Pituitary Growth Hormone Research Articles

Seasonal Related Multifactorial Control of Pituitary Gonadotropin and Growth Hormone in Female Goldfish: Influences of Neuropeptides and Thyroid Hormone.

Female reproduction is under multifactorial control of brain-pituitary-peripheral origin. The present study provides information on seasonal changes in circulating LH and GH concentrations, as well as transcript levels for a number of genes involved in the regulation of reproduction and growth in female goldfish. We also provide information on the effects of treatments with GnRH and/or GnIH, and their interaction with T3, at three stages of gonadal recrudescence. Maximum basal concentration of LH was observed at late recrudescence (Spring) while no seasonal changes in basal serum GH levels was detected. Serum LH and GH levels were stimulated by GnRH as expected, depending on the season. GnIH stimulated basal GH concentrations in gonadally regressed fish. GnIH inhibitory action on GnRH-induced LH response was observed in late, but not in mid recrudescence. T3 actions on basal and GnRH- or GnIH-induced GH secretion were generally inhibitory, depending on season. Administration of T3 attenuated GnRH-induced LH responses in mid and late stages of gonadal recrudescence, and the presence of GnIH abolished inhibitory actions of T3 in fish at mid recrudescence. Our results also demonstrated seasonal patterns in basal and GnRH- and/or GnIH-induced transcript levels for ERα, ERβI, FSHR, aromatase, TRαI, TRβ, IGF-I, and Vtg in the liver and ovary. However, there were no clear correlations between changes in transcript levels and circulating levels of LH and GH. The results support the hypothesis that GnRH, GnIH, and T3 are contributing factors in complex reciprocal control of reproduction and growth in goldfish.

BRD4 as a therapeutic target for nonfunctioning and growth hormone pituitary adenoma.

BackgroundNonfunctioning pituitary adenoma (NFPA) and growth hormone pituitary adenoma (GHPA) are major subtypes of pituitary adenomas (PAs). The primary treatment is surgical resection. However, radical excision remains challenging, and few effective medical therapies are available. It is urgent to find novel targets for the treatment. Bromodomain-containing protein 4 (BRD4) is an epigenetic regulator that leads to aberrant transcriptional activation of oncogenes. Herein, we investigated the pathological role of BRD4 and evaluated the effectiveness of BRD4 inhibitors in the treatment of NFPA and GHPA.MethodsThe expression of BRD4 was detected in NFPA, GHPA, and normal pituitary tissues. The efficacies of BRD4 inhibitors were evaluated in GH3 and MMQ cell lines, patient-derived tumor cells, and in vivo mouse xenograft models of PA. Standard western blots, real-time PCR, and flow cytometry experiments were performed to investigate the effect of BRD4 inhibitors on cell cycle progression, apoptosis, and the expression patterns of downstream genes.ResultsImmunohistochemistry studies demonstrated the overexpression of BRD4 in NFPA and GHPA. In vitro and in vivo studies showed that treatment with the BRD4 inhibitor ZBC-260 significantly inhibited the proliferation of PA cells. Further mechanistic studies revealed that ZBC-260 could downregulate the expression of c-Myc, B-cell lymphoma 2 (Bcl2), and related genes, which are vital factors in pituitary tumorigenesis.ConclusionIn this study, we determined the overexpression of BRD4 in NFPA and GHPA and assessed the effects of BRD4 inhibitors on PA cells in vitro and in vivo. Our findings suggest that BRD4 is a promising therapeutic target for NFPA and GHPA.

MiR-709 inhibits GHRP6 induced GH synthesis by targeting PRKCA in pituitary

Pituitary growth hormone (GH) plays an essential role in processes of organism growth and metabolism. MicroRNA (miRNA) could also participate in diverse biological processes. However, the role of miRNA in the regulation of pituitary GH during the growth process remains unclear. In this study, we firstly confirmed that the second highly expressed pituitary miRNA (miR-709) significantly inhibited the GH synthesis and suppressed the viability of GH3 cells. The bioinformatics analysis and dual luciferase report system were used to ascertain the PRKCA is the direct target gene of miR-709, which is the coding gene of PKCα. Then the transcription and translation levels of Prkca were obvious reduced by the over-expression of miR-709 in GH3 cells, followed by the inhibition of the transcription factor (CREB1) of Gh1 gene and the ERK1/2 signaling pathway or the possible cross-talk signaling pathway (cAMP/PKA signaling pathway) detected by western blot, suggesting that ERK1/2 maybe an important factor involved in the GH3 cell viability mediated by PKCα. At last, GHRP6 increased PKCα and GH expression but reduced miR-709 expression in vitro and vivo assays, and this conclusion was further confirmed by the result of GHRP6 attenuated the inhibition of miR-709 on GH expression. These findings will provide new molecular mechanism on the regulation of pituitary GH.

