Effect of growth hormone replacement therapy on pituitary hormone secretion and hormone replacement therapies in GHD adults

OBJECTIVE: We tested the impact of commencement of GH replacement therapy in GH-deficient (GHD) adults on the circulating levels of other anterior pituitary and peripheral hormones and the need for re-evaluation of other hormone replacement therapies, especially the need for dose changes. METHODS: 22 GHD patients were investigated in a double-blind randomized study and 90 GHD patients in an open study at baseline and after 6 and 12 months of GH replacement therapy. RESULTS: In the placebo-controlled trial, the FT(3) levels increased after 6 months in the GH-treated group, and in the open study the FT(3) levels tended to increase. Other hormone concentrations did not change in either part of the study. Four patients required an increase in thyroxine dose, while 2 patients needed dose reduction. One originally euthyroid patient required thyroxine replacement. Two patients with originally conserved pituitary-adrenal function developed ACTH insufficiency. The hydrocortisone dose was increased in 1 and decreased in 1 of the 66 patients with secondary hypocortisolism. None of the females required any adjustment of sex hormone replacement therapy. Two of 37 males needed dose increase of testosterone, while 1 needed dose reduction. CONCLUSION: GH replacement therapy required dose adjustments regarding other hormone replacement therapies in 12.2% (n = 11), while initiation of new hormone replacement was performed in 3.3% (n = 3) of the 90 patients during the 1-year follow-up. Monitoring of pituitary hormone axes is advisable after commencement of GH replacement therapy, since changes of hormone replacement therapy was observed in a small but clinically significant number of patients.     

Long-term challenges in growth hormone treatment

Growth hormone deficiency (GHD) is defined biochemically as a response to hypoglycaemia with a peak GH concentration of less than 5 microg/l. The 'GHD syndrome' is a range of psychological and physical symptoms that are associated with GHD, which include increased central adiposity, decreased bone mineral density, abnormal lipid profiles, decreased cardiovascular performance, reduced lean body mass (LBM), social isolation, depressed mood and increased anxiety. Importantly, the combination of physical and psychological problems can often result in a reduced quality of life. A number of trials have shown that GH replacement therapy can lead to a substantial improvement in GHD associated symptoms. Following up to 12 months of treatment with GH, LBM increased, left ventricular systolic function improved and the mean volume of adipose tissue fell. After only 4 months of treatment, a rise in exercise capacity was recorded, and after 2 years' treatment, isokinetic and isometric muscle strength had normalized in proximal muscle groups. Feelings of well-being and vitality also improved significantly. However, studies on the effects of treatment on insulin sensitivity in GH-deficient patients have had conflicting results. In this paper, we will discuss the long-term consequences of GHD and the effects of GH replacement therapy.     

Cognitive function in growth hormone deficiency and growth hormone replacement

There is converging evidence from neuropsychological studies that growth hormone (GH) is associated with cognitive function. The aim of the current study was to review the existing neuropsychological literature for studies in which cognitive assessment had been conducted in patients with GH deficiency (GHD), and where change in cognitive function had been assessed following treatment with GH. Studies that have investigated relationships between GH and cognitive function and those that have developed methodological and statistical approaches that could be useful in future GH studies were identified. In this review, GH levels were found to be associated with cognitive function. Untreated individuals with GHD showed reliable impairment in memory and attentional functions when compared with matched controls. Appropriately designed prospective studies also indicated that cognitive function improved with GH treatment. It was concluded that individuals with GHD do show cognitive impairment and that this is ameliorated to some extent by GH treatment. It is now important to establish the clinical importance of these findings, and further work is required to understand better the nature, magnitude and meaning of GH-related cognitive impairments and improvements.     

