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Purpose: It is unclear whether the age-related decline in the somatotropic axis stems from a reduced growth hormone (GH) production in the pituitary gland, or from a peripheral origin akin to an acquired GH resistance. With the help of a GHRH/arginine test, high-aged multimorbid hospitalized patients with IGF-I deficiency are to be tested to determine whether there is primarily a pituitary GH deficiency in the sense of a somatopause., Methods: Seventeen multimorbid patients (eleven men and six women) with a mean age of 82 years, with IGF-I concentrations below two standard deviations of 30-year-old men and women were identified. Patients suffered from a variety of common age-related stable diseases including coronary artery disease, chronic liver or kidney disease, chronic heart failure as well as acute conditions e.g., urosepsis or endocarditis. To assess the somatotropic axis they underwent a GHRH/arginine test. Results were evaluated using descriptive statistics., Results: In average, the peak concentration of GH after stimulation was 14.8 µg/L with a range from 2.76 to 47.4 µg/L. Taking into account both, gender and BMI (with a mean of 26.5 kg/m²) for each participant, the pituitary gland was adequately stimulated in 16 out of the 17 patients. No patient reported common side effects related to the GHRH/arginine test., Conclusion: The somatotroph pituitary gland retains its secretory capacity in the advanced aged. Therefore, age does not seem to be the driving pacemaker for the functional decline of the somatotropic axis within the aged population., (© 2024. The Author(s).)

Non-pituitary growth hormone (npGH) expression is well established in extrapituitary tissues, but an understanding of the physiological role of npGH remains rather limited. Pro-tumorigenic npGH impacting the tumor microenvironment has been reviewed. We focus here on autocrine/paracrine npGH effects in non-tumorous tissues and discuss its mechanisms of action in the normal tissue microenvironment. We address the tissue-specific effects of npGH in regulating stem, endothelial, immune, and epithelial cells and highlight the related role of npGH-associated changes in tissue aging.

Lipotoxicity has been shown to cause dysfunction of many organs and tissues. However, it is unclear whether lipotoxicity is harmful to the somatotrophs, a kind of cell that synthesize growth hormone (GH) in the pituitary. In this study, we performed an epidemiological study, serum levels of triglyceride (TG) and GH showed a negative correlation, even after adjustment for potential confounders. In an animal study, male Sprague-Dawley rats were fed a high-fat diet (HFD) or a control diet for 28 weeks. HFD rats showed impaired GH synthesis, resulting in a decrease in circulating GH levels. The expression of pituitary Pit-1, a key transcription factor of GH, was inhibited. We found that the inositol-requiring enzyme 1α (IRE1α) pathway of endoplasmic reticulum (ER) stress was triggered in HFD rat pituitary glands and palmitic acid-treated GH3 cells, respectively. On the contrary, applying 4-phenyl butyric acid (4-PBA) to alleviate ER stress or 4µ8c to specifically block the IRE1α pathway attenuated the impairment of both Pit-1 and GH expression. In conclusion, we demonstrated that lipotoxicity directly inhibits the synthesis of GH, probably by reducing Pit-1 expression. The IRE1α signaling pathway of ER stress may play an important role in this process., (© 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Salmonids have four subtypes of insulin-like growth factor binding protein (IGFBP)-1, termed -1a1, -1a2, -1b1 and 1b2, owing to teleost- and a lineage-specific whole-genome duplications. We have previously produced recombinant proteins of masu salmon IGFBP-1a1 and -1b2 and conducted functional analysis. To further characterize salmonid-specific IGFBP-1s, we cloned cDNAs encoding mature proteins of IGFBP-1a2 and -1b1 from the liver of masu salmon (Oncorhynchus masou). IGFBP-1a2 and -1b1 shared a 56% amino acid sequence homology whereas their homologies with their counterparts (i.e. -1a1 and -1b2) were 77% and 82%, respectively. We next expressed recombinant masu salmon (rs) IGFBP-1a2 and -1b1 with fusion partners thioredoxin (Trx) and a His-tag using the pET-32a(+) vector system in Escherichia coli. Trx.His.rsIGFBP-1s were detected in the insoluble faction, solubilized in a buffer containing urea, and isolated by Ni-affinity chromatography. They were refolded by dialysis and cleaved from the fusion partners by enterokinase. rsIGFBP-1a2 and -1b1 were purified by reversed-phase high performance liquid chromatography. Purified rsIGFBP-1a2 and -1b1 had the ability to bind digoxigenin-labeled human IGF-I on ligand blotting. We then examined the effects of rsIGFBP-1a1, -1a2, -1b1 and -1b2 in combination with human IGF-I on growth hormone (GH) release from cultured pituitary cells of masu salmon. IGF-I alone reduced GH release while the addition of rsIGFBP-1a1, -1b1 or -1b2, but not rsIGFBP-1a2, diminished the suppressive effect of IGF-I. Addition of rsIGFBP-1s without IGF-I had no effect on GH release. These results show that rsIGFBP-1b1, along with rsIGFBP-1a1 and -1b2, inhibits IGF-I action on the pituitary in masu salmon. The lack of the effect by rsIGFBP-1a2 suggests that salmon IGFBP-1 subtypes underwent subfunction partitioning and have different degrees of IGF-inhibitory action., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: Acromegaly is usually due to growth hormone (GH)-secreting pituitary adenomas, but it may be exceptionally caused by GH-secreting ectopic pituitary adenomas (EPA). EPA are defined as extra-sellar pituitary tumours, extra- or intra-cranially sited, entirely separated from the pituitary stalk and gland. The aim of the study is to address the challenges in the management of clival GHEPA., Methods: We reported a case of a 53-year-old acromegalic patient with a primary clival GHEPA and reviewed systematically the relevant English literature between 1975 and 2019, in keeping with the PRISMA guidelines., Results: Four cases of primary clival GHEPA have been described in literature apart from ours. All patients presented with acromegalic features, elevated circulating GH and/or insulin-like growth factor-1 levels. Hyperprolactinemia and empty sella were described in two cases, respectively. These tumours show the typical imaging characteristics of pituitary adenomas, but their neuroradiological diagnosis may be challenging due to their sizes and the difficulty in defining the absence of connections with the pituitary fossa., Conclusion: Although primary clival GHEPA are exceedingly rare, even if likely under-reported in literature, they should be considered in the differential diagnosis of clival tumours because of their specific management. Surgery represents the first-line treatment option, while medical and radiation therapies can be adopted as neo-adjuvant, adjuvant or primary treatments according to tumour and patient characteristics.

A homozygous mutation in growth hormone 1 ( GH1 ) was recently identified in an individual with growth failure. This mutation, c.705G>C, causes replacement of cysteine at position 53 of the 191-amino-acid sequence of 22 kDa human GH (hGH) with serine (p.C53S). This hGH molecule (hereafter referred to as GH-C53S) lacks the disulfide bond between p.Cys-53 and p.Cys-165, which is highly conserved among species. It has been reported previously that monomeric GH-C53S has reduced bioactivity compared with WT GH (GH-WT) because of its decreased ability to bind and activate the GH receptor in vitro In this study, we discovered that substitution of p.Cys-53 in hGH significantly increased formation of hGH dimers in pituitary cells. We expressed His-tagged hGH variants in the cytoplasm of genetically modified Rosetta-gami B DE3 Escherichia coli cells, facilitating high-yield production. We observed that the bioactivity of monomeric GH-C53S is 25.2% of that of GH-WT and that dimeric GH-C53S-His has no significant bioactivity in cell proliferation assays. We also found that the expression of GH-C53S in pituitary cells deviates from that of GH-WT. GH-C53S was exclusively stained in the Golgi apparatus, and no secretory granules formed for this variant, impairing its stimulated release. In summary, the unpaired Cys-165 in GH-C53S forms a disulfide bond linking two hGH molecules in pituitary cells. We conclude that the GH-C53S dimer is inactive and responsible for the growth failure in the affected individual., (© 2020 Sander et al.)

