GH-deficient Patients Research Articles

Growth hormone replacement therapy regulates microRNA-29a and targets involved in insulin resistance.

Replacement of growth hormone (GH) in patients suffering from GH deficiency (GHD) offers clinical benefits on body composition, exercise capacity, and skeletal integrity. However, GH replacement therapy (GHRT) is also associated with insulin resistance, but the mechanisms are incompletely understood. We demonstrate that in GH-deficient mice (growth hormone-releasing hormone receptor (Ghrhr)lit/lit), insulin resistance after GHRT involves the upregulation of the extracellular matrix (ECM) and the downregulation of microRNA miR-29a in skeletal muscle. Based on RNA deep sequencing of skeletal muscle from GH-treated Ghrhrlit/lit mice, we identified several upregulated genes as predicted miR-29a targets that are negative regulators of insulin signaling or profibrotic/proinflammatory components of the ECM. Using gain- and loss-of-function studies, five of these genes were confirmed as endogenous targets of miR-29a in human myotubes (PTEN, COL3A1, FSTL1, SERPINH1, SPARC). In addition, in human myotubes, IGF1, but not GH, downregulated miR-29a expression and upregulated COL3A1. These results were confirmed in a group of GH-deficient patients after 4 months of GHRT. Serum IGF1 increased, skeletal muscle miR-29a decreased, and miR-29a targets were upregulated in patients with a reduced insulin response (homeostatic model assessment of insulin resistance (HOMA-IR)) after GHRT. We conclude that miR-29a could contribute to the metabolic response of muscle tissue to GHRT by regulating ECM components and PTEN. miR-29a and its targets might be valuable biomarkers for muscle metabolism following GH replacement.Key messagesGHRT most significantly affects the ECM cluster in skeletal muscle from mice.GHRT downregulates miR-29a and upregulates miR-29a targets in skeletal muscle from mice.PTEN, COL3A1, FSTL1, SERPINH1, and SPARC are endogenous miR-29a targets in human myotubes.IGF1 decreases miR-29a levels in human myotubes.miR-29a and its targets are regulated during GHRT in skeletal muscle from humans.Electronic supplementary materialThe online version of this article (doi:10.1007/s00109-015-1322-y) contains supplementary material, which is available to authorized users.

Auxologic parameters and response to 2-year therapy with recombinant human growth hormone in growth hormone deficient children with an ectopic posterior pituitary.

Structural defects of the hypothalamic-pituitary area in MRI are suggested as being a more accurate marker of growth hormone deficiency (GHD) than laboratory assays. To compare auxological characteristics in GHD children with normal pituitary (NP) function and with ectopic posterior pituitary (EPP), prior to therapy with recombinant human growth hormone (rhGH), extending the follow-up to two years following treatment. Eighty-six (86) GHD patients were divided into two groups depending on the pituitary MRI: the EPP (23 children, 3.2-16.8 years old) and the NP group (63 children, 3.3-14.8 years old). Height deficits in the population (hSD) and parents (hSD-mpSD) and the change of hSD and bone/chronological age ratio were assessed before and after 12 and 24 months of rhGH therapy. Height deficits before treatment were significantly greater in EPP compared to NP [median -4.07 (-7.06, -2.75) vs -3.15 (-4.9, -2.35) for hSD, and -3.65 (-7.06, -1.21) vs -1.83 (-4.31, -0.28) for hSD-mpSD; p<0.05]. Bone age was significantly delayed in the EPP group [0.62 (0.27, 0.92) vs 0.75 (0.21, 0.71); p<0.05]; differences remained significant during follow-up. After 12 months of rhGH therapy, EPP showed significantly greater catch-up growth compared to NP [ΔhSD=1.2 (0.42, 2.69) vs 0.74 (0.05, 1.48); p<0.05]. In the 2nd year, height velocity slowed down and was comparable in the two groups. At the conclusion of the study, hSD was similar in both groups, but hSD-mpSD was more deviated in EPP [-1.79 (-3.71, -1.21) vs -1.1 (0.98, -0.07); p<0.05]. The study showed relevant auxologic differences between EPP and NP children, as well as beneficial effects of rhGH therapy in both groups.

Auxological outcome of growth hormone therapy at cessation of treatment in a cohort of growth hormone deficient Sri Lankan patients.

