Growth Hormone Deficiency Syndrome Research Articles

The long-term growth, cost-effectiveness, and glycemic effects of growth hormone therapy on children born small for gestational age over 10years: a retrospective cohort study.

We aimed to report our 10-year experience of treating short children born small for gestational age (SGA) by comparing the long-term growth, metabolic safety, and cost-effectiveness of recombinant human growth hormone (rhGH) therapy in short children born SGA with those in rhGH-treated children with growth hormone deficiency (GHD) and Turner syndrome. We performed a 10-year retrospective cohort study at King Saud University Medical City. We included children aged 3-16years who received rhGH for GHD, SGA, or Turner syndrome for >1year. A total of 166 children received rhGH therapy for GHD, 58 for SGA, and 16 for Turner syndrome. During the last study visit, the average height change was 21cm for GHD children and 14cm for children born SGA (p-value <0.001). The height SDS change was 0.84 forGHD children and 0.55 for SGA children (p-value=0.004). The average cost-effectiveness ratios for treating GHD and SGA children were USD 1,717.22 and USD 1,157.19 per centimeter gained, respectively. Moreover, the mean incremental cost-effectiveness ratio for GHD vs. SGA patients was USD 2,820.39 per centimeter gained. Dysglycemia developed in 70 patients: 43 (36.44%), 22 (40.74%), and 5 (13%) in the GHD, SGA, and Turner syndrome groups, respectively. rhGH is effective in height improvement of short children. However, pursuing rhGH treatment for children born SGA requires a shared decision-making approach to balance the modest benefit of final adult height gain with the long-term metabolic effects, considering the acceptable costs on the Saudi healthcare system.

Compliance to Growth Hormone Therapy in Children and Adolescents with Growth Hormone Deficiency and Turner Syndrome and Impact on Height Velocity: A Prospective Study

Adherence to recombinant growth hormone (rGH) in children is necessary to ensure good treatment outcome. Reported non-compliance to rGH in children varied from 5-82% with little data involving Asian population. The objectives of this study are to evaluate the compliance of children and adolescents to rGH, effect of non-compliance on growth and factors affecting non-adherence. Methods: This is a prospective cohort study over 1-year aiming at all patients age less than 18 years old treated with rGH in our centre. Compliance was assessed from the number of returned medications and electronic record within device. Poor compliance was defined as utilised dose &lt;86% prescribed (equivalent to missing injection ≥1 per week). Result: Thirty-four patients were recruited including 20 (59%) patients with GH deficiency and 14 (41%) with Turner syndrome. Poor compliance was noted in 35% of patients. Poor compliance in GHD patients was significantly associated with an older age (mean 12.55 ± 3.33 vs 9.28 ± 3.20 years old, p=0.038) and longer duration of treatment (mean 5.41 ± 3.0 vs 2.93 ± 2.18 years, p=0.046). Frequent reasons for missing doses were forgetfulness and inadequate medications. Participants with poor compliance had significantly reduced height velocity (HV) and HV standard deviation score (SDS) compared to those with good compliance (p&lt;0.05). Conclusion: Poor compliance is more common in adolescents, those on longer duration of treatment and leads to significantly reduced height velocity. Regular monitoring throughout the course of rGH is important. Measures to improve compliance must address the underlying reasons.

Gene expression signatures predict response to therapy with growth hormone

Recombinant human growth hormone (r-hGH) is used as a therapeutic agent for disorders of growth including growth hormone deficiency (GHD) and Turner syndrome (TS). Treatment is costly and current methods to model response are inexact. GHD (n = 71) and TS patients (n = 43) were recruited to study response to r-hGH over 5 years. Analysis was performed using 1219 genetic markers and baseline (pre-treatment) blood transcriptome. Random forest was used to determine predictive value of transcriptomic data associated with growth response. No genetic marker passed the stringency criteria for prediction. However, we identified an identical set of genes in both GHD and TS whose expression could be used to classify therapeutic response to r-hGH with a high accuracy (AUC > 0.9). Combining transcriptomic markers with clinical phenotype was shown to significantly reduce predictive error. This work could be translated into a single genomic test linked to a prediction algorithm to improve clinical management. Trial registration numbers: NCT00256126 and NCT00699855.

Treatment of the adult growth hormone deficiency syndrome with growth hormone: What are the implications for other hormone replacement therapies for hypopituitarism?

