Two different 5′ splice site mutations in the growth hormone gene causing autosomal dominant growth hormone deficiency

Four distinct types of isolated growth hormone deficiency (IGHD) have been described to date. Of these IGHD type II has been defined as having a dominant mode of inheritance. We performed a molecular genetic analysis of two patients clinically characterized as IGHD type II. One of the patients and her father shared a heterozygous G–A transition in the first 5′ donor splice site of intron III. The second father and daughter studied also showed a heterozygous G–A transition in the fifth base from the 5′ donor splice site in the same intron. Both mutations altered the correct splicing of the growth hormone pre-mRNA when the corresponding genes were expressed in COS-7 cells. We propose that both inherited mutations are responsible for IGHD type II in these patients. Received: 7 April 1997 / Accepted: 13 June 1997     

Oral clonidine provocative test in the diagnosis of growth hormone deficiency in childhood: should we make the timing uniform?

INTRODUCTION: Oral clonidine is one of the most frequent drugs used for the diagnosis of growth hormone deficiency (GHD), but the duration of the test, depending on which European centres use it, is not uniform and can vary from 120 to 150 min or even 180 min. SUBJECTS AND METHODS: To standardize this test, evaluating the possibility to shorten it to 90 min, we investigated the response of GH to the oral clonidine test in 291 children evaluated for short stature (height <-2 SD). Of these, 164 were diagnosed as idiopathic short stature (ISS) and 127 as GHD. In these patients, we calculated: (1) the frequency distribution of the GH peaks to clonidine in GHD and in ISS at various times; (2) the percentage of GH peaks to clonidine before and after 90 min in all and in ISS children; (3) the percentage of the first GH value >or=10 ng/ml before 90 min and after 90 min in ISS. RESULTS: GH peak distribution varied between 30 and 180 min, even though the vast majority of peaks occurred between 30 and 60 min. There was no significant difference (p > 0.05) in the peak distribution between ISS and GHD children. The percentages of GH peaks within 90 min were 92.1% in all children and 95.7% in ISS. If considering the first value of GH >or=10 ng/ml this last percentage reaches 96.3%. CONCLUSION: Our study suggests that the oral clonidine test can be administered for only 90 min without significantly changing its validity. This test should be standardized at 90 min in European protocols just as in those currently used in the USA in order to reduce the discomfort of patients and the cost of this diagnostic procedure.     

Does growth hormone treatment alter skeletal muscle mitochondrial respiration in rats?

OBJECTIVE: Growth hormone (GH) has been shown to stimulate lipolysis and enhance lipid oxidation. We investigated whether GH could improve mitochondrial oxidative capacity. METHOD: Fourteen male Wistar rats received 14-day treatment with biosynthetic human GH (10 IU/kg/24 h) or placebo. Mitochondria were isolated from the total muscle of one hind limb of the rat. Mitochondrial oxygen consumption was measured in vitro using a Clark-type electrode with three substrates: palmitoyl-L-carnitine, pyruvate and succinate (+ rotenone). RESULTS: Muscle mitochondrial yield was not significantly different in the GH-treated group from that in controls. Neither the basal nor ADP-stimulated respiratory state reached a significant difference between the 2 groups with palmitoyl-L-carnitine, pyruvate, and succinate. CONCLUSION: GH treatment did not improve the oxidative capacity of skeletal muscle mitochondria.     

Human growth hormone: 1974–1981

Summary Chemical investigations of the human growth hormone (HGH) molecule were briefly reviewed for the period between 1974 and 1981. These include chemical modification, selective enzymic cleavage, the 20K HGH, synthetic peptide fragments, complementation of the natural NH₂ terminal 134-amino acid fragment with natural or synthetic COO H-terminal fragments of various chain lengths, covalent reconstitution of two contiguous fragments of HGH with thrombin and bacterially synthesized methionyl-HGH.Abbreviations GH growth hormone or somatotropin - HGH human GH - CD circular dichroism - NMR nuclear magnetic resonance - DEAE diethylaminoethyl - CMC carboxymethyl cellulose - HPLC high performance liquid chromatography - RA-HGH reduced-carbamidomethylated HGH - PL-HGH plasmin-modified HGH - Cam Carbamidomethyl - BGH bovine GH - SDS sodium dodecylsulfate     

A polymorphism in the growth hormone-releasing hormone receptor gene: clinical significance?

