Onset Growth Hormone Deficiency Research Articles

IGF-1 as screening tool for acromegaly and adult-onset growth hormone deficiency in the Netherlands.

Insulin-like growth factor 1 (IGF-1) measurements play a central role in the diagnosis and follow-up of acromegaly and growth hormone deficiency. However, improving health care outcomes for these patients involves an intricate process of laboratory diagnostics and skilled health care professionals. The integrated effects of IGF-1 reports on diagnosis and treatment decisions are yet unknown. Extended quality assessment, distributing the description of five (real) patient cases with accompanying blood samples. Patients suspected or during follow up for acromegaly or adult onset of growth hormone deficiency were included. Laboratory specialists and endocrinologists in the same centre were asked to interpret their centre-specific IGF-1 results by using a laboratory and medical questionnaire. This way, insight could be obtained into the combined effects of different assays, assay harmonisation, reference value sets, and individual physician interpretation in relation to guidelines, thus reviewing the entire diagnostic and management process. Limited variation (CV 13.8 ± 2.8) was found in IGF-1 concentrations despite different use of the harmonization sample and factor among laboratories. This interlaboratory variation increased upon conversion to SD scores (CV 15.7 ± 40.7) as a consequence of the use of different reference value sets. Furthermore, there was a lack of adherence to international guidelines among endocrinologists. Highly variable diagnostic and treatment outcomes in acromegaly and AGHD in the Netherlands can be attributed to increased variability of IGF-1 upon conversion to SD scores and low adherence to clinical guidelines.

Individual sensitivity to growth hormone replacement in adults.

The metabolic actions of growth hormone (GH) last a lifetime and involve several physiological functions associated with the control of body composition, energy metabolism, water regulation, immune response, cardiovascular performance, physical and mental work. Adult patients with GH deficiency (GHD) present a constellation of clinical findings, which include increased total and visceral body fat, low bone and muscle mass, reduced muscle strength, impaired anaerobic physical capacity, unfavorable cardiovascular profile, and poor quality of life. Recombinant human GH (rhGH) therapy has been proved to reverse or improve many abnormalities associated with GHD in adult life, but the therapeutic response is highly variable among patients and influenced by multiple factors, which are the main focus of this narrative review. Given the individual sensitivity of adult GHD patients to rhGH replacement, dose regimens evolved from weight-based to individualized dose-titration strategies, which improved efficacy and reduced the frequency of adverse events. Individual tailoring and maintenance doses of rhGH are mainly influenced by age, age at GHD onset, sex, body mass index, baseline GH status, quality of life and other pituitary hormone replacements. In addition, genetic background and poor adherence due to patient or product-related factors might play a role in the responsiveness to rhGH therapy. There have been attempts to develop predictive mathematical models to distinguish good and poor responders to rhGH therapy, but thus far none of them have been prospectively tested and validated in a large cohort of adult GHD individuals.

Body composition and bone mineral density in 107 patients with childhood onset growth hormone deficiency (CO-GHD) at the time of transition from pediatric to adulthood endocrine care

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Effect of long term rhgh treatment on bone mineral density in patients with childhood onset growth hormone deficiency

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

SUN-310 Growth Hormone Deficiency and Replacement Therapy: Association with Health-Related Physical Fitness

