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Experimental Physiology Nov 2008In 1990, a single amino acid substitution in the growth hormone (GH) gene at position 119 was found to transform the consequent protein from an agonist to an antagonist... (Review)
Review
In 1990, a single amino acid substitution in the growth hormone (GH) gene at position 119 was found to transform the consequent protein from an agonist to an antagonist at the growth hormone receptor (GHR). Further amino acid substitutions plus prolongation of the half-life of the protein by pegylation resulted in the first clinically effective GHR antagonist, pegvisomant. Following extensive clinical trials, this medication has emerged as the most efficacious therapy for treatment-resistant acromegaly. Subsequent advances in our understanding of GH-GHR interactions and downstream GH signalling pathways suggest that pegvisomant binds to preformed GHR dimers and prevents rotational changes within the receptor-GH complex necessary for intracellular signalling to occur. This article reviews the discovery of pegvisomant, from initial experimental data to successful licensing of the drug for treatment-resistant acromegaly, and discusses its other potential therapeutic uses in diseases with abnormalities in the GH-IGF-I axis.
Topics: Acromegaly; Animals; Antineoplastic Agents; Carrier Proteins; Hormone Antagonists; Human Growth Hormone; Humans; Hypoglycemic Agents; Models, Molecular; Mutation; Protein Binding; Protein Conformation; Protein Multimerization; Signal Transduction
PubMed: 18617577
DOI: 10.1113/expphysiol.2008.042515 -
Bailliere's Clinical Endocrinology and... Jul 1997The syndrome associated with lack of growth hormone (GH) in adults can be reversed by treatment with recombinant human GH (rhGH) with apparently beneficial clinical... (Review)
Review
The syndrome associated with lack of growth hormone (GH) in adults can be reversed by treatment with recombinant human GH (rhGH) with apparently beneficial clinical effects. This syndrome is strikingly similar to the characteristics of normal older adults which are known as the somatopause. GH secretion and insulin-like growth factor I levels are reduced in healthy older people and it has been suggested that the somatopause is an age-related GH deficiency state. This review describes the physiological control of GH secretion in adults and seeks an explanation for the age-related decline, considering the impact of other factors such as nutrition and mobility, and particularly whether exercise offers a physiological approach to changing both the GH decline and the somatopause. The benefits and side-effects of treatment with rhGH for normal older people or older patients facing catabolic stresses are reviewed together with alternative approaches to stimulate GH such as GH-releasing hormone and the new pharmaceutical GH secretagogues.
Topics: Aged; Aged, 80 and over; Aging; Exercise; Growth Hormone-Releasing Hormone; Human Growth Hormone; Humans; Hypothalamus; Insulin-Like Growth Factor I; Male; Middle Aged; Nutritional Physiological Phenomena
PubMed: 9403121
DOI: 10.1016/s0950-351x(97)80257-1 -
Expert Opinion on Pharmacotherapy Nov 1999The main function of growth hormone (GH) is to promote linear growth during childhood; however, GH secretion persists throughout life after cessation of skeletal growth.... (Review)
Review
The main function of growth hormone (GH) is to promote linear growth during childhood; however, GH secretion persists throughout life after cessation of skeletal growth. This hormone has important physiological functions apart from growth stimulation. Many aspects of the physiological and pharmacological actions of GH have been recently clarified. Accordingly, in the last years, especially since the introduction of recombinant human GH (rhGH), GH therapeutical applications have increased. In the last years, the main clinical application of rhGH has been to stimulate growth of growth-retarded GH deficient (GHD) children. More recently, rhGH therapy has been approved for other conditions associated with short stature, including Turner syndrome and end stage renal disease. In adults, the only therapeutic indications approved are the adult GHD syndrome and the AIDS-associated wasting. This review outlines the present knowledge of the physiological effects, clinical applications, therapeutic perspectives, side effects, precautions and contraindications of rhGH therapy in adults.
