Growth hormone and bone health

Growth hormone (GH) and insulin-like growth factor-I have major effects on growth plate chondrocytes and all bone cells. Untreated childhood-onset GH deficiency (GHD) markedly impairs linear growth as well as three-dimensional bone size. Adult peak bone mass is therefore about 50% that of adults with normal height. This is mainly an effect on bone volume, whereas true bone mineral density (BMD; g/cm(3)) is virtually normal, as demonstrated in a large cohort of untreated Russian adults with childhood-onset GHD. The prevalence of fractures in these untreated childhood-onset GHD adults was, however, markedly and significantly increased in comparison with normal Russian adults. This clearly indicates that bone mass and bone size matter more than true bone density. Adequate treatment with GH can largely correct bone size and in several studies also bone mass, but it usually requires more than 5 years of continuous treatment. Adult-onset GHD decreases bone turnover and results in a mild deficit, generally between -0.5 and -1.0 z-score, in bone mineral content and BMD of the lumbar spine, radius and femoral neck. Cross-sectional surveys and the KIMS data suggest an increased incidence of fractures. GH replacement therapy increases bone turnover. The three controlled studies with follow-up periods of 18 and 24 months demonstrated a modest increase in BMD of the lumbar spine and femoral neck in male adults with adult-onset GHD, whereas no significant changes in BMD were observed in women. GHD, whether childhood- or adult-onset, impairs bone mass and strength. Appropriate substitution therapy can largely correct these deficiencies if given over a prolonged period. GH therapy for other bone disorders not associated with primary GHD needs further study but may well be beneficial because of its positive effects on the bone remodelling cycle.     

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.     

Adolescents with childhood-onset GHD: how do we get them to peak bone mass?

The development of osteoporosis, with its attendant risk of fragility fracture, is in part related to the peak bone mass (PBM) achieved in early adulthood. Adolescence is a critical time for the acquisition of bone mass, with around 40% of skeletal mass being accrued during pubertal maturation. Growth hormone (GH) plays an integral role in the achievement of PBM after completion of linear growth, and several recent studies have suggested that GH replacement should continue in individuals with childhood-onset GHD until PBM has been attained - irrespective of the height achieved. In those with severe GHD after growth and pubertal development are complete, a seamless transition of GH therapy into adult life may be preferable to allowing a gap in GH treatment. The 'window of opportunity' concept for achieving PBM will, nevertheless, continue to be challenged by GHD teenagers who may resent the seamless continuation of GH replacement beyond adolescence. Preparation for this possibility should therefore begin during childhood, with all GHD teenagers being encouraged to remain on GH therapy until at least their mid-20s.     

Bone markers and bone mineral density during growth hormone treatment in children with growth hormone deficiency

Growth hormone (GH) has a positive impact on muscle mass, growth and bone formation. It is known to interact with the bone-forming unit, with well-documented increases in markers of bone formation and bone resorption within weeks of the start of GH therapy. These changes relate significantly to short-term growth rate, but it is not evident that they predict long-term response to GH therapy. The consequences of GH deficiency (GHD) and GH replacement therapy on bone mineral density (BMD) have been difficult to interpret in children because of the dependency of areal BMD on height and weight. Some studies have tried to overcome this problem by calculating volumetric BMD, but results are conflicting. The attainment of a normal peak bone mass in an individual is considered important for the future prevention of osteoporosis. From the limited data available, it appears difficult to normalize bone mass totally in GH-deficient individuals, despite GH treatment for long periods. Studies to date examining the interaction between GH and bone have included only small numbers of individuals, making it difficult to interpret the study findings. It is hoped that these issues can be clarified in future research by the direct measurement of bone density (using quantitative computer tomography). Mineralization is only one facet of bone strength, however; other important components (e.g. bone structure and geometry) should be addressed in future paediatric studies. Future studies could also address the importance of the degree of GHD in childhood; how GH dose and insulin-like growth factor-I levels achieved during therapy relate to the final outcome; whether or not the continuation of GH therapy after the attainment of final height may further enhance bone mass; whether the timing and dose of other treatments (e.g. sex hormone replacement therapy) are critical to the outcome; and whether GHD in childhood is associated with an increased risk of fracture.     