When initiating growth hormone replacement therapy, it is important to consider a patient's other pituitary hormone replacement medications, as adjustments are often necessary. Growth hormone therapy can increase the metabolism of hydrocortisone or endogenous cortisol, unmasking borderline ACTH deficiency and leading to the development of adrenal insufficiency and adrenal crisis. In addition, growth hormone can enhance the metabolism of thyroxine to triiodothyronine, uncovering borderline TSH deficiency. In many patients, thyroid hormone replacement therapy must be started, or the dose of levothyroxine must be increased. Oral estrogen replacement therapy leads to a state of relative growth hormone resistance, and the dose of GH may need to be increased substantially. Physicians have long been cognizant of the fact that adding a new prescription medication may lead to important drug-drug interactions. Starting growth hormone therapy may lead to hormone-hormone interactions that can pose serious complications for the hypopituitary patient unless the interaction of growth hormone on other pituitary hormone systems is understood.

Craniofacial Morphology in Children with Growth Hormone Deficiency and Turner Syndrome.

The review aims to collect and demonstrate recent knowledge about craniofacial morphology in growth hormone (GH)-deficient children and children with Turner syndrome. The review describes also the effects of growth hormone treatment on craniofacial morphology of children with growth hormone deficiency and Turner syndrome. Regardless of the disorder it accompanies, short stature is associated with similar craniofacial features characteristic of all short-statured children. Characteristic craniofacial features involve lesser dimensions of the cranial base and mandibular length, proportionately smaller posterior than anterior facial height, retrognathic face, and posterior rotation of the mandible. We also analyze orthodontic treatment in children affected by disorders associated with GH deficiency or provided with growth hormone treatment in the aspect of craniofacial growth. Recent publications show also the connection between growth hormone receptor polymorphism and craniofacial growth. Specialists and orthodontists treating short-statured children must be aware of the results of studies on craniofacial morphology and educate themselves on the topic of craniofacial growth in children with short stature. Moreover, knowledge of the influence of GH therapy on growth of craniofacial structures is necessary to decide the proper timing and planning of orthodontic treatment.

Untreated adult GH deficiency is not associated with the development of metabolic risk factors: a long-term observational study.

Uncertainties exist about the predictors of the severity of the clinical picture of GH deficiency (GHD) syndrome. Aim of the study was to evaluate, in adult patients with GHD, the predictors of the development of hypercholesterolemia, hypertension, diabetes mellitus, and osteoporosis. We retrospectively studied 327 adult patients (age 47.1 ± 17.1years) with untreated severe GHD (mean follow-up 110.9 ± 56.8months). GHD was defined by GHRH + arginine test using BMI cut-offs. The possible development of hypercholesterolemia, hypertension, diabetes mellitus, and osteoporosis was investigated by Kaplan-Meier survival analysis. For each clinical outcome, either a univariate or multivariate analysis according to the Cox proportional-hazards model was performed to identify those factors that were associated with the development of the event. GH secretion parameters were not associated with the outcomes. Hypercholesterolemia was positively and negatively predicted by a BMI ≥ 30kg/m2 (HR 2.50, p 0.00) and the dose of l-thyroxine possibly in place (HR 0.98, p 0.02), respectively. Hypertension was positively predicted by a BMI ≥ 30kg/m2 (HR 2.64, p 0.00) and IGF-I SDS values (HR 2.26, p 0.00). Diabetes mellitus was positively predicted by hypertension (HR 11.76, p 0.01). Osteoporosis was positively and negatively predicted by hypercholesterolemia (HR 3.25, p 0.01) and hypertension (HR 0.21, p 0.00), respectively. The severity of the impairment of GH secretion does not predict the development of the clinical picture of GHD syndrome: untreated adult GHD does not increase the development of metabolic risk factors in hypopituitaric patients.

Growth Hormone and ACTH Deficiency in a Diabetic Adult

Adult growth hormone deficiency (AGHD) syndrome has a constellation of features, like impaired cognitive function, altered body composition, poor quality of life and various metabolic changes. Most of its features resemble signs of aging as growth hormone (GH) secretion decreases with age. Hypothalamic-pituitary-adrenal (HPA) axis should be thoroughly investigated in this disease as patients with AGHD are at risk of life-threatening consequences due to partial or complete ACTH deficiency, especially in stressful conditions. GH deficiency has also been related to diabetes or glucose intolerance. It is relatively underdiagnosed problem in adults and requires a thorough workup including dynamic function tests like insulin tolerance test (ITT), which has been termed as the gold standard for the diagnosis of patients with ACTH deficiency.