Plasma growth hormone response to synthetic GH-RH1-44 in 52 children and adults with growth hormone deficiency of various etiologies

52 patients (42 children and 10 adults) with growth hormone deficiency (GHD), grouped into four diagnostic categories, and 6 children with constitutional short stature who served as controls were tested for plasma GH response to synthetic GH-RH1-44 given in an intravenous bolus. The response was classified into three degrees according to the magnitude of the maximal rise: Good, greater than 9 ng/ml; Partial, 3.1-9.0 ng/ml; None, less than or equal to 3 ng/ml. Among the GHD patients the highest response was observed in patients with partial growth hormone deficiency (PGHD), and 60% of the children with isolated GH deficiency (IGHD) showed an increase in plasma GH levels. Nevertheless, the response of the GHD patients was lower than that in the control group. In the children and adolescents with PGHD and IGHD the response was not age related. Among those with multiple pituitary hormone deficiencies-idiopathic (MPHD-ID) there was no response in the adolescents although a hypothalamic disorder had been documented by other tests. Among those with MPHD-organic (MPHD-ORG) the GH-RH stimulated GH secretion in the patients with glioma, who had received only irradiation treatment, and in the youngest of the patients with craniopharyngioma. Of the 10 young adults tested none showed a good response. It is concluded that GH-RH is useful in differentiating between GH deficiency of hypothalamic origin and that of pituitary origin, and in selecting those patients who might benefit from long-term treatment with GH-RH in the future.     

Effect of Growth Hormone Replacement Therapy on the Quality of Life In Women with Growth Hormone Deficiency who Have A History of Acromegaly Versus Other Disorders

ObjectiveTo compare the response in quality of life (QoL) to growth hormone (GH) replacement in women with GH deficiency (GHD) and a history of acromegaly with that in women with GHD of other causes.MethodsFifty-five women with GHD were studied: 17 with prior acromegaly and 38 with other causes of GHD. We compared two 6-month, randomized, placebo controlled studies of GH therapy in women with hypopituitarism conducted with use of the same design—one in women with a history of acromegaly and one in women with no prior acromegaly. QoL was assessed with the following questionnaires: the QoL-Assessment of Growth Hormone Deficiency in Adults (AGHDA), the Symptom Questionnaire, and the 36-Item Short-Form Health Survey (SF-36).ResultsThe 2 groups had comparable mean pretreatment age, body mass index, and QoL scores and comparable mean GH dose at 6 months (0.61 ± 0.30 versus 0.67 ± 0.27 mg daily). After 6 months of GH replacement therapy, women with GHD and prior acromegaly demonstrated a greater improvement in AGHDA score, four SF-36 subscales (Role Limitations due to Physical Health, Energy or Fatigue, Emotional Well-Being, and Social Functioning), and the Somatic Symptoms subscale of the Symptom Questionnaire than did women with GHD of other causes. Poorer pretreatment QoL was associated with a greater improvement in QoL after administration of GH.ConclusionIn this study, GH replacement therapy improved QoL in women with GHD and a history of acromegaly but not in women with GHD due to other hypothalamic and pituitary disorders. Further studies are needed to determine the long-term risks versus benefits of GH replacement in patients who develop GHD after definitive treatment for acromegaly. (Endocr Pract. 2012;18:209-218)     

Changes of thyroid function during long-term hGH therapy in GHD children. A possible relationship with catch-up growth?

BACKGROUND: Growth hormone (GH) treatment in patients with GH deficiency (GHD) can determine changes in the thyroid function. The clinical significance of these changes remains controversial, and all studies have so far covered rather a short period--usually no longer than one year. OBJECTIVE: To determine the effect of long-term recombinant hGH treatment in children with idiopathic GHD on the thyroid function. PATIENTS AND METHODS: Nineteen prepubertal children (12 boys and 7 girls, mean age 9.2 +/- 3.1 years) with idiopathic GHD were studied and followed for twenty-four months. None of the patients showed multiple pituitary hormone deficiencies. Nineteen healthy children matched for age and sex acted as controls. RESULTS: Patients with GHD showed a significant increase in TT (3) at twelve months and in FT (3) at six and twelve months after starting GH treatment, with a significant decrease at eighteen and twenty-four months. TT (4) level decreased significantly at twelve months and increased significantly at eighteen and twenty-four months. FT (4) also decreased, but only slightly, after twelve months of hGH treatment, and then increased significantly at twenty-four months. TSH levels did not vary significantly during the course of therapy. TT (3)/TT (4) and FT (3)/FT (4) ratios increased significantly after six and twelve months of therapy and significantly decreased later, approaching pre-therapy values. The SDS of Growth Velocity (SDS-GV) increased remarkably during the first year of therapy and then decreased significantly during the second year, although it remained significantly higher than the pre-therapy values. TT (3) and TT (3)/TT (4) ratio displayed a significant correlation with SDS-GV at twelve months of therapy. In a multiple regression analysis with age, bone age, parental height, GH dose, TT (3,) TT (3)/TT (4), and the SDS of IGF-I, only the TT (3)/TT (4) ratio at twelve months of therapy (p < 0.001) was identified as a significant predictor of SDS-GV. CONCLUSION: Our data confirm that changes in thyroid function are present in GHD children during long-term hGH therapy. These changes probably resulted from the effect of hGH on the peripheral metabolism of thyroid hormones and appear to be transitory, disappearing during the second year of hGH treatment. We speculate on the functional significance of these changes, and in particular, on their role in catch-up growth after hGH therapy.     

