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Growth Hormone

Reduced longevity in untreated patients with isolated growth hormone deficiency

Besson a et al. J Clin Endocrinol Metab. 2003 Aug;88(8):3664-7

Increased longevity of hypopituitary dwarf mice and GH-resistance knockout mice appears to be in contrast with observations made in clinical practice. In humans, on one hand hypopituitarism and GH deficiency (GHD) are believed to constitute risk factors for cardiovascular disease and, therefore, early death. But on the other hand, patients with a PROP-1 G mutation, presenting with a combined pituitary-derived hormonal deficiency, can survive to a very advanced age, apparently longer than normal individuals in the same population. The aim of this study was to analyze the impact of untreated GHD on lifespan. Hereditary dwarfism was recognized in 11 subjects. Genetic analysis revealed an underlying 6.7-KB spanning deletion of genomic DNA encompassing the GH-1 gene causing isolated GHD. These patients (5 males and 6 females) were never treated for their hormonal deficiency and thus provide a unique opportunity to compare their lifespan and cause of death directly with their brothers and sisters (11 male and 14 females) as well as with the normal population (100 males and females). Although the cause of death did not vary between the 2 groups, median lifespan in the GH-deficient group was significantly shorter than that of unaffected brothers and sisters [males, 56 vs. 75 year (P <0.0001); females, 46-vs.80 year (P<0.0001)]. Therefore, with the wealth of information regarding the beneficial effects of GH replacement and the dramatic findings of this study, GH treatment in adult patients in adult patients from either childhood or adult onset GHD is crucially important.

GH Treatment of abdominally obese men reduces abdominal fat mass, Improves glucose and lipoprotein metabolism and reduces diastolic BP

Johannssen G et al. J Clin Edocrinol Metab 1997; 82:727-734

The most central findings in both GH deficiency in adults and the metabolic syndrome are the abdominal/visceral obesity and insulin resistance.  Abdominal obesity is associated with blunted GH secretion and demonstrated favorable effects on most of the features of GH-deficiency in adults, but it is not known whether GH can improve some of the metabolic aberrations observed in abdominal/visceral obesity.  30 men, 48-66yr old, with abdominal/visceral obesity were treated with recombinant human GH (rhGH) in a 9-month randomized, double/blind, placebo-control trial.  The daily dose of rhGH was 9.5 micrograms/kg.  Body fat was assessed from total body potassium, and abdominal sc and visceral adipose tissue was measured using computed tomography.  The glucose disposal rate (GDR) was measured during an euglycemic, hyperinsulinemic glucose clamp in response to the rhGH treatment total body fat and abdominal sc and visceral adipose tissue decreased by 9.2+/- 2.4%, 6.1+/- 3.2%, and 18.1+/- 7.6%, respectively.  After an initial decrease in the GDR at 6 weeks, the GDR increased in the rhGH-treated group as compared with the placebo/treated group (P<0.05).  The mean serum concentrations of total cholesterol (P<0.01) and triglyceride (P<0.05) decreased, whereas blood glucose and serum insulin concentrations were unaffected by the rhGH treatment.  Furthermore, diastolic blood pressure decreased and systolic blood pressure was unchanged in response to rhGH treatment.  This trial has demonstrated that GH can favorably affect some of the multiple perturbations associated with abdominal/visceral obesity.  This includes a reduction in abdominal/visceral obesity, and improved insulin sensitivity, and favorable effects on lipoprotein metabolism and diastolic blood pressure.

 

Risk factors of cardiovascular disease in GH-deficient adults with hypopituitarism; a preliminary report

Bohdanowicz-pawalk A et al. Med sci monit.2006 Feb;12(2);CR75-80.E pub 2206 Jan 26

Background; we estimated the influence of GH deficiency (GHD) in adults on chosen risk factors of cardiovascular disease and bone density.

Materials/Methods: 54 adults (mean age;50.4 years) with hypopituitarism were studied. We measured blood pressure, body mass index, waist to hip ratio, total body fat, and bone mineral density and the serum levels of lipids, glucose, insulin, pituitary hormones, estradiol, testosterone, and thyroxine, and the excretion of free cortisol in 24-hour urine. GHD was confirmed with the insulin intravenous test (IIT) with a GH response to IIT of <3 microgram/ml. The control group consisted of 73 healthy adults.

Results: increased levels of LDL-Cholesterol and triglycerides and decreased levels of HDL-cholesterol in the GHD group were observed. Fasting serum glucose and insulin levels were significantly higher in the GHD group than in controls. Significant differences in the QUICKI and FIRI were observed. 23%of hypopituitary patients were hypersensitive and 65% were obese. The percentage of total body fat was significantly higher in the studies group than in controls. 37% of the GHD patients were osteoporotic and 23% were osteopenic.

