Elevated Serum Growth Hormone Research Articles

Experimental Autoimmune Encephalomyelitis Influences GH-Axis in Female Rats.

Inflammation, demyelination, and axonal damage to the central nervous system (CNS) are the hallmarks of multiple sclerosis (MS) and its representative animal model, experimental autoimmune encephalomyelitis (EAE). There is scientific evidence for the involvement of growth hormone (GH) in autoimmune regulation. Previous data on the relationship between the GH/insulin like growth factor-1 (IGF-1) axis and MS/EAE are inconclusive; therefore, the aim of our study was to investigate the changes in the GH axis during acute monophasic EAE. The results show that the gene expression of Ghrh and Sst in the hypothalamus does not change, except for Npy and Agrp, while at the pituitary level the Gh, Ghrhr and Ghr genes are upregulated. Interestingly, the cell volume of somatotropic cells in the pituitary gland remains unchanged at the peak of the disease. We found elevated serum GH levels in association with low IGF-1 concentration and downregulated Ghr and Igf1r expression in the liver, indicating a condition resembling GH resistance. This is likely due to inadequate nutrient intake at the peak of the disease when inflammation in the CNS is greatest. Considering that GH secretion is finely regulated by numerous central and peripheral signals, the involvement of the GH/IGF-1 axis in MS/EAE should be thoroughly investigated for possible future therapeutic strategies, especially with a view to improving EAE disease.

Structural and proteomic repercussions of growth hormone receptor deficiency on the pituitary gland: Lessons from a translational pig model.

Growth hormone receptor deficiency (GHRD) results in low serum insulin-like growth factor 1 (IGF1) and high, but non-functional serum growth hormone (GH) levels in human Laron syndrome (LS) patients and animal models. This study investigated the quantitative histomorphological and molecular alterations associated with GHRD. Pituitary glands from 6 months old growth hormone receptor deficient (GHR-KO) and control pigs were analyzed using a quantitative histomorphological approach in paraffin (9 GHR-KO [5 males, 4 females] vs. 11 controls [5 males, 6 females]), ultrathin sections tissue sections (3 male GHR-KO vs. 3 male controls) and label-free proteomics (4 GHR-KO vs. 4 control pigs [2 per sex]). GHR-KO pigs displayed reduced body weights (60% reduction in comparison to controls; p < .0001) and decreased pituitary volumes (54% reduction in comparison to controls; p < .0001). The volume proportion of the adenohypophysis did not differ in GHR-KO and control pituitaries (65% vs. 71%; p = .0506) and GHR-KO adenohypophyses displayed a reduced absolute volume but an unaltered volume density of somatotrophs in comparison to controls (21% vs. 18%; p = .3164). In GHR-KO pigs, somatotroph cells displayed a significantly reduced volume density of granules (23.5%) as compared to controls (67.7%; p < .0001). Holistic proteome analysis of adenohypophysis samples identified 4660 proteins, of which 592 were differentially abundant between the GHR-KO and control groups. In GHR-KO samples, the abundance of somatotropin precursor was decreased, whereas increased abundances of proteins involved in protein production, transport and endoplasmic reticulum (ER) stress were revealed. Increased protein production and secretion as well as significantly reduced proportion of GH-storing granules in somatotroph cells of the adenohypophysis without an increase in volume density of somatotroph cells in the adenohypophysis could explain elevated serum GH levels in GHR-KO pigs.

Elevated insulin growth factor-1 in dentate gyrus induces cognitive deficits in pre-term newborns.

Prematurely born infants are deprived of maternal hormones and cared for in the stressful environment of Neonatal Intensive Care Units (NICUs). They suffer from long-lasting deficits in learning and memory. Here, we show that prematurity and associated neonatal stress disrupt dentate gyrus (DG) development and induce long-term cognitive deficits and that these effects are mediated by insulin growth factor-1 (IGF1). Nonmaternal care of premature rabbits increased the number of granule cells and interneurons and reduced neurogenesis, suggesting accelerated premature maturation of DG. However, the density of glutamatergic synapses, mature dendritic spines, and synaptic transmission were reduced in preterm kits compared with full-term controls, indicating that premature synaptic maturation was abnormal. These findings were consistent with cognitive deficits observed in premature rabbits and appeared to be driven by transcriptomic changes in the granule cells. Preterm kits displayed reduced weight, elevated serum cortisol and growth hormone, and higher IGF1 expression in the liver and DG relative to full-term controls. Importantly, blocking IGF-1 receptor in premature kits restored cognitive deficits, increased the density of glutamatergic puncta, and rescued NR2B and PSD95 levels in the DG. Hence, IGF1 inhibition alleviates prematurity-induced cognitive dysfunction and synaptic changes in the DG through modulation of NR2B and PSD95. The study identifies a novel strategy to potentially rescue DG maldevelopment and cognitive dysfunction in premature infants under stress in NICUs.

