Chronic Growth Hormone Excess Research Articles

Acromegaly in the elderly patients.

Acromegaly is a rare disease characterized by a chronic exposition to growth hormone (GH) and insulin-like growth factor-1 (IGF-1), caused in most cases by a pituitary GH-secreting adenoma. Chronic GH excess induces systemic complications (metabolic, cardiovascular, respiratory, neoplastic, and musculoskeletal) and increased mortality if not appropriately treated. Recent epidemiological data report an improved life span of patients with acromegaly probably due to better acromegaly management; additionally, the number of pituitary incidentaloma in general population also increased over time due to more frequent imaging. Therefore, the number of elderly patients, newly diagnosed with acromegaly or in follow-up, is expected to grow in the coming years and clinicians will need to be aware of particularities in managing these patients. This review aims to explore different aspects of acromegaly of the elderly patients, focusing on epidemiology, diagnosis, clinical presentation, complications, and management options. Available literature has been assessed through PubMed (data until August 2019) by specific keywords. Available data on acromegaly in the elderly patient are sparse, but point to important differences. Further studies are needed comparing elderly with younger patients with acromegaly to better define a tailored diagnostic and therapeutic management.

MON-479 Gross and Microscopic Intestinal Morphology of Bovine Growth Hormone Transgenic Mice Longitudinally

Growth hormone (GH) has been shown to have important effects on the intestines, demonstrated by its use in treatment of short bowel syndrome and the increase in colon polyps seen in acromegaly. Accordingly, GH has been shown to affect intestinal morphology at the gross and microscopic levels, including increased intestinal length and increased villus height in situations of excess GH aged 2 months. However, the effect of excess GH on intestinal morphology longitudinally or at advanced ages has not been extensively examined. This study measured the gross and microscopic intestinal morphology at multiple ages in bovine GH (bGH) transgenic mice, a mouse model of acromegaly. Adult bGH mice and littermate controls aged 6, 11, or 13 months were used for this study. The intestines were dissected, mesenteric fat was removed, and the small intestine (SI) was separated from the large intestine (LI). The length and circumference of the SI and the LI were measured. Intestinal portions were processed using the Swiss roll method, paraffin embedded, sectioned, and stained. The images of the sections were then used to measure the villus height, crypt depth and muscle thickness. In accordance with previous reports in humans and mice, chronic GH excess causes increased intestinal length. This difference was present in both the SI and LI and at 6, 11, and 13 months of age. bGH mice at all three ages had increased SI weight. LI weight was increased in bGH mice at 6 and 13 months of age, but there was no increase at 11 months of age. At 13 months of age, the LI circumference was increased in bGH mice, and the SI circumference at 6 months of age was also increased. At the microscopic level, the 6-month-old bGH mice had significantly increased crypt depth in the duodenum and jejunum, and a trend in the ileum. There is also a trend towards increased villus height in the 6-month bGH mice in all three sections of the SI that did not reach significance. The only change observed in the 11-month bGH mice was increased muscle thickness in the duodenum. The results of this study indicate that chronic GH excess indeed increases intestinal length, a change that persists longitudinally. The previously reported increase in intestinal villus height in response to GH excess was not observed in this experiment, but increased crypt depth was observed in the youngest cohort. The oldest group had an increase in SI circumference that coincided with increased muscle thickness in the 11-month bGH mice. In summary, our data show a potent trophic effect of GH on the intestinal tract, as well as an effect on the microscopic morphology of the intestines; however, the microscopic changes differ from those previously reported and do not seem to persist over the lifespan of a mouse. Acknowledgements: This work was supported by the State of Ohio’s Eminent Scholar Program that includes a gift from Milton and Lawrence Goll, by AMVETS, and by the Diabetes Institute at Ohio University

GH replacement causing acute hyperglycaemia and ketonuria in a type 1 diabetic patient

