Growth Hormone Group Research Articles

An interaction between growth hormone/insulin-like growth factor-1 and vitamin D in children with short stature

There are disorders in the growth hormone (GH)/growth factors system in a significant part of patients with short stature; first of all, this concerns such diseases as growth hormone deficiency, where there is a sharp decrease in GH, insulin-like growth factor-1 (IGF-1). The association between vitamin D and GH/growth factor system remains unclear. It was found that vitamin D is able to increase IGF-1 level in healthy individuals. Linear growth is accelerated after treatment of vitamin D deficiency in children, which may indicate the linking role of vitamin D between the proliferative cells of the growth plate cartilage and GH/growth factor system.Research objective: to determine 25-hydroxyvitamin D level in blood plasma in children with short stature, depending on the state of GH/IGF-1 system.Materials and methods. Study included 101 children with short stature: 33 children with partial somatotropic insufficiency (group 1); 44 children with complete somatotropic insufficiency (group 2); 24 children with syndrome of biologically inactive GH (group 3). Patients in groups 1 and 2 had a confirmed GH deficiency and a decrease or sharp decrease in of IGF-1 level; patients in group 3 had a normal stimulated release of GH against the background of a reduced IGF-1 level. GH, IGF-1, 25-hydroxyvitamin D, thyroid-stimulating hormone, and free thyroxine were determined in all children.Results. The average level of vitamin D in three groups corresponded to the vitamin deficiency according to international standards and was 52.24 ± 5.99 nmol/l in patients with partial somatotropic insufficiency, 67.6 ± 5.35 nmol/l in patients with complete somatotropic insufficiency and 58, ± 7.91 nmol/l in patients with syndrome of biologically inactive GH. A direct correlation was found between vitamin D and background GH level, stimulated GH level in children with both partial and complete somatotropic insufficiency. A direct correlation between vitamin D and IGF-1 level in this group of patients was also detected.Conclusions. It is advisable to determine the serum 25(OH)D in all children with short stature. Vitamin D levels should be taken into account in insulin/clonidine diagnostic tests in order to obtain a realistic indication of stimulated GH and IGF-1 levels.

Efficacy and safety of long-acting growth hormone in adult growth hormone deficiency: A systematic review and meta-analysis

Background & aimsNo meta-analysis has analysed efficacy and safety of long-acting growth hormone (GH) therapy in adult GH deficiency. We undertook this meta-analysis to address this gap in knowledge MethodsElectronic databases were searched for RCTs involving adult GH deficiency patients receiving weekly long-acting GH as compared to daily GH/placebo controls. Primary outcome was to evaluate changes in body-composition parameters. Secondary outcomes were to evaluate alterations in glycaemia and adverse-events. ResultsData from 5 studies involving 648 patients were analysed (4 studies having daily GH as active controls; 1 study having placebo as passive controls). Over 24–34 weeks clinical use, patients receiving long-acting GH had comparable change in lean mass [MD-0.28 kg (95%CI: 0.94 – 0.38); P = 0.41; I2 = 29% (low heterogeneity)] and fat mass [MD-0.10 kg (95%CI: 1.97–1.78); P = 0.92; I2 = 77%(considerable heterogeneity)] as compared to daily GH injections. Long-acting GH use was associated with significantly lower visceral adipose tissue [MD-1.75 cm2(95%CI: 2.14 to −1.35); P < 0.01; I2 = 0% (low heterogeneity)] and higher gynoid fat-mass [MD 0.14 kg(95%CI:0.02–0.26); P = 0.03] compared to daily GH injections. Total adverse events [Risk ratio (RR) 1.65 (95% CI: 0.83–3.29); P = 0.15; I2 = 68%] and severe adverse events [RR 0.60 (95% CI: 0.30–1.19); P = 0.14; I2 = 0%] were not significantly different in long-acting GH group compared to controls. Occurrence of headache, arthralgia, nasopharyngitis, new onset diabetes, anti-GH antibodies were comparable among groups. Long-acting GH users had significantly higher treatment adherence compared to controls [OR 4.80 (95%CI:3.58–6.02); P < 0.01; I2 = 0%]. ConclusionLong-acting GH has comparable beneficial impact on body composition parameters in adult GH deficiency, is well tolerated without any increased adverse events.