Serum soluble urokinase plasminogen activator receptor (suPAR) in adults with growth hormone deficiency.

Growth hormone deficiency (GHD) syndrome is associated with adverse levels of several risk factors for cardiovascular diseases (CVD), including metabolic inflammation. However, the impact of GHD and GH treatment on low-grade inflammation is unknown. The aim of the study was to establish the level of the low-grade inflammation biomarker soluble urokinase plasminogen activator receptor (suPAR) in adults with GHD and the response to long-term GH treatment. Measurements of suPAR and CRP were performed in bio-bank serum samples from 72 adults, 34 males and 38 females, with GHD before and during at least 5 years of GH treatment. Mean age was 52.5 ± 15.5 years, BMI 27.3 ± 5 kg/m2. Clinical evaluations and blood sampling were performed at routine visits. Data on demography, anthropometry, lab results and clinical events were retrieved from post-marketing surveillance study databases and medical records. suPAR and high-sensitive (hs) CRP were analysed using ELISA and immunochemistry, respectively. At baseline blood pressure, lipid profile and fasting glucose were within the normal reference range. Baseline geometric mean and 95% CI of suPAR was 2.9 (2.7–3.3) ng/mL and of CRP 2.3 (0.6–4.0) mg/L. Mean follow-up was 8 ± 2 years. The suPAR levels remained stable during follow-up, although individual increases were seen on occurrence or presence of co-morbidities. In contrast, levels of CRP decreased. In conclusion, the decrease in CRP and indirectly the absence of an expected increase in suPAR over time indicates a favourable effect of GH on low-grade inflammation.

SUN-257 Adherence Rates to Growth Hormone Therapy: ECOS Study Analysis of Australian Data Compared with Global Adherence Rates

Background: The ECOS observational study was a long term, multicentre, observational study that looked at assessing the level of adherence to paediatric patients’ prescribed recombinant GH (r-hGH) Saizen (somatropin) via the Easypod® electromechanical auto-injector device, and to then further analyse possible clinical and socioeconomic factors that influence adherence. Aim: To evaluate and compare Australian adherence rates of r-hGH compared with existing global data. Method: Adherence data was determined directly from data downloaded from each Easypod device, while standard baseline and outcomes measures were obtained directly from patient medical notes including socioeconomic, demographic, auxological and diagnostic data. Patients were included on the basis of eligibility for subsidised hGH - diagnoses included growth hormone deficiency (GHD), (sub-analysed as prior GH exposure and GH-naive), small for gestation age, those with chronic renal insufficiency and girls with Turner syndrome. The following data was collected on all patients with a complete data set (CAS): (CAS: Easypod start date documented, no gap in injection data of more than a week, and height documented at baseline and 1 year after the start of easypod). Results: Globally 2417 patients were analysed and, within this, 1203 met the complete data set analysis set (CAS) and were further analysed. The Australian cohort consisted of 28 patients of whom 19 had a complete CAS. This included patients with both GHD (n = 13) and Turner syndrome (n = 6). The median adherence rate was 98.4% at 1 year and 92.6% at 4 years. There was a positive correlation between adherence and change in height (cms), r = 0.739 p = 0.0061 and adherence and height velocity (cms), r = 0.664 p = 0.023, for patients with GHD The greatest response was seen in the GH-naïve dataset. 13 patients had a medium change at 1-year SDS >0.5, indicating an equal to greater positive response. Conclusion: The Australian data from the ECOS study provides additional information regarding adherence to Growth Hormone therapy and growth outcomes. Electronic monitoring potentially provides clinicians an early opportunity to address adherence in a timely manner to promote maximum outcomes.

Gene expression signatures in children with growth hormone deficiency (GHD) and Turner syndrome (TS) predict response to growth hormone

Gene expression signatures in children with growth hormone deficiency (GHD) and Turner syndrome (TS) predict response to growth hormone

Plasmatic free light chains as inflammatory marker in insulin resistance: comparison of metabolic syndrome with adult growth hormone deficiency.

