Effects Of GH Research Articles

Growth hormone supplementation may improve the pregnancy rate and endometrial receptivity among women aged more than 40 years undergoing in vitro fertilization

BackgroundGrowth hormone (GH) supplements have been shown to improve pregnancy and live-birth rates, suggesting that GH has a beneficial effect on oocyte quality. However, the effects of GH on implantation and receptivity remain unknown. This study evaluated the efficacy of GH in women aged more than 40 years participating in assisted reproductive technology (ART) programs. MethodsCycles of in vitro fertilization/intracytoplasmic sperm injection-embryo transfer (IVF/ICSI-ET) in women aged more than 40 years (range, 40–43 years) between January 2009 and March 2014 at a university-based reproductive center were reviewed. Women were divided into two groups, those with and without GH co-stimulation. ART outcomes were evaluated. ResultsSupplement of GH significantly lowered cycle cancellation rate by increasing the per cycle rates of harvesting at least one oocyte and transferring at least one embryo (80.2% vs. 69.4%). GH increased the per cycle clinical pregnancy (15.9% vs. 6.8%) and favorable ultrasonic endometrial pattern (60.9% vs. 39.3%) rates. GH also increased the per transfer clinical pregnancy (19.9% vs. 9.9%) and implantation (11.2% vs. 5.2%) rates and the rate of a favorable ultrasonic endometrial pattern (65.1% vs. 45.0%). ConclusionGH supplementation reduces the cycle cancellation rate in women aged more than 40 years, and increases the favorable ultrasonic endometrial pattern, pregnancy, and implantation rates by its beneficial actions on embryo quality and endometrial receptivity.

Goos-Hänchen effect of spin waves at heterochiral interfaces

We theoretically investigate the Goos-H\"{a}nchen (GH) effect of spin-wave beams reflected from the interface between two ferromagnetic films with different Dzyaloshinskii-Moriya interactions (DMIs). The formula of the GH shift as functions of the incident angle and material parameters is derived analytically. We show that the GH effect occurs only when spin waves are totally reflected at the interface and vanishes otherwise. We further explore the GH shift of spin waves by narrow DMI strips of different widths. It is found that the induced shift is independent of the strip width down to $10$ nm, offering a novel approach to measure the DMI strength of ultra-narrow magnetic strips which is out the scope of current technology. Full micromagnetic simulations compare well with our theoretical findings. Strong distortion of edge magnetizations for narrower strips however generates a width dependence of the GH shift. The results presented in this work are helpful for understanding the GH effect in chiral magnets and for quantifying the DMI parameter in magnetic strips of sub-$50$ nm scales.

Decreased Activity of the Ghrhr and Gh Promoters Causes Dominantly Inherited GH Deficiency in Humanized GH1 Mouse Models.

Isolated growth hormone deficiency type II (IGHD2) is mainly caused by heterozygous splice-site mutations in intron 3 of the GH1 gene. A dominant-negative effect of the mutant GH lacking exon 3 on wild-type GH secretion has been proposed; however, the molecular mechanisms involved are elusive. To uncover the molecular systems underlying GH deficiency in IGHD2, we established IGHD2 model mice, which carry both wild-type and mutant copies of the human GH1 gene, replacing each of the endogenous mouse Gh loci. Our IGHD2 model mice exhibited growth retardation along with intact cellular architecture and mildly activated endoplasmic reticulum stress in the pituitary gland, caused by decreased GH-releasing hormone receptor (Ghrhr) and Gh gene promoter activities. Decreased Ghrhr and Gh promoter activities were likely caused by reduced levels of nuclear CREB3L2, which was demonstrated to stimulate Ghrhr and Gh promoter activity. To our knowledge, this is the first in vivo study to reveal a novel molecular mechanism of GH deficiency in IGHD2, representing a new paradigm that differs from widely accepted models.