Impact of growth hormone supplementation on improving oocyte competence in unexplained poor embryonic development patients of various ages

Objectives To evaluate the effectiveness of Growth hormone (GH) co-treatment during in vitro fertilization (IVF) cycles in women of different ages who manifest unexplained poor embryonic development. Method This cohort study included a total of 2647 patients with unexplained poor embryonic development in their previous IVF procedures: 872 women received GH co-treatment and 1775 untreated women served as a control group. Patients were divided into 6 groups according to treatment and stratified by age (<35 years of age, A-GH group and A-control group; 35–40 years, B-GH group and B-control group; and ≥40 years, C-GH group and C-control group). The primary outcome was the oocyte-cleavage rate and the clinical pregnancy rate (CPR). Results The oocyte-cleavage rates among the three age groups were significantly higher in the GH group compared to the same-aged control group. In both group A and group B, there was no significant difference in clinical pregnancy rate between the GH group and controls. However, in patients ≥40 years of age, the clinical pregnancy rate in the GH group was significantly higher than in the control group (31.8% vs. 13.7%, p = 0.019). In the three age groups, there was no significant difference in the live birth rate between the GH group and controls. In the multivariate logistic regression analysis model, in both group A and group B, the number of cleaved embryos was independent predictors for CPR (OR = 1.464, 95% CI: 1.311–1.634; respectively, OR = 1.336, 95% CI: 1.126–1.586); Besides, in both group B and group C, age was independent predictors for CPR (OR = 0.657, 95%CI: 0.555–0.778; respectively, OR = 0.622, 95%CI: 0.391–0.989). However, only in group C, supplementation GH increased CPR as compared with not supplementation GH (OR = 2.339, 95%CI: 1.182–6.670). Conclusions For patients with unexplained poor embryonic development, supplementation with GH increased the oocyte-cleavage rates in all three age groups, and the clinical pregnancy rate gradually improved commensurate with increasing age. There was no difference in the clinical pregnancy rate in group A and group B, but group C improved significantly. Therefore, compared with patients under 40 years of age, patients ≥40 may benefit more from GH supplementation.

Effects of Astragalus Extract Mixture HT042 on Circulating IGF-1 Level and Growth Hormone Axis in Rats.

Astragalus extract mixture HT042 is a standardized functional food granted by the Korean FDA for promoting “Children’s Height Growth”. In this study, we determined whether HT042 affects circulatory Insulin-like growth factor-1 (IGF-1) after administration and investigated whether Growth hormone (GH), Growth hormone-releasing hormone receptor (GHRH-R), and Growth hormone secretagogue receptor (GHS-R) mRNAs are expressed in the pituitary, and whether Growth hormone-releasing hormone (GHRH) and Somatostatin (SST) are expressed in the hypothalamus. We also evaluated the growth effect of HT042 on endochondral bone formation. Male Sprague-Dawley rats in the control and HT042 groups were orally administered a single dose of the control and HT042, respectively, and those in the recombinant human GH (rhGH) group were subcutaneously injected with rhGH. Tetracycline was injected intraperitoneally 72 h prior to sacrifice to decide endochondral bone formation. To determine the endocrine or paracrine/autocrine mechanism, we evaluated the expression of local BMP-2 and IGF-1, an immunohistochemical study after HT042 administration. It was confirmed that the growth-promoting effect of HT042 can be contributed to the increase in serum IGF-1, which can be stimulated by GH secretion. Administration of HT042 modulated the activity of GHRH-R and GHR-S in the pituitary gland and promoted GH secretion, thereby changing longitudinal growth through GH/IGF-1 mediation. Results for GHRH and SST expression demonstrated that the hypothalamus can be influenced and mediated by HT042 through a complex neuroendocrine regulatory system. In addition, it was confirmed by oral administration for 10 days that HT042 increased bone formation in cartilage, which is important for height growth. The effect of HT042 could be owing to upregulation of local Bone morphogenetic protein-2 (BMP-2) and IGF-1 expression in the growth plate, which could be regarded as a GH-dependent autocrine/paracrine pathway, as well as circulatory IGF-1.

Effect of growth hormone on thin endometrium via intrauterine infusion.