Objective: To compare health-related physical fitness (HRPF) in patients with severe adult growth hormone deficiency (AGHD) according to the deficiency onset phase, and to evaluate the effects of a six-months human growth hormone (rhGH) replacement therapy on HRPF, in a subgroup of patients. Methods: First arm: cross-sectional observational study at baseline of naive rhGH multiple pituitary hormonal deficiency (MPHD) hypopituitarism patients - adult-onset growth hormone deficiency (AO-GHD) versus child onset growth hormone deficiency (CO-GHD). Second arm: a 6-month intervention clinical trial in a selected group of a non-randomized, non-controlled cohort. HRPF was evaluated by measuring isokinetic and isometric torque stensor strength at the knee using an isokinetic dynamometer, handgrip strength and six-minute walk test. Body composition was assessed by DXA. Results: Patients who presented AO-GHD had higher BMI than CO-GHD (28.1±3.5 x 22.4±4.8; p=0.017), but body composition (lean body mass%:57.9±7.9 x 58.9±8.6;p=0.816/fatty body mass%:39.3±6.8 x 36.0±9.1;p=0.434), stensor peak torque/body weight at 60, 90 and 180deg/s (2.18±0.6 x 2.18±0.6; p=0.580/1.99±0.5 x 2.14±0.5;p=0.546/1.52±0.4 x 1.64±0.4;p=0.547), isometric torque/body weight at the knee (2.62±0.7 x 2.91±0.6;p=0.357) and six-minute walk test (570.2±76.0cm x 554.1±91.0cm;p= 0.703) did not differ between groups. Handgrip strength test also showed significant reduction in scores for age and gender in both groups of GHD patients. After six months of rhGH, no improvement in muscular strength tests was found. There was a significant worsening in the six-minute walk test (575.1±84cm x 545.4±90.6cm; p=0.033) despite the improvement in body composition (lean body mass%:59.7±8.6 x 63.6±11.1;p=0.005/fatty body mass%:35.7±9.2 x 32.9±10.0;p=0.003). Conclusion: Despite differences in BMI, there were no other differences in HRPF between AO-GHD and CO-GHD patients. The decrease of the six-minute walking test performance after rhGH replacement therapy supports the clinical evidence that the GH regulates bioenergetics in human skeletal muscle fibers. Although the treatment had a short period, GH might have stimulated the anaerobic and suppressed the aerobic energy system.

MON-LB56 Metabolic Profile in 107 Patients With Childhood Onset Growth Hormone Deficiency (CO-GHD) at the Time of Transition From Pediatric to Adulthood Endocrine Care

Vulnerability of the transitional period from childhood to adulthood is particularly challenging in treatment of adolescents with CO-GHD. Altered metabolic profile is well described in GHD, but relevant large monocentric studies in transition patients and young adults with CO-GHD are lacking.Patients and Methods: In a monocentric, observational, retrospective cross-sectional study conducted from 2005-2019, 107 CO-GHD patients were analyzed (17-26 years old, 80 males) at the time of transfer from pediatric to adult endocrine care. Median age at transfer was 19.6 ± 2.2 years. Subjects with congenital and idiopathic GHD (CON) were compared with age-, sex- and BMI-matched patients with hypothalamic/pituitary tumor history (TUM). Glycaemia and insulin during OGTT (peak and AUC), HbA1c, serum total cholesterol, HDL, LDL and triglycerides were analyzed in all patients.Results: Congenital and idiopathic causes of CO-GHD were more frequent than hypothalamic/pituitary tumoral causes (74.8% vs. 25.2%). All patients received GH replacement during childhood for average duration of 5.4 ± 1.4yrs. GH replacement was discontinued prior to transfer for 2.7 ± 0.9yrs. Glycaemia peak, glycaemia AUC and insulin peak in OGTT were not significantly different in TUM vs. CON (p>0.05). However, insulin AUC in OGTT was significantly higher in TUM compared to CON (134.38 ± 23.2 vs 114.62 ± 12.4; p<0.05). HbA1c was similar between the two groups (5.2 ± 0.4% TUM vs 5.0 ± 0.3% CON; p>0.05). Total cholesterol (5.2 ±1.1 vs 4.5 ± 0.8 mmol/l; p>0.05), LDL (3.1 ± 0.9 vs 2.7 ± 0.8 mmol/l; p>0.05) and triglycerides (2.1 ± 1.1 vs 1.1 ± 0,7 mmol/l; p<0.05) were increased in TUM compared to CON, while HDL was decreased in TUM group (1.0±0.1 vs 1.4±0,3 mmol/l; p<0.05).Conclusion: Patients with CO-GHD caused by hypothalamic/pituitary tumors are burdened with a worse metabolic profile at the time of childhood to adulthood transition compared to matched transition patients with congenital CO-GHD.

Personalized approach to growth hormone replacement in adults.

