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Acromegaly is a chronic systemic disease characterized by facial and peripheral changes caused by soft tissue overgrowth and is associated with multiple comorbidities. Despite available surgical and medical therapies, suitable treatments for acromegaly are still lacking. Efficient drug development requires an understanding of the exposure-response (E-R) relationship based on nonclinical and early clinical studies. We aimed to establish a platform to facilitate the development of novel drugs to treat acromegaly. We evaluated the E-R relationship of the growth hormone (GH)-inhibitory effect of the somatostatin analog octreotide under growth hormone-releasing hormone + arginine stimulation in healthy participants and compared the results with historical data for patients with acromegaly. This randomized five-way crossover study included two placebo and three active-treatment periods with different doses of octreotide acetate. GH secretion in the two placebo periods was comparable, which confirmed the reproducibility of the response with no carryover effect. GH secretion was inhibited by low-, medium-, and high-dose octreotide acetate in a dose-dependent manner. We also examined the E-R relationship in monkeys as a preclinical drug evaluation study and in rats as a more convenient and simple system for screening candidate drugs. The E-R relationships and EC 50 values were similar among animals, healthy participants, and patients with acromegaly, which suggests that GH stimulation studies in early research and development allowed simulation of the drug response in patients with acromegaly. SIGNIFICANCE STATEMENT: This study demonstrated similar exposure-response relationships in terms of the growth hormone-inhibitory effect of octreotide after growth hormone-releasing hormone stimulation among healthy participants, monkeys, and rats. The research methods and analyses utilized in this study will be useful for simulating the dosages and therapeutic effects of drugs for acromegaly and will facilitate the research and development of novel therapeutic agents with similar modes of action., (Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics.)

Mice carrying an RGS-insensitive Gαi2 mutation display growth retardation early after birth. Although the growth hormone (GH)-axis is a key endocrine modulator of postnatal growth, its functional state in these mice has not been characterized. The present study was undertaken to address this issue. Results revealed that pituitary mRNA levels for GH, prolactin (PRL), somatostatin (SST), GH-releasing-hormone receptor (GHRH-R) and GH secretagogue receptor (GHS-R) were decreased in mutants compared to controls. These changes were reflected by a significant decrease in plasma levels of GH, IGF-1 and IGF-binding protein-3 (IGFBP-3). Mutants were also less responsive to GHRH and ghrelin (GhL) on GH stimulation of release from pituitary primary cell cultures. In contrast, they were more sensitive to the inhibitory effect of SST. These data provide the first evidence for an alteration of the functional state of the GH-axis in Gαi2G184S mice that likely contributes to their growth retardation., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Purpose: To investigate the involvement of growth hormone-releasing hormone (GHRH) - growth hormone (GH) signaling in pathogenesis of proliferative diabetic retinopathy (PDR)., Design: Experimental laboratory study., Methods: Vitreous humor, aqueous humor, and serum were obtained from 36 eyes of 36 patients with or without type 2 diabetes from 2017 to 2019. For histologic examination, 6 fibrovascular membranes were excised from eyes with active PDR. Three fibrovascular membranes were excised from nondiabetic patients with proliferative vitreoretinopathy (PVR) as controls., Results: In PDR, the fibrovascular tissues consisted of a mature region containing fibrocytes, and an immature region populated by abundant polymorphonuclear leukocytes in a fibrinogen meshwork. Clusters of leukocytes were found adhering to the vascular walls. In PVR, no fibrinogen and polymorphonuclear leukocyte was observed in the fibrovascular membranes. The levels of GHRH and GH in PDR were significantly increased (P < .001), with 1.8-fold and 72.8-fold in vitreous humor, and 2-fold and 4.9-fold in aqueous humor, respectively, when compared with corresponding levels in controls. No significant difference was detected for insulin-like growth factor-1. Immunohistochemistry showed intense expression of GHRH and its receptor GHRH-R in polymorphonuclear leukocytes, vascular endothelial cells, and fibrocytes in fibrovascular membranes of PDR. GHRH staining was not detectable in infiltrating cells within the fibrovascular membrane of PVR., Conclusions: These findings reveal a possible involvement of GHRH/GHRH-R in fibrinous inflammation that might contribute to the formation of fibrovascular membrane in PDR through mediating activities of leukocytes, vascular endothelial cells, and fibrocytes. Targeting GHRH/GHRH-R may be considered as a potential therapeutic approach for the treatment of PDR., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Bioactive peptides pose a great threat to sports integrity. The detection of these peptides is essential for enforcing their prohibition in sports. Identifying the catabolites of these peptides that are formed ex vivo in plasma may improve their detection. In the present study, the stability of 27 bioactive peptides with protection at both termini in equine plasma was examined under different incubation conditions, using HILIC coupled to HRMS. Of the 27 peptides, 13 were stable after incubation at 37°C for 72 hr, but the remaining 14 were less stable. Ex vivo catabolites of these 14 peptides were detected using their theoretical masses generated in silico, their appearance was monitored over the time course of incubation, and their identity was verified by their product ion spectra. Catabolites identified for chemotactic peptide, DALDA, dmtDALDA, deltorphins I and II, Hyp 6 -dermorphin, Lys 7 -dermorphin, and dermorphin analog are novel. A d-amino acid residue at position 2 or 1 of a peptide or next to its C-terminus protected the relevant terminal from degradation by exopeptidases, but such a residue at position 3 did not. A pGlu residue or N-methylation at the N-terminus of a peptide did not protect its N-terminal. Ethylamide at the C-terminus of a peptide provided the C-terminal protection from attacks by carboxypeptidases. The C-terminal Lys amide in DALDA, dmtDALDA, and Lys 7 -dermorphin was susceptible to cleavage by plasma enzymes, which is the first report, to the authors' knowledge. The results from the present study provide insights into the stability of peptides in plasma., (© 2020 John Wiley & Sons, Ltd.)

Purpose: Obstructive sleep apnea (OSA) is associated with a variety of neuroendocrine disorders and may lead to many complications, including cognitive dysfunction. The aim of this study was to assess the change of somatotropic axis and to detect the relation between somatotropic axis hormone and cognitive dysfunction., Methods: Sixty-six patients with OSA and 16 healthy controls were enrolled in this cross-sectional study. Cognitive function assessment using the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) and polysomnography were performed on all individuals. Blood samples were taken the next morning following the polysomnography and the level of serum growth hormone-releasing hormone (GHRH) and growth hormone (GH) were analyzed by enzyme-linked immunosorbent assay., Results: Compared with the control group, OSA patients showed significantly lower serum GH level (p < 0.05), whereas no statistical significance of GHRH level was found. In addition, lower MMSE and MoCA scores were found only in the severe OSA patients when compared with the controls. Furthermore, in severe OSA patients with cognitive dysfunction (MMSE score < 27 and MoCA score < 26), serum GHRH and GH levels were significantly lower than those without cognitive dysfunction. Logistic analysis revealed that cognitive dysfunction in severe OSA patients was associated with micro-arousal index and the level of serum GHRH and GH., Conclusion: Decreased serum GH and GHRH levels were found among severe OSA patients with cognitive dysfunction who were overweight, which might promote the occurrence of cognitive dysfunction.

CJC-1295 is a peptide-based drug that stimulates the production of growth hormone (GH) from the pituitary gland. It incorporates a functional maleimido group at the C-terminus that allows it to covalently bind plasma proteins such as serum albumin. These CJC-1295-protein conjugates have a much greater half-life compared to the unconjugated peptide and are capable of stimulating GH production for more than six days in humans after a single administration. Conjugated CJC-1295 is difficult to detect in blood by mass spectrometry due to its low abundance, high molecular weight, and conjugation to a range of different protein substrates. Previously we described a screening procedure for the detection of CJC-1295 in equine plasma using an immuno-PCR assay. Here we demonstrate the confirmation of CJC-1295 in equine plasma by LC-MS/MS after immuno-affinity capture and tryptic digestion. Using this method, CJC-1295 was identified down to concentrations as low as 180 pg/mL in 1 mL of equine plasma., (© 2019 John Wiley & Sons, Ltd.)

