Evaluation of the anticonvulsant and neuroprotective effect of intracerebral administration of growth hormone in rats / Evaluación del efecto anticonvulsivante y neuroprotector de la administración intracerebral de la hormona de crecimiento en ratas

Introduction The growth hormone (GH) has been reported as a crucial neuronal survival factor in the hippocampus against insults of diverse nature. Status epilepticus (SE) is a prolonged seizure that produces extensive neuronal cell death. The goal of this study was to evaluate the effect of intracerebroventricular administration of GH on seizure severity and SE-induced hippocampal neurodegeneration. Methodology Adult male rats were implanted with a guide cannula in the left ventricle and different amounts of GH (70, 120 or 220 ng/3 μl) were microinjected for 5 days; artificial cerebrospinal fluid was used as the vehicle. Seizures were induced by the lithium–pilocarpine model (3 mEq/kg LiCl and 30 mg/kg pilocarpine hydrochloride) one day after the last GH administration. Neuronal injury was assessed by Fluoro-Jade B (F-JB) staining. Results Rats injected with 120 ng of GH did not had SE after 30 mg/kg pilocarpine, they required a higher number of pilocarpine injections to develop SE than the rats pretreated with the vehicle, 70 ng or 220 ng GH. Prefrontal and parietal cortex EEG recordings confirmed that latency to generalized seizures and SE was also significantly higher in the 120 ng group when compared with all the experimental groups. FJ-B positive cells were detected in the hippocampus after SE in all rats, and no significant differences in the number of F-JB cells in the CA1 area and the hilus was observed between experimental groups. Conclusion Our results indicate that, although GH has an anticonvulsive effect in the lithium–pilocarpine model of SE, it does not exert hippocampal neuroprotection after SE. (AU)

Introducción La hormona de crecimiento (HC) es un factor que favorece la supervivencia neuronal en el hipocampo ante agresiones de diversa naturaleza. El status epilepticus (SE) es un tipo de crisis epiléptica de larga duración que produce muerte neuronal. El objetivo de este estudio fue evaluar el efecto de la administración intracerebroventricular de HC en la severidad de las convulsiones y la neurodegeneración hipocampal debida al SE. Metodología A ratas macho adultas se les implantó una cánula guía en el ventrículo lateral izquierdo y se les microinyectaron diferentes cantidades de HC (70, 120 o 220 ng/3 μl) durante 5 días; como vehículo se inyectó líquido cefalorraquídeo artificial. Las convulsiones se generaron con el modelo de litio-pilocarpina (3 mEq/kg LiCl y 30 mg/kg clorhidrato pilocarpina) un día después de la última inyección de HC. La neurodegeneración se identificó con la tinción de Fluoro-Jade B (F-JB). Resultados Las ratas a las que se les inyectaron 120 ng de HC requirieron 2 o 3 inyecciones de pilocarpina para desarrollar SE, en comparación con el resto de los grupos experimentales que requirieron solo una aplicación del convulsivante. Los registros EEG de la corteza prefrontal y parietal confirmaron que la latencia a las crisis generalizadas y al SE fue mayor en dicho grupo experimental. Todas las ratas con SE presentaron células positivas al FJ-B en el área CA1 e hilus del hipocampo, y no se identificaron diferencias entre los tratamientos. Conclusión Nuestros resultados muestran que, aunque la HC tiene un efecto anticonvulsivante, una vez que se ha desarrollado el SE no promueve neuroprotección en el hipocampo. (AU)

Evaluation of the anticonvulsant and neuroprotective effect of intracerebral administration of growth hormone in rats / Evaluación del efecto anticonvulsivante y neuroprotector de la administración intracerebral de la hormona de crecimiento en ratas

Introduction The growth hormone (GH) has been reported as a crucial neuronal survival factor in the hippocampus against insults of diverse nature. Status epilepticus (SE) is a prolonged seizure that produces extensive neuronal cell death. The goal of this study was to evaluate the effect of intracerebroventricular administration of GH on seizure severity and SE-induced hippocampal neurodegeneration. Methodology Adult male rats were implanted with a guide cannula in the left ventricle and different amounts of GH (70, 120 or 220 ng/3 μl) were microinjected for 5 days; artificial cerebrospinal fluid was used as the vehicle. Seizures were induced by the lithium–pilocarpine model (3 mEq/kg LiCl and 30 mg/kg pilocarpine hydrochloride) one day after the last GH administration. Neuronal injury was assessed by Fluoro-Jade B (F-JB) staining. Results Rats injected with 120 ng of GH did not had SE after 30 mg/kg pilocarpine, they required a higher number of pilocarpine injections to develop SE than the rats pretreated with the vehicle, 70 ng or 220 ng GH. Prefrontal and parietal cortex EEG recordings confirmed that latency to generalized seizures and SE was also significantly higher in the 120 ng group when compared with all the experimental groups. FJ-B positive cells were detected in the hippocampus after SE in all rats, and no significant differences in the number of F-JB cells in the CA1 area and the hilus was observed between experimental groups. Conclusion Our results indicate that, although GH has an anticonvulsive effect in the lithium–pilocarpine model of SE, it does not exert hippocampal neuroprotection after SE. (AU)