Diagnosis of Chromosome 15q-Terminal Deletion Syndrome through Elevated Fasting Serum Growth Hormone Levels

Chromosome 15q26-qter deletion syndrome is a rare disease that causes prenatal and postnatal growth retardation, microcephaly, developmental delay, and congenital heart diseases, mainly due to haploinsufficiency of IGF1R. In addition, patients with pathogenic variants of the IGF1R show similar symptoms. We report the case of a 5-month-old girl with prenatal and postnatal growth retardation, microcephaly, and congenital heart disease. At 5 months of age, her length was 54.7 cm (−4.3 SD), her weight was 4.4 kg (−3.1 SD), and her head circumference was 37.4 cm (−2.8 SD), thus presenting severe growth retardation. Repeated pre-feeding serum GH levels were abnormally high (26.1–85.5 ng/mL), and IGF-1 levels (+0.16 to +1.2 SD) were relatively high. The 15q sub-telomere fluorescence in situ hybridization analysis revealed a heterozygous deletion in the 15q terminal region. Whole-genome single nucleotide polymorphism microarray analysis showed a terminal deletion of 6.4 Mb on 15q26.2q26.3. This is the first report showing that fasting GH levels are high in early infancy in patients with IGF1R abnormalities. In addition to relatively high IGF-1 levels, elevated fasting GH levels in early infancy may contribute to the diagnosis of IGF1R abnormalities.

Genetic Characterization of Short Stature Patients With Overlapping Features of Growth Hormone Insensitivity Syndromes.

ContextGrowth hormone insensitivity (GHI) in children is characterized by short stature, functional insulin-like growth factor (IGF)-I deficiency, and normal or elevated serum growth hormone (GH) concentrations. The clinical and genetic etiology of GHI is expanding.ObjectiveWe undertook genetic characterization of short stature patients referred with suspected GHI and features which overlapped with known GH–IGF-I axis defects.MethodsBetween 2008 and 2020, our center received 149 GHI referrals for genetic testing. Genetic analysis utilized a combination of candidate gene sequencing, whole exome sequencing, array comparative genomic hybridization, and a targeted whole genome short stature gene panel.ResultsGenetic diagnoses were identified in 80/149 subjects (54%) with 45/80 (56%) having known GH–IGF-I axis defects (GHR n = 40, IGFALS n = 4, IGFIR n = 1). The remaining 35/80 (44%) had diagnoses of 3M syndrome (n = 10) (OBSL1 n = 7, CUL7 n = 2, and CCDC8 n = 1), Noonan syndrome (n = 4) (PTPN11 n = 2, SOS1 n = 1, and SOS2 n = 1), Silver–Russell syndrome (n = 2) (loss of methylation on chromosome 11p15 and uniparental disomy for chromosome 7), Class 3-5 copy number variations (n = 10), and disorders not previously associated with GHI (n = 9) (Barth syndrome, autoimmune lymphoproliferative syndrome, microcephalic osteodysplastic primordial dwarfism type II, achondroplasia, glycogen storage disease type IXb, lysinuric protein intolerance, multiminicore disease, macrocephaly, alopecia, cutis laxa, and scoliosis syndrome, and Bloom syndrome).ConclusionWe report the wide range of diagnoses in 149 patients referred with suspected GHI, which emphasizes the need to recognize GHI as a spectrum of clinical entities in undiagnosed short stature patients. Detailed clinical and genetic assessment may identify a diagnosis and inform clinical management.

Status epilepticus and diabetes ketoacidosis: uncommon clinical presentations of acromegaly.