Conclusions: an atherogenic lipid profile, insulin resistance, obesity, and increased body and trunk fat in GHD adults may cause the higher risk of cardiovascular disease in these patients. GHD adults should receive human recombinant GH along with conventional replacement therapy. This may be a useful method in protecting against in early onset atherosclerosis and metabolic disturbances, and osteoporosis especially in young patients.

Growth hormone (GH) treatment reverses early atherosclerotic changes in GH deficient adults

Pfeifer M et al. J Clin Endocrinol Metab 84;453-457,1999.

Hypopituitary patients have increased mortality from vascular disease, and in these patients, early markers of atherosclerosis [increased carotid artery intima-media thickness (IMT) and reduced distensibility] are more prevalent. As GH replacement can reverse some risk factors of atherosclerosis, the present study examined the effect of GH treatment on morphological and functional changes in the carotid and brachial arteries of GH deficient adults.

There was a significant improvement in flow-mediated endothelium- dependant dilation (EDD) of the brachial artery at 3 months, which was sustained at 6 and 18 months of GH treatment (p<0.05). GH treatment increased high density lipoprotein cholesterol at 3 and 6 months, but did not reduce total or low density lipoprotein cholesterol and was without effect on lipoprotein (a). There was no correlation between plasma lipids and changes in IMT or EDD of the arteries examined.  In conclusion, GH treatment of hypopituitary GHD men reverses early morphological and functional atherosclerotic changes in major arteries and, if maintained, may reduce vascular morbidity and mortality. GH seems to act via IGF-I which is known to have important effects on endothelial cell function.

No evidence of tumor growth stimulation in human tumors in vitro following treatment with recombinant human growth hormone.

Fibeig HH et al. Anti-cancer drugs 2000 Sept; 11(8);659-64

In a recent study we demonstrated that recombinant human growth hormone (rhGH; Saizen) delayed tumor-induced cachexia in human tumor xenografts in vivo. Such a therapeutic effect could have a great impact in the supportive care of advanced cancer patients. Before large clinical studies are initiated possible growth stimulation should be excluded. This question was investigated In Vitro in 20 human tumor models, which had been established in nude mice. The effect of continuous exposure of rhGH was investigated at dose levels ranging from 0.3ng/ml up to 0.0Microg/ml in colorectal (n=2), gastric (n=1), non-small cell lung (n=4), small cell lung (n=1), mammary (n=3), ovarian (n=2), prostate (n=2) and renal cancers (n=2), and melanoma (n=3) using a modified Hamburger and Salmon clonogenic assay. The results show that there was neither tumor growth inhibition nor any evidence for tumor growth stimulation in any of the tumors studied. Therefore this pre clinical study in 20 human tumor models indicated no direct risk for tumor growth enhancement.

Growth hormone and adipocyte function in obesity.

Nam SY et al. Horm Res 2000 Jul; 53 Suppl S1: 87-97

In obesity growth hormone (GH) secretion is impaired which is considered a consequence rather than a cause of obesity. GH regulates the expression of GH receptor and the synthesis of insulin-like growth factor I (IGF-I) in adipocytes. Although GH hyposecretion in obesity may decrease the generation of IGF-I in each adipocyte, increased amounts of IGF-I and GH binding protein could be secreted from the excessively enlarged amounts of adipose tissue. This may contribute to the normal/high serum-IGF-1 and high GH-binding protein levels in obesity. Hyperinsulinemia and increased GH receptor activity may also affect the GH-IGF-I axis. Favorable effects of GH treatment have been observed in obese children and adults.  GH treatment decreases adipocity, reduces triglyceride accumulation by inhibiting lipoprotein lipase and enhances lipolysis both via increased hormone sensitive lipase activity and via induction of beta adrenoreceptors. GH treatment also has a favorable effect on obesity-associated dyslipidemia, but the effects on insulin sensitivity have been conflicting.

 

Low serum insulin-like growth factor 1 (IGF-1): a significant association with prostate cancer

Baffa R; Reiss K; El-Gabry EA; Sedor J; Moy ML; Shupp-Byrne D; Strup SE; Hauck WW; Baserga R; Gomella LG Department of Urology, Thomas Jefferson University, Kimmel Cancer Center, Philadelphia, Pennsylvania 19107, USA.

