State Of Growth Hormone Deficiency Research Articles

Growth hormone/insulin-like growth factor I axis in health and disease states: an update on the role of intra-portal insulin.

Growth hormone (GH) is the key regulator of insulin-like growth factor I (IGF-I) generation in healthy states. However, portal insulin delivery is also an essential co-player in the regulation of the GH/IGF-I axis by affecting and regulating hepatic GH receptor synthesis, and subsequently altering hepatic GH sensitivity and IGF-I generation. Disease states of GH excess (e.g., acromegaly) and GH deficiency (e.g., congenital isolated GH deficiency) are characterized by increased and decreased GH, IGF-I and insulin levels, respectively, where the GH/IGF-I relationship is reflected by a "primary association". When intra-portal insulin levels are increased (e.g., obesity, Cushing's syndrome, or due to treatment with glucocorticoids and glucagon-like peptide 1 receptor agonists) or decreased (e.g., malnutrition, anorexia nervosa and type 1 diabetes mellitus), these changes secondarily alter hepatic GH sensitivity resulting in a "secondary association" with discordant GH and IGF-I levels (e.g., high GH/low IGF-I levels or low GH/high IGF-I levels, respectively). Additionally, intra-portal insulin regulates hepatic secretion of IGFBP-1, an inhibitor of IGF-I action. Through its effects on IGFBP-1 and subsequently free IGF-I, intra-portal insulin exerts its effects to influence endogenous GH secretion via the negative feedback loop. Therefore, it is important to understand the effects of changes in intra-portal insulin when interpreting the GH/IGF-I axis in disease states. This review summarizes our current understanding of how changes in intra-portal insulin delivery to the liver in health, disease states and drug therapy use and misuse that leads to alterations in GH/IGF-I secretion that may dictate management decisions in afflicted patients.

Growth Hormone and Metabolic Homeostasis

Pituitary growth hormone (GH) is a peptide hormone predominantly secreted by somatotrophs in the anterior pituitary under the tight control of the hypothalamic–pituitary axis and GH secretagogues. GH elicits its effects directly on target organs and cells interacting with GH receptors and through stimulation of insulin-like growth factor 1 production. GH plays critical roles in regulating somatic growth and the metabolism of carbohydrates, lipids, and protein. GH increases insulin secretion and glucose uptake. Conversely, a GH deficient state is characterised by enhanced insulin sensitivity. Diabetogenic actions of GH are evident in conditions of GH excess, such as acromegaly or poorly controlled Type 1 diabetes mellitus. In patients with GH deficiency, administration of GH resulted in impaired glucose tolerance and insulin sensitivity. Owing to its multiple and complex effects, the regulation of GH secretion and its function in normal health and metabolic diseases is a major research interest in the field of molecular endocrinology. This review provides an overview of the effects of GH on glucose, lipid, and protein metabolism, insulin resistance, and metabolic homeostasis.

Skin manifestations of growth hormone-induced diseases.

The human skin is a well-organized organ bearing different types of cells in a well-structured interference to each other including epidermal and follicular keratinocytes, sebocytes, melanocytes, dermal papilla cells and fibroblasts, endothelial cells, sweat gland cells as well as nerves. Several hormones act on different cell types of the skin, while it is also considered an endocrine organ secreting hormones that act at several sites of the organism. GH receptors are found in almost all cell types forming the skin, while IGF-1 receptors' expression is restricted to the epidermal keratinocytes. Both Growth Hormone (GH) excess, as in the case of Acromegaly in adults, or Gigantism in growing children, and GH deficiency states lead to skin manifestations. In case of GH excess the main dermatological findings are skin thickening, coarsening of facial features, acrochordons, puffy hands and feet, oily skin and hyperhidrosis, while GH deficiency, on the contrary, is characterized by thin, dry skin and disorder of normal sweating. Moreover, special disorders associated with GH excess may have specific characteristics, as is the case of café-au-lait spots in Neurofibromatosis, or big café-au-lait skin hyperpigmented regions with irregular margins, as is the case in McCune-Albright syndrome. Meticulous examination of the skin may therefore contribute to the final diagnosis in cases of GH-induced disorders.

