How effective is octreotide-LAR as a primary treatment for growth-hormone-secreting tumors?
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Journal Article↗
Biomedical subjects
Gerhard Baumann
Publications and source records attributed to Gerhard Baumann.
Voice abnormality in adults with congenital and adult-acquired growth hormone deficiency.
CONTEXT: Adult males with congenital, untreated, severe GH deficiency (GHD) due to genetic GHRH receptor deficiency exhibit distinctive, high-pitched, and raspy voice characteristics. OBJECTIVE/DESIGN: To determine the physical underpinning of this phenomenon, we performed voice recordings, translarynx impedance measurements, spectral analysis, and estimates of spectral complexity [approximate entropy (ApEn)] in four affected men. Results were compared with those obtained in four men with untreated adult-onset GHD and a normal male population. RESULTS: Congenital GHD subjects had a high-pitched voice with a fundamental frequency typical of normal females (174-266 Hz). Their frequency spectra were characterized by abnormal harmonics, with reversal/interruption of the normal amplitude decay among higher-order harmonics, findings consistent with a creaky quality of the voice. Patients with adult-onset GHD, acquired at ages 31, 38, and 40 yr, had a normal male pitch (fundamental frequency, 117-154 Hz) but pathologically low ApEn values, corresponding to a breathy quality of the voice and suggesting abnormal vocal fold function. A fourth patient who acquired GHD at age 22 yr had a pitch intermediate between male and female, high ApEn, and a spectral pattern similar to the congenital GHD patients. CONCLUSIONS: This study demonstrates an effect of GH on laryngeal size and vocal fold compliance that results in a high pitch and disordered spectral quality. The time of onset of GHD determines which type of abnormality predominates.
Adult↗
Growth hormone receptor is a target for presenilin-dependent gamma-secretase cleavage.
Growth hormone receptor (GHR) is a cytokine receptor superfamily member that binds growth hormone (GH) via its extracellular domain and signals via interaction of its cytoplasmic domain with JAK2 and other signaling molecules. GHR is a target for inducible metalloprotease-mediated cleavage in its perimembranous extracellular domain, a process that liberates the extracellular domain as the soluble GH-binding protein and leaves behind a cell-associated GHR remnant protein containing the transmembrane and cytoplasmic domains. GHR metalloproteolysis can be catalyzed by tumor necrosis factor-alpha-converting enzyme (ADAM-17) and is associated with down-modulation of GH signaling. We now study the fate of the GHR remnant protein. By anti-GHR cytoplasmic domain immunoblotting, we observed that the remnant induced in response to phorbol ester or platelet-derived growth factor has a reliable pattern of appearance and disappearance in both mouse preadipocytes endogenously expressing GHR and transfected fibroblasts expressing rabbit GHR. Lactacystin, a specific proteasome inhibitor, did not appreciably change the time course of remnant appearance or clearance but allowed detection of the GHR stub, a receptor fragment slightly smaller than the remnant but containing the C terminus of the remnant (receptor cytoplasmic domain). In contrast, MG132, another (less specific) proteasome inhibitor, strongly inhibited remnant clearance and prevented stub appearance. Inhibitors of gamma-secretase, an aspartyl protease, also prevented the appearance of the stub, even in the presence of lactacystin, and concomitantly inhibited remnant clearance in the same fashion as MG132. In addition, mouse embryonic fibroblasts derived from presenilin 1 and 2 (PS1/2) knockouts recapitulated the gamma-secretase inhibitor studies, as compared with their littermate controls (PS1/2 wild type). Confocal microscopy indicated that the GHR cytoplasmic domain became localized to the nucleus in a fashion dependent on PS1/2 activity. These data indicate that the GHR is subject to sequential proteolysis by metalloprotease and gamma-secretase activities and may suggest GH-independent roles for the GHR.
ADAM Proteins↗
Laboratory measurement of growth hormone.
Growth hormone (GH) measurements are complicated by the heterogeneous nature of GH, as well as by the presence of the GH binding protein in plasma. Several isoforms of GH exist, and specific assays for each are currently either unavailable, impractical, or not clinically indicated. Bioassays include the in vivo assays based on rat weight gain, tibial line widening, or IGF-I generation. In vitro bioassays, based on the proliferation of cell lines expressing the prolactin receptor or GH receptor, are sensitive but prone to nonspecific interference by factors present in serum. Immunoassays (RIA, IRMA, ELISA, and immunofunctional assay design) are widely used in the clinical laboratory because of speed, sensitivity, and convenience. Discrepancies among results rendered by different immunoassays have become more apparent as monoclonal assays have superseded polyclonal assays, presumably because different antibodies recognize different epitopes among the heterogeneous mixture of GH isoforms in serum. Some assays, especially those with short, nonequilibrium incubation times are vulnerable to interference by the GH binding protein present in serum. Recommendations are given for strategies designed to minimize disparity of results obtained by different GH immunoassays applied to serum. Urinary GH measurements, while technically feasible, are of limited clinical utility because of biological variation in urinary GH excretion.