Stepping into adulthood: the transition period

The period of growth from late puberty to full adult maturation, termed the transition period, is important for tissue maturation. Peak bone mass, muscle mass and strength are usually attained in this period. However, it is common clinical practice in children with growth hormone deficiency (GHD) to discontinue growth hormone (GH) treatment in adolescence after attainment of final height. Therefore, patients with childhood-onset GHD that continues into adulthood and who do not receive treatment as adults may experience more severe consequences than patients who acquire GHD as an adult. Recent studies indicate that bone and muscle maturation are attenuated if GH treatment is discontinued at final height. Furthermore, these patients will also develop cardiovascular risk factors that are normally associated with GHD in adults. Much debate surrounds when retesting for GHD should be carried out and when GH treatment should be restarted in adolescents; many of these patients will not have severe GHD according to the criteria set for adults. The transition period is an appropriate time to modify GH doses. Finally, registries exist that have recorded clinical treatment experiences for children and adults. Tools that collect and analyse data provide an important opportunity to investigate issues related to transition.     

Bone densitometry: assessing the effects of growth hormone treatment in adults

Dual-energy X-ray absorptiometry (DXA) is the reference method for the measurement of bone mineral mass at different skeletal sites. It has been widely used in recent years to assess the effects of growth hormone (GH) treatment on bone metabolism. In normal individuals, bone mineral content (BMC) and density (BMD), as assessed using DXA, correlate with body size. Therefore, using DXA in patients with congenital GH deficiency (GHD), who have a smaller body frame, would be expected to result in lower bone mass. Thus, comparisons with reference data derived from populations of normal body size are invalid. The evaluation of the effects of GH administration should take into account the possible effects of GH on bone size, not only in children, but also in adults. The enlargement of bone, due to stimulation of the periosteal apposition, may partially mask an increase in BMC, resulting in little or no change in BMD. The ability of GH to affect bone area therefore requires analysis of the possible changes in bone area and BMC, as well as BMD. This issue has been poorly handled in the studies published to date. Lastly, the acceleration of bone turnover induced by GH leads to an increase in bone remodelling space, which in turn is associated with a reduction in BMC and BMD, independent of the net balance between breakdown and formation in each metabolic unit. This bone loss is completely reversible when the remodelling space returns to previous levels. This phenomenon must be taken into account when analysing the effects of GH treatment on bone mass, because a net gain in bone mass may be found in long-term GH treatment or after GH discontinuation, even if bone loss was evident during the first 6 months of treatment. In conclusion, the interpretation of bone density data in patients with GHD, and after GH administration, should take into account some of the methodological aspects of bone densitometry, as well as the specific actions of GH on bone metabolism and body composition.     

Effects of one-year low-dose growth hormone (GH) therapy on body composition, lipid profile and carbohydrate metabolism in young adults with childhood-onset severe GH deficiency confirmed after completion of growth promotion

Introduction: The symptoms of GH deficiency (GHD) in adults include: abnormalities in body composition, unfavourable lipid profile, early atherosclerosis and impaired quality of life. The aim of the study was the selection of patients with confirmed severe GHD from among all the children treated due to GHD, who could benefit from GH therapy continuation in adulthood and the optimization of GH dosage in young adults with severe GHD. Material and methods: The study group consisted of 54 young adults (38 male), age 17.6 +/- 1.5 years, with childhood-onset GHD, who had reached final height. At least 1 month after the GH therapy withdrawal, the second evaluation of GH secretion was performed in all the patients. In 24% of patients, permanent severe GHD (PSGHD) was confirmed, but a group of 9 patients (4 male) was involved in renewed GH therapy. Results: The renewed GH therapy gave positive effects, including a significant increase in fat-free mass and a decrease in fat mass, and a significant decrease in LDL-cholesterol, but connected with an insignificant decrease of HDL-cholesterol serum concentration and improved results of quality of life (QoL) assessment. During the therapy, an insignificant increase of fasting insulin was observed, with no change in fasting glucose and only a slight increase in HbA(1c) percentage. A decrease of insulin sensitivity was also observed, but both insulin secretion and the values of insulin resistance indices still remained within the reference range. Conclusions: The observed positive effects on body composition, lipid metabolism and QoL, together with the absence of adverse events, confirm the indications for GH therapy in young adults with severe GHD.     

