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.     

Growth hormone - hormone replacement for the somatopause?

Twenty-four-hour growth hormone (GH) secretion reaches a peak at around puberty and by the age of 21 has begun to decrease. Thereafter the fall in GH secretion is progressive such that by the age of 60 most adults have total 24-hour secretion rates indistinguishable from those of hypopituitary patients with organic lesions in the pituitary gland. Patterns of GH secretion are similar to those in younger people but GH pulses are markedly reduced in amplitude. Sleep and exercise remain the major stimuli for GH secretion. The fall in GH secretion seen with ageing coincides with changes in body composition and lipid metabolism that are similar to those seen in adults with GH deficiency. In elderly subjects, although GH secretion is markedly reduced, remaining GH secretion correlates closely with body composition (particularly with lean body mass and inversely with central abdominal fat). Pioneering studies carried out by Rudman showed that GH administration to elderly subjects with low insulin-like growth factor-I levels resulted in reversal of many of the changes associated with GH deficiency, namely an increase in lean body mass and bone mineral density and a reduction in body fat and plasma cholesterol. These changes were remarkably similar to those shown a year earlier in adults with GH deficiency given GH replacement. Subsequent studies of GH replacement in elderly adults have confirmed Rudman's initial observations but have been dominated by side effects which have led to a high number of dropouts. It is now clear that the elderly are very sensitive to GH and the doses used need to be very low, increased very slowly and tailored to the individual needs of each patient. Using this more cautious approach, recent studies have been very positive. A series of papers from Blackman's group, presented at the US endocrine meeting in San Diego in 1999, investigated the effects of GH with or without testosterone supplements (in men) and oestrogen supplements (in women). Their results showed positive effects of GH on lean body mass, central fat, low-density lipoprotein cholesterol and aerobic capacity. In many instances there was a positive interaction between GH and hormone replacement with testosterone and oestrogen, but it appeared that GH showed the most potent anabolic effects. Clearly more studies are needed before GH replacement for the elderly becomes established. Safety issues will require close scrutiny, but the data available so far are sufficiently positive to undertake large multicentre, placebo-controlled trials, particularly looking at endpoints associated with prevention of frailty and loss of independence.     

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.     

Stentless Versus Stented Bioprosthetic Aortic Valves: A Consensus Statement of the International Society of Minimally Invasive Cardiothoracic Surgery (ISMICS) 2008

OBJECTIVE:: The purpose of this consensus conference was to determine whether stentless bioprosthetic valves improve clinical and resource outcomes compared with stented valves in patients undergoing aortic valve replacement, and to outline evidence-based recommendations for the use of stentless and stented bioprosthetic valves in adult aortic valve replacement. METHODS:: Before the consensus conference, the best available evidence was reviewed in that systematic reviews, randomized trials, and nonrandomized trials were considered in descending order of validity and importance. At the consensus conference, evidence-based statements were created, and consensus processes were used to determine the ensuing recommendations. The American Heart Association/American College of Cardiology system was used to label the level of evidence and class of recommendation. RESULTS AND RECOMMENDATIONS:: Seventeen randomized studies published in 23 articles involving 1317 patients, and 14 nonrandomized trial published in 18 articles involving 2485 patients were included in the meta-analysis and consensus conference. All randomized trials inserted the stentless bioprosthetic valves in the subcoronary configuration. The consensus panel agreed upon the following statements and recommendations in patients undergoing aortic valve replacement:Because there were no randomized control trial comparing subcoronary stentless prosthetic valve and root replacement, the following recommendations are derived from expert opinion:     

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.     

Effects of Growth Hormone Administration in Human Obesity

Objective: To summarize the reports in the literature regarding the effect of growth hormone (GH) treatment of obesity. Research Methods and Procedures: Clinical trials of GH treatment of obese adults were reviewed and summarized. Specifically, information regarding the effects of GH on body fat and body fat distribution, glucose tolerance/insulin resistance, and adverse consequences of treatment were recorded. Results: GH administered together with hypocaloric diets did not enhance fat loss or preserve lean tissue mass. No studies provided strong evidence for an independent beneficial effect of GH on visceral adiposity. In all but one study, glucose tolerance during GH treatment suffered relative to placebo. Conclusion: The bulk of studies indicate little or no beneficial effects of GH treatment of obesity despite the low serum GH concentrations associated with obesity.     

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.     