Introducción La hormona de crecimiento (HC) es un factor que favorece la supervivencia neuronal en el hipocampo ante agresiones de diversa naturaleza. El status epilepticus (SE) es un tipo de crisis epiléptica de larga duración que produce muerte neuronal. El objetivo de este estudio fue evaluar el efecto de la administración intracerebroventricular de HC en la severidad de las convulsiones y la neurodegeneración hipocampal debida al SE. Metodología A ratas macho adultas se les implantó una cánula guía en el ventrículo lateral izquierdo y se les microinyectaron diferentes cantidades de HC (70, 120 o 220 ng/3 μl) durante 5 días; como vehículo se inyectó líquido cefalorraquídeo artificial. Las convulsiones se generaron con el modelo de litio-pilocarpina (3 mEq/kg LiCl y 30 mg/kg clorhidrato pilocarpina) un día después de la última inyección de HC. La neurodegeneración se identificó con la tinción de Fluoro-Jade B (F-JB). Resultados Las ratas a las que se les inyectaron 120 ng de HC requirieron 2 o 3 inyecciones de pilocarpina para desarrollar SE, en comparación con el resto de los grupos experimentales que requirieron solo una aplicación del convulsivante. Los registros EEG de la corteza prefrontal y parietal confirmaron que la latencia a las crisis generalizadas y al SE fue mayor en dicho grupo experimental. Todas las ratas con SE presentaron células positivas al FJ-B en el área CA1 e hilus del hipocampo, y no se identificaron diferencias entre los tratamientos. Conclusión Nuestros resultados muestran que, aunque la HC tiene un efecto anticonvulsivante, una vez que se ha desarrollado el SE no promueve neuroprotección en el hipocampo. (AU)

Growth Hormone Cotreatment for Low-Prognosis Patients According to the POSEIDON Criteria.

Background: Poor ovarian response (POR) remains one of the most challenging conditions in assisted reproduction technology. Previous studies seemed to indicate that growth hormone (GH) was a potential solution for the dilemma of POR; however, the role GH played on the low-prognosis patients diagnosed and stratified by the POSEIDON criteria remains indistinct. Methods: This retrospective study was performed among women with POR according to the POSEIDON criteria who failed a previous in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) cycle, and the subsequent cycle was under GH cotreatment and conducted within 12 months. These participants were stratified into four groups according to the POSEIDON criteria. The comparison was implemented between the failed cycle and the cycle treated with GH. Generalized estimating equation (GEE) multivariate regression was applied for data analysis. Results: A total of 428 low-prognosis women were included in this study. GH supplementation improved the live birth rates (47.66%, 28.33%, 45.45%, and 24.07%; in groups 1, 2, 3, and 4, respectively) and the clinical pregnancy rates (OR 19.16, 95% CI 7.87-46.63, p < 0.001; OR 7.44, 95% CI 1.65-33.55, p = 0.009; OR 10.19, 95% CI 2.39-43.52, p = 0.002; OR 27.63, 95% CI 4.46-171.11, p < 0.001; in groups 1, 2, 3, and 4, respectively) in all four POSEIDON groups. The number of oocytes retrieved was significantly elevated in the subgroups with normal ovarian reserve (IRR 1.47, 95% CI 1.36-1.59, p < 0.001; IRR 1.31, 95% CI 1.15-1.49, p < 0.001; in groups 1 and 2, respectively). The number of day-3 good-quality embryos was significantly elevated in the subgroups with either normal ovarian reserve or aged young (IRR 2.13, 95% CI 1.78-2.56, p < 0.001; IRR 1.54, 95% CI 1.26-1.89, p < 0.001; IRR 1.47, 95% CI 1.10-1.98, p = 0.010; in groups 1, 2, and 3, respectively). Conclusion: Growth hormone cotreatment could ameliorate the pregnancy outcome for women with POR under the POSEIDON criteria who failed a previous IVF/ICSI cycle. The application of growth hormone for low-prognosis women who experienced a failed cycle might be considered and further studied.