SummaryA state of insulin resistance is common to the clinical conditions of both chronic growth hormone (GH) deficiency and GH excess (acromegaly). GH has a physiological role in glucose metabolism in the acute settings of fast and exercise and is the only anabolic hormone secreted in the fasting state. We report the case of a patient in whom knowledge of this aspect of GH physiology was vital to her care. A woman with well-controlled type 1 diabetes mellitus who developed hypopituitarism following the birth of her first child required GH replacement therapy. Hours after the first dose, she developed a rapid metabolic deterioration and awoke with hyperglycaemia and ketonuria. She adjusted her insulin dose accordingly, but the pattern was repeated with each subsequent increase in her dose. Acute GH-induced lipolysis results in an abundance of free fatty acids (FFA); these directly inhibit glucose uptake into muscle, and this can lead to hyperglycaemia. This glucose–fatty acid cycle was first described by Randle et al. in 1963; it is a nutrient-mediated fine control that allows oxidative muscle to switch between glucose and fatty acids as fuel, depending on their availability. We describe the mechanism in detail.Learning points There is a complex interplay between GH and insulin resistance: chronically, both GH excess and deficiency lead to insulin resistance, but there is also an acute mechanism that is less well appreciated by clinicians.GH activates hormone-sensitive lipase to release FFA into the circulation; these may inhibit the uptake of glucose leading to hyperglycaemia and ketosis in the type 1 diabetic patient.The Randle cycle, or glucose–fatty acid cycle, outlines the mechanism for this acute relationship.Monitoring the adequacy of GH replacement in patients with type 1 diabetes is difficult, with IGF1 an unreliable marker.

The strange case of a patient affected by acromegaly with osteoporomalacia without hypogonadism

Acromegaly is a rare disease that, in the majority of cases, is due to the presence of a benign growth hormone (GH)-producing tumor of the pituitary. Growth hormone has profound effects on linear bone growth, bone metabolism, and bone mass. In acromegaly, the skeletal effects of chronic GH excess have been mainly addressed by evaluating bone mineral density (BMD). Most data were obtained in patients with active acromegaly, and apparently high or normal BMD was observed in the absence of hypogonadism. The Autors describe a case of patient affected by acromegaly without hypogonadism with serious osteoporosis and biological signs of osteomalacia.

Surgical Management of Obstructive Sleep Apnea in Acromegaly With Mandibular Prognathism and Macroglossia: A Treatment Dilemma

Acromegaly is a rare disease resulting from chronic growth hormone excess largely owing to a growth hormone-secreting pituitary adenoma. Males and females appear to be equally affected, with an annual incidence of 3 to 4 per million. The diagnosis of the disease often occurs late, with an average age of 40 years, owing to its insidious onset and slow progression. 1 The prominent cosmetic features include enlarged extremities, thickened skin, widened nose, prominent cheekbones, course facial lines, and, occasionally, frontal bossing. The oral manifestations include mandibular overgrowth, resulting in prognathism, maxillary widening, dental malocclusion, macroglossia, and enlarged lips. 2 Systemic manifestations, including rheumatologic, cardiovascular, respiratory, and metabolic consequences, determine the prognosis. Obstructive sleep apnea (OSA) has been reported with a frequency of 60%. 3 The treatment of acromegaly is directed at reducing the growth hormone and insulin-like growth factor 1 levels to normal values and excising the adenoma. The present available therapies for acromegaly include transphenoidal surgery, radiotherapy, and medical therapy. 4 Although many of the systemic manifestations of acromegaly can be relieved with growth hormone homeostasis, relevant OSA remains. This can often be attributed to skeletal and soft tissue craniofacial changes that remain despite treatment of the primary condition. The treatment dilemma arises when attempts are made to correct the facial deformities by reducing hyperplastic bone, resulting in a decreased posterior airway space and worsening OSA. 3