Objective: To investigate the effects of chronic intermittent hypoxia on somatotropic axis hormone levels in rats. Methods: Mature male Wistar rats were exposed to air or intermittent hypoxia randomly.The serum levels of growth hormone-releasing hormone (GHRH), growth hormone (GH) and somatostatin (SS) were measured before exposure, at the 4th, 8th, and 12th week after exposure. Different hormone levels in two groups were compared and analyzed. Results: Compared with the control group, GHRH levels in chronic intermittent hypoxic group showed a significant decline at the 4th week [(732.77±46.99)pg/ml vs. (893.59±40.00) pg/ml, P< 0.05], while SS levels at the 8th week [(30.71±2.27) pg/ml vs. (44.69±3.36) pg/ml, P< 0.05] and GH levels at the 12th week [(1.20±0.29) ng/ml vs. (2.06±0.13) ng/ml, P< 0.05] were similarly reduced. As the duration of intermittent hypoxia was prolonged, the GHRH levels did not decrease further [4th week (732.77±46.99) pg/ml vs. 8th week (607.54±131.61) pg/ml vs. 12th week (730.05±40.63) pg/ml, P> 0.05].However, the serum SS levels decreased further from the 8th week to the 12th week [(30.71±2.27) pg/ml vs. (24.41±4.06) pg/ml, P< 0.05]. Conclusion: Chronic intermittent hypoxia might inhibit the function of somatotropic axis. Hypothalamic hormones are the earlyonesto be influenced, thereafter the entire axis.

CJC-1295 is a 30 amino acid peptide-based drug that stimulates the release of growth hormone (GH) from the pituitary gland. It is unique among performance-enhancing peptides due to the presence of a reactive maleimidopropionic acid group that covalently links the peptide to free thiols on the surface of plasma proteins. Once conjugated, CJC-1295 remains active in the bloodstream for significantly longer than non-conjugated peptide-based drugs that are rapidly excreted. Conjugation of CJC-1295 to plasma proteins prevents its detection by top-down mass-spectrometry-based peptide screening protocols as it effectively becomes a macromolecular protein with an undefined molecular weight. Using a pair of monoclonal antibodies raised against the CJC-1295 peptide, we present an immuno-polymerase chain reaction (I-PCR) assay that is capable of detecting the CJC-1295-protein conjugate at concentrations down to 0.8 pg/mL. Detection of endogenous equine GHRH necessitated a screening threshold for CJC-1295 in equine plasma of 50 pg/mL. The effectiveness of the assay for controlling the illicit use of CJC-1295 was confirmed in equine blood samples after administration in thoroughbred race horses., (© 2018 John Wiley & Sons, Ltd.)

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 19-65 years [mean body mass index (BMI), 39.4 ± 9.4 kg/m 2 ]. 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 12 months after LSG. In conclusion, GH secretion was decreased in obese patients and improved by LSG.

Purpose: IgG4-related disease is a systemic inflammatory disease characterized by infiltration of IgG4-positive plasma cells into multiple organs, including the pituitary gland. Autoimmunity is thought to be involved in the pathogenesis of IgG4-related disease. The diagnosis of IgG4-related hypophysitis (IgG4-RH) is difficult because its clinical features, such as pituitary swelling and hypopituitarism, are similar to those of other pituitary diseases, including lymphocytic hypophysitis and sellar/suprasellar tumors. The presence and significance of anti-pituitary antibodies (APA) in IgG4-RH is unclear., Methods: In this case-control study, we used single indirect immunofluorescence on human pituitary substrates to assess the prevalence of serum APA in 17 patients with IgG4-RH, 8 control patients with other pituitary diseases (lymphocytic infundibulo-neurohypophysitis, 3; craniopharyngioma, 2; germinoma, 3), and 9 healthy subjects. We further analyzed the endocrine cells targeted by the antibodies using double indirect immunofluorescence., Results: APA were found in 5 of 17 patients with IgG4-RH (29%), and in none of the pituitary controls or healthy subjects. The endocrine cells targeted by the antibodies in the 5 IgG4-RH cases were exclusively corticotrophs. Antibodies were of the IgG1 subclass, rather than IgG4, in all 5 cases, suggesting that IgG4 is not directly involved in the pathogenesis. Finally, antibodies recognized pro-opiomelanocortin in 2 of the cases., Conclusions: Our study suggests that autoimmunity is involved in the pathogenesis of IgG4-RH and that corticotrophs are the main antigenic target, highlighting a possible new diagnostic marker for this condition.

Gonadotropin-inhibitory hormone (GnIH) is a potent positive regulator of the growth axis. The present study was aimed to comparatively investigate the effects of surgical and immunologic castration on hypothalamic GnIH expression and endocrine function of the growth axis. Thirty-six prepubertal male rats were randomly allocated into three groups (n = 12): control, surgically castrated or immunized against 100-μg D-Lys6-GnRH-tandem peptide conjugated to ovalbumin in Specol adjuvant at 6 weeks of age (with a booster 8 weeks later). Blood samples were collected (for hormone and urea nitrogen concentrations) at 2-week intervals, and growth performance was evaluated. Compared to intact controls, surgical castration reduced (P < 0.05) messenger RNA (mRNA) expressions of hypothalamic GnIH and growth hormone-releasing hormone (GHRH), pituitary growth hormone (GH), and liver insulin-like growth factor-1 (IGF-1), reduced (P < 0.05) serum concentrations of GH and IGF-1 and increased (P < 0.05) serum concentrations of urea nitrogen. In contrast, immunocastration did not alter messenger RNA expressions of hypothalamic GnIH, GHRH and pituitary GH, and the serum concentrations of GH (P > 0.05). Moreover, serum concentrations of IGF-1 and urea nitrogen in immunocastrates were substantially higher and lower than those in surgical castrates, respectively (P < 0.05). Compared to surgical castrates, immuncastrates had superior feed conversion efficiency and faster daily weight gain (P < 0.05). We concluded that surgical castration but not immunocastration is associated with reduced hypothalamic GnIH and GHRH/GH/IGF-I axis function in male rats., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The use of growth hormone-releasing hormones (GHRHs) is prohibited in sports according to the regulations of the World Anti-Doping Agency (WADA). The aim of the present study was to develop a method for the simultaneous detection of four different GHRHs and respective metabolites from human plasma by means of immunoaffinity purification and subsequent nano-ultrahigh performance liquid chromatography-high resolution/high accuracy (tandem) mass spectrometry. The target analytes included Geref (Sermorelin), CJC-1293, CJC-1295, and Egrifta (Tesamorelin) as well as two metabolites of Geref and CJC-1293, which were captured from plasma samples using a polyclonal GHRH antibody in concert with protein A/G monolithic MSIA™ D.A.R.T.'S® (Disposable Automation Research Tips) prior to separation and detection. The method was fully validated and found to be fit for purpose considering the parameters specificity, linearity, recovery (19-37%), lower limit of detection (<50 pg/mL), imprecision (<20%), and ion suppression/enhancement effects. The analytes' stability and metabolism were elucidated using in vitro and in vivo approaches. EDTA blood samples were collected from rats 2, 4, and 8 h after intravenous administration of GHRH (one compound per test animal). All intact substances were detected for at least 4 h but no anticipated metabolite was confirmed in laboratory rodents' samples; conversely, a Geref metabolite (GHRH3-29) was found in a human plasma sample collected after subcutaneous injection of the drug to a healthy male volunteer. The obtained results demonstrate that GHRHs are successfully detected in plasma using an immunoaffinity-mass spectrometry-based method, which can be applied to sports drug testing samples. Further studies are however required and warranted to account for potential species-related differences in metabolism and elimination of the target analytes.

X-linked acrogigantism (X-LAG) syndrome is a newly described form of inheritable pituitary gigantism that begins in early childhood and is usually associated with markedly elevated GH and prolactin secretion by mixed pituitary adenomas/hyperplasia. Microduplications on chromosome Xq26.3 including the GPR101 gene cause X-LAG syndrome. In individual cases random GHRH levels have been elevated. We performed a series of hormonal profiles in a young female sporadic X-LAG syndrome patient and subsequently undertook in vitro studies of primary pituitary tumor culture following neurosurgical resection. The patient demonstrated consistently elevated circulating GHRH levels throughout preoperative testing, which was accompanied by marked GH and prolactin hypersecretion; GH demonstrated a paradoxical increase following TRH administration. In vitro, the pituitary cells showed baseline GH and prolactin release that was further stimulated by GHRH administration. Co-incubation with GHRH and the GHRH receptor antagonist, acetyl-(d-Arg(2))-GHRH (1-29) amide, blocked the GHRH-induced GH stimulation; the GHRH receptor antagonist alone significantly reduced GH release. Pasireotide, but not octreotide, inhibited GH secretion. A ghrelin receptor agonist and an inverse agonist led to modest, statistically significant increases and decreases in GH secretion, respectively. GHRH hypersecretion can accompany the pituitary abnormalities seen in X-LAG syndrome. These data suggest that the pathology of X-LAG syndrome may include hypothalamic dysregulation of GHRH secretion, which is in keeping with localization of GPR101 in the hypothalamus. Therapeutic blockade of GHRH secretion could represent a way to target the marked hormonal hypersecretion and overgrowth that characterizes X-LAG syndrome., (© 2016 Society for Endocrinology.)