Recombinant human growth hormone (r-hGH) for growth hormone deficiency (GHD) has been available free in the state hospitals of Sri Lanka since 2009. The aims were to compare height standard deviation scores (SDS) before and after treatment and compare heights at final assessment in relation to the target height (TH) and TH range. Patients with confirmed GHD followed up at the University Unit of the Lady Ridgeway Hospital, Colombo were studied. Anthropometric data were prospectively recorded from presentation to cessation of therapy. The height SDS before and after treatment were calculated and the heights at final assessment were compared with the TH and TH range. Sixteen patients (15 boys) had completed treatment. The mean age at diagnosis was 145.38 (SD=34.28) months with a mean skeletal age of 97.5 (SD=42.85) months. Mean ages at commencement was 164.75 (SD=36.81) months and at cessation of therapy 212.06 (SD=30.12) months duration of therapy was 47.31 (SD=23.99) months.Majority had isolated GHD and 8 patients had pituitary hypoplasia on neuro-imaging. The height SDS improved significantly with treatment from -4.438 (1.18) to -3.37 (0.81), p<0.001. When finally assessed at ages ranging from 15 years 10 months to 26 years 9 months, one patient had reached the TH while six were in the TH range. Auxological response to therapy was significant although treatment was started late due to financial constraints.

Decreased 6-Sulfatoxymelatonin Excretion in Male GH-Deficient Children and Adolescents

Aim: To evaluate melatonin secretion in a group of untreated and treated male growth hormone (GH)-deficient children and adolescents. Methods: We studied 44 male subjects: 8 untreated GH-deficient patients (GHDnt), 16 treated GH-deficient patients (GHDt) and 20 healthy children and adolescents as control group (CG). We measured urinary 6-sulfatoxymelatonin (6-SM) in total (24-hour samples), nocturnal (18.00-8.00 h) and diurnal samples (8.00-18.00 h). Levels of 6-SM were expressed as micrograms excreted per time interval and Δ values (difference between nighttime and daytime values). Results: Significant differences were observed among the 3 groups of pediatric subjects studied for total 6-SM (p < 0.0001), nocturnal 6-SM (p < 0.0001) and Δ values (p < 0.0001). Subsequent analysis showed significantly higher levels for total 6-SM, nocturnal 6-SM and nighttime-daytime Δ in the CG versus the GHDnt (p < 0.01) and in the CG versus the GHDt group (p < 0.01). No significant correlations were found between 6-SM excretion and insulin-like growth factor-1 values in the children and adolescents studied. Conclusions: GH-deficient patients showed lower levels of 6-SM. Our findings provide a different insight to a further understanding of some chronobiological disorders involved in GH deficiency in children.

Growth Hormone Inhibits Hepatic De Novo Lipogenesis in Adult Mice.

Patients with nonalcoholic fatty liver disease (NAFLD) are reported to have low growth hormone (GH) production and/or hepatic GH resistance. GH replacement can resolve the fatty liver condition in diet-induced obese rodents and in GH-deficient patients. However, it remains to be determined whether this inhibitory action of GH is due to direct regulation of hepatic lipid metabolism. Therefore, an adult-onset, hepatocyte-specific, GH receptor (GHR) knockdown (aLivGHRkd) mouse was developed to model hepatic GH resistance in humans that may occur after sexual maturation. Just 7 days after aLivGHRkd, hepatic de novo lipogenesis (DNL) was increased in male and female chow-fed mice, compared with GHR-intact littermate controls. However, hepatosteatosis developed only in male and ovariectomized female aLivGHRkd mice. The increase in DNL observed in aLivGHRkd mice was not associated with hyperactivation of the pathway by which insulin is classically considered to regulate DNL. However, glucokinase mRNA and protein levels as well as fructose-2,6-bisphosphate levels were increased in aLivGHRkd mice, suggesting that enhanced glycolysis drives DNL in the GH-resistant liver. These results demonstrate that hepatic GH actions normally serve to inhibit DNL, where loss of this inhibitory signal may explain, in part, the inappropriate increase in hepatic DNL observed in NAFLD patients.

Changes in circulating IGF1 receptor stimulating activity do not parallel changes in total IGF1 during GH treatment of GH-deficient adults.