Effects of Growth Hormone on Bone.

Describe the effects of growth hormone (GH) and insulin-like growth factor 1 (IGF-1) on the skeleton. The GH and IGF-1 axis has pleiotropic effects on the skeleton throughout the lifespan by influencing bone formation and resorption. GH deficiency leads to decreased bone turnover, delayed statural growth in children, low bone mass, and increased fracture risk in adults. GH replacement improves adult stature in GH deficient children, increases bone mineral density (BMD) in adults, and helps to optimize peak bone acquisition in patients, during the transition from adolescence to adulthood, who have persistent GH deficiency. Observational studies suggest that GH replacement may mitigate the excessive fracture risk associated with GH deficiency. Acromegaly, a state of GH and IGF-1 excess, is associated with increased bone turnover and decreased BMD in the lumbar spine observed in some studies, particularly in patients with hypogonadism. In addition, patients with acromegaly appear to be at an increased risk of morphometric-vertebral fractures, especially in the presence of active disease or concurrent hypogonadism. GH therapy also has beneficial effects on statural growth in several conditions characterized by GH insensitivity, including chronic renal failure, Turner syndrome, Prader-Willi syndrome, postnatal growth delay in patients with intrauterine growth retardation who do not demonstrate catchup growth, idiopathic short stature, short stature homeobox-containing (SHOX) gene mutations, and Noonan syndrome. GH and IGF-1 have important roles in skeletal physiology, and GH has an important therapeutic role in both GH deficiency and insensitivity states.

The Glomerular Podocyte as a Target of Growth Hormone Action: Implications for the Pathogenesis of Diabetic Nephropathy

Involvement of the growth hormone (GH) / insulin-like growth factor 1 (IGF-I) axis in the pathogenesis of diabetic nephropathy (DN) is strongly suggested by studies investigating the impact of GH excess and deficiency on renal structure and function. GH excess in both the human (acromegaly) and in transgenic animal models is characterized by significant structural and functional changes in the kidney. In the human a direct relationship has been noted between the activity of the GH/IGF-1 axis and renal hypertrophy, microalbuminuria, and glomerulosclerosis. Conversely, states of GH deficiency or deficiency or inhibition of GH receptor (GHR) activity confer a protective effect against DN. The glomerular podocyte plays a central and critical role in the structural and functional integrity of the glomerular filtration barrier and maintenance of normal renal function. Recent studies have revealed that the glomerular podocyte is a target of GH action and that GH's actions on the podocyte could be detrimental to the structure and function of the podocyte. These results provide a novel mechanism for GH's role in the pathogenesis of DN and offer the possibility of targeting the GH/IGF-1 axis for the prevention and treatment of DN.

Anthropometry, CT, and DXA as predictors of GH deficiency in premenopausal women: ROC curve analysis

Visceral adiposity is a strong determinant of growth hormone (GH) secretion, and states of GH deficiency are associated with increased visceral adiposity and decreased lean body mass. The purpose of our study was to determine the sensitivity and specificity of different methods of assessing body composition [anthropometry, dual-energy X-ray absorptiometry (DXA), and computed tomography (CT)] to predict GH deficiency in premenopausal women and threshold values for each technique to predict GH deficiency, using receiver operator characteristic (ROC) curve analysis. We studied a group of 45 healthy lean, overweight, and obese premenopausal women who underwent anthropometric measurements (body mass index, waist and hip circumferences, skin fold thickness), DXA, CT, and a GH-releasing hormone-arginine stimulation test. ROC curve analysis was used to determine cutoff values for each method to identify GH deficiency. Visceral adiposity measured by CT showed the highest sensitivity and specificity for identifying subjects with GH deficiency with a cutoff of >9,962 mm(2) [area under the curve (AUC), 0.95; sensitivity, 100%; specificity, 77.8%; P = 0.0001]. Largest waist circumference showed high sensitivity and specificity with a cutoff of >101.7 cm (AUC, 0.89; sensitivity, 88.9%; specificity, 75%; P = 0.0001). When the ROC curves of visceral fat measured by CT and largest waist circumference were compared, the difference between the two methods was not statistically significant (P = 0.36). Our study showed that the largest waist circumference predicts the presence of GH deficiency in healthy premenopausal women with high sensitivity and specificity and nearly as well as CT measurement of visceral adiposity. It can be used to identify women in whom GH deficiency is likely and therefore in whom formal GH stimulation testing might be indicated.