BackgroundA thin endometrium has become a common reason for the repeated implantation failure. Growth hormone (GH) can regulate the proliferation and metabolism of endometrial cells. The aim of this study was to explore the effect of GH on thin endometrium.MethodsA total of 48 female Sprague-Dawley (SD) rats were randomly assigned to the following 4 groups with 12 rats in each group: blank control, model, subcutaneous, and GH groups. The blank control group was untreated and maintained in a routine manner. The model, subcutaneous, and GH groups were intrauterine perfused with 95% ethanol during estrus. After 6–8 h, the model group was intrauterine perfused with 0.2 mL normal saline, the subcutaneous group received subcutaneous injection of 0.12 mg/kg GH dissolved in 0.2 mL normal saline, and the GH group was intrauterine perfused with 0.12 mg/kg GH dissolved in 0.2 mL normal saline. Hematoxylin and eosin (HE) staining was used to examine the thickness of the endometrium. The expression of cytokeratin and vimentin was detected by western blotting and immunohistochemistry.ResultsThe intima thickness in the GH group and blank control group was increased compared with that in the model group (P<0.01). The intima thickness in the subcutaneous group was increased compared with that in the model group, but there was no significant difference. The expression of vimentin and cytokeratin was increased in the GH (P<0.01) and blank control (P<0.01) groups compared with that in the model group.ConclusionsIntrauterine perfusion of GH can promote the regeneration and repair of thin endometrium in rats. The therapeutic effect of uterine infusion of GH is better than that of subcutaneous injection of GH.

Once-Weekly Somapacitan Versus Daily Growth Hormone in Growth Hormone Deficiency: 2-Year Efficacy Results From REAL 3, a Randomized Phase 2 Trial

Abstract Current treatment for growth hormone (GH) deficiency (GHD) requires daily injections, which can be burdensome for the patients/caregivers. Once-weekly somapacitan is a long-acting GH derivative currently in phase 3 for use in children with GHD and phase 2 for short children born small for gestational age. A phase 2, multinational, randomized, open-label, controlled trial (NCT02616562) investigated the efficacy and safety of somapacitan in children compared with daily GH (Norditropin®). GH-treatment-naïve prepubertal children with GHD received 0.04 (n=16), 0.08 (n=15) or 0.16 mg/kg/week (n=14) subcutaneous (s.c.) somapacitan, or s.c. daily GH 0.034 mg/kg/day (0.24 mg/kg/week; n=14) for 52 weeks, followed by a 104-week safety extension. In the extension phase, all patients on somapacitan received 0.16 mg/kg/week; daily GH dose remained unaltered. The 52-week efficacy and safety results have been reported previously. We report here the efficacy results after 104 weeks of GH treatment. At week 104, mean (standard deviation [SD]) height velocity (HV) in the first year of the safety extension was: 10.6 (1.4), 10.0 (1.6) and 9.2 (1.7) cm/year for 0.04/0.16 mg/kg/week (n=13), 0.08/0.16 mg/kg/week (n=15) and 0.16/0.16 mg/kg/week (n=14) somapacitan, respectively, versus 9.0 (2.3) cm/year for daily GH (n=11). Mean (SD) change from baseline in HV standard deviation score (SDS) was 8.04 (2.52), 6.21 (2.90) and 6.40 (3.04) for somapacitan, respectively, versus 6.58 (3.15) for daily GH. Compared with week 52, mean HV and HV SDS at week 104 were increased in children in the somapacitan 0.04/0.16 mg/kg/week and 0.08/0.16 mg/kg/week treatment groups. Height SDS values improved during the second year of treatment with somapacitan and daily GH, with the greatest change from baseline in the somapacitan 0.16/0.16 mg/kg/week treatment group. The mean (SD) change in height SDS from baseline to week 104 was 1.73 (0.76), 1.87 (0.81) and 2.18 (1.18) for somapacitan, respectively, versus 1.72 (0.65) for daily GH. The observed mean (SD) change in insulin-like growth factor-I (IGF-I) SDS from baseline was similar between the somapacitan 0.08/0.16 and 0.16/0.16 mg/kg/week treatment groups (3.15 [1.17] and 3.21 [1.12], respectively), and slightly higher compared with IGF-I SDS in the 0.04/0.16 mg/kg/week group (2.99 [1.05]) and the daily GH group (3.06 [1.26]). Mean IGF-I SDS values remained below the upper limit (+2) of the normal range for all treatment groups throughout the 104-week trial duration. Somapacitan was well tolerated at all doses investigated, with no new safety or local tolerability issues identified during the 104 weeks of treatment. In conclusion, at week 104, height-based outcomes were similar between somapacitan 0.16/0.16 mg/kg/week and daily GH, with comparable mean change in IGF-I SDS. Furthermore, the key improvements observed in the first year were maintained in the second year of the study.

