Growth Hormone Replacement Therapy In Adults Research Articles

Growth Hormone Replacement Therapy in Patients without Adult Growth Hormone Deficiency: What Answers Do We Have So Far?

Growth hormone (GH) and insulin-like growth factor 1 (IGF-1) have been suggested as “anti-aging” therapies, or for improving quality of life with aging. In this study, we focus on the actions of GH in the main organs and organ systems of the human body, like skeletal muscle, bones and brain, particularly in regard to data and research on the use of GH replacement therapy in adults without growth hormone deficiency, especially elderly patients. Several different studies have been carried out to show what the effects and side effects of GH replacement in healthy people and what would be the impact in quality of life and life span. In this review, we demonstrate what answers we have so far about the effects of GH replacement in many organs and systems in healthy people.

Predictors of the effects of 4 years of growth hormone replacement on bone mineral density in patients with adult‐onset growth hormone deficiency – a KIMS database analysis

Growth hormone (GH) replacement may increase bone mineral density (BMD) in GH-deficient (GHD) adults. The goal of this study was to identify predictors of BMD response to GH replacement in GH naïve adults. This was a retrospective analysis of data extracted from KIMS (Pfizer International Metabolic Database), an international pharmacoepidemiological survey of adult GHD patients from 31 countries. A total of 231 GH naive adults were identified (115 women and 116 men) who had BMD measured on the same densitometer in the lumbar spine (LS) and/or femoral neck (FN) both at baseline and after 4 years of GH replacement. After 4 years, there was a median (10th, 90th percentile) 4·6% (-5·2%, 12·2%) increase in LS BMD over baseline (P = 0·0001). There was a positive correlation between per cent change in LS BMD and age at the onset of pituitary disease (r = 0·25, P = 0·001). There was no change in FN BMD over baseline [0·0% (-7·3%, 8·5%)]. On multivariate analysis, older age at the onset of pituitary disease predicted a greater increase in LS BMD on GH replacement (r = 0·55, P < 0·0001). In a population of GH naïve adults, GH replacement led to a significant increase in LS BMD over baseline, but no change in FN BMD. The potential for greater BMD improvement on GH replacement therapy in adults with disease of later onset should be considered when making treatment decisions in this patient population.

How useful are serum IGF-I measurements for managing GH replacement therapy in adults and children?

The optimal dosing of growth hormone (GH) therapy is challenging due to high inter-individual variability in subcutaneous GH absorption and sensitivity to the drug. Optimal dosing would maximize patient gains in height, body composition, and metabolic outcomes while minimizing GH adverse events. The pulsatile secretion of GH, however, does not allow direct assessment of circulating GH levels as a measure of response to GH therapy. Insulin-like growth factor (IGF-I), a key marker of GH activity, has been shown to be useful in monitoring and adjusting GH dose during treatment of GH deficiency (GHD). Traditionally, monitoring IGF-I levels in response to GH therapy has been recommended for assessment of treatment compliance and safety. More recently, GH treatment guidelines have stated that IGF-I levels should also be used to guide GH dosing. This review examines whether individualized GH dosing based on the IGF-I response to GH therapy provides a better method for determining the GH replacement needs of pediatric and adult patients compared with conventional GH dosing, and whether IGF-I-based dosing improves outcomes such as height and body composition, with reduced side effects. Because IGF-I measurement presents its own difficulties, the current state of IGF-I assays is also discussed. The reviewed studies show that the use of GH dose adjustments based on IGF-I responses to GH therapy successfully reduces adverse events in adults with GHD and results in greater positive height attainment in children, without increasing adverse events. Long-term outcome studies are needed, as are internationally accepted guidelines for IGF-I measurement.