Recombinant Bovine Growth Hormone-Induced Metabolic Remodelling Enhances Growth of Gilthead Sea-Bream (Sparus aurata): Insights from Stable Isotopes Composition and Proteomics.

Growth hormone and insulin-like growth factors (GH/IGF axis) regulate somatic growth in mammals and fish, although their action on metabolism is not fully understood in the latter. An intraperitoneal injection of extended-release recombinant bovine growth hormone (rbGH, Posilac®) was used in gilthead sea bream fingerlings and juveniles to analyse the metabolic response of liver and red and white muscles by enzymatic, isotopic and proteomic analyses. GH-induced lipolysis and glycogenolysis were reflected in liver composition, and metabolic and redox enzymes reported higher lipid use and lower protein oxidation. In white and red muscle reserves, rBGH increased glycogen while reducing lipid. The isotopic analysis of muscles showed a decrease in the recycling of proteins and a greater recycling of lipids and glycogen in the rBGH groups, which favoured a protein sparing effect. The protein synthesis capacity (RNA/protein) of white muscle increased, while cytochrome-c-oxidase (COX) protein expression decreased in rBGH group. Proteomic analysis of white muscle revealed only downregulation of 8 proteins, related to carbohydrate metabolic processes. The global results corroborated that GH acted by saving dietary proteins for muscle growth mainly by promoting the use of lipids as energy in the muscles of the gilthead sea bream. There was a fuel switch from carbohydrates to lipids with compensatory changes in antioxidant pathways that overall resulted in enhanced somatic growth.

Recombinant growth hormone therapy in children with Turner Syndrome in Korea: a phase III Randomized Trial.

BACKGROUND: Short stature is the most consistent characteristic feature of Turner syndrome (TS). To improve final heights of children with TS effectively, it is important to provide them with early and appropriate treatment using growth hormone (GH). The objective of this study was to assess the efficacy and safety of a new recombinant human GH, Growtropin®-II (DA-3002, Dong-A ST Co., Ltd) versus a comparator (Genotropin®, Pfizer Inc.) for Korean children with TS. METHODS: This open-label, active-controlled, parallel-group, randomized controlled phase III trial was conducted at 11 hospitals in Korea. Eligible patients (n = 58) were randomized to two groups: 1) DA-3002 group (administrated with DA-3002 at 0.14 IU [0.0450-0.050 mg] /kg/day); and 2) comparator group (administrated with the comparator at 0.14 IU [0.0450-0.050 mg] /kg/day). RESULTS: The change from baseline in annualized height velocity (HV) after a 52-week treatment period was 4.15 ± 0.30 cm/year in the DA-3002 group and 4.34 ± 0.29 cm/year in the comparator group. The lower bound of 95% two-sided confidence interval for group difference in the change of annualized HV (- 1.02) satisfied the non-inferiority margin (- 1.5). The change in height standard deviation score (HtSDS) at 52-week was 0.70 ± 0.23 for the DA-3002 group and 0.66 ± 0.39 for the comparator group, showing no significant (p = 0.685) difference between the two groups. The change of skeletal maturity defined as change in bone age/change in chronological age between the two groups was not significantly different (1.25 ± 0.58 for the DA-3002 group and 1.47 ± 0.45 for the comparator group, p = 0.134). Changes from baseline in serum insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) after 52 weeks of treatment did not differ significantly between the two groups (p = 0.565 and p = 0.388, respectively) either. The occurrence of adverse events was not statistically different between groups. CONCLUSIONS: This study demonstrates that the efficacy and safety of GH treatment with DA-3002 in children with TS are comparable with those of the comparator. It is expected to analysis the long-term effect of DA-3002 on the increase of final adult height in children with TS and possible late-onset complications in the future. TRIAL REGISTRATION: The study was registered at ClinicalTrials.gov. ClinicalTrials.gov identifier: NCT01813630 (19/03/2013).

Analysis of N15-rat growth hormone after incubation with rat subcutaneous tissue and immune cells using ultra-pressure chromatography-mass spectrometry.