Unlabelled: The objective of this study was to investigate the effects of growth hormone-releasing peptide-2 (GHRP-2) and cysteamine (CS) administration on growth performance in yaks with growth retardation and try to elucidate its regulatory mechanisms. Trial 1, thirty-six 1-year-old Qinghai high plateau yaks (body weight 38-83.2 kg) were randomly chosen for body weight and jugular blood samples collection. The relationship between body weight and serum GHRH (P < 0.05, R = 0.45), GH (P < 0.05, R = 0.47), IGF-1 (P < 0.05, R = 0.62) was significantly correlated in yaks colonies with lighter body weights. Trial 2, fifteen 1-year-old Qinghai high plateau yaks with growth retardation (average body weight 54.8 ± 8.24 kg) were randomly selected and assigned to negative control group (NG), GHRP-2 injection group (GG) and cysteamine feeding group (CG), with 5 yaks per group. Another five 1-year-old Qinghai high plateau yaks with normal growth performance (average body weight 75.3 ± 2.43 kg) were selected as positive control group (PG). The average daily gain (ADG) of the GG and CG were significantly higher than those in the PG and NG (P < 0.05). Both GHRP-2 and CS administration significantly enhanced the myofiber diameter and area of skeletal muscle (P<0.05). GHRP-2 significantly enhanced the serum GH and IGF-1 levels (P < 0.05), and up-regulated GHR, IGF-1 and IGF-1R mRNA expression in the liver and skeletal muscle (P < 0.05), enhanced the mRNA expression of PI3K, AKt and mTOR in the skeletal muscle (P<0.05). CS significantly reduced the serum SS levels and the hypothalamus SS mRNA expression (P < 0.05), and enhanced GHR and IGF-1 mRNA expression in the liver (P < 0.05), decreased the mRNA expression of muscle atrophy F-box (Atrogin-1) and muscle ring finger 1 (MuRF1) mRNA (P < 0.05)., Conclusions: Growth retardation in yaks was primarily due to somatotropic axis hormones secretion deficiency. Both GHRP-2 and CS administration can accelerate growth performance and GH, IGF-1 secretion in yaks with growth retardation. GHRP-2 enhanced muscle protein deposition mainly by up-regulated the protein synthesis pathways, whereas CS worked mainly by down-regulated the ubiquitin-proteasome pathway.

The Uniform Determination of Death Act (UDDA) states that an individual is dead when "all functions of the entire brain" have ceased irreversibly. However, it has been questioned whether some functions of the hypothalamus, particularly osmoregulation, can continue after the clinical diagnosis of brain death (BD). In order to learn whether parts of the hypothalamus can continue to function after the diagnosis of BD, we performed 2 separate systematic searches of the MEDLINE database, corresponding to the functions of the posterior and anterior pituitary. No meta-analysis is possible due to nonuniformity in the clinical literature. However, some modest generalizations can reasonably be drawn from a narrative review and from anatomic considerations that explain why these findings should be expected. We found evidence suggesting the preservation of hypothalamic function, including secretion of hypophysiotropic hormones, responsiveness to anterior pituitary stimulation, and osmoregulation, in a substantial proportion of patients declared dead by neurological criteria. We discuss several possible explanations for these findings. We conclude by suggesting that additional clinical research with strict inclusion criteria is necessary and further that a more nuanced and forthright public dialogue is needed, particularly since standard diagnostic practices and the UDDA may not be entirely in accord., (© The Author(s) 2014.)

Objective: Limited data are available on pituitary gigantism, as it is a rare disorder. This study was carried out to assess the clinical, hormonal, and radiologic profiles and management outcomes of patients with pituitary gigantism., Methods: We conduced a retrospective analysis of 14 patients with pituitary gigantism who presented to a single tertiary care institute from 1990 to 2014., Results: Thirteen patients were male, and 1 was female. The mean age at diagnosis was 21.9 ± 6.1 years, with a mean lag period of 6.5 ± 5.6 years. The mean height SD score at the time of diagnosis was 3.2 ± 0.6. Symptoms of tumor mass effect were the chief presenting complaint in the majority (50%) of patients, while 2 patients were asymptomatic. Six patients had hyperprolactinemia. At presentation, the nadir PGGH (postglucose GH) and insulin-like growth factor (IGF 1)-ULN (× upper limit of normal) were 63.2 ± 94.9 ng/mL and 1.98 ± 0.5, respectively. All (except 1 with mild pituitary hyperplasia) had pituitary macroadenoma. Six patients had invasive pituitary adenoma. Transsphenoidal surgery (TSS) was the primary modality of treatment in 13/14 patients, and it achieved remission in 4/13 (30.76%) patients without recurrence over a median follow-up of 7 years. Post-TSS radiotherapy (RT) achieved remission in 3/5 (60%) patients over a median follow-up of 3.5 years. None of the patients received medical management at any point of time., Conclusion: Gigantism is more common in males, and remission can be achieved in the majority of the patients with the help of multimodality treatment (TSS and RT).

The current study was designed to determine the effect of centrally administrated arachidonic acid (AA) on plasma gonadotropin hormone-releasing hormone (GnRH), follicle stimulating hormone (FSH), luteinizing hormone (LH) and testosterone level, and sperm parameters, and to show the mediation of the central cyclooxygenase (COX) to thromboxane A2 (TXA2) signaling pathway in AA-induced hormonal and sperm parameter effects. Studies were performed in male Sprague-Dawley rats. A total of 150 or 300 μl/5 μl doses of AA were injected intracerebroventricularly (icv). AA significantly caused dose- and time-dependent increases in plasma FSH, LH and testosterone levels of animals, but not plasma GnRH level. AA also significantly increased sperm motility of the rats without change sperm number. Pretreated with ibuprofen, a nonselective COX inhibitor (250 μg/5 μl; icv), and furegrelate, a TXA2 synthesis inhibitor (250 μg/5 μl; icv), prevented AA-evoked increase in plasma FSH, LH and testosterone levels, and sperm motility. In conclusion, our findings show that centrally administered AA increases plasma FSH, LH and testosterone levels and sperm motility of conscious male rats. Moreover, according to our findings, central COX-TXA2 signaling pathway mediates these AA-induced effects., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Objective: Impaired systemic hormonal activity caused by hypothalamic and pituitary injury may contribute to neuropsychologic disturbances and poor quality of life after aneurysmal subarachnoid hemorrhage (SAH). This prospective study was designed to longitudinally evaluate long-term clinical outcome and pituitary function after SAH using dynamic tests for adrencorticotropic and somatotropic secretory capacity., Methods: Endocrine function was assessed by basal hormonal concentrations at 6-12 months and 12-24 months after SAH. At the 12-24 months follow-up, dynamic provocative evaluation of adrenocorticotropic hormone (ACTH) and growth hormone (GH) was performed using the insulin tolerance test (ITT). In patients where ITT was contraindicated, an ACTH stimulation test was used to assess ACTH capacity, and a growth hormone releasing hormone (GHRH)-arginine stimulation test was used to assess GH capacity., Results: Of 60 patients with SAH screened, 51 were included in the study, and 44 remained to be tested at the two follow-up visits. As assessed by basal hormone concentrations alone, the prevalence of pituitary dysfunction was 34% at 6-12 months and 41% at 12-24 months. When using dynamic tests (12-24 months), impaired pituitary function was detected in 43%. The ITT detected more cases of central hypoadrenalism and GH deficiency compared with the ACTH- and GHRH-arginine-stimulation tests, respectively., Conclusions: Application of dynamic endocrine tests revealed a high frequency of long-term hypothalamic-pituitary dysfunction after aneurysmal SAH. The role of pituitary dysfunction in the recovery after SAH merits further evaluation., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background and Objectives: Tesamorelin is a synthetic analogue of growth hormone-releasing factor (GRF), which increases basal and pulsatile growth hormone (GH) secretion and subsequently increases insulin-like growth factor (IGF)-1. Limited information is available about the pharmacokinetics of this compound. Consequently, the aim of this study was to characterize the population pharmacokinetics of tesamorelin in HIV-infected patients and healthy subjects., Methods: A total of 38 HIV-infected patients and healthy subjects receiving subcutaneous tesamorelin doses of 1 or 2 mg administered daily during 14 consecutive days were included in the analysis. An open one-compartment model with first- and zero-order absorption and first-order elimination was developed to best describe the data using NONMEM(®) VII. The effect of different covariates on tesamorelin pharmacokinetics was investigated. Model evaluation was performed using predictive checks and non-parametric bootstrap., Results: Plasma clearance and its interindividual variability [% coefficient of variation (CV)] was estimated to be 1,060 L/h (33.6 %). Volume of distribution was calculated to be 200 L (17.7 %). Age, body size measures, race and health status were not related to tesamorelin pharmacokinetic parameters within the range of covariates studied. The fraction of tesamorelin absorbed by a first-order process is 13.1 % higher on day 14 compared with day 1. Predictive checks and non-parametric bootstrap demonstrated that the model is appropriate in describing the time course of tesamorelin plasma concentrations in both HIV-infected patients and healthy subjects., Conclusions: An open one-compartment model with first and zero order absorption processes and linear elimination is suitable to characterize the pharmacokinetics of tesamorelin. The fraction of tesamorelin absorbed by a first-order process evolves with time. No clinically relevant covariates were identified as predictors of tesamorelin pharmacokinetics.