Biological functions of immunoglobulin-free light chains (FLCs), other than in chronic inflammatory diseases, are still poorly defined; the field of insulin resistance (IR) has not been investigated, despite the strict relationships with oxidative stress (OS) and inflammation. Therefore, we evaluated FLCs levels and their relationships with metabolic parameters in adult growth hormone deficiency (GHD) and metabolic syndrome (MetS), both characterized by IR. One hundred subjects were enrolled: group A, patients with GHD [n =31, 24-69 years, mean ± SEM body mass index (BMI) 26.8 ± 1.5 kg/m2 ]; group B, patients with MetS (n = 29, 21-70 years, BMI 31.9 ± 1.3); group C, controls (N = 40, 21-62 years, BMI 21.6 ± 1.1). Groups were matched by age range and, for patients, by BMI. Morning blood sample was collected for metabolic parameters and FLCs, assessed by turbidimetric assay. GHD patients show levels of FLCs significantly higher than MetS and controls (mean ± SEM κ 37.21 ± 6.97, 15.27 ± 0.86, 12.34 ± 0.85 mg/l; λ 19.44 ± 2.61, 11.78 ± 0.72 and 11.67 ± 0.77 mg/l; κ/λ ratio 1.77 ± 0.13, 1.38 ± 0.09; and 1.10 ± 0.06, respectively); only κ were higher in MetS versus controls. Therefore, the ratio showed progressive declining values in GHD versus MetS versus controls. Our data show increased FLCs levels in GHD and MetS, with the highest values in the former. Both conditions show OS, but with different molecular patterns. FLCs may contribute to chronic inflammation, leading to OS, and cardiovascular complications of GHD. Prognostic and therapeutic implications require further investigation. © 2018 BioFactors, 44(5):480-484, 2018.

Treatment with Growth Hormone for Adults with Growth Hormone Deficiency Syndrome: Benefits and Risks.

Pharmacological treatment of growth hormone deficiency (GHD) in adults began in clinical practice more than 20 years ago. Since then, a great volume of experience has been accumulated on its effects on the symptoms and biochemical alterations that characterize this hormonal deficiency. The effects on body composition, muscle mass and strength, exercise capacity, glucose and lipid profile, bone metabolism, and quality of life have been fully demonstrated. The advance of knowledge has also taken place in the biological and molecular aspects of the action of this hormone in patients who have completed longitudinal growth. In recent years, several epidemiological studies have reported interesting information about the long-term effects of GH replacement therapy in regard to the possible induction of neoplasms and the potential development of diabetes. In addition, GH hormone receptor polymorphism could potentially influence GH therapy. Long-acting GH are under development to create a more convenient GH dosing profile, while retaining the excellent safety, efficacy, and tolerability of daily GH. In this article we compile the most recent data of GH replacement therapy in adults, as well as the molecular aspects that may condition a different sensitivity to this treatment.

Deregulation of the growth hormone/insulin-like growth factor-1 axis in adults with cystic fibrosis.

Patients with cystic fibrosis (CF) present with signs and symptoms that overlap with those of adult growth hormone deficiency (GHD) syndrome: loss of muscle mass, bone fragility and lower stress tolerance. In literature, the prevalence of GHD in pediatric CF patients is higher than general population, but these studies have been performed on children with growth delay. To our knowledge, there are no studies on adult patients. The aim of this paper is to evaluate GH-IGF1 axis in an adult CF population. Fifty clinically stable adult patients, 30 males; age 36±2years; BMI 21.39±0.22kg/m2 and FEV1 67±4% were studied. Data regarding glycometabolic status and results of pituitary, thyroid, parathyroid, gonadal and adrenal function tests were recorded. All patients underwent a GH releasing hormone (GHRH)+Arginine stimulation test to confirm a GHD. GHRH+Arginine test revealed the presence of GHD in 16 patients (32%); specifically 7 patients had a severe deficiency and 9 a partial deficiency. Adult patients with CF may show GHD. These patients should be followed over time to assess if the GHD could impact the clinical progression of CF.

018–Local Tolerability and Safety Profile of Somatropin (Recombinant Human Growth Hormone) in Pediatric Patients With Growth Hormone Deficiency or Turner Syndrome