The benefit of long-term growth hormone (GH) replacement therapy in hypopituitary adults with GH deficiency: Results of the German KIMS database

Objective To evaluate the treatment effects of long-term growth hormone (GH) replacement therapy in adults with GH deficiency (GHD) who were followed in KIMS Germany (Pfizer International Metabolic Database), a national surveillance study. Design The analysis was performed using baseline and long-term data (range: 4–10 years) of 440 consecutively documented patients (216 women and 224 men) with GHD, aged 20 to 49 years, enrolled in KIMS Germany. Serum insulin-like growth factor I (IGF-I), fasting blood glucose, fasting serum total cholesterol and low-density lipoprotein cholesterol (LDL-C) as well as body mass index (BMI), waist circumference (WC) and hip circumference (HC) at baseline and at last visit were studied. Furthermore, QoL-AGHDA score was determined to assess quality-of-life (QoL). Results The mean dose of GH over all years was 0.41 mg per day in women and 0.37 mg per day in men. IGF-I and IGF-I SDS levels (standard deviation score) increased significantly (p < 0.001) during GH treatment. The QoL-AGHDA score decreased significantly (p < 0.001), indicating long-lasting improvement in QoL. In total cholesterol, LDL-C and fasting blood glucose, no significant changes were found. Only six patients developed type 2 diabetes during follow-up. Females and males similarly increased significantly in BMI, WC and HC. During GH treatment, recurrences of pituitary or central nervous system tumours or further de novo neoplasia were reported in 6 or 11 patients, respectively. The number of the most frequently reported GH treatment-associated adverse events was low. Conclusion These observational data show long-term beneficial effects of GH replacement therapy on QoL and show no significant effects on total cholesterol, LDL-C or BMI, WC and HC. Additionally, our data indicate that GH replacement therapy in adults is well tolerated.

Influence of the Exon 3-Deleted/Full-Length Growth Hormone (GH) Receptor Polymorphism on the Response to GH Replacement Therapy in Adults with Severe GH Deficiency

There is considerable individual variation in the clinical response to GH replacement therapy in GH deficient (GHD) adults. Useful predictors of treatment response are lacking. The aim of the study was to assess the influence of the exon 3-deleted (d3-GHR) and full-length (fl-GHR) GH receptor isoforms on the response to GH replacement therapy in adults with severe GHD. A total of 124 adult GHD patients (79 men; median age, 50 yr) were studied before and after 12 months of GH therapy. GHD patients were divided into those bearing fl/fl alleles (group 1) and those bearing at least one d3-GHR allele (group 2), and the genotype was related to the effects of GH therapy on IGF-I levels and total body fat (BF). GH dose was individually titrated to obtain normal serum IGF-I levels. GHR genotype was determined by PCR amplification, IGF-I levels by immunoassay, and BF by a four-compartment model. Seventy-two (58%) patients had fl/fl genotype and were classified as group 1, whereas 52 (42%) had at least one d3-GHR allele and were classified as group 2 (40 were heterozygous and 12 were homozygous). At baseline, there were no significant differences in the study groups. Changes in IGF-I and BF after 12 months of GH treatment did not differ significantly between the two genotype groups. The presence of d3-GHR allele did not influence the response to GH replacement therapy in our cohort of adults with severe GHD.

Growth Hormone Deficiency in Adults

Growth hormone (GH) has been in clinical use for almost 40 years to promote linear growth in growth hormone deficient children. Treatment has usually been stopped after the epiphyseal plates have fused or when the person reaches a proper height. Previously, GH replacement therapy in adults was not deemed clinically indicated. GH-deficiency in adults is now accepted as a clinical entity, manifested by cardiovascular dysfunction, dyslipidemia, reduced capacity for exercise and muscular weakness, altered body composition, increased prevalence of osteoporosis, and impaired psychological well-being. The treatment of adults used to be unrealistic, because of the limited supply of human pituitary-derived GH. Moreover, the risk of transferring Creutzfeldt-Jakobs disease led to a stop in the therapeutic use of pituitary GH preparations. The availability of recombinant human prion-free GH has made replacement therapy possible in GH-deficient adults. In this review, the GH deficiency syndrome in adults is described, together with the results of recent clinical studies of GH replacement treatment in adults.