Growth hormone (GH) deficiency (GHD) in adults is well-characterized and includes abnormal body composition, reduced bone mass, an adverse cardiovascular risk profile, and impaired quality of life. In the early 1990s, it was also shown that patients with hypopituitarism without GH replacement therapy (GHRT) had excess mortality. Today, GHRT has been shown to decrease or reverse the negative effects of GHD. In addition, recent papers have shown that mortality and morbidity are approaching normal in hypopituitary patients with GHD who receive modern endocrine therapy including GHRT. Since the first dose-finding studies, it has been clear that efficacy and side effects differ substantially between patients. Many factors have been suggested as affecting responsiveness, such as sex, age, age at GHD onset, adherence, and GH receptor polymorphisms, with sex and sex steroid replacement having the greatest impact. Therefore, the individual tailoring of GH dose is of great importance to achieve sufficient efficacy without side effects. One group that stands out is women receiving oral estrogen replacement, who needs the highest dose. Serum insulin-like growth factor-1 (IGF-1) is still the most used biochemical biomarker for GH dose titration, although the best serum IGF-1 target is still debated. Patients with GHD due to acromegaly, Cushing's disease, or craniopharyngioma experience similar effects from GHRT as others. Arch Endocrinol Metab. 2019;63(6):592-600.

Towards a Göttingen minipig model of adult onset growth hormone deficiency: evaluation of stereotactic electrocoagulation method

BackgroundAdult onset growth hormone (GH) deficiency (AGDH) is a potentially underdiagnosed condition, caused by damage to the pituitary gland. AGHD is treated with growth hormone replacement therapy. A large variety of clinical symptoms and changes in the metabolic homeostasis can be observed and quantified. New large animal models are needed for future drug development. New methodIn this study, we evaluate methods for a new large non-primate animal model of GH deficiency in post pubertal Göttingen Minipigs (minipig). Lesions in the pituitary gland were made by stereotaxic monopolar thermo-coagulation guided by magnetic resonance imaging (MRI), and pituitary function was evaluated using insulin tolerance test (ITT) with measurements of growth hormone secretion induced by hypoglycemia. ResultsLesions were successfully applied to the pituitary gland without any damage to surrounding tissue including the hypothalamus, which was confirmed by post-operative MRI and post mortem histology. Plasma levels of GH during ITT showed no decrease in secreted levels one week after surgery compared to levels obtained before surgery. Comparison with existing methodsCompared to other GH insufficiency models, eloquent brain tissue is spared. Furthermore, alternatively to rodent models, a large animal model would allow the use of human intended equipment to evaluate disease. Using the minipig avoids social, economical and ethical issues, compared with primates. ConclusionThe lesions did not remove all GH production, but proof of concept is demonstrated. In addition, the ITT is presented as a safe and efficient method to diagnose GH deficiency in minipigs.

Metabolic status, body composition and bone mineral density in 85 patients with childhood onset growth hormone deficiency (COGHD) in transition period

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Analysis of characteristics and outcomes by growth hormone treatment duration in adult patients in the Italian cohort of the Hypopituitary Control and Complications Study (HypoCCS)

PurposeTo examine differences in effects according to growth hormone (GH) treatment duration in adult GH-deficient patients.MethodsIn the Italian cohort of the observational Hypopituitary Control and Complications Study, GH-treated adults with GH deficiency (GHD) were grouped by duration of treatment; ≤ 2 years (n = 451), > 2 to ≤ 6 years (n = 387) and > 6 years (n = 395). Between-group differences in demographics, medical history, physical characteristics, insulin-like growth factor-I standard deviation score (IGF-I SDS) and lipid profile at baseline, last study visit and changes from baseline to last study visit were assessed overall, for adult- and childhood-onset GHD and by gender using ANOVA for continuous variables and Chi-squared test for categorical variables.ResultsAt baseline, treatment duration groups did not differ significantly for age, gender, body mass index, GHD onset, IGF-I SDS, lipid profile, and quality of life. Mean initial GH dose did not differ significantly according to treatment duration group in any subgroup, except female patients, with highest mean dose seen in the longest duration group. In the longest duration group for patients overall, adult-onset patients and male patients, there were significant decreases in GH dose from baseline to last visit, and in total and low-density lipoprotein (LDL)-cholesterol concentrations. IGF-I SDS increased, to a greater extent, in the longest duration group for patients overall and female patients.ConclusionsThe results show that long-term GH treatment is associated with decreasing GH dose, increased IGF-I, decreased LDL-cholesterol and the presence of surrogate markers that help to give confidence in a diagnosis of GHD.

Response to growth hormone treatment in very young patients with growth hormone deficiencies and mini-puberty.

