Decreased Growth Hormone Secretion Research Articles

Inclusion and Withdrawal Criteria for Growth Hormone (GH) Therapy in Children with Idiopathic GH Deficiency—Towards Following the Evidence but Still with Unresolved Problems

According to current guidelines, growth hormone (GH) therapy is strongly recommended in children and adolescents with GH deficiency (GHD) in order to accelerate growth rate and attain normal adult height. The diagnosis of GHD requires demonstration of decreased GH secretion in stimulation tests, below the established threshold value. Currently, GHD in children is classified as secondary insulin-like growth factor-1 (IGF-1) deficiency. Most children diagnosed with isolated GHD present with normal GH secretion at the attainment of near-final height or even in mid-puberty. The most important clinical problems, related to the diagnosis of isolated GHD in children and to optimal duration of rhGH therapy include: arbitrary definition of subnormal GH peak in stimulation tests, disregarding factors influencing GH secretion, insufficient diagnostic accuracy and poor reproducibility of GH stimulation tests, discrepancies between spontaneous and stimulated GH secretion, clinical entity of neurosecretory dysfunction, discrepancies between IGF-1 concentrations and results of GH stimulation tests, significance of IGF-1 deficiency for the diagnosis of GHD, and a need for validation IGF-1 reference ranges. Many of these issues have remained unresolved for 25 years or even longer. It seems that finding solutions to them should optimize diagnostics and therapy of children with short stature.

Long-term effects of somatostatin analogues in rat GH-secreting pituitary tumor cell lines

PurposeFirst-generation somatostatin analogs, octreotide (OCT) and lanreotide, are the cornerstone for the medical treatment of growth hormone (GH)-secreting pituitary tumors. A new multireceptor analog, such as pasireotide (PAS), showed better activity than OCT in long-term treatment of patients with acromegaly, but modulation of intracellular key processes is still unclear in vitro. In this study, we evaluated the antitumor activity of OCT and PAS in two GH-secreting pituitary tumor cell lines, GH3 and GH4C1, after a long-term incubation.MethodsThe effects of PAS and OCT on the cell viability, cell cycle, apoptosis, GH secretion, and tumor-induced angiogenesis have been evaluated through a colorimetric method (MTS Assay), DNA flow cytometry with propidium iodide, and Annexin V-FITC/propidium iodide staining, ELISA assay and zebrafish platform, respectively.ResultsPAS showed a more potent antitumor activity compared to OCT in GH3 cell line exerted through inhibition of cell viability, perturbation of cell cycle progression, and induction of apoptosis after 6 days of incubation. A concomitant decrease in GH secretion has been observed after 2 days of incubation only with PAS. No effect on tumor-induced angiogenesis has been reported after treatment with OCT or PAS in zebrafish/tumor xenograft model.ConclusionLong-term incubation with PAS showed a more potent antitumor activity than that reported after OCT in GH3 cells, mainly modulated by a cell cycle perturbation and a relevant induction in apoptosis.

Evaluation of Body Mass Index of 3–10-year-old Children with Adenotonsillar Hypertrophy, who Referred to Khatamolanbia Hospital during 2017–2018

BACKGROUND: Adenotonsillar hypertrophy is a common disorder in the children’s population that can lead to growth disorders. Chronic adenotonsillar hypertrophy can cause a break in the normal growth of children, weight loss, and decreased growth hormone secretion.
 AIM: The purpose of this study was to evaluate adenotonsillar hypertrophy in the growth rate of children with height, weight, and body mass index (BMI).
 METHODS: In this descriptive-analytical cross-sectional study, after examining 312, 3–10-year-old children with adenotonsillar hypertrophy, who met the inclusion criteria, growth scales were evaluated and entered into the patient evaluation form.
 RESULTS: There was a significant relationship between BMI, height, weight, and severity of tonsillar hypertrophy at Brodsky’s scale (P <0.001). Our studies showed well that with increasing severity of adenotonsillar hypertrophy disease, the growth indicators are also decreased in children.
 CONCLUSION: Adenotonsillar hypertrophy decreases growth indicators in children. There was also a relationship between growth indicators and severity of adenotonsillar hypertrophy in patients.