Insulin-like growth factor I levels and the diagnosis of adult growth hormone deficiency

The current guidelines state that, within the appropriate clinical context, the diagnosis of adult growth hormone (GH) deficiency must be made biochemically using provocative tests. Measurement of insulin-like growth factor I (IGF-I) and binding protein 3 (IGFBP-3) levels cannot always distinguish between healthy and GH-deficient individuals. In particular, IGFBP-3 as a marker of GH status is clearly less sensitive than IGF-I and there is general agreement that its measurement does not provide useful diagnostic information. However, the diagnostic value of measuring IGF-I levels has been revisited recently. It has been confirmed that normal IGF-I levels do not rule out severe GH deficiency (GHD) in adults, in whom the diagnosis has therefore to be based on the demonstration of severe impairment of the peak GH response to provocative tests. It has also been emphasized that very low IGF-I levels in patients with high suspicion of GHD could be considered to be definite evidence for severe GHD. This assumption particularly applies to patients with childhood-onset, severe GHD or with multiple hypopituitary deficiencies acquired in adulthood. In addition, the use of IGF-I levels to monitor the efficacy and adequacy of recombinant human GH replacement remains widely accepted.     

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.     

Effects of long-term treatment with GH in the bone mineral density of adults with hypopituitarism and GH deficiency and after discontinuation of GH replacement.

BACKGROUND: Only few previous studies have assessed the effects of long-term growth hormone (GH) replacement therapy on bone mineral density (BMD) in adult patients with GH deficiency. The aim of this study was to investigate the effects of long-term GH therapy on bone metabolism and BMD. MATERIAL AND METHODS: At the start of the study, 20 adults with GH deficiency were randomized to receive either GH, 0.25 IU x kg per week, or placebo. After 6 months, patients in the placebo group were switched to GH therapy, and they received GH for a further 18 months. Of the 20 patients, 14 were male and 6 female with GH deficiency of adult-onset. The mean age of the patients at the start of the study was 40.3+/-10.9 years and the duration of GH deficiency was 10.6+/-6.4 years. Patients deficient in pituitary hormones other than GH had been receiving stable replacement doses of appropriate hormones for at least 6 months before the start of the study. Rates of bone metabolism were assessed by measuring calcium, phosphate, alkaline phosphatase, calciuria, phosphaturia and osteocalcin. BMD was measured by dual X-ray absorptiometry. Body composition was calculated from measurements of bioelectrical impedance. RESULTS: Before GH treatment, BMD in the femoral neck was lower in patients than in controls. The rate of bone resorption markers increased significantly after 6 months and remained stable during the whole treatment period. BMD significantly increased in L2-L4 after 12 months of treatment with an increase of Z-score. The total BMD increase was 4.5+/-6.5%. BMD in the femoral neck increased after 12 months with an increase of Z-score after 18 months. The total increase was 10.4+/-18%. The total BMD increase was not different among patients with or without basal osteopenia. In both groups BMD in L2-L4 and in the femoral neck remained stable after 12 months without GH treatment. Sex, age, BMI and the time in which GH deficiency started, before or after the end of the peak of BMD, did not correlate with BMD. The BMD values and their response to GH treatment did not correlate with other associated deficiencies, and we did not find differences among BMD increase and GH dose, levels of insulin-growth factor-I, insulin growth factor binding protein-3, and parameters of body composition. CONCLUSIONS: The results of the study support previous ones that BMD is subnormal in adults with GH deficiency; that GH replacement therapy stimulates bone turnover with initial biochemical changes; and that in the long term, this stimulation results in a significant augmentation in BMD that continues to increase after 2 years and remains stable after 12 months of GH withdrawal.     