Background: Somatropin is indicated for treatment of pediatric growth hormone deficiency (GHD) in the United States and for treatment of pediatric GHD and Turner syndrome (TS) in the European Union. Aims: To assess the local tolerability and safety profile of somatropin administered using the ZomaJet™ needle-free transjector. Methods: This prospective, open-label, multicenter study enrolled children (aged 3–17 years) with GHD or TS receiving recombinant human growth hormone for ≥6 months. Patients received 12 weeks of individualized doses of somatropin 10 mg administered with the ZomaJet™. The primary endpoint was proportion of patients discontinuing treatment due to unacceptable transjection-related local tolerability reactions. Secondary endpoints included cumulative assessment of local tolerability reactions at initiation and weeks 2, 6, and 12 by the local investigator, followed by evaluation of transjection area photographs by a central dermatologist. Immediate local tolerability reactions and adverse events (AEs) were also assessed. Patients at 1 site were then enrolled in a 24-week extension study. Results: Patients (N=27) with a mean (standard deviation [SD]) age of 10.3 (3.8) years received a mean (SD) number of 78.6 (14.6) transjections. One patient (3.7%; 95% confidence interval: 0.1%, 19.0%) withdrew because of an unacceptable transjection-related local tolerability reaction. The majority of reactions (74%–98%) were classified as mild in severity. Bruising and punctual hemorrhage were the most frequently reported reactions by week 12 per both local (58%–62%) and central (50%–58%) assessments. One reaction (bruising) was classified as severe by the local investigator but moderate by the central assessor. Most immediate local tolerability reactions decreased in incidence starting 15 minutes after transjection. Three AEs were reported: influenza (n=2) and application site pain (n=1; patient withdrew). No AEs or unexpected reactions occurred in the 24-week extension (n=6). Conclusions: Incidence of local tolerability reactions with somatropin 10 mg administered via the ZomaJet™ needle-free transjector was low; more data are needed to precisely determine the incidence of unacceptable reactions. Clinical implications: Routine use of Somatropin 10 mg and the ZomaJet™ needle-free transjector may be well tolerated in children with GHD and TS; immediate local reactions may dissipate within 15 minutes after administration.

Thyroid, cortisol and growth hormone levels in adult nigerians with metabolic syndrome

IntroductionThe similarities in presentation of cortisol excess, growth hormone deficiency, hypothyroidism and metabolic syndrome suggest that subtle abnormalities of these endocrine hormones may play a causal role in the development of metabolic syndrome. The aim of this study is to determine the levels of cortisol, thyroid and growth hormones in adult Nigerians with metabolic syndrome and determine the relationship between levels of these hormones and components of the syndrome.MethodsThis was a case control study conducted at the Lagos University Teaching Hospital, Lagos, Nigeria. Participants were fifty adult men and women with the metabolic syndrome, and fifty, age and sex matched males and females without the metabolic syndrome. Metabolic syndrome was defined based on the NCEP-ATPIII criteria. Written Informed consent was obtained from the participants. Socio demographic and clinical data were collected using a structured questionnaire. Venous blood was collected after an over-night fast. The Ethics committee of the Lagos University Teaching Hospital, Lagos, Nigeria, approved the study protocol. Comparison of continuous variables was done using the Student's t test. Correlation analysis was employed to determine the associations between variables. Statistical significance was set at P<0.05.ResultsTriiodotyronine (T3) was significantly decreased (p<0.001) and thyroxine (T4 ) significantly increased ( p<0.001) in metabolic syndrome compared to healthy controls. T3 correlated positively and significantly with waist circumference (p=0.004), glucose (p= 0.002), total cholesterol ( p=0.001) and LDL- cholesterol ( p<0.001 ) and negatively with body mass index ( p<0.001 )and triglyceride ( p=0.026). T4 had a negative significant correlation with waist circumference (p=0.004). Cortisol and growth hormone levels were similar in metabolic syndrome and controls. Cortisol however had a positive significant correlation with waist/hip ratio (p<0.001) while growth hormone correlated positively with HDL ( p=0.023)and negatively with diastolic blood pressure (p=0.049).ConclusionThyroid hormones T3 and T4 were associated with metabolic syndrome. The thyroid hormones, cortisol and growth hormones correlated with components of the syndrome. A therapeutic role may exit for these hormones in the management of metabolic syndrome and related disorders.

A Critical Appraisal of Growth Hormone Therapy in Growth Hormone Deficiency and Turner Syndrome Patients in Turkey.

Early detection of abnormal growth, identification of the underlying cause, and appropriate treatment of the medical condition is an important issue for children with short stature. Growth hormone (GH) therapy is widely used in GH-deficient children and also in non-GH-deficient short stature cases who have findings conforming to certain indications. Efficacy of GH therapy has been shown in a multitude of short- and long-term studies. Age at onset of GH therapy is the most important factor for a successful treatment outcome. Optimal dosing is also essential. The aim of this review was to focus on challenges in the early diagnosis and appropriate management of short stature due to GH deficiency (GHD) and Turner syndrome. These are the most frequent two indications for GH therapy in Turkey approved by the Ministry of Health for coverage by the national insurance system.