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.     

Effect of growth hormone therapy on the proinflammatory cytokine profile in growth hormone-deficient children

The aim of the present study was to establish whether growth hormone (GH) treatment in vivo affects pro-inflammatory cytokine production by resting or in vitro, activated, cultured, peripheral blood mononuclear cells (PBMC) from children with complete growth hormone deficiency (GHD). We evaluated 11, pre-pubertal children (6 males and 5 females) with GHD, aged between 6 and 14 years, and 9, age- and sex-matched healthy subjects were studied as controls (CTRLs). Freshly isolated PBMC were cultured for 4 or 24 h in X-VIVO medium in the presence or absence of 0.01 microg/mL lipopolysaccharide for the determination of TNF-alpha and IL-6 production; alternatively, cells were incubated 24 h in X-VIVO medium with or without 25 microg/mL Concanavalin A for IFN-gamma production. Cytokines were measured in the cell supernatants by enzyme-linked immunosorbent assay kits. The results of the present study provide evidence that spontaneous and/or mitogen-induced, in vitro PBMC production of pro-inflammatory cytokines is lower in GHD children than in healthy, age-matched individuals (p<0.05 by the Mann-Whitney U-test). After 3 months of GH therapy, cytokine production was significantly (p<0.05 by the Wilcoxon test) increased, but was still lower than in healthy controls. It is reasonable to speculate that severe GH deficiency can cause alterations in the pro-inflammatory cytokine-induced immune response in humans, and that GH treatment can ameliorate this important immunological function.     

Effects of growth hormone treatment on B-type natriuretic peptide as a marker of heart failure in adults with growth hormone deficiency.

OBJECTIVE: Patients with growth hormone deficiency (GHD) have abnormalities of cardiac structure and function. Growth hormone replacement (GHR) therapy can induce an increase in cardiac mass and improvement in left ventricular ejection fraction. B-type natriuretic peptide (BNP) levels have been successfully used to identify patients with heart failure and they correlate with both disease severity and prognosis. DESIGN: To investigate the effect of growth hormone replacement on BNP and inflammatory cardiovascular risk factors in adults with GHD we determined NT-proBNP and high sensitive C-reactive protein (CrP) before, 6 and 12 months after GHR. PATIENTS: Thirty adults (14 males, 16 females) with GHD mean age: 41.7+/-14.5 years (range: 17.2 to 75.4 years) were recruited from the German KIMS cohort (Pfizer's International Metabolic Database). RESULTS: During 12 months of GHR, a significant increase of IGF-1 (85.4+/-72.1 VS. 172.0+/-98 mug/dl; p=0.0001; IGF-1 SDS mean+/-SD: -3.85+/-3.09 VS. -0.92+/-1.82) was detectable. Mean baseline NT-proBNP was 112+/-130 pg/ml (range: 7 to 562). Twelve patients had normal BNP, whereas 18 revealed NT-proBNP values corresponding to those of patients with heart failure NYHA classification I (n=10), NYHA II (n=6) and NYHA III (n=2), respectively. Baseline BNP levels correlated significantly (p=0.044) with increased baseline CrP values. After 12 months of GHR, a significant decrease (p=0.001) in NT-proBNP levels mean: 68+/-81 pg/ml (range: 5 to 395) was detectable, associated with an improvement in NYHA performance status in 10 of the 18 with increased baseline NT-proBNP. CONCLUSIONS: Based on our study, approximately two-thirds of patients with GHD have increased NT-proBNP levels which may be useful as screening/diagnostic laboratory parameter for heart failure in such patients. GHR therapy decreases BNP levels in most patients with GHD.     