The effects of growth hormone deficiency and growth hormone replacement therapy on bone. A meeting report

Recently, several reports have described the effects of growth hormone (GH) deficiency (GHD) on bone and the associated potential benefits of GH therapy. Not all of these reports have, however, been consistent and the results are debated. Some of the contention surrounding this issue reflects disagreement about which bone parameters are the best indicators of bone strength and fracture risk. In November 1999, a meeting was held in Taormina, Italy, to discuss the assessment of bone in patients with GHD and the effects of GH therapy on the skeleton. The participants included endocrinologists, orthopaedists and biophysicists from around the world. During the meeting, the advantages and disadvantages of the various indicators of bone strength were defined. In considering GH therapy, the delegates agreed that it had beneficial effects on bone in adults with GHD, but that further studies were needed in GH-deficient children. Finally, the participants stressed the need for more data to clarify which indicator of bone strength is the most appropriate to use in adults and children with GHD, and to define fully the role of GH therapy in bone metabolism. It was recognized that pharmacoepidemiological surveys, such as KIGS (Pharmacia International Growth Database) and KIMS (Pharmacia International Metabolic Database), are valuable sources of such data, and are, therefore, important in the development of evidence-based medicine.     

Long-term monitoring of insulin-like growth factor I in adult growth hormone deficiency: a critical appraisal

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

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.     

Neurocognitive function in adults with growth hormone deficiency

The clinical condition of growth hormone deficiency (GHD) as a consequence of pituitary or hypothalamic disease has been associated with reduced cognitive performance. In several studies, neuropsychological assessment has been performed in adults with GHD both before and after growth hormone (GH) replacement therapy. Interpretation of the available data is complicated by the variation in patient selection as well as the neuropsychological tests used in such studies. Most of the available studies indicate that GHD can lead to small, but clinically relevant changes in memory, processing speed and attention. Some of these changes may be reversed by GH replacement, although the number of reliable intervention studies is limited. In addition to the possible clinical relevance of neuropsychological improvement following GH replacement in patients with GHD, the observed findings may be of interest for studies in neurocognitive performance in other conditions associated with changes in the activity of the somatotrophic axis, and in the understanding of underlying pathophysiological mechanisms.     

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.     

International clinical recommendations on scar management

Many techniques for management of hypertrophic scars and keloids have been proven through extensive use, but few have been supported by prospective studies with adequate control groups. Several new therapies showed good results in small-scale trials, but these have not been repeated in larger trials with long-term follow-up. This article reports a qualitative overview of the available clinical literature by an international panel of experts using standard methods of appraisal. The article provides evidence-based recommendations on prevention and treatment of abnormal scarring and, where studies are insufficient, consensus on best practice. The recommendations focus on the management of hypertrophic scars and keloids, and are internationally applicable in a range of clinical situations. These recommendations support a move to a more evidence-based approach in scar management. This approach highlights a primary role for silicone gel sheeting and intralesional corticosteroids in the management of a wide variety of abnormal scars. The authors concluded that these are the only treatments for which sufficient evidence exists to make evidence-based recommendations. A number of other therapies that are in common use have achieved acceptance by the authors as standard practice. However, it is highly desirable that many standard practices and new emerging therapies undergo large-scale studies with long-term follow-up before being recommended conclusively as alternative therapies for scar management.     

Determination of insulin-like growth factor-I in the monitoring of growth hormone treatment with respect to efficacy of treatment and side effects: should potential risks of cardiovascular disease and cancer be considered?

Insulin-like growth factor (IGF)-I has proven to be important in the diagnosis of childhood-onset growth hormone (GH) deficiency (GHD). However, the variability of IGF-I should be taken into account before it can be used in a clinical setting. GH replacement therapy in GHD patients increases IGF-I into the normal range, although there is a large variation. Excessively high (supranormal) GH-induced IGF-I levels are associated with increased prevalence of side effects in adults with GHD. Consequently, at most centres, GH doses are titrated according to IGF-I levels in GHD adults. Whether or not this should also be done in children has not been established. Due to the known variability of IGF-I, individual changes in IGF-I must exceed approximately 35% to be sufficiently significant to warrant a dose adjustment. Novel epidemiological studies have suggested that higher IGF-I levels are associated with an increased risk of prostate, breast and colorectal cancer compared with lower IGF-I levels in otherwise healthy subjects. Consequently, life-time exposure to IGF-I should be considered in all patients treated with GH, and IGF-I should preferably be kept within normal age-related ranges in children as well as in adults.     

Evidence-based medicine,opinion-based medicine,and real-world medicine

The freedom of a doctor to treat an individual patient in the way he believes best has been markedly limited by the concept of evidence-based medicine. Clearly all would wish to practice according to the best available evidence, but it has become accepted that "evidence-based" means that which is derived from randomized, and preferably double-blind, clinical trials. The history of clinical trial development, which can be traced to the use of oranges and lemons for the treatment of scurvy in 1747, has reflected a progressive need to establish whether smaller and smaller effects of treatment are real. It has led to difficult concepts such as "equivalence" and aberrations such as "meta-analysis." An examination of evidence-based practice shows that it has usually been filtered through the opinions of experts and journal editors, and "opinion-based medicine" would be a more appropriate term. In the real world of individual patients with multiple diseases who are receiving a number of different drugs, the practice of evidence-based (or even opinion-based) medicine is extremely difficult. For each patient a judgment has to be made by the clinician of the likely balance of risks and benefits of any therapy. Good practice still requires clinical freedom for doctors.     