One Year of GH Treatment for Growth Failure in Children With Anorexia Nervosa: A Randomized Placebo-Controlled Trial.

Children with anorexia nervosa (AN) are at risk of adult height deficit due to prolonged low height velocity (HV). To investigate the effects of human growth hormone (GH) injections on HV in children with AN and severe growth impairment. In this prospective, randomized, double-blind, single-center, proof-of-concept trial, children with AN and low HV (≤2 cm/year) for at least 18 months, and a bone age ≤12 years for girls and ≤14 years for boys, were randomized to receive daily subcutaneous injections of human GH (0.050 mg/kg/day) or placebo for 12 months. Change in HV after 12 months. In total, 8 patients were assigned to the GH group and 6 to the placebo group. Patients had a median (25th-75th percentile) HV of 1.0 (0.5;1.5) cm/year. The effect of GH treatment increased strongly after 6 months, with a height gain after 12 months of 9.65 (8.0;11.6) cm for the GH group vs 3.85 (1.7;7.3) cm for the placebo group, with an absolute median (2.5th-97.5th percentile) difference between the groups of 5.8 (-1.85;9.68) cm after bootstrapping. The percentage of patients with a HV > 5 cm/year during the study period was higher in the GH group than in the placebo group (100% vs 50%, P = 0.05). Adverse events occurred in similar numbers in the 2 groups, were mild or nonfatal, and did not lead to treatment being stopped. GH administration to improve HV is a potentially valid option for increasing HV in children with AN and prolonged severe growth failure.

Supplementation of the In Vitro Maturation Culture Medium of Mouse Oocytes with Growth Hormone Improves Pregnancy Outcomes.

This study aimed to examine the effects of adding growth hormone (GH) into the in vitro maturation (IVM) culture medium of mouse oocytes on pregnancy outcomes. Cumulus-oocyte complexes (COCs) were cultured in a medium with (GH group, 100 ng/mL) or without (Con group) GH. Thereafter, chromosome morphology, spindle morphology, and mitochondrial function were examined. Embryo development and blastocyst quality after in vitro fertilization were evaluated. After the embryo transfer, the implantation sites and pregnancy outcomes were evaluated. The oocyte maturation rate of the GH group (81.8 ± 9.6%) was compared to that of the Con group (81.3 ± 6.9%, P = 0.928). The proportion of morphologically abnormal spindles in GH-treated oocytes (7.1 ± 0.9%) was significantly lower than control oocytes (13.7 ± 1.3%, P = 0.032), whereas the proportion of morphologically abnormal chromosomes and mitochondrial distribution was similar between the groups. The mitochondrial membrane potential (P < 0.001) and ATP concentration (P < 0.001) in GH-exposed oocytes were higher than those in control oocytes. After fertilization, the blastocyst rate in the GH group (33.8 ± 13.2%) was significantly higher than the Con group (16.2 ± 2.0%, P = 0.003). In addition, inner cell mass (ICM) number (13.91 ± 3.48 vs. 7.00 ± 1.91, P < 0.001), total cell number (47.45 ± 8.39 vs. 37.71 ± 4.15, P = 0.007), and the ratio of ICM/total cell number (29.9 ± 8.2% vs. 18.6 ± 5.0%, P = 0.002) of blastocyst were all higher in GH group. The implantation rate (71.2 ± 1.9% vs. 39.4 ± 16.4%, P < 0.001) and litter size (8.50 ± 3.99 vs. 3.00 ± 1.22, P = 0.018) were significantly higher in the GH group. Although addition of GH into IVM culture medium does not improve oocyte maturation rate, it improves oocyte and embryo quality, which leads to better embryo development and pregnancy outcomes.

Clinical Outcomes of Frozen-Thawed Embryos Generated From Growth Hormone Stimulation in Expected Poor Responders.

