Growth Hormone Substitution Therapy Research Articles

Clinical, Diagnostic, and Therapeutic Aspects of Growth Hormone Deficiency During the Transition Period: Review of the Literature.

The role of growth hormone (GH) during childhood and adulthood is well established. Once final stature is reached, GH continues to act during the transition, the period between adolescence and adulthood in which most somatic and psychological development is obtained. The achievement of peak bone mass represents the most relevant aspect of GH action during the transition period; however, equally clear is its influence on body composition and metabolic profile and, probably, in the achievement of a complete gonadal and sexual maturation. Despite this, there are still some aspects that often make clinical practice difficult and uncertain, in particular in evaluating a possible persistence of GH deficiency once final stature has been reached. It is also essential to identify which subjects should undergo re-testing and, possibly, replacement therapy, and the definition of unambiguous criteria for therapeutic success. Moreover, even during the transition phase, the relationship between GH substitution therapy and cancer survival is of considerable interest. In view of the above, the aim of this paper is to clarify these relevant issues through a detailed analysis of the literature, with particular attention to the clinical, diagnostic and therapeutic aspects.

Results of growth hormone substitution therapy in children with brain tumours

Aim of the study. To estimate the effectiveness and safety of substitution therapy with growth hormone (GH) in children with various brain tumours. Materials and methods. The study involved 68 patients admitted to N.N. Burdenko Institute of Neurosurgery between 2001 and 2011 including 35 ones with craniopharyngioma, 18 with medulloblastoma, and 15 with germ cell tumours (GCT) in the chiasmosellar region. All patients suffered growth hormone insufficiency and received GH replacement therapy. Their antropometric characteristics (height and growth rate) and IGF-1 levels were measured before, 6 and 12 months after the onset of the treatment. The doses of GH varied from 0.03 to 0.034 mg/kg/day. Results. The substitution therapy with GH resulted in an increase of the growth rate in patients with craniopharyngioma from 2.3±1.6 to 9.4±1.9 cm/year (p<0.001), in those with GCT from 1.2±0.9 to 7.4±2.6 cm/year (p=0.01), and in patients with medulloblastoma from 2.3±1.5 to 6.2±2.6 cm/year (p<0.01). The growth rate in patients treated by spinal irradiation was lower than that in those given no such treatment (6.0±2.3 cm/year and 9.2±2.1 cm/year respectively; p<0.001). The tumour recurred in eight of 35 (23%) patients with craniopharyngioma during GH therapy. The frequency of relapses was not significantly different from that in patients who did not receive growth hormone. Patients with medulloblastoma and GCT did not develop relapses. No adverse reactions to GH therapy were documented in this study.

Growth hormone replacement—implications for bone health

Hypopituitarism, including growth hormone (GH) deficiency, is accompanied by increased morbidity and mortality. These factors may be due to the underlying disease and treatments such as surgery or radiotherapy, but can also arise from GH substitution therapy at nonphysiological doses. Nevertheless, emerging long-term data on GH replacement therapy now indicate benefits for bone health.

Growth hormone and the cardiovascular system

This review highlights current concepts of physiological and pathophysiological effects of growth hormone on the heart. The data of international clinical studies concerning the influence of GH deficit and excess on the cardiovascular system are discussed with special reference to such clinical conditions as somatotrophic pituitary insufficiency and acromegaly. Result of analysis of parameters of the cardiovascular system in the patients receiving growth hormone substitution therapy for somatotrophic insufficiency and GH-suppressive therapy of acromegaly are presented

Hepatoblastoma in a 4‐year‐old girl with Fanconi anaemia

Hepatoblastoma was diagnosed in a 4-year-old girl receiving growth hormone substitution therapy for short stature. Owing to multiple congenital malformations, VACTERL-H (vertebral, anal, cardiac, tracheal, renal and limb anomalies with hydrocephalus) association had been suggested. Elevated chromosomal breakage rates and G2 phase arrest induced by DNA-crosslinking agents in cellular assays confirmed the diagnosis of Fanconi anaemia (FA), a tumour susceptibility syndrome known to be associated with hepatocellular carcinoma following androgen therapy. Subsequent genotyping revealed biallelic mutations in the FANCD1/BRCA2 gene. We describe the first case of hepatoblastoma in a patient with FA to raise awareness of this tumour type in the close clinical observation of early cancer-prone forms of this condition, particularly in the presence of FANCD1/BRCA2 mutations. The present case also underscores the importance of FA testing in patients with VACTERL(-H).