Previously we demonstrated that IGF1 receptor stimulating activity (IGF1RSA) offers advantages in diagnostic evaluation of adult GH deficiency (GHD). It is unknown whether IGF1RSA can be used to monitor GH therapy. To investigate the value of circulating IGF1RSA for monitoring GH therapy. 106 patients (54 m; 52 f) diagnosed with GHD were included; 22 were GH-naïve, 84 were already on GH treatment and discontinued therapy 4 weeks before baseline values were established. IGF1RSA was determined by the IGF1R kinase receptor activating assay, total IGF1 by immunoassay (Immulite). GH doses were titrated to achieve total IGF1 levels within the normal range. After 12 months, total IGF1 and IGF1RSA increased significantly (total IGF1 from 8.1 (95% CI 7.3-8.9) to 14.9 (95% CI 13.5-16.4) nmol/l and IGF1RSA from 115 (95% CI 104-127) to 181 (95% CI 162-202) pmol/l). After 12 months, total IGF1 normalized in 81% of patients, IGF1RSA in 51% and remained below normal in more than 40% of patients in whom total IGF1 had normalized. During 12 months of GH treatment, changes in IGF1RSA did not parallel changes in total IGF1. Despite normalization of total IGF1, IGF1RSA remained subnormal in a considerable proportion of patients. At present our results have no short-term consequences for GH therapy of GHD patients. However, based on our findings we propose future studies to examine whether titrating GH dose against IGF1RSA results in a better clinical outcome than titrating against total IGF1.

Bilaterally slipped capital femoral epiphysis in growth hormone-deficient patient: osteosynthesis also needs the oestrogen epiphyseal fusion- case report

Bilaterally slipped capital femoral epiphysis in growth hormone-deficient patient: osteosynthesis also needs the oestrogen epiphyseal fusion- case report

Early Identification of Pituitary Dysfunction in Congenital Nasal Pyriform Aperture Stenosis: Recommendations Based on Experience in a Single Centre

Background: Congenital nasal pyriform aperture stenosis (CNPAS) is an increasingly recognised cause of upper airway obstruction associated with midline abnormalities. Studies have described pituitary dysfunction in 40% of patients. We aimed to develop guidelines for: (a) the early identification of pituitary insufficiency to minimise surgical risk and (b) to stratify patients for follow-up. Methods: Retrospective case note review of patients with CNPAS between 2000 and 2014 in a tertiary paediatric unit. Results: 20 patients (12 female:8 male) were analysed; 16 were diagnosed during the neonatal period while 4 were diagnosed later. There was no consistent approach in the evaluation of the pituitary axis at diagnosis. Pituitary dysfunction was identified in 3 (15%) patients, 2 of whom were found during evaluation of short stature in mid-late childhood. Hypoglycaemia and conjugated hyperbilirubinaemia, but not the degree of stenosis, were highly predictive of pituitary dysfunction (p < 0.05). Available height standard deviation score (SDS) data at 1 year of 70% of our patients identified both of the late-diagnosed growth hormone-deficient patients, with SDS of -2.6 and -3.6, respectively. Conclusion: All CNPAS patients should have MRI of the brain and baseline endocrine investigations at diagnosis. Growth monitoring for at least 1 year is recommended as low, or falling, height SDS at 1 year is a good predictor of pituitary dysfunction.

Short-term efficacy of recombinant human GH therapy in cured acromegaly patients with GH deficiency: a single-center experience.

The effectiveness and short-term safety of recombinant human GH (r-hGH) in acromegaly patients with GH deficiency (GHD) after treatment are not well established. The study includes ten subjects with acromegaly who had GHD treated with r-hGH for 6 months. Control groups consisted of ten age-, gender-, and BMI-matched healthy subjects and ten active acromegaly patients who were treatment naïve. Body composition, quality of life (QoL), muscle strength, lipid profile, and cardiovascular risk factors were assessed in all subjects at baseline, and the same parameters were reassessed after 6 months of therapy with r-hGH in acromegaly with GHD. Repeat magnetic resonance imaging of the sella was performed in treated subjects. Optical colonoscopy was done and biopsies were taken from multiple sites for proliferation indices (Ki67). The median duration of GHD was 17.8 months and dose of r-hGH administered was 5.7±1.5 μg/kg per day. There was improvement in bone mineral content (P=0.01), bone mineral density (P=0.04), muscle strength (P<0.001), total cholesterol (P=0.003), high-density cholesterol (P<0.001), and QoL – score (P=0.005), and reduction in low-density cholesterol (P=0.003) and triglyceride (P=0.004) after treatment. There was no change in lean body mass, total body fat, hsCRP, lipoprotein (a), and fibrinogen levels. There was a modest increase in plasminogen activator inhibitor 1 (P=0.002), but it was lower compared with healthy controls and treatment naïve acromegalics (P=0.007). Six month-r-hGH therapy improves body composition, atherogenic lipid profile, QoL, and muscle strength in GHD patients who had acromegaly. Long-term prospective studies are needed to evaluate the effect of r-hGH therapy in these patients.