ObjectiveThis study aimed to elucidate whether growth hormone (GH) adjuvant therapy significantly improves clinical outcomes for expected poor responders in frozen-thawed cycles.MethodsExpected poor responders undergoing controlled ovarian stimulation with or without GH adjuvant therapy, and subsequently underwent the first frozen-thawed transfer from January 2017 to March 2020 were retrospectively reviewed. Maternal age was matched at a 1:1 ratio between the GH and control groups. All statistical analyses were performed with the Statistical Package for the Social Sciences software.ResultsA total of 376 frozen-thawed cycles comprised the GH and control groups at a ratio of 1:1. The number of oocytes (7.13 ± 3.93 vs. 5.89 ± 3.33; p = 0.001), two pronuclei zygotes (4.66 ± 2.76 vs. 3.99 ± 2.31; p = 0.011), and day 3 available embryos (3.86 ± 2.62 vs. 3.26 ± 2.04; p = 0.014) obtained in the GH group was significantly higher than the control group in corresponding fresh cycles. The clinical pregnancy (30.3 vs. 31.0%; p = 0.883), implantation (25.3 vs. 26.2%; p = 0.829), early abortion (16.1 vs. 15.8%; p = 0.967), and live birth rates (20.6 vs. 20.8%; p=0.980) were comparable between the two groups in frozen-thawed cycles. Improvement in the clinical pregnancy (46.8 vs. 32.1%; p = 0.075), early miscarriage (10.3 vs. 20.0%; p = 0.449), and live birth rates (35.7 vs. 18.9%; p = 0.031) was found in the subgroup of poor ovarian responders (PORs) with good quality blastocyst transfer (≥4BB) following GH co-treatment.ConclusionsGH administration would increase oocyte quantity and quality, in turn, improve live birth rate in PORs.

The Effect of 3-Month Growth Hormone Administration and 12-Month Follow-Up Duration among Heart Failure Patients Four Weeks after Myocardial Infarction: A Randomized Double-Blinded Clinical Trial.

Background The probable impact of growth hormone (GH) as a heart failure (HF) treatment strategy is still less investigated. Therefore, we aimed to evaluate the relation of 3-month GH prescription on left ventricular ejection fraction (LVEF), interventricular septum (IVS), posterior left ventricle (LV) thickness, end systolic and end diastolic diameters (ESD and EDD), and pulmonary arterial pressure (PAP) among Iranian individuals suffering from HF due to MI attack. Methods A total of 16 clinically stable participants with HF diagnosis and LVEF < 40% were selected for enrollment in this pilot randomized double-blinded study. They were randomly assigned equally to groups received 5 IU subcutaneous GH or placebo. Injections were done every other day for a total of 3-month duration. After termination of intervention and nine months afterwards, cardiac outcomes were assessed. Results Baseline and 12-month posttrial participants' characteristics were similar. LVEF was increased significantly by three months started from baseline in individuals receiving GH (32 ± 3.80% to 43.80 ± 4.60%, P = 0.002). During the next 9 months of follow-up concurrent with cessation of injections, LVEF was declined (43.80 ± 4.60% to 32.20 ± 6.97%, P = 0.008). LVEF and ESD were remarkably higher and lower in GH group compared with controls by the end date of injections (43.80 ± 4.60% vs. 33.14 ± 4.84%, P = 0.02 and 39.43 ± 3.45 mm vs. 33 ± 3.16 mm, P = 0.03, respectively). No other considerable association was found in terms of other predefined variables in neither GH nor placebo groups. Conclusions GH administration in HF patients was associated with increased LVEF function. Several randomized clinical trials are necessary proving this relation. This trial is registered with IRCT201704083035N1.

Desmopressin Suppresses Gonadotropin-Induced Spermatogenesis in Patients With Pituitary Stalk Interruption Syndrome: A Retrospective, Single-Center Cohort Study

ObjectiveTo explore the influence of desmopressin on gonadotropin-induced spermatogenesis in patients with pituitary stalk interruption syndrome (PSIS). MethodsA single-center retrospective cohort study was conducted. All patients with PSIS had both gonadotropin and growth hormone (GH) deficiency. Patients were divided into desmopressin and nondesmopressin groups. The desmopressin and nondesmopressin groups were defined by the presence or absence of central diabetes insipidus, which determined whether the patient received desmopressin or not. ResultsThe average age of gonadotropin therapy was 24.3 and 26.1 in the desmopressin and nondesmopressin groups, respectively. The rate of successful spermatogenesis in the 2 groups was 31.58% and 77.27%, respectively. The period for first sperm appearance was 13.62 ± 5.95 and 13.48 ± 6.69 months, respectively. A multivariable Cox proportional hazards model found that the adjusted hazard ratio for desmopressin was 0.260, indicating a “possible” detrimental effect of desmopressin on spermatogenesis. Central diabetes insipidus would be expected to show a similar detrimental effect. The spermatogenesis rate decreased with increased dosage of desmopressin. In the nondesmopressin group, the rate of spermatogenesis was similar between the GH group and the non-GH subgroup. The GH group had higher sperm count and concentration than the non-GH group. ConclusionA minority of patients with PSIS had mild diabetes insipidus and received desmopressin therapy. The spermatogenesis rate decreased with increasing desmopressin dosage. In addition, GH supplementation did not affect the spermatogenesis rate.