Cardiovascular effects of growth hormone treatment: potential risks and benefits

Growth hormone (GH) and insulin-like growth factor-I are involved in heart development and in maintaining cardiac structure and performance. Cardiovascular disease has been reported to reduce life expectancy both in GH deficiency (GHD) and in GH excess. Patients with GHD suffer from abnormalities of left ventricular performance, i.e. reduced diastolic filling and impaired response to peak exercise. Patients with GHD also have increased intima-media thickness at the common carotid arteries, associated with a higher occurrence of atherosclerotic plaques, which may further aggravate the haemodynamic conditions. This may contribute to increased cardiovascular and cerebrovascular risk. These cardiovascular abnormalities can be reversed, at least partially, with GH replacement therapy. In recent years, GH therapy has been used to increase cardiac mass in ischaemic or dilated cardiomyopathy, but the results have produced contradictory data.     

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.     

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.     

Trabecular Bone Score Change Differs with Regard to 25(OH)D Levels in Patients Treated for Adult-Onset Growth Hormone Deficiency

Objective: Vitamin D is important in bone health. However, potential relationships of concomitant vitamin D deficiency with growth hormone deficiency (GHD) and the possibility that vitamin D inadequacy may alter the skeletal effects of growth hormone (GH) replacement therapy have not been adequately evaluated.Methods: A prospective study was conducted in adult-onset GHD patients treated with recombinant human GH (rhGH) for 2 years. Trabecular bone score (TBS), lumbar spine (LS) bone mineral density (BMD), total hip (TH) BMD, and 25-hydroxyvitamin D (25(OH)D) levels were assessed at baseline and 24 months. The study cohort was divided based on 25(OH)D levels into 2 groups with the cutoff defined as the 50^th percentile at each follow-up time point.Results: Fifty-seven patients (29 males/28 females, mean age 34.4 years) were studied. After 24 months of GH replacement, LS BMD increased by 7.6% and TH BMD increased by 4.5% (both P<.05), with no difference according to 25(OH)D levels. TBS increased (+1.39 ± 3.6%) in those whose 25(OH)D was above the 50^th percentile but decreased (-1.36 ± 5.6%, P<.05) in the cohort below the 50^th percentile of 25(OH)D. Positive correlations were observed between baseline levels of IGF-1 and 25(OH)D (R = 0.37, P<.001) and between 24-month 25(OH)D and TBS (R = 0.25, P<.05).Conclusion: A differential effect of GH on TBS change was observed; TBS increased only in the cohort with 25(OH)D above the 50^th percentile. Vitamin D sufficiency may be required to obtain optimal effects of GH treatment on bone quality, as assessed by TBS, in GHD adults.Abbreviations:AO-GHD = adult-onset GHDBMD = bone mineral densityBMI = body mass indexCa = calciumCTx = carboxyterminal collagen crosslinksCV = coefficient of variationDXA = dual energy X-ray absorptiometryECLIA = enzyme-labeled chemiluminescent immunometric assayGH = growth hormoneGHD = growth hormone deficiencyIGF-1 = insulin-like growth factor 1LS BMD = lumbar spine BMDOC = osteocalcin25(OH)D = 25-hydroxyvitamin DP = phosphorusPTH = parathyroid hormonerhGH = recombinant human GHTBS = trabecular bone scoreTH BMD = total hip BMD     

Defining growth hormone status in adults with hypopituitarism

The identification of adults with severe growth hormone (GH) deficiency (GHD) is not straightforward. The insulin tolerance test remains the gold standard diagnostic test, although other stimuli such as GH-releasing hormone-arginine are gaining acceptance. Insulin-like growth factor-I has a poor diagnostic sensitivity in adult-onset GHD, but is more useful in the subgroup of adults with childhood-onset GHD. Therapeutic developments include increasing recognition of the need to continue GH therapy beyond final height in young adults with severe GHD on retesting. Consensus guidelines have provided a useful algorithm to identify individuals requiring retesting and the number of tests needed. The concept of partial GHD, recognized by paediatric endocrinologists for many years, is being examined in adults with hypothalamic-pituitary disease. Preliminary evidence suggests that this entity is associated with metabolic and anthropometric abnormalities intermediate between those in severe GHD and in healthy controls. It remains to be seen whether this subgroup will derive benefit from GH therapy. To date, therapeutic benefits of GH have been demonstrated only in adults with severe GHD. It is, therefore, imperative that these individuals are unequivocally identified; the diagnosis becomes more uncertain in the presence of obesity, increasing age, and in the absence of additional pituitary hormone deficits.     