The effects of the DNA Demethylating reagent, 5-azacytidine on SMCHD1 genomic localization

BackgroundDNA methylation is an epigenetic modification that mainly repress expression of genes essential during embryogenesis and development. There are key ATPase-dependent enzymes that read or write DNA methylation to remodel chromatin and regulate gene expression. Structural maintenance of chromosome hinge domain containing 1 (SMCHD1) is an architectural protein that regulates expression of numerous genes, some of which are imprinted, that are sensitive to DNA methylation. In addition, SMCHD1 germline mutations lead to developmental diseases; facioscapulohumoral muscular dystrophy (FSHD), bosma arhinia and micropthalmia (BAMS). Current evidence suggests that SMCHD1 functions through maintenance or de novo DNA methylation required for chromatin compaction. However, it is unclear if DNA methylation is also essential for genomic recruitment of SMCHD1 and its role as an architectural protein. We previously isolated SMCHD1 using a methylated DNA region from mouse pituitary growth hormone (Gh1) promoter, suggesting that methylation is required for SMCHD1 DNA binding. The goal of this study was to further understand DNA methylation directed role of SMCHD1 in regulating gene expression. Therefore, we profiled SMCHD1 genome wide occupancy in human neuroblastoma SH-SY5Y cells and evaluated if DNA methylation is required for SMCHD1 genomic binding by treating cells with the DNA demethylating reagent, 5-azacytidine (5-azaC).ResultsOur data suggest that the majority of SMCHD1 binding occurs in intron and intergenic regions. Gene ontology analysis of genes associated with SMCHD1 genomic occupancy that is sensitive to 5-azaC treatment suggests SMCHD1 involvement in central nervous system development. The potassium voltage-gated channel subfamily Q member1 (KCNQ1) gene that associates with central nervous system is a known SMCHD1 target. We showed SMCHD1 binding to an intronic region of KCNQ1 that is lost following 5-azaC treatment suggesting DNA methylation facilitated binding of SMCHD1. Indeed, deletion of SMCHD1 by CRISPR- Cas9 increases KCNQ1 gene expression confirming its role in regulating KCNQ1 gene expression.ConclusionThese findings provide novel insights on DNA methylation directed function of SMCHD1 in regulating expression of genes associated with central nervous system development that impact future drug development strategies.

Evaluation towards stud bulls with different mixed genotypes relating to somatotropin cascade genes by origin

A preliminary evaluation towards a breeding value of the Holstein breeding bulls with different genotypes of somatotropin cascade genes is presented: pituitary transcription factor or growth hormone factor (PIT1), prolactin (PRL), somatotropin (GH), somatotropin releasing hormone (GHRH), insulin-like (IGF-1) in the conditions of the Republic of Tatarstan. The research studies the signs (indices) of milk productivity (milk yield and fat in milk) of the closest female ancestors of bulls with different genotypes of somatotropin cascade genes. Studies and analysis have shown that the bulls with the mixed genotypes ABAALLBBAA (10269 kg), AAAALLBBAB (4.13 %) and BBAALLABBB (9402 kg and 4.06 %) had the highest and optimum evaluation by origin, judging by the bulls’ pedigree (geneological) index. The frequency to meet bulls with the desired mixed genotypes was low and amounted to 4.28–5.71 %.