Animals↗
Haplotype analysis of the growth hormone releasing hormone receptor locus in three apparently unrelated kindreds from the indian subcontinent with the identical mutation in the GHRH receptor.
The growth hormone releasing hormone receptor (GHRHR) plays a critical role in growth. We identified three nominally unrelated kindreds harboring the identical mutation (E72X) in GHRHR, the gene that encodes GHRHR; all three families originated in the Indian subcontinent. Because of the relative geographic proximity of these populations, we employed haplotype analysis in the region of GHRHR to determine the likelihood that this mutation occurred in a common ancestor rather than having occurred on separate occasions in different individuals. Members of all three kindreds segregating the E72X mutation were genotyped for highly polymorphic dinucleotide repeat microsatellites in a 15.5 centimorgan (cM) region around GHRHR on chromosome 7p15. We conclude that the affected individuals share a common ancestor, and we use the association with linked markers to estimate the age of this unique mutation.
Chromosomes, Human, Pair 7↗
Reduced proteolysis of rabbit growth hormone (GH) receptor substituted with mouse GH receptor cleavage site.
GH binding protein (GHBP) is a circulating form of the GH receptor (GHR) extracellular domain, which derives by alternative splicing of the GHR gene (in mice and rats) and by metalloprotease-mediated GHR proteolysis with shedding of the extracellular domain as GHBP (in rabbits, humans, and other species). Inducible proteolysis of either mouse (m) or rabbit (rb) GHR is detected in cell culture in response to phorbol ester and other stimuli, yielding a cell-associated GHR remnant (comprised of the cytoplasmic and transmembrane domains and a small portion of the proximal extracellular domain) and down-regulating GH signaling. In this report, we map the mGHR cleavage site by adenoviral overexpression of a membrane-anchored mGHR mutant lacking its cytoplasmic domain and purification and N-terminal sequencing of the phorbol 12-myristate 13-acetate-induced remnant protein. The sequence obtained was LEACEEDI, which matches the mGHR extracellular domain stem region sequence L265EACEEDI272, indicating that mGHR cleavage occurs in the extracellular domain nine residues outside of the transmembrane domain, in the same region (but at different residues) as the rbGHR cleavage site we recently mapped. We studied the effects on receptor proteolysis and GHBP shedding of replacing rbGHR cleavage site residues with those corresponding to the mGHR cleavage site. We analyzed five separate rodentized rbGHR mutants incorporating mGHR amino acids either at or surrounding the cleavage site. Each mutant was normally processed, displayed at the cell surface, and responded to GH stimulation by undergoing tyrosine phosphorylation. Only the mutants replaced with mGHR cleavage site residues, rather than surrounding residues, exhibited deficient inducible proteolysis and GHBP shedding. These findings suggested that the GHR cleavage sites in the two species differ in their susceptibility to cleavage. This difference may underlie interspecies variation in utilization of proteolysis to generate GHBP.
Amino Acid Sequence↗
The Impact of congenital, severe, untreated growth hormone (GH) deficiency on bone size and density in young adults: insights from genetic GH-releasing hormone receptor deficiency.
GH and IGF-I have well recognized effects on bone elongation during development, but their importance for bone mineralization and structure during the growth phase are less well understood. Because children with GH deficiency are generally treated with GH, little detailed information exists in humans about the effects of long-term GH deficiency on bone development. The recently described syndrome of genetic GHRH receptor deficiency in Pakistan (dwarfism of Sindh) affords a unique opportunity to examine the question of GH deficiency on bone development because the affected patients have congenital, severe, isolated GH deficiency, which had never been treated because of societal reasons. We performed dual energy x-ray absorptiometry scans in four adult males (age, 23-30 yr) to address the question of bone mineralization. Areal bone mineral density (BMD) was low (mean Z scores: -3.3, -2.1, -3.7, and -1.7) in the lumbar spine, femoral neck, forearm, and total skeleton, respectively. This low areal BMD is in part caused by the small bone size in these dwarfed patients. When corrected for size, volumetric BMD (bone mineral apparent density) was normal to near normal (mean Z scores: -1.2, +0.8, and +0.8 for lumbar spine, femoral neck and total skeleton, respectively). We conclude that GH/IGF-I deficiency has relatively little impact on bone mineralization during the bone accretion phase. This is in marked contrast to their effect on bone elongation and overall bone size.
Absorptiometry, Photon↗
Metalloprotease-mediated GH receptor proteolysis and GHBP shedding. Determination of extracellular domain stem region cleavage site.