Effects of 10 years of growth hormone (GH) replacement therapy in adult GH‐deficient men

GH-deficient adults have changes in body composition, bone mineral density (BMD) and lipid profile that can be altered by GH substitution. However, long-term data on GH substitution (up to 10 years of follow-up) are limited. The effects of 10 years of GH replacement therapy on BMD, body composition, bone parameters, serum lipids and glucose metabolism were studied. Twenty-three childhood-onset GH-deficient men (mean age at baseline 28.6 years) were studied during 10 years of GH substitution therapy. A group of 19 age-matched healthy men served as a control group for BMD measurements at baseline and after 10 years. BMD of the lumbar spine increased during the 10 years of GH therapy. Bone markers and BMD in the hip increased during the first 5 years of GH therapy, but were not different from baseline after 10 years. BMD changes over time in the lumbar spine and femoral neck were significantly different in the patients compared to the controls. After 10 years the difference between the groups had decreased, but BMD was still higher in the controls than in the patients. Lipid profile had improved after 10 years of GH therapy, but body mass index (BMI), waist-hip ratio (WHR), fasting glucose and glycosylated haemoglobin (HbA1c) had increased compared to baseline. This long-term follow-up study found that 10 years of GH substitution in GH-deficient men causes sustained improvements in BMD in the lumbar spine and lipid profile but not in body composition.

Growth Hormone Receptor mRNA Expression in Non-Functioning and Somatotroph Pituitary Adenomas: Implications for Growth Hormone Substitution Therapy?

The use of growth hormone (GH) in patients with GH deficiency induced by pituitary adenoma is widely accepted, but the safety of this mitogenic hormone, particularly in patients with residual tumor after neurosurgery, continues to be a concern. Since the mitogenic potency of GH is dependent upon the presence of the GH receptor (GH-R) and the subsequent IGF-1/IGF receptor (IGF-1-R) system we investigated the expression of the members of the growth hormone cascade in endocrine inactive and GH-producing pituitary adenomas. Tissue specimens of 18 clinically non-functioning pituitary adenomas and 6 GH-producing adenomas were collected following transsphenoidal surgery while normal cadaver pituitary glands served as controls. After RNA extraction, semi-quantitative RT-PCR amplification with specific primers for GH, GH-R, IGF-1 and IGF-1-R was performed. Applying this sensitive RT-PCR based approach, GH-R expression was demonstrated in all normal pituitaries, most inactive adenomas (94%), and the majority of GH-producing adenomas (66%). Both IGF-1 and IGF-1-R mRNA was detectable in the majority of inactive (72% and 77%, respectively) and somatotrophic adenomas (83% and 83%). While IGF-1-R mRNA was expressed in all normal pituitary specimen studied, IGF-1 was detectable in only 55% of them. In summary, expression of members of the GH-IGF-1 cascade could be demonstrated in a substantial subset of patients with non-functioning and GH-producing pituitary adenomas. These factors might serve as a substrate for the transduction of mitogenic effects of GH on remnant pituitary tumors during GH replacement therapy. Therefore, GH therapy should be carefully considered and patients on GH therapy kept under close observation.

Carotid artery intima-media thickness and cardiac mass after the growth hormone substitution therapy

Carotid artery intima-media thickness and cardiac mass after the growth hormone substitution therapy

Gene expression of a truncated and the full-length growth hormone (GH) receptor in subcutaneous fat and skeletal muscle in GH-deficient adults: impact of GH treatment.