Growth and Bone Mineral Density Changes in Ovariectomized Rats Treated with Estrogen Receptor Alpha or Beta Agonists

BackgroundEstrogen controls the pubertal growth spurt, growth plate closure, and accretion of bone mineral density (BMD) of long bones after biding estrogen receptor (ER). There are two subtypes of ER, ERα and ERβ. If each ER subtype has different effects, we may control those actions by manipulating the estrogen binding intensity to each ER subtype and increase the final adult height without markedly reducing BMD or impairing reproductive functions. The purpose of our study was to compare these effects of ERα and ERβ on long bones in ovariectomized rats.MethodsThirty female rats were ovariectomized and randomly divided into 3 groups. The control, propylpyrazole triol (PPT), and 2,3-bis (4-hydroxyphenyl) propionitrile (DPN) groups were subcutaneously injected for 5 weeks with sesame oil, PPT as an ERα agonist, and DPN as an ERβ agonist, respectively. The crown-lump length and body weight were measured weekly. BMD, serum levels of growth hormone (GH) and estradiol were checked before and after 5 weeks of injections. Pituitary GH1 expression levels were determined with quantitative real-time polymerase chain reaction, the proximal tibias were dissected, decalcified and stained with hematoxylin-eosin, and the thicknesses of epiphyseal plates including proliferative and hypertrophic zones were measured in 20-evenly divided sites after 5 weeks of injections. Comparisons for auxological data, serum hormone and pituitary GH1 expression levels, BMD, and epiphyseal plate thicknesses among 3 groups before and after injections were conducted.ResultsThere was no significant difference in body lengths among 3 groups. The body weights were significantly lower, but, serum GH, pituitary GH1 expression levels, and BMDs were higher in PPT group than the other 2 groups after 5 weeks of injections. There was no significant difference in the thicknesses of the total epiphyseal plate, proliferative, and hypertrophic zone among 3 groups.ConclusionERα is more involved in pituitary GH secretion and bone mineral deposition than ERβ. Weight gain might be prevented with the ERα agonist.

Pregnancy management in patients with acromegaly

Acromegaly is a rare, chronic, endocrine disorder, usually caused by hypersecretion of growth hormone (GH) for a prolonged period from a somatotroph adenoma. Hormonal evaluation becomes more complex in pregnant women due to physiological changes in the pituitary and target hormone levels, binding globulins, and placental hormones. Evaluation of pituitary functions in pregnant women is quite different from nonpregnant women because of physiological hormonal changes. Pregnancy in acromegaly continues to be an uncommon event and a challenge for clinicians despite the positive impact of current treatments on survival and quality of life. Diagnosis of acromegaly during pregnancy is difficult because of changes in GH and insulin like growth factor 1 (IGF 1) levels, GH production by placenta, and the inability of routine methods to distinguish the pituitary GH from placental GH.In the majority of patients with acromegaly pregnancy does not have an adverse effect on mother or fetus and pituitary mass does not increase in size. Tumor enlargement may theoretically occur if pre-existing therapies such as somatostatin analogues are discontinued with the onset of pregnancy. Acromegalic symptoms may improve during pregnancy, possibly from the increased estrogen production inhibiting hepatic IGF 1 production. Pregnancy course is mostly uneventful but the literature indicates an increased risk of gestational diabetes and gravid hypertension in women with non-controlled GH/IGF 1 hypersecretion before gestation.In case of tumor enlargement frequent monitoring is required, surgery can be considered in the second trimester. Dopamine agonists and somatostatin analogs can be used without any adverse consequences on mother or fetus. In pregnancy acromegaly medical therapy should be withheld and administered only for tumor growth and headache control during pregnancy. Breast feeding does not affect the course of acromegaly. Postpartum pituitary imaging demonstrates no increased tumor growth after pregnancy.

Achieving Optimal Short- and Long-term Responses to Paediatric Growth Hormone Therapy

It is over sixty years since the first administration of human growth hormone (GH) to children with GH deficiency, and over thirty years since recombinant human GH has been available for treatment of GH deficiency and a wider range of non-GH deficiency disorders. From a diagnostic perspective, genetic analysis, using single gene or Sanger sequencing and more recently next generation or whole exome sequencing, has brought advances in the diagnosis of specific causes of short stature, which has enabled therapy to be targeted more accurately. Genetic discoveries have ranged from defects of pituitary development and GH action to abnormalities in intracellular mechanisms, paracrine regulation and cartilage matrix formation. The strategy of GH therapy using standard doses has evolved to individualised GH dosing, depending on diagnosis and predictors of growth response. Evidence of efficacy of GH in GH deficiency, Turner syndrome and short children born small for gestational age is reviewed. The importance of critical assessment of growth response is discussed, together with the recognition and management of a poor or unsatisfactory growth response and the organisational issues related to prevention, detection and intervention regarding suboptimal adherence to GH therapy.