Clinical utility of measurements of insulin-like growth factor 1

Plasma insulin-like growth factor 1 (IGF-I) concentrations are regulated by genetic factors, nutrient intake, growth hormone (GH) and other hormones such as T4, cortisol and sex steroids. The accuracy of IGF-I measurement in diagnosing GH deficiency or excess depends, in part, on the relative contributions of each of these variables. Since their respective influence may vary widely between individuals, the establishment of well-defined normal ranges is necessary, which requires adequate numbers of normal individuals, in order for IGF-I measurements to have maximum utility. In states of GH deficiency, the influence of these non-GH-related factors predominates. Although IGF-I levels have utility as a screening test in children and young adults, they cannot be used as a stand-alone test for the diagnosis of GH deficiency. By contrast, in acromegaly, GH is the predominant determinant of IGF-I levels and, therefore, measurement of IGF-I is a very useful diagnostic test. In acromegaly, IGF-I levels are useful for assessing the relative degree of GH excess, because changes in IGF-I correlate with changes in symptoms and soft-tissue growth. IGF-I is also very useful in monitoring the symptomatic response to therapy.

Expression of growth hormone and its receptor in the lungs of embryonic chicks

The lung is well established as being a postnatal target site for growth hormone (GH) action, since pathophysiological states of GH excess and deficiency are both associated with impaired pulmonary function. Pituitary GH is therefore probably involved in normal lung growth or development, although perinatal lung development occurs prior to the differentiation of pituitary somatotrophs and the ontogeny of pituitary GH secretion. The lung itself may, however, be a site of GH production during prenatal development, since a specific GH-response gene (a marker of GH activity) is expressed in the lungs of early chick embryos, in which GH immunoreactivity is widespread in many other peripheral tissues. We have assessed this possibility in embryonic chicks. A 690-bp cDNA, identical in size and nucleotide sequence to the full-length pituitary GH transcript, was amplified by reverse transcription/polymerase chain reaction from total RNA extracted from the lungs of embryos at 11, 13, 15, and 18 days of the 21-day incubation period. This transcript was localized by in situ hybridization to mesenchymal and epithelial cells of the developing lungs, in which specific GH immunoreactivity was similarly located. Intense GH immunoreactivity was also present after embryonic day 15 (ED15) in the smooth muscle surrounding blood vessels in the lung and surrounding the bronchioles. Lung GH immunoreactivity was primarily associated with a 15-kDa protein, rather than the 26-kDa protein in the pituitary gland. After the onset of pituitary GH secretion (at ED17), GH mRNA was barely detectable in the lungs of ED20 embryos, at the start of lung breathing. GH immunoreactivity was, however, still present in some cells in the lungs of ED20 embryos. GH-receptor mRNA and immunoreactivity were also widespread and abundant within the embryonic lung. Lung GH may thus have autocrine or paracrine roles in lung development or in pulmonary function prior to the ontogeny of the pituitary gland and the appearance of GH in peripheral plasma.

Growth hormone expression in the perinatal and postnatal rat lung

It is now established that the lung is a target site for pituitary growth hormone (GH) action, because pathophysiological states of pituitary GH excess and deficiency are associated with impaired pulmonary function. The onset of lung development and differentiation is, however, before the ontogenic differentiation of pituitary somatotrophs. GH may be involved, nevertheless, in lung development, because it is present in extrapituitary tissues of preimplantation mouse embryos and in the lung buds of embryonic chickens. The possibility that GH may be expressed in the rat lung during fetal and neonatal development, therefore, has been assessed. GH mRNA was detected in the lung, and its 693-bp sequence was identical to that in the pituitary gland. By in situ hybridization, this transcript was found to be abundantly expressed in the lungs of embryonic day (ED) 17 rats in mesenchymal, mucosal epithelial, and smooth muscle cells. This transcript was expressed in neonates until at least day 14 postnatally and was localized to type I and II epithelial cells and to pulmonary tissue macrophages and alveolar macrophages. GH immunoreactivity paralleled GH mRNA cellular localization throughout the time course studied. This immunoreactivity was specific and was lost after antibody preabsorption. The perinatal and postnatal lung is, therefore, an extrapituitary site of GH gene expression during development. Given that the GH receptor is present in the lung from early development, lung GH may have autocrine and/or paracrine roles in lung growth or differentiation or in pulmonary function.