Severe growth hormone deficiency and empty sella in obesity: a cross-sectional study.

Obesity is associated with blunted growth hormone (GH) secretion. In some individuals, hypothalamic-pituitary (HP) structural lesions may contribute to GH deficiency (GHD). We explored pituitary morphology in obese patients with suspected GHD and its association with cardiovascular risk factors, body composition, and cardiac morphology. One hundred and eighty-four adults obese patients with symptoms and signs of GHD (147 females and 37 males; mean age 46.31 ± 12.11 years), out of 906 consecutive white obese outpatients, were evaluated. The main measures were anthropometric data, blood pressure, lipid profile, glycemic parameters, pituitary hormones, and insulin-like growth factor-1 values, echocardiography, magnetic resonance imaging (MRI) of the HP region, body composition, and growth hormone-releasing hormone plus arginine test. Seventy patients had GHD (GH peak values <4.2 μg/mL). GHD patients showed significantly higher body mass index and fat mass, lower lumbar bone mineral density, increased left ventricular mass index, and epicardial fat thickness. The MRI of the HP region showed empty sella (ES) in 69 and normal pituitary in one of the 70 GHD patients; the 114 patients with normal GH response had ES (n = 62, 54 %), normal pituitary (n = 37, 32 %), microadenomas (n = 10, 8 %), and other pituitary abnormalities (n = 5, 4 %). ES was a significant independent predictor of GH secretory capacity as determined by multiple regression analysis. The close relationship between ES and GH secretory capacity points out to the possibility of the organic nature of GHD in a portion of obese individuals and opens a new scenario with regard to the potential of GH treatment on metabolic consequences of obesity.

Dynamic changes in the hypothalamic-pituitary-adrenal axis during growth hormone therapy in children with growth hormone deficiency: a multicenter retrospective study.

The objective of this study was to investigate changes in the hypothalamic-pituitary-adrenal (HPA) axis after recombinant human growth hormone (rhGH) therapy. Subjects included children with growth hormone deficiency (GHD). We conducted a multicenter, retrospective study that assessed 72 GHD patients treated with rhGH during 6 months. Patients were classified into two groups: isolated GHD (IGHD; n=20) and multiple pituitary hormone deficiencies (MPHD; n=52). The HPA axis and other hormones were evaluated at baseline and every 3 months. In the MPHD group, 32 patients had adrenocorticotrophic hormone deficiency and received hydrocortisone before rhGH therapy. In the other 20/52 MPHD patients, the cortisol (COR) level was significantly reduced after rhGH therapy. Moreover, 10 patients showed low COR levels. In the IGHD group, COR levels also decreased, but remained within the normal range. During rhGH therapy, COR levels were reduced, particularly in patients with MPHD. HPA axis should be monitored during rhGH therapy.

Final Height and Pubertal Development in 150 Children with Growth Hormone Deficiency in Algeria