Cortisol Levels in Glucagon Stimulation Test in Children Assessed for Short Stature: Clinical and Laboratorial Correlations.

To assess total cortisol levels in children being evaluating for short stature with normal cortisol reserve and to correlate this response to clinical and laboratory data. Children assessed with glucagon test in our department were recruited in this study retrospectively. Inclusion criteria were: i) age>1 year, ii) absence of chronic illness or medication interfering with ACTH-cortisol axis, iii) GH stimulation levels>3ng/mL at least in one provocation test (glucagon or clonidine), iv) absence of multiple pituitary growth hormone deficiencies, v) normal short Synacthen test in cases of low cortisol response in glucagon test.Two hundred and thirty-seven subjects (160 males, 67.5%) with a mean age of 9.02±3.19 years, were finally included in the analysis. Cortisol peak levels but not cortisol AUC were significantly increased in females compared to males (26.83±7.31 μg/dl vs. 24.04±7.20 μg/dl). When linear correlations were studied, both cortisol peak levels and cortisol AUC were linearly but inversely correlated to age (r=-0.234, p<0.001 and r=-0.315, p<0.001, respectively). Finally, cortisol AUC was inversely correlated to weight Z-scores (r=-0.160, p=0.014). When our analysis was limited only to subjects with intact GH response (GH peak> 7 ng/mL), age was still inversely correlated to cortisol AUC (r=-0.312, p<0.001), and cortisol AUC was linearly correlated to GH AUC assessed with clonidine test (r=0.223, p=0.013). Girls, younger and thinner children exhibit higher cortisol response to glucagon test.

Interleukin-1α leads to growth hormone deficiency in adamantinomatous craniopharyngioma by targeting pericytes: implication in pituitary fibrosis

BackgroundThe incidence of growth hormone deficiency (GHD) in adamantinomatous craniopharyngioma (aCP) is significantly higher than in other sellar region tumors, but the possible mechanism is still elusive. A high level of inflammatory responses is another feature of aCP. We investigated the internal connection between interleukin-1α (IL-1α) and GHD, while focusing on its biological activities in pituitary fibrosis. Materials and methodsTo diagnosis of GHD, the Body Mass Index (BMI), Insulin Like Growth Factor-1(IGF-1) and peak growth hormone (GH) values after insulin stimulation test of 15 aCP patients were recorded. Histological staining was performed on the aCP samples. Levels of 9 proinflammatory cytokines in tumor tissue and cell supernatant were detected using Millipore bead arrays. The effect of IL-1α on GH secretion was evaluated in vivo and in vitro. Western blot, qRT-PCR and cell functional assays were used to explore the potential mechanism through which IL-1α acts on GH secretion. The stereotactic ALZET osmotic pump technique was used to simulate aCP secretion of proinflammatory cytokines in rats. Recombinant IL-1α (rrIL-1α) and conditioned media (CM) prepared from the supernatant of aCP cells was infused directly into the intra-sellar at a rate of 1 μl/h over 28 days, and then the effects of IL-1α treatment on pathological changes of pituitary gland and GH secretion were measured. To further confirm whether IL-1α affects GH secretion through IL-1R1, an IL-1R1 blocker (IL-1R1a, 10 mg/kg body weight, once daily) was administered subcutaneously from the first day until day 28. ResultsThere was a significant positive correlation between pituitary fibrosis and GHD (rS = 0.756, P = 0.001). A number of cytokines, in particular IL-1α, interleukin-8 (IL-8), and monocyte chemoattractant protein-1 (MCP-1), were elevated in tumor tissue and cell supernatant. Only IL-1α showed a significant difference between the GHD group and the No-GHD group (P < 0.001, F = 6.251 in tumor tissue; P = 0.003, F = 1.529 in cell supernatant). IL-1α significantly reduced GH secretion in coculture of GH3 and pericytes. The activation of pericytes induced by IL-1α was mediated by the IL-1R1 signaling pathway. In vivo, IL-1α induces pituitary fibrosis, further leading to a decreased level of GH. This pathological change was antagonized by IL-1R1a. ConclusionThis study found that the cross talk between aCP cells and stroma cells in the pituitary, i.e. pericytes, is an essential factor in the formation of GHD, and we propose that neutralization of IL-1α signaling might be a potential therapy for GHD in aCP.