The Challenges of Reliance on Insulin-Like Growth Factor I in Monitoring Disease Activity in Patients with Acromegaly

Serum insulin-like growth factor I (IGF-I) is an important marker of disease activity in patients with acromegaly, and epidemiological data indicate control of circulating IGF-I in patients with acromegaly restores life expectancy to normal. Improvements in the quality of, and access to, IGF-I assays has encouraged monitoring of acromegaly with IGF-I, although circulating growth hormone (GH) and IGF-I values provide different information, so ideally both should be monitored. However, the introduction of the GH receptor antagonist pegvisomant poses new challenges. Pegvisomant binds with high affinity to GH receptors, thereby blocking the action of GH at the tissue level and rendering the hormone biologically inactive. This leaves IGF-I as the principal marker of disease activity. It is conceptually possible to induce a state of functional GH deficiency (GHD) with pegvisomant with IGF-I values within the normal range. With the goal of minimizing the risk of over-treatment and GHD, we have provided preliminary guidance on the target range for IGF-I in patients receiving pegvisomant based on the gender- and decade-based percentile ranges for IGF-I of adult patients with untreated GHD enrolled in the Pfizer International Metabolic Database (KIMS).

Somatropin Therapy in Adults with Prader-Willi Syndrome

Prader-Willi syndrome is a complex genetic disorder with a characteristic cognitive, behavioral, and endocrinologic phenotype. Obesity, partial growth hormone (GH) secretion, and hypogonadism are common. Results of several somatropin (GH therapy) studies in children with Prader-Willi syndrome have shown improvement in growth, body composition, physical strength, and agility. GH deficiency in adults without Prader-Willi syndrome is associated with abdominal obesity, insulin resistance, and an unfavorable lipid profile, and the partial state of GH deficiency seen in Prader-Willi syndrome thus renders these patients exposed to a lifelong risk of metabolic diseases. The nongrowth effects of somatropin in children with Prader-Willi syndrome have directed interest towards adults in preventing long-term consequences of GH deficiency, but the potential impact of somatropin therapy in adults with Prader-Willi syndrome is not known in detail. To date, only one study has been published. In this study, 17 patients (9 men and 8 women) with a mean age of 25 years and a mean body mass index of 35 +/- 3.2 kg/m2 were examined. Eleven had the Prader-Willi syndrome genotype. They were treated with somatropin (Genotropin) for 12 months after an initial placebo-controlled period of 6 months. Compared with placebo, somatropin increased insulin-like growth factor-1 levels (p < 0.01) and decreased body fat (p = 0.04). During the 12-month period with somatropin therapy, the mean reduction in body fat was 2.5% (p < 0.01), concomitant with a mean increase in lean body mass of 2.2kg (p < 0.05). Lipid profiles were normal in most patients before treatment and did not change. The oral glucose tolerance test was impaired in one patient at study start and in five patients at 12 months. No patients developed diabetes mellitus. Furthermore, insulin levels remained unchanged, and estimation of insulin resistance by homeostasis model assessment did not disclose any change. Transient adverse effects attributed to water retention occurred in three patients. In conclusion, the one published study of somatropin therapy in adults with Prader-Willi syndrome showed beneficial effects on body composition without pronounced adverse effects. However, further studies are required to establish the definite role and optimal dosage of somatropin, as well as long-term effects, in adults with Prader-Willi syndrome.

GH-related and extra-endocrine actions of GH secretagogues in aging.