Two forms of the growth hormone-releasing hormone (GHRH) receptor (GHRH-R) exist in terms of a polymorphism at codon 57. The most common allele possesses GCG, coding for Ala. This codon can also be ACG, replacing the Ala with Thr. The present study demonstrates that the latter occurs in about 20% of pituitary somatotrophinomas, removed from patients with acromegaly. Somatotrophinomas possessing the alternative allele respond, on average, more strongly to GHRH in terms of GH secretion in vitro than tumors which are homozygous for the more common allele. The distribution of the two allelic forms of the GHRH-R did not significantly differ between acromegalic and non-acromegalic subjects. Thus, while the alternative allelic forms may, at least partially, contribute to the variable response of serum GH levels to i.v. GHRH observed in acromegalic and normal subjects, it is unlikely that subjects possessing the rarer form containing Thr in place of Ala at residue 57 are at increased risk of developing acromegaly.     

Metabolic effects of growth hormone therapy in an Alström syndrome patient

AIM: To investigate the metabolic effects of recombinant human growth hormone (rhGH) in an Alstr?m syndrome patient with growth hormone deficiency. METHODS: A 15-year-old Alstr?m syndrome boy with growth hormone deficiency received rhGH therapy for 1 year. Biochemical parameters, including hepatic enzyme levels, lipid profiles, and insulin sensitivity, were measured. Body composition analysis and computed tomography scans of the liver were performed. RESULTS: After 1 year of rhGH treatment, body fat mass, fat infiltration in the liver, and serum lipid profiles had all decreased. Insulin sensitivity and acanthosis nigricans improved. CONCLUSION: rhGH therapy might have beneficial effects on body composition, liver fat content, lipid profiles, and insulin resistance in Alstr?m syndrome patients, with improvement of the glucose homeostasis.     

Growth hormone induces transforming growth factor-β1 in podocytes: Implications in podocytopathy and proteinuria

Pituitary growth hormone (GH) is essential for growth, metabolism, and renal function. Overactive GH signaling is associated with impaired kidney function. Glomerular podocytes, a key kidney cell type, play an indispensable role in the renal filtration and express GH receptors (GHR), suggesting the direct action of GH on these cells. However, the precise mechanism and the downstream signaling events by which GH leads to diabetic nephropathy remain to be elucidated. Here we performed proteome analysis of the condition media from human podocytes and confirmed that GH-induces TGF-β1. Inhibition of GH/GHR stimulated-JAK2 signaling abrogates GH-induced TGF-β1 secretion. Mice administered with GH showed glomerular manifestations concomitant with proteinuria. Pharmacological inhibition of TGF-βR1 in mice prevented GH-induced TGF-β dependent SMAD signaling and proteinuria. Conditional deletion of GHR in podocytes protected mice from streptozotocin-induced diabetic nephropathy. GH and TGF-β1 signaling components expression was elevated in the kidneys of human diabetic nephropathy patients. Our study identifies that GH induces TGF-β1 in podocytes, contributing to diabetic nephropathy.     

ABA in bryophytes: how a universal growth regulator in life became a plant hormone?