Early-life exposure to 17β-estradiol and 4-nonylphenol impacts the growth hormone/insulin-like growth-factor system and estrogen receptors in Mozambique tilapia, Oreochromis mossambicus

It is widely recognized that endocrine disrupting chemicals (EDCs) released into the environment through anthropogenic activities can have short-term impacts on physiological and behavioral processes and/or sustained or delayed long-term developmental effects on aquatic organisms. While numerous studies have characterized the effects of EDCs on temperate fishes, less is known on the effects of EDCs on the growth and reproductive physiology of tropical species. To determine the long-term effects of early-life exposure to common estrogenic chemicals, we exposed Mozambique tilapia (Oreochromis mossambicus) yolk-sac fry to 17β-estradiol (E2) and nonylphenol (NP) and subsequently characterized the expression of genes involved in growth and reproduction in adults. Fry were exposed to waterborne E2 (0.1 and 1 μg/L) and NP (10 and 100 μg/L) for 21 days. After the exposure period, juveniles were reared for an additional 112 days until males were sampled. Gonadosomatic index was elevated in fish exposed to E2 (0.1 μg/L) while hepatosomatic index was decreased by exposure to NP (100 μg/L). Exposure to E2 (0.1 μg/L) induced hepatic growth hormone receptor (ghr) mRNA expression. The high concentration of E2 (1 μg/L), and both concentrations of NP, increased hepatic insulin-like growth-factor 1 (igf1) expression; E2 and NP did not affect hepatic igf2 and pituitary growth hormone (gh) levels. Both E2 (1 μg/L) and NP (10 μg/L) induced hepatic igf binding protein 1b (igfbp1b) levels while only NP (100 μg/L) induced hepatic igfbp2b levels. By contrast, hepatic igfbp6b was reduced in fish exposed to E2 (1 μg/L). There were no effects of E2 or NP on hepatic igfbp4 and igfbp5a expression. Although the expression of three vitellogenin transcripts was not affected, E2 and NP stimulated hepatic estrogen receptor (erα and erβ) mRNA expression. We conclude that tilapia exposed to E2 and NP as yolk-sac fry exhibit subsequent changes in the endocrine systems that control growth and reproduction during later life stages.

Venus by Botticelli and Her Pituitary Adenoma

Objective: Simonetta Vespucci, considered the most beautiful woman of the Renaissance, is the inspiration and face of one of the most famous paintings of all times, "The Birth of Venus," by Botticelli. She died in 1476 at the age of 23 years. We postulate she suffered from a pituitary-secreting tumor progressing to pituitary apoplexy. The goals of this study were 3-fold: (i) verify that the subject depicted by Botticelli in different paintings represents the same woman; (ii) identify the facial traits affected by the progression of a growth hormone- and prolactin-secreting tumor; and (iii) confirm that the observed changes of the face traits observed in the portraits of Simonetta Vespucci are compatible with the facial traits changes identified earlier. Methods: Comparison among face traits was based on the analysis of the face regions measured by means of fiducial points and their distances, and after pose compensation based on three-dimensional head modelling. Results: In favor of the hypothesis that Simonetta suffered from a pituitary growth hormone- and prolactin-secreting tumor stands changes of her lineaments, a feature which becomes evident over the years and particularly manifest in the Allegorical Lady, where galactorrhea is depicted. Conclusion: We conclude that sufficient evidence is presented to suggest that Simonetta Vespucci, the Venus depicted by Botticelli, suffered from pituitary adenoma secreting prolactin and growth hormon with parasellar expansion. The current interpretation of the Venus strabism should be revisited according to this finding. Abbreviation: GH = growth hormone.