Growth hormone replacement therapy in adults with growth hormone deficiency: benefits and cost-effectiveness

In recent years, growth hormone deficiency in adults has been accepted as a clinical entity. Although beneficial effects of growth hormone replacement therapy (GHRT) in adults – including improvements in body composition, lipid profile, quality of life and bone mineral density – have been shown in many studies, there are still controversies and ongoing debates regarding GHRT in adults. It seems that this subject will continue to be a hot topic in the near future. Therefore, the aim of this review is to re-evaluate the current understanding on GHRT in adults in the light of recent data. Additionally, the clinical aspects, risks, benefits and cost–effectiveness of GHRT are summarized.

The influence of growth hormone (GH) therapy on cardiac performance in patients with childhood onset GH deficiency

Objective: There is accumulating evidence that growth hormone (GH) plays an important role in the maintenance of normal cardiac growth and function. Abnormalities in left ventricular diastolic function and impairment of systolic function have also been reported in patients with GHD. In this study, we investigated the effects of 12 months GH replacement therapy on cardiac functional indices measured by echocardiography, the ECG stress test and SPECT imaging. Design: Sixteen patients with childhood onset GHD (age 42.3 ± 13.1 years, 10 males) were investigated before, and after, 12 months of GH treatment at a dosage of 0.02 IU/kg/day (7 μg/kg/day). The GH administration resulted in serum IGF-I levels within the normal range in all the patients. The following investigations were performed initially and after 12 months: electrocardiography, systolic and diastolic blood pressure, heart rate measurement, a complete Doppler-echocardiographic examination, treadmill exercise test and Technetium-99m sestamibi single-photon emission computer tomography (SPECT) imaging at rest and after exercise. Results: Echocardiography showed improvement in left ventricular systolic function after GH treatment. End-systolic volume fell from 29.9 ± 12.4 to 24.4 ± 6.9 ml ( p < 0.05) and the ejection fraction increased from 56.2 ± 7.2% to 63.2 ± 6,1% ( p < 0.01). Left ventricular diameter and wall thickness did not change after GH treatment, although systolic increase in interventricular septum thickness (IVS%) and systolic increase in posterior wall thickness (PWT%) increased significantly (IVS% 52.2 ± 31.9% vs. 67.3 ± 30.4% and PWT% 48.7 ± 20.2% vs. 58.0 ± 17.7%, p < 0.01, p < 0.01, respectively). Contractile function, measured at midwall level, improved as left ventricular midwall fractional shortening (MWS) increased (16.11 ± 6.55 vs. 23.30 ± 5.89 %, p < 0.01) and stress-corrected MWS increased between the examinations performed before and after 12 months of GH treatment (90.97 ± 36.66 vs. 133.10 ± 32.84 %, p < 0.01). Diastolic function did not change, as assessed by early diastolic flow ( E), diastolic flow secondary to atrial contraction ( A), or the E/A ratio. The LV-mass index did not change significantly after GH treatment (78.4 ± 22.1 vs. 81.9 ± 21.1 g/m 2). After 12 months of GH treatment the myocardial performance index (MPI) decreased significantly from 0.483 ± 0.146 at baseline to 0.410 ± 0.086 at the end of the study ( p < 0.05). There was a trend towards an increase in exercise duration and capacity after GH treatment but the differences did not reach levels of statistical significance. SPECT imaging basally and after 12 months showed normal myocardial perfusion at rest and after exercise in all the patients. In conclusion, GH replacement therapy in adults with GHD demonstrated the beneficial effects on cardiac functions.