Therapeutic proteins (TPs) are exposed to various immune cells like macrophages and neutrophils, especially after subcutaneous (SC) administration. It is well known that the immune cells can generate reactive oxygen species (ROS) and this may lead to oxidation of TPs. The oxidation can occur in the SC tissue after SC administration, during distribution to the immune organs like lymph nodes and spleen, and even in the blood circulation. The oxidation can lead to alteration of their pharmacokinetics and efficacy. Therefore, it is important to study the oxidation of TPs in the biological matrices using ultra-pressure chromatography-mass spectrometry. Rat growth hormone (rGH) was selected as a test protein due to its similarity with human growth hormone (hGH), which is widely used for treatment of growth hormone deficiency. In this manuscript, we have summarized sample processing strategy and ultra-pressure chromatography-mass spectrometry methodology to identify rGH and its degradation products after ex-vivo incubation with rat SC tissue, and in vitro incubation with rat splenocytes and canine peripheral blood mononuclear cells (cPBMCs) as a model foreign host species. We did not observe oxidation of rGH in these biological matrices. This could be due to very minor yields of oxidation products, lack of sensitivity of the mass spectrometry method, loss of protein during sample processing, rapid turnover of oxidized protein or a combination of all factors.

RNA-seq and nuclear proteomics provide insights into the lactation regulation mechanism of goat transfected IGF-I and GH recombinant vectors.

There exists little available information on the mechanisms of lactation regulation until now. In order to explore the underlying mechanism, we injected IGF-I and GH recombinant vectors into the mammary gland, then RNA-seq analysis and nuclear proteomics were used for rapid high-throughput screening of DEGs and DEPs in the two groups linked to lactation regulation. KEGG analysis of 206 DEGs showed that the same 4 of top 10 enrichment pathways (ECM receptor interaction, protein digestion and absorption, focal adhesion and phagosome) involved in 4 co-expressed genes (IDO, BTG1, ITGB6 and keratin 83), the two groups enriched different metabolic pathways yet. Nuclear proteomics analysis showed 75 and 36 DEPs in the IGF-I and GH group respectively; Sixteen common proteins were identified between the IGF-I group and GH group, four of which (ALB, TPT1, CXXC-5 and ACTR2) significantly decreased and three of which (PRP1, PAG-9 and Hsp70) significantly increased. Similarly, DEPs in the two groups were enriched in same one of top 10 enrichment pathways (PI3K-Akt signaling pathway). Protein-protein interaction networks highlighted the contribution of glycosphingolipid biosynthesis, porphyrin and chlorophyll metabolism and the Jak-STAT signaling pathway to lactation regulation of GH and IGFI. GH and IGF-I improve milk yield, which may be linked to important nodal proteins (ALB and ACTB). Our research advances the understanding of the mammary gland transcriptome and nuclear proteomics during GH and IGF-I overexpression. Individual genes, proteins and pathways in this study point towards potential targets for lactation regulation.

Growth hormone promotes hepatic gluconeogenesis by enhancing BTG2-YY1 signaling pathway.

Growth hormone (GH) is one of the critical factors in maintaining glucose metabolism. B-cell translocation gene 2 (BTG2) and yin yang 1 (YY1) are key regulators of diverse metabolic processes. In this study, we investigated the link between GH and BTG2-YY1 signaling pathway in glucose metabolism. GH treatment elevated the expression of hepatic Btg2 and Yy1 in primary mouse hepatocytes and mouse livers. Glucose production in primary mouse hepatocytes and serum blood glucose levels were increased during GH exposure. Overexpression of hepatic Btg2 and Yy1 induced key gluconeogenic enzymes phosphoenolpyruvate carboxykinase 1 (PCK1) and glucose-6 phosphatase (G6PC) as well as glucose production in primary mouse hepatocytes, whereas this phenomenon was markedly diminished by knockdown of Btg2 and Yy1. Here, we identified the YY1-binding site on the Pck1 and G6pc gene promoters using reporter assays and point mutation analysis. The regulation of hepatic gluconeogenic genes induced by GH treatment was clearly linked with YY1 recruitment on gluconeogenic gene promoters. Overall, this study demonstrates that BTG2 and YY1 are novel regulators of GH-dependent regulation of hepatic gluconeogenic genes and glucose production. BTG2 and YY1 may be crucial therapeutic targets to intervene in metabolic dysfunction in response to the GH-dependent signaling pathway.

Efficacy of growth hormone supplementation with ultrashort GnRH antagonist in IVF/ICSI for poor responders; randomized controlled trial.