The surfacing of the glucose transporter GLUT4 driven by insulin receptor activation provides the prototypic example of a homeostasis response dependent on mobilization of an intracellular storage compartment. Here, we generalize this concept to a G protein-coupled receptor, somatostatin receptor subtype 2 (SSTR2), in pituitary cells. Following internalization in corticotropes, SSTR2 moves to a juxtanuclear syntaxin-6-positive compartment, where it remains until the corticotropes are stimulated with corticotropin releasing factor (CRF), whereupon SSTR2 exits the compartment on syntaxin-6-positive vesicular/tubular carriers that depend on Rab10 for their fusion with the plasma membrane. As SSTR2 activation antagonizes CRF-mediated hormone release, this storage/resurfacing mechanism may allow for a physiological homeostatic feedback system. In fact, we find that SSTR2 moves from an intracellular compartment to the cell surface in pituitary gland somatotropes, concomitant with increasing levels of serum growth hormone (GH) during natural GH cycles. Our data thus provide a mechanism by which signaling-mediated plasma membrane resurfacing of SSTR2 can fine-tune pituitary hormone release., (© 2019 McGill University.)

Background and purpose To demonstrate the clinical feasibility of a novel MRI pulse sequence, Golden-angle radial sparse parallel MRI (GRASP) through comparison to the current imaging technique, dynamic T1- weighted contrast enhanced (DCE) imaging in terms of image quality and lesion depiction in the detection of microlesions (microadenomas and cysts) of the pituitary gland., Materials and Methods: 16 patients (11 microadenomas, 5 cysts) underwent two MRI examinations (Siemens 1.5T and 3T) on separate dates, one using standard DCE (temporal resolution 30 s) and the other using GRASP (temporal resolution of 4.4 s). Two neuroradiologists separately recorded measures of image quality (Scale 1-5, 5 = best), lesion size and contrast arrival times in terms of first and best lesion conspicuity., Results: In qualitiative analysis there were no significant differences in terms of average visual image sharpness (DCE 3.9 ± 0.9, GRASP 3.9 ± 0.9) or visual contrast scores (DCE 4.1 ± 1.2, GRASP 4.4 ± 0.8). Pearson's correlation coefficients for interreader lesion measurements (width and height, mm) ranged from substantial to almost perfect agreement (r = 0.73 to 0.88). Analysis of contrast arrival times revealed an average lesion first-conspicuity time of 60.7 ± 16.7 s for DCE compared to 50.2 ± 10.3 s for GRASP with a difference of 10.5 ± 16.2 s (p = 0.023)., Conclusion: Depiction of pituitary microlesions is feasible with GRASP, which has the potential to increase sensitivity through higher temporal resolutions combined with isotropic acquisition allowing for multi-planar reconstructions; this remains to be proven in larger cohorts., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Intense immunoreactivity was observed in several neurons of the nucleus preopticus (NPO) located in the preoptic area (POA), in addition to several GH cells in the proximal pars distalis (PPD) of the pituitary gland of Clarias batrachus. The immunoreactive cells were located in the paraventricular as well as supraoptic subdivisions of the NPO. GH immunoreactive fibers projecting from the neurons were traced caudally to the pituitary gland via the conspicuous preoptico-hypophysial tract (PHT) in the ventral tuberal area to the neurohypophysis of the pituitary. Apart from these immunoreactive fibers in the preoptico-hypophysial tract, some fine caliber fiber probably arising from the neurons located dorsally in the NPO also showed GH immunoreactivity, and these fibers constituted an independent tract. Bilaterally, it extended caudally through the dorsal hypothalamus almost as far as the saccus vasculosus where it curved sharply to descend into the caudal tuberal region and finally entered into the pituitary gland. The fibers of this tract were mainly distributed in the rostral pars distalis (RPD). This tract is quite distinct from the preoptico-hypophysial tract and herein called as the accessory preoptico-hypophysial tract (APHT). Expression of GH mRNA in the NPO was found 65-fold more than that of the control region, rostral cerebellum. These results altogether suggest that GH secreted by NPO neurons might serve as a neuro-modulatory role in the brain of C. batrachus. Transportation of GH to the pituitary via two independent tracts may represent the duality of neuroendocrine function. The present study underscores the possibility that GH in the brain of vertebrates may be a phylogenetically conserved phenomenon and provide clues to our understanding of the evolutionary course taken by the hormone.

Purpose: After traumatic brain injury was accepted as an important etiologic factor of pituitary dysfunction (PD), awareness of risk of developing PD following sports-related traumatic brain injury (SR-TBI) has also increased. However there are not many studies investigating PD following SR-TBIs yet. We aimed to summarize the data reported so far and to discuss screening algorithms and treatment strategies., Methods: Recent data on pituitary dysfunction after SR-TBIs is reviewed on basis of diagnosis, clinical perspectives, therapy, screening and possible prevention strategies., Results: Pituitary dysfunction is reported to occur in a range of 15-46.6% following SR-TBIs depending on the study design. Growth hormone is the most commonly reported pituitary hormone deficiency in athletes. Pituitary hormone deficiencies may occur during acute phase after head trauma, may improve with time or new deficiencies may develop during follow-up. Central adrenal insufficiency is the only and most critical impairment that requires urgent detection and replacement during acute phase. Decision on replacement of growth hormone and gonadal deficiencies should be individualized. Moreover these two hormones are abused by many athletes and a therapeutic use exemption from the league's drug policy may be required., Conclusions: Even mild and forgotten SR-TBIs may cause PD that may have distressing consequences in some cases if remain undiagnosed. More studies are needed to elucidate epidemiology and pathophysiology of PD after SR-TBIs. Also studies to establish screening algorithms for PD as well as strategies for prevention of SR-TBIs are urgently required.

Thyrotropin (TSH)-secreting pituitary tumors are the rarest functioning pituitary tumors. Nonetheless, they are not infrequently plurihormonal, as they may express/secrete hormones made by other pituitary cells derived from the Pit-1 lineage such as growth hormone (GH), prolactin (PRL), and α-subunit (αSU). However, adrenocorticotropin (ACTH) or gonadotropin secretion by such a tumor is exceptional. Although double pituitary tumors are rare, they often combine ACTH and GH secretion. A 41-year-old presented almost 2 years after delivering her 10th child; she had thyrotoxicosis (goiter and palpitations) masquerading as autoimmune postpartum thyroiditis. She was still breastfeeding and amenorrheic. She proved to have TSH, GH, PRL, and ACTH hypersecretion. Imaging revealed an invasive pituitary macrotumor. She had stigmata neither of Cushing's disease nor of acromegaly. Prior to surgery, hormonal control was achieved for close to 1 year by combined octreotide and cabergoline treatment with significant shrinking of the tumor. Following surgery, pathology revealed a collision tumor; the dominant lesion was positive for GH, βTSH, βFSH, and αSU and expressed both Pit-1 and SF-1.The smaller lesion was a corticotroph tumor. We report an unusual plurihormonal tumor co-expressing Pit-1 and SF-1 along with hormones made by cells of both lineages. Its simultaneous occurrence adjacent to a corticotroph tumor raises questions regarding the pathogenesis of these tumors. We propose the possibility of a stem cell tumor with multiple lineage differentiation. We hypothesize that pregnancy might have played a permissive role in tumorigenesis.