Abstract 2865: AsiDNATM, a novel DNA repair inhibitor to sensitize aggressive medulloblastoma subtypes

Abstract Purpose: Medulloblastoma is paediatric tumor of the cerebellum. It represents the most frequent malignant brain tumor in childhood. It can be classified into four disparate molecular subgroups but current therapies are not yet tailored to their specificities. This is particularly important for subgroups with worse prognosis as Group3. Patients who survive often present severe treatment-related morbidity, which can be largely attributed to brain radiation in ages of development. It is therefore important to improve treatment efficacy in more aggressive subgroups as well as reduce treatment-related morbidity across all subgroups. We investigated whether AsiDNATM, a radiosensitizer in clinical trials which works through DNA repair inhibition, could be used to improve radiotherapy efficacy with no additional toxicity allowing radiation dose de-escalation in groups with better prognosis and improved radiotherapy efficacy in those with high-risk disease. Experimental design: The cytotoxic effect of AsiDNATM was determined in a panel of 4 human medulloblastoma cell lines from different subgroups and different P53 status. We analyzed the ability of AsiDNATM to reach brain tissue and toxicity of treatments with or without irradiation in pups (10 days old mice). Distribution of AsiDNA was estimated by quantification of Cy-5-AsiDNA in brain tissues. Radiation toxicity was estimated by survival to high doses, monitoring of circulating growth hormone (GH), weight loss, bones size at adult age and neuro histology analysis. We assessed the AsiDNATM radio-enhancing efficacy in Group3 xenografted preclinical models using X-RAD 320 (PXI Inc) X-ray irradiator. Local brain irradiation was performed with an image-guided X-ray system (SARPP, Xstrahl Ldt), in which dosimetry and animal setting were controlled at each treatment session. Results: AsiDNATM treatments exhibit an additive effect to radiation in all cell lines, leading to an approximate 2-fold reduction of the radiation dose to reach 50% survival. Cy5-AsiDNA distributed to pup brain but not to adult brain devoid of tumors. However, in adults AsiDNATM distributed in tumors in brain through permeability of tumor vessels. Irradiation toxicity in pups was confirmed by a significant decrease in GH secretion and associated reduction of bone size. The lethal dose after irradiation was 20 Gy. No increase of irradiation toxicity was observed with AsiDNATM. In vivo, AsiDNATM alone significantly enhances survival rates (p=0.005) and increases radiotherapy efficacy. When combined with radiotherapy, AsiDNATM led to delay in tumor growth and survival improvement as compared to radiotherapy alone. Conclusion: Overall, our current results show AsiDNATM as an attractive candidate to improve radiation therapy in medulloblastoma in both standard- and high-risk patients with no indication of additional toxicity in healthy developing brain tissues. Citation Format: Sofia Ferreira, Chloe Foray, Sophie Heinrich, Celio Pouponnot, Marie Dutreix. AsiDNATM, a novel DNA repair inhibitor to sensitize aggressive medulloblastoma subtypes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2865.

Hormonal changes in men due to ageing (all hormonal axes)