OBJECTIVES: To compare the ICSI-ET outcomes in poor responders who underwent ovarian stimulation by the ultrashort GnRH antagonist protocol with or without adjuvant GH injection. MATERIAL AND METHODS: This randomized controlled study was conducted at Al-Azhar University from December-2018 to June-2019 upon 156 participants. All patients received the same preparations. After randomization, in the study group, women have received GH 4 IU/day subcutaneous injection from the second day of the cycle stopped one day before ovum pickup. While in the control group, women have received subcutaneous saline in the same dosing as in the study group. After intervention, all procedures were the same in both groups. The main outcome measure was the clinical pregnancy rate. Statistical analysis was based on the intention-to-treat population. RESULTS: Both groups were comparable with regard their baseline characteristics (p-values > 0.05). Ovulation characteristics were comparable (p-values > 0.05). The level of E2 is significantly (p-value = 0.003) higher in the GH group. The oocyte retrieved number was significantly (p-value < 0.001) higher in the GH group 4.94 ± 1.77 than in the control group 3.74 ± 1.82. The mean number of MII oocytes was significantly (p-value < 0.001) higher in the GH group 3.3 ± 1.36 than in the control group 2.29 ± 1.24. Fertilization characteristics, implantation rate, pregnancy rate were comparable (p-values > 0.05). CONCLUSION: Despite the fact that this study showed no significant increase in the clinical and chemical pregnancy rates by the addition of GH to the ultrashort antagonist protocol in poor responders, the number of retrieved oocytes was significantly higher in the GH group. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03759301.

Comparison of Frozen Embryo Transfer Outcomes Between Uterine Infusion of Granulocyte Colony-Stimulating Factor and Growth Hormone Application in Patients With Thin Endometrium: A Retrospective Study.

Objective: To investigate the effect of two treatments on the outcome of freeze-thaw embryo transfer for pregnancy assistance in thin endometrium. Methods: A retrospective study was conducted on 66 patients who failed in the first cycle treated in the reproductive medicine center of the Second Hospital of Hebei Medical University from January 2018 to December 2019. Granulocyte colony stimulating factor (G-CSF) was used through cavity infusion in one group (n=25, and growth hormone (GH) was subcutaneously injected in the group (n=41). The clinical data of the two groups were compared, including morphology and thickness of the endometrium, biochemical pregnancy rate, clinical pregnancy rate, implantation rate, miscarriage rate, and live birth rate in each period of the hormone replacement cycle. Results: There was no significant difference in age, BMI, AMH, FSH, LH, E2, infertility years, number of transferred embryos, basal endometrium, and thickness of endometrium on the day of P administration before and after treatment (P> 0.05). After treatment, compared to the GH group, the G-CSF group presented higher biochemical pregnancy rate (56% versus 48.8%; P=0.569), clinical pregnancy rate (52% versus 46.3%; P=0.655), implantation rate (34.8% versus 27.5%; P=0.391), and live birth rate (40% versus 31.7%; P=0.493), but the differences were not statistically significant (P > 0.05). On the 5th day of treatment, the endometrial thickness in the G-CSF group was thinner than that in the GH group (4.83 ± 0.85 versus 5.75 ± 1.27; P< 0.05), but it had no correlation with pregnancy outcome (P > 0.05). There was no significant difference in endometrial thickness between the two groups on the 7th, 9th day of treatment and the day of P administration (P > 0.05). On the 5th day of treatment, the proportion of endometrial type A morphology in the GH group was significantly higher than that in the G-CSF group (P < 0.05), while the type B morphology in the G-CSF group was significantly higher than that in the GH group (P< 0.05). Conclusion: Although G-CSF and GH may not have a role in increasing endometrium, both of them can improve the pregnancy outcomes of patients with thin endometrium in the FET cycle. And the effects of the two treatments were similar.

CASE REPORT OF THE ROLE OF OPTICAL COHERENCE TOMOGRAPHY IN RECOMBINANT GROWTH HORMONE THERAPY.

PURPOSE: To report the correlation between recombinant growth hormone (rhGH) dosage and retinal nerve fiber layer (RNFL) thickness values measured by optical coherence tomography in a case of pseudotumor cerebri syndrome (PTCS) after rhGH. METHODS: An 11-year-old girl was receiving rhGH for panhypopituitarism. The patient developed PTCS, and her rhGH dose was adjusted using optical coherence tomography RNFL thickness measurements. The linear correlation coefficient (r) and coefficient of determination (r2) were calculated to assess the relationship between RNFL thickness and rhGH dose. RESULTS: As the rhGH dosage was increased, the RNFL thickness values also increased, especially when acetazolamide was excluded because of its confounding effect. (r = 0.64) In separate subgroup analysis, a higher acetazolamide dosage strongly correlated with reduced RNFL thickness (r = 0.77). CONCLUSION: Although PTCS is a rare complication after rhGH therapy, its detrimental effects cannot be ignored. In our case report, we used optical coherence tomography RNFL values in addition to clinical findings to carefully titrate the rhGH dosage to prevent a flare-up of PTCS. Despite the obvious need for larger studies, our case report shows the value of RNFL thickness measured by optical coherence tomography and the valuable additional data it provides to refine rhGH therapy as an adjunct noninvasive method in PTCS.