The analytical method for detecting growth hormone (GH) doping, the so-called GH isoform differential immunoassay, is currently approved by the World Anti-Doping Agency (WADA). Anti-doping laboratories often face challenges by athletes' lawyers and need to have various types of scientific evidence against the claim that the adverse analytical finding (AAF) result was caused by excess ectopic or abnormal excretion. In this work, a population study of Japanese athletes (255 male and 256 female) and administration studies of recombinant human GH (rhGH) in Japanese females were conducted to confirm the applicability of GH isoform differential immunoassay. The present paper describes the effectiveness of the GH isoform differential immunoassay under abnormal excretion of endogenous GH as determined by administration studies of GH releasing hormone (GHRH(1-44)) and insulin-like growth factor-1 (IGF-1). No false positive findings were found in Japanese athletes. The GH isoform differential immunoassays could detect application of rhGH for approximately 12-24 h. The administration of GHRH(1-44) and IGF-1 as well as ghrelin receptor agonists did not affect the isoform ratio (no false positives). We conclude that the GH isoform differential immunoassay is a highly specific method for detecting rhGH doping. Subject-based profiling (i.e. athlete biological passport) very likely will represent a highly sensitive approach for detecting rhGH doping., (Copyright © 2012 John Wiley & Sons, Ltd.)

Purpose of Review: This article summarizes recent advances in testing for growth hormone deficiency (GHD) in adults, focusing on critical appraisal of existing growth hormone (GH) provocative tests as well as newer tests in development., Recent Findings: The diagnosis of GHD can be challenging and often requires the use of GH provocative testing. The most widely validated of these is insulin-induced hypoglycemia (ITT), which requires close supervision and has significant contraindications and side-effects. The arginine-growth hormone-releasing hormone (GHRH) test had become widely used as a safe and accurate alternative to the ITT, but GHRH is currently unavailable for clinical use in the USA. On the basis of review of recent literature we recommend that in the absence of GHRH, glucagon stimulation testing should be the preferred alternative to ITT. Several synthetic GH secretagogues that mimic the gastric peptide ghrelin are currently in development and may become available for use in the diagnosis of GHD in the near future. Other GH provocative tests suitable for use in children lack adequate specificity for the diagnosis of GHD in adults., Summary: Due to the current unavailability of the arginine-GHRH test in the USA, when ITT is contraindicated or impractical we recommend the glucagon stimulation testing as the GH provocative test of choice. There remains a need for a simple, safe and accurate test for the diagnosis of GHD.

Objective: To investigate the changes of plasma ghrelin, growth hormone (GH) and growth hormone releasing hormone (GHRH) and gastric ghrelin in patients with chronic obstructive pulmonary disease (COPD) and to explore their clinical significances., Methods: Plasma ghrelin, GH, GHRH, TNFα, IL-6 and C reactive protein (CRP) were measured in 40 COPD patients and 20 controls with chronic bronchitis. Correlated factors of plasma ghrelin, TNFα, IL-6, CRP were analyzed. Body composition was assessed with bioelectrical impedance analysis. The expression of gastric ghrelin in patients with COPD was detected., Results: Plasma ghrelin was higher in the underweight patients than in the normal weight patients and in the controls [(1.78 ± 0.46) ng/L, (1.39 ± 0.46) ng/L, (1.36 ± 0.39) ng/L, respectively]. Plasma GH was lower in the underweight patients than in the normal weight patients and in the controls [(4.12 ± 0.83) µg/L, (5.17 ± 0.72)µg/L, (6.49 ± 1.13) µg/L, respectively]. Plasma GHRH was lower in the underweight patients than in the normal weight patients and in the controls [(20.43 ± 4.41) ng/L, (23.47 ± 3.97) ng/L, (27.48 ± 10.06) ng/L, respectively]. Plasma ghrelin was higher in the underweight patients than in the controls (P < 0.01). Plasma ghrelin was higher in the underweight patients than in the normal weight patients with COPD. Plasma ghrelin (log transformed) was negatively correlated with BMI and percentage of body fat in the COPD patients. Plasma GHRH was positively correlated with ghrelin in the underweight patients (r = 0.515, P < 0.05), while no correlation was found between plasma GH and ghrelin in the underweight patients (r = 0.415, P > 0.05). Plasma ghrelin was positively correlated with TNFα and IL-6 in the underweight patients. The gastric expression of ghrelin showed no evident difference between the patients with COPD and the controls., Conclusions: The plasma GH in COPD patients may not be correlated with ghrelin. The plasma ghrelin level may be a useful indicator for malnutrition in COPD patients. Plasma ghrelin might be involved in the pathogenesis of CODP by affecting the body energy metabolism.

Context: Ectopic GHRH secretion is a rare cause of acromegaly, and case reports are mainly isolated., Setting: From the registry of the sole laboratory performing plasma GHRH assays in France, we identified cases of ectopic GHRH secretion presenting with acromegaly between 1983 and 2008., Patients: Twenty-one patients aged 14-77 yr were identified from 12 French hospitals. Median GHRH was 548 (270-9779) ng/liter., Main Outcome Measures: Outcome measures included description of tumor features and outcome and the relation between plasma GHRH values and tumor site, size, and spread., Results: The primary neuroendocrine tumor was identified for 20 of 21 patients (12 pancreatic, seven bronchial, one appendicular). Tumors were large (10-80 mm), identified on computed tomography scan in 18 cases and by endoscopic ultrasound and somatostatin receptor scintigraphy in two. Somatostatin receptor scintigraphy had a similar sensitivity to computed tomography scan (81 vs. 86%). Tumors were all well differentiated; 47.6% had metastasized at the time of diagnosis of acromegaly. After a median follow-up of 5 yr, 85% of patients were alive. Ninety-one percent of patients whose tumor was completely removed were considered in remission, and most had normalized plasma GHRH. The remaining patients were treated with somatostatin analogs: IGF-I normalized except for one patient who required pegvisomant, but GHRH levels remained elevated. No correlations were found between GHRH levels and tumor site or size or the existence of metastases. Identification of increased plasma GHRH during follow-up was an accurate indicator of recurrence., Conclusions: The prognosis of endocrine tumors responsible for GHRH secretion appears relatively good. Plasma GHRH assay is an accurate tool for diagnosis and follow-up.