Insulin synthesized in the paraventricular nucleus of the hypothalamus regulates body length by modulating pituitary growth hormone production

Insulin synthesized in the paraventricular nucleus of the hypothalamus regulates body length by modulating pituitary growth hormone production

Surgical Outcomes of the Endoscopic Endonasal Transsphenoidal Approach for Anterior Skull Base Lesions: Experience in Combined Military Hospital, Dhaka

Introduction:The endoscopic endonasal approach is a minimally invasive surgical technique for removal of skull base lesions by using nose and sinuses as natural corridors. This study represents our institutional experience with endoscopic endonasal trans-sphenoidal approach for anterior skull base lesions.&#x0D; Objective: To find out surgical outcomes of endoscopic endonasal trans-sphenoidal approach for treatment of anterior skull base lesions.&#x0D; Materials and Methods: Cross-sectional observational study of 38 consecutive patients who underwent endoscopic endonasal trans-sphenoidal surgery for anterior skull base lesions in Combined Military Hospital, Dhaka from July 2013 to June 2017.&#x0D; Results:This study included 16 men and 22 women, ranging from 24 to 68 years of age where median was 38 years. Common presentations were visual disorder (60%), headache (30%), features of pituitary apoplexy (5%), Cushing disease (0.35%), acromegaly (0.7 %), galactorrhoea (0.35%). Radiological evaluation revealed intrasellar (12), sellar and suprasellar (22), sellar and parasellar (1), tuberculum sella and planum sphenoidale (3), clival (1) lesions. Recurrent cases (3/38) were nonfunctioning pituitary macroadenoma, prolactinoma, and growth hormone secreting macroadenoma. The surgical resection in relation to post op imaging were 45% as gross total resection, near-total in 35%, subtotal in 15%, and partial in 5%. We found fifteen patients experienced improvement in visual acuity, while one patient worsened. Common complications were transient diabetes insipidus (53%), new pituitary deficit (35%), endonasal adhesions (20%), and cerebrospinal fluid leak (5%). Surgical mortality was (0.35%). The histological diagnoses included twenty-eight pituitary adenomas, five craniopharyngioma, three meningioma, one Rathke’s cleft cyst and one clival chordoma.&#x0D; Conclusion: Endoscopic endonasal transsphenoidal surgery is a valuable treatment option for an anterior skull base lesion.&#x0D; Journal of Armed Forces Medical College Bangladesh Vol.14(1) 2018: 66-68

Amyloid-β: Can One Bad Apple Really Spoil the Whole Brain? Transmission of Amyloid-β Protein Pathology From Cadaveric Pituitary Growth Hormone.

Amyloid-β: Can One Bad Apple Really Spoil the Whole Brain? Transmission of Amyloid-β Protein Pathology From Cadaveric Pituitary Growth Hormone.

Melatonin Receptor Mel1b- and Mel1c-mediated Green Light Induced the Secretion of Growth Hormone in Anterior Pituitary of Chicks.

Previous studies have found that melatonin was related to the growth and development in avian. Therefore, the newly hatched broilers were exposed to colors of light to establish a model of pinealectomy and explored the mechanism of pineal melatonin promoting growth hormone (GH) secretion. The results showed that green light (GL) promoted the levelsof GH, pituitary-specific transcription factor-1 (Pit-1) genes and proteins in pituitary. Moreover, the mRNA and proteinlevels of melatonin receptor subtypes Mel1b and Mel1c in the pituitary in GL were higher than other monochromatic light groups. After pinealectomy, the expression of Pit-1, GH, Mel1b and Mel1c in pituitary decreased. In vitro, exogenous melatonin promoted the level of Pit-1 mRNA and the secretion of GH in anterior pituitary cells. However, when melatonin was added with exogenous selective Mel1b antagonist (4-phenyl-2-propionamideotetralin) and selective Mel1c antagonist (prazosin), the levelof Pit-1 mRNA and the GH secretion decreased. When selective Mel1b and Mel1c antagonists were added simultaneously, the decrease in Pit-1 mRNA and GH secretion was more significant. These results indicated that pineal melatonin promotes the expression of Pit-1 under GL by binding to melatonin receptor subtypes Mel1b and Mel1c in the pituitary, thereby increasing GH secretion and promoting the growth.