Topics: Adult; Clinical Trials as Topic; Growth Hormone; Human Growth Hormone; Humans
PubMed: 11249568
DOI: 10.1517/14656566.1.1.97 -
Pituitary 2007Growth hormone release and IGF-I synthesis decrease with increasing age. The regulation of the GH/IGF-I system is dependent on the integrity of the hypothalamus,... (Review)
Review
Growth hormone release and IGF-I synthesis decrease with increasing age. The regulation of the GH/IGF-I system is dependent on the integrity of the hypothalamus, pituitary and liver. During aging there are several changes which contribute to the decline in GH/IGF-I including changes in signal to the somatotrophs from growth hormone releasing hormone, somatostatin and other factors such as body composition, exercise, diet and sleep. All of these factors are discussed in detail within this review. The phenotypic similarities between aging and adult growth hormone deficiency syndrome combined with this decrease in GH/IGF-I with aging have prompted the question whether aging is a GH deficient state. The advent of recombinant growth hormone has led to a number of studies treating elderly patients with GH alone or in combination with sex steroids or exercise. The results of these studies would not back up the use of GH in elderly non-hypopituitary patients as they did not show efficacy, showed high rates of adverse events and there is also some evidence associating GH/IGF-I and risk of neoplasia. If GH therapy is to be used in this cohort of patients further long term efficacy and safety studies are required.
Topics: Aged; Aged, 80 and over; Aging; Hormone Replacement Therapy; Human Growth Hormone; Humans; Insulin-Like Growth Factor I; Longevity
PubMed: 17492509
DOI: 10.1007/s11102-007-0039-5 -
Annales D'endocrinologie Feb 2004Pegvisomant is a GH analogue that includes a single amino acid substitution at position 120 that generates the GHR antagonist. Additional changes include amino acid... (Review)
Review
Pegvisomant is a GH analogue that includes a single amino acid substitution at position 120 that generates the GHR antagonist. Additional changes include amino acid substitutions within binding site 1 and a further modification by the addition of polyethylene glycol moieties that increase the half-life and reduce the immunogenicity of the molecule. In acromegalics, pegvisomant is the most effective treatment for normalizing the IGF-I, and pegvisomant significantly improves insulin sensitivity in patients suffering from acromegaly. However, there are simply no data available that might support a role for pegvisomant treatment in disorders in which glucose metabolism is disturbed and in which reducing GH action would be theoretically beneficial.
Topics: Animals; Diabetes Mellitus; Glucose; Growth Hormone; Human Growth Hormone; Humans; Receptors, Somatotropin
PubMed: 15122098
DOI: 10.1016/s0003-4266(04)95636-3 -
Growth Hormone & IGF Research :... Jun 2001Pegvisomant is a recombinant protein, structurally similar to natural human growth hormone (GH), which is capable of binding to the GH receptor as a competitive... (Review)
Review
Pegvisomant is a recombinant protein, structurally similar to natural human growth hormone (GH), which is capable of binding to the GH receptor as a competitive antagonist. As well as being evaluated for the treatment of acromegaly, pegvisomant is being investigated as a possible antineoplastic agent, initially in mice. So far, in vitro efficacy against meningioma and in vivo efficacy against colon and breast cancer cell lines have been examined.
Topics: Animals; Breast Neoplasms; Human Growth Hormone; Humans; Insulin-Like Growth Factor I; Meningioma; Mice; Neoplasms; Receptors, Somatotropin; Tumor Cells, Cultured
PubMed: 11527083
DOI: 10.1016/s1096-6374(01)80020-4 -
Current Opinion in Pediatrics Aug 2002During the year 2000, several original studies were published regarding the metabolic effects of growth hormone therapy in pediatric patients. Pharmacologic doses of... (Review)
Review
During the year 2000, several original studies were published regarding the metabolic effects of growth hormone therapy in pediatric patients. Pharmacologic doses of growth hormone were rarely associated with abnormalities in glucose tolerance in children with intrauterine growth retardation and Turner syndrome; however, serum insulin levels were elevated. A report from the Pharmacia International Growth Study database suggested a possible increase in type 2 diabetes in growth hormone-treated patients, indicating the need for continued surveillance for this condition. Growth hormone therapy increased markers of bone turnover and bone mineral density in children with chronic renal failure and Prader-Willi syndrome. In Prader-Willi syndrome, 2 years of growth hormone therapy also induced a sustained decrease in body fat, improvement in strength and physical skills, and increased lean body mass. Serum leptin, a reflection of body fat, declined with growth hormone therapy in a dose-dependent manner in intrauterine growth retardation children; the magnitude of the decline correlated with linear growth response. Skin is a target organ for growth hormone in children; growth hormone increased dermal thickness and reduced skin stiffness in growth hormone-deficient children. Reassuring data were published regarding the risk of tumor recurrence and mortality in children with brain tumors treated with growth hormone. Growth hormone administered to short children prior to kidney transplantation did not have adverse effects on subsequent graft survival or number of rejection episodes.