Effects of Growth Hormone Supplementation on Poor Ovarian Responders in Assisted Reproductive Technology: a Systematic Review and Meta-analysis.

To investigate whether additional growth hormone (GH) treatment can improve pregnancy outcomes in poor ovarian responders (POR), this systematic review and meta-analysis is prospectively designed and has been registered in PROSPERO (Registration number: CRD42019137866). Literature search was conducted in PubMed, EMBASE, Web of Science, and Cochrane Library from January 2010 to June 2019, and studies before 2010 were included based on a Cochrane review published in 2010. Only English articles and randomized clinical trial studies were included. A total of 12 studies were included for analysis. GH treatment in poor ovarian responders significantly increased the clinical pregnancy rate (odds ratio (OR) = 1.75 (1.23, 2.50)), and the live birth rate also tended to increase after GH treatment (OR = 1.51 (0.97, 2.35)). Other outcomes including the gonadotropin requirement, oocyte retrieval number, endometrium thickness, and the number of patients with available embryos for transfer were also improved by growth hormone treatment (weighted mean differences (WMD) = - 0.78 (- 1.23, - 0.33), 1.41 (0.72, 2.09), 0.36 (0.18, 0.53), OR = 2.67 (1.47, 4.68), respectively). Based on the current study, GH treatment in POR can increase clinical pregnancy rate and show a higher but not statistically significant likelihood of live birth rate. The effect is likely to be mediated by improving ovarian response and endometrium thickness. The effect of GH treatment on live birth rate should be tested by further studies with a larger sample size.

Effects of growth hormone and cortisol administration on plasma insulin-like growth factor binding proteins in juveniles of three subspecies of masu salmon (Oncorhynchus masou).

In this study, we examined the effects of porcine growth hormone (GH) and cortisol on plasma insulin-like growth factor binding proteins (IGFBPs) in juveniles of three subspecies of Oncorhynchus masou (masu, amago, and Biwa salmon). Ligand blotting using digoxigenin-labeled human IGF-I was used to detect and semi-quantify three major circulating IGFBP bands at 41, 28, and 22 kDa, corresponding to IGFBP-2b, -1a, and -1b, respectively. GH increased plasma IGFBP-2b concentration in masu and Biwa salmon but suppressed it in amago salmon. Plasma IGFBP-2b levels were increased by cortisol in the three subspecies. Cortisol induced plasma IGFBP-1a in the three subspecies, whereas GH had a suppressive effect in masu and Biwa salmon. Sham and cortisol injections increased plasma IGFBP-1b levels after 1 day in masu and amago salmon, suggesting that IGFBP-1b is induced following exposure to stressors via cortisol. Increased IGFBP-1b levels were restored to basal levels when co-injected with GH in Biwa salmon, and the same trend was seen in masu and amago salmon. However, the suppressive effect of GH disappeared 2 days after injection in the three subspecies. Despite some differences among subspecies, the findings suggest that cortisol is a primary inducer of plasma IGFBP-1b; however, GH counteracts it in the short term. Therefore, GH has the potential to modulate the degree of increase in circulating IGFBP-1b levels during acute stress.

The Unusual Case of Fibroma of Tendon Sheath in a Young Girl with Turner Syndrome Undergoing Growth Hormone Treatment

Fibroma of tendon sheath (FTS) is an uncommon mass that arises from the tendon sheath of extremities. The tumor typically affects adults between ages 20 and 50 years with a predominance in males. To date, growth hormone (GH) treatment is safe for children with Turner syndrome without risk factors and is accepted worldwide. This article reports the case of a nine-year-old female patient with Turner syndrome and FTS during GH treatment. She had been treated with daily subcutaneous GH to improve growth failure with a mean dose of 0.28 mg/kg/week and the level of insulin-like growth factor-1 was within the normal range. During the follow-up period, she complained about a mass in her hand, subsequently diagnosed as FTS. This report illustrates the clinical impact of Turner syndrome and GH treatments on the occurrence of this tumor through literature reviews. Further studies are needed to highlight the association between FTS and GH treatment, especially in Turner syndrome.