Growth Hormone Deficiency (GHD) may happen when the body is unable to produce enough growth hormone (GH) or use it effectively. GH plays a fundamental role in helping young bodies grow and develop puberty. When levels of GH are too low, there may be an impact on growth and many functions of the body.We report in this study, the results on the final height and pubertal development of 150 Algerian patients followed in our department of endocrinology. The average age at diagnosis was 8 ± 2.4 in girls and 9 ± 1.2 in boys. The GH deficiency was isolated in half of the cases, associated with other hypophyseal deficits in the other half; hormonal deficiencies were all substituted. Patients received irregular treatment with GHr the average height of patients GHD at diagnosis in boys: -4,7DS ± 1,8) /(Sempe) and -4,1DS 0,8/ TC; In girls -4,9DS ± 2,3(- 11,8, - 2,8)/(Sempe) and -5, 2 1,2/TC. Average final height: -3,4 1,02/ Sempe; - 2,1 1,1/TC in boys and - 3,8 1,06/ Sempe and - 3,8 1,03/TC in girls. The average age at onset of puberty in girls: 13.9 2.8 years. At the end of puberty: 17.4 2.8 years. The age of menarche: 15.52 years. In boys, the average At the end of puberty: 19.8 2.2 years. The average duration of the course of puberty is 3.7 0.7 years in boys, 3.1 1,1 years in girls. Delayed puberty is higher in boys than in girls (p <0.04).

Acromegaly as a Complication of Growth Hormone Therapy

ABSTRACT Objective: Growth hormone (GH) replacement is widely used; however, acromegaly as a complication of overreplacement is rarely reported. This case report explores this complication with the use of weight-based dosing regimens of human GH. Methods: We report progressive features of acromegaly as a consequence of inadvertent overreplacement of GH, initiated for treatment of GH deficiency in an 11-year-old male treated for craniopharyngioma. Results: An 11-year-old male developed panhypopituitarism after transsphenoidal resection of a craniopharyngioma. Human GH (hGH) replacement therapy was subsequently initiated for hypopituitarism, using a weight-based dosing regimen, achieving adequate linear growth. After 9 years of hGH replacement therapy, prognathism and an increase in shoe size were noted, with supporting radiographic evidence of hGH overreplacement. Conclusion: Clinical features of acromegaly can develop as a rare adverse effect of overreplacement of hGH in GH-deficient patients treated with...

Cross-sectional and prospective study of the effects of GH therapy on metabolic panel in children with GH deficiency.

Numerous studies have shown that GH, in addition to promoting linear growth, exerts a key role in many metabolic processes. However, there are only few studies aiming at evaluating the metabolic panel of children with GH deficiency (GHD). The aims of the study were: to verify the presence of metabolic alterations in GHD children in comparison with age-matched controls and to check the possible effects of two year GH therapy on the metabolic parameters in GHD. cross-sectional and prospective; one center experience We enrolled 32 pediatric GHD patients (group A) and 33 sex- and age-matched healthy controls (group B). Baseline serum assays (lipid, insulin, glucose) were performed in both groups. GHD children underwent replacement therapy with GH. The same assays were repeated after 12 and 24 months of GH treatment. No differences, in basal assays were found between the two groups. In group A, after initiation of GH, there was a significant increase of basal insulin and HOMA- insulin resistance (IR) index (p &lt;0.001). In children with severe GHD (peak GH &lt;3 ng / ml), after beginning of GH therapy a significant improvement in the lipid profile was found (p &lt; 0.05). a) At the time of diagnosis GHD children had a metabolic picture that was not different from non- GHD group; b) in children with severe GHD, the metabolic profile showed a trend towards at improvement after the initiation of replacement therapy with GH, with beneficial effects in terms of total cholesterol, LDL cholesterol and cardiovascular risk indices; c) GHD patients with unfavorable metabolic profile (high BMI and hypercholestorolemia) need a monitoring of glucose metabolism by periodical evaluations of insulin and HOMA - IR.

Increased serum and bone matrix levels of the secreted Wnt antagonist DKK-1 in patients with growth hormone deficiency in response to growth hormone treatment.

Growth hormone (GH) substitution of adult-onset growth hormone deficiency (aoGHD) patients partially reverses unfavorable body composition profile. Wnt signaling pathway has being acknowledged as an important modulator of bone mass and of energy metabolism in adipose tissue and in β-cells. To assess the role of selected Wnt antagonists in bone and glucose metabolism before and after GH replacement in aoGHD. Patients from two randomized placebo-controlled studies of GH replacement in aoGHD were used. In study 1, 39 patients received GH or placebo for 9 months with 4 months wash-out. In study 2, iliac bone biopsies were obtained before and after GH or placebo (n = 10 each) for 12 months. Body composition and serum (study 1) and bone matrix (study 2) levels of Wnt antagonists (DKK-1, sFRP-3, WIF-1, and SOST) were quantified before and after GH. In vitro effect of GH and IGF-1 on DKK-1 secretion and expression of Wnt signaling modulators was assessed in human osteoblasts and mature adipocytes. GH replacement increased circulating and bone matrix levels of DKK-1, but not sFRP-3, WIF-1, and SOST. Furthermore, DKK-1 secretion increased in human osteoblasts stimulated by GH in vitro, with no effects on other cells. At baseline and after treatment, circulating DKK-1 was negatively associated with bone mass, but not fat mass or measures of insulin resistance, in aoGHD patients. An increase in DKK-1 may limit the effects of GH on bone mass, but does not seem to impact the increase in insulin resistance following GH substitution.