Growth hormone (GH) secretion declines with aging in mammals, including humans. Defective pituitary function does not play a major role in this event. Rather, age-related changes involving the function of specific hypothalamic peptides for GH regulation, GH-releasing hormone (GHRH) and somatostatin (SS), appear to be the fundamental factors. Experimental evidence indicates that GHRH synthesis is impaired with aging in the rat hypothalamus, and that a relative hyperfunction of the SS-ergic system is present. In the elderly, systemic, short-term administration of GHRH enhances GH secretion and increases the formation of the GH-dependent peptide IGF-1. In old dogs, a combination of GHRH and clonidine (CLO), an alpha(2)-adrenoceptor agonist, reportedly acting via GHRH stimulation and SS inhibition, is the most effective stimulus to rejuvenate the apulsatile GH secretion. Discovery of GH secretagogues (GHSs), a series of peptydil and non-peptydil synthetic molecules endowed with a strong GH-releasing activity, the cloning of a GHS receptor (GHS-R), present in the hypothalamus and the pituitary, the isolation of the endogenous ligand of GHS-R, ghrelin, a 28-amino acid peptide whose main source is the stomach, pose the issue for the physiologic role of the GHS/ghrelin system and forces revision of our current understanding of GH regulation in different GH deficiency (GHD) states, including aging. GHSs are very effective for enhancing GH secretion in old subjects, but long-term studies are needed to assess their safety and the real biological impact of GHS replacement therapy in aging. Therapeutic use of GHSs can also be envisaged to restore, via GH-independent mechanisms, functional, and structural age-related alterations, such as anorexia, sexual dysfunction, cardiovascular damage, bone loss.

Growth hormone-induced alterations in the insulin-signaling system.

Growth hormone (GH) counteracts insulin action on lipid and glucose metabolism. However, the sequence of molecular events leading to these changes is poorly understood. Insulin action is initiated by binding of the hormone to its cell surface receptor (IR). This event activates the intrinsic tyrosine kinase activity residing in the beta-subunit of the IR and leads to autophosphorylation of the cytoplasmic portion of the beta-subunit and further activation of its tyrosine kinase towards several intermediate proteins, including the family of IR substrates (IRS) and the Shc proteins. When tyrosine phosphorylated, these cellular substrates connect the IR with several downstream signaling molecules. One of them is the enzyme phosphatidylinositol (PI) 3-kinase. The insulin antagonistic action of GH is not a consequence of a direct interaction with the IR. Instead, long-term exposure to GH is, in general, associated with hyperinsulinemia, which leads to a reduction of IR levels and an impairment of its tyrosine kinase activity. The signals of GH and insulin may converge at post-receptor levels. The signaling pathway leading to activation of PI 3-kinase appears to be an important site of convergence between the signals of these two hormones and seems to be mediated principally by IRS-1. Rodent models of chronic GH excess have been useful tools to investigate the mechanism by which GH induces insulin resistance. Decreased IR, IRS-1, and IRS-2 tyrosyl phosphorylation in response to insulin was found in skeletal muscle, whereas a chronic activation of the IRS-PI 3-kinase pathway was found in liver. The induction of the expression of proteins that inhibit IR signaling such as suppressors of cytokine signaling (SOCS)-1 and -6 may also be involved in this alteration. Interestingly, the modulation of insulin signaling and action observed in states of GH excess, deficiency, or resistance seems to be relevant to the changes in longevity associated with those states.

Issues in the Transition From Childhood to Adult Growth Hormone Therapy

The consequences of severe growth hormone deficiency (GHD) in adults and the beneficial effects of GH replacement therapy are clear. However, the majority of children who have a diagnosis of GHD and who are treated with GH do not have permanent GHD and will not require treatment during adulthood. Several issues must be considered in selecting candidates for adult GH treatment and transitioning their care from pediatrics to adult medicine. Counseling about possible lifelong treatment should focus on children with panhypopituitarism and those with severe isolated GHD that is associated with central nervous system abnormalities. When to terminate growth-promoting GH therapy should be guided by balancing the high cost of late-adolescent treatment with the attainment of reasonable statural goals. Retesting for GH secretion is appropriate for all candidates for adult GH therapy; the GH axis can be tested within weeks after the cessation of treatment, but confirming an emerging adult GHD state with body composition, blood lipid, and quality-of-life assessments may require 1 year or more of observation. Selecting patients for lifelong adult GH replacement therapy will present diagnostic, therapeutic, and ethical problems similar to those in treating childhood GHD. The experience and expertise of pediatric endocrinologists in diagnosing and treating GHD should be offered and used in identifying and transitioning appropriate patients to adult GH therapy.