Long-Term Monitoring of Insulin-Like Growth Factor I in Adult Growth Hormone Deficiency: A Critical Appraisal

Serum insulin-like growth factor I (IGF-I) levels predominantly reflect the hepatic effect of growth hormone (GH). Compared with serum GH levels, which reflect pulsatile GH secretion, serum IGF-I levels exhibit no major diurnal variation and thus provide a better estimate of integrated GH secretion in an individual patient. Measurement of serum IGF-I levels allows reliable identification of states of GH excess. In contrast, in a large proportion of adults with severe GH deficiency, serum IGF-I levels are within the normal range. Serum IGF-I levels increase markedly in response to GH administration and are often used as a surrogate variable for overall responsiveness to such treatment. Current data, however, suggest a poor relationship between changes in or levels of IGF-I and efficacy variables such as body composition, muscle function and well-being. The use of serum IGF-I as a guide during dose titration in the initial phase of treatment and during long-term monitoring of GH replacement therapy in adults, and its use as a safety marker or predictor of future morbidity and mortality are discussed here.

Growth Hormone Therapy in Adults

The importance of growth hormone (GH) deficiency in adults became evident 10 to 15 years ago, when the first clinical studies on GH replacement therapy in adults were published. Since then, a number of studies have been reported showing that GH replacement therapy can improve this condition. Adult GH deficiency (GHD) is now recognized as a specific clinical syndrome and the first reports of long-term use of GH (up to 10 years) are now being published. The aim of this paper was to review the accumulated data on the various clinical aspects of adult GHD.

Effects of two years of growth hormone (GH) replacement therapy on bone metabolism and mineral density in childhood and adulthood onset GH deficient patients.

The aim of the current study was to evaluate bone metabolism and mass before and after 2 years of GH replacement therapy in adults with childhood or adulthood onset GH deficiency. Thirty-six adults with GH deficiency, 18 with childhood onset, 18 with adulthood onset GH deficiency and 28 sex-, age-, height- and weight-matched healthy subjects entered the study. Biochemical indexes of bone turnover such as serum osteocalcin, serum carboxyterminal telopeptide of type-I procollagen, urinary hydroxyproline/creatinine and deoxypyridinoline/creatinine, of soft tissue formation such as aminoterminal propeptide of type-III and bone mineral density were evaluated. Childhood onset GH deficient patients had significantly decreased bone (osteocalcin: 2.5+/-1.3 vs 6.6+/-4.8 mcg/l, p<0.001) and soft tissue formation (aminoterminal propeptide of type III: 273+/-49 vs 454+/-23 U/I, p<0.001) indexes and normal bone resorption indexes (serum carboxyterminal telopeptide of type-I procollagen: 105+/-48 vs 128+/-28 mcg/l p=NS; urinary hydroxyproline/creatinine: 0.19+/-0.16 vs 0.28+/-0.16 mmol/mol, p=NS; urinary deoxypyridinoline/creatinine: 21 +/-10 vs 25+/-8 mcmol/mol, p=NS) compared to healthy subjects. On the contrary, no significant difference in bone turnover indexes between adulthood onset GH deficient patients and healthy subjects was found. Moreover, significantly decreased bone mineral density at any skeletal site and at whole skeleton was found in GH deficient patients compared to healthy subjects (e.g. femoral neck: 0.74+/-0.13 vs 0.97+/-0.11 g/cm2, p<0.001). In addition, a significant reduction of bone mineral density was found in childhood compared to adulthood onset GH deficient patients at any skeletal site, except at femoral neck. After 3-6 months of treatment, both groups of patients had a significant increase in bone turnover and in soft tissue formation. In particular, in childhood onset GH deficient patients after 3 months osteocalcin increased from 2.5+/-1.3 to 7.9+/-2.1 mcg/l, p<0.001 aminoterminal propeptide of type-III from 273+/-49 to 359+/-15 U/I p<0.001; serum carboxyterminal telopeptide of type-I procollagen from 105+/-48 to 201+/-45 mcg/l, p<0.001; urinary hydroxyproline/creatinine from 0.19+/-0.16 to 0.81+/-0.17 mmol/mol, p<0.001; urinary deoxypyridinoline/creatinine from 21 +/-10 to 54+/-20 mcmol/mol, p<0.001; while in adulthood onset GH deficient patients after 6 months osteocalcin increased from 4.2+/-3.6 to 6.5+/-1.9 mcg/l, p<0.05; aminoterminal propeptide of type- III from 440+/-41 to 484+/-37 U/I, p<0.05; serum carboxyterminal telopeptide of type-I procollagen from 125+/-40 to 152+/-22 mcg/l, p<0.05; urinary hydroxyproline/creatinine from 0.24+/-0.12 to 0.54+/-0.06 mmol/mol, p<0.001; urinary deoxypyridinoline/creatinine from 23+/-8 to 42+/-5 mcmol/mol, p<0.001. No significant difference in bone turnover between pre- and post-treatment period was found after 18-24 months of GH therapy. Conversely, bone mineral density was slightly reduced after 3-6 months of GH therapy, while it was significantly increased after 18-24 months. In fact, femoral neck bone mineral density values significantly rose from 0.74+/-0.13 g/cm2 to 0.87+/-0.11 g/cm2 (pre-treatment vs 2 years of GH treatment values). In conclusion, patients with childhood or adulthood onset GH deficiency have osteopenia that can be improved by long-term treatment with GH.