SummaryAcromegaly is a rare disease caused by hypersecretion of the growth hormone (GH). Most cases are caused by either pituitary microadenoma or macroadenoma. The GH producing tumors present with clinical manifestations of acromegaly due to excessive GH secretion or symptoms resulting from mass effects of the enlarging tumor. The physical changes are usually slow and, therefore, recognition of the disease is delayed. These adenomas are never malignant but can have significant morbidity and mortality. A subgroup of patients with acromegaly present with severe hyperglycemia resulting in diabetic ketoacidosis (DKA) which requires insulin. Rarely are pituitary tumors responsible for generalized convulsions except when they are too large. We hereby present two cases, the first is that of a 26-year-old female who presented with new onset status epilepticus, DKA with a 1-year history of diabetes mellitus (DM). On examination, she had clinical features of acromegaly. The second case is that of a 34-year-old female who presented with new onset status epilepticus, hyperglycemia with a history of recently diagnosed DM, and features of gigantism. In both cases, their diagnosis was confirmed by elevated serum GH and later by elevated insulin-like growth factor type 1 levels, and CT of the head demonstrating large pituitary macroadenoma. The importance of clinical history and examination, as well as investigations is vital in the recognition of acromegaly. The prognosis of acromegalic patients depends on early clinical recognition and tumor size reduction by either medical or surgical therapy.Learning pointsConditions such as status epilepticus and DKA may be clinical presentations in patients presenting with acromegaly.Seizures are rare in people with pituitary adenoma and typically occur when the tumor invades the suprasellar area due to mass effect on the brain.This article shows how best we were able to manage the acromegaly complications in a low resource setting.Hyperprolactinemia in acromegaly may be due to disruption of the normal dopaminergic inhibition of prolactin secretion due to mass effect of the macroadenoma, and around 25% of GH-secreting adenomas co-secrete prolactin.

Somatotrope Responses to Acute and Prolonged Loss of Leptin Signaling

In mice and humans, fasting results in a rise of serum growth hormone (GH). In mice, this coincides with increased Gh and growth hormone releasing hormone receptor (Ghrhr) mRNA. Fasting also results in increased serum ghrelin and decreased serum leptin. We have shown that pituitary somatotropes are dependent on circulating leptin to maintain sufficient stores of GH and GHRHR proteins. We hypothesized that the GH rise seen in fasted mice with reduced serum leptin was due to ghrelin‐stimulated pathways. However, a review of the literature revealed a study by Steyn et al. (2011) which demonstrated an acute decline in GH pulses in male mice after 12–18 h of fasting. This study suggests that somatotropes may have time‐dependent responses, with shorter fasting responses driven by the absence of leptin signals.Our fasting study was composed of three groups of male mice: 1) mice fasted for 6, 12, 24, or 48 hours, 2) mice fasted for 24 and 48 hours with 10% glucose in the drinking water, and 3) mice fed ad libitum. Body weight and serum glucose were significantly reduced with all fasting times. After 6 h of fasting, serum leptin levels were reduced from 9625.63 pg/ml (fed controls) to 1798.15 pg/mL with a further reduction to 774.17 pg/ml after 12 h, which was maintained following 24 and 48 h fasting. Ghrelin levels were unchanged with 6, 12 and 24 h fasting but significantly increased by 55.4% with 48 h fasting. Serum GH was unchanged with 6 and 12 h fasting, but was significantly reduced from 7765 pg/ml (fed) to 2253 pg/ml after the 24 h fast (p=0.03 ANOVA). In the 48 h fasted mice, serum GH was significantly increased over fed mice, from 1828 pg/ml (fed) to 10569 pg/ml (p=0.01 ANOVA). There were significant increases in pituitary Ghrhr mRNA after 24 and 48 h fasting and Gh mRNA was increased after 6 and 48 h of fasting. However, GH and GHRHR content were unchanged.This study has uncovered time‐dependent differential responses to fasting by somatotropes in male mice. The reduced serum GH after 24 h correlated well with the reduction in serum leptin. Similarly, the prolonged fasting (48 h) and elevated serum GH correlated well with the rise in ghrelin. The high Gh and Ghrhr mRNA levels corresponds with rising ghrelin levels. Reduced serum GH at 24 h indicates that somatotropes remain dependent on leptin signals for GH secretion. However, with normal GH or GHRHR content, this points to a defect in a signaling pathway needed for secretion that has yet to be determined.Support or Funding InformationNIH grants 5 R01 HD087057‐03 (GVC and AM), 5 R01 HD 093461‐01 (AM and GVC), and 5 R01 DK113776‐02 (GVC and AM). NIGMS grants P20 GM103425 and P30GM11070 (PI Dr. Edgar Garcia‐Rill). NSF funded Southern Regional Education Board Dissertation Award (TKM).