Substance P is ubiquitous undecapeptide belonging to the tachykinins family. It has been found in the hypothalamus and is involved in the hypothalamo-hypophysial axis in several mammals, including human. Previous studies have shown that substance P increases GH secretions in rats and human. In this study, we have shown that intravenously infused substance P in sheep caused an increased level of Growth Hormone (GH) and GH-Releasing Hormone (GHRH), and decreased Somatotropin Release Inhibiting Hormone (SRIH) secretions. GH was obtained from peripheral blood. GHRH and SRIH were directly collected from hypophysial portal blood, using a trans-nasal surgery technique in a vigil sheep that allowed accessing to hypothalamo-hypophysial portal vessels. Hormones assays were performed by radioimmunoassay (RIA). Moreover, we showed that substance P-induced GH and GHRH secretion appears to be mediated by NK2 tachykinin receptors, since it is specifically blocked by a non peptidic tachykinin NK2 receptor antagonist (SR48968, Sanofi, Montpellier, France) whereas a non peptidic tachykinin NK1 antagonist (SR140333, Sanofi, Montpellier, France) failed to modify GH and GHRH hormones secretions., (Copyright © 2012 Elsevier Inc. All rights reserved.)

For most peptide hormones prohibited in elite sports the concentrations in plasma or urine are very low (pg/mL). Accordingly, hyphenated purification and enrichment steps prior to mass spectrometric detection are required to obtain sufficient doping control assays. Immunoaffinity purification in combination with nano-scale liquid chromatography coupled to high resolution/high accuracy mass spectrometry was found to have the potential of providing the necessary sensitivity and unambiguous specificity to produce reliable results. With the presented methodology 12 prohibited peptides (porcine insulin, Novolog, Apidra, Lantus DesB30-32 metabolite, Humalog and human insulin, Synacthen (synthetic ACTH analogue), luteinizing hormone-releasing hormone (LH-RH), growth hormone releasing hormone (GH-RH(1-29)) and CJC-1295 (GH-RH analogue), LongR(3)-IGF-1 and IFG-1) were simultaneously purified from plasma/serum or urine. With limits of detection for each target compound ranging in the low pg/mL level (urine), the method enables the determination of urinary peptides at physiologically relevant concentrations. For each class of peptides an appropriate antibody and a respective internal standard was implemented ensuring robust analysis conditions. Due to the fast and simple sample preparation procedure (∼25 samples per day) and the fact that all materials are commercial available, the implementation of the methodology to laboratories from other analytical fields (forensics, pharmacokinetic sciences, etc.) is enabled., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Because cloned dogs are genetically identical, variations among these animals can be a useful tool to elucidate mechanisms underlying phenotypic differences. To estimate the influence of genetic factors on phenotypic variation, changes in concentration patterns of growth hormone (GH), insulin like growth factor-1 (IGF-1), and IGF binding protein 3 (IGFBP-3) were compared among cloned and age-matched control dogs. In addition, the concentrations of GH and IGF-1 following administration of growth hormone releasing hormone (GHRH) and somatostatin (SRIF) were measured in both groups. In comparing hormone profiles, the control dogs had larger standard deviations from the means for GH, IGF-1, and IGFBP-3 than the clones. Also, the mean concentration of IGFBP-3 in clones was significantly lower than in the controls between 7 to 12 months of age, whereas the IGFBP-3 changes in clones and controls followed the same pattern. GHRH induced increased serum growth hormone concentration both in clones and controls. However, the concentration of IGF-1 was lower in clones than in controls, and larger standard variations were noted in the control group. In conclusion, the measured traits were more homogeneous in cloned animals than in controls, so cloned animals could be valuable for assessing effects of genotype and environment interactions.

Objective: To evaluate the impact of different peak GH cut-off limits after GHRH-Arg test, IGF1 measurement, or their combination in identifying patients with GH deficit (GHD)., Design and Patients: Totally, 894 normal subjects (used for determining IGF1 normative limits) and 302 patients with suspected GHD were included. Different peak GH cut-off limits (used by European (depending on body mass index (BMI)) or North American (4.1 μg/l) Endocrine Societies, by HypoCCs (2.5 μg/l), or with 95% specificity (based on BMI), Method 1, 2, 3, or 4 respectively) and IGF1 were considered., Methods: Peak GH after GHRH-Arg and IGF1., Results: Different peak GH cut-off limits recognized different proportions of GHD (range, 24.8-62.9%). Methods 1 and 2 with high sensitivity recognized a higher proportion (95.5 and 92.5% respectively) of GHD among patients with three (T) pituitary hormone deficits (HD), whereas Method 4 (with high specificity) identified 96.7% normal subjects among those without pituitary HD; on the contrary, Method 4 identified only 75% GHD among patients with THD, whereas Method 1 recognized a high proportion (40%) of GHD among subjects without HD. Of the total patients, 82% with THD and 84.5% without HD were recognized as GHD or normal respectively by IGF1. Among the remaining patients with THD and normal IGF1, 75% was recognized as GHD by Method 1; among patients without HD and abnormal IGF1, 87.5% was identified as normal by Method 4. Overall, combination of IGF1 and Method 1 or Method 4 identified 95.5% GHD among patients with THD and 98.1% normal subjects among those without HD., Conclusions: Single peak GH cut-offs have limits to sharply differentiate GHD from normal subjects; IGF1 may be used for selecting patients to be submitted to the GHRH-Arg test; the peak GH cut-off limits to be used for identifying healthy or diseased patients depend mainly on the clinical context.

Acromegaly is usually caused by a growth hormone (GH)-secreting pituitary adenoma. In rare cases, however, it is caused by the ectopic production of growth hormone-releasing hormone (GHRH). We report a case of acromegaly due to ectopic production of GHRH from a bronchial carcinoid in a 42-year-old female. The carcinoid tumor was successfully treated with bilobectomy., (© Georg Thieme Verlag KG Stuttgart · New York.)

Context: Autoimmune hypophysitis can result in GH deficiency (GHD) and is associated with other autoimmune endocrine diseases like Hashimoto's thyroiditis. Recent studies suggest a high prevalence (5%) of GHD in Hashimoto's thyroiditis., Objective: Our objective was to establish the prevalence of GHD in patients with treated autoimmune hypothyroidism (AIH)., Patients: We included patients with spontaneous AIH [thyroid peroxidase antibodies (TPO-Ab) >or=100 kU/liter], who were adequately treated with T(4) (TSH 0.2-5.0 mU/liter). Exclusion criteria were previous I(131) treatment, thyroid surgery, or a history of hypothalamic or pituitary disease. Patients were recruited via our outpatient clinics and via patient self-help organizations., Design: We measured serum TSH, free T(4), TPO-Ab, and IGF-I. If the IGF-I concentration was below the 10th percentile of age-specific reference values, a GHRH/GH-releasing peptide (GHRP)-6 test was done. GHD was defined as a GH peak after GHRH/GHRP-6 below the 2.5th percentile of age-specific reference values., Main Outcome Measures: IGF-I concentration and GH peak after GHRH/GHRP-6 test were measured., Results: From 860 patients who applied, 322 did not satisfy inclusion criteria (157 because TPO-Ab was <100 kU/liter, 165 because TSH was <0.2 or >5.0 mU/liter), and 23 had an exclusion criterion. In the remaining study population of 515 patients (476 female, 39 male), 49 patients (9.5%) had an IGF-I concentration below the 10th percentile. These patients underwent a GHRH/GHRP-6 test. Two patients had a GH peak below the 2.5th percentile., Conclusion: The prevalence of GHD in Dutch patients with AIH is 0.4% (two of 515).

Background: Discontinuation of growth hormone (GH) treatment upon attainment of final height has been associated with impaired somatic development and altered body composition. Therefore, optimal care of patients with GH deficiency (GHD) in the transition phase from adolescence to adulthood is a challenge for all parties involved. We analyzed the current clinical practice in Germany., Methods: In 2008, 124 endocrinologists (69 pediatric, 55 adult endocrinologists) in Germany were interviewed using a structured questionnaire., Results: Overall, 67 % of pediatric endocrinologists (PE) and adult endocrinologists (AE) declared to have a contact physician for their patients. 13 endocrinologists declared to have a common transition clinic with their corresponding colleague. 74 % of PE stated to transfer their patients after the end of GH therapy to an AE. 62 % of the patients were transferred at the age of 18 years. 70 % of the PE stated to retest their patients themselves, while 70 % of the AE answered that the patients had not been retested when they first came to the adult clinic. For the evaluation of GH-secretion, PE most frequently used the arginine (86 %), ITT (35 %) and clonidine test (33 %), whereas AE utilized the GHRH/arginine test (71 %), and the ITT (67 %). The level of patient's information about his disease status was considered as "good" by 44 % of AE (77 % by AE having established a transition clinic). The quality of patient files transferred from the PE was considered as "good" by 54 % of all AE (100 % by AE with transition clinic)., Conclusion: To a significant extent, there is an inconsistence in diagnostic methods and treatment modalities performed by PE and AE compared to recently published consensus guidelines. Only 13 PE interviewed in this study transfer their GHD patients in a transition clinic setting. Communication and transfer of information between both groups appears to be impaired in centres without a transition clinic. In those clinics having established transition clinics, patient's status of information and quality of patient files is considered to be much better.