Context: A somatostatin-dopamine chimera (BIM23B065) was under investigation to reduce GH secretion for the treatment of pituitary adenomas., Objective: To determine pharmacokinetics, safety, and tolerability and to monitor hormonal changes after single and multiple subcutaneous BIM23B065 administrations., Design: Randomized, double-blind, placebo-controlled, parallel-group design with five single and three 13-day multiple ascending-dose cohorts., Patients: A total of 63 healthy male white volunteers were enrolled (47 active, 16 placebo)., Main Outcome Measures: Pharmacokinetics, GH, prolactin (PRL), IGF-1, GH after GHRH administration, and general clinical safety criteria., Results: The maximum dosage of BIM23B065 administered in this study was 1.5 mg. BIM23B065 reduced the mean GH concentrations after 8 and 13 days of treatment. A decrease in GH release after GHRH administration indicated inhibition of the hypothalamic-pituitary-somatotropic axis. IGF-1 was not altered after single doses but showed a significant change from baseline after multiple dosing. PRL secretion was reduced in all subjects who were treated. Orthostatic hypotension and injection site reactions were commonly observed at high dosages. A 6-day uptitration period was included to successfully lower the cardiovascular effects in the multiple ascending dose part of the study., Conclusions: Proof of pharmacology of BIM23B065 was shown by a reduction in GH, IGF-1, and PRL concentrations in healthy male volunteers, supporting activity of the somatostatin analog and dopamine agonist moieties. The safety and tolerability of the higher dosing regions was limited mainly by orthostatic hypotension.

Primary empty sella (PES) is characterized by the herniation of the subarachnoid space within the sella, which is often associated with variable degrees of flattening of the pituitary gland in patients without previous pituitary pathologies. PES pathogenetic mechanisms are not well known but seem to be due to a sellar diaphragm incompetence, associated to the occurrence of upper sellar or pituitary factors, as intracranial hypertension and change of pituitary volume. As PES represents in a majority of cases, a neuroradiological findings without any clinical implication, the occurrence of endocrine, neurological and opthalmological symptoms, due to the above describes anatomical alteration, which delineates from the so called PES syndrome. Headache, irregular menses, overweight/obesity and visual disturbances compose the typical picture of PES syndrome and can be the manifestation of an intracranial hypertension, often associated with PES. Although hyperprolactinemia and growth hormone deficit represent the most common endocrine abnormalities, PES syndrome is characterized by heterogeneity both in clinical manifestation and hormonal alterations and can sometime reach severe extremes, as occurrence of papilledema, cerebrospinal fluid rhinorrhea and worsening of visual acuity. Consequently, a multidisciplinary approach, with the integration of endocrine, neurologic and ophthalmologic expertise, is strongly advocated and recommended for a properly diagnosis, management, treatment and follow-up of PES syndrome and all of the related abnormalities., (© 2017 European Society of Endocrinology.)

BackgroundIn the neonatal period, the pituitary hormones including prolactin (PRL) and human growth hormone (hGH) are secreted in high amounts due to immature feedback mechanisms. As both hormones are secreted in part by the same somatomammotrophic cells, we investigated their relationship in newborns with respect to sex, gestational week, method of delivery, and anthropometric data.MethodsThe serum levels of PRL and hGH were measured in blood drawn from 225 newborns. The newborn data were extracted from medical records.ResultsA positive correlation was found between log-transformations of PRL and hGH (r=0.17; P=0.01; n=225), with a stronger correlation in newborns whose blood samples were taken more than 2 days after birth (r=0.42; P<0.001; n=130). Log-transformations of the PRL/hGH ratio demonstrated a positive correlation with the gestational week (r=0.39; P<0.001; n=200). Multiple regression analysis showed that 15% of the variance in the logarithm of this ratio is attributed to the gestational week.ConclusionIn newborns, serum PRL and hGH levels show a positive correlation that can be explained by common regulatory factors or a drift phenomenon. A higher gestational week is associated with a higher PRL/hGH ratio. Further studies are needed to look for possible confounders and to determine the PRL-hGH relationship in different conditions.

Biochemical growth hormone deficiency is prevalent among human immunodeficiency virus-infected patients, but if this condition is clinically relevant remains challenging. The aim is to prospectively compare the growth hormone deficiency/insulin-like growth factor-1 status of 71 human immunodeficiency virus-infected patients with impaired growth hormone response to growth hormone releasing hormone + Arginine with that of 65 hypopituitary patients affected by a true growth hormone deficiency secondary to pituitary disease. The main outcomes were: basal serum growth hormone, insulin-like growth factor-1, insulin-like growth factor binding protein 3, growth hormone peak and area under the curve after growth hormone response to growth hormone releasing hormone + Arginine test, body mass index, waist and hip circumference, and body composition by dual energy X-ray absorptiometry. Insulin-like growth factor-1 binding protein 3, basal growth hormone (p < 0.005), growth hormone peak and area under the curve after growth hormone response to growth hormone releasing hormone + Arginine, waist to hip ratio, insulin-like growth factor-1, fasting glucose, insulin, and triglycerides (p < 0.0001) were lower in hypopituitary than human immunodeficiency virus-infected patients. Total and trunk fat mass by dual energy X-ray absorptiometry were higher in hypopituitary than in human immunodeficiency virus-infected patients (p < 0.0001). In all the patients total body fat was associated with both growth hormone peak and area under the curve at stepwise linear regression analysis. The degree of growth hormone deficiency is more severe in hypopituitary than in human immunodeficiency virus-infected patients, suggesting that the function of growth hormone/insulin-like growth factor-1 axis is partially rescued in the latter thanks to a preserved pituitary secretory reserve. Data from the current study suggest that human immunodeficiency virus-infected patients with peak growth hormone < 9 mg/L may have partial growth hormone deficiency and clinicians should be cautious before prescribing recombinant human growth hormone replacement treatment to patients living with human immunodeficiency virus.

Objective: To evaluate the therapeutic trends and long-term outcome of treatment modalities for acromegaly in our center over a 40-year period., Design: We retrospectively studied 321 acromegalic patients (145 males/176 females) diagnosed and treated from the 1970s until September 2013. Patients were divided into two subgroups: group A consisted of 166 patients diagnosed before 1990 and group B of 155 patients diagnosed after 1990. Outcome was assessed with GH (random and/or post OGTT) and IGF1 measurements., Results: More group A than group B patients were submitted to radiotherapy (57.8% vs 16.8% patients, respectively, p <0.001). In contrast, more patients of group B were offered surgery (70.3% vs 42.1% in group A, p <0.001) and/or medical treatment (70.3% vs 23.4% in group A, p <0.001). At latest follow-up, 68.4 % of patients in group B achieved GH <2.5 μg/l after treatment vs 39.8% in group A, p=0.001, 46.9% of patients in group B achieved GH <1 μg/l vs 20.3% in group A, p=0.001 and 47.1% of patients in group B achieved during OGTT GH nadir <0.4 μg/l vs 18.6% in group A, p=0.001., Conclusions: Transsphenoidal resection and medical treatment resulted in improved outcome in acromegalic patients treated over the last 20 years. However, the disease still remains uncontrolled in a considerable number of patients.