Abscisic acid (ABA) is not a plant-specific compound but one found in organisms across kingdoms from bacteria to animals, suggesting that it is a ubiquitous and versatile substance that can modulate physiological functions of various organisms. Recent studies have shown that plants developed an elegant system for ABA sensing and early signal transduction mechanisms to modulate responses to environmental stresses for survival in terrestrial conditions. ABA-induced increase in stress tolerance has been reported not only in vascular plants but also in non-vascular bryophytes. Since bryophytes are the key group of organisms in the context of plant evolution, clarification of their ABA-dependent processes is important for understanding evolutionary adaptation of land plants. Molecular approaches using Physcomitrella patens have revealed that ABA plays a role in dehydration stress tolerance in mosses, which comprise a major group of bryophytes. Furthermore, we recently reported that signaling machinery for ABA responses is also conserved in liverworts, representing the most basal members of extant land plant lineage. Conservation of the mechanism for ABA sensing and responses in angiosperms and basal land plants suggests that acquisition of this mechanism for stress tolerance in vegetative tissues was one of the critical evolutionary events for adaptation to the land. This review describes the role of ABA in basal land plants as well as non-land plant organisms and further elaborates on recent progress in molecular studies of model bryophytes by comparative and functional genomic approaches.     

Can glutamine and growth hormone promote protein anabolism in children with cystic fibrosis?

To determine whether recombinant human growth hormone (rhGH), glutamine (GLN) or a combination of both agents can enhance protein synthesis in cystic fibrosis (CF) patients, six 9.6 +/- 0.5-year-old prepubertal children (4 M, 2 F) with CF and stable lung disease with undernutrition (weight/height <50th percentile) or delayed growth (height <5th percentile) received stable isotope infusions, in the postabsorptive state and on 4 separate study days: (a) at baseline, and after a 4-week treatment with either, (b) oral GLN (0.7 g/kg/day), (c) rhGH (0.3 mg/kg/week, SC), or (d) both GLN and rhGH. Four-hour infusions of (13)C-leucine were used to assess leucine appearance rate (Ra, an index of protein breakdown), oxidation (Ox), and non-oxidative leucine disposal (NOLD, an index of protein synthesis). Results are expressed as changes (%) from baseline:We conclude that in children with CF: (1) due to high inter-subject variability, oral glutamine does not significantly enhance protein gain; (2) rhGH has significant anabolic effects which are mediated by stimulation of protein synthesis, and (3) glutamine does not enhance the effect of rhGH.     

Effects of 2-bromo-α-ergocryptine on β-endorphin-induced growth hormone,prolactin and luteining hormone release in urethane anesthetized rats

Adult male rats were injected intraperitoneally either with saline or 2-Br- α-ergocryptine(CB-154)(10 ng/0.5 ml/rat) 30 min prior to an intraventricular injection of saline or β-endorphin (1 μg/10 μl or 5 μg/10 μl) and 30 min after β-endorphin, they were sacrificed by decapitation. Intraventricular injection of β-endorphin elicited significant increases in serum GH, prolactin and LH levels in a dose-related manner. Pretreatment with CB-154 inhibited the release of GH, prolactin and LH induced by β-endorphin. These results indicate that the stimulatory effects of β-endorphin on GH, prolactin and LH may be involved in an inhibition of dopaminergic mechanism in the central nervous system.     

Does bovine growth hormone possess rapid lipolytic activity?

The growth promoting and rapid lipolytic activity associated with bovine growth hormone can be separated by chromatography on QAE Sephadex A-25. The contaminant responsible for the lipolytic effect was identified as bovine thyroid-stimulating hormone.     

Treatment of growth hormone excess in dogs with the progesterone receptor antagonist aglépristone