Topics: Adolescent; Age Factors; Child; Child Development; Human Growth Hormone; Humans
PubMed: 12130908
DOI: 10.1097/00008480-200208000-00014 -
Endocrine Apr 2000GH exerts its actions through binding with two receptor molecules at the cell surface and interaction with Janus kinase and signal transducers and activators of... (Review)
Review
GH exerts its actions through binding with two receptor molecules at the cell surface and interaction with Janus kinase and signal transducers and activators of transcription, and other likely effectors to stimulate metabolic effects and IGF synthesis. The circulating GH binding protein is the proteolytic product of the cell surface receptor and serves as a marker of receptor number and function. Thirty-six distinct mutations of the receptor in the extracellular and transmembrane domains cause a clinical picture of severe GH/IGF-I deficiency, whereas two dominant negative mutations of the intracellular domain result in a milder clinical syndrome. These mutations have provided insight into the physiology of the GH receptor. A few patients have been described with what appears to be primary GH insensitivity due to defective signal transduction by the GH-GH-receptor complex. Clinical and biochemical features of primary GH insensitivity are not a function of genotype, with as much variability in a genetically homogeneous population as in a heterogeneous one. Except for those dominant negative mutations where co-transfection of the mutant GH receptor gene with wild-type receptor gene has been informative, evidence for an effect of a single mutant allele remains speculative. Treatment of GH receptor deficiency with recombinant human IGF-I suggests that the absence of a direct effect of GH limits growth response.
Topics: Animals; Child; Craniofacial Abnormalities; Growth Disorders; Growth Hormone; Human Growth Hormone; Humans; Insulin-Like Growth Factor I; Receptors, Somatotropin; Signal Transduction
PubMed: 10905371
DOI: 10.1385/ENDO:12:2:107 -
Advanced Drug Delivery Reviews Sep 2003Epidemiological studies have highlighted the need for tight control of growth hormone (GH) and insulin-like growth factor I (IGF-I) in patients with acromegaly. Studies... (Review)
Review
Epidemiological studies have highlighted the need for tight control of growth hormone (GH) and insulin-like growth factor I (IGF-I) in patients with acromegaly. Studies highlighting the events involved in GH receptor signaling have allowed the development of a pegylated GH receptor antagonist (pegvisomant) for use in humans, which has been designed to outcompete GH for the GH receptor, but which contains a position 120 amino acid substitution that prevents recruitment of a second GH receptor. This process of receptor dimerisation is crucial for signal transduction and IGF-I generation. Clinical trials of pegvisomant suggest it is the most effective treatment for acromegaly to date, as this therapy is capable of normalising serum IGF-I in up to 97% of patients when doses of 40 mg per day are used. This paper reviews the development of pegvisomant and the clinical experience in patients with acromegaly to date.
Topics: Acromegaly; Human Growth Hormone; Humans; Randomized Controlled Trials as Topic; Receptors, Somatotropin
PubMed: 14499709
DOI: 10.1016/s0169-409x(03)00111-x -
Growth Hormone & IGF Research :... Apr 2022Growth hormone (GH) is an important regulator of the female reproductive system. In vitro and non-human in vivo studies demonstrate a role of GH in steroidogenesis,...
Growth hormone (GH) is an important regulator of the female reproductive system. In vitro and non-human in vivo studies demonstrate a role of GH in steroidogenesis, folliculogenesis, and post-fertilization development. Given its ability to modulate the reproductive system and potentiate the effects of gonadotropins, a beneficial role of GH replacement therapy to optimize fertility has been suggested. Women with hypopituitarism have lower pregnancy and live birth rates. Limited data suggest a role of GH in enhancing fertility management in women with hypopituitarism. GH replacement therapy may be especially relevant in women with hypopituitarism as well as in women considered poor ovarian responders and require assisted reproductive techniques.
Topics: Female; Fertility; Growth Hormone; Hormone Replacement Therapy; Human Growth Hormone; Humans; Hypopituitarism; Pregnancy
PubMed: 35398725
DOI: 10.1016/j.ghir.2022.101458