Amyloids are cross-β-sheet fibrillar aggregates, associated with various human diseases and native functions such as protein/peptide hormone storage inside secretory granules of neuroendocrine cells. In the current study, using amyloid detecting agents, we show that growth hormone (GH) could be stored as amyloid in the pituitary of rat. Moreover, to demonstrate the formation of GH amyloid in vitro, we studied various conditions (solvents, glycosaminoglycans, salts and metal ions) and found that in presence of zinc metal ions (Zn(II)), GH formed short curvy fibrils. The amyloidogenic nature of these fibrils was examined by Thioflavin T binding, Congo Red binding, transmission electron microscopy and X-ray diffraction. Our biophysical studies also suggest that Zn(II) initiates the early oligomerization of GH that eventually facilitates the fibrillation process. Furthermore, using immunofluorescence study of pituitary tissue, we show that GH in pituitary significantly co-localizes with Zn(II), suggesting the probable role of zinc in GH aggregation within secretory granules. We also found that GH amyloid formed in vitro is capable of releasing monomers. The study will help to understand the possible mechanism of GH storage, its regulation and monomer release from the somatotrophs of anterior pituitary.

Pierre Marie coined the term 'acromegaly' in 1886 and linked it to a distinct clinical disease with a characteristic clinical picture. However, Pierre Marie was not the first physician to give a full record of the clinical picture of acromegaly; others had preceded him, like the Dutch physician Johannes Wier. After Marie, pituitary enlargement was noted in almost all patients with acromegaly. Subsequently it was discovered that pituitary hyperfunction caused by a pituitary tumour was indeed the cause of acromegaly. The cause of acromegaly could be further determined after the discovery of growth hormone (GH) and insulin-like growth factor I (IGF-I) and after demonstrating an association with GH hypersecretion and elevated circulating IGF-I. From the beginning of the 20th century, acromegaly could be treated by pituitary surgery and/or radiotherapy. After 1970, medical therapies were introduced that could control acromegaly. First, dopamine agonists were introduced, followed by somatostatin analogues and GH receptor blockers., (© 2015 S. Karger AG, Basel.)

The hypersecretion of pituitary growth hormone (GH) is associated with an increased risk of cancer, while reducing pituitary GH signaling reduces this risk. Roles for pituitary GH in cancer are therefore well established. The expression of the GH gene is, however, not confined to the pituitary gland and it is now known to occur in many extrapituitary tissues, in which it has local autocrine or paracrine actions, rather than endocrine function. It is, for instance, expressed in cancers of the prostate, lung, skin, endometrium and colon. The oncogenicity of autocrine GH may also be greater than that induced by endocrine or exogenous GH, as higher concentrations of GHR antagonists are required to inhibit its actions. This may reflect the fact that autocrine GH is thought to act at intracellular receptors directly after synthesis, in compartments not readily accessible to endocrine (or exogenous) GH. The roles and actions of extrapituitary GH in cancer may therefore differ from those of pituitary GH. The possibility that GH may be expressed and act in glioma tumors was therefore examined by immunohistochemistry. These results demonstrate, for the first time, the presence of abundant GH- and GH receptor (GHR-) immunoreactivity in glioma, in which they were co-localized in cytoplasmic but not nuclear compartments. These results demonstrate that glioma differs from most cancers in lacking nuclear GHRs, but GH is nevertheless likely to have autocrine or paracrine actions in the induction and progression of glioma., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The aim of this study is to evaluate aromatase expression in prolactin (PRL), thyroid stimulating hormone (TSH), and growth hormone (GH) secreting cells. Nontumoral human pituitary specimens were obtained from autopsy samples. Aromatase co-expression was determined by double immunohistochemical staining and assessed using H scores. H scores for GH-aromatase co-expression (GH-aromatase), TSH-aromatase co-expression (TSH-aromatase), and PRL-aromatase co-expression (PRL-aromatase) were 83.1 ± 13.1, 95.6 ± 16.1, and 83.7 ± 14.5, respectively. TSH producing cells exhibited the highest H score for co-expression of aromatase (p < 0.001). There was no gender difference in terms of H scores for aromatase expression and double immunohistochemical staining results (p > 0.05 for all). There was a negative correlation between the H scores for aromatase and PRL-aromatase, GH-aromatase and TSH-aromatase, respectively (r = -0.592, p < 0.001; r = -0.593, p < 0.001; r = -0.650, p < 0.001, respectively). Also, H scores for aromatase co-expression of each hormone were negatively correlated with the H scores for the corresponding hormone (r = -0.503, p < 0.001 for PRL-aromatase and PRL; r = -0.470, p < 0.001 for GH-aromatase, and GH; r = -0.641, p < 0.001 for TSH-aromatase and TSH). H scores for mean aromatase, GH-aromatase, TSH-aromatase were invariant of age (p > 0.05 for all). Age was negatively correlated with PRL-aromatase H score (r = -0.373, p = 0.008). Our study demonstrated significant aromatase co-expression in PRL, GH, and TSH secreting cells of the human anterior pituitary gland. The mutual paracrinal regulation between aromatase and three adenohypophyseal hormones indicates that aromatase may have a regulatory role on the synthesis and secretion of these hormones.

Context: TNF-α generates inflammatory responses and insulin resistance, lipolysis, and protein breakdown. It is unclear whether these changes depend on intact hypothalamo-pituitary stress hormone responses to trigger the release of cortisol and growth hormone., Objective: To define differential effects of TNF-α on glucose, protein, and lipid metabolism in hypopituitary patients (without intact hypothalamo-pituitary axis) and healthy controls., Design: Randomized, placebo controlled, single-blinded. Setting, Participants, and Intervention: We studied eight hypopituitary (HP) patients and eight matched control subjects [control volunteers (CTR)] twice during 4-h basal and 2-h hyperinsulinemic clamp conditions with isotope dilution during infusion of saline or TNF-α(12 ng/kg/h) for 6 h., Main Outcome Measures: Phenylalanine, urea, palmitate, and glucose fluxes and fat biopsies in basal and clamp periods., Results: TNF-α infusion significantly increased cortisol and GH levels in CTR but not in HP. TNF-α increased phenylalanine fluxes in both groups, with the increase being significantly greater in CTR, and raised urea flux by 40 % in CTR without any alteration in HP. Endogenous glucose production (EGP) was elevated in CTR compared to HP after TNF-α administration, whereas insulin sensitivity remained similarly unaffected in both groups. TNF-α increased whole body palmitate fluxes and decreased palmitate specific activity in CTR, but not in HP without statistical difference between groups. We did not detect significant effects TNF-α on lipase expression or regulation in fat., Conclusions: TNF-α increased both urea and amino acid fluxes and EGP significantly more in CTR compared to HP, suggesting that increases in endogenous cortisol and GH release are significant components of the metabolic response to TNF-α.