Effects of growth hormone on cognitive, motor, and behavioral development in Prader-Willi syndrome children: a meta-analysis of randomized controlled trials.

The benefits of growth hormone (GH) therapy in Prader-Willi syndrome (PWS) children are well established, but there is still considerable controversy regarding whether GH treatment can improve cognitive, motor, and behavioral development in PWS children. The objectives of this meta-analysis were to quantitatively evaluate the effects of GH on cognitive, motor function, and behavioral development in PWS children. Randomized controlled trials (RCTs) examining the effects of GH on cognitive, motor, and behavioral development in PWS children were identified by searching the MEDLINE, EMBASE, and Cochrane Library databases. Intervention effects were represented by Hedges'g and pooled to calculate effect sizes using a random-effects model. Ten relevant studies comprising data from 302 participants were finally included. We observed no significant difference in cognitive performance between the GH treatment group and the control group (p = 0.197). GH treatment was shown to remarkably improve motor development in PWS children compared with the control treatment (p < 0.001), with moderate positive treatment effects (Hedges'g [95% CI] = 0.71 [0.38, 1.03]). There were no significant differences between the GH group and the control group based on objective assessments of behavioral development (p = 0.53). The meta-analysis suggested that GH treatment had a significantly positive effect on motor development, with moderate treatment effects in PWS children; however, there was no evidence of effects on cognitive or behavioral development.

Comparative study of the influence of dehydroepiandrosterone versus growth hormone on the improvement of ovarian reserve markers in women with diminished ovarian reserve

Background: The study aimed to evaluate the effects of dehydroepiandrosterone (DHEA) and growth hormone (GH) supplementation on the improvement of the ovarian reserve markers in women with history of POR in the previous In vitro fertilization (IVF) cycles. Patients and methods: 90 adult female with POR were randomly allocated into 3 groups; each group included 30 patients. Control group received HMG/GnRH antagonist protocol. GH group received GH/HMG/GnRH antagonist protocol. Patients received daily subcutaneous injection of 2.5mg of GH from day 21 of previous cycle, until the day of HCG injection. DHEA group received DHEA/HMG/GnRH antagonist protocol. Patients received 25 mg of micronized DHEA, administered orally three times a day, for 12 weeks before starting the cycle of ovulation induction. The number of retrieved oocytes, fertilized oocytes, and embryos transferred, chemical pregnancy rate, the clinical pregnancy rate and LBR were recorded. Results: The mean values of the number of the oocytes retrieved, the fertilized oocytes, the transferred embryo, the chemical pregnancy rate, clinical pregnancy rate, ongoing pregnancy rate and live birth rate (LBR) were statistically significant higher in the DHEA group compared to the control and the GH groups (P 0.05). Conclusion: The DHEA supplementation to the IVF protocol improved the number and quality of retrieved oocytes, the rate of clinical pregnancy and the LBR compared to the control group or the GH co-treatment to the IVF protocol.

Does growth hormone supplementation improve oocyte competence and IVF outcomes in patients with poor embryonic development? A randomized controlled trial