Medical Therapy of Acromegaly

Acromegaly is a chronic disease with signs and symptoms due to growth hormone (GH) excess. The most frequent cause of acromegaly is a GH-producing pituitary adenoma. Chronic GH excess is accompanied by long-term complications of the locomotor (arthrosis) and cardiovascular (atherosclerosis, cardiomyopathy) systems and is, when untreated, associated with an increased mortality. The aim of treatment of acromegaly is to improve symptoms, to achieve local tumour mass control, and to decrease morbidity and mortality. Treatment options include surgery, medical therapy and radiotherapy. Transsphenoidal surgery is the first choice of treatment when a definitive cure can be achieved, particularly in the case of microadenomas and when decompression of surrounding structures (optic chiasm, ophthalmic motor nerves) is indicated. Primary medical therapy has been increasingly applied in recent years, especially when a priori chances of surgical cure are low (because of adenoma size and localization) and in patients with advanced age and/or serious co-morbidity. In addition, preoperative primary medical therapy may result in tumour shrinkage, facilitating tumour resection, and may reduce perioperative complications due to GH excess. Within the spectrum of medical therapy, long-acting somatostatin analogues (somatostatins) are considered as first-line treatment. Treatment with somatostatin analogues results in GH control in approximately 60% of patients. In addition, somatostatin analogues induce tumour shrinkage in 30-50% of patients, particularly when applied as primary therapy. Prolonged treatment with somatostatin analogues appears to be safe and is usually well tolerated. The currently available somatostatin analogues, octreotide and lanreotide, seem to be equally effective; however, this should still be evaluated in prospective, randomized trials evaluating efficacy with respect to GH control and tumour shrinkage. In patients with an insufficient clinical and biochemical response to somatostatin analogues, combination therapy with dopamine receptor agonists or the GH receptor antagonist pegvisomant usually leads to disease control. New developments in the medical therapy of acromegaly include the universal somatostatin receptor agonist pasireotide, which has a broader affinity for all somatostatin receptor (sst) subtypes compared with the currently available somatostatin analogues with preferential affinity for the sst2 receptor, and chimeric compounds that interact with both somatostatin and dopamine receptors with synergizing effects on GH secretion.

Chronic Growth Hormone Excess Is Associated with Increased Aldosterone: A Study in Patients with Acromegaly and in Growth Hormone Transgenic Mice

Acromegaly is a disease characterized by chronic growth hormone (GH) excess. Since hypertension is a common finding in patients with acromegaly, interactions between GH and the renin-angiotensin-aldosterone system (RAAS) are under controversial debate. We examined GH, IGF-I, aldosterone, and renin in a well-defined group of acromegalic patients before and after cure by surgery. In addition, we analyzed the impact of chronic GH excess on the RAAS in mouse models over-expressing GH alone (G) or in combination with insulin-like growth factor-binding protein-2 (IGFBP-2; GB). Normalization of GH secretion after cure by surgery was accompanied by significant decreases of serum aldosterone in acromegalic patients (pre-op: 96.5 +/- 37.1 pg/mL, post-op: 41.3 +/- 28.2 pg/ mL; P < 0.001; n = 13), but renin concentrations were unaffected. In addition, aldosterone concentrations were positively correlated to GH levels (Spearman r = 0.39; P = 0.025; n = 26). To further study this association, we analysed two transgenic mouse models and found a similar relationship between GH and aldosterone in G mice, which showed about 3-fold elevated serum aldosterone levels in comparison to non-transgenic controls (males: 442 +/- 331 pg/mL vs. 151 +/- 84 pg/mL; P = 0.002; n > or = 12; females: 488 +/- 161 pg/mL vs. 108 +/- 125 pg/mL; P = 0.05; n > or = 4). Expression of aldosterone synthase was similar in adrenal glands of C and G mice. Aldosterone levels in G and GB mice of both genders were not different, indicating that the elevated aldosterone was due to GH excess and not caused by elevated IGF-I, which is known to be blocked by IGFBP-2 overexpression. Also in the mouse models, changes in aldosterone were independent from renin. In summary, we show that chronic GH excess is associated with increased aldosterone in humans and mice. GH-induced increases of aldosterone potentially contribute to the increased cardiovascular risk in acromegalic patients. The underlying mechanism is likely to be independent of renin, excess IGF-I, or adrenal aldosterone synthase expression.

Decreased Peripheral Insulin Sensitivity in Acromegalic Patients

In 13 nondiabetic acromegalic patients glucose homeostasis was studied by use of the hyperglycaemic clamp technique and compared to a group of sex and age matched and a group of sex, age and weight matched controls. When compared to a control group of normal weight glucose stimulated insulin release (I) was significantly increased and tissue sensitivity to insulin (M/I) significantly decreased. However, no significant differences were observed when the parameters were compared with a weight matched group. Glucose stimulated insulin release correlated positively with growth hormone (GH) and somatomedin-C levels, whereas no such a correlation could be obtained for M/I. Thus, chronic growth hormone excess seems to induce hyperinsulinaemia which in turn leads to obesity and metabolic changes comparable to those of obesity.