Temporal patterns of lipolytic regulators in adipose tissue after acute growth hormone exposure in human subjects: A randomized controlled crossover trial

ObjectiveGrowth hormone (GH) stimulates lipolysis, but the underlying mechanisms remain incompletely understood. We examined the effect of GH on the expression of lipolytic regulators in adipose tissue (AT). MethodsIn a randomized, placebo-controlled, cross-over study, nine men were examined after injection of 1) a GH bolus and 2) a GH-receptor antagonist (pegvisomant) followed by four AT biopsies. In a second study, eight men were examined in a 2 × 2 factorial design including GH infusion and 36-h fasting with AT biopsies obtained during a basal period and a hyperinsulinemic-euglycemic clamp. Expression of GH-signaling intermediates and lipolytic regulators were studied by PCR and western blotting. In addition, mechanistic experiments in mouse models and 3T3-L1 adipocytes were performed. ResultsThe GH bolus increased circulating free fatty acids (p < 0.0001) together with phosphorylation of signal transducer and activator of transcription 5 (STAT5) (p < 0.0001) and mRNA expression of the STAT5-dependent genes cytokine-inducible SH2-containing protein (CISH) and IGF-1 in AT. This was accompanied by suppressed mRNA expression of G0/G1 switch gene 2 (G0S2) (p = 0.007) and fat specific protein 27 (FSP27) (p = 0.002) and upregulation of phosphatase and tensin homolog (PTEN) mRNA expression (p = 0.03). Suppression of G0S2 was also observed in humans after GH infusion and fasting, as well as in GH transgene mice, and in vitro studies suggested MEK-PPARγ signaling to be involved. ConclusionsGH-induced lipolysis in human subjects in vivo is linked to downregulation of G0S2 and FSP27 and upregulation of PTEN in AT. Mechanistically, in vitro data suggest that GH acts via MEK to suppress PPARγ-dependent transcription of G0S2. ClinicalTrials.govNCT02782221 and NCT01209429.

Plasma Agouti-Related Protein Levels in Acromegaly and Effects of Surgical or Pegvisomant Therapy.

GH activates agouti-related protein (AgRP) neurons, leading to orexigenic responses in mice. The relationship between serum GH and plasma AgRP, which has been shown to reflect hypothalamic AgRP, has not been evaluated in humans. To test the hypothesis that central stimulatory actions of GH on hypothalamic AgRP could be reflected in plasma AgRP in acromegaly. We studied 23 patients with active acromegaly before and for ≤2 years after surgical (n = 13) or GH receptor antagonist therapy with pegvisomant (n = 10), and 100 healthy subjects with morning fasting blood samples for AgRP, leptin, GH, and IGF-1 and anthropometric measurements. The plasma AgRP levels were higher in those with active acromegaly than in the matched healthy subjects [median, 100 pg/mL; interquartile range (IQR), 78 to 139 pg/mL vs median, 63 pg/mL; IQR, 58 to 67 pg/mL; P < 0.0001]. Plasma AgRP decreased from before to after surgery (median, 102 pg/mL; IQR, 82 to 124 pg/mL vs median, 63 pg/mL; IQR, 55.6 to 83 pg/mL; P = 0.0024) and from before to during pegvisomant therapy (median, 97 pg/mL; IQR, 77 to 175 pg/mL vs median, 63; IQR, 61 to 109 pg/mL; P = 0.006). The plasma AgRP level correlated with GH (r = 0.319; P = 0.011) and IGF-1 (r = 0.292; P = 0.002). In repeated measure analysis, AgRP was significantly associated with IGF-1. Our data have provided evidence of a stimulatory effect of GH on plasma AgRP in humans. The levels were greater in active acromegaly and decreased in parallel with GH and IGF-1 decreases with acromegaly treatment. Data from mice suggest that AgRP may mediate some of the known effects of GH on energy metabolism. This warrants further study in patients with acromegaly and other populations.

Treatment of Children With GH in the United States and Europe: Long-Term Follow-Up From NordiNet® IOS and ANSWER Program.