In humans at least two GH receptors are significantly expressed. One is the full-length receptor (GHR); the other is a truncated form (GHRtr), that lacks most of the intracellular domain. This receptor may inhibit the action of the full-length receptor. Circulating GH-binding protein (GHBP) is a proteolytically cleaved product from both of these receptors. The clinical relevance of the different receptor types is unknown. We examined the gene expression of GHR and GHRtr in human adipose tissue and skeletal muscle and the influence of GH treatment on this expression. Furthermore, we studied the relationship of circulating GHBP and body composition to GHR and GHRtr gene expression. Eleven adult GH-deficient patients were studied before and after 4 months of GH substitution therapy. Abdominal fat obtained by liposuction and femoral muscle biopsies were taken at baseline and after 4 months. Gene expression of GHR and GHRtr in adipose tissue and skeletal muscle was determined and expressed relative to the expression of beta-actin. Gene expression of GHR in abdominal sc adipose tissue was not altered, whereas the expression of GHRtr increased significantly. In skeletal muscle inverse changes were seen in the expression of messenger ribonucleic acid (mRNA) levels for the two GH receptor forms: expression of GHR increased significantly, whereas mRNA levels for GHRtr decreased. As expected, body composition changed with reduction of body fat mass after 4 months of GH treatment. Levels of circulating GHBP decreased significantly. We conclude that GH treatment in GH-deficient adults changes the expression of mRNA for GHR and GHRtr in adipose tissue and skeletal muscle. Whether these changes are responsible for the observed changes in body composition in response to GH treatment and the observed changes in levels of circulating GHBP, however, needs further elucidation.

Growth hormone, insulin-like growth factor I and cognitive function in adults.

This review focuses on the possible contribution of the growth hormone (GH)-insulin-like growth factor I (IGF-I) axis to cognitive function. Binding sites for GH and IGF-I are found in various areas of the brain. Their distribution suggests that GH and IGF-I contribute to the function of the hippocampus, a brain structure important for the maintenance of cognitive functions such as learning and memory. Evidence for cognitive deficits in GH-deficient individuals has been found in various studies, some of which have shown that these deficits can be reversed by GH substitution therapy. In addition to examining conditions of GH deficiency, this article reviews studies evaluating the correlation between the cognitive deficits associated with ageing and age-related decreases in GH or IGF-I secretion. Based on the available data, one might hypothesize that relative GH or IGF-I deficiency could contribute to the deterioration of cognitive functions observed in the elderly.

Effects of Growth Hormone Replacement Therapy on Bone Markers and Bone Mineral Density in Growth Hormone-Deficient Adults

During the 1990s, interest in the effects of growth hormone deficiency (GHD) in adults increased, and several studies were performed to evaluate the effects of growth hormone (GH) substitution therapy in these patients. Because adults with GHD have reduced bone mineral density (BMD) and an increased risk of fractures, the effects of GH replacement therapy on bone metabolism have been evaluated in long-term studies. A universal finding is that the serum and urinary levels of biochemical bone markers increase during GH substitution therapy, and these increases are dose dependent. After years of GH substitution therapy, the levels of biochemical bone markers remain elevated, according to some studies, whereas other studies report that these levels return to baseline. BMD of the spine, hip and forearm increase after 18–24 months of treatment. Bone mineral content (BMC) increases to a greater extent than BMD, because the areal projection of bone also increases. This difference could be caused by increased periosteal bone formation, but a measurement artefact resulting from the use of dual-energy X-ray absorptiometry cannot be excluded as a possible explanation. One study of GH-deficient adults found that, after 33 months of GH treatment, BMD and BMC increased to a greater extent in men with GHD than in women. There is also a gender difference in the increases in serum levels of insulin-like growth factor I and biochemical bone markers during GH treatment. The reason for these findings is unknown, and the role of sex steroids in determining the response to GH therapy remains to be fully elucidated.