Early surgical intervention for patients with possible clinically silent somatotroph adenoma: a case series

IntroductionClinically silent somatotroph adenoma is characterized by elevated serum growth hormone but without the clinical symptoms of acromegaly, and it is considered rare. The natural history is not well understood, progress to symptomatic is uncertain, and treatment strategy has not been established.Case presentationThe first patient was a 48-year-old-Asian woman who presented with serum growth hormone 6.99 ng/ml and insulin-like growth factor 1 of 476 ng/ml, but no characteristic features of acromegaly. Five years after initial diagnosis, she presented with acromegalic facial appearance. Transsphenoidal surgery achieved gross total removal and endocrinological remission. The second patient was a 40-year-old-Asian woman who presented with serum growth hormone 31.14 ng/ml and insulin-like growth factor 1 of 709.6 ng/ml, but no characteristic features of acromegaly. Three years after initial diagnosis, she presented with acromegalic facial appearance. Transsphenoidal surgery achieved gross total removal and endocrinological remission. The third patient was a 64-year-old-Asian woman who presented with serum growth hormone 6.0 ng/ml and insulin-like growth factor 1 of 341 ng/ml, but no characteristic features of acromegaly. Eight months after initial diagnosis, hand enlargement was detected. Transsphenoidal surgery achieved gross total removal and endocrinological remission.ConclusionDue to its potential for evolving to symptomatic disease, the risks of surgery and observation for patients with somatotroph adenoma should be carefully compared from the viewpoint of better health outcome.

Biochemical assessment of disease control in acromegaly: reappraisal of the glucose suppression test in somatostatin analogue (SA) treated patients.

It is recommended not to measure growth hormone during oral glucose suppression (oral glucose tolerance test) during somatostatin analog treatment in acromegaly. However, we have observed that failure to suppress growth hormone in response to oral glucose tolerance test during somatostatin analog unmasks insufficient disease control and hypothesize that somatostatin analog also induces insufficient growth hormone suppression to mixed meals. We therefore compared serum growth hormone levels during two mixed meals in patients with controlled insulin-like growth factor-I levels after either surgery alone (n = 9) or somatostatin analog treatment (n = 9). The patients were unbiasedly matched for gender and insulin-like growth factor-I and studied twice in the following order: (1) during a 6 h growth hormone day curve including two mixed meals and (2) during a 3 h growth hormone profile including 60 min fasting followed by a 2-h oral glucose tolerance test. During the day curve growth hormone levels were elevated in the somatostatin analog group (P = 0.008) and growth hormone levels 1 h after each meal declined significantly only in the surgery group (P = 0.02). During the oral glucose tolerance test the two groups had similar growth hormone levels prior to the glucose load (P = 0.6), whereas a significant 66% suppression was observed after glucose only in the surgery group (P = 0.001). (1) Patients controlled by somatostatin analog fail to suppress growth hormone in response to both mixed meals and oral glucose tolerance test (2) This phenomenon is likely to result in elevated serum growth hormone levels during everyday life in somatostatin analog-treated patients, (3) We postulate that measuring growth hormone levels during oral glucose tolerance test is useful to unmask potential somatostatin analog under-treatment in the presence of 'safe' insulin-like growth factor-I levels.

