patients born SGA, response to GH therapy varied with GH status. Therefore, unlike previous guidelines, we recommend that GH status be established in patients born SGA to optimize GH therapy.

scholarly journals Kaleidoscope

2014 ◽  
Vol 205 (4) ◽  
pp. 334-335
Author(s):  
Derek K. Tracy ◽  
Dan W. Joyce ◽  
Sukhwinder S. Shergill
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Genetic Variant ◽  
Age At Onset ◽  
Epidemiological Data ◽  
Gene Encoding ◽  
Rate Limiting Step ◽  
Limiting Step ◽  
The Impact ◽  
Rate Limiting

It cannot have escaped our readers' notice that there has been a public increase in the awareness of the impact of dementia on people's lives: politicians have raised concerns about a dementia ‘time bomb’ as a greater number of people live to an older age; and even the 2013 G8 summit declared1 that there was a need for international initiatives to tackle this illness. The inevitable call for more research is underscored by the lack of any new licenced medications for Alzheimer's disease since 2002. There has been much interest in a putative role for statins – which inhibit the HMGCR enzyme, the rate-limiting step in cholesterol production – as retrospective epidemiological data have shown that they can reduce the risk of developing Alzheimer's disease by up to 70%; but, frustratingly, administration of these drugs to those with the illness appears to produce little benefit. Recent data have now shown that the gene encoding this HMGCR enzyme is a potent modifier for the age at onset and rate of conversion from mild cognitive impairment to Alzheimer's disease.2 Indeed, this work would indicate that its G-negative allele is second only to APOE2 as the most common and important protective genetic variant for spontaneous Alzheimer's disease.

scholarly journals Growth Hormone Receptor (Ghr) 6ω Pseudoexon Activation: A Novel Cause Of Severe Growth Hormone Insensitivity (Ghi)

2021 ◽  
Author(s):  
Emily Cottrell ◽  
Avinaash Maharaj ◽  
Jack Williams ◽  
Sumana Chatterjee ◽  
Grazia Cirillo ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Growth Hormone Receptor ◽  
Growth Failure ◽  
Index Patient ◽  
Postnatal Growth ◽  
The Novel ◽  
Growth Hormone Insensitivity ◽  
In Vitro Splicing ◽  
The Impact

Abstract Context Severe forms of Growth Hormone Insensitivity (GHI) are characterized by extreme short stature, dysmorphism and metabolic anomalies. Objective Identification of the genetic cause of growth failure in 3 ‘classical’ GHI subjects. Design A novel intronic GHR variant was identified, and in vitro splicing assays confirmed aberrant splicing. A 6Ω pseudoexon GHR vector and patient fibroblast analysis assessed the consequences of the novel pseudoexon inclusion and the impact on GHR function. Results We identified a novel homozygous intronic GHR variant (g.5:42700940T&gt;G, c.618 + 836T&gt; G), 44bp downstream of the previously recognized intronic 6Ψ GHR pseudoexon mutation in the index patient. Two siblings also harbored the novel intronic 6Ω pseudoexon GHR variant in compound heterozygosity with the known GHR c.181C&gt;T (R43X) mutation. In vitro splicing analysis confirmed inclusion of a 151bp mutant 6Ω pseudoexon not identified in wild-type constructs. Inclusion of the 6Ω pseudoexon causes a frameshift resulting in a non-functional truncated GHR lacking the transmembrane and intracellular domains. The truncated 6Ω pseudoexon protein demonstrated extracellular accumulation and diminished activation of STAT5B signaling following growth hormone stimulation. Conclusion Novel GHR 6Ω pseudoexon inclusion results in loss of GHR function consistent with a severe GHI phenotype. This represents a novel mechanism of Laron syndrome and is the first deep intronic variant identified causing severe postnatal growth failure. The 2 kindreds originate from the same town in Campania, Southern Italy, implying common ancestry. Our findings highlight the importance of studying variation in deep intronic regions as a cause of monogenic disorders.

scholarly journals Impact of IGF-1 Normative Datasets on Indication and Outcome of Growth Hormone Stimulation Testing

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A678-A679
Author(s):  
Prim de Bie ◽  
Annemieke C Heijboer ◽  
Martine M L Deckers
Keyword(s):  
Growth Hormone ◽  
Growth Hormone Deficiency ◽  
Stimulation Test ◽  
Hormone Deficiency ◽  
Growth Disorders ◽  
Z Score ◽  
Hormone Stimulation ◽  
Stimulation Tests ◽  
Z Scores ◽  
The Impact