ContextUnderstanding real-world prescribing of GH may help improve treatment of eligible patients.ObjectiveOverall: to assess real-world effectiveness and safety of GH (Norditropin). This analysis: to compare clinical characteristics of GH-treated children in the United States and Europe.DesignThe American Norditropin Studies: Web-Enabled Research Program (ANSWER; 2002 to 2016, United States) and the NordiNet International Outcome Study (NordiNet IOS; 2006 to 2016, Europe) were multicenter longitudinal observational cohort studies.SettingData were recorded in 207 (United States) and 469 (Europe) clinics.ParticipantsPatients with GH deficiency, Turner syndrome, Noonan syndrome, idiopathic short stature, Prader–Willi syndrome, or born small for gestational age, who commenced GH treatment aged <1 year.InterventionGH was prescribed by treating physicians according to local practice.Main Outcomes MeasuresBaseline data and drug doses were recorded. Data on effectiveness and safety were collected.ResultsANSWER had 19,847 patients in the full analysis set (FAS; patients with birthdate information and one or more GH prescription) and 12,660 in the effectiveness analysis set (EAS; GH-naive patients with valid baseline information). NordiNet IOS had 17,711 (FAS) and 11,967 (EAS). Boys accounted for 69% (ANSWER) and 57% (NordiNet IOS). Treatment start occurred later than optimal to improve growth. The proportion of boys treated was generally larger, children were older at treatment start, and GH doses were higher in the United States vs Europe. No new safety signals of concern were noted.ConclusionsIn most indications, more boys than girls were treated, and treatment started late. Earlier diagnosis of GH-related disorders is needed. The data support a favorable benefit–risk profile of GH therapy in children.

Serum soluble urokinase plasminogen activator receptor (suPAR) in adults with growth hormone deficiency.

Growth hormone deficiency (GHD) syndrome is associated with adverse levels of several risk factors for cardiovascular diseases (CVD), including metabolic inflammation. However, the impact of GHD and GH treatment on low-grade inflammation is unknown. The aim of the study was to establish the level of the low-grade inflammation biomarker soluble urokinase plasminogen activator receptor (suPAR) in adults with GHD and the response to long-term GH treatment. Measurements of suPAR and CRP were performed in bio-bank serum samples from 72 adults, 34 males and 38 females, with GHD before and during at least 5 years of GH treatment. Mean age was 52.5 ± 15.5 years, BMI 27.3 ± 5 kg/m2. Clinical evaluations and blood sampling were performed at routine visits. Data on demography, anthropometry, lab results and clinical events were retrieved from post-marketing surveillance study databases and medical records. suPAR and high-sensitive (hs) CRP were analysed using ELISA and immunochemistry, respectively. At baseline blood pressure, lipid profile and fasting glucose were within the normal reference range. Baseline geometric mean and 95% CI of suPAR was 2.9 (2.7–3.3) ng/mL and of CRP 2.3 (0.6–4.0) mg/L. Mean follow-up was 8 ± 2 years. The suPAR levels remained stable during follow-up, although individual increases were seen on occurrence or presence of co-morbidities. In contrast, levels of CRP decreased. In conclusion, the decrease in CRP and indirectly the absence of an expected increase in suPAR over time indicates a favourable effect of GH on low-grade inflammation.

Characterization of an intestine-specific GH receptor knockout (IntGHRKO) mouse

ObjectiveGrowth hormone (GH) has been reported to enhance the intestinal barrier; as such, recombinant GH has been administered for several intestinal diseases. However, excess GH action has been implicated in increasing the risk of intestinal dysfunction. The goal of this study was to examine the direct effects of GH on the small and large intestines to clarify the role GH plays in intestinal function through the use of a mouse model. DesignAn intestinal epithelial-specific GH receptor (GHR) knockout (IntGHRKO) mouse line was generated using Cre-lox with the villin promoter driving Cre expression. The generated mice were characterized with respect to growth and intestinal phenotypes. ResultsIntGHRKO mice showed no significant changes in body length, weight, or composition compared to floxed controls. Male IntGHRKO mice had significantly shorter large intestines at 4 and 12 months of age. Intestinal barrier function was assessed by measuring the expression of tight junction related genes, as well as levels of serum endotoxin and fecal albumin. Results showed sex differences as males had an increase in occludin levels but normal serum endotoxin and fecal albumin; while, females had changes in fecal albumin levels with normal occludin and serum endotoxin. Evaluation of glucose tolerance and fat absorption also showed sex differences as females were glucose intolerant, while males had impaired fat absorption. Histopathology revealed a trend towards decreased villus height in males, which could explain the sex difference in glucose homeostasis. ConclusionsOverall, the data demonstrate that disruption of GH on the intestinal epithelial cells modestly affects the intestinal gross anatomy, morphology, and function in a sex-specific manner.