BackgroundMany studies have demonstrated the benefits of the addition of growth hormone (GH) to the controlled ovarian stimulation protocol in vitro fertilization (IVF) cycles in poor-respond patients, but the effect of GH on patients with poor embryonic development remain unclear. This paper was designed to investigate the efficacy of GH co-treatment during IVF for the patients with poor embryonic development.MethodA randomized controlled trial including 158 patients with poor embryo development was conducted between July 2017 and February 2019. One hundred and seven patients were randomized for GH treatment (GH group) and 51 patients for untreated (control group). The primary end-points were the clinical pregnancy and live birth rates in the two groups. The oocyte competence were assessed through calculating the mitochondrial DNA (mtDNA) copy number in corresponding cumulus granulosa cells (CGCs). Quantitative PCR were used for calculation of mtDNA copy number.ResultsRelative to the control group, GH co-treatment resulted in a significantly higher number of retrieved oocytes (10.29 ± 5.92 versus 8.16 ± 4.17, P = 0.023) and cleaved embryos (6.73 ± 4.25 versus 5.29 ± 3.23, P = 0.036). The implantation rate, clinical pregnancy rates per cycle, and live birth rate per cycle were higher in the GH group than in the control group (36.00% versus 17.86%, P = 0.005; 43.93% versus 19.61%, P = 0.005; 41.12% versus 17.65%, P = 0.006). CGCs of the GH group had significantly higher mtDNA copy numbers than CGCs of the control group (252 versus 204, P < 0.001).ConclusionsThese data provided further evidence to indicate that GH supplementation may support more live births during IVF, in patients with poor embryonic development. It also appears that oocytes generated under GH co-treatment have a better developmental competence.Trial registrationChiCTR1900021992 posted March 19, 2019 (retrospectively registered).

MON-265 Once-Weekly Somapacitan in Japanese Adults with GH Deficiency Was Well Tolerated, with Similar Efficacy to Daily GH: A Randomized Trial

Somapacitan is a long-acting, reversible albumin-binding human growth hormone (GH) derivative based on a proven protraction technology. The objective of this trial was to evaluate the safety, efficacy and treatment satisfaction of once-weekly somapacitan compared with daily GH (Norditropin®) over 52 weeks in Japanese patients with adult GH deficiency (AGHD).This was a phase 3, multicenter, randomized, open-label, parallel-group, active-controlled trial (NCT03075644). Patients previously treated with human GH were randomized 1:3 to either daily GH or somapacitan, respectively, to undergo 20 weeks of dose titration and 32 weeks of fixed-dose treatment. The primary endpoint was the incidence of adverse events (AEs) from baseline to week 53. Secondary endpoints included change from baseline in visceral, subcutaneous and total adipose tissue (VAT, SAT and TAT, respectively) assessed with computerized tomography scans; change from baseline in treatment satisfaction evaluated using Treatment Satisfaction Questionnaire for Medication (TSQM-9) scores; and occurrence of anti-somapacitan antibodies.In total, 62 patients were randomized (16 to the daily GH and 46 to the somapacitan treatment arm), of which 60 completed the trial. Baseline characteristics for daily GH vs somapacitan groups, respectively, were: 43.8% vs 47.8% female, 87.5% vs 80.4% adult-onset GH deficiency, mean (SD) age 49.3 (11.5) vs 54.1 (12.1) years, weight 67.9 (12.0) vs 69.4 (22.7) kg, body mass index 24.8 (3.7) vs 26.4 (6.7) kg/m2, and GH dose at screening 0.29 (0.14) vs 0.31 (0.17) mg. Rate of AEs per 100 patient-years was similar between treatment arms (309.8 for daily GH, 312.7 for once-weekly somapacitan); most AEs were mild (97.9% and 93.1%, respectively) and none were severe. Four AEs in the somapacitan arm were serious; all were considered unlikely related to treatment. No anti-somapacitan antibodies were detected during treatment. Mean insulin-like growth factor-I standard deviation score (IGF-I SDS) at baseline was maintained with both treatments. The majority of the patients had IGF-I SDS values below +2. No significant differences in VAT, SAT and TAT were seen in both treatment groups after 52 weeks (estimated difference, somapacitan – daily GH [95% CI]): –1.74 [–18.13; 14.66], –11.53 [–35.54; 12.48], and –12.85 [–47.31; 21.62] cm2, respectively. TSQM-9 scores were not significantly different between treatments, but showed a tendency in favor of somapacitan (estimated difference [95% CI]): 4.87 [–3.46; 13.20] for effectiveness, 6.79 [–1.04; 14.61] for convenience, and 6.88 [–1.08; 14.85] for overall satisfaction.No new safety concerns were identified. Improvements in body composition were similar in the GH and somapacitan cohorts. The safety and tolerability of somapacitan in Japanese patients with AGHD were consistent with results from the global phase 3 trial (REAL 1).