The influence of growth hormone substitution therapy on erythroid and myeloid progenitor cells and on peripheral blood cells in adult patients with growth hormone deficiency

It has been reported that hypophysectomized rats exhibit normochromic, normocytic anaemia. Pancytopenia with impaired DNA synthesis in the bone marrow can be restored in these hypophysectomized rats by syngeneic pituitary grafts placed under the kidney capsule or treatment with growth hormone (GH). Until now, adults with hypopituitarism have received adequate replacement therapy with thyroxine, cortisol and sex steroids, but not with GH. We therefore investigated the effects of GH replacement therapy on the proliferation and differentiation of erythroid and myeloid progenitor and peripheral blood cells in 11 adult patients with growth hormone deficiency in a double-blind, placebo-controlled study for the first 6 months of therapy. The placebo group showed no changes during the first 6 months without therapy in either insulin-like growth factor I (IGF-I) levels, erythroid and myeloid progenitor precursor cells or peripheral blood cells. After commencement of GH therapy, IGF-I levels rose significantly during 24 months of therapy from 75.3 +/- 13.5 to 225 +/- 34.7 ng mL-1 (P < 0.001). Erythroid and myeloid progenitor precursor cells showed a steep and significant increase after 18 and 24 months of therapy (erythroid: from 10.7 +/- 3.5 to 261.4 +/- 79.8, P < 0.02, after 18 months and to 276.8 +/- 149.8 x 10(5) mononuclear cell colonies, P < 0.03, after 24 months; granulocyte-macrophage colony-forming units: from 39.7 +/- 9.8 to 316.9 +/- 124.6, P < 0.002, after 18 months and to 366 +/- 188.7 x 10(5) mononuclear cell colonies, P < 0.03, after 24 months), whereas the peripheral red and white blood cells exhibited only minimal non-significant changes. The principal regulators of erythropoiesis, such as erythropoietin, and parameters reflecting erythropoiesis in the peripheral blood, such as reticulocytes, remained almost unchanged throughout the whole study period. We therefore conclude that patients with GH deficiency do not have anaemia, but have haematopoietic precursor cells in the lower normal range, and that GH substitution therapy over a period of 24 months has a marked effect on erythroid and myeloid progenitor precursor cells but only negligible effects on peripheral blood cells in GH-deficient adults.

Factors modifying growth hormone estimates in immunoassays.

Growth hormone (GH) in human serum has been measured for more than 30 years and during this period it has been used diagnostically in growth disturbances and GH disorders. The first GH determinations were by radioimmunoassays using polyclonal antibodies. Due to the low specificity of these assays and the variable molecular appearance of GH, higher levels were obtained than with later assays employing two highly specific monoclonal antibodies. Because of this variability between assays, empiric GH cutoff levels had to be developed in different laboratories. However, with the growing need for more sophisticated diagnosis, especially in adulthood GH deficiency, knowledge of factors influencing the individual GH assays is required. Since GH deficiency in adulthood is now treated with GH substitution therapy, the relevance of factors influencing GH estimates has become increasingly evident, because no specific symptoms exist in adult GH deficiency.

Reduced bone mineral density in adults with growth hormone (GH) deficiency: increased bone turnover during 12 months of GH substitution therapy

To evaluate the consequences of growth hormone (GH) deficiency on bone mineral density and to evaluate the effects of GH substitution therapy, 68 adults (25 females and 43 males) aged 22-61 (mean 44.2 +/- 1.2) years with GH deficiency (GHD) were studied. Fifty-eight patients had panhypopituitarism, three had isolated GHD and in seven patients at least one additional pituitary function was affected. Twenty-one patients had childhood onset GHD. The patients were randomized to receive either GH in daily injections (0.125 IU.kg-1. week-1 for the first 4 weeks and subsequently 0.25 IU.kg-1. week-1) or placebo for 6 months. The trial continued as an open study with GH treatment for 6 to 12 months, with data presented as compiled data of 12 months of GH treatment in 64 patients. Bone mineral density (BMD) was measured by dual energy x-ray absorptiometry and bone turnover was assessed by serum markers of bone metabolism (osteocalcin, procollagen I peptide, cross-linked telopeptide of type I collagen and alkaline phosphatase activity), In women with adult onset GHD (N = 19) and in men with childhood onset GHD (N = 15), total body, spine and hip BMD was significantly reduced at baseline compared to Swedish age- and sex-matched control material. In men with adult onset of GHD (N = 28), BMD did not differ from male controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Short and long‐term cardiovascular effects of growth hormone therapy in growth hormone deficient adults