Metabolomics: a tool for the diagnosis of GH deficiency and for monitoring GH replacement?

The diagnostic value of insulin-like growth factor 1 (IGF1) for GH deficiency (GHD) in adults is not optimal. Molecular profiling could be used for biomarker discovery. The aim of this pilot study was to compare the serum metabolome between GHD patients and healthy controls, and identification of potential markers for diagnosis and/or for individual GH dosing. A total of ten patients with GHD, median age of 55 years and BMI of 27 kg/m2, were compared with ten healthy age- and gender-matched controls. The serum metabolic profiles were generated using gas chromatography-coupled mass spectroscopy on fasting samples taken in the morning from the controls and at baseline and during 6 months of GH replacement in the patients with GHD. The difference in low-molecular weight compounds (LMC) distinguished the healthy controls from GHD patients. Among 285 measured metabolites, 13 were identified as being most important in differentiating GHD patients from controls. Of these, 11 could not be structurally annotated but many were classified as lipids. The difference in the LMC pattern persisted despite normalisation of IGF1 following GH replacement. GH replacement increased the levels of specific fatty acid compounds and decreased the levels of certain amino acids. No metabolite changed in response to GH treatment, to the same extent as IGF1. The measurement of 285 metabolites resulted in a unique pattern in GHD, but changes in the metabolite patterns during GH treatment were limited. The utility of metabolomics to find new markers in GHD and GH replacement remains to be further elucidated.

Incidence and predictors of persistent growth hormone deficiency (GHD) in patients with isolated, childhood-onset GHD.

In a considerable proportion of patients with childhood-onset growth hormone (GH) deficiency (GHD), a normalisation of GH secretion at the attainment of final height (FH) is observed. The aim of the present study was to assess the incidence of, and to find out the predictors of, persistent and transient GHD, available in the pre-treatment period, in patients with childhood-onset isolated, non-acquired GHD. The analysis comprised 150 short children (117 boys), with childhood-onset isolated, non-acquired GHD who completed GH therapy and attained FH. Before treatment and at FH (in retesting), auxological parameters were measured, GH peak in stimulation tests and IGF-I concentration were assessed, and pituitary height (PHt) was measured before treatment. The incidence of persistent GHD was 12.0%. The patients with persistent GHD had before treatment significantly lower GH and IGF-I secretion, as well as significantly better increase of height SDS (DHSDS) during GH therapy than those with transient GHD. A negative correlation was observed between DHSDS and IGF-I concentration, but not between DHSDS and GH peak. There was no significant difference in the incidence of pituitary hypoplasia between the patients with persistent and transient GHD. The incidence of persistent GHD in patients with childhood-onset, isolated, non-acquired GHD is relatively low. Despite the fact that the predictors of persistent and transient GHD may be identified in childhood, a diagnosis of GHD should be verified in retesting after the attainment of FH in each case.

Effect of long-term GH replacement therapy on cardiovascular outcomes in GH-deficient patients previously treated for acromegaly: a sub-analysis from the Dutch National Registry of Growth Hormone Treatment in Adults.