The aim of the study was to assess the response to growth hormone (GH) treatment in very young patients with GH deficiency (GHD) through a national, multi-center study. Possible factors affecting growth response were assessed (especially mini-puberty). Medical reports of GHD patients in whom treatment was initiated between 0 and 3 years of age were retrospectively evaluated. The cohort numbered 67. The diagnosis age was 12.4±8.6 months, peak GH stimulation test response (at diagnosis) as 1.0±1.4 ng/mL. The first and second years length gain was 15.0±4.3 and 10.4±3.4 cm. Weight gain had the largest effect on first year growth response; whereas weight gain and GH dose were both important factors affecting second year growth response. In the multiple pituitary hormone deficiency (MPHD) group (n=50), first year GH response was significantly greater than in the isolated GH deficiency (IGHD) group (n=17) (p=0.030). In addition first year growth response of infants starting GH between 0 and 12 months of age (n=24) was significantly greater than those who started treatment between 12 and 36 months of age (n=43) (p<0.001). These differences were not seen in the second year. Δ Length/height standard deviation score (SDS), Δ body weight SDS, length/height SDS, weight SDS in MPHD without hypogonadism for the first year of the GH treatment were found as significantly better than MPHD with hypogonadism. Early onsets of GH treatment, good weight gain in the first year of the treatment and good weight gain-GH dose in the second year of the treatment are the factors that have the greatest effect on length gain in early onset GHD. The presence of the sex steroid hormones during minipubertal period influence growth pattern positively under GH treatment (closer to the normal percentage according to age and gender).

An audit of the management of childhood-onset growth hormone deficiency during young adulthood in Scotland.

BackgroundAdolescents with childhood onset growth hormone deficiency (CO-GHD) require re-evaluation of their growth hormone (GH) axis on attainment of final height to determine eligibility for adult GH therapy (rhGH).AimRetrospective multicentre review of management of young adults with CO-GHD in four paediatric centres in Scotland during transition.PatientsMedical records of 130 eligible CO-GHD adolescents (78 males), who attained final height between 2005 and 2013 were reviewed. Median (range) age at initial diagnosis of CO-GHD was 10.7 years (0.1–16.4) with a stimulated GH peak of 2.3 μg/l (0.1–6.5). Median age at initiation of rhGH was 10.8 years (0.4–17.0).ResultsOf the 130 CO-GHD adolescents, 74/130(57 %) had GH axis re-evaluation by stimulation tests /IGF-1 measurements. Of those, 61/74 (82 %) remained GHD with 51/74 (69 %) restarting adult rhGH. Predictors of persistent GHD included an organic hypothalamic-pituitary disorder and multiple pituitary hormone deficiencies (MPHD). Of the remaining 56/130 (43 %) patients who were not re-tested, 34/56 (61 %) were transferred to adult services on rhGH without biochemical retesting and 32/34 of these had MPHD. The proportion of adults who were offered rhGH without biochemical re-testing in the four centres ranged between 10 and 50 % of their total cohort.ConclusionsA substantial proportion of adults with CO-GHD remain GHD, particularly those with MPHD and most opt for treatment with rhGH. Despite clinical guidelines, there is significant variation in the management of CO-GHD in young adulthood across Scotland.

EXTENSIVE EXPERTISE IN ENDOCRINOLOGY: UK stance on adult GH replacement: the economist vs the endocrinologist

In the UK, through the use of a forced economic model, endocrinologists are in the curious position of offering GH replacement to some patients with severe GH deficiency (GHD) but withholding it from other patients with even more severe GHD. This approach is counter-intuitive to endocrine practice in treating endocrine deficiency states. For all other endocrine deficiencies, one would opt for treating those with the most severe biochemical evidence of deficiency first. If this endocrine approach was applied to adult GH replacement in an era of rationing, one would start with the GHD patients with a pathologically low IGF1 level. Given that the prevalence of subnormal IGF1 levels in a GHD population is age-dependent, this would result in GH replacement being offered to more young adult onset (AO) GHD and childhood onset GHD adults, and less often to middle-aged and elderly AO GHD adults. This in itself has the added advantage that the skeletal benefits appear more real in the former cohort of patients.

Could zinc supplementation improve bone status in growth hormone (GH) deficient children?