STAT5 drives abnormal proliferation in autosomal dominant polycystic kidney disease

Autosomal dominant polycystic kidney disease (ADPKD) leads to renal failure. The hallmark of ADPKD is increased epithelial proliferation, which has been proposed to be due to atypical signaling including abnormal JAK-STAT activity. However, the relative contribution of JAK-STAT family members in promoting proliferation in ADPKD is unknown. Here, we present siRNA JAK-STAT-focused screens discovering a previously unknown proliferative role for multiple JAK-STAT components (including STAT1, STAT2, STAT4, STAT5a, and STAT5b). Amongst these, we selected to study the growth hormone/growth hormone receptor/STAT5-axis because of its known role as a regulator of growth in nonrenal tissues. Loss of STAT5 function, facilitated by pharmacological inhibition or siRNAs, significantly reduced proliferation with an associated reduction in cyst growth invitro. To study whether STAT5 is abnormally activated invivo, we analyzed its expression using two independent mouse models of ADPKD. STAT5 was nuclear, thus activated, in renal epithelial cyst lining cells in both models. To test whether forced activation of STAT5 can modulate proliferation of renal cells invivo, irrespective of the Pkd1 status, we overexpressed growth hormone. These mice showed increased STAT5 activity in renal epithelial cells, which correlated with de novo expression of cyclin D1, a STAT5 target gene. Chromatin immunoprecipitation experiments revealed that STAT5 transcriptionally activated cyclin D1 in a growth hormone-dependent fashion, thus providing a mechanism into how STAT5 enhances proliferation. Finally, we provide evidence of elevated serum growth hormone in Pkd1 mutant mice. Thus, the growth hormone/STAT5 signaling axis is a novel therapeutic target in ADPKD.

Somatotroph-Specific Aip-Deficient Mice Display Pretumorigenic Alterations in Cell-Cycle Signaling.

Patients with familial isolated pituitary adenoma are predisposed to pituitary adenomas, which in a subset of cases is due to germline inactivating mutations of the aryl hydrocarbon receptor–interacting protein (AIP) gene. Using Cre/lox and Flp/Frt technology, a conditional mouse model was generated to examine the loss of the mouse homolog, Aip, in pituitary somatotrophs. By 40 weeks of age, >80% of somatotroph specific Aip knockout mice develop growth hormone (GH) secreting adenomas. The formation of adenomas results in physiologic effects recapitulating the human syndrome of acromegaly, including increased body size, elevated serum GH and insulin-like growth factor 1 levels, and glucose intolerance. The pretumorigenic Aip-deficient somatotrophs secrete excess GH and exhibit pathologic hyperplasia associated with cytosolic compartmentalization of the cyclin-dependent kinase (CDK) inhibitor p27kip1 and perinuclear accentuation of CDK-4. Following tumor formation, the Aip-deficient somatotrophs display reduced expression of somatostatin receptor subtype 5 with impaired response to octreotide. The delayed tumor emergence, even with loss of both copies of Aip, implies that additional somatic events are required for adenoma formation. These findings suggest that pituitary hyperplasia precedes adenomatous transformation in somatotroph-specific Aip-deficient mice and reveal potential mechanisms involved in the pretumorigenic state that ultimately contribute to transformation.

Chapter 14 - Acromegaly

Acromegaly is due to excessive production of growth hormone (GH), generally by a pituitary GH-secreting adenoma. Its prevalence is estimated at 40-130 cases per million inhabitants. Acromegaly is characterized by slowly progressive acquired somatic disfigurement (mainly involving the face and extremities) and systemic manifestations. The rheumatologic, cardiovascular, respiratory, and metabolic consequences of acromegaly determine the prognosis. The diagnosis is confirmed by elevated serum GH concentrations that cannot be suppressed by an oral glucose load, and by increased levels of insulin-like growth factor 1 (IGF-1). Treatment is aimed at correcting (or preventing) tumor compression of surrounding tissues by excising the disease-causing lesion, and at reducing GH and IGF-1 levels to normal values. When surgery (the usual first-line treatment) fails to correct GH/IGF-1 hypersecretion, medical treatment with dopamine agonists (particularly cabergoline), somatostatin analogs, and/or radiotherapy can be used. The GH receptor antagonist pegvisomant is helpful in patients who are resistant to somatostatin analogs. Thanks to this multistep therapeutic strategy, adequate hormonal disease control is achieved in most patients, giving them a normal life expectancy. Comorbidities associated with acromegaly generally improve after treatment, but persistent sequelae may nonetheless impair quality of life.