The increase in life expectancy achieved in the last decades has raised the proportion of the elderly in the general population, rendering health problems of the 3rd age more relevant than ever. Ageing is accompanied by adaptations in endocrine functions, most of them in the form of regression, affecting the secretory capacity of the cells that comprise the endocrine system, the corresponding hormone receptors and the post-receptor processes in the target cells. A reduction of the gonadal axis output has been demonstrated in both cross-sectional and longitudinal studies in healthy men, predicting a fall of Testosterone concentrations by approximately 110 ng/dL per decade, after the age of 60 yrs. The primary event of this gradually established, mild form of hypogonadism (late-onset; LOH) has not been elucidated as yet and is believed to be a combined result of reduced hypothalamic GnRH secretion, decreased testicular responsiveness to hCG/LH, and blunted androgenic negative feedback. Similarly, a decline in circulating Growth hormone (GH) and IGF-I levels is observed with ageing, due principally to decreased GH secretion. This decline starts at young adulthood and progresses exponentially until advanced age, when it may even reach cessation. Many of the manifestations of normal ageing resemble those of pathologic GH deficiency, implying a crucial role of hyposomatotropism in the process of ageing. The functionality of the thyroid axis is also characterized by regression with increasing age, concerning both the production of thyroid hormones, as well as their metabolism: TRH secretion is blunted, resulting in a decrease of the TSH drive on the thyroid, while conversion of T4 to T3 from deiodinases D1 and D2 is reduced. The net result of these changes is a frank reduction of the active T3 metabolite, an increase of the inactive reverse T3 metabolite (rT3), while T4 levels remain relatively unchanged. On the contrary, cortisol secretion from the adrenal glands remains relatively unaffected, while the secretion of androgens and in particular DHEA, show a gradual decline since the age of 40, reaching almost 20% of the young adult levels by the age of 80 yrs. Whether these changes reflect the failure of the endocrine glands to fulfill their mission or normal adaptations to protect the frail ageing body is still a matter of considerable debate.

Benzene affects the response to octreotide treatment of growth hormone secreting pituitary adenoma cells

Growth hormone (GH) secreting pituitary adenomas are the main cause of acromegaly. Somatostatin analogs are the gold standard of medical therapy; however, resistance represents a big drawback in acromegaly management. We recently demonstrated that benzene (BZ) modifies the aggressiveness of GH-secreting rat pituitary adenoma cells (GH3), increasing GH secretion and altering the synthesis of molecules involved in the somatostatin signaling pathway. Based on these pieces of evidence, this study aimed to evaluate the effects of BZ on octreotide (OCT) efficacy in GH-secreting adenoma cells. In GH3 cells, BZ counteracted the anti-proliferative action of OCT. GH gene expression, unmodified by OCT, remained high in BZ-treated cells as well as after treatment with the association of both. GH secretion, reduced by OCT, was increased after treatment with BZ alone or when the pollutant was used with OCT. The combination of BZ and OCT greatly reduced the gene expression of ZAC1 and SSTR2; and this reduction was also present at a protein level. BZ caused an increase in the protein level of the transcription factor STAT3 and in its phosphorylated form. In the presence of BZ, OCT lost the ability to reduce the phosphorylated protein levels. Finally, in primary cultures of human pituitary adenoma cells, BZ caused an increase in GH secretion. OCT decreased GH secretion, but the addition of BZ reversed the OCT effect. In conclusion, our results suggest that BZ may have an important role in the resistance of pituitary adenomas to the pharmacological treatment with somatostatin analogs.

Growth hormone and chronic kidney disease.

Elevated circulating levels of growth hormone (GH) and/or increased expression of the GH receptor in the kidney are associated with the development of nephropathy in type1 diabetes and acromegaly. Conditions of GH excess are characterized by hyperfiltration, glomerular hypertrophy, glomerulosclerosis and albuminuria, whereas states of decreased GH secretion or action are protected against glomerulopathy. The direct role of GH's action on glomerular cells, particularly podocytes, has been the focus of recent studies. In this review, the emerging role of GH on the biological function of podocytes and its implications in the pathogenesis of diabetic and chronic kidney disease will be discussed. Elevated GH levels impair glomerular permselectivity by altering the expression of podocyte slit-diaphragm proteins. GH stimulates the epithelial-mesenchymal transition of podocytes and decreases podocyte count. GH also induces the expression of prosclerotic molecules transforming growth factor beta, and TGFBIp. Our understanding of the cellular and molecular effects of GH in the pathogenesis of renal complications of diabetes and acromegaly has significantly progressed in recent years. These observations open up new possibilities in the prevention and treatment of diabetic nephropathy.