American Association of Clinical Endocrinologists and American College of Endocrinology Guidelines for Management of Growth Hormone Deficiency in Adults and Patients Transitioning from Pediatric to Adult Care

Objective: The development of these guidelines is sponsored by the American Association of Clinical Endocrinologists (AACE) Board of Directors and American College of Endocrinology (ACE) Board of Trustees and adheres with published AACE protocols for the standardized production of clinical practice guidelines (CPG).Methods: Recommendations are based on diligent reviews of clinical evidence with transparent incorporation of subjective factors, according to established AACE/ACE guidelines for guidelines protocols.Results: The Executive Summary of this 2019 updated guideline contains 58 numbered recommendations: 12 are Grade A (21%), 19 are Grade B (33%), 21 are Grade C (36%), and 6 are Grade D (10%). These detailed, evidence-based recommendations allow for nuance-based clinical decision-making that addresses multiple aspects of real-world care of patients. The evidence base presented in the subsequent Appendix provides relevant supporting information for the Executive Summary recommendations. This update contains 357 citations of which 51 (14%) are evidence level (EL) 1 (strong), 168 (47%) are EL 2 (intermediate), 61 (17%) are EL 3 (weak), and 77 (22%) are EL 4 (no clinical evidence).Conclusion: This CPG is a practical tool that practicing endocrinologists and regulatory bodies can refer to regarding the identification, diagnosis, and treatment of adults and patients transitioning from pediatric to adult-care services with growth hormone deficiency (GHD). It provides guidelines on assessment, screening, diagnostic testing, and treatment recommendations for a range of individuals with various causes of adult GHD. The recommendations emphasize the importance of considering testing patients with a reasonable level of clinical suspicion of GHD using appropriate growth hormone (GH) cut-points for various GH–stimulation tests to accurately diagnose adult GHD, and to exercise caution interpreting serum GH and insulin-like growth factor-1 (IGF-1) levels, as various GH and IGF-1 assays are used to support treatment decisions. The intention to treat often requires sound clinical judgment and careful assessment of the benefits and risks specific to each individual patient. Unapproved uses of GH, long-term safety, and the current status of long-acting GH preparations are also discussed in this document.LAY ABSTRACTThis updated guideline provides evidence-based recommendations regarding the identification, screening, assessment, diagnosis, and treatment for a range of individuals with various causes of adult growth-hormone deficiency (GHD) and patients with childhood-onset GHD transitioning to adult care. The update summarizes the most current knowledge about the accuracy of available GH–stimulation tests, safety of recombinant human GH (rhGH) replacement, unapproved uses of rhGH related to sports and aging, and new developments such as long-acting GH preparations that use a variety of technologies to prolong GH action. Recommendations offer a framework for physicians to manage patients with GHD effectively during transition to adult care and adulthood. Establishing a correct diagnosis is essential before consideration of replacement therapy with rhGH. Since the diagnosis of GHD in adults can be challenging, GH–stimulation tests are recommended based on individual patient circumstances and use of appropriate GH cut-points. Available GH–stimulation tests are discussed regarding variability, accuracy, reproducibility, safety, and contraindications, among other factors. The regimen for starting and maintaining rhGH treatment now uses individualized dose adjustments, which has improved effectiveness and reduced reported side effects, dependent on age, gender, body mass index, and various other individual characteristics. With careful dosing of rhGH replacement, many features of adult GHD are reversible and side effects of therapy can be minimized. Scientific studies have consistently shown rhGH therapy to be beneficial for adults with GHD, including improvements in body composition and quality of life, and have demonstrated the safety of short- and long-term rhGH replacement.Abbreviations: AACE = American Association of Clinical Endocrinologists; ACE = American College of Endocrinology; AHSG = alpha-2-HS-glycoprotein; AO-GHD = adult-onset growth hormone deficiency; ARG = arginine; BEL = best evidence level; BMD = bone mineral density; BMI = body mass index; CI = confidence interval; CO-GHD = childhood-onset growth hormone deficiency; CPG = clinical practice guideline; CRP = C-reactive protein; DM = diabetes mellitus; DXA = dual-energy X-ray absorptiometry; EL = evidence level; FDA = Food and Drug Administration; FD-GST = fixed-dose glucagon stimulation test; GeNeSIS = Genetics and Neuroendocrinology of Short Stature International Study; GH = growth hormone; GHD = growth hormone deficiency; GHRH = growth hormone–releasing hormone; GST = glucagon stimulation test; HDL = high-density lipoprotein; HypoCCS = Hypopituitary Control and Complications Study; IGF-1 = insulin-like growth factor-1; IGFBP = insulin-like growth factor–binding protein; IGHD = isolated growth hormone deficiency; ITT = insulin tolerance test; KIMS = Kabi International Metabolic Surveillance; LAGH = long-acting growth hormone; LDL = low-density lipoprotein; LIF = leukemia inhibitory factor; MPHD = multiple pituitary hormone deficiencies; MRI = magnetic resonance imaging; P-III-NP = procollagen type-III amino-terminal pro-peptide; PHD = pituitary hormone deficiencies; QoL = quality of life; rhGH = recombinant human growth hormone; ROC = receiver operating characteristic; RR = relative risk; SAH = subarachnoid hemorrhage; SDS = standard deviation score; SIR = standardized incidence ratio; SN = secondary neoplasms; T3 = triiodothyronine; TBI = traumatic brain injury; VDBP = vitamin D-binding protein; WADA = World Anti-Doping Agency; WB-GST = weight-based glucagon stimulation test     