Growth Hormone Induces Colon DNA Damage Independent of IGF-1.

DNA damage occurs as a result of environmental insults and aging and, if unrepaired, may lead to chromosomal instability and tumorigenesis. Because GH suppresses ataxia-telangiectasia mutated kinase phosphorylation, decreases DNA repair, and increases DNA damage accumulation, we elucidated whether GH effects on DNA damage are mediated through induced IGF-1. In nontumorous human colon cells, GH, but not IGF-1, increased DNA damage. Stably disrupted IGF-1 receptor (IGF-1R) by lentivirus-expressing short hairpin RNA in vitro or treatment with the IGF-1R phosphorylation inhibitor picropodophyllotoxin (PPP) in vitro and in vivo led to markedly induced GH receptor (GHR) abundance, rendering cells more responsive to GH actions. Suppressing IGF-1R triggered DNA damage in both normal human colon cells and three-dimensional human intestinal organoids. DNA damage was further increased when cells with disrupted IGF-1R were treated with GH. Because GH induction of DNA damage accumulation appeared to be mediated not by IGF-1R but probably by more abundant GH receptor expression, we injected athymic mice with GH-secreting xenografts and then treated them with PPP. In these mice, high circulating GH levels were associated with increased colon DNA damage despite disrupted IGF-1R activity (P < 0.01), whereas GHR levels were also induced. Further confirming that GH effects on DNA damage are directly mediated by GHR signaling, GHR-/- mice injected with PPP did not show increased DNA damage, whereas wild-type mice with intact GHR exhibited increased colon DNA damage in the face of IGF-1 signaling suppression. The results indicate that GH directly induces DNA damage independent of IGF-1.

Sleep-Related Breathing Disorders in Young Adults With Prader-Willi Syndrome: A Placebo-Controlled, Crossover GH Trial.

Sleep-related breathing disorders (SRBD) are common in people with Prader-Willi syndrome (PWS). Young adults with PWS benefit from GH continuation after attaining adult height by maintaining the improved body composition obtained during childhood. There are, no studies about the effects of GH on SRBD in young adults with PWS who were treated with GH during childhood. Investigate the effects of GH vs placebo on SRBD in young adults with PWS who were treated with GH during childhood and had attained adult height. Two-year, randomized, double-blind, placebo-controlled, crossover study in 27 young adults with PWS, stratified for sex and body mass index. Dutch PWS Reference Center. Crossover intervention with GH (0.67 mg/m2/d) and placebo, both over one year. Apnea hypopnea index (AHI), obstructive apnea index (OAI), central apnea index (CAI), measured by polysomnography. Compared with placebo, GH did not increase AHI, CAI, or OAI (P > 0.35). The effect of GH vs placebo was neither different between men and women, nor between patients with a deletion or maternal uniparental disomy/imprinting center defect. After two years, there was no difference in AHI, CAI, or OAI compared with baseline (P > 0.18). Two patients (7%) fulfilled the criteria of obstructive sleep apnea regardless of GH or placebo. GH compared with placebo does not cause a substantial increase in AHI, CAI, or OAI in adults with PWS who were treated with GH during childhood and have attained adult height. Our findings are reassuring and prove that GH can be administered safely.