Transgenic Mice Overexpressing Growth Hormone (GH) Have Reduced or Increased Cardiac Apoptosis through Activation of Multiple GH-Dependent or -Independent Cell Death Pathways

GH has antiapoptotic effects in cardiac or noncardiac cell lines; however, increased apoptosis has been found in myocardial samples of patients with acromegaly. The aim of this study was to investigate cardiac apoptosis and underlying molecular mechanisms in transgenic mice overexpressing bovine GH [acromegalic mice (Acro)] aged 3 or 9 months. Cardiomyocyte apoptosis was evaluated by terminal deoxynucleotidyl transferase assay and annexin V; expression of pro- or antiapoptotic proteins was assessed by Western blot. Specificity of GH action was confirmed using a selective GH receptor antagonist. Apoptosis was lower in 3-month-old Acro than in controls; reduction was abolished by a GH receptor antagonist. The effects of GH were consistent with an antiapoptotic phenotype (increased Bcl2 and Bcl-XL and reduced Bad and cytochrome c levels, leading to lower activation of caspase-9 and caspase-3). In contrast, apoptosis was higher in 9-month-old Acro than in littermate controls; in addition, a GH receptor antagonist was without effect; the proapoptotic phenotype consisted in increased Bad, cytochrome c, caspase-9, and caspase-3. GH reduced apoptosis through p38 and p44/42 kinase pathways at young ages, whereas phosphatidylinositol-3-kinase was silent; on the contrary, the effects of GH on p38 and p44/42 kinase pathways were overcome by GH-independent stimuli in 9-month-old Acro. In addition, the antiapoptotic effect of GH was still present at this age as shown by phosphatidylinositol-3-kinase/Akt pathway activation. In conclusion, chronic GH excess reduced apoptosis at a young age, whereas its antiapoptotic action was overwhelmed in older animals by GH-independent mechanisms, leading to increased cell death.

Systemic overexpression of growth hormone (GH) in transgenic FVB/N inbred mice: an optimized model for holistic studies of molecular mechanisms underlying GH-induced kidney pathology

Transgenic mice overexpressing growth hormone (GH) display a plethora of phenotypic alterations and provide unique models for studying and influencing consequences of chronic GH excess. Since the first report on GH transgenic mice was published in 1982, many different mouse models overexpressing GH from various species at different levels and with different tissue specificities were established, most of them on random-bred or hybrid genetic background. We have generated a new transgenic mouse model on FVB/N inbred background, expressing bovine (b) GH under the control of the chicken beta-actin promoter (cbetaa). cbetaa-bGH transgenic mice exhibit ubiquitous expression of bGH mRNA and protein and circulating bGH levels in the range of several microg/ml, resulting in markedly stimulated growth and the characteristic spectrum of pathological lesions which were described in previous GH overexpressing mouse models. Importantly, a consistent sequence of renal alterations is observed, mimicking progressive kidney disease in human patients. The novel, genetically standardized GH transgenic mouse model is ideal for holistic transcriptome and proteome studies aiming at the identification of the molecular mechanisms underlying GH-induced pathological alterations especially in the kidney. Moreover, genetically defined cbetaa-bGH mice facilitate random mutagenesis screens for modifier genes which influence the effects of chronic GH excess and associated pathological lesions.

Growth Hormone Regulation of p85α Expression and Phosphoinositide 3-Kinase Activity in Adipose Tissue