Transition care of patients with growth hormone deficiency from pediatric endocrinologists to adult endocrinologists

ObjectiveTo review whether growth hormone (GH) therapy should be continued into young adulthood, beyond achievement of final height, when GH deficiency persists, to summarize the recent evidence of the benefits of GH treatment during the transition period, and to address cur-rently debated issues involving diagnosis, treatment, and transition of care.MethodsPrimary literature was reviewed in the fol-lowing areas: the benefits and risks of GH therapy during the transition period, the diagnostic criteria for GH defi-ciency and recommended testing procedures during transi-tion, the optimal dose of GH therapy during transition, and the factors to consider in the transition of care from the pediatric to the adult endocrinologist.ResultsStudies support the continuation of GH therapy through the transition period until accrual of peak bone mass, rather than cessation of GH treatment when adult height has been achieved. Continued GH treatment in patients with persistent GH deficiency after achieving final height has been associated with significant additional bone maturation and improved overall metabolic profile. The selection of the most appropriate methods and cutoff val-ues for retesting GH deficiency during the transition period remains a challenge. Reassessment of the optimal GH dose is a key component of transition care.ConclusionFor patients with GH deficiency that will likely persist into adulthood, it is important to begin discussing possible continuation of GH treatment early in the management of GH deficiency. Clear communica-tion between pediatric and adult endocrinologists will be needed to determine the timing of the patient-care transi-tion and to minimize the interruption of GH therapy during the transition period. (Endocr Pract. 2012;18:256-268)     

The phenotype of adults with partial growth hormone deficiency

The concept of partial growth hormone (GH) deficiency (GHD) is well established within the paediatric setting having been validated against height velocity. In hypopituitary adults, GHD is defined by a peak GH response <3 microg/l to stimulation. This cut-off is arbitrary due to the lack of a biological marker equivalent of height velocity. The majority of normal adults achieve peak GH levels several fold higher than this cut off during stimulation. It can be argued, therefore, that there is a cohort of hypopituitary adults with intermediate peak GH values (3-7 microg/l), who have relatively impaired GH secretion, and for whom the impact of this partial GHD (GH insufficiency, GHI) on biological endpoints is not known. Studies of GHI adults have demonstrated an abnormal body composition, adverse lipid profile, impaired cardiac performance, reduced exercise tolerance and insulin resistance. The severity of these abnormalities lies between GHD adults and normal subjects. Whether these anomalies translate into increased mortality, as observed in GHD hypopituitary adults, is not yet known. Given the presence of similar sequelae in GHI and GHD adults, and the improvements during GH replacement in GHD adults, a randomized placebo-controlled study of GH replacement in GHI patients is warranted.     