Objectives: Most of the retrospective studies have demonstrated that traumatic brain injury mediated hypopituitarism could be more frequent than previously known. Therefore, this study has prospectively investigated pituitary function and their correlation with severity, pressure effect and Glasgow Outcome Scale in the acute phase of moderate-to-severe traumatic brain injury., Patients and Methods: One hundred consecutive moderate-to-severe traumatic brain injury patients from August 2012 to November 2013 formed the study group. Apart from clinical assessment, non-contrast computed tomography of the head was performed on all patients on admission. The hormonal analysis (fT3, fT4, TSH, GH, Cortisol, Prolactin) was performed within 24 hours of traumatic brain injury and was repeated on the 7th day amongst the patients who survived., Results: Growth hormone was the most common hormone to decrease. Cortisol was the most common hormone to increase. Risk of pituitary insufficiency was increased in patients with severe traumatic brain injury, patients with increased intracranial pressure and who had low Glasgow Outcome Scale., Conclusion: Neuroendocrine dysfunction occurs often in the acute phase of moderate-to-severe traumatic brain injury, more commonly in patients with severe traumatic brain injury, patients with pressure effects and low Glasgow Outcome Scale. Hormonal analysis should be considered in patients with moderate-to-severe traumatic brain injury, so that appropriate hormonal replacement can be done to optimize the clinical outcome.

Objective: The quantitative and qualitative aspects of the pituitary response in children and adults with Prader-Willi syndrome (PWS) are compared in order to verify the possible age-dependent and genotype-related differences in terms of GH secretion., Design: 29 young subjects (21 males and 8 females) and 65 adults (24 males and 41 females) with PWS were studied. All subjects underwent a standard GH Releasing Hormone (GHRH 1-29, 1 μg/kg as i.v. bolus at 0 minutes)+arginine (0.5 g/kg) test. Peak GH values, standard GH area under the curve (AUC), AUC of the instantaneous secretion rate (ISR), and secretion response analysis (i.e. half-secretion time) were evaluated. A regression analysis was performed to investigate which are the patient characteristics that affect the amplitude and shape of the GH secretion response., Results: Peak GH values and AUCGH were significantly higher in PWS children than in PWS adults, these differences being also significant both in PWS DEL15 (only peak GH value) and PWS UPD15. Moreover, PWS children showed significantly lower half secretion time than PWS adults, this delayed response being present both in PWS DEL15 and PWS UPD15. Significant negative correlations between AUCGH and BMISDS were observed in the two groups (adults and children), as well as in adults and children DEL15, but not in adults and children PWS UPD15. A regression analysis performed on the whole dataset showed that for PWS DEL15 the statistically significant variable explaining GH responsiveness was BMISDS (p<0.0001), while for UPD15 no statistically significant covariate was found. Conversely, when the delay of the secretion response was considered, the regression model yielding the best performances was the one with only age as a regressor (p<0.001)., Conclusions: The quantitative and qualitative analyses of GH responsiveness to GHRH+arginine highlight relevant differences between PWS children and PWS adults and genotype-related traits. The negative influence of BMISDS on GH secretion reinforces the need for an early start of life-long weight management in PWS subjects., (© 2013.)

Context: Targeted secretion inhibitors (TSIs), a new class of recombinant biotherapeutic proteins engineered from botulinum toxin, represent a novel approach for treating diseases with excess secretion. They inhibit hormone secretion from targeted cell types through cleavage of SNARE (soluble N-ethylmaleimide-sensitive factor-activating protein receptor) proteins. qGHRH-LH(N)/D is a TSI targeting pituitary somatotroph through binding to the GHRH-receptor and cleavage of the vesicle-associated membrane protein (VAMP) family of SNARE proteins., Objective: Our objective was to study SNARE protein expression in pituitary adenomas and to inhibit GH secretion from somatotropinomas using qGHRH-LH(N)/D., Design: We analyzed human pituitary adenoma analysis for SNARE expression and response to qGHRH-LH(N)/D treatment., Setting: The study was conducted in University Hospitals., Patients: We used pituitary adenoma samples from 25 acromegaly and 47 nonfunctioning pituitary adenoma patients., Outcome: Vesicle-SNARE (VAMP1-3), target-SNARE (syntaxin1, SNAP-23, and SNAP-25), and GHRH-receptor detection with RT-qPCR, immunocytochemistry, and immunoblotting. Assessment of TSI catalytic activity on VAMPs and release of GH from adenoma cells., Results: SNARE proteins were variably expressed in pituitary samples. In vitro evidence using recombinant GFP-VAMP2&3 or pituitary adenoma lysates suggested sufficient catalytic activity of qGHRH-LH(N)/D to degrade VAMPs, but was unable to inhibit GH secretion in somatotropinoma cell cultures., Conclusions: SNARE proteins are present in human pituitary somatotroph adenomas that can be targeted by TSIs to inhibit GH secretion. qGHRH-LH(N)/D was unable to inhibit GH secretion from human somatotroph adenoma cells. Further studies are required to understand how the SNARE proteins drive GH secretion in human somatotrophs to allow the development of novel TSIs with a potential therapeutic benefit.

Introduction: Acromegaly is frequently associated with impaired glucose tolerance and/or diabetes. To evaluate the relationship between glucose metabolism and acromegaly disease, we evaluated 269 consecutive patients from two referral centres., Methods: Clinical presentation, pituitary tumor size and invasiveness, and pituitary pathology were captured in a dedicated database., Results: 131 women and 138 men with a mean age of 53.8 years were included. Of these, 201 (74.7%) presented with a macroadenoma and 18 (6.7%) with a microadenoma. Radiographic invasion was present in 91 cases (33.8%). Mean tumor diameter was 1.86 cm (0.2-4.6). Pituitary histopathologic findings revealed pure GH-producing somatotroph adenomas (SA) in 147 patients, prolactin-production by mixed lactotroph (LA) and SA or mammosomatotroph adenoma (MSA) in 46 [22.4%], acidophil stem cell adenoma in 6 [2.9%], and other diagnoses in 6 [2.9%]. Medical treatment included octreotide in 96 [36.9%] and in combination with pegvisomant or dopamine agonists in 63 [24.2%]. Nearly 80% of patients achieved IGF-1 normalization. Importantly, patients with pure somatotroph adenomas were significantly more likely to present with abnormal glucose metabolism [48.7%] than those with mixed adenomas [9.7%] [p<0.001] independent of GH/IGF-1 levels or tumor invasiveness. Abnormal glucose metabolism and pituitary pathology also remained linked following IGF-1 normalization. Moreover patients with pure SA and abnormal glucose metabolism were significantly (p<0.001) less likely to achieve disease remission despite the same therapeutic strategies. Conversely, patients with mixed adenomas were more likely (OR: 2.766 (95% CI: 1.490-5.136) to achieve disease remission., Conclusions: Patients with pure somatotroph adenomas are more likely than those with mixed adenomas to exhibit abnormal glucose metabolism.

Objective: The assessment of GH deficiency in adult patients with Prader-Willi syndrome (PWS) has been previously assessed through the evaluation of quantitative parameters, such as the peak value of GH response to exogenous stimuli. A comprehensive description of the pattern of secretory response obtainable by deconvolution analysis is still lacking. The aim of our study was to characterize the time evolution of responses of PWS subjects compared with obese controls., Design and Subjects: GH responsiveness was measured following the combined administration of GHRH+arginine to 65 PWS adults (24 males, 41 females) aged 18-41·2 years, and 17 age-, gender- and body mass index-matched obese controls. PWS subjects were analysed considering the stratification on different genotypes., Measurements: GH response to GHRH+arginine was analysed in terms of peak values, standard area under the curves (AUCs), AUCs due to the stimulus, AUCs of the Instantaneous Secretion Rate signal and Secretion Response Analysis., Results: In terms of both peak values and AUC, GH responses were statistically different between PWS UPD15 and PWS DEL15 subjects as well as between PWS UPD15 and obese controls. PWS subjects showed a lower and a more delayed GH response compared with obese controls. Moreover, PWS UPD15 subjects had the most delayed GH response., Conclusions: Our findings demonstrate that impaired GH secretion in PWS subjects compared with obese controls regards not only amplitude parameters such as peak value and AUC, but also the shape of the secretory response, which is more delayed, especially for UPD15 subjects., (© 2013 John Wiley & Sons Ltd.)