Phosphoinositide (PI) 3-kinase is involved in insulin-mediated effects on glucose uptake, lipid deposition, and adiponectin secretion from adipocytes. Genetic disruption of the p85alpha regulatory subunit of PI 3-kinase increases insulin sensitivity, whereas elevated p85alpha levels are associated with insulin resistance through PI 3-kinase-dependent and -independent mechanisms. Adipose tissue plays a critical role in the antagonistic effects of growth hormone (GH) on insulin actions on carbohydrate and lipid metabolism through changes in gene transcription. The objective of this study was to assess the role of the p85alpha subunit of PI 3-kinase and PI 3-kinase signaling in GH-mediated insulin resistance in adipose tissue. To do this, p85alpha mRNA and protein expression and insulin receptor substrate (IRS)-1-associated PI 3-kinase activity were measured in white adipose tissue (WAT) of mice with GH excess, deficiency, and sufficiency. Additional studies using 3T3-F442A cells were conducted to confirm direct effects of GH on free p85alpha protein abundance. We found that p85alpha expression 1) is decreased in WAT from mice with isolated GH deficiency, 2) is increased in WAT from mice with chronic GH excess, 3) is acutely upregulated in WAT from GH-deficient and -sufficient mice after GH administration, and 4) is directly upregulated by GH in 3T3-F442A adipocytes. The insulin-induced increase in PI 3-kinase activity was robust in mice with GH deficiency, but not in mice with GH excess. In conclusion, GH regulates p85alpha expression and PI 3-kinase activity in WAT and provides a potential explanation for 1) the insulin hypersensitivity and associated obesity and hyperadiponectinemia of GH-deficient mice and 2) the insulin resistance and associated reduced fat mass and hypoadiponectinemia of mice with GH excess.

Long-term maintenance of the anabolic effects of GH on the skeleton in successfully treated patients with acromegaly

Introduction: The anabolic actions of growth hormone (GH) are well documented. In acromegaly, the skeletal effects of chronic GH excess have been mainly addressed by evaluating bone mineral density (BMD). Most data were obtained in patients with active acromegaly, and apparently high or normal BMD was observed in the absence of hypogonadism. Data on BMD are not available after successful treatment of acromegaly. Whether the positive effect of GH excess on bone mass is maintained in the long term after clinical and biochemical cure of acromegaly remains to be established. Patients and methods: In a cross-sectional study design, lumbar spine and femoral neck BMD was measured in 79 acromegalic patients cured or well controlled on octreotide treatment (45 male and 34 female patients; mean age 57±1 years). Successful treatment (by surgery, radiotherapy and/or use of octreotide) was defined as normal age-adjusted IGF-I. Mean time after biochemical remission was 10.2±7 years. Results: Normal or increased BMD was observed at the femoral neck and lumbar spine in both men and women in remission after treatment for acromegaly. Similar results were obtained in patients in remission for 5 years or longer. Osteoporosis was present in 15% of the patients, with similar prevalence in men and women. There was no relationship between BMD and duration or severity of GH excess before treatment, gonadal status and presence of pituitary hormone deficiencies. Pituitary irradiation was a strong negative predictor of bone mass at the femoral neck. Long-term bone loss was observed only at the femoral neck. Conclusion: Our data suggest that the anabolic effect of GH on trabecular and cortical bone remains demonstrable after remission of acromegaly, although it may not be maintained at cortical sites in the long term. In the present study, the lack of effect of gonadal status on BMD may be explained by the presence of only mild hypogonadism and by our policy of prompt hormonal replacement therapy for severe hypogonadism. The negative effect of pituitary irradiation on femoral neck BMD remains intriguing, although it is probably related to some degree of the diminished GH secretion frequently observed after this form of treatment.

Muscle mechano growth factor is preferentially induced by growth hormone in growth hormone-deficient lit/lit mice.

Two muscle insulin-like growth factor-I (IGF-I) mRNA splice variants (IGF-IEa and IGF-IEb) have been identified in rodents. IGF-IEb, also called mechano growth factor (MGF) has been found to be upregulated by exercise or muscle damage. Growth hormone (GH) is the principal regulator of IGF-I expression in several tissues including skeletal muscle. Therefore, we investigated the effect of chronic GH excess or disruption of GH receptor (GHR) signalling, and the acute effect of GH administration on expression of muscle IGF-I isoforms using transgenic mice that express bovine GH (bGH), GHR gene-disrupted (GHR-/-) mice and GH-deficient lit/lit mice before and after exogenous GH administration. MGF mRNA in skeletal muscle was increased in bGH mice whereas it was decreased in GHR-/- mice compared with control animals. Exogenous GH administration to dwarf lit/lit mice significantly increased muscle MGF but not IGF-IEa mRNA 4 h after treatment. Twelve hours after GH treatment, both MGF and IGF-IEa mRNAs in muscle were increased compared with vehicle-treated lit/lit mice. In contrast in GH-sufficient lit/+ mice, both MGF and IGF-IEa mRNAs were increased 4 h after and returned to the basal level 12 h after GH treatment. Hepatic IGF-I isoforms were regulated in parallel by GH. Thus, our results demonstrated that: (1) MGF mRNA in skeletal muscle is expressed in parallel with GH action; (2) MGF mRNA in muscle is produced preferentially in the situation of GH deficiency in contrast to the pattern in the GH-sufficient state; and (3) the induction of IGF-I isoforms by GH is tissue-specific.