Effect of growth hormone-releasing factor on plasma growth hormone, prolactin and somatomedin C in hypopituitary and short normal children

We studied the effect of a single intravenous bolus of 0.5 microgram/kg of growth hormone-releasing factor (GRF) on plasma GH, prolactin (PRL) and somatomedin C (SMC) in 12 short normal children and 24 patients with severe GH deficiency (GHD), i.e. GH less than 5 ng/ml after insulin and glucagon tolerance tests. GRF elicited an increase in plasma GH in both short normal and GHD children. The mean GH peak was lower in the GHD than in the short normal children (8.2 +/- 2.5 vs. 39.2 +/- 5.1 ng/ml, p less than 0.001). In the GHD patients (but not in the short normals) there was a negative correlation between bone age and peak GH after GRF (r = -0.58, p less than 0.005); GH peaks within the normal range were seen in 5 out of 8 GHD children with a bone age less than 5 years. In the short normal children, GRF had no effect on plasma PRL, which decreased continuously between 8.30 and 11 a.m. (from 206 +/- 22 to 86 +/- 10 microU/ml, p less than 0.005), a reflection of its circadian rhythm. In the majority of the GHD patients, PRL levels were higher than in the short normal children but had the same circadian rhythm, except that a slight increase in PRL was observed 15 min after GRF; this increase in PRL was seen both in children with isolated GHD and in those with multiple hormone deficiencies; it did occur in some GHD patients who had no GH response to GRF. Serum SMC did not change 24 h after GRF in the short normal children. We conclude that: (1) in short normal children: (a) the mean GH response to a single intravenous bolus of 0.5 microgram/kg of GRF is similar to that reported in young adults and (b) GRF has no effect on PRL secretion; (2) in GHD patients: (a) normal GH responses to GRF are seen in patients with a bone age less than 5 years and establish the integrity of the somatotrophs in those cases; (b) the GH responsiveness to GRF decreases with age, which probably reflects the duration of endogenous GRF deficiency, and (c) although the PRL response to GRF is heterogeneous, it does in some patients provide additional evidence of responsive pituitary tissue.     

Cardiovascular disease and risk factors: the role of growth hormone

Clinical studies in patients with acromegaly have shown that growth hormone (GH) exerts both short- and long-term effects on the structure and function of the heart. Moreover, chronic growth hormone deficiency (GHD) has been associated with impaired cardiac performance, low heart rate and impaired left ventricular systolic function. Exercise capacity in patients with GHD is significantly reduced and in some severely affected individuals, dilated cardiomyopathy and heart failure has been reported. GHD has also been associated with a number of risk factors for cardiovascular disease. Altered lipoprotein metabolism and elevated fibrinogen and plasminogen activator inhibitor-1 activity are associated with GHD, and the risk of hypertension is increased in GH-deficient men. Subcutaneous and intra-abdominal fat mass have also been found to be abnormally high in these patients. These effects may contribute to an increased risk of death from cardiovascular disease. GH is therefore an important factor in the development and function of the cardiovascular system. In this paper, the effects of GH on the physiological mechanisms of the cardiovascular system are discussed, including the effect of GHD on cardiovascular disease risk. We will also discuss the effects of long-term GH replacement therapy in this patient population.     