Reduced bone mineral density (BMD) and increased fracture rate have been reported in subjects with either childhood or adult onset growth hormone (GH) deficiency (GHD), more severe in childhood onset GHD [1, 2]. A longer gap in GH replacement in adults with childhood onset GHD is associated with a lower bone mineralization and GH replacement has been suggested having a critical role in transition to adulthood to optimize bone accrual [3]. Furthermore, also a delay in starting GH replacement in GHD adults may be associated with a persistent increase in vertebral fracture risk [4]. However, many criticisms have been raised on these assumptions. Limitations of current bone imaging techniques have caused many artefacts about BMD and bone structure. Using appropriate size corrections, BMD is normal in children and adults with isolated GHD in several studies and the anabolic changes in muscle mass and strength may contribute to the observed bone changes [for critical reviews see 5, 6]. Briefly, many historical studies used T-scores in GHD children, comparing children’s BMD with adult reference data. On the other hand, when age—and sex—Z scores have been introduced for the pediatric population, height remained a confounding factor and being tall or short for age leads to a false negative or a false positive result for BMD Z-score, respectively. Since 2008, official positions of the International Society for Clinical Densitometry strongly recommend size correction for DXA measurements in the pediatric age [7]; however, no consensus exists how to correct measurements. To date, the most real effect of GHD on bone seems to be a reduction in bone volume ratio and trabecular thickness in both animal and human studies [5, 6]. Moreover, we must not forget that GH replacement causes biphasic effects on the bone remodeling with early stimulation of bone resorption followed by a sustained increase in bone formation [8]: some controversial results of published literature could be due to the time from the start of the therapy. On the other hand, it is unclear whether changes in BMD may really predict the fracture risk in patients with GHD, as well as other forms of secondary osteoporosis, being other markers of bone quality still searched. The first point in favor of the paper by Ekbote et al. [9] in this issue of Endocrine is that the Authors performed size correction for DXA bone mineral content (BMC) and bone area (BA) measurements using height. They showed that in Indian prepubertal children with isolated GHD, height adjusted BMC and BA significantly increased of 48 and 40 %, respectively, after 1 year of GH treatment. These changes were associated with an increase in height adjusted lean body mass and a decrease in height adjusted body fat. Many previous studies in childhood onset GHD, in particular in Italian and Dutch cohorts, reported an increase in BMC in the range of 2–10 %, significantly lower than that observed in the present study [5, 6]. However, it has to be emphasized that the majority of other studies did not perform any size correction. Furthermore, the population investigated in this study [9] presented a very low BMC at baseline and this aspect could have influenced the results. However, we can first speculate that when BMC is clearly reduced in GHD patients, a treatment with rhGH works in improving bone health. Bone metabolism is complex. Many factors tightly regulate BMC and bone accrual, mainly, among others, F. Prodam SCDU of Pediatrics, Department of Health Sciences, Universita del Piemonte Orientale ‘‘A. Avogadro’’, Novara, Italy

Effect of growth hormone on bone status in growth hormone-deficient adults

Growth hormone deficiency (GHD) is associated with reduced bone mineral content and increased risk of osteoporotic fractures. Reduced peak bone mass might explain the low bone mineral density (BMD) among patients with childhood onset GHD (CO-GHD) whilst the cause of osteopenia in adult-onset GHD (AO-GHD) is not fully understood. Prospective multicentric study to asses bone status in GHD adults after two years of recombinant growth hormone replacement treatment. In 94 GHD adults (49 men; Ø 34.5 yrs) we have measured BMD and bone markers (CTX, osteocalcin) during two years of rhGH treatment (at baseline, after 3 and 6 months, and after 1 and 2 years). Patients were adequately substituted for GHD and other pituitary deficiencies. We have observed an increase in BMD-lumbar spine: n=42, 0.8155 →0.9418 g/cm2, p<0.0001; femoral neck n=41; 0.8468 →0.9031; p= 0.0004; BMD-whole body 1.0179 →1.0774; p=0.0003. We have compared gender difference: BMD-L-spine by 15.8 % in men (n=21) and by 5.6 % in women (n=19) (p= 0.008); BMD-femoral neck increased by 11.03 % in men and by about 3.0 % in women (p=0.032). In women, the initial decrease in BMD was recorded after 3 months. CO-GHD adults yielded a higher increase in BMD -L-spine (16.6 %, p=0.022). A correlation exists between IGF-I levels and BMD in lumbar spine (1st year: R=0.348, p=0.026; 2nd year: R= 0.33, p=0.0081) and between IGF-I and osteocalcin (1st year: R=0.383; p=0.0038). Two-year therapy with recombinant human growth hormone improved bone status. IGF-I appears to be a good indicator of rhGH effect on bone (Tab. 3, Fig. 9, Ref. 36). Text in PDF www.elis.sk.