Growth Hormone Treatment at Nippon Medical School Chiba Hokusoh Hospital.

BACKGROUND: Since 2002, the Department of Pediatrics of Nippon Medical School Chiba Hokusoh Hospital has offered educational activities for children with short stature. We analyzed outcomes of growth hormone (GH) treatment for children with short stature treated at our hospital, particularly outcomes after the growth spurt. METHODS: We analyzed data from children aged 0 to 17 years who were treated with recombinant GH during the period from 2000 through 2016 and were followed for at least 2 years after the start of treatment. RESULTS: Among children with short stature, 85 had GH deficiency, 5 had Turner syndrome, 9 were small for gestational age, and 1 had Noonan syndrome. The outcomes of GH treatment was similar to those previously reported in Japan. Children with GH deficiency who started GH treatment before the growth spurt exhibited marked height catch-up until the second year, but the effect decreased after 3 years. The effect of treatment for GH deficiency that was started after the growth spurt continued for 4 to 5 years after the start of treatment. CONCLUSIONS: Improvement in height standard deviation score was similar when treatment was started before and after the growth spurt.

Growth hormone activates PI3K/Akt signaling and inhibits ROS accumulation and apoptosis in granulosa cells of patients with polycystic ovary syndrome.

BACKGROUND: It is reported that growth hormone (GH) can alleviate oxidative stress (OS) induced apoptosis in some types of cells by activating the PI3K/Akt signaling pathway. This study investigated the role and underlying mechanism of GH in OS and apoptosis in granulosa cells (GCs) of patients with polycystic ovary syndrome (PCOS). METHODS: Primary GCs were collected from patients with and without PCOS (controls, n = 32) during oocyte retrieval. The patients with PCOS were randomly assigned to take GH treatment (PCOS-GH, n = 30) or without GH treatment (PCOS-C, n = 31). Reactive oxygen species (ROS) level was determined by spectrophotometry and fluorescence microscopy. GC apoptosis and mitochondrial membrane potential (MMP) were detected by Annexin V-FITC/PI double-staining and JC-1 staining, respectively (flow cytometry). The expression of apoptosis-related genes and proteins involved in PI3K/Akt signaling was determined by quantitative reverse-transcription polymerase chain reaction and western blotting, while active caspase-9 and caspase-3 levels of GCs were determined by enzyme-linked immunosorbent assay. RESULTS: Our study found that in GCs of the PCOS-GH group, the ROS levels and apoptotic rates were significantly decreased, whereas MMP was significantly increased when compared to those in the PCOS-C group (P < 0.05). The mRNA levels of FOXO1, Bax, caspase-9, and caspase-3 were significantly decreased, whereas Bcl-2 was increased in GCs of the PCOS-GH group than those in the PCOS-C group (P < 0.05). The protein levels of FOXO1, Bax, cleaved caspase-9/caspase-9 and cleaved caspase-3/caspase-3 were decreased, whereas p-PI3K/PI3K, p-Akt/Akt, p-FOXO1 and Bcl-2 were increased in GCs of the PCOS-GH group, compared with those in the PCOS-C group (P < 0.05). CONCLUSION: OS induced apoptosis and downregulated the PI3K/Akt signaling pathway in patients with PCOS. GH could alleviate apoptosis and activate the PI3K/Akt signaling pathway. CLINICAL TRIAL REGISTRATION NUMBER: Chinese Clinical Trial Registry. ChiCTR1800019437 . Prospectively registered on October 20, 2018.

Acromesomelic Dysplasia, Type Maroteaux: Impact of Long-Term (8 Years) High-Dose Growth Hormone Treatment on Growth Velocity and Final Height in 2 Siblings.