Insulin-like growth factor I (IGF-I) and IGF-binding protein 3 as diagnostic markers of growth hormone deficiency in infancy

BACKGROUND: The diagnosis of growth hormone deficiency (GHD) in infancy is difficult, and no specific cutoff value during GH provocative testing is recommended in early life. METHODS: Serum insulin-like growth factor I (IGF-I) and serum IGF-binding protein 3 (IGFBP-3) levels were evaluated as diagnostic markers of GHD. Measurements of IGF-I and IGFBP-3 during the 1st year of life were analyzed in 11 patients clinically suspected of having GHD (neonatal hypoglycemia, micropenis, or evidence of other pituitary hormone deficiencies), in whom the diagnosis was later verified. A prospective cohort of 51 healthy infants served as controls. RESULTS: The sensitivity of IGF-I as a diagnostic marker of GHD was 90% (10 out of 11 patients) with a cutoff value of -2 standard deviations (SD), and the sensitivity of IGFBP-3 measurements was 81% (9 out of 11 patients) with a cutoff value below -2 SD. One patient had serial measurements before initiation of GH treatment where the IGF-I was fluctuating (3 of 6 slightly above -2 SD), whereas all IGFBP-3 measurements were below -2 SD. CONCLUSIONS: The IGF-I had a high sensitivity in detecting infants with GHD. The combination of IGF-I and IGFBP-3 increased the diagnostic sensitivity. We speculate that assessment of IGF-I and IGFBP-3 may add diagnostic value in infants suspected of having GHD and furthermore that values below -2 SD are highly suggestive of GHD.     

Long-term effects of growth hormone therapy on bone mineral density,body composition,and serum lipid levels in growth hormone deficient children: a 6-year follow-up study

AIM: To study the effects of growth hormone (GH) deficiency (GHD) and GH replacement therapy (GHRx) on bone mineral density (BMD) and body composition. METHODS: 59 GHD children participated (age range 0.4-16.9 years); the follow-up period was 6 years. Lumbar spine BMD (BMD(LS)), total-body BMD (BMD(TB)), and body composition were measured prospectively using dual-energy X-ray absorptiometry. RESULTS: Mean BMD(LS )and BMD(TB) were significantly reduced at the time of the diagnosis. The bone mineral apparent density of the lumbar spine (BMAD(LS)) was reduced to a lesser degree. The BMAD(LS) increased to normal values after 1 year; BMD(LS) and BMD(TB) normalized 1 year later. At the time of the diagnosis, the lean body mass was reduced and steadily increased during GHRx. Percentage of body fat was increased at baseline and normalized within 6 months. The severity of GHD was not associated with the BMD at diagnosis or the response to GHRx. CONCLUSION: Areal BMD(LS) and BMD(TB) and, to a lesser extent, BMAD(LS) are decreased in GHD children, but normalize within 1-2 years.     

Long-term evolution of endocrine disorders and effect of GH therapy in 35 patients with pituitary stalk interruption syndrome

We report long-term evolution of endocrine functions and the results of GH treatment in 35 patients (26 male and 9 female) with pituitary stalk interruption. At diagnosis, mean chronological age was 4.8 +/- 2.7 years, mean SDS for height -3.1 +/- 0.8 with a bone age retardation of 2.3 +/- 1.3 years and a mean SDS for growth velocity of -0.5 +/- 1.1; 80% presented complete GH deficiency (GHD) and 20% partial GHD; thyroid deficiency was present in 47.1% of children with complete GHD but absent in all partial GHD. Diagnosis was made during the first months of life in only 2 patients while 23% presented with severe neonatal distress; neonatal signs were only observed in the group with pituitary height below 2 mm (45.7% of patients). GHD was isolated in 40.6% of patients below 10 years while multiple hormone deficiencies was consistent at completion of growth in all patients. Height gain was significantly higher in patients who started GH treatment before 4 years (p = 0.002). GH treatment is very effective: in 13 patients, final height was -0.4 +/- 1.0, total height gain 3.2 +/- 1.2 and distance to target height -0.3 +/- 1.6 SDS.     

Body composition as a clinical endpoint in the treatment of growth hormone deficiency

Endpoints in the treatment and management of adults with growth hormone (GH) deficiency (GHD) can be problematic. Changes in body composition with recombinant human GH (rhGH) treatment may be one of the most objective measures that could be applied in judging the effectiveness and long-term efficacy. The relative strengths and weaknesses of measures of body composition and their potential for clinical utility in the setting of rhGH replacement in GHD in adults are discussed. Measurement of changes in body fat, regardless of the method employed, from pretreatment baseline through 2-6 months of treatment may be quite useful in demonstrating the efficacy of rhGH in each patient. Other changes in body composition are compromised by the imprecision of the measurements, shifts in extracellular water, and the small real changes which occur in bone and muscle in the GHD subject. Use of body composition measures of change in fat content as an endpoint in determining the efficacy of rhGH treatment in adults with GHD cannot be implemented on the basis of current data and would require a carefully designed prospective, controlled study. Until such criteria are established and accepted, endocrinologists must continue to manage these patients purely on the basis of their clinical judgment.     