Changes in BMI and Management of Patients with Childhood Onset Growth Hormone Deficiency in the Transition Phase

We aimed at evaluating BMI changes during GH therapy pause, to assess the transfer pattern between children and adult medical services in our clinic and to confirm the previous growth hormone deficiency (GHD) diagnosis. Retrospective cohort study. We identified 75 transition patients (age at first visit <25 years) with pituitary deficiency (ICD-10:E.23) and GHD referred to our clinic between 2000-2009. Out of 75 patients with GHD (45 males, 30 females), 20 subjects suffered from an idiopathic GHD (iGHD) and 55 from an organic GHD (oGHD). During the GH therapy pause (26.4±34.8 months), we observed a significant BMI increase (23.6±4.4 to 27.1±7.2, p=0.02). Most males with iGHD discontinued endocrinologic control and GH substitution completely (5 patients out of 20) or after the first contact (3 patients out of 20). Most females with GHD continued medical control after transferral (22 patients). We retested 34/75 patients with GHD (45.3%). The preferred test was the growth hormone-releasing hormone-arginine (GHRH-arginine) (20/34 patients, 58.9%), followed by the insulin hypoglycemia test (IHT) alone (9 patients). 4 patients received both, the GHRH-arginine and the IHT. Seven retested patients with iGHD (63.6%) and all oGHD retested patients were still deficient. Our results provide information on negative effects of the discontinuation of GH treatment during the transition phase and should help to improve the compliance with treatment in this group of patients. Paediatric and adult endocrinologists participating together in a transition programme should emphasize on the positive effect of GH substitution in adulthood. Efforts should be made to particularly improve the transferral of male adolescents with iGHD, since they seem to escape medical care.

Study of the leptin levels and its gene polymorphisms in patients with idiopathic short stature and growth hormone deficiency

Leptin levels may regulate fat metabolism, skeletal growth, and puberty. Leptin gene variants affect risk of obesity, cancer, but their effect on onset of growth hormone deficiency (GHD) and idiopathic short stature (ISS) is unknown. We tested the hypothesis that the phenotype of GHD and ISS may be associated with polymorphism in the leptin gene. The prevalence of a single nucleotide polymorphism (SNP) in the leptin gene (LEP) promoter at -2548 and the leptin and insulin growth factor-1 (IGF-1) concentrations in GHD and ISS were compared to those of healthy controls. IGF-1 and leptin concentrations were significantly lower in both the GHD and ISS groups than in the control group. The ISS and GHD groups had a significantly different distribution of SNP alleles at the LEP -2548 (P = 0.010). Individuals with LEP -2548A/G or G/G genotype in ISS group (47.5%) showed a significantly lower weight and body mass index (BMI) (but not leptin levels) than individuals carrying the A/A genotype (52.5%). LEP -2548A/A in GHD patients (65.8%) was associated with lower weight, BMI, leptin concentrations than those of individuals carrying the A/G or G/G genotype (34.2%). These data suggest that the LEP -2548A polymorphism may associate with the weight and BMI of the children with ISS and GHD.