Acromegaly or hypersomatotropism in dogs is almost always due to progestin-induced hypersecretion of GH originating from the mammary gland. The aim of this study was to investigate whether aglépristone, a progesterone receptor antagonist, can be used to treat this form of canine acromegaly. In five Beagle bitches hypersomatotropism was induced by administration of MPA for over 1 year. Subsequently, aglépristone was administered. Blood samples were collected before MPA administration, immediately before, during, and 3.5 and 5.5 weeks after the last administration of aglépristone for determination of the plasma concentrations of GH and IGF-I. In addition, blood samples for the determination of the 6-h plasma profile of GH were collected before MPA administration, before aglépristone administration, and 1 week after the last aglépristone treatment. MPA administration resulted in a significant increase of the mean plasma IGF-I concentration, whereas analysis of the pulsatile plasma profile demonstrated a trend (P=0.06) for a higher mean basal plasma GH concentration and a higher mean AUC(0) for GH. Treatment with aglépristone resulted in a significant decrease of the mean plasma GH and IGF-I concentrations. Analysis of the pulsatile plasma profile showed a trend (P=0.06) for a lower mean basal plasma GH concentration and a lower mean AUC(0) for GH 1 week after the last aglépristone treatment compared with these values before aglépristone administration. Three and a half and 5.5 weeks after the last aglépristone administration the mean plasma IGF-I concentration increased again. In conclusion, aglépristone can be used successfully to treat dogs with progestin-induced hypersomatotropism.     

Suppression of FAT/CD36 mRNA by human growth hormone in pancreatic β-cells

Fatty acid-induced damage in pancreatic β-cells is assumed to play an important role in the development of type 2 diabetes. Lactogens (prolactin, placental lactogen and growth hormone) improve β-cell survival via STAT5 activation but the molecular targets are incompletely characterized. The aim of this study was to examine the effect of human growth hormone (hGH) on mRNAs of fatty acid transport and binding proteins expressed in pancreatic β-cells, and to examine this in relation to β-cell survival after exposure to fatty acids. hGH decreased mRNA levels of FAT/CD36, whereas mRNAs of GPR40, FASN, FABP2, FATP1 and FATP4 were unchanged. RNAi against FAT/CD36 decreased fatty acid-induced apoptosis. Over-expression of constitutively active STAT5 was able to mimic hGH’s suppression of FAT/CD36 expression, whereas dominant negative STAT5 was unable to block the effect of hGH indicating that STAT5 did not bind directly to the FAT/CD36 promoter. The hGH-mediated suppression of FAT/CD36 mRNA was associated with a decrease in palmitate uptake and fatty acid-induced basal hyper-secretion of insulin resulting in improved glucose-stimulated insulin secretion. This study suggests that hGH can protect β-cells against fatty acid-induced damages.     

Anti-Müllerian hormone: Hormone or growth factor?

Anti-Müllerian hormone (AMH) is a dimeric glycoprotein member of the TGF-β family. It is synthesized by immature Sertoli cells, and, to a lesser degree, by adult Sertoli and granulosa cells. AMH is responsible for the regression of Müllerian ducts in the male fetus; it also has deleterious effects on the female fetal reproductive tract, destroying Müllerian primordia and germ cells, and masculinizing the fetal ovary on the rare occasions female fetuses become exposed to its effects. All other suggested actions for AMH—retardation of oocyte meiosis, inhibition of EGF receptor autophosphorylation, anti-cancer activity—have been reported with crude hormone preparations, and have not been confirmed using pure AMH. Its relatively limited sphere of action—the fetal genital tract—and the fact that it is secreted into the general circulation and can act at long range, imply that AMH is more like a hormone than a growth factor, but the complex interaction between hormones and growth factors make a formal distinction impossible.     

How robust are laboratory measures of growth hormone status?

Biochemical assessment of growth hormone (GH) status is required in both suspected GH deficiency and GH excess. GH secretion can either be measured through investigation of the pituitary or by monitoring markers that change as a consequence of GH action on its target tissues. The two most widely used and, to date, best validated biochemical parameters are immunoassay measurement of either human GH (hGH) or insulin-like growth factor (IGF)-I. The fundamental difference between measurement of hGH and IGF-I is that the first reflects GH secretion while the second reflects GH action. However, because GH secretion is pulsatile in nature, random blood sampling for determination of hGH levels is only minimally informative. Analytical methods for measuring GH and IGF-I show considerable between-method variability. Since these parameters are used in establishing diagnoses and in monitoring GH-related diseases, the endocrinologist should be aware of the specifications and limitations of the analytical methods available.