The pituitary gland has a role in puberty, reproduction, stress-adaptive responses, sodium and water balance, uterine contractions, lactation, thyroid function, growth, body composition and skin pigmentation. Ageing is marked by initially subtle erosion of physiological signalling mechanisms, resulting in lower incremental secretory-burst amplitude, more disorderly patterns of pituitary hormone release and blunted 24 h rhythmic secretion. Almost all pituitary hormones are altered by ageing in humans, often in a manner dependent on sex, body composition, stress, comorbidity, intercurrent illness, medication use, physical frailty, caloric intake, immune status, level of exercise, and neurocognitive decline. The aim of this article is to critically discuss the mechanisms mediating clinical facets of changes in the hypothalamic-pituitary axis during ageing, and the extent to which confounding factors operate to obscure ageing-related effects.

Subarachnoid haemorrhage (SAH) is known to be related to pituitary dysfuntion in retrospective and short-term prospective studies. We aimed to investigate pituitary functions in patients with SAH in longer follow-up periods to demonstrate if pituitary hormone deficiencies recover, persist or new hormone deficiencies occur. Twenty patients with SAH, who were followed up for 3 years, were included in the present study. Patients were evaluated with basal hormone levels and glucagon stimulation test (GST).Serum basal cortisol and adrenocorticotropic hormone (ACTH) levels were found to be significantly elevated at 3rd year of SAH compared to 1st year. Other basal hormone levels at 3rd year did not show a significant change from the levels found at 1st year. One of the patients had ACTH deficiency at 1st year of SAH and recovered at 3rd year. Growth hormone (GH) deficiency, according to GST,was diagnosed in 4 patients. One patient with GH deficiency at first year was still deficient, 3 of them recovered and 3 patients were found to have new-onset GH deficiency 3 years after SAH. SAH is associated with anterior pituitary dysfunction and GH is the most frequently found deficient hormone in the patients. Although one year after SAH seems to be an appropriate time for the evaluation of pituitary functions, further follow-up may be required at least in some cases due to recovered and new-onset hormone deficiencies at 3rd year of SAH.

Background: A typical peak timing in the glucagon stimulation test has been reported as an indication of growth hormone (GH) deficiency. Other stimulation tests have not been evaluated., Objective: To evaluate the clinical usefulness of peak timing in the arginine stimulation test (AST) for growth hormone deficiency., Methods: Retrospective review of 199 ASTs from one center. Outcomes included correlation of peak times with (a) frequency of deficient peak; (b) growth velocity standard deviation scores (GVSDSs); (c) other evidence of pituitary pathology; (d) results of confirmatory clonidine test; and (e) response to GH treatment., Results: The peak in 83/109 (76.14%) sufficient tests occurred at typical times vs. 45/72 (62.5%) deficient tests (p<0.05). GVSDS on GH treatment was greater among patients with typical timing in the AST compared with atypical timing (2.67 ± 0.59 vs. 0.46 ± 1.17, p=0.021). No other variable correlated significantly with AST timing., Conclusions: Timing of peak in the AST is not a clinically useful parameter.

Growth hormone (GH) producing adenomas of the pituitary gland are usually macroadenomas (>10 mm in size). Often these adenomas are locally invasive by the time of diagnosis. Acromegaly secondary to a very small pituitary microadenoma not visualized on pituitary magnetic resonance (MR) imaging is rare. We report a patient with acromegaly and an unremarkable pituitary MR imaging who had negative work up for ectopic growth hormone-releasing hormone (GHRH) or GH secreting tumors. Transsphenoidal pituitary exploration revealed a pituitary adenoma located on the left side of the sella against the medial wall of the cavernous sinus extending posteriorly along the floor of the sella all the way to the right side. The acromegaly was treated with resection of the pituitary adenoma and normalization of serum insulin-like growth factor 1 (IGF-1) and GH levels. In a patient with acromegaly and unremarkable pituitary MR imaging, with no evidence of ectopic GH and GHRH production, transsphenoidal pituitary exploration is a reasonable approach and may result in clinical improvement and biochemical cure in the hand of experienced surgeon. This approach may avoid long term medical treatment with its associated cost.

Growth hormone (GH) is regulated by pituitary and hypothalamic factors as well as peripheral endocrine factors including glucocorticoids and thyroid hormone. Studies on human GH are limited largely to the assessment of plasma levels in endocrine disorders. Thus, insight into the regulation of synthesis versus secretion has come mainly from studies done on non-human GH and/or pituitary tumor cells. However, primate and non-primate GH gene loci have differences in their structure and, by extension, regulation. We generated transgenic (171hGH/CS-TG) mice containing the intact hGH1 gene and locus control region, including sequences required for integration-independent and preferential pituitary expression. Here, we show hGH co-localizes with mouse (m) GH in somatotrophs in situ and in primary pituitary cells. Dexamethasone treatment increased hGH and mGH, as well as GH releasing hormone (GHRH) receptor RNA levels, and hGH release was stimulated by GHRH treatment. By contrast, triiodothyronine decreased or had no effect on hGH and mGH production, respectively, and the negative effect on hGH was also seen in the presence of dexamethasone. Thus, 171hGH/CS-TG mouse pituitary cultures represent a model system to investigate hormonal control of hGH synthesis and secretion., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Background: In adults with Prader-Willi syndrome (PWS), limited information is available about pituitary function, more specifically the prevalence of growth hormone deficiency (GHD). The aim of this study was to gain more insight into endocrine function in PWS adults, with emphasis on GH secretion., Methods: 15 randomly selected adult PWS individuals were included and 14 healthy brothers and sisters served as a control group. Main outcome measures were IGF-I, IGFBP-3 and peak GH level after a combined GHRH-arginine test. Other pituitary hormone deficits are diagnosed based on serum levels of the concerning hormones. The size of the pituitary gland was measured on MRI images., Results: In PWS adults, IGF-I levels were low and IGFBP-3 levels normal when compared to healthy controls. GHD was diagnosed in 8-38% of the PWS patients, depending on the criteria used. Hypogonadism was present in 87% of the patients. Hypothyroidism and adrenal insufficiency could also be demonstrated. Anterior pituitary size was lower in PWS individuals when compared to healthy controls., Conclusion: In this study, pituitary hormone deficiencies are demonstrated in a considerable number of adults with PWS, hypogonadism and GHD being most prominent. Furthermore, the anterior pituitary is smaller in comparison with healthy controls., (Copyright © 2011 S. Karger AG, Basel.)

Background: Children who sustain traumatic brain injury (TBI) are at risk for developing hypopituitarism, of which growth hormone deficiency (GHD) is the most common manifestation., Objective: To determine the prevalence of GHD and associated features following TBI among children and adolescents., Study Design: A total of 32 children and adolescents were recruited from a pediatric TBI clinic. Participants were diagnosed with GHD based on insufficient growth hormone release during both spontaneous overnight testing and following arginine/glucagon administration., Results: GHD was diagnosed in 5/32 participants (16%). Those with GHD exhibited more rapid weight gain following injury than those without GHD and had lower levels of free thyroxine and follicle-stimulating hormone. Males with GHD had lower testosterone levels., Conclusions: GHD following TBI is common in children and adolescents, underscoring the importance of assessing for GHD, including evaluating height and weight velocities after TBI. Children and adolescents with GHD may further exhibit absence or intermediate function for other pituitary hormones.