MON-475 Growth Hormone Induces Colon Tissue DNA Damage Independently of IGF-1

Environmental insults and aging lead to DNA damage, which, if unrepaired, results in chromosomal instability and tumorigenesis. We have shown that GH suppresses phosphorylation of ATM and its target proteins p53, Chk2, and H2AX in DNA damaged non-tumorous human colon cells. We show that GH decreased DNA repair by non-homologous end-joining and DNA damage accumulation, enhancing cell transformation as evidenced by increased growth in soft agar. Prolonged high circulating GH levels in mice bearing human GH-secreting colon cell xenografts resulted in 60% increase in unrepaired DNA damage and increased number of metastatic lesions. We sought to elucidate whether GH effects on DNA damage are mediated through induced IGF-1. In non-tumorous human colon cells treated with etoposide, GH but not IGF-1 showed enhanced DNA damage. Stable disruption of IGF-1R by lentivirus expressing shRNA in vitro, or treatment with IGF-1R inhibitor PPP in vitro and in vivo, markedly induced GH receptor expression, rendering cells more sensitive to effects of GH. Suppressing IGF-1R in normal human colon cells triggered DNA damage, while when cells with disrupted IGF-1R were treated with GH, levels of DNA damage were further increased, indicating that GH effects on DNA damage were not mediated by IGF-1R, but likely by induced GH receptor. Similar results were obtained when 3-dimensional human intestinal organoid cultures were treated with PPP. To confirm these observations in vivo, nude mice were injected with GH-secreting xenografts and 7 weeks later treated with PPP (20 mg/kg, i.p., twice daily, total 4 injections). Similar to results observed in vitro, in mice with high circulating GH colon DNA damage were significantly increased when IGF-1R was disrupted by PPP, and GH receptor levels were again induced. To further confirm that GH effects on DNA damage are directly mediated by GH signaling, GHR-/- mice were injected with PPP to block IGF-1R, resulting in increased colon DNA damage in WT mice, but animals lacking GHR did not respond to induced DNA damage in the face of IGF-1 suppression. The results imply that GH directly induces DNA damage independently of IGF-1.

MON-484 Adipocyte-Specific GH Receptor Knockout Mice (AdGHRKO) Have Enhanced Insulin Sensitivity with Reduced Liver Triglycerides and Depot Specific Analyses in These Mice Suggest that GH May Have a More Substantial Effect on Subcutaneous White Adipose Tissue (WAT) Than Other WAT Depots

Global GH receptor “knockout” (GHRKO) mice have enhanced insulin sensitivity despite obesity, with a disproportionate increase in subcutaneous white adipose tissue (WAT). To better understand the direct effects of GH on WAT, we previously generated Fat-specific GHR knockout (FaGHRKO) mice using the aP2 promoter/enhancer driving Cre expression. These mice are obese but show no improvement in insulin sensitivity and have a uniform increase in WAT; therefore, FaGHRKO mice differ from global GHRKO mice with regards to insulin sensitivity and WAT distribution. FaGHRKO mice also have an unexpected increase in IGF-1 and are significantly longer (nasal-anal length). Extensive analysis of the aP2 promotor/enhancer has revealed it to be expressed in non-adipose tissues (such as hypothalamus), confounding interpretation of results when using this promoter to generate adipose-specific mice and may help explain the unexpected increase in IGF-1 and body length observed in FaGHRKO mice. In the current study we used the adiponectin promoter/enhancer to drive Cre expression and generated a new line of adipocyte-specific GHR knockout (AdGHRKO) mice. Body length, GH and IGF-1 levels are unchanged in AdGHRKO mice compared to controls. AdGHRKO mice have an improved metabolic profile with enhanced insulin sensitivity and reduced liver triglycerides despite increased adiposity. Depot specific analysis of WAT in AdGHRKO mice shows that the subcutaneous WAT depot is more dramatically influenced by removal of GHR as 1) subcutaneous depot mass and 2) adipocytes within the subcutaneous depot are enlarged to a greater extent than perigonadal fat, and 3) the subcutaneous depot has a significant reduction in fibrosis while perigonadal fat does not. In conclusion, this mouse line should provide a valuable tool for understanding the direct actions of GH on adipose tissue.

MON-311 GH Action Upregulates ABC Transporters And EMT Markers In A Syngeneic Melanoma Mouse Model