Abstract In the Netherlands, the diagnosis of growth hormone deficiency in children follows the Dutch national guidelines for Triage and Diagnosis of Growth Disorders in Children. Initial biochemical evaluation includes an IGF-1 measurement as screening parameter for growth hormone deficiency. Based on the clinical probability of growth hormone deficiency and the IGF-1 Z-score, a growth hormone stimulation test is performed if serum IGF-1 Z-score is &lt; 0 SD in case of a high probability and if serum IGF-1 Z-score is &lt; -1 SD in case of low probability. An IGF-1 Z-score &gt; 0 SD virtually excludes a growth hormone deficiency disorder. The interpretation of growth hormone stimulation testing is dependent on both the peak growth hormone concentration, but also on the baseline IGF-1 Z-score, particularly in cases of partial deficiency. Although, nation wide, Dutch laboratories have harmonized their measurement for IGF-1 (as was previously done for growth hormone), a Dutch harmonized normative data set has not been widely adopted. Moreover a clinical evaluation of the implementation of this dataset based on dynamic testing has not been published. To assess the impact of choice of a particular normative dataset on the diagnosis of growth hormone deficiency we recalculated Z-scores of IGF-1 measurements between 2016 and 2019, using our home reference values based on de normative dataset by Elmlinger (E)1, and using the normative datasets defined by Bidlingmaier (B)2 and by the Dutch IGF-1 harmonization program (NL). Based on these three Z-scores, the outcomes of growth hormone stimulation tests performed in this period (n=86) were reassessed according to the interpretation described in the Dutch guideline. Using all three normative datasets the same 4 patients were identified as likely to have a growth hormone deficiency, whereas 10(E), 10(B), or 8(NL) patients were identified as possible partial growth hormone deficiency. In 70(E), 66(B) or 72(NL) patients the growth hormone stimulation test was unaffected. Using normative dataset B, 6 patients displayed a pattern associated with a possible growth hormone resistance, or of bio-inactive growth hormone syndromes, which based on its incidence would be unlikely for a secondary care setting. A striking observation was however, that of all patients with a normal stimulation test 9 (E)/16 (B) or 30 (NL) had a IGF-1 Z-score of &gt; 0 SD. This implies that, for the diagnosis of growth hormone deficiency, it is safe to implement the Dutch harmonized dataset, which in addition could result in a reduction in the number of growth hormone stimulation tests that have to be performed. References: 1. Elmlinger MW et al. Clin Chem Lab Med. 2004;42(6):654-64. 2. Bidlingmaier M et al. J Clin Endocrinol Metab. 2014 May;99(5):1712-21.

scholarly journals The Growth Hormone and Insulin-Like Growth Factor Axis: Its Manipulation for the Benefit of Growth Disorders in Renal Failure

2001 ◽  
Vol 12 (6) ◽  
pp. 1297-1306 ◽  
Author(s):  
VINCENT ROELFSEMA ◽  
ROSS G. CLARK
Keyword(s):  
Growth Hormone ◽  
Renal Failure ◽  
Growth Factor ◽  
Animal Studies ◽  
Growth Failure ◽  
Growth Disorders ◽  
Insulin Like Growth Factor ◽  
Growth Responses ◽  
Beneficial Effects ◽  
Igf I

Abstract. Renal failure is associated with dramatic changes in the growth hormone/insulin-like growth factor (GH/IGF) axis. In children, this results in growth retardation, which is treated with injections of recombinant human GH (rhGH). Given the many recent advances in the knowledge of the components of the GH/IGF axis, it is timely to review the role of GH in renal failure and to discuss likely new treatments for growth failure. Renal failure is not a state of GH deficiency but a state of GH and IGF resistance, making other approaches to manipulating the GH axis more logical than treatment with rhGH alone. Although in children rhGH is safe, in critically ill adults it can be lethal. As the mechanisms of these lethal actions of rhGH are unknown, caution is advised when using rhGH outside approved indications. In renal failure, an optimal balance between safety and efficacy for growth may be achieved with the use of the combination of rhGH and rhIGF-I, as animal studies have shown synergistic growth responses. However, inhibition of the GH axis, with the use of GH antagonists, is likely to be tested clinically given the beneficial effects of GH antagonists on renal function in animal models of renal disease. Manipulating IGF-I by either administering rhIGF-1 or its binding proteins or increasing IGF-I bioavailability with the use of IGF displacers could prove to be a safer and more effective alternative to the use of rhGH in renal failure. In the future, both rhGH and rhIGF-1 likely will be included in growth-promoting hormone cocktails tailored to correct specific growth disorders.

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