Traumatic brain injury (TBI) is an important public health problem all over the world. The level of consciousness of the patients and the severity of the brain injury is commonly evaluated by the Glascow Coma Scale as mild, moderate and severe TBI. When we consider the high frequency of mild TBI (MTBI) among the all TBI patients the burden of the pituitary dysfunction problem in this group could not be ignored. However, one of the most important and still unresolved questions is which patients with MTBI should be screened for hypopituitarism? Another type of head trauma which could be considered as the subgroup of MTBI is sports related chronic repetitive head trauma. Therefore, in this review we will discuss the frequency, characteristics and current management of pituitary dysfunction in patients with MTBI including the subjects exposed to sports related chronic mild head trauma.

In teleosts, growth hormone (GH) production is governed by multiple neuroendocrine factors from the hypothalamus and other regulators from the pituitary and peripheral organs. Exploring the principles followed by pituitary somatotropes when differentiating and integrating the signals from these regulators at the cellular and intracellular level is essential for understanding the endocrine regulation network of growth hormone synthesis and secretion in fish. This paper discusses recent advances in the action mechanisms of GH regulation factors, including the neuroendocrine regulators, pituitary level factors and peripheral factors, primarily involved in their receptor systems as well as in post-receptor signal transduction pathways.

Growth hormone releasing hormone (GHRH) is one of the hypothalamus hormones. For its potential applications in agriculture and medicine, GHRH analog with higher activity and longer half-life has been looked for. By using the fusion expression with unique acid labile linker Asp-Pro and biochemical purification, the three novel GHRH peptides, Pro-Pro-hGHRH(1-44)-Gly-Gly-Cys, Pro-hGHRH(1-44)-Gly-Gly-Cys, and (1)Pro-GHRH(2-44)-Gly-Gly-Cys, were obtained. The peptide molecular weight with 5,455, 5,373 or 5,210 Da measured by EIS-MS is coincident with the actual values. The peptides at 0.1-10 microg/ml increased rat pituitary GH releases in a dose-dependent manner and at 5 microg/ml increased human pituitary GH releases. The activity comparisons showed that at 10 microg/ml there were significant between (1)Pro-hGHRH(2-44)-Gly-Gly-Cys and Pro-Pro-hGHRH(1-44)-Gly-Gly-Cys or Pro-hGHRH(1-44)-Gly-Gly-Cys, (1)Pro-hGHRH(2-44) (P<0.05). The (1)Pro-hGHRH(2-44)-Gly-Gly-Cys showed the highest GH release from rat pituitary. The activity results showed that the N-terminal Pro modulations and the C-terminal Gly-Gly-Cys extension regulate GH release from pituitary. The results showed that the three peptides had good GH release, function-selectivity and species specificity.

Background: To explore the relationship between magnetic resonance imaging (MRI) findings and multiple pituitary-target hormones in patients with panhypopituitarism or multiple pituitary hormone deficiency (MPHD)., Methods: 125 patients with MPHD (102 boys, MPHD group) and 90 age-, sex- and Tanner stage-matched normal children (control group) were enrolled. 96 of the patients with MPHD underwent MRI scans of the hypothalamic-pituitary area. The patients were subdivided into five stages according to their MRI findings. The serum concentrations of GH, IGF-1, FT(4), TSH, ACTH, cortisol, FSH, LH, prolactin, testosterone and estradiol were measured in patients and in controls., Results: MRI stage was significantly positively correlated with the number of pituitary hormone deficiencies (r = 0.9, p < 0.001). MRI stage was negatively correlated with peak GH, IGF-1, FT(4), cortisol and anterior pituitary height (r = -0.43, -0.47, -0.67, -0.54, and -0.49, respectively, p < 0.01). Diabetes insipidus patients could be stratified according to their MRI stage; diabetes insipidus was found mainly in patients with absence of the posterior pituitary bright spot or small ectopic posterior pituitary bright spot on MRI., Conclusion: An abnormal MRI finding is evidence of MPHD and, correspondingly, there is a noteworthy correlation between MRI and pituitary function., (Copyright 2010 S. Karger AG, Basel.)

Introduction: Irradiation of brain tumors (BT) in children can lead to the loss of pituitary function, predominantly manifesting as deficiencies in GH and ACTH., Objective: To assess the incidence and nature of pituitary deficiency in relation to initial tumor location in children after radiotherapy of BT., Methods: Twenty survivors (16 males and 4 females) of radiation-treated BT aged 1.4-10.9 (median 3.6) yr at diagnosis were studied, 10 with supratentorial and 10 with infratentorial BT. Radiation doses to the hypothalamus- pituitary (HP) area ranged from 30 to 54 (median 45) Gray. Follow-up was 9.4-16.9 (median 12.2) yr. Basal pituitary hormone levels were measured every 6 months. When growth failure became evident or pituitary deficiency was suspected, provocation tests of the HP axis were performed to assess GH, ACTH, and TSH function., Results: GH deficiency (GHD) developed in 17/20 (85%) children. In 10 patients, it occurred 4 yr after radiotherapy and in 2, 11 and 12 yr after radiotherapy. Six (30%) patients developed secondary hypothyroidism and 4 (20%) developed ACTH deficiency. Precocious puberty occurred in 2 girls. The course of development and the severity of hormone deficiencies were similar for supratentorial and infratentorial tumors., Conclusion: The major hormonal effect of BT irradiation in children is GHD, which may sometimes take more than 10 yr to manifest. We confirm findings by others that ACTH insufficiency occurs less frequently in children than reported for adults. Tumor location has no prognostic significance regarding the loss of HP function.

Context: The insulin tolerance test (ITT) is the gold standard for assessment of ACTH and GH reserve in patients with suspected hypopituitarism. It is labor intensive and costly., Objective: The objective of the study was to determine whether use of the overnight metyrapone test (OMT) and plasma IGF-I sd scores (SDS) could provide a cost-effective alternative to the ITT., Design: This was a retrospective chart review., Setting: The study was conducted at a teaching hospital., Participants and Intervention: Charts from 100 patients with organic pituitary disorders were reviewed. All underwent the OMT unless 0900 h plasma cortisol was less than 80 or greater than 450 nmol/liter when ACTH deficiency or ACTH sufficiency, respectively, was diagnosed. Patients were considered GH deficient if the age-related IGF-I SDS was less than -3 or if they had three or more other pituitary hormone deficiencies. Patients were considered GH sufficient if age-related IGF-I SDS was greater than the 95th centile established from patients with known GH deficiency. Thirty-three underwent an ITT., Main Outcome Measures: The proportion of patients in whom ACTH and GH reserve could be assessed using OMT/IGF-I SDS was measured. The concordance with results was obtained from ITT., Results: Fifty-five patients were ACTH sufficient and 45 were ACTH deficient. Twenty-one were GH sufficient and 33 were GH deficient based on IGF-I SDS and other pituitary hormone deficiencies, whereas 46 could not be classified. There was near-uniform concordance between OMT/IGF-I SDS and ITT. Initial investigation using OMT/IGF-I SDS resulted in a significant cost saving., Conclusions: ACTH and GH reserve can be accurately and cost-effectively investigated using OMT/IGF-I SDS in approximately 50% of patients with organic pituitary disorders.