Compared to many other forms of malignancies, melanoma expresses growth hormone receptors (GHRs) to a uniquely higher degree than other human cancers. Attenuating these receptors in cultured human melanoma cells resulted in decreased proliferation, and suppressed expression of ATP-binding cassette (ABC) transporters and epithelial-mesenchymal transition (EMT) markers. We hypothesize that GH promotes both the growth of mouse melanoma in vivo and the expression of ABC transporters and EMT markers. Thus, we propose that the use of a GH antagonist (GHA) could be effective at reversing these changes. To test these hypotheses, a syngeneic mouse B16-F10 melanoma model, cell proliferation assays, Western blotting, ELISAs, and real-time RT-qPCR were used. First, the high expression levels of GHR in B16-F10 cells were verified. Then, by knocking down GHR expression via small interfering RNA, the increased cell growth stimulated by GH administration was effectively reversed, independent of (insulin-like growth factor-1) IGF-1. To distinguish the effects of GH and IGF-1 on melanoma in vivo, bovine GH overexpressing transgenic mice (bGH) and GHR-knock out mice (GHR-/-) were used. Both mouse lines have significantly elevated GH, while bGH mice also exhibit high levels of IGF-1 whereas extremely low levels found in GHR-/- mice. Mouse melanoma cells were subcutaneously injected into bGH mice, GHR-/- mice, and their corresponding wild type (WT) littermate controls. Our data revealed that the ABC transporters and EMT markers in both bGH and GHR-/- mouse melanomas were significantly higher compared to their WT controls, implying that some of these effects were attributable directly to GH as opposed to IGF-1. Data analyzed from the Cancer Genome Atlas repository also suggests that human melanomas with higher GHR levels have significantly elevated expression levels of EMT markers, validating this syngeneic mouse melanoma model. On the other hand, transgenic mice that express a GHA and that have decreased GH action as well as circulating IGF-1 showed significantly decreased melanoma sizes, suggesting that targeting GHR, resulting in a compromised GH/IGF-1 axis, could delay the progression of melanoma. In summary, these results reveal the role of GH action in the upregulation of ABC transporters and EMT markers in vivo, both relevant with regards to tumor progression and poor clinical prognoses. Importantly, GH antagonism may inhibit the progression of melanoma in vivo. Studies are ongoing to determine whether GHA treatment is beneficial in the treatment of mouse melanoma in mice, and if so, blocking GH action may be considered as an anti-melanoma therapy in humans.

Hormonal regulation of menstrual function in patients of reproductive age with acromegaly

Background: The frequency of menstrual disorders in patients with acromegaly is 4084% and are caused by three main reasons the development of normal or hypogonadotropic hypogonadism due to hyperprolactinemia or a mass effect of the tumor and direct effects of GH and IGF-1 on the reproductive system. Nevertheless the exact mechanisms of reproductive dysfunction are not clear now. Hypothalamic structures play significant role in the regulation of hypothalamic-pituitary-ovary axis, so its important to study key neuropeptides and evaluate their effects to the pathogenesis of ovarian dysfunction during excessive secretion of growth hormone.&#x0D; Aim: The aim of the work is to study the hormonal regulation of menstrual function in patients of reproductive age with acromegaly in the active stage of the disease.&#x0D; Material and methods: The study included patients with a confirmed diagnosis of acromegaly and healthy women, comparable in age and BMI. Blood serum samples were taken in the morning (89 hours) on an empty stomach for 35 days of the menstrual cycle or on any day with amenorrhea and frozen at -70C. The hormonal study was carried out by an enzyme immunoassay, in the case of a kisspeptin, with the preliminary extraction of serum samples.&#x0D; Results: The study included 31 patients with acromegaly and 15 healthy women. Between groups there was a statistically significant decrease in levels of LH (p = 0.001), FSH (p = 0.09), inhibin B (p = 0.003), and kisspeptin (p = 0.00005). The frequency of hyperprolactinemia in the cohort of patients was 51.6%. During the correlation analysis, a negative dependence of kisspeptin on the levels of GH and IGF-1 was detected (r = -0.54, p = 0.002 and r = -0.63, p = 0.0002).&#x0D; Conclusions: The severity of the central depression of regulation of menstrual function in patients with acromegaly may be due to the degree of disease activity.

Soluble delta-like 1 homolog decreases in patients with acromegaly following pituitary surgery: A potential mediator of adipogenesis suppression by growth hormone?