INTRODUCTION: Acromesomelic dysplasia, type Maroteaux (AMDM) is a rare autosomal recessive skeletal dysplasia, characterized by severe dwarfism and disproportionate limb shortening. It results from loss-of-function NPR2 mutations affecting the C-type natriuretic peptide receptor. Resistance to growth hormone (GH) action has previously been suggested. We describe outcomes of 2 siblings with AMDM after prolonged high-dose GH treatment. PATIENTS/METHODS: Two siblings (Pt-A and Pt-B; consanguineous parents) presented in early childhood with severe disproportionate short stature and radiological features of AMDM. Subsequent genetic testing identified a novel homozygous NPR2 mutation. GH provocation testing showed relatively high GH levels. Serum insulin-like growth factor 1 (IGF-1) was ∼2 SD below age/sex-specific mean. High-dose GH (0.075 mg/kg/day) was started. Pre-GH height velocities were 3.7 (Pt-A) and 4.5 (Pt-B) cm/year. GH dose was adjusted to sustain serum IGF-1 towards +3 SDS for age/sex. Annualized height velocities for first 3 years on GH were 7.0, 5.4, and 4.7 cm/year for patient A and 9.4, 8.0, and 5.9 cm/year for patient B. Height gain during puberty was 10.6 (Pt-A) and 5.9 (Pt-B) cm. Final heights after 8.5 years of GH treatment were 130.5 cm (-6.57 SDS, Pt-A) and 134 cm (-4.58 SDS, Pt-B). CONCLUSIONS: To the best of our knowledge, this is the first report of final height in patients with AMDM after long-term GH treatment. Our results confirm the finding of relative GH resistance in AMDM, which when overcome with high-dose GH treatment resulted in improved height SDS during childhood and adolescence and associated quality of life. The final height of our patients was significantly higher than average reported final height (120 cm) of AMDM patients.

Skeletal muscle repair in a rat muscle injury model: the role of growth hormone (GH) injection.

OBJECTIVE: Muscle injury tends to heal with incomplete functional recovery. Among the growth factors released in the physio-pathological response of muscle lesion, the Insulin-like Growth-Factor-1 (IGF-1) results in an engine factor of the reparation program. The therapeutic use of growth factors has been exploited to improve healing. As IGF-1 is a primary mediator of the effects of growth hormone (GH), we exploited its systemic administration to muscle recovery in a rat model of muscle injury. MATERIALS AND METHODS: Monolateral lesion of the longissimus dorsi muscle of rats was performed. Animals were divided into 5 groups: four groups for histological studies and serum hormone dosage, whilst the fifth group represented the uninjured control. Rat GH was intraperitoneally administered after 24h from the surgical lesion at three different concentrations (0.1, 0.2, 0.4 mg/kg). At 3 days from surgery, immunohistochemical and histological analyses evaluated the expression of MyoD and Myogenin, and the presence of neovascularization and inflammation, respectively. After 2 months, we analyzed the presence of muscle regeneration and fibrosis. RESULTS: The treatment with GH resulted in a significant increase in neovascularization and Myogenin expression at 24h from injury in comparison with the control. This suggested speed up biological recovery times. After two-months, a dose-dependent increase of the connective component was observed. CONCLUSIONS: The potential effect of GH on muscle repair and regeneration, through the activation of satellite cells already demonstrated in vitro, was confirmed in this in vivo experimental approach. This study sheds light on the role of growth factors in damage repair mechanisms to find an appropriate biological treatment for muscle injury.

Growth hormone cotreatment for poor responders undergoing in vitro fertilization cycles: a systematic review and meta-analysis.

OBJECTIVE: To evaluate the effectiveness of growth hormone (GH) supplementation in improving the in vitro fertilization (IVF) outcomes of poor responders. DESIGN: Systematic review and meta-analysis. SETTING: Not applicable. PATIENT(S): Poor ovarian responders undergoing conventional IVF or intracytoplasmic sperm injection (ICSI). INTERVENTION(S): Randomized controlled trials (RCTs) of poor ovarian responders undergoing a single IVF/ICSI cycle with GH supplementation versus conventional controlled ovarian stimulation. This review was registered in the PROSPERO database before starting data extraction (CRD42020151681). MAIN OUTCOME MEASURE(S): Primary outcome was live birth rate. Clinical pregnancy rate, miscarriage rate, ongoing pregnancy rate, number of oocytes, number of mature (metaphase II [MII]) oocytes and the number of embryos available to transfer were considered as secondary outcomes. RESULT(S): Twelve RCTs were included; 586 women were assigned to the intervention group and 553 to the control group. The analysis revealed that patients receiving GH supplementation did not show an increased live birth rate, miscarriage rate, or ongoing pregnancy rate. However, GH supplementation in poor responders increased clinical pregnancy rate, number of oocytes retrieved (mean difference 1.62), number of MII oocytes (mean difference 2.06), and number of embryos available to transfer (mean difference 0.76). Sensitivity and subgroup analyses did not provide statistical changes to pooled results. CONCLUSION(S): The present meta-analysis provides evidence that GH supplementation may improve some reproductive outcomes in poor responders, but not live birth rates.