Leptin’s effect on accelerated fracture healing after traumatic brain injury

Objective: To investigate mechanisms behind the faster rehabilitation of limb fractures when associated with traumatic brain injury (TBI).Methods: New Zealand rabbits were divided into TBI group and sham-operation group for four studies as follows: (1) blood and cerebrospinal fluid (CSF) were drawn on days 1, 3, and 7 to demonstrate changes in serum leptin, growth hormone (GH), insulin-like growth factor 1 (IGF-1), and CSF leptin; (2) bone defection was created by drilling in the tibial bone and either leptin or normal saline was injected into rabbit’s cerebellomedullary cistern. X-ray was taken at 1 days, 2 weeks, and 5 weeks and evaluated by criteria to determine rate of bone healing; (3) FITC-labeled rabbit leptin was injected into TBI and sham-operation groups, and frozen sections of rabbit brain were observed to identify differences in central nervous system (CNS) leptin by fluorescence; (4) polymerase chain reaction (PCR) was used to evaluate the expression of leptin production by brain tissue.Results: Serum and CSF leptin, GH, and IGF-1 concentrations were found to be higher in the TBI group than the sham-operation group at days 1, 3, and 7 (P<0·05). CSF leptin of the TBI group was positively correlated with serum leptin on day 1 (P<0·05), and positively correlated with GH and IGF-1 on days 3 and 7 (P<0·05). X-ray criteria demonstrated that leptin administration caused significantly faster healing calluses at 3 and 5 weeks as compared to control animals (P<0·05). FITC-labeled leptin study demonstrated that TBI animals had stronger expression of leptin in the brain than sham-operated animals. However, PCR of brain tissue leptin showed no significant differences between TBI and sham-operated animals in the expression of leptin.Conclusions: Our study suggests that increased CSF leptin, likely from blood–brain barrier breakdown, combined with elevated serum GH and IGF-1 after TBI, leads to accelerated fracture healing.

Insulin-Like Growth Factor 1 Mediates Negative Feedback to Somatotroph GH Expression via POU1F1/CREB Binding Protein Interactions

Circulating insulin-like growth factor 1 (IGF-1) has been shown to act as a negative feedback regulator of growth hormone (GH) gene expression; however, the mechanism of this negative feedback is poorly understood. Activation and regulation of GH gene expression require the binding of the transcription factor POU1F1 to the GH promoter along with cyclic AMP (cAMP) response element binding protein (CREB) binding protein (CBP). We investigate the role of CBP as a target of IGF-1 somatotroph regulation using the MtT/S somatotroph cell line. IGF-1 significantly inhibits basal GH mRNA levels but not POU1F1 levels. Chromatin immunoprecipitation assays demonstrate inhibition of CBP binding to the GH promoter after IGF-1 treatment. We hypothesized that IGF-1 receptor (IGF-1R) signaling disrupts the POU1F1/CBP complex to inhibit gene expression. In support, the use of a mutant CBP (S436A) construct, which lacks a critical phosphorylation site, leads to the loss of IGF-1 inhibition. The studies of CBP (S436A) knock-in mice show elevated serum GH levels, a greater response to GH releasing hormone (GHRH) stimulation along with lower weight gain, and decreased body fat. Our data confirm the inhibitory effects of IGF-1 on GH expression at the level of the promoter and provide evidence of CBP's role as a target of IGF-1R signaling.

STAT5b Deficiency: An Unsuspected Cause of Growth Failure, Immunodeficiency, and Severe Pulmonary Disease