Bone age progression during the first year of growth hormone therapy in pre-pubertal children with idiopathic growth hormone deficiency, Turner syndrome or idiopathic short stature, and in short children born small for gestational age: analysis of data from KIGS (Pfizer International Growth Database)

BACKGROUND/AIMS: The beneficial effects of growth hormone (GH) therapy on statural growth in children are well established, but the effects on skeletal maturation are less clear. The progression of bone age (BA) was therefore studied during the first year of GH treatment in pre-pubertal children with idiopathic GH deficiency (GHD), Turner syndrome (TS) or idiopathic short stature (ISS), and in short pre-pubertal children born small for gestational age (SGA). METHODS: Cross-sectional data on 2,209 short children with idiopathic GHD, 694 with TS, 569 with ISS and 153 with SGA were analysed. Longitudinal data were also analysed from 308 children with idiopathic GHD, 99 with TS, 57 with ISS and 29 with SGA. All patients included in the study were enrolled in KIGS (Pfizer International Growth Database) and were being treated with recombinant human GH (Genotropin). BA was assessed using the Greulich and Pyle method at baseline and after 1 year of GH therapy. RESULTS: In all groups of patients the mean progression of BA was 1 year during the year of GH therapy, although there was considerable individual variation. Progression of BA was not correlated with chronological age, BA, height SD score (SDS) or body mass index SDS at the onset of GH therapy. There was also no consistent effect of the GH dose on BA progression. CONCLUSION: Progression of BA appears to be normal in patients receiving GH in these diagnostic groups, at least over the first year of treatment in pre-puberty.     

Eventos adversos perinatales y anomalías neuroanatómicas en pacientes con hipopituitarismo idiopático

ObjectiveTo analyze the possible causes of growth hormone (GH) deficiency, whether isolated (GHD) or in combination with other pituitary deficiencies classified as idiopathic.Patients and methodsWe studied patients with idiopathic GHD included in a protocol of recombinant GH treatment in adults attending the outpatient clinic of the Endocrinology and Nutrition Service of the San Cecilio University Hospital. Perinatal history, findings on magnetic resonance imaging (MRI) of the hypothalamic-pituitary axis and diagnosis of GHD and other deficiencies were retrospectively evaluated.ResultsA total of 17 patients were included: 14 men and 3 women with a mean age at diagnosis of 8.4±7.3 years. Perinatal adverse events occurred in 12 patients (69.2%). MRI showed empty sella (2 patients), pituitary hypoplasia or absence of the pituitary stalk (7 patients) and pituitary hypoplasia with ectopic posterior pituitary gland (6 patients); in the remaining 2 patients these data were not available. All had an established diagnosis of GHD: 15 with (88.2%) gonadotropin deficiency, 9 (52.9%) with adrenocorticotropic hormone (ACTH) deficiency and 8 (47.1%) with thyroid-stimulating hormone (TSH) deficiency.ConclusionsIn our patients, adverse events during pregnancy or the perinatal period and the presence of anatomical abnormalities identified by MRI are a marker of pituitary dysfunction and may be important in the pathogenesis of this entity. The clinical spectrum of disease varies from isolated GH deficiency to multiple pituitary hormone deficiencies.     