The relationship between serum IGF-1, handgrip strength, physical performance and falls in elderly men and women.

Human aging is accompanied by a decrease in growth hormone secretion and serum insulin-like growth factor (IGF)-1 levels. Also, loss of muscle mass and strength and impairment of physical performance, ending in a state of frailty, are seen in elderly. We aimed to investigate whether handgrip strength, physical performance and recurrent falls are related to serum IGF-1 levels in community-dwelling elderly. Observational cohort study (cross-sectional and prospective). We studied the association between IGF-1 and handgrip strength, physical performance and falls in participants of the Longitudinal Aging Study Amsterdam. A total of 1292 participants were included (633 men, 659 women). Serum IGF-1 levels were divided into quartiles (IGF-1-Q1 to IGF-1-Q4). Data on falls were collected prospectively for a period of 3 years. All analyses were stratified for age and physical activity and adjusted for relevant confounders. Men with a low physical activity score in IGF-1-Q1 and IGF-1-Q2 of the younger age group had a lower handgrip strength compared to IGF-1-Q4. In younger more active males in IGF-1-Q2 physical performance was worse. Recurrent fallers were less prevalent in older, low active males with low IGF-1 levels. In females, recurrent fallers were more prevalent in older, more active females in IGF-1-Q2. IGF-1 quartile may predict changes in handgrip strength and physical performance in men and women. Our results indicate that lower IGF-1 levels are associated with lower handgrip strength and worse physical performance, but less recurrent fallers especially in men. Associations were often more robust in IGF-1-Q2. Future studies on this topic are desirable.

Laparoscopic Sleeve Gastrectomy Resolves Low GHRP-2-Stimulated Growth Hormone Levels in Obese Patients.

Because growth hormone (GH) secretion is reportedly decreased in obese patients, we examined not only the factors associated with the decreased GH secretion but also GH response to the GH-releasing peptide (GHRP)-2-load test before and after laparoscopic gastrectomy (LSG). The study comprised 28 individuals aged 19-65years [mean body mass index (BMI), 39.4±9.4kg/m2]. In the univariate analysis, GH secretion peaks correlated negatively with BMI (r=-0.59, p=0.001), visceral adipose tissue (r=-0.47, p=0.005), and subcutaneous adipose tissue (r=-0.40, p=0.04). In the two obese patients, the response to the GHRP-2-load test markedly improved by weight loss 12months after LSG. In conclusion, GH secretion was decreased in obese patients and improved by LSG.

High doses of caffeine reduce invivo osteogenic activity in prepubertal rats.

Caffeine adversely affects endochondral ossification during fetal skeletal growth, and results in increased incidence of delayed and abnormal fetal skeletal development. Chronic caffeine intake also decreases growth hormone secretion. Thus, it is conceivable that caffeine may disrupt bone growth during the peripubertal period. This study aimed to investigate the impact of high-caffeine consumption on bone growth throughout puberty. A total of 51 male rats (21days old) were divided randomly into three groups: a control group and two groups fed caffeine via gavage with 120 and 180mgkg(-1) day(-1) for 4weeks. After death, the final length and weight of leg bones were measured, and the tibia processed for histomorphometric analysis. Caffeine caused a significant decrease in body mass gain. This was accompanied with proportional decreases in lean body mass and body fat. In addition, bone mass and osteogenic activity invivo were assessed using dual-energy X-ray absorptiometry and (18) F-NaF positron emission tomography. The results showed significant decreases of bone mass and invivo osteogenic activity in the caffeine-fed groups. Rats fed with caffeine showed a significantly shorter and lighter tibia and femur and the vertebral column compared with controls. In addition, caffeine does not increase the width of the growth plates (GPs), it slows the rate at which the GP closes due to a slower rate of growth. These results demonstrated that caffeine altered osteogenic activity, leading to delayed peripubertal longitudinal bone growth and maturation. Given that osteogenic cells undergo dynamic changes in metabolic activity and that the pubertal growth spurt is mainly stimulated by growth hormone/insulin-like growth factor-1 and sex steroids during pubertal development, caffeine could suppress ossification by interfering with both physiological changes in hormonal secretion and osteogenic activity during this critical period. Further study will be needed to investigate the cellular/molecular mechanism by which caffeine affects osteogenesis using invitro experimental models.