Dosing, Monitoring, and Safety of Growth Hormone-Replacement Therapy in Adults With Growth Hormone Deficiency

Dosing, Monitoring, and Safety of Growth Hormone-Replacement Therapy in Adults With Growth Hormone Deficiency

Growth hormone treatment for growth hormone deficient adults.

Growth hormone (GH) deficiency in adults is now recognized as a clinical syndrome with characteristic signs and symptoms. Numerous trials with daily subcutaneous biosynthetic human growth hormone (hGH) have been conducted in this patient group. Generally, improvements in insulin-like growth factor levels, decreases in total fat mass and increases in lean body mass are recorded with no overall effect on total body weight. Variable effects on serum cholesterol, bone mineral density and quality of life have also been reported. The true place of GH replacement therapy in adults has yet to be defined. Several questions relating to the dose, duration of treatment, long-term side-effects, quality of life changes and health economic implications of treatment still need to be assessed.

Bone turnover and bone mineral density in young adult patients with panhypopituitarism before and after long-term growth hormone therapy

We examined the effects of biosynthetic growth hormone (GH) on biochemical indices of bone turnover and on bone mineral density in a group of GH-deficient adults. Thirteen patients (eight males and five females) aged 24 +/- 5 years (range 16-35) were studied before and 12 and 24 months after GH treatment (0.1 IU.kg-1 day-1, 6 days a week). Serum levels of insulin-like growth factor I (IGF-I), calcitonin, parathyroid hormone, alkaline phosphatase, intact osteocalcin, fasting urinary hydroxyproline/creatinine ratio and bone mineral density (BMD), measured at the lumbar spine by dual-photon absorptiometry, were evaluated. After 12 months of treatment, IGF-I, alkaline phosphatase, osteocalcin and the fasting urinary hydroxyproline/creatinine ratio increased significantly. However, after 24 months of therapy, serum levels of osteocalcin decreased to pretreatment values while IGF-I, fasting urinary hydroxyproline/creatinine ratio and alkaline phosphatase remained elevated significantly. No changes were found in parathyroid hormone and calcitonin plasma levels or in BMD either after 12 or 24 months of treatment. These data demonstrate that GH, at the dosage that we used, activates bone turnover during 24 months of therapy in adults with panhypopituitarism, even if a downward trend for osteocalcin became apparent at 24 months. However, this activation in bone turnover was not accompanied by an increase in BMD. We can hypothesize that GH, at the relatively high dosage used, may stimulate osteoclastic activity to a greater extent than osteoblastic activity. It is probable that the dose of GH replacement therapy in adults plays a key role.