The status of psychodynamic psychotherapy as an empirically supported treatment for common mental disorders – an umbrella review based on updated criteria

To assess the current status of psychodynamic therapy (PDT) as an empirically supported treatment (EST), we carried out a pre-registered systematic umbrella review addressing the evidence for PDT in common mental disorders in adults, based on an updated model for ESTs. Following this model, we focused on meta-analyses of randomized controlled trials (RCTs) published in the past two years to assess efficacy. In addition, we reviewed the evidence on effectiveness, cost-effectiveness and mechanisms of change. Meta-analyses were evaluated by at least two raters using the proposed updated criteria, i.e. effect sizes, risk of bias, inconsistency, indirectness, imprecision, publication bias, treatment fidelity, and their quality as well as that of primary studies. To assess the quality of evidence we applied the GRADE system. A systematic search identified recent meta-analyses on the efficacy of PDT in depressive, anxiety, personality and somatic symptom disorders. High quality evidence in depressive and somatic symptom disorders and moderate quality evidence in anxiety and personality disorders showed that PDT is superior to (inactive and active) control conditions in reducing target symptoms with clinically meaningful effect sizes. Moderate quality evidence suggests that PDT is as efficacious as other active therapies in these disorders. The benefits of PDT outweigh its costs and harms. Furthermore, evidence was found for long-term effects, improving functioning, effectiveness, cost-effectiveness and mechanisms of change in the aforementioned disorders. Some limitations in specific research areas exist, such as risk of bias and imprecision, which are, however, comparable to those of other evidence-based psychotherapies. Thus, according to the updated EST model, PDT proved to be an empirically-supported treatment for common mental disorders. Of the three options for recommendation provided by the updated model (i.e., “very strong”, “strong” or “weak”), the new EST criteria suggest that a strong recommendation for treating the aforementioned mental disorders with PDT is the most appropriate option. In conclusion, PDT represents an evidence-based psychotherapy. This is clinically important since no single therapeutic approach fits all psychiatric patients, as shown by the limited success rates across all evidence-based treatments.     

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     

The role of the GH/IGF-I axis for cardiac function and structure.

There is ample evidence to support a role for the GH/IGF-I axis in regulation of cardiac growth, structure and function. GH may act directly on the heart or through circulating IGF-I (Fig. 1). Moreover, GH has been found to regulate local production of IGF-I in the heart. Both the GH-R and IGF-I-R are expressed in cardiac tissue. Hence, the IGF-I-R receptor can theoretically be activated through locally produced IGF-I acting via autocrine/paracrine mechanisms, or via circulating IGF-I exerting its effects as an endocrine agent. During conditions of pressure and volume overload, an increased systolic wall stress triggers an induction of gene expression of IGF-I GH-R and possibly IGF-J-R implying a potential role for the GH/IGF-I axis in the development of adaptive hypertrophy of the heart and vessels. Cardiovascular effects of GH in clinical studies include beneficial effects on contractility, exercise performance and TPR, and experimental studies suggest an increased Ca2+ responsiveness as one possible underlying cause, although effects of GH and IGF-I on apoptosis may possibly also play a role. The GH secretagogue hexarelin improves cardiac function after experimental myocardial infarction either through an increased GH secretion or possibly through a cardiac GHS receptor, although this needs further investigation. Moreover, it is clear that further basic and clinical studies are required to gain insight into the GH and IGF-I mechanisms of action and to monitor long-term effects when GH is administered as substitution therapy or as an agent in the treatment of congestive heart failure.     

Evidence-Based Medicine,Clinical Practice Guidelines,and Common Sense in the Management of Osteoporosis

ObjectiveTo evaluate the benefits and limitations of randomized controlled trials (RCTs), clinical practice guidelines (CPGs), and clinical judgment in the management of osteoporosis.MethodsA review was conducted of the English-language literature on the origins and applications of RCTs, CPGs, evidence-based medicine, and clinical judgment in the management of osteoporosis.ResultsEvidence-based medicine is use of the currently available best evidence in making clinical decisions for individual patients. CPGs are recommendations for making clinical decisions based on research evidence, sometimes with consideration of expert opinion, health care policy, and costs of care. The highest levels of medical evidence are usually thought to be RCTs and meta-analyses of high-quality RCTs. Although it is desirable and appropriate for clinicians to consider research evidence from RCTs and recommendations presented in CPGs in making clinical decisions, other factors—such as patient preference, comorbidities, affordability, and availability of care—are important for the actual implementation of evidence-based medicine.ConclusionDecisions about who to treat, which drug to use, how best to monitor, and how long to treat require clinical skills in addition to knowledge of medical research. The necessity of integrating common sense and clinical judgment is highlighted by the fact that many patients treated for osteoporosis in clinical practice would not qualify for participation in the pivotal clinical trials that demonstrated efficacy and safety of the drugs used to treat them. (Endocr Pract. 2009;15:573-579)     

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.