Since GH substitution therapy is now available for adult GH deficient patients, information on the cardiovascular effects of GH substitution has assumed major clinical interest. We have therefore assessed cardiovascular effects of short and long-term growth hormone substitution therapy in these patients. Doppler echocardiography was performed in 21 GH deficient patients after 4 months placebo and 4 months GH therapy, in a double blind cross-over study. In an open design study, 13 patients were reinvestigated following 16 months and 9 patients following 38 months of GH therapy. Twenty-one age and sex-matched normal control subjects were also investigated. Heart rate was increased in placebo treated patients as compared to controls. After 4 months of GH treatment, heart rate showed a further increase (10%, P < 0.01) and seemed to remain elevated after 16 months of GH therapy. Systolic and diastolic blood pressures were significantly lower in placebo treated patients than in controls, and did not change significantly after GH treatment. The left ventricular diastolic diameter was reduced in patients as compared to controls, but increased after 4 months GH therapy (P > 0.05) and seemed to increase further during prolonged GH treatment. Cardiac index was at the same level in controls and in placebo-treated patients, but increased by 20% following GH therapy and remained elevated after 16 and 38 months (P < 0.05) of GH substitution. Following GH substitution in GH deficient adult patients, left ventricular diastolic dimensions increased and seemed to normalize, while heart rate and cardiac output were found to be increased to supranormal levels.

Physical and psychological capabilities during substitution therapy with recombinant growth hormone in adults with growth hormone deficiency

In a double-blind cross-over study with recombinant methionyl growth hormone (GH) and placebo during 12 weeks, the effect of GH substitution therapy (0.5-06 IU.kg-1.week-1) on physical performance, muscle strength, bone mineral density, and mood and cognitive functions was investigated in 6 GH-deficient adults. During GH substitution serum concentrations of insulin-like growth factor-I and procollagen-III peptide increased in all 6 patients, whereas concentrations of serum urea decreased. Five of the patients identified the GH period and reported improved well-being with increased mental alertness and vitality and improved physical capacity and muscle strength. There was, however, no change of the isokinetic muscle strength during GH substitution therapy, and the working capacity on the bicycle ergometer was just slightly improved in some patients. The bone mineral density was low and unchanged in all patients. Mood and cognitive functions did not change during GH therapy. A reversible fluid retention was observed in one patient during the GH period. In conclusion, short-term GH substitution therapy to GH-deficient adults induced a subjective improvement of general well-being. Longer treatment periods will be necessary to establish the effect on physical capacity, muscle strength, bone mineral density, and mood and cognitive functions.

Should Adults with Growth Hormone Deficiency be Maintained on Growth Hormone Substitution Therapy?

Should Adults with Growth Hormone Deficiency be Maintained on Growth Hormone Substitution Therapy?

Long-term monitoring of treatment with recombinant human growth hormone by serial determinations of type III procollagen-related antigens in serum.

Inasmuch as recombinant human growth hormone is now more generally available for the treatment of different types of short stature, there is a need for better short-term indicators of treatment success. In healthy children, serum concentrations of antigens related to the aminoterminal propeptide of type III procollagen (P-III-NP) closely follow the growth velocity curve. P-III-NP was measured longitudinally in 20 children with growth hormone deficiency during 6 months of human growth hormone substitution therapy. Two different radioimmunoassay systems were used; one recognizes predominantly the intact propeptide showing a lesser affinity to a smaller monomeric peptide (RIAgnost assay), while the other assay detects both forms equally (FAB assay). These results were compared to the growth response [median 5.6 (0.4 to 13.9) cm in 6 months] and to other established growth correlated parameters (somatomedin C, alkaline phosphatase). A relatively better growth response correlated significantly with high pretreatment P-III-NP (RIAgnost assay) values (r = 0.56) and delayed bone age (r = -0.70). A combination of these parameters in multiple regression analysis increased the cumulative prediction value to above 60% (r2 = 0.61). On the other hand, P-III-NP (FAB assay) values proved to be best in monitoring treatment, correlating with the individual growth rate during the first 3 months (r = 0.40; p less than 0.05), during the consecutive 3 months (r = 0.66; p less than 0.001), and during the total 6-month period (r = 0.46; p less than 0.05). All other parameters showed associations to growth only during some treatment periods.(ABSTRACT TRUNCATED AT 250 WORDS)