Validating genetic markers of response to recombinant human growth hormone in children with growth hormone deficiency and Turner syndrome: the PREDICT validation study.

ObjectiveSingle-nucleotide polymorphisms (SNPs) associated with the response to recombinant human growth hormone (r-hGH) have previously been identified in growth hormone deficiency (GHD) and Turner syndrome (TS) children in the PREDICT long-term follow-up (LTFU) study (Nbib699855). Here, we describe the PREDICT validation (VAL) study (Nbib1419249), which aimed to confirm these genetic associations.Design and methodsChildren with GHD (n = 293) or TS (n = 132) were recruited retrospectively from 29 sites in nine countries. All children had completed 1 year of r-hGH therapy. 48 SNPs previously identified as associated with first year growth response to r-hGH were genotyped. Regression analysis was used to assess the association between genotype and growth response using clinical/auxological variables as covariates. Further analysis was undertaken using random forest classification.ResultsThe children were younger, and the growth response was higher in VAL study. Direct genotype analysis did not replicate what was found in the LTFU study. However, using exploratory regression models with covariates, a consistent relationship with growth response in both VAL and LTFU was shown for four genes – SOS1 and INPPL1 in GHD and ESR1 and PTPN1 in TS. The random forest analysis demonstrated that only clinical covariates were important in the prediction of growth response in mild GHD (>4 to <10 μg/L on GH stimulation test), however, in severe GHD (≤4 μg/L) several SNPs contributed (in IGF2, GRB10, FOS, IGFBP3 and GHRHR).ConclusionsThe PREDICT validation study supports, in an independent cohort, the association of four of 48 genetic markers with growth response to r-hGH treatment in both pre-pubertal GHD and TS children after controlling for clinical/auxological covariates. However, the contribution of these SNPs in a prediction model of first-year response is not sufficient for routine clinical use.

Baixa Estatura e haploinsuficiência do gene SHOX

Introduction: SHOX gene (short stature homeobox gene) deficiency is one of the most frequent genetic causes of isolated or familial short stature, with highly variable clinical severity.Case-report: The authors describe a 14 year-old-girl, with short limbs and short stature. The wrist X-ray showed Madelung deformity. The molecular study showed deletion of the SHOX gene (FISH del (X) (Xp22.3Xp22.3) (SHOX). A very careful physical examination, including measurement of body proportions, is of extreme importance in the clinical evaluation of short stature. The Madelung deformity can only appear in the adolescence. Treatment with growth hormone can improve the final height.Discussion/Conclusions: The prevalence of short stature due to SHOX gene mutations among children with short stature appears to be similar to that of Growth Hormone deficiency or Turner syndrome. The authors’ intention is to draw attention to this clinical entity, since a timely diagnosis can have therapeutic implications.

PDB37 - Treatment of Brazilian children with growth hormone deficiency and turner syndrome: Implications of a data-driven approach to guide decisions

PDB37 - Treatment of Brazilian children with growth hormone deficiency and turner syndrome: Implications of a data-driven approach to guide decisions

Adult Growth Hormone Deficiency: Current Concepts

The clinical syndrome of adult growth hormone deficiency (AGHD) was widely recognized in the 1980s. In this review, we first describe the clinical features and diagnosis of AGHD and then state the effects of growth hormone (GH) therapy for these patients. The main characteristics of AGHD are abnormal body composition, dyslipidemia, insulin resistance, and an impaired quality of life (QoL) due to decreased psychological well-being. For diagnosing AGHD, the international consensus guidelines have suggested that an insulin tolerance test (ITT) is the gold standard, but in Japan, the growth hormone releasing peptide-2 (GHRP-2) test is available and is recommended as a convenient and safe GH stimulating test. The cut-off for diagnosing severe AGHD is a peak GH concentration of 9 g/L during the GHRP-2 test. Since 2006, GH therapy has been approved for Japanese patients with severe AGHD. For adults, GH replacement therapy should be initiated at a low dose (3 g/kg body weight/day), followed by individualized dose titration while monitoring patients' clinical status and serum insulin-like growth factor-I (IGF-I) concentrations. A variety of favorable effects of GH replacement have been indicated; however, it has not yet been established fully whether there is a direct effect of GH treatment on reducing mortality.