Appraisal of growth hormone (GH) secretion: evaluation of a composite pharmacokinetic model that discriminates multiple components of GH input.

Criteria for a diagnosis of GH deficiency include inadequate GH secretion as assessed by provocative testing. The changes in serum GH concentration in such tests, however, do not uniformly predict treatment responses. We questioned whether the changes in serum GH have a uniform dependence among subjects on the mass of secreted GH. We simulated spontaneous GH secretory events with bolus infusions of recombinant human GH (rhGH) in 15 somatostatin-infused adult subjects. Maximum serum GH responses, the GH areas under the curve, and GH mass calculated from deconvolution techniques are all indexes of GH secretion influenced by GH clearance and distribution volume. In this group, these indexes showed a nonuniform dependence on the known GH dose. Despite somatostatin infusion, we found evidence for low level basal GH secretion with oscillatory characteristics that may have influenced the GH concentration dependence on GH dose. We then developed and evaluated a new pharmacokinetic model to account for pulsatile, basal, and oscillatory inputs to the serum GH concentration profile. The new model is comprised of three terms. The first describes plasma GH concentrations from exogenous administration of rhGH according to a one- or a two-compartment model. The second term accounts for basal GH secretion. The third is a cosinor function that describes the oscillatory pattern of basal GH. The composite pharmacokinetic model predicted plasma GH concentrations well (r2 = 0.88-0.97); pharmacokinetic and cosinor parameters had high precision and narrow 95% confidence intervals. The pharmacokinetic parameters were stable and independent. The mean values and coefficients of variance (SD/mean) of GH pharmacokinetic parameters in our 15 subjects were: clearance, 0.236 L/min (24%); volume of distribution, 3.46 L (30%); and terminal half-life, 12.3 min (37%). The values for the cosinor parameters were: basal concentration, 0.22 ng/mL (85%); amplitude, 0.758 (50%); cycle, 121 min (27%); and time shift (acrophase), 60.3 min (53.6%). During the 9-h study, clearance decreased from 0.259 +/- 0.09 to 0.214 +/- 0.06 L/min (P < 0.03), and basal concentration increased from 0.20 +/- 0.22 to 0.33 +/- 0.33 ng/mL (P < 0.5). We conclude that our model can provide useful estimates of GH pharmacokinetics in the presence of basal, oscillating, endogenous concentrations without administering a dose of radiolabeled GH. The substantial inter- and intrasubject variance in pharmacokinetic parameters between subjects negates the assumption of a uniform relationship between GH secretion and serum GH concentration and detracts from the utility of a GH concentration cut-off point in GH testing. These findings have implications to the valid appraisal of GH deficiency states, selection of rhGH treatment candidates, and physiological regulation of the GH axis.

Growth hormone improves body composition, fat utilization, physical strength and agility, and growth in Prader-Willi syndrome: A controlled study