ObjectiveGH excess in acromegaly leads to lower fat mass and insulin resistance; both reverse following pituitary surgery. Soluble delta like-1 homolog (sDlk1) inhibits adipocyte differentiation and may mediate the antiadipogenic effects of GH. It is released into the circulation by ectodomain shedding through ‘A Disintegrin And Metalloproteinase domain 17’ (ADAM17), which also sheds soluble α-Klotho (sKlotho). Klotho is a transmembrane protein, which influences life span. sKlotho inhibits insulin signalling, and is markedly elevated in acromegaly and decreases after surgery. Therefore, we examined if sDlk1 parallels the course of sKlotho, which could explain the well-known changes in fat mass in patients with acromegaly after surgery. DesignWe measured serum levels of GH, IGF-1, sDlk1 and sKlotho (both by ELISA) in 42 treatment-naïve acromegaly patients (20 females/22 males) before and 1–3 months after transsphenoidal surgery. Data are presented as median(interquartile range). ResultsGH decreased in all patients postoperatively (in 32/42 to <1 ng/ml during oral glucose tolerance testing). Likewise, IGF-1 and sKlotho decreased in all patients, from 587 (432–708) to 195 (133–270) ng/ml, and from 4.0 (2.7–5.9) to 0.7 (0.6–1.2) ng/ml, respectively; sDlk1 fell in 40/42 subjects, from 10.7 (5.8–13.4) to 7.1 (3.7–10.4) ng/ml following pituitary surgery. P < 0.0001 for all parameters. ConclusionssDlk1 declined after pituitary surgery in our patients with acromegaly, but to a lesser extent than sKlotho. It remains to be seen whether this may contribute to the well-known postoperative changes in body composition. Our findings may extend beyond the scope of acromegaly, and thus further elucidate mechanisms in the fields of obesity and anti-ageing.

Using Alkali-Activated Cementitious Materials to Solidify High Organic Matter Content Dredged Sludge as Roadbed Material

It is difficult to treat dredged sludge with high organic matter content by solidification. A new solidification of dredged sludge with high organic matter content was developed, using cement, fly ash, slag, and phosphogypsum as a solidifier and strong oxidant KMnO4and GH as additives, to improve the engineering performance of dredged sludge and make it as a roadbed material possible. The properties of the solidified samples were determined in terms of unconfined compressive strength, products of hydration, toxicity characteristics, water stability, freeze-thaw resistance, and volume stability. The microstructure and hydration products of the dredged sludge after solidification were evaluated by X-ray diffraction analysis, scanning electron microscopy, and thermogravimetry-differential scanning calorimetry analysis. Experimental results showed that the strength of the solidified samples has been significantly improved after treatment by strong oxidants. The effect of GH is better than that of KMnO4. Hydration products (ettringite) were well formed. After solidification by using the binders and strong oxidant GH, the samples had sufficient strength and good water stability performance, freeze-thaw resistance performance, and volume stability performance. The leach liquid of the dredged sludge solidified body meets the standard requirements. So, the dredged sludge after solidification can reach the requirement of the roadbed material.

Expression of the growth hormone receptor isoforms and its correlation with the metabolic profile in morbidly obese subjects.

Given the lipolytic effect of GH and its potential role in determining adipose tissue distribution, we evaluated the expression of the GH hormone receptor (GHR) isoforms in patients with morbid obesity seeking associations with metabolic parameters. 262 morbidly obese subjects (mean age 42.5 ± 11 years, 75% women) underwent PCR-genotyping of the exon 3 GHR polymorphism. In 17 of these subjects, who proved to be heterozygous for the exon 3 genotype (+3/-3), subcutaneous and visceral adipose tissue was obtained during bariatric surgery; total RNA was extracted, reversely transcribed, and the different isoforms of the GHR (exon 3 containing and lacking flGHR as well as the trGHR) were PCR-amplified using specific primers. 27% were +3/+3 homozygous, 20% -3/-3 homozygous and 53% were +3/-3 heterozygous. Compared to subjects homozygous for the +3 genotype, homozygous and heterozygous carriers of the -3 genotype were significantly heavier and tended to have a higher HOMA 2-IR. Expression of the flGHR and trGHR mRNA was demonstrated in all evaluated samples of subcutaneous and visceral adipose tissue from the 17 patients. The exon 3+ isoform was expressed in all adipose tissue samples, whereas only six subjects expressed the 3- isoform as well. The only distinctive feature of these six patients was a higher HbA1c. The heterozygous GHR +3/-3 genotype is more prevalent in subjects with morbid obesity. Patients expressing the exon +3 and exon -3 isoforms in adipose tissue had a higher HbA1c, than those expressing only the exon -3 isoform.