Background: Estradiol (E(2)) stimulates GH and prolactin secretion and suppresses FSH secretion in postmenopausal women. Whether central nervous system (CNS) or pituitary mechanisms (or both) mediate such actions is not known., Objective: Our objective was to distinguish between hypothalamic and pituitary or peripheral (hepatic) actions of E2., Setting: This study was performed in an academic medical center., Design: This was a double-blind, prospectively randomized, placebo (Pl)-controlled study., Methods: The capability of a selective, noncompetitive, non-CNS permeant estrogen receptor (ER)-alpha antagonist, fulvestrant (FUL) to antagonize the effects of transdermal E2 and Pl on GH, prolactin, and FSH secretion was assessed in 43 women (ages 50-80 yr) in a four parallel-cohort study. Each woman received four secretagogue infusions to stimulate GH secretion. IGF-I and its binding proteins were measured secondarily., Results: Administration of Pl/E2 increased GH and prolactin concentrations by 100%, and suppressed FSH concentrations by more than 50% (each P

Unlabelled: Many factors may be involved in the growth and gonadal dysfunction of Fanconi anemia (FA)., Objective: To evaluate the (1) relationship between FA presentation, including genital abnormalities and pituitary stalk interruption syndrome (PSIS), (2) markers of growth hormone (GH) deficiency and gonadal function, and (3) factors influencing final height and gonadal function., Patients: Twenty five patients with FA were included, 17 of them were given bone marrow transplantation., Results: Six patients were diagnosed with GH deficiency and PSIS (group A), whereas 19 had no evidence of GH deficiency (group B). In group A, all patients had more than 3 FA malformations and all 5 boys had cryptorchidism associated with microphallus in 4. All patients had heights and plasma insulin-like growth factor I < -3SD. Final height was reached in 15 patients and was < or = -2SD in 12 of them, all but 3 were born small for gestational age and/or given norethandrolone and/or corticosteroids. Gonadal function was abnormal in 5/7 boys and 4/5 girls evaluated at pubertal age. The plasma concentrations were low in 4/9 for antimüllerian hormone and in 3/9 for inhibin B, 3 of them had been given bone marrow transplantation., Conclusions: PSIS can be part of a severe FA phenotype. It seems to occur mainly in boys, with more than 3 malformations, microphallus and cryptorchidism. This phenotype is associated with normal blood counts, defining a new clinical subgroup of patients.

Introduction: Coeliac disease (CD) is usually associated with impaired growth in children. A gluten-free diet (GFD) induces a catch-up growth with the recovery of height in about 2 years. AIM AND DISCUSSION: The lack of the height improvement has been related to growth hormone (GH) secretion impairment. CD is an autoimmune disease often associated with other endocrine and non-endocrine autoimmune disease. The aim of this study was to evaluate antipituitary autoantibodies (APA) and antihypothalamus autoantibodies in CD children with poor clinical response to a GFD and growth hormone deficiency (GHD). We diagnosed CD on the basis of specific antibodies and endoscopic biopsies in 130 patients aged 1-15 years. Seven CD children, without catch-up growth after at least 12-months GFD, were tested for GH secretion and, in five out of seven patients, the diagnosis of GHD was made in the absence of metabolic and systemic diseases., Results: APA and antihypothalamus antibodies were detected by the indirect immunofluorescence method in the seven CD children without catch-up growth factor and in 25 CD children without growth impairment matched for sex and age, and in 58 healthy children as control groups. APA resulted positive at high titres in four out of five CD-GHD patients and were also positive at low titres (<1:8) in three of only CD children and in two out of 58 controls. Hypothalamic-pituitary magnetic resonance imaging (MRI) was normal in all patients except in one with cystic pineal. APA have been previously detected not only in adults with GHD, but also in idiopathic GHD children, suggesting the occurrence of an autoimmune hypophysitis in these patients., Conclusion: In our study, the presence of APA in CD children without catch-up growth after GFD seems to be able to identify an autoimmune form of hypophysitis involving the somatotrophs cells.

Context: Cortistatin (CST) is a neuropeptide that shares high homology with somatostatin and binds with high affinity to all somatostatin receptor (SSTR) subtypes. Many of its endocrine and biological activities overlap with those of somatostatin., Objective/design: The objective of the study was to assess the direct in vitro effects of CST on human pituitary hormone secretion., Setting: This study was performed in the endocrine laboratory of a tertiary academic medical center., Materials: Primary cell cultures of human fetal (21-25 wk gestation) pituitary tissues and cultured hormone-secreting adenoma cells were used in this study., Interventions: Cell cultures were incubated with CST-14 or CST-17, somatostatin, GHRH, SSTR analogs, and ghrelin analogs, and hormone secretion was analyzed., Outcome Measures: GH and prolactin (PRL) medium concentrations were tested by hormone assay, and SSTR mRNA was tested by RT-PCR., Results: CST-14 (10 nm) inhibited GH secretion by up to 65% in all fetal pituitary specimens after 4-h incubation (P < 0.05). CST-14 or CST-17 (10 nm) inhibited basal GH secretion in six of the 13 GH-cell adenomas and two of the three GH-PRL mixed adenomas. CST-17 (100 nm) suppressed the GH response to GHRH and ghrelin analog (10 nm each) by 30-50% in adenomas (P < 0.05). Three PRL-adenomas treated with CST-17 (10 nm) showed a 20-40% inhibition of PRL release (P < 0.05), whereas in three others no suppression or mild response was achieved at this concentration. A comparable inhibition of PRL secretion was obtained with SSTR5-selective analog but significantly less with SSTR2-preferential compounds. RT-PCR revealed the expression of both SSTR2 and SSTR5 in all GH-cell and mixed adenomas studied and all PRL-secreting adenomas studied, except for two of the CST-resistant prolactinomas, in which SSTR5 was absent., Conclusions: This is the first report of in vitro CST suppression of human GH and PRL in cultured pituitary tissues. The regulation of PRL release from cultured adenomas appears to be primarily mediated by SSTR5.

Hesx1 is a paired-like homeobox gene first expressed during mouse embryogenesis in the anterior midline visceral endoderm. As gastrulation proceeds, Hesx1 is expressed in the ventral prosencephalon and, subsequently, at E9.0 appears in the ventral diencephalon and in the thickened layer of oral ectoderm that give rise to Rathke's pouch, the primordium of the anterior pituitary gland. Hesx1 continues to be expressed in the developing anterior pituitary until E11.5 when its transcripts disappear in a spatiotemporal sequence corresponding to progressive pituitary cell differentiation, becoming undetectable by E15.5. In the present study, we investigated whether HESX1 is expressed during adult life in human normal pituitaries and in different types of human pituitary adenomas. We analysed, using quantitative RT-PCR method, three normal pituitaries, seven GH-, two TSH-, two PRL-, one ACTH-secreting adenomas, and seven nonfunctioning pituitary tumors. HESX1 mRNA was found to be expressed in normal pituitaries and in all the pituitary tumors that we have analysed. These results suggest that in humans HESX1 is not turned-off during the adult life as it occurs in mice. Thus, HESX1 in humans might play a role in the maintenance of the anterior pituitary cell types and function, as well as in the differentiation of pituitary adenomas, whose pathogenetic mechanisms remain to be further investigated. This is the first study on HESX1 expression in humans during adult life.