Tech Urol. 2000; 6(3):236-9 (ISSN: 1079-3259)

PURPOSE: Insulin-like growth factor 1 (IGF-1) is an important mitogenic and antiapoptotic peptide that affects the proliferation of normal and malignant cells. Contradictory reports on the association between serum IGF-1 level and prostate cancer have been highlighted in the recent literature. The purpose of this study was to investigate the relation between serum levels of IGF-1 and prostate cancer.

MATERIALS AND METHODS: We analyzed a population of 57 patients who underwent radical prostatectomy (RP) for adenocarcinoma. Serum samples were collected before RP (T0), 6 months after RP (T6), and from 39 age-matched controls. IGF-1 levels were determined by the active IGF-1 Elisa kit (Diagnostic Systems Laboratories, Inc.). Parallel samples were evaluated for prostate-specific antigen (PSA) levels. Data between groups were analyzed using Welch's t-test and levels before RP and after 6 months were compared by paired t-test.

RESULTS: The normal mean serum IGF-1 for case patients at T0 (124.6+/-58.2 ng/mL) was significantly lower than the control subjects (157.5+/-70.8 ng/mL; p = .0192). The normal mean serum IGF-1 for case patients at T0 (124.91+/-58.6 ng/mL) also was significantly lower when it was compared with the T6 group (148.49+/-57.2 ng/mL; p = .0056). No association was found between IGF-1 and PSA blood levels, or IGF-1 and patient weight (p = 0.2434). An inverse relation between IGF-1 levels and age in the normal controls (p = .0041) was observed.

 

A preliminary study of growth hormone therapy for Crohn’s disease

Slonim A E et al. N Engl J Med 2000 Jun 1;342 (22):1633-7

Background: Crohn’s disease is chronic inflammatory disorder of the bowel. In apreliminary study, we evaluated whether the administration of growth hormone (somatropin) as well as a high-protein diet would ameliorate the symptoms of the disease.

Methods: we randomly assigned 37 adults with moderate to severe active Crohn’s (CR) disease to 4 months of self administered injections of GH (loading dose 5mg/day subcutaneously for 1 week, followed by a maintenance dose of 1.5mg/day) or placebo. We instructed all patients to increase their protein intake to at least 2grams/kg of body weight/day. Patients continued to be treated by their usual physicians and receive other medications for Crohn’s.  The primary endpoint was the change in scores on the Crohn’s disease activity index from baseline to month 4. Scores can range from 0-600 with higer scores indicating more disease activity.

Results: at baseline, the mean (+/-SD) score on the Crohn’s Disease Activity Index was somewhat higher among the 19 patients in the GH group than among the 18 patients in the placebo group (287 +/- 134 vs 213 +/- 120, P=0.09). At 4 months the Crohn’s disease activity Index Score had decreased by a mean of 143 +/-144 points in the GH group, as compared with a decrease of 19 +/-63 points in the placebo group: P=0.004. Side effects in the GH group included edema in 10 patients, headache in 5 and usually resolved within the first month of treatment.

Conclusions: our preliminary suggests that GH may be of beneficial treatment for patients with Crohn’s disease.

Effect of recombinant human growth hormone in elderly osteoporotic women

Sugimoto T et al. Clin Endocrinol (Oxf) 1999 Dec; 51(6):715-724

Objective: bone mineral density and growth hormone secretion rate both decline during normal human ageing. We evaluated the effects of recombinant human GH (rhGH) on markers of body composition and bone turnover in an open study in eight elderly osteoporotic women aged 68-75 years (mean age 71).

Results: GH treatment caused a rapid (within 2 weeks) increase in serum levels of IGF-I and IGF-binding protein-3 (IGF-BP-3) which was sustained throughout the study. Markers of bone formation and resorption were both gradually increased up to 24 weeks of GH treatment. The bone formation markers, osteocalcin (OC) and bone alkaline phosphatase, remained high during GH treatment, while the bone resorption marker deoxypiridinoline (D-Pyr), tended to return to baseline levels after 24wks of GH therapy. GH treatment for 48wks caused a significant increase in hand grip and a decrease in waist/hip ratio.  The mean percentage changes of bone mineral density (BMD) of mid-radius and lumbar spine were +2.1% and +1.2%, respectively, although they were not statistically significant. GH treatment was well tolerated and no major side effects except mild edema and joint pain were found. Since GH treatment produced durable increases in bone formation markers, BMD continued to be monitored after discontinuation of GH treatment for another 48 weeks, during which significant increases in radial and lumbar BMD (8.1 +/-2.1 and 3.8 +/-1.4% above pre-treatment values, respectively) were reported.

Conclusion: the results indicate that GH attenuates the decrease in muscle strength and bone mass as well as the gain in abdominal fat with ageing in elderly women. The present data provide useful information about the application of GH treatment in elderly women.