Calcium supplementation increases bone mass in GH-deficient prepubertal children during GH replacement

BACKGROUND/AIMS: Since GH plays an important role in bone mineralization, and several studies demonstrated the positive influence of a higher calcium intake on bone mass, we studied the effect of calcium supplementation in GHD children during GH therapy. METHODS: 28 prepubertal GHD children, 5.0-9.9 years old, were assigned to two groups: group A (n = 14; 7 females) treated with GH, and group B (n = 14; 7 females) treated with GH + calcium gluconolactate and carbonate (1 g calcium/day per os). Auxological parameters, total bone mineral content (TBMC) and density (TBMD), leg BMC and BMD, lumbar BMD, fat mass (FM) and lean tissue mass (LTM), blood 25-hydroxyvitamin D (25-OHD), parathyroid hormone (PTH), osteocalcin (OC) and urinary N-terminal telopeptide of type I collagen (NTx) were determined at the start of therapy and after 1 and 2 years of treatment. RESULTS: During the 2 years of the study, TBMC, TBMD, leg BMC and BMD (but not lumbar BMD) increased in both groups of patients, however after 2 years of treatment they were significantly higher in the calcium-supplemented group B than in group A (p < 0.05, for all parameters). At the start of therapy, in both groups of patients percentage FM was higher and total and leg LTM lower than in controls (p < 0.05 for each parameter). Thereafter, FM decreased and LTM increased and after 2 years they were both different from baseline (p < 0.05). After 2 years of treatment, leg BMC and BMD were more positively correlated with regional leg LTM in patients of group B (r = 0.834 and r = 0.827, respectively; p < 0.001) than in patients of group A (r = 0.617 and r = 0.637, respectively; p < 0.05). 25-OHD and PTH levels were in the normal range in all patients at the start and during treatment. OC levels were lower and urinary NTx levels higher in patients than in controls (p < 0.05 for both parameters), either at the start and after 1 year of treatment. After 2 years of treatment, OC levels were significantly higher than at the start of the study (p < 0.05) in both groups of patients, but they were higher in group B than in group A (p < 0.05); on the contrary, urinary Ntx levels were lower in group B than in group A (p < 0.05). CONCLUSION: In GHD children, treated with GH, calcium supplementation improved bone mass; it may aid in reaching better peak bone mass and in protecting weight-bearing bones, usually completed in childhood to maximum levels, from risk of osteoporosis and fractures later in life.     

Effect of short-term therapy with recombinant human growth hormone (GH) on metabolic parameters and preclinical atherosclerotic markers in hypopituitary patients with growth hormone deficiency.

OBJECTIVE: This study examines the effects of growth hormone replacement on body composition, insulin sensitivity, lipid profile, endothelial dysfunction and carotid intima media thickness in patients with adult-onset growth-hormone (GH) deficiency. METHODS: Twelve patients with severe GH deficiency received GH replacement for one year. In all patients, the following parameters were evaluated before and after six and twelve months of therapy: fasting glucose, insulin levels and lipid profile, bone mineral density and body composition. Carotid intima media thickness and brachial flow-mediated dilatation were also evaluated by arterial ultrasonography at basal condition and after one year of therapy. RESULTS: No significant changes were seen in body weight and blood pressure, total fat and lean mass, or bone mineral density after six months of GH replacement. There was an increase in triglycerides (p = 0.05), while total and HDL cholesterol, blood glucose, insulin levels did not change significantly. After twelve months, an increase in lean mass and a decrease in fat mass (p < 0.01 vs. baseline), a decrease in insulin resistance (p < 0.01 vs. six months; p = 0.01 vs. baseline) and a decrease in triglycerides (p < 0.01) were observed. Intima media thickness was greater in GH deficiency than in controls (p = 0.01) before therapy, and was unchanged after twelve months of therapy, whereas the flow-mediated dilatation tended to improve (p = 0.05). CONCLUSIONS: GH replacement is able to reverse typical metabolic and body composition alterations in patients with adult GH deficiency after twelve months, but it is unable to revert the vascular alteration completely. Flow-mediated dilatation seems to be a more precocious marker of the remission of arterial damage.