Giant mice reveal new roles for GH in regulating the adipose immune microenvironment.

Giant mice reveal new roles for GH in regulating the adipose immune microenvironment.

Alteration of the miRNA expression profile in male porcine anterior pituitary cells in response to GHRH and CST and analysis of the potential roles for miRNAs in regulating GH

ObjectiveGrowth hormone releasing hormone (GHRH) is a major positive regulator of growth hormone (GH) in the anterior pituitary gland, while cortistatin's (CST) role is negative. miRNAs (microRNAs or miRs) are small RNA molecules modulating gene expression at the post-transcriptional level. However, little is known about the function of miRNAs in the regulation of GH synthesis and/or secretion. This study investigated potential functional miRNAs involved in GH secretion in the normal porcine pituitary. DesignPrimary porcine anterior pituitary cells were cultivated and then treated with 10nmol/L GHRH and 100nmol/L CST, respectively. The effects of GHRH and CST on GH secretion were determined using RIA. miRNA microarrays were employed to analyze miRNA expression after treatment and then differentially expressed miRNAs were screened. Bioinformatics analysis was used to analyze the potential targets in growth hormone regulation of altered miRNAs. Furthermore, functional experiments were conducted to study the function of ssc-let-7c. ResultsGHRH significantly promoted GH secretion, while CST suppressed GH secretion. 19 and 35 differentially expressed miRNAs were identified in response to GHRH and CST treatments respectively. Verification of 5 randomly selected miRNAs by quantitative real-time PCR (qRT-PCR) showed similar changes with microarray analysis. Target analysis showed that some miRNAs may be involved in GH secretion-related pathways. Importantly, ssc-let-7c was predicted to target GH1 and GHRHR mRNA 3′untranslated regions (3′UTRs), which was supported by luciferase reporter assay. Furthermore, functional experimental results showed that ssc-let-7c was involved in GH secretion regulation, and overexpression of ssc-let-7c inhibited GH secretion in porcine anterior pituitary cells. ConclusionsGHRH and CST modulated porcine pituitary cell miRNA expression. Bioinformatics analysis revealed a complicated network among differentially expressed miRNAs, GH regulation-related genes and hormones. More interestingly, ssc-let-7c inhibited both GH1 and GHRHR mRNA 3′UTR reporter vectors' luciferase activity and overexpression of ssc-let-7c led to a decrease of GH secretion.

Sleep disturbances and PTSD: a perpetual circle?