Background: Obesity and hypotonia in children with Prader-Willi syndrome (PWS) are accompanied by abnormal body composition and diminished energy expenditure resembling a growth hormone–deficient state. Hypothalamic dysfunction in PWS often includes decreased growth hormone (GH) secretion, suggesting a possible therapeutic role for exogenous GH treatment. Objectives and methods: After 6 months of observation to determine baseline growth rate, and with the use of a 12-month randomized controlled study design, the effects of GH treatment (1 mg/m 2/d) on growth, body composition, strength and agility, pulmonary function, resting energy expenditure (REE), and fat utilization were assessed in 54 children with PWS (n = 35 treatment and n = 19 control). Percent body fat and bone mineral density were measured by dual x-ray absorptiometry. Indirect calorimetry was used to determine REE and to calculate respiratory quotients. Results: Stimulated levels of GH in response to clonidine testing were low in all patients (peak, 2.0 ng/mL). After 12 months, GH-treated subjects showed significantly increased height velocity Z scores (mean, –1.0 ± 1.7 to 4.6 ± 2.9; P < .001), decreased percent body fat (mean, 46.3% ± 8.4% to 38.3% ± 10.7%; P < .001), and improved respiratory muscle function, physical strength, and agility (sit-ups, weight-lifts, running speed, and coordination). A significant decline in respiratory quotients occurred during GH therapy (0.81 to 0.77, P < .001), but total REE did not change. Conclusions: GH treatment of children with PWS accelerated growth, decreased percent body fat, and increased fat oxidation but did not significantly increase total REE. Improvements in respiratory muscle strength, physical strength, and agility also occurred, suggesting that GH treatment may have value in reducing some physical disabilities experienced by children with PWS. (J Pediatr 1999;134:215-21)

Growth hormone pulsatility in acromegaly following radiotherapy.

Radiotherapy continues to have an important role in the treatment of acromegaly and is particularly effective at halting tumour growth, causing tumour shrinkage and reducing growth hormone (GH) concentrations in the long term. The major disadvantages of radiotherapy include the slow reduction in GH levels and damage to the other hypothalamic-pituitary axes. The 24 hour GH profile in active acromegaly compared with normals, characteristically shows an increased frequency of GH pulses, increased disorderliness (approximate entropy) of GH release, increased mean GH valley nadir, increased non-pulsatile fraction of GH and either similar or increased GH pulse amplitude. Complete surgical excision of a GH secreting adenoma may reverse these abnormalities and reduce circulating insulin-like growth factor-1 (IGF-1) concentrations to normal. However, very few data are available regarding the effects of radiotherapy on GH pulsatility in patients with acromegaly. Radiotherapy rarely leads to normalisation of the pattern of spontaneous GH release and may therefore be associated with an elevated IGF-1 even when 24 hour GH concentrations are comparable to healthy controls. The impact of such a biochemical state on morbidity and mortality in acromegaly is unknown. The continuing effects of radiotherapy may potentially transform an individual from a state of GH excess, to a state of GH deficiency, with as yet undetermined effects. In addition, radiotherapy leads to significant hypothalamic dysfunction, with the possible loss of endogenous somatostatin (SMS) production. This may potentially alter somatostatin (SMS) receptor expression on somatotroph adenomas and alter their responsiveness to subsequent SMS analogue therapy.

Growth hormone secretion in the elderly: Ageing and the somatopause

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.

Effect of growth hormone on fatty liver in panhypopituitarism

A 17 year old boy was admitted because of short stature and hepatomegaly. He was diagnosed with panhypopituitarism and fatty liver. The fatty liver improved, not with hydrocortisone or levothyroxine...

Effects of growth hormone on neuroendocrine function.

Although the role of growth hormone (GH) in the control of reproductive functions is not well understood, there is considerable evidence that the states of both GH deficiency and GH excess are typically associated with reproductive deficits. To identify the possible involvement of functional alterations in the hypothalamic-pituitary system in producing these deficits, we are studying neuroendocrine function related to reproduction in transgenic animals overexpressing GH, in animals with congenital GH deficiency, and in animals with selective immunoneutralization of GH. The results indicate that GH acts on the hypothalamus to alter dopaminergic and noradrenergic control of prolactin and gonadotropin release. Life-long elevation of GH levels outside the physiological ranges disrupts feedback control of luteinizing hormone (LH) release by gonadal streroids. Plasma LH and follicle-stimulating hormone (FSH) levels and feedback control of LH release are also abnormal in GH-deficient animals indicating that physiological levels of endogenous GH are normally involved in the control of gonadotropin release. Differences between the effects of bovine vs. human GH in transgenic mice and differential effects of GH deficiency in mice and rats should facilitate identification of the mechanisms involved in the actions of GH on the hypothalamic-pituitary system.