Growth hormone-binding protein (GHBP) is complexed to a substantial fraction of circulating GH. In humans, rabbits, and other species, GHBP derives from proteolytic shedding of the GH receptor (GHR) extracellular domain. In cell culture studies, stimuli such as phorbol ester, platelet-derived growth factor, or serum induce GHR proteolysis, which concomitantly yields shed GHBP in cell supernatants and a cell-associated cytoplasmic domain-containing GHR remnant. This process is sensitive to metalloprotease inhibition, and genetic reconstitution studies identify tumor necrosis factor-alpha converting enzyme (TACE/ADAM-17), a transmembrane metalloprotease, as a GHR sheddase. Stimuli that induce GHR proteolysis render cells less responsive to GH, but the mechanism(s) of this desensitization is not yet understood. In this study, we mapped the rabbit (rb) GHR cleavage site. We adenovirally expressed a C-terminal epitope-tagged rbGHR lacking most of its cytoplasmic domain, purified the remnant protein induced by the phorbol ester, PMA, and derived the cleavage site by N-terminal sequencing of the purified remnant. The N-terminal sequence, (239)FTCEEDFR(246), matched perfectly the rbGHR and suggests that cleavage occurs eight residues from the membrane in the proximal extracellular domain stem region. Deletion and alanine substitution mutagenesis indicated that, similar to other TACE substrates, the spacing of residues in this region, more than their identity, influences GHR cleavage susceptibility. Further, we determined that PMA pretreatment desensitized a cleavage-sensitive GHR mutant, but not a cleavage-insensitive mutant, to GH-induced JAK2 activation. These results suggest that inducible GHR proteolysis can regulate GH signaling.
Amino Acid Sequence↗
Pulsatile growth hormone secretion persists in genetic growth hormone-releasing hormone resistance.
Growth hormone (GH) secretion is regulated by GH-releasing hormone (GHRH), somatostatin, and possibly ghrelin, but uncertainty remains about the relative contributions of these hypophysiotropic factors to GH pulsatility. Patients with genetic GHRH receptor (GHRH-R) deficiency present an opportunity to examine GH secretory dynamics in the selective absence of GHRH input. We studied circadian GH profiles in four young men homozygous for a null mutation in the GHRH-R gene by use of an ultrasensitive GH assay. Residual GH secretion was pulsatile, with normal pulse frequency, but severely reduced amplitude (<1% normal) and greater than normal process disorder (as assessed by approximate entropy). Nocturnal GH secretion, both basal and pulsatile, was enhanced compared with daytime. We conclude that rhythmic GH secretion persists in an amplitude-miniaturized version in the absence of a GHRH-R signal. The nocturnal enhancement of GH secretion is likely mediated by decreased somatostatin tone. Pulsatility of residual GH secretion may be caused by oscillations in somatostatin and/or ghrelin; it may also reflect intrinsic oscillations in somatotropes.
Adult↗
Growth hormone binding protein, insulin-like growth factor-I and short stature in two pygmy populations from the Philippines.
The molecular basis and biochemical mediators of genetic growth propensity and adult height achievement in the general population are largely unknown. Pygmies represent one extreme of the height spectrum that may provide important clues regarding this issue. Previous studies in pygmies from Africa and Papua-New Guinea have shown decreased serum levels of growth hormone binding protein (GHBP), the circulating ectodomain of the growth hormone receptor (GHR). By inference, a similar limitation in tissue GHR expression has been assumed to be responsible for the partial growth hormone (GH) resistance observed in African pygmies. It is not clear how generalizable this concept is to other populations. To address this question, we studied two pygmy populations from the Philippines (Aeta and Mamanwa people) that are unrelated to the African pygmies. Serum GHBP and IGF-I levels were significantly decreased in both pygmy populations, compared to normal-statured Philippino controls. The results, together with previous observations in African and New Guinean pygmies, indicate that short stature is associated with low serum GHBP levels in pygmy populations of diverse origins and in different parts of the world. This strengthens the tentative postulate that the GHBP/GHR system plays an important role in the genetic and perhaps nutritional determination of adult stature in humans. Molecular genetic studies of the GHR gene in various pygmy populations may shed further light on the mystery of pygmy short stature.
Adult↗
Genetic characterization of growth hormone deficiency and resistance: implications for treatment with recombinant growth hormone.
Growth failure can be caused by deficient growth hormone production or action. The genes involved in pituitary development, somatotrope function, as well as growth hormone synthesis, secretion, and action have recently been characterized in considerable detail. Familial growth failure has played an important role in identifying these genes, and a large number of mutations adversely affecting the development and function of the growth hormone/insulin-like growth factor axis have been discovered. Inactivating mutations leading to growth retardation in humans have been identified in several pituitary transcription factor genes (HESX1, PITX2, LHX3, PROP1, POU1F1) as well as in genes encoding the growth hormone-releasing hormone receptor (GHRH-R), the G(s) protein alpha subunit (GNAS1), growth hormone itself (GH-1), the growth hormone receptor (GHR), and in a single case each, the insulin-like growth factor I (IGF-I) and the IGF-I receptor. Mutations in pituitary transcription factors cause developmental abnormalities of the pituitary and deficiency of multiple pituitary hormones [growth hormone (GH), prolactin (Prl), thyrotropin (TSH) and lutropin/follitropin (LH/FSH)]. Most of the syndromes respond well to therapy with recombinant GH; exceptions are antibody-mediated resistance in GHD type IA (not all patients) and cases of Laron syndrome (GHR deficiency). Such patients respond to IGF-I therapy. This review summarizes the molecular genetics, functional defects, phenotypes, diagnostic considerations and therapeutic aspects of syndromes associated with mutations in the relevant genes.
Animals↗
When should we measure growth hormone binding protein?
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Aging↗