Evaluation of coagulation and fibrinolytic parameters in adult onset GH deficiency and the effects of GH replacement therapy: A placebo controlled study

ObjectiveIncreased cardiovascular mortality/morbidity observed in patients with hypopituitarism is ascribed to growth hormone deficiency (GHD) because of its unfavorable cardiovascular risk profile. Abnormalities in the coagulation system may also contribute to increased cardiovascular morbidity/mortality. To get a better insight into the role of hemostasis in GHD we assessed several hemostatic markers at baseline and after 6months of GH replacement therapy (GHRT). Design-patientsNineteen patients with adult onset GHD were enrolled (twelve patients into the treatment and seven patients into the placebo group) into the study. Platelet count, collagen/epinephrine closure time, collagen/ADP closure time, fibrinogen, prothrombin time (PT), activated partial thromboplastin time (aPTT), antithrombin III (AT III), protein C activity, protein S activity, lupus anticoagulant, antiphospholipid antibody immunoglobulin M, and antiphospholipid antibody immunoglobulin G were measured at baseline and 6months after treatment. ResultsThe investigated parameters in the groups were similar at baseline except for low protein S (PS) activity. Protein S deficiency was observed in three of the patients in the GH treatment group at baseline, however the PS activity values normalized following GHRT. AT III and protein C activities decreased when compared to baseline values in the treatment group but not in the placebo group. ConclusionsWe observed protein S deficiency more frequent than seen in the general population and normalization of protein S activity and decreases, in other natural anticoagulants following GHRT. Further studies are required to understand the impact of these changes in cardiovascular morbidity and mortality in this patient population.

Predictors of Bone Responsiveness to Growth Hormone (GH) Replacement in Adult GH-Deficient Patients

Growth hormone (GH) replacement in adulthood results in variable bone responses as a function of the gonadic hormonal milieu. We performed a retrospective analysis of a large cohort of adult males and females with confirmed GH deficiency (GHD) prior to treatment and during 3 years of replacement therapy. Potential confounders and effect modifiers were taken into account. Sixty-four adult patients with GHD (20 females and 44 males; mean age 34 years, range 18-64) were included in the analysis. GH replacement induced a different effect on bone in males compared to females. Bone mineral content increased in males and decreased in females at the lumbar spine, total femur, and femoral neck; bone mineral density showed a similar trend at the lumbar spine and femoral neck. There was no significant gender difference in bone area at any measured bone site. In both sexes we observed a similar trend for serum markers of bone remodeling. Sex predicted bone outcome on multivariate analysis, as did age, onset of GHD (childhood/adulthood), pretreatment bone mass, baseline body mass index (BMI), and BMI change during GH replacement. Serum IGF-I levels during treatment did not show any relationship with bone outcome at any measured site. This study confirms that bone responsiveness to GH replacement in adult GHD varies as a function of sex even after controlling for potential confounders and highlights the importance of other cofactors that may affect the interaction between GH replacement therapy and bone remodeling.

Harmonization of growth hormone measurements with different immunoassays by data adjustment

The aim of our study was to evaluate the between-assay variability of commercially available immunoassays for the measurement of human growth hormone (hGH). In addition, we asked whether the comparability of the diagnosis of childhood onset growth hormone deficiency could be improved by adjusting hGH results by statistical methods, such as linear regression, conversion factors, and quantile transformation. In archived sera from 312 children and adolescents (age: 17 days-17 years) hGH values between 0.01 and 16.5 ng/mL were determined by using the following immunoassays: AutoDELFIA (PerkinElmer), BC-IRMA (Beckman-Coulter), ELISA (Mediagnost), IMMULITE 2000 (Siemens), iSYS (IDS), Liaison (DiaSorin), UniCel DxI 800 Access (BeckmanCoulter) and "In house"-RIA (Tübingen). The assays differed in median hGH concentrations by as much as 5.44 ng/mL (Immulite), and as little as 2.67 ng/mL (BC-IRMA). The mean difference between assays ranged from 0.35 to 2.71 ng/mL, whereas several samples displayed differences up to 11.4 ng/mL. The best correlation (r=0.992) was found between AutoDELFIA and Liasion, the lowest (r=0.864) was between an in-house RIA and iSYS. The between-assay CV (mean ± SD) of values within the cut-off range was 24.3% ± 7.4%, resulting in an assay-dependent diagnosis of growth hormone deficiency (GHD) in more than 27% of patients. Yet, adjustment of this data by linear regression or a conversion factor reduced the CV below 14%, and the ratio of assay-dependent diagnoses below 8%. Using quantile transformation, the CV and ratio were reduced to 11.4% and <1%, respectively. hGH measurements using different assays vary significantly. Linear regression, conversion factors, or particularly quantile transformation are useful tools to improve comparability in the diagnostic procedure for the confirmation of GHD in childhood and adolescence.