Context: Visceral adiposity is a strong determinant of GH secretion, and low endogenous GH secretion is associated with increased insulin resistance, a key component of the metabolic syndrome. Increased fat accumulation in skeletal muscle and liver may play an etiological role in the development of insulin resistance and other complications of the metabolic syndrome. Little is known about the role of decreased endogenous GH secretion in the pathogenesis of insulin resistance in obesity., Objective: To investigate the relationship between intramyocellular lipids (IMCL), intrahepatic lipids, and peak-stimulated GH in premenopausal women with obesity., Design and Setting: We conducted a cross-sectional study at a clinical translational research center., Patients: Patients included 21 premenopausal women with obesity (mean body mass index, 34.0 +/- 4.5 kg/m(2)) and 17 normal-weight controls (mean body mass index, 21.9 +/- 2.0 kg/m(2)) of comparable mean age., Main Outcomes Measures: IMCL and intrahepatic lipids were measured with proton magnetic resonance spectroscopy ((1)H-MRS). Body composition was measured with magnetic resonance imaging. Peak GH was measured after stimulation with GHRH-arginine., Results: Obese subjects had higher IMCL, intrahepatic lipids, abdominal and thigh fat, and thigh muscle mass compared with normal-weight controls. There were strong inverse associations between peak GH and both IMCL and intrahepatic lipids independent of age and visceral adiposity. There were positive associations between IMCL and intrahepatic lipids with measures of insulin resistance and serum triglycerides., Conclusion: In premenopausal women with obesity, peak GH is inversely associated with IMCL and intrahepatic lipids independent of age and visceral adiposity. This suggests that low GH may contribute to insulin resistance in obesity through effects on muscle and intrahepatic lipids.

Growth hormone (GH) secretion in male rats exhibits a 3.3 h ultradian rhythm generated by the reciprocal interaction of GH-releasing hormone (GHRH) and somatostatin (SRIF). SRIF receptor subtypes sst(1) and sst(2) are highly expressed in GHRH neurons of the hypothalamic arcuate nucleus (ARC). We previously demonstrated an ultradian oscillation in binding of SRIF analogs to the ARC in relation to GH peaks and troughs. Here we tested the hypothesis that these ultradian changes in SRIF binding are due to differential plasma membrane targeting of sst(1) receptors in ARC neurons using immunocytochemistry and electron microscopy. We found that 87% of sst(1)-positive ARC neurons also synthesized GHRH. Subcellularly, 80% of sst(1) receptors were located intracellularly and 20% at the plasma membrane regardless of GH status. However, whereas 30% of the cell-surface sst(1) receptors were located perisynaptically or subsynaptically following exposure to high GH secretion, this fraction was increased to 42% following a GH trough period (p = 0.05). Furthermore, the relative abundance of symmetric and asymmetric synapses on sst(1)-positive dendrites also varied significantly, depending on the GH cycle, from approximately equal numbers following GH troughs to 70:30 in favor of symmetric, i.e., inhibitory, inputs after GH peaks (p < 0.02). These findings suggest that postsynaptic localization of sst(1) receptors and synaptic connectivity in the ARC undergo pronounced remodeling in parallel with the GH rhythm. Such synaptic plasticity may be an important mechanism by which sst(1) mediates SRIF's cyclical effects on ARC GHRH neurons to generate the ultradian rhythm of GH secretion.

Background: Plasma insulin-like growth factor (IGF-I) concentration can be used as a rough indicator of the growth-hormone status. However, for the diagnosis of growth hormone deficiency, dynamic tests are required. The growth hormone (GH) response in the insulin tolerance test (ITT) is considered to be the gold standard in this respect. An alternative for the ITT is the GHRH/ GHRP-6 test, which has fewer side effects. In this study we established reference values for IGF-I levels and for the GH response in both dynamic tests., Methods: We studied 296 subjects recruited from the general population, equally distributed according to sex and aged between 20 and 70 years. Serum IGF-I level was measured in all subjects and an insulin tolerance test (0.15 U/kg Actrapid iv) and GHRH/GHRP-6 test (1 microg GHRH/kg and 1 microg GHRP-6/kg) were performed in 49 subjects., Results: In multivariate analyses both IGF-I and the GH response in the ITT were significantly influenced by age, whereas the GH response in the GHRH/GHRP-6 test was significantly affected by BMI. There was no sex difference in IGF-I and in the GHRH/GHRP-6 test, but in the ITT males had a higher GH peak. There was a significant correlation between the GH responses in both tests, and the GH response was significantly higher in the GHRH/GHRP-6 test than in the ITT. Age-adjusted reference values were established for each test., Conclusion: We have established age-adjusted reference values for serum IGF-I and for the GH response in the ITT and GHRH/GHRP-6 test.

Acute administration of cortisol increases non-rapid-eye movement (non-REM) sleep, suppresses rapid-eye movement (REM) sleep and stimulates growth hormone (GH) release in healthy subjects. This study investigates whether cortisol has similar endocrine and electrophysiological effects in patients with depression who typically show a pathological overactivity of the hypothalamus-pituitary-adrenal (HPA) system. Fifteen depressed inpatients underwent the combined dexamethasone/corticotropin-releasing hormone test followed by three consecutive sleep EEG recordings in which the patients received placebo (saline) and hourly injections of cortisol (1mg/KG BW). Cortisol increased duration and intensity of non-REM sleep in particular in male patients and stimulated GH release. The activity of the HPA axis appeared to influence the cortisol-induced effects on non-REM sleep and GH levels. Stimulation of delta sleep was less pronounced in patients with dexamethasone nonsuppression. In contrast, REM sleep parameters were not affected by the treatment. These data demonstrate that the non-REM sleep-promoting effects of acute cortisol injections observed in healthy controls could be replicated in patients with depression. Our results suggest that non-REM and REM sleep abnormalities during the acute state of the disease are differentially linked to the activity of the HPA axis.

There is growing concern about the use of recombinant human growth hormone (rhGH) by individuals taking part in competitive sports. Although rhGH is banned by the international organizations, the detection of GH doping is difficult. We postulated that rhGH will suppress endogenous GH production, which can be assessed by the measurement of mRNA for GH and growth hormone-releasing hormone (GHRH). In order to prove this concept, we undertook a pilot study to examine whether circulating nucleic acids are useful in the detection of endogenous GH production. Blood samples were collected into PAXgene tubes from 37 healthy controls and 12 acromegalic patients. RNA was extracted from the samples, cDNA was obtained, and the quantities of mRNA for GH and GHRH were measured using real-time PCR. In acromegalic patients, median mRNA concentration for GHRH (corrected for beta-actin mRNA) was 30.7 times lower than in controls (median delta C(T)) value of -0.128 versus 3.927, P < 0.001). There was a significant correlation between serum IGF-1 SD score and mRNA for GHRH (r= 0.407). In acromegalic patients, mRNA for GH was significantly higher than in controls (median values of -4.694 versus -0.044, P < 0.05). As GH production is known to decline with age, we also examined mRNA for GH and GHRH according to age subgroups. Both markers were significantly lower in the older age group (>50 years) compared to the younger age group (<34 years). These results show that mRNA for GH and GHRH can be detected in the peripheral circulation and raises the possibility of using these markers in the detection of exogenously administered GH.

To explore and compare hypothalamic-pituitary-somatotropic (HPS) axis function and hypothalamic-pituitary-adrenocortical (HPA) axis function in depression, the dexamethasone (DEX)/CRH test and growth hormone releasing hormone (GHRH) test were prospectively performed on patients with depression at the time of admission and discharge. The patients who relapsed within six months after discharge exhibited significantly lower growth hormone (GH) responses to GHRH at the time of discharge than those who did not relapse. There were no significant correlations between GH response to GHRH and the results of DEX/CRH tests after controlling for age, sex, and body mass index. The findings of this study suggest that results of the GHRH test may be a predictor of future relapse in patients with depression.