Background: Sleep facilitates the consolidation of fear extinction memory. Nightmares and insomnia are hallmark symptoms of posttraumatic stress disorder (PTSD), possibly interfering with fear extinction and compromising recovery. A perpetual circle may develop when sleep disturbances increase the risk for PTSD and vice versa. To date, therapeutic options for alleviating sleep disturbances in PTSD are limited.Methods: We conducted three studies to examine the relationship between sleep and posttraumatic symptoms: (1) a prospective longitudinal cohort study examining the impact of pre-deployment insomnia symptoms and nightmares on the development of PTSD; (2) a cross-sectional study examining subjective sleep measures, polysomnography, endocrinological parameters, and memory in veterans with PTSD, veterans without PTSD, and healthy controls (HCs); (3) a randomized controlled trial (RCT) (n=14) comparing the effect of prazosin and placebo on sleep disturbances in veterans with PTSD. In addition to these studies, we systematically reviewed the literature on treatment options for sleep disturbances in PTSD.Results: Pre-deployment nightmares predicted PTSD symptoms at 6 months post-deployment; however, insomnia symptoms did not. Furthermore, in patients with PTSD, a correlation between the apnea index and PTSD severity was observed, while obstructive sleep apnea syndrome was not more prevalent. We observed a significant increase in awakenings during sleep in patients with PTSD, which were positively correlated with adrenocorticotropic hormone (ACTH) levels, negatively correlated with growth hormone (GH) secretion, and the subjective perception of sleep depth. Also, heart rate was significantly increased in PTSD patients. Interestingly, plasma levels of GH during the night were decreased in PTSD. Furthermore, GH secretion and awakenings were independent predictors for delayed recall, which was lower in PTSD. In our RCT, prazosin was not associated with improvement of any subjective and objective sleep parameters. Only a few RCTs have been published. They show promising results for atypical antipsychotics and prazosin, the latter especially on nightmare reduction.Conclusions: Disturbed sleep due to nightmares increases the risk for PTSD. PTSD in turn leads to increased sleep fragmentation, decreased GH secretion, and frequent nightmares, which may again compromise fear extinction, synaptic plasticity, and recovery. This suggests that disturbed sleep is a precipitating and perpetuating factor in PTSD symptomatology, creating a perpetual circle. This dissertation suggests that activity of the hypothalamic–pituitary–adrenal axis and the sympathetic nervous system (SNS) is involved in disturbed sleep in patients with PTSD.Mentors: Prof. Dr. R.S. Kahn (University Medical Centre, Department of Psychiatry, the Netherlands), Prof. Dr. J.B.A.M. Arends (Technical University Eindhoven, the Netherlands) and Dr. E. Vermetten (Military Mental Health, the Netherlands). Theses defended in Utrecht, June 21, 2012. For the abstract or full text in other languages, please see Supplementary files under Reading Tools online.

Decreased nocturnal growth hormone secretion and sleep fragmentation in combat-related posttraumatic stress disorder; potential predictors of impaired memory consolidation

Healthy sleep facilitates the consolidation of newly acquired memories. Although patients with posttraumatic stress disorder (PTSD) often complain of sleep disturbances and memory deficits, the interrelatedness of these symptoms is not well understood. Sleep may be disturbed in PTSD by increased awakenings during sleep, which has been associated with decreased growth hormone (GH) secretion. We conducted a controlled study in which we assessed sleep fragmentation, nocturnal secretion of GH, and memory consolidation in patients with PTSD. While sleep EEG was being monitored, 13 veterans with PTSD, 15 trauma controls (TC) and 15 healthy controls (HC) slept with an iv catheter, through which blood was collected every 20 min from 23:00 h to 08:00 h. Declarative memory encoding was assessed with the 15 word task before sleep, and consolidation was assessed the next morning by a free recall. Sleep was more fragmented in patients with PTSD, with more awakenings in the first half of the night (p<0.05). Plasma levels of GH during the night were significantly decreased in PTSD compared with HC (p<0.05). Furthermore, GH secretion and awakenings were independent predictors for delayed recall, which was lower in PTSD compared to HC (p<0.05). These data show that PTSD is associated with increased awakenings during sleep and decreased nocturnal GH secretion. Furthermore, decreased GH secretion may be related to sleep fragmentation and both variables may exert a negative effect on sleep dependent memory consolidation.

Growth hormone secretory in healthy aged women and men of Tunisian population

With aging, men and women experience multiple hormonal changes, and in particular the activity of the growth hormone (GH)/insulin-like growth factor-I (IGF-I) axis. This perturbation may be involved in aggravations of numerous abnormalities. In 64 healthy elderly, we determined the concentrations of GH in both sexes and its correlation with thyroid-stimulating hormone (TSH), the descriptive data, BMI, electrolytic assessment and some biochemical parameters. Collected data suggest that there was an age-dependent decrease in GH secretion. For TSH, there was a slight increase. The simple regression analysis revealed non-significant direct relation between these two hormones. We also found that BMI values were inversely related to the serum concentrations of these hormones. For the lipid metabolism, the positively correlated relation only exists between GH and total-cholesterol, on one hand, and between GH and LDL-cholesterol, on the other. For the other parameters such as glucose and triglycerides as well as HDL-cholesterol, this relation does not exist. For the BMI, this index shows a positively correlated relation with glucose and triglycerides. The electrolytic assessment shows that in men, phosphorus was positively related to GH. In women, calcium and sodium were positively related to GH. Aging was found to be associated with decreased morning serum GH levels and slightly increased TSH levels in healthy elderly Tunisian population. Reduction of the GH-IGF-I axis in the elderly has important clinical implications. Indeed, this deficiency in GH could contribute to the decline of various functions associated with normal aging.