Adult-Onset Hepatocyte GH Resistance Promotes NASH in Male Mice, Without Severe Systemic Metabolic Dysfunction.

Nonalcoholic fatty liver disease (NAFLD), which includes nonalcoholic steatohepatitis (NASH), is associated with reduced GH input/signaling, and GH therapy is effective in the reduction/resolution of NAFLD/NASH in selected patient populations. Our laboratory has focused on isolating the direct vs indirect effects of GH in preventing NAFLD/NASH. We reported that chow-fed, adult-onset, hepatocyte-specific, GH receptor knockdown (aHepGHRkd) mice rapidly (within 7 days) develop steatosis associated with increased hepatic de novo lipogenesis (DNL), independent of changes in systemic metabolic function. In this study, we report that 6 months after induction of aHepGHRkd early signs of NASH develop, which include hepatocyte ballooning, inflammation, signs of mild fibrosis, and elevated plasma alanine aminotransferase. These changes occur in the presence of enhanced systemic lipid utilization, without evidence of white adipose tissue lipolysis, indicating that the liver injury that develops after aHepGHRkd is due to hepatocyte-specific loss of GH signaling and not due to secondary defects in systemic metabolic function. Specifically, enhanced hepatic DNL is sustained with age in aHepGHRkd mice, associated with increased hepatic markers of lipid uptake/re-esterification. Because hepatic DNL is a hallmark of NAFLD/NASH, these studies suggest that enhancing hepatocyte GH signaling could represent an effective therapeutic target to reduce DNL and treat NASH.

Regulatory Role for Growth Hormone in Statural Growth: IGF-Dependent and IGF-Independent Effects on Growth Plate Chondrogenesis and Longitudinal Bone Growth.

It was initially thought that the growth-promoting effects of GH were exclusively mediated by liver-derived Insulin-like Growth Factor-I (IGF-I). Subsequent studies demonstrated that GH promotes IGF-I synthesis and activity in other organs and in the growth plate. GH has also IGF-I-independent growth-promoting effects. In Igf1 null mice, high circulating GH levels may be responsible for normal chondrocyte proliferation. Furthermore, tibial growth is reduced more in Ghr null mice than in Igf1 null mice, while the body of mice lacking both Ghr and Igf1 is smaller than that of mice lacking Igf1 or Ghr. The increased IGF-II expression in the growth plate in Igf1 null mice suggests that the IGF-I-independent effects of GH may be mediated by IGF-II. The effects of Igf1 receptor (Igf1r) gene deletion in chondrocytes indicate that GH may promote growth directly at the growth plate even when the local effects of IGF-I and IGF-II are abrogated.

Improved Mental and Motor Development During 3 Years of GH Treatment in Very Young Children With Prader-Willi Syndrome.

Infants and toddlers with Prader-Willi syndrome (PWS) have mental and motor developmental delay. Short-term data suggest a positive effect of GH on mental and motor development in infants and children with PWS. There are, however, no longer-term results about the effects of GH treatment on mental and motor development. To investigate the longer-term effects of GH on psychomotor development in infants and toddlers with PWS and the effect of age at start of GH treatment on psychomotor development. Prospective cohort study during 3 years of GH treatment. The PWS Reference Center in the Netherlands. All children were treated with GH 1 mg/m2/d (≈0.035 mg/kg/d). Mental and motor developmental age assessed with Bayleys Scales of Infant Development II and expressed as percentage of the expected development (100%). During 3 years of GH, mean (SEM) mental development increased from 58.1% (2.8) at baseline to 79.6% (3.7), and motor development increased from 41.9% (2.9) to 78.2% (3.9; both P < 0.01). A lower baseline psychomotor development and a younger age at start of GH treatment were associated with a higher increase in mental and motor development (P < 0.01). Mental and motor development increased significantly during 3 years of GH treatment, reducing the gap between infants with PWS and healthy peers. A younger age at start of GH treatment leads to greater improvement in psychomotor development.