Background: Diagnosis of growth hormone deficiency (GHD) in childhood is usually based on growth hormone (GH) response to at least two provocative stimuli. The aim of this study was to determine whether sequential administration of arginine (Arg) plus GH releasing hormone (GHRH) could be a useful tool in evaluating GHD in children., Methods: Thirty patients with short stature (mean age 9.0 years) with decreased growth rate were tested for GHD with Arg and the insulin tolerance test (ITT). Patients with confirmed GHD (peak GH <8 ng/ml) were subsequently tested with Arg + GHRH., Results: Maximum GH stimulation for Arg and ITT was 6.3 (1.0-7.8) and 6.7 (0.5-7.7) ng/ml, respectively. Peak GH for the Arg + GHRH test was 36.3 (4.3-84.5) ng/ml and significantly different from the other provocative tests. Peak GH values for the three tests were not significantly correlated between tests or with clinical parameters. There were no significant differences in Arg + GHRH results between children with or without abnormal hypothalamic-pituitary MRI scans., Conclusion: Arg + GHRH gave higher GH levels than insulin or Arg alone. Because of the different causes of childhood GHD (hypothalamic and/or pituitary dysfunction), the Arg + GHRH test is unsuitable .for evaluating GHD and deciding whether GH replacement therapy is indicated.

Context: The current criteria for definition of partial GHD in young adults are still a subject of debate., Objectives: The objective of the study was to reinvestigate anterior pituitary function in young adults with congenital childhood-onset GHD associated with structural hypothalamic-pituitary abnormalities and normal GH response at the time of first reassessment of GH secretion., Design and Setting: This was a prospective explorative study conducted in a university research hospital., Patients and Methods: Thirteen subjects with a mean age of 17.2 +/- 0.7 yr and a peak GH after insulin tolerance test (ITT) higher than 5 microg/liter were recruited from a cohort of 42 patients with childhood-onset GHD and ectopic posterior pituitary at magnetic resonance imaging. GH secretion after ITT and GHRH plus arginine, IGF-I concentration, and body mass index, waist circumference, blood pressure, total cholesterol, and fibrinogen were evaluated at baseline and at 2-yr follow-up., Results: At mean age of 19.2 +/- 0.7 yr, the mean peak GH response decreased significantly after ITT (P = 0.00001) and GHRH plus arginine (P = 0.0001). GH peak values after ITT and GHRH plus arginine were less than 5 and 9 microg/liter in 10 and eight patients, respectively. Additional pituitary defects were documented in eight patients. Significant changes were found in the values of IGF-I sd score (P = 0.0026), waist circumference (P = 0.00001), serum total cholesterol (P = 0.00001), and serum fibrinogen (P = 0.0004)., Conclusions: The results of this study underline the importance of further reassessment of pituitary function in young adults with GHD of childhood-onset and poststimulation GH responses suggestive of partial GHD.

Current guidelines for the diagnosis of adult growth hormone deficiency (GHD) state that the diagnosis must be proven biochemically by provocative testing that is done within the appropriate clinical context. The need for reliance on provocative testing is based on evidence that the evaluation of spontaneous growth hormone (GH) secretion over 24 h and the measurement of IGF-I and IGFBP-3 levels do not distinguish between normal and GHD subjects. Regarding IGF-I, it has been demonstrated that very low levels in patients highly suspected for GHD (i.e., patients with childhood-onset, severe GHD, or with multiple hypopituitarism acquired in adulthood) may be considered definitive evidence for severe GHD obviating the need for provocative tests. However, normal IGF-I levels do not rule out severe GHD and therefore adults suspected for GHD and with normal IGF-I levels must undergo a provocative test of GH secretion. The insulin tolerance test (ITT) is the test of choice, with severe GHD being defined by a GH peak less than 3 microg/l, the cut-off that distinguishes normal from GHD adults. The ITT is contraindicated in the presence of ischemic heart disease, seizure disorders, and in the elderly. Other tests are as reliable as the ITT, provided they are used with appropriate cut-off limits. Glucagon stimulation, a classical test, and especially new maximal tests such as GHRH in combination with arginine or GHS (i.e., GHRP-6) have well-defined cut-off limits, are reproducible, are independent of age and gender, and are able to distinguish between normal and GHD subjects. The confounding effect of overweight or obesity on the interpretation of the GH response to provocative tests needs to be considered as the somatotropic response to all stimuli is negatively correlated with body mass index. Appropriate cut-offs for lean, overweight, and obese subjects must be used in order to avoid false-positive diagnoses of severe GHD in obese adults.

Hypothalamic GHRH is secreted into the portal system, binds to specific surface receptors of the somatotroph cell and elicits intracellular signals that modulate pituitary GH synthesis and/or secretion. Moreover, GHRH is synthesized and expressed in multiple extrapituitary tissues. Excessive peripheral production of GHRH by a tumor source would therefore be expected to cause somatotroph cell hyperstimulation, increased GH secretion and eventually pituitary acromegaly. Immunoreactive GHRH is present in several tumors, including carcinoid tumors, pancreatic cell tumors, small cell lung cancers, endometrial tumors, adrenal adenomas, and pheochromocytomas which have been reported to secrete GHRH. Acromegaly in these patients, however, is uncommon. The distinction of pituitary vs. extrapituitary acromegaly is extremely important in planning effective management. Regardless of the cause, GH and IGF-1 are invariably elevated and GH levels fail to suppress (<1 microg/l) after an oral glucose load in all forms of acromegaly. Dynamic pituitary tests are not helpful in distinguishing acromegalic patients with pituitary tumors from those harbouring extrapituitary tumors. Plasma GHRH levels are usually elevated in patients with peripheral GHRH-secreting tumors, and are normal or low in patients with pituitary acromegaly. Unique and unexpected clinical features in an acromegalic patient, including respiratory wheezing or dyspnea, facial flushing, peptic ulcers, or renal stones sometimes are helpful in alerting the physician to diagnosing non pituitary endocrine tumors. If no facility to measure plasma GHRH is available, and in the absence of MRI evidence of pituitary adenoma, a CT scan of the thorax and abdominal ultrasound could be performed to exclude with good approximation the possibility of an ectopic GHRH syndrome. Surgical resection of the tumor secreting ectopic GHRH should be the logical approach to a patient with ectopic GHRH syndrome. Standard chemotherapy directed at GHRH-producing carcinoid tumors is generally unsuccessful in controlling the activated GH axis. Somatostatin analogs provide an effective option for medical management of carcinoid patients, especially those with recurrent disease. In fact, long-acting somatostatin analogs may be able to control not only the ectopic hormonal secretion syndrome, but also, in some instances, tumor growth. Therefore, although cytotoxic chemotherapy, pituitary surgery, or irradiation still remain available therapeutic options, long-acting somatostatin analogs are now preferred as a second-line therapy in patients with carcinoid tumors and ectopic GHRH-syndrome.

Background: Low GH levels, probably due to insulin resistance and increased abdominal fat mass, are well described in polycystic ovary syndrome (PCOS). GH acts as an important ovarian cogonadotropin, and GH disturbances may be an additional pathogenic factor in PCOS. Decreased abdominal fat mass and improved insulin sensitivity during pioglitazone treatment may affect GH secretion., Objective: The objective of the study was to investigate the effect of pioglitazone on GH levels in PCOS., Design: Thirty insulin-resistant PCOS patients were randomized to either 16 wk pioglitazone (30 mg/d) or placebo treatment. Before and after intervention, levels of fasting insulin, GH, total IGF-I, free IGF-I, IGF binding protein-1, IGF-II, free fatty acids, testosterone, and SHBG were measured. Patients underwent whole-body dual x-ray absorptiometry scans, pyridostigmine-GHRH tests, and 24-h 20-min integrated blood sampling for measurement of GH., Results: Peak GH and area under the curve for GH in pyridostigmine-GHRH tests and 24-h mean GH concentrations and pulsatile GH secretion significantly increased after pioglitazone treatment. No significant changes were observed in GH pulse frequency, pulse duration, approximate entropy levels, or basal GH release. Levels of IGF binding protein-1 significantly increased, whereas no significant differences were measured in total IGF-I and free IGF-I. Pioglitazone treatment significantly decreased fasting insulin and homeostasis model assessment levels. No significant changes were observed in Ferriman Gallwey score or androgen levels., Conclusion: Pioglitazone treatment significantly increased GHRH-stimulated GH levels and 24-h pulsatile GH secretion, probably directly or indirectly due to improved insulin sensitivity.