Body composition, bone mass and microstructural analysis in GH-transgenic mice reveals that skeletal changes are specific to bone compartment and gender.

Experimental and clinical studies suggest that high serum levels of growth hormone (GH) increase cortical but not trabecular bone. We studied body composition and bone structure in transgenic mice (MT-bGH) with systemic overexpression of GH. Body composition was examined with dual-energy X-ray absorptiometry (DXA), ashing, and chemical analysis, and the femora with DXA and micro computerized tomography. The absolute fat and bone tissue contents were significantly higher in GH transgenic mice vs controls (P < or = 0.05), but no significant difference was noted when normalizing the values to body weight. Male transgenics displayed no change in apparent (volumetric) femoral bone density, relative cortical area and trabecular bone volume fraction. Female transgenic mice demonstrated an increase in apparent femoral density and in trabecular bone volume fraction (+130%; P < or = 0.01). The mineralized tissue matrix density was decreased in male and female transgenic mice (P < or = 0.05). The results show that chronic GH excess affects trabecular bone in a gender-specific manner and that bone changes depend on the compartment investigated.

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.

Sleep of transgenic mice producing excess rat growth hormone

The effects of chronic excess of growth hormone (GH) on sleep-wake activity was determined in giant transgenic mice in which the metallothionein-1 promoter stimulates the expression of rat GH (MT-rGH mice) and in their normal littermates. In the MT-rGH mice, the time spent in spontaneous non-rapid eye movement sleep (NREMS) was enhanced moderately, and rapid eye movement sleep (REMS) time increased greatly during the light period. After a 12-h sleep deprivation, the MT-rGH mice continued to sleep more than the normal mice, but there were no differences in the increments in NREMS, REMS, and electroencephalogram (EEG) slow-wave activity (SWA) during NREMS between the two groups. Injection of the somatostatin analog octreotide elicited a prompt sleep suppression followed by increases in SWA during NREMS in normal mice. These changes were attenuated in the MT-rGH mice. The decreased responsiveness to octreotide is explained by a chronic suppression of hypothalamic GH-releasing hormone in the MT-rGH mice. Enhancements in spontaneous REMS are attributed to the REMS-promoting activity of GH. The increases in spontaneous NREMS are, however, not consistent with our current understanding of the role of somatotropic hormones in sleep regulation. Metabolic, neurotransmitter, or hormonal changes associated with chronic GH excess may indirectly influence sleep.

Free radical defenses in the liver and kidney of human growth hormone transgenic mice: possible mechanisms of early mortality.

The long-term effects of growth hormone (GH) administration are unknown. Although limited data on its short-term effects purport health benefits, numerous detrimental effects are the consequence of chronically elevated GH. We used spectrophotometric assay and Western blot to determine the effects of chronic GH excess on hepatic and renal antioxidant enzymes (AOEs) in young and middle-aged PEPCK (phosphoenolpyruvate carboxykinase) hGH (human GH) transgenic mice. In the liver, glutathione peroxidase (GPx) was reduced in transgenics of both age groups, catalase was reduced only in young transgenics, and Cu-Zn superoxide dismutase (SOD) was similar to normal mice, but declined with age. In all groups, hepatic AOE activity correlated significantly with AOE level. In the kidney, AOEs in young transgenics were similar to those of normal mice. However, middle-aged transgenics showed reduced renal SOD and GPx activities when compared with young transgenic or middle-aged normal mice. Similarly, renal SOD and GPx levels in middle-aged transgenics were reduced when compared with those of middle-aged normal mice. AOE activity in the kidney correlated significantly with AOE protein level among middle-aged animals only. These data suggest the following: ((1)) GH excess is associated with early declines in SOD and GPx in the kidney and reductions of hepatic GPx at all ages examined, perhaps increasing the risk of free radical-induced damage to these tissues; ((2)) in the liver of young animals and in the liver and kidney of middle-aged animals, AOE activity reflects the amount of enzyme protein; and ((3)) age-related reductions in GPx in transgenics may be related to the increased incidence of liver tumors and renal failure in these animals.