The effect of GH deficiency (GHD) on the metabolic profile of acromegaly patients is unclear in patients previously treated for acromegaly, as are the efficacy and safety of GH treatment in this particular group. The aim of the study is to describe the characteristics of patients with severe GHD who were previously treated for acromegaly, and to investigate the effects of long-term GH treatment on cardiovascular risk factors and morbidity, compared with patients who were treated for a nonfunctioning pituitary adenoma (NFPA). A nationwide surveillance study. Sixty-five patients from the Dutch National Registry of Growth Hormone Treatment in Adults with previous acromegaly were compared with 778 patients with previous NFPA. Cardiovascular indices, including body composition, lipid profile, glucose metabolism, blood pressure, and morbidity were investigated. GHD patients with previous acromegaly had an unfavorable metabolic profile comparable with or more than GHD patients with previous NFPA. GH treatment led to improvement of the lipid profile in both groups, also after excluding patients using lipid-lowering medication. In patients with previous acromegaly, HbA1c levels increased more than in patients with previous NFPA (estimate 0.03, 95% CI 0.002-0.06, P=0.04). The risk for developing cardiovascular diseases was not different between the groups. The patients with GHD after previous acromegaly have an unfavorable metabolic profile comparable with patients with GHD after previous NFPA. In both groups, the lipid profile improves during GH treatment. Changes in glucose metabolism should be monitored closely. GH treatment in patients with GHD previously treated for acromegaly had no deleterious effect on cardiovascular morbidity.

Extracellular water and blood pressure in adults with growth hormone (GH) deficiency: a genotype-phenotype association study.

ObjectivesGrowth hormone deficiency (GHD) in adults is associated with decreased extracellular water volume (ECW). In response to GH replacement therapy (GHRT), ECW increases and blood pressure (BP) reduces or remains unchanged. Our primary aim was to study the association between polymorphisms in genes related to renal tubular function with ECW and BP before and 1 year after GHRT. The ECW measures using bioimpedance analysis (BIA) and bioimpedance spectroscopy (BIS) were validated against a reference method, the sodium bromide dilution method (Br−).Design and MethodsUsing a candidate gene approach, fifteen single-nucleotide polymorphisms (SNPs) in nine genes with known impact on renal tubular function (AGT, SCNN1A, SCNN1G, SLC12A1, SLC12A3, KCNJ1, STK39, WNK1 and CASR) were genotyped and analyzed for associations with ECW and BP at baseline and with their changes after 1 year of GHRT in 311 adult GHD patients. ECW was measured with the Br−, BIA, and BIS.ResultsBoth BIA and BIS measurements demonstrated similar ECW results as the reference method. At baseline, after adjustment for sex and BMI, SNP rs2291340 in the SLC12A1 gene was associated with ECW volume in GHD patients (p = 0.039). None of the SNPs influenced the ECW response to GHRT. One SNP in the SLC12A3 gene (rs11643718; p = 0.024) and three SNPs in the SCNN1G gene [rs5723 (p = 0.02), rs5729 (p = 0.016) and rs13331086 (p = 0.035)] were associated with the inter-individual differences in BP levels at baseline. A polymorphism in the calcium-sensing receptor (CASR) gene (rs1965357) was associated with changes in systolic BP after GHRT (p = 0.036). None of these associations remained statistically significant when corrected for multiple testing.ConclusionThe BIA and BIS are as accurate as Br− to measure ECW in GHD adults before and during GHRT. Our study provides the first evidence that individual polymorphisms may have clinically relevant effects on ECW and BP in GHD adults.

Socioeconomic factors do not but GH treatment does affect mortality in adult-onset growth hormone deficiency.

GH deficiency is associated with changes in body composition, increased cardiovascular risk markers, and reduced bone mineral density. There seem to be multiple causes of the reported increased morbidity and mortality. The objective was to study the socioeconomic status in patients with adult-onset GH deficiency and its impact on mortality. This is a nationwide registry study in which the socioeconomic status in adult-onset GH deficient patients was identified in the Danish registries and compared with controls matched on age and gender. The socio-economic status included cohabitation, education, income, parenthood, convictions, and retirement. All patients had adult-onset GH deficiency and were born between 1950 and 1980. Two-hundred seventy-six patients (53.6% men) and 25 717 controls were included. GH-treated patients had a reduced mortality in total and due to malignancy compared with untreated patients. This difference remained after adjustment for cohabitation and education. Compared with the background population, the incidence of cohabitation, parenthood, and convictions was significantly reduced in patients, whereas education was unaffected. Retirement was significantly increased. Mortality was increased in patients, especially among patients not treated with GH. In GH-treated patients, mortality was decreased in total and due to malignancy compared with untreated patients, even after adjustment for all possible measured confounders. The patients had an impaired socioeconomic profile on most parameters compared with controls. This study does not support the suggestion that GH replacement therapy causes increased mortality.