Antagonists of growth hormone-releasing hormone (GHRH) were shown to inhibit the growth of various cancers. We investigated the antitumor activity and the mechanism of action of GHRH antagonists in human non-Hodgkin's lymphomas (NHL). Nude mice bearing xenografts of RL and HT human NHL were treated with GHRH antagonists MZ-5-156 and MZ-J-7-138 at a dose of 40 microg twice daily. The concentrations of serum IGF-1 and GHRH, bFGF, and VEGF in tumor tissue were measured by radioimmunoassays. Expression of GHRH and splice variant 1 of the GHRH receptor in both cell lines was examined by RT-PCR. The effects of MZ-5-156, MZ-J-7-138 and GHRH on cell proliferation were evaluated in vitro. Treatment with MZ-5-156 and MZ-J-7-138 significantly (P < 0.05) inhibited the growth of RL and HT tumors by 59.9-73.9%. High-affinity binding sites for GHRH and mRNA for GHRH and splice variant-1 of the GHRH receptors were found on RL and HT tumors. RL and HT cells contained GHRH peptide, and their growth in vitro was significantly inhibited by both antagonists. IGF-I levels in serum of mice were significantly decreased by antagonist MZ-5-156. Therapy with GHRH antagonists also significantly reduced tumoral bFGF, whereas VEGF levels were not suppressed. Our findings suggest that GHRH antagonists inhibit the growth of RL and HT lymphomas by direct effects mediated by tumoral receptors for GHRH. GHRH antagonists could offer a new therapeutic modality for the management of advanced NHL.

Ghrelin is a native ligand for the growth hormone secretagogue (GHS) receptor that stimulates pulsatile GH secretion markedly. At present, no formal construct exists to unify ensemble effects of ghrelin, GH-releasing hormone (GHRH), somatostatin (SRIF), and GH feedback. To model such interactions, we have assumed that ghrelin can stimulate pituitary GH secretion directly, antagonize inhibition of pituitary GH release by SRIF, oppose suppression of GHRH neurons in the arcuate nucleus (ArC) by SRIF, and induce GHRH secretion from ArC. The dynamics of such connectivity yield self-renewable GH pulse patterns mirroring those in the adult male and female rat and explicate the following key experimental observations. 1) Constant GHS infusion stimulates pulsatile GH secretion. 2) GHS and GHRH display synergy in vivo. 3) A systemic pulse of GHS stimulates GH secretion in the female rat at any time and in the male more during a spontaneous peak than during a trough. 4) Transgenetic silencing of the neuronal GHS receptor blunts GH pulses in the female. 5) Intracerebroventricular administration of GHS induces GH secretion. The minimal construct of GHS-GHRH-SRIF-GH interactions should aid in integrating physiological data, testing regulatory hypotheses, and forecasting innovative experiments.

Objectives: Ghrelin is a 28-amino-acid peptide, predominantly produced by the stomach. It displays a strong GH-releasing activity mediated by the hypothalamus-pituitary GH secretagogue (GHS)-receptor (GHS-R). There are different studies that suggest the importance of ghrelin in feeding and weight homeostasis. In obesity there is a markedly decreased GH secretion. For both children and adults, the greater the body mass index (BMI), the lower the GH response to provocative stimuli, including the response to GHRH. However, the response to the natural GH secretaogogue ghrelin is unclear at the present time. The aim of the present study was to evaluate the GH response to ghrelin alone or combined with GHRH in a group of obese patients, in order to further understand the deranged GH secretory mechanisms in obesity and to clarify the mechanism of action of ghrelin., Patients and Measurements: Six obese female patients (31 +/- 3.4 years) with a BMI of 36.1 +/- 7.7 kg/m(2) were studied. As a control group, six normal nonobese female subjects of similar age and sex were studied. Four tests were performed: placebo, GHRH [1 micro g/kg, no more than 100 micro g, intravenous (i.v.)], ghrelin (1 micro g/kg, no more than 100 micro g, i.v.) and GHRH (1 micro g/kg, no more than 100 micro g, i.v.) plus ghrelin (1 micro g/kg, no more than 100 micro g, i.v.). Blood samples were taken at appropriate intervals for determination of GH. Statistical analyses were performed by Wilcoxon and by Mann-Whitney tests., Results: After GHRH, the median peak GH secretion in obese patients was 2.4 micro g/l (range 0.9-8.9 micro g/l). Ghrelin-induced GH secretion showed in obese patients a median peak of 24.4 micro g/l (range 7.4-85.0 micro g/l), significantly greater than the response after GHRH (P < 0.05). After the combined administration of GHRH plus ghrelin in obese patients the median peak GH secretion was 39.9 micro g/l (range 19.2-120.0 micro g/l), significantly greater than the response after GHRH (P < 0.05) or ghrelin (P < 0.05). GHRH-induced GH secretion in normal control subjects showed a median peak of 25.0 micro g/l (range 16.5-33.4 micro g/l). Ghrelin-induced GH secretion in normal showed a median peak of 68.5 micro g/l (range 22.5-119.5 micro g/l), significantly greater than the response after GHRH (P < 0.05). After the combined administration of GHRH plus ghrelin, in normal subjects the median peak GH secretion was 117.8 micro g/l (range 77.5-280.1 micro g/l), significantly greater than the response after GHRH or ghrelin alone (P < 0.05). When we compare the response of normal and obese patients, after GHRH alone, it was markedly decreased in obese people when compared with normal patients (P < 0.05) with a median GH peak of 25.0 micro g/l (range 16.5-33.4 micro g/l) and 2.4 micro g/l (range 0.9-8.9 micro g/l) for normal and obese patients, respectively. When we compare the response of normal and obese patients, after ghrelin alone or GHRH plus ghrelin, it was only blunted in obese subjects when compared with normal subjects with a median GH peak of 68.5 micro g/l (range 22.5-119.5 micro g/l) and 24.4 micro g/l (range 7.4-85 micro g/l) for normal and obese subjects, respectively, after ghrelin alone (P < 0.05) and a median GH peak of 117.8 micro g/l (range 77.5-280.1 micro g/l) and 39.9 micro g/l (range 19.2-120.0 micro g/l) for normal and obese patients, respectively, after GHRH plus ghrelin (P < 0.05)., Conclusions: This study has demonstrated a massive GH response to ghrelin alone or combined with GHRH in obese patients, suggesting that altered ghrelin secretion could play a major role in the blunted GH secretion present in obese patients.

Idiopathic diffuse hyperplasia of pulmonary neuroendocrine cells (IDHPNC) is a rare disorder that most often presents clinically as obliterative bronchiolitis, but has also been associated with ectopic corticotropin syndrome. We describe a 49-year-old lifetime non-smoking female with longstanding cough, progressive exertional dyspnoea, and fixed airflow limitation, who presented with acromegaly. Head magnetic resonance imaging revealed a pituitary microadenoma and open lung biopsy revealed a multifocal proliferation of neuroendocrine cells which were immunopositive for both corticotropin and growth hormone-releasing hormone. To our knowledge, this is the first report of acromegaly associated with IDHPNC, and supports the possibility that IDHPNC may fall at one extreme of the spectrum of disorders encountered in multiple endocrine neoplasia type 1.

The aim of this study was to assess the in vivo efficacy of monoPEGylated GRF(1-29)NH(2) having one PEG(5000) chains attached to either lysine 12 or 21 as compared to the GRF(1-29)NH(2) in rats and pigs. This analogue termed GRF-1PEG(5000) was tested after a single intravenous administration in rats and after a single intravenous or subcutaneous injection in pigs. After 1 h administration, GH concentrations returned to values close to controls in the group of rats injected with GRF(1-29)NH(2). In animals injected with the same dose of GRF-1PEG(5000), the AUC values corresponding to the whole period 0.5-48 h and particularly to the 0.5-8 h period were higher than in the placebo or in the GRF(1-29)NH(2) groups. Interestingly, two additional peaks were observed at about 6 and 8 h following administration. An increase in the response of the endogenous GH peaks was also observed in pigs administered GRF-1PEG(5000) by intravenous route. When GRF-1PEG(5000) was administered subcutaneously to pigs, a significant increase, as compared to placebo and GRF(1-29)NH(2,) in both GH and IGF-I levels was observed. This new analogue might find therapeutic application in paediatric growth hormone deficiency or in aging.