Long-term experience with GH replacement therapy: efficacy and safety

Monson JP

Eur J Endocrinol. 2003; 148 Suppl 2:S9-14 (ISSN: 0804-4643)

Department of Endocrinology, Division of General and Developmental Medicine, St Bartholomew's Hospital, West Smithfield, London ECIA 7BE, UK. J.P.Monson@qmul.ac.uk

Demonstration of the long-term efficacy of GH replacement in GH-deficient adults has depended on a combination of single-centre studies and data from large multinational databases, which, by virtue of their size, are likely to detect rare adverse events and also permit analysis of mortality rates. The Pharmacia International Metabolic Surveillance (KIMS) study (a pharmacoepidemiological survey of the safety and efficacy of GH replacement in adults, sponsored by Pharmacia) is currently the largest database, with information on over 8000 patients from a total of 27 countries. Abundant epidemiological evidence confirms that hypopituitarism is associated with premature mortality, with an increase in cardiovascular and cerebrovascular disease as a primary underlying cause. Central adiposity, hyperlipidaemia, insulin resistance, and diabetes mellitus are common in adults with hypopituitarism. GH replacement is associated with improvements in central fat mass and mean reductions in serum total and low-density lipoprotein cholesterol which may be additive to those achieved with hydroxymethylglutaryl-coenzyme A reductase inhibitors.

These beneficial effects are maintained for at least 2 Years after initiation of therapy, as are reductions in central adiposity, with similar benefits seen in men and women when the GH dose is titrated to achieve a serum IGF-I between the median and the upper end of the age-related reference range. Fasting plasma glucose and glycated haemoglobin increase, usually within the reference range, during prolonged GH replacement, but do not tend to rise further above baseline in subjects with pre-existing impaired glucose tolerance. Bone remodelling increases during GH replacement therapy, but indices tend to return to baseline within 5 Years of commencing treatment. Bone mineral density increases in men whereas, in women, improvement is limited to stabilisation of bone density.

Data from the KIMS study demonstrate that prolonged GH replacement is associated with a reduction in the number of patients requiring assistance with daily living and a significant reduction in sick leave and hospital admissions. GH replacement therapy improves psychological well-being, particularly in those patients with the greatest deficit prior to treatment, with improvement maintained beyond 6 Months of therapy and sustained during long-term follow-up. Data from the KIMS population show that there is no increase in the overall occurrence of de novo neoplasia or the rate of regrowth of primary pituitary tumours. There is an apparent increase in intracranial neoplasia, which may be an artefact of comparing a surveillance population with general population data. Unlike mortality in untreated hypopituitary GH-deficient patients, mortality in the KIMS study is currently similar to that predicted for the normal population.

Possible role of human growth hormone in penile erection

J Urol. 2000; 164(6):2138-42 (ISSN: 0022-5347)

Becker AJ; Uckert S; Stief CG; Truss MC; Machtens S; Scheller F; Knapp WH; Hartmann U; Jonas U
Department of Urology, Hannover Medical School, Hannover, Germany.

PURPOSE: Treatment with recombinant human growth hormone in adult patients with growth hormone deficiency increases nitric oxide and cyclic guanosine monophosphate (cGMP). We examined the functional in vitro effects of recombinant human growth hormone on tissue tension and cyclic nucleotide levels of human corpus cavernosum and detected changes in growth hormone in the cavernous and peripheral blood during different phases of penile erection.

MATERIALS AND METHODS: Relaxant responses of human corpus cavernosum were investigated using the organ bath technique. Tissue levels of cGMP were determined by a specific radioimmunoassay after dose dependent exposition of isolated human corpus cavernosum strips to recombinant human growth hormone. In 35 healthy potent volunteers blood samples were obtained simultaneously from the corpus cavernosum and cubital vein during different functional conditions of the penis, including flaccidity, tumescence, rigidity and detumescence.Penile erection was induced by audiovisual and tactile stimulation. Serum growth hormone was determined by an immunoradiometric assay.

RESULTS: Recombinant human growth hormone elicited dose dependent relaxation of human corpus cavernosum strips in vitro. The relaxing potency of recombinant human growth hormone was paralleled by its ability to elevate intracellular levels of cGMP. In vivo the peripheral growth hormone serum profile of the respective penile conditions did not significantly differ from those of cavernous serum. The main increase in growth hormone to greater than 90% was determined during developing penile tumescence, followed by a transient decrease afterward.

CONCLUSIONS: These results suggest that penile erection may probably be induced by growth hormone through its cGMP stimulating activity on human corpus cavernosum smooth muscle.