Insulin sensitivity in adults with growth hormone deficiency and effect of growth hormone treatment

Adult growth hormone deficiency (GHD) is a multifactorial disorder in which pituitary dysfunction associated with pituitary adenomas or their treatment plays a major role. The introduction of recombinant growth hormone (GH) for the treatment of GHD has opened up new treatment avenues but has also raised concerns about possible untoward long-term metabolic effects of GH, such as the potential effect of GH on insulin sensitivity and a deterioration in glucose tolerance. Research has shown that GH induces insulin resistance by the stimulation of lipolysis and a concomitant switch from oxidation of glucose to oxidation of lipids, during both acute and chronic treatment. However, although this is a consistent effect of GH therapy, it does not mean per se that it leads to abnormal glucose tolerance and diabetes mellitus. This article discusses this and other potential long-term metabolic effects of GH, and raises a number of questions to be addressed by future research.     

Effects of growth hormone on cognitive function

Whether growth hormone deficiency (GHD) and/or treatment in childhood and adolescence influences cognitive outcome in children with GHD or girls with Turner syndrome (TS) is controversial. Previous studies also suggest that quality of life (QoL) is reduced in adults with GHD, particularly in the areas of social isolation and fatigue. Baseline QoL scores were significantly lower in patients with GHD than in the general population of the same age, gender, and nationality. Unfortunately, few data are available describing QoL in children with GHD. TS is a genetic disorder characterized by short stature, gonadal dysgenesis, and a particular neurocognitive profile of normally developed language abilities (particularly verbal intelligence quotients) and impaired visual-spatial and/or visual-perceptual abilities. This study evaluated the effects of GH treatment on neurocognitive function in girls with TS who were enrolled in a long-term, double-blind, placebo-controlled trial of the effects of GH treatment on final adult height. Treatment duration ranged from 1 to 7 years. The major result of this study was the absence of GH treatment effects on cognitive function in girls with TS. GHD and/or treatment in childhood and adulthood influences cognitive and/or QoL outcomes in some but not all studies. This study did not support a role for GH in influencing the characteristic nonverbal neurocognitive deficits associated with TS. However, evaluation of QoL should be a part of the routine clinical management of patients with GHD or TS.     

Impact of growth hormone status on body composition and the skeleton

Severe growth hormone (GH) deficiency (GHD) induces a well-defined clinical entity encompassing, amongst the most reported features, abnormalities of body composition, in particular increased fat mass, especially truncal, and reduced lean body mass. The results from virtually all treatment studies are in agreement that GH replacement improves the body composition profile of GHD patients by increasing lean body mass and reducing fat mass. More recently, the observations have been extended to adults with partial GHD, defined by a peak GH response to insulin-induced hypoglycaemia of 3-7 microg/l. These patients exhibit abnormalities of body composition similar in nature to those described in adults with severe GHD; these include an increase in total fat mass of around 3.5 kg and a reduction of lean body mass of around 5.5 kg. The increase in fat mass is predominantly distributed within the trunk. The degree of abnormality of body composition is intermediate between that of healthy subjects and that of adults with GHD. The impact of GH replacement on body composition in adults with GH insufficiency, although predictable, has not been formally documented. The skeleton is another biological endpoint affected by GH status: in adults with severe GHD, low bone mass has been reported using dual energy x-ray absorptiometry (DEXA) and other quantitative methodologies. The importance of low bone mass, in any clinical setting, is as a surrogate marker for the future risk of fracture. Several retrospective studies have documented an increased prevalence of fractures in untreated GHD adults. Hypopituitary adults with severe GHD have reduced markers of bone turnover which normalize with GH replacement, indicating that GH, directly or via induction of insulin-like growth factor-I, is intimately involved in skeletal modelling. Whilst the evidence that GH plays an important role in the acquisition of bone mass during adolescence and early adult life is impressive, the impact of GHD acquired later in adulthood is less clear. Recently we examined the relationship between bone mineral density (BMD) and age in 125 untreated adults with severe GHD using DEXA. A significant positive correlation was observed between BMD (z-scores) and age at all skeletal sites studied. Overall, few patients, except those aged less than 30 years, had significantly reduced bone mass (i.e. a BMD z-score of less than -2); correction of BMD to provide a pseudo-volumetric measure of BMD suggested that reduced stature of the younger patients may explain, at least in part, this higher frequency of subnormal BMD z-scores. Despite normal BMD, however, an increase in fracture prevalence may still be observed in elderly GHD adults as a consequence of increased falls related to muscle weakness and visual field defects.