Over the past 20 years, more than 150 new genetic disorders related to primary immunodeficiencies have been described, most of which initially present in the pediatric population. 1 Pediatric researchers and medical personnel should be cognizant of signs and symptoms associated with diseases related to immunodeficiency. STAT5b deficiency is a recently identified disease entity that involves both severe growth hormone‐resistant growth failure and severe immunodeficiency. Due to the early growth failure and the key role of STAT5b in growth hormone (GH) action, most of the cases have been published in the endocrinology literature until now. However, the identification of rare, human STAT5Bmutations has highlighted the distinct and critical role of STAT5b in both growth and immunity. 2-5 The possibility of a STAT5b disorder in children should be considered by the general pediatrician when chronic infection and/or unexplained pulmonary disease are concomitant with growth failure. The aim of this review is to provide updated information toward recognition of possible STAT5b deficiencies and to help provide an appropriate workup to mitigate symptoms associated with the disease. In this way, careful monitoring, timely therapy, frequent health care visits, and prophylactic medicines can be initiated. The molecular etiology and clinical consequences of STAT5b deficiencies will be described. First Cases of STAT5b Deficiency The cardinal feature of GH insensitivity (GHI) is severe growth failure, associated with elevated serum concentrations of GH, resulting in a clinical phenotype that is essentially indistinguishable from that of congenital GH deficiency. The phenotype of GHI has been attributed to more than 70 mutations in the GHR gene, encoding the GH receptor (GHR). 7 GHI in the presence of normal GHR, in contrast to classic GHI, has remained largely uninvestigated. The molecular basis has been determined in only a few cases, including three reports of homozygous mutations in the IGF-I (insulin growth factor-I) gene. 3-5 Beginning in 2003, a series of GHI cases with normal GHR were identified 3-5 and found to be associated with mutations in the STAT5B gene. 3 The first STAT5B mutation was a homozygous autosomal recessive missense mutation identified in a female patient with extremely short stature (‐7.5 SD) and who had serum IGF-I levels less than 15% of normal, despite elevated serum GH concentrations.Shortly thereafter, several additional cases, each harboring novel mutations of STAT5B, were reported. All of these cases were characterized by severe growth failure and GHI. Together, these cases convincingly implicated STAT5B mutations as potential etiologies of the GHI syndrome and pointed to STAT5b playing an important role in normal postnatal human growth. The first cases of identified STAT5b deficiency, 3-5 distinct from GHI caused by mutations in the GHR or IGF1 genes, were also found to be associated with symptoms of severe infection, autoimmune diatheses, and lymphocytic interstitial pneumonitis. The combination of severe GH-resistant growth failure and chronic infection led to evaluation of potential disorders of cytokine receptor signaling. In the first described case, the patient, 3 with a missense mutation (p.A630P) in the STATB gene, had lymphocytic interstitial pneumonitis, chronic lung disease, hemorrhagic varicella, atopy, and autoimmune disease diagnosed at a young age. More detailed evaluations indicated that the patient had decreased numbers of regulatory CD4+CD25hi T cells (Treg). 8

A Case of Juvenile Acromegaly that was Initially Diagnosed as Severe Congestive Heart Failure from Acromegaly-Induced Dilated Cardiomyopathy

Acromegaly is characterized by chronic hypersecretion of growth hormone (GH) and is associated with increased mortality rate because of the potential complications such as cardiovascular disease, respiratory disease, or malignancy, which are probably caused by the long-term exposure of tissues to excess GH, for at least 10 years, before diagnosis and treatment. A 22-year-old man with a 2-month history of fatigue was admitted to our hospital because of chest discomfort, dyspnea, and pitting edema of the lower limbs experienced over a 1-month period. On admission, his height and body weight were 186 cm and 138.5 kg, respectively, with a BMI of 39.8 kg/m(2). He showed acromegalic features and elevated serum GH and IGF-1 levels, which were 11.5 ng/mL and 960 ng/mL, respectively. There was no GH suppression in the 75-g oral glucose tolerance test. Pituitary magnetic resonance imaging (MRI) revealed microadenoma. Chest X-ray revealed cardiomegaly, and echocardiogram showed dilated left ventricular (LV) cavity and diffuse hypokinesis with extremely decreased ejection fraction (EF). He was diagnosed as having acromegaly with congestive heart failure from diastolic cardiomyopathy. After the successful transsphenoidal resection of the pituitary adenoma, the level of GH was normalized. However, the cardiac dysfunction did not show any improvement even after the administration of β-blockers, angiotensin-converting enzyme inhibitor (ACE-I), or diuretics. The patient was re-hospitalized, and he died of cardiac failure at the age of 25 years. Patients with acromegaly have been reported to have about 30% higher mortality rate, and cardiovascular disease accounts for 60% of the deaths. We report a case of a patient with juvenile acromegaly who was diagnosed with severe cardiac failure at the time of diagnosis and failed to recover cardiac function even after the successful resection of the pituitary adenoma. Immediate diagnosis and treatment are required for better control of acromegalic cardiomyopathy.