Acute intravenous acyl ghrelin infusion induces thirst but does not affect sodium excretion: two randomized, double-blind, placebo-controlled crossover studies in hypopituitary patients.

Acyl ghrelin, which is the endogenous ligand for the growth hormone secretagogue receptor, potently stimulates pituitary growth hormone release, and to some degree adrenocorticotropic hormone and prolactin. Ghrelin is also orexigenic and has recently been shown to stimulate renal sodium absorption in rodent models. Increased thirst sensation has been observed as a side effect of acyl ghrelin administration in some human studies. The objective of this clinical trial was to investigate the direct effects of acyl ghrelin on thirst sensation and sodium excretion in hypopituitary patients. Hypopituitary patients on stable replacement with hydrocortisone and growth hormone were investigated in two double-blind and placebo-controlled crossover studies. The patients received a 5-h intravenous infusion of acyl ghrelin (5 pmol/kg/min in the first study and 1 pmol/kg/min in the second study). Thirst sensation was measured on a Visual Analog Scale (VAS). In the second study plasma osmolality, vasopressin, copeptin, water intake, diuresis and urinary excretion of sodium and creatinine were measured. In the initial study, acyl ghrelin (5 pmol/kg/min) increased thirst sensation (time × treatment analysis of variance for the effect of acyl ghrelin infusion P = 0.003). In the second study acyl ghrelin (1 pmol/kg/min) also increased thirst (P = 0.04) but did not affect urinary excretion of either sodium or water. We demonstrate that acyl ghrelin infusion increases thirst sensation, without affecting sodium excretion or diuresis in human subjects.

Prevalence of endocrine disorders in childhood brain tumor survivors in South Korea: A nationwide population-based, longitudinal study.

e21517 Background: Brain tumors are the most common solid cancers in child patients with a current expected 5-year overall survival rate of 73%. Also, patients with brain cancer tend to have a high rate of neuroendocrine disorders. These endocrine problems may have a significant negative effect on quality of life and treatment compliance. Methods: The aim of this longitudinal study was to analyze the prevalence of endocrine disorders in childhood brain tumor survivors using claims data in South Korea. We confirmed endocrine disorders in a nationwide cohort of 1,058 patients who were diagnosed with brain tumor between January 1, 2009 and March 29, 2016 and who survived &gt; 2 years after diagnosis. Multivariable logistic regression was used to evaluate association between demographic and treatment related variables and the prevalence of endocrine disorders. Results: After a median follow-up of 60.0 months, a total of 393 (37.1%) patients were diagnosed with at least one endocrine disorder. The median follow-up time from primary brain tumor diagnosis to diagnosis of first endocrine disorders was 26.3 months (range, 0.06 to 96.7). Of those patients, 333 childhood brain tumor survivors were diagnosed with endocrine disorders during their first 5 years after diagnosis. The overall frequency of endocrine disorders peaked during 2 months after the cancer diagnosis. The most common endocrine disorders were pituitary dysfunction (21.9%), thyroidal disease (6.1%), precocious puberty (4.6%), and growth hormone deficiency (4.3%). Female patients were at a higher risk for endocrine disorders (odds ratio: 1.45, p = 0.005). The patients with radiotherapy were more likely to have endocrine disorders compared without radiotherapy (odds ratio: 1.79, p &lt; 0.001). Conclusions: Endocrine disorders in childhood brain tumor survivors was high and showed different patterns of prevalence depending on the nature of disease and time sequence. In childhood brain tumor survivors who are risk of endocrine disorders, regular assessment of endocrine function and timely intervention were needed. [Table: see text]

The Role of Different NO Synthase Isoforms in the Regulatory Effect of Prolactin and Growth Hormone on the State of Chromosomes in Mature Oocytes Aging in vitro