Insights into a role of GH secretagogues in reversing the age-related decline in the GH/IGF-I axis

Growth hormone (GH) secretion and serum insulin-like growth factor-I (IGF-I) decline with aging. This study addresses the role played by the hypothalamic regulators in the aging GH decline and investigates the mechanisms through which growth hormone secretagogues (GHS) activate GH secretion in the aging rats. Two groups of male Wistar rats were studied: young-adult (3 mo) and old (24 mo). Hypothalamic growth hormone-releasing hormone (GHRH) mRNA and immunoreactive (IR) GHRH dramatically decreased (P < 0.01 and P < 0.001) in the old rats, as did median eminence IR-GHRH. Decreases of hypothalamic IR-somatostatin (SS; P < 0.001) and SS mRNA (P < 0.01), and median eminence IR-SS were found in old rats as were GHS receptor and IGF-I mRNA (P < 0.01 and P < 0.05). Hypothalamic IGF-I receptor mRNA and protein were unmodified. Both young and old pituitary cells, cultured alone or cocultured with fetal hypothalamic cells, responded to ghrelin. Only in the presence of fetal hypothalamic cells did ghrelin elevate the age-related decrease of GH secretion to within normal adult range. In old rats, growth hormone-releasing peptide-6 returned the levels of GH and IGF-I secretion and liver IGF-I mRNA, and partially restored the lower pituitary IR-GH and GH mRNA levels to those of young untreated rats. These results suggest that the aging GH decline may result from decreased GHRH function rather than from increased SS action. The reduction of hypothalamic GHS-R gene expression might impair the action of ghrelin on GH release. The role of IGF-I is not altered. The aging GH/IGF-I axis decline could be rejuvenated by GHS treatment.

Effects of ghrelin administration on decreased growth hormone status in obese animals

Obesity is characterized by markedly decreased ghrelin and growth hormone (GH) secretion. Ghrelin is a GH-stimulating, stomach-derived peptide that also has orexigenic action. Ghrelin supplement may restore decreased GH secretion in obesity, but it may worsen obesity by its orexigenic action. To reveal effects of ghrelin administration on obese animals, we first examined acute GH and orexigenic responses to ghrelin in three different obese and/or diabetic mouse models: db/db mice, mice on a high-fat diet (HFD mice), and Akita mice for comparison. GH responses to ghrelin were significantly suppressed in db/db, HFD, and Akita mice. Food intake of db/db and Akita mice were basally higher, and further stimulation of food intake by ghrelin was suppressed. Pituitary GH secretagogue receptor mRNA levels in db/db and HFD mice were significantly decreased, which may partly contribute to decreased GH response to ghrelin in these mice. In Akita mice for comparison, decreased hypothalamic GH-releasing hormone (GHRH) mRNA levels may be responsible for decreased GH response, since maximum GH response to ghrelin needs GHRH. When ghrelin was injected into HFD mice with GHRH coadministrated, GH responses to ghrelin were significantly emphasized. HFD mice injected with low-dose ghrelin and GHRH for 10 days did not show weight gain. These results indicate that low-dose ghrelin and GHRH treatment may restore decreased GH secretion in obesity without worsening obesity.