Preoperative Elevated Serum Growth Hormone is Preventive of Osteopenia in Postsurgical Patients With Pituitary Somatotroph Adenomas

To investigate the influence of preoperatively elevated growth hormone to bone mass in acromegalic patients, bone mineral density (BMD), and urinary type I collagen N-telopeptide were analyzed in postoperative patients with somatotroph adenomas (SA), in comparison with patients with clinically nonfunctioning adenomas (NF). The mean T and z scores of BMD in the radius of postoperative patients with SA were significantly higher than those of postoperative patients with NF. There was no significant difference in the mean T and z scores of BMD in the lumbar spine between postoperative patients with SA and those with NF. Thus, BMD in the radius is preferentially maintained in postoperative patients with SA. This result suggests that the preoperative elevation of growth hormone and insulin-like growth factor-1 are beneficial in the maintenance of bone mass in acromegalic patients.

Duration and nature of altered pituitary function in the male rat after a single large dose of estrogen.

The effects of a single large dose (10 and 20 mg) of diethylstilbestrol dipropionate on the pituitary gland of the mature male rat were investigated at intervals up to 312 days. The initial rise in pituitary weight and serum radioimmunoassayable growth hormone and fall in pituitary growth hormone concentration were followed by gradual recovery to normal extending over 5 to 6 months. Testicular weight was diminished until day 136 and adrenal weight was raised until day 114. The early pituitary mitotic activity had subsided to normal by day 69. Pituitary prolactin concentrations as indicated by starch gel electrophoresis were raised on day 28. Enlarged pituitary glands during the period 69 to 140 days also contained increased prolactin concentrations. The individual variations among the rats killed during the latter period included greatly elevated serum growth hormone either with or without increased pituitary weight.

Novel Splice Site Mutation in the Growth Hormone Receptor Gene in Turkish Patients with Laron-type Dwarfism

Growth hormone (GH) is involved in growth, and fat and carbohydrate metabolism. Interaction of GH with the GH receptor (GHR) is necessary for systemic and local production of insulin-like growth factor-I (IGF-I) which mediates GH actions. Mutations in the GHR cause severe postnatal growth failure; the disorder is an autosomal recessive genetic disease resulting in GH insensitivity, called Laron syndrome. It is characterized by dwarfism with elevated serum GH and low levels of IGF-I. We analyzed the GHR gene for mutations and polymorphisms in eight patients with Laron-type dwarfism from six families. We found three missense mutations (S40L, V125A, I526L), one nonsense mutation (W157X), and one splice site mutation in the extracellular domain of GHR. Furthermore, G168G and exon 3 deletion polymorphisms were detected in patients with Laron syndrome. The splice site mutation, which is a novel mutation, was located at the donor splice site of exon 2/ intron 2 within GHR. Although this mutation changed the highly conserved donor splice site consensus sequence GT to GGT by insertion of a G residue, the intron splicing between exon 2 and exon 3 was detected in the patient. These results imply that the splicing occurs arthe GT site in intron 2, leaving the extra inserted G residue at the end of exon 2, thus changing the open reading frame of GHR resulting in a premature termination codon in exon 3.

The Effects of Gammahydroxybutyrate on Hypermetabolism and Wound Healing in a Rat Model of Large Thermal Injury

Growth hormone (GH) improves wound healing and ameliorates pediatric postburn tissue catabolism associated with deficient endogenous GH/IGF-1 levels. Expense, parenteral administration, and compliance have limited widespread usage. Gammahydroxybutyrate (GHB), an upstream neuromodulatory gamma-amino butyric acid (GABA) derivative, is known to increase slow wave sleep and stimulate endogenous GH secretion. In this study, improvement in GH levels in turn has been shown to accelerate wound healing. Body composition in male Sprague-Dawley rats with > or =40% total body surface area scald burn, receiving incremental GHB doses orally, was assessed by Dual Energy X-Ray Absorptiometry. Serum GH and IGF-1 levels were measured. Wound cross sections were scored semiquantitatively for wound healing variables. Incremental elevation in GH and IGF-1 were associated with significantly improved wound edge epithelialization and cell-layer thickness at high doses (p < 0.005). However, body composition was similar to that of burned controls. GHB sufficiently elevated serum GH and IGF-1 levels to significantly improve epithelialization rates and layer thickness at high doses. Substantially greater elevations of serum GH and IGF-1 levels are required in the rat burn model than for humans. GHB may improve postburn hypermetabolism in humans by elevating endogenous GH levels, though only improved epithelialization was demonstrated in this study.