The fertility of female mammals depends on the quality of oocytes, which decreases in the process of biological aging. We found an inhibitory effect of two related pituitary hormones (prolactin (PRL) and growth hormone (GH)) on destructive modifications of metaphase chromosomes in the eggs of domestic cow (Bos taurus taurus), aging in vitro. The involvement of different NO synthase (NOS) isoforms in realization of the effect of PRL and GH on age-related changes of MII chromosomes with prolonged cultivation of in vitro matured cow oocytes was studied in the present work. In the absence of hormones NPLA, neuronal NOS (nNOS) inhibitor had no effect on the frequency of chromosomal abnormalities in aging oocytes. At the same time, 1400 W (inducible NOS (iNOS) inhibitor) and L-NAME (efficient endothelial NOS (eNOS and nNOS ) inhibitor) decreased this frequency, while the blocking of all three NO synthase isoforms led to the opposite effect. The inhibitory effect of PRL on destructive chromosome modifications in aging eggs increased in the presence of L-NAME, but was not expressed with the inhibition of nNOS, iNOS, or all NO synthase isoforms simultaneously. Neither NPLA nor L-NAME modulated the inhibitory effect of GH on abnormal chromosome changes in oocytes. On the contrary, the blocking of iNOS, as well as all three NO synthase isoforms, led to an increase in the portion of oocytes with destructive changes of MII chromosomes. At the same time, the level of total activity of NO synthase in oocytes did not depend on the presence of the studied hormones or NOS inhibitors during the prolonged cultivation of oocyte–cumulus complexes. Data obtained suggest that the inhibitory effect of PRL and GH on abnormal changes of metaphase chromosomes in aging cow eggs is associated with a decrease in the activity of endothelial NO synthase, as well as (in the case of PRL) with an increase in the activity of neuronal NO synthase in the cumulus cells surrounding the oocytes.

SUN-038 Role Of The Satb 1 Gene In Growth Across Species: Findings In A Cohort Of Patients With Short Stature And In A Knockout Zebrafish Model

Background: Short stature is a common pediatric disorder, affecting 3% of the population; however, the identification of its cause is limited by its largely variable clinical presentation and genetic heterogeneity. Identification of novel genetic causes of short stature is of great importance to customize the therapeutic approach of this entity. The especial AT-rich sequence binding protein1 gene (SATB1) encodes a chromatin organizer with important roles in cell growth and immunosuppression. SATB1 is highly expressed in the pituitary gland, where it regulates the differentiation of PIT1 positive cells. Indeed, the conditional knockout of Satb1 in the mouse pituitary decreases growth hormone expression, leading to reduced growth. Aim: To investigate the putative role of SATB1 in growth in a cohort of individuals with short stature and in a zebrafish knockout (KO) model. Methods: We obtained germline DNA samples from a cohort of 287 Brazilian patients diagnosed with short stature (height <2 SDS for age and sex), including 52 patients small for gestational age (SGA), 5 cases with growth hormone deficiency (GHD), 10 cases with syndromic short stature and 220 cases with idiopathic short stature. All cases were screened for SATB1 copy number variations (CNVs) using droplet digital PCR, and 190 cases were screened for mutations via Sanger sequencing. In silico predictions were retrieved from the Varsome browser. All variants were annotated to RefSeq NM_002971.5. Using CRISPR-Cas9, we generated two lines of zebrafish satb1 bearing frameshift mutations; both lines were crossed to obtain full KOs. Growth was monitored from 3 to 12 weeks post-fertilization (wpf) and expression of pituitary hormones was analyzed at 6 wpf by quantitative PCR. Results: No variants predicted as damaging were found in the short stature cohort. Nevertheless, variants of uncertain significance (VUS, mostly intronic) were found in 11% of our cohort, in which 57% of the individuals that carry a VUS presented familial short stature while 43% were non-familial. Interestingly, the variant c.515+112G>A was identified in 3/33 (9.1%) of SGA patients, but only in 2/143 (1.4%) of ISS patients. No CNVs were observed. In the zebrafish model, satb1 knockout led to significantly smaller size at 3 wpf, compared with heterozygous and wild type controls (median standard length: 6.6, 7.4, and 7.8 cm, and mean weight: 2.7, 4.3, and 4.6 mg, respectively, P<0.05 for all comparisons). At 6 wpf, we identified a trend for lower gh1 expression in the KOs vs. heterozygous zebrafish (relative quantification: 0.68 vs. 1.79, P=0.06). Conclusion: Our results support a role for SATB1 in regulating growth hormone production across species. Although loss of SATB1 function could theoretically lead to growth hormone deficiency in humans, defects in this gene do not seem to play a crucial role in the height of individuals with short stature.