Growth hormone upregulates gastrin and peptide YY gene expression.

The purpose of these studies was to examine the effects of excess growth hormone (GH) on gastrin and peptide YY (PYY) gene expression. Transgenic mice with the bovine GH gene linked to a mouse metallothionein I promoter were used as a model of chronic GH excess. Antral gastrin mRNA and peptide levels were elevated significantly (P < 0.05) in GH transgenic mice compared with wild type littermates. Ileal PYY mRNA and ileal and colonic PYY levels were significantly elevated in GH transgenic mice compared with wild type littermates. The elevations in gastrin and PYY gene expression in GH transgenic mice were independent of food intake. Serum concentrations of gastrin and PYY were also elevated in GH transgenic mice. Immunohistochemical analysis showed that the density of PYY-containing cells in the colon of GH transgenic mice and wild type littermates did not differ. In addition, the mRNA and protein levels of chromogranin A, a marker of endocrine cells, were not increased in the colon of GH transgenic mice. Together, these data indicate that GH, insulin-like growth factor I, or both can upregulate gastrointestinal gastrin and PYY gene expression directly.

Insulin resistance in rats harboring growth hormone—secreting tumors: Decreased receptor number but increased kinase activity in liver

Growth hormone (GH) is a potent antagonist of insulin action, and this resistance occurs primarily at a post-binding step(s). To elucidate the underlying mechanisms, the effects of chronic GH excess on the structure and function of insulin receptors partially purified from the liver were examined in rats harboring GH-secreting tumors. Insulin resistance was established in this animal model of GH hypersecretion by a hyperinsulinemic euglycemic clamp. Specific binding of 125I-insulin and receptor number were reduced in tumor animals by 40% and 62%, respectively, reflecting downregulation of the insulin receptor by hyperinsulinemia in these animals. Receptors from tumor animals showed a 50% increase in β-subunit phosphorylation and in the kinase activity toward the synthetic polypeptide Glu4: Tyr1 when measured in vitro in the absence of insulin; however, the incremental stimulation by insulin (170 nmol/L) of the phosphorylation of either the β-subunit or Glu4:Tyr1 was not different between control and experimental animals. There was no difference between the two groups in Glu4:Tyr1 phosphorylation measured after immunodepletion of receptors by antibodies to the insulin receptor, indicating that the observed alteration in the kinase activity of tumor animals was intrinsic to the insulin receptor. Exposure to chronic GH excess did not alter insulin receptor structure, as evidenced by electrophoretic mobility under reducing and nonreducing conditions. The enhanced basal kinase activity of the receptor from tumor animals may reflect a more highly phosphorylated state of the receptor (and hence elevated enzyme activity) in these animals due to elevated serum insulin levels. These results demonstrate that the hepatic insulin resistance in rats chronically exposed to GH excess is not due to impaired insulin receptor kinase activity.

Enhanced growth of small bowel in transgenic mice overexpressing bovine growth hormone

Background: Transgenic mice with a bovine growth hormone gene linked to a mouse metallothionein I promoter (growth hormone transgenics) are a model of chronic growth hormone excess. Methods: Growth of small bowel mucosa in ad libitum-fed growth hormone transgenics and wild type littermates and in growth hormone transgenics pair fed with wild-type littermates were compared. Results: In both groups, body weight and small bowel weight were greater in growth hormone transgenics. Similarly, mucosal mass was 50%–100% greater in growth hormone transgenics, and the effect was greatest in proximal bowel. Villus height, measured in jejunum, was also greater in growth hormone transgenics. Measurements of mucosal proliferation did not differ between the growth hormone transgenics and wild type. Abundance of insulinlike growth factor-I messenger RNA in bowel was greater in growth hormone transgenics. Conclusions: Chronic growth hormone excess results in increased growth of small bowel mucosa. This effect appears to be specific because it occurred in ad libitum-fed and diet-restricted growth hormone transgenics, influenced villus height, and was more pronounced in upper than lower small bowel. The effect of chronic growth hormone excess does not appear to be secondary to an increase in the rate of mucosal proliferation, suggesting an effect on lifespan of mucosal cells.