Increased melatonin concentrations in children with growth hormone deficiency

A relationship between melatonin and growth hormone (GH) is poorly understood. We compare circadian melatonin rhythms in short children with normal and decreased GH secretion. The analysis included 22 children (20 boys and 2 girls) aged 11.1-16.9 yr (mean +/- S.E.M. = 14.1 +/- 0.3 yr) with short stature (height SDS below -2.0). Based on the GH peak in stimulation tests patients were divided into two groups: idiopathic short stature (ISS, n = 11; GH peak > or = 10 ng/mL) and GH deficiency (GHD, n = 11; GH peak < 10 ng/mL). In all patients the circadian melatonin rhythm was assessed on the basis of nine blood samples, collected in 4-hr intervals during the daytime and 2-hr intervals at night, with dark period lasting from 22:00 to 06:00 hr. Magnetic resonance imaging examination excluded organic abnormalities in central nervous system in all patients. Melatonin concentration at 24:00, 02:00 and 04:00 hr as well as the area under curve of melatonin concentrations (AUC) were significantly higher in the patients with GHD than in individuals with ISS. Significant correlations between GH secretion and melatonin concentrations at 24:00, 02:00 and 04:00 hr, and AUC were also observed. On the basis of these data it seems that the assessment of nocturnal melatonin secretion might be a valuable diagnostic tool used for the improvement of the difficult diagnosis of short stature in children.

Wirkungen von Strahlentherapie und inhibierenden Medikamenten auf die Hypophyse und ihre Adenome

Radiation therapies of pituitary adenomas induce an increase in fibroses and nuclear pleomorphism. Most growth hormone (GH) secreting pituitary adenomas react to somatostatin analogues by a distinct decrease of GH secretion. In two thirds, levels of IGF-1 can be normalized. Some cases show a shrinkage of adenomas that correlates with fibrosis of the tumor. With these drugs, thyroid stimulating hormone secreting adenomas can also be treated. Prolactin secreting adenomas are mostly treated primarily with dopamine agonists. Up to 90% of cases show a strong decrease in hormone secretion and a distinct shrinkage of the adenomas based on strong decrease in adenoma cell volume. Long-term medication with high doses of glucocorticoids induces Crooke's cells in the anterior pituitary. These are suppressed ACTH cells and characterized by increased numbers of large lysosomes and dense bundles of cytofilaments.

Structural Analysis of Human Growth Hormone with Respect to the Dominant Expression of Growth Hormone (GH) Mutations in Isolated GH Deficiency Type II

Human GH protein consists of four alpha-helices and contains two disulfide bridges. Isolated GH deficiency type II (IGHD II) is mainly caused by heterozygous splice site mutations of GH-1 leading to the disruption of one disulfide bridge (Cys53-Cys165) and to the loss of amino acids (aa) 32-71, which comprise the complete loop between alpha-helices 1 and 2. The mutant GH protein exerts a dominant negative effect on wild-type (wt) GH secretion by unclear mechanisms. For study of the structure-function relationship of GH mutants concerning the dominant negative effect, expression vectors harboring mutated GH cDNAs were transiently cotransfected with a vector encoding wtGH (pwtGH) into GH4C1 cells. Plasmids encoding beta-galactosidase, luciferase, or IGF-binding protein-2 were cotransfected with pwtGH and either of the GH mutants. Compared with the control transfection with pwtGH, GH secretion was mildly decreased by coexpressing wtGH and different GH point mutants with isolated disruption of the disulfide bridge Cys53-Cys165. Similar results were observed with GH mutants deleted in aa 32-46 or 32-52. Deletion of more aa (32-53, 32-63, 32-69, 32-71) ascendingly decreased GH secretion and content in parallel with the increasing length of the deleted stretch. An inhibitory dose-dependent effect of del32-69GH and del32-71GH on the activity/amount of coexpressed beta-galactosidase, luciferase, and IGF-binding protein-2 was found, whereas mRNA levels were unaffected. Hence, the extent of deletion played the major role in expression of the dominant negative effect. The inhibitory effect of GH mutants on heterologously expressed, non-GH proteins suggests that the dominant negative effect is not limited to GH or to proteins of the regulated secretory pathway, but may depend on expression levels.