Outcomes of in vitro fertilization–embryo transfer in women with diminished ovarian reserve after growth hormone pretreatment

The study was to evaluate the in vitro fertilization–embryo transfer (IVF-ET) outcomes in women with diminished ovarian reserve (DOR) after pretreatment with growth hormone (GH). Retrospective propensity score matching study, which included 92 women received GH over 4 weeks pretreatment before their subsequent IVF cycles and 92 matched controls who underwent IVF cycles between July 2017 and August 2018. The evaluation parameters included ovarian response, embryological parameters, and pregnancy outcomes after embryo transfer (ET). The mean number of retrieved oocytes and transferable day-3 embryos were significantly higher after GH pretreatment. The implantation rate, clinical pregnancy rate, and ongoing pregnancy rate per fresh ET cycle were similar between the GH group and control group. In women who either achieved pregnancy or utilized all the embryos resulting from the index stimulation cycle, the cumulative clinical pregnancy rate was significantly higher in women with GH compared to the control group. 4 weeks pretreatment with GH could increase ovarian response to stimulation and then improved IVF-ET outcomes in women with DOR.

Adjuvant treatment strategies in ovarian stimulation for poor responders undergoing IVF: a systematic review and network meta-analysis.

Despite great advances in assisted reproductive technology, poor ovarian response (POR) is still considered as one of the most challenging tasks in reproductive medicine. The aim of this systemic review is to evaluate the role of different adjuvant treatment strategies on the probability of pregnancy achievement in poor responders undergoing IVF. Randomized controlled trials (RCTs) comparing 10 adjuvant treatments [testosterone, dehydroepiandrosterone (DHEA), letrozole, recombinant LH, recombinant hCG, oestradiol, clomiphene citrate, progesterone, growth hormone (GH) and coenzyme Q10 (CoQ10)] were included. Relevant studies published in the English language were comprehensively selected using PubMed, Embase and the Cochrane Central Register of Controlled Trials (CENTRAL) until 11 July 2018. We included studies that investigated various adjuvant agents, including androgen and androgen-modulating agents, oestrogen, progesterone, clomiphene citrate, GH and CoQ10, during IVF treatment and reported subsequent pregnancy outcomes. The administration of GnRH analogs and gonadotrophins without adjuvant treatment was set as the control. We measured study quality based on the methodology and categories listed in the Cochrane Collaboration Handbook. This review protocol was registered with PROSPERO (CRD42018086217). Of the 1124 studies initially identified, 46 trials reporting on 6312 women were included in this systematic review, while 19 trials defining POR using the Bologna criteria reporting 2677 women were included in the network meta-analysis. Compared with controls, DHEA and CoQ10 treatments resulted in a significantly higher chance of clinical pregnancy [odds ratio (OR) 2.46, 95% CI 1.16 to 5.23; 2.22, 1.08-4.58, respectively]. With regard to the number of retrieved oocytes, HCG, oestradiol and GH treatments had the highest number of oocytes retrieved [weighted mean difference (WMD) 2.08, 0.72 to 3.44; 2.02, 0.23 to 3.81; 1.72, 0.98 to 2.46, compared with controls, respectively]. With regard to the number of embryos transferred, testosterone and GH treatment led to the highest number of embryos transferred (WMD 0.72, 0.11 to 1.33; 0.67, 0.43 to 0.92; compared with controls, respectively). Moreover, GH resulted in the highest oestradiol level on the HCG day (WMD 797.63, 466.45 to 1128.81, compared with controls). Clomiphene citrate, letrozole and GH groups used the lowest dosages of gonadotrophins for ovarian stimulation (WMD 1760.00, -2890.55 to -629.45; -1110.17, -1753.37 to -466.96; -875.91, -1433.29 to -282.52; compared with controls, respectively). CoQ10 led to the lowest global cancelation rate (OR 0.33, 0.15 to 0.74, compared with controls). For patients with POR, controlled ovarian stimulation protocols using adjuvant treatment with DHEA, CoQ10 and GH showed better clinical outcomes in terms of achieving pregnancy, and a lower dosage of gonadotrophin required for ovulation induction. Furthermore, high-level RCT studies using uniform standards for POR need to be incorporated into future meta-analyses.

Bone biochemical markers in acromegaly: An association with disease activity and gonadal status.

Objective:We aim to demonstrate the effect of disease activity and gonadal status on bone biochemical parameters in patients with acromegaly.Methods:In this cross-sectional,case–control study, 73 patients with acromegaly and 64 healthy controls were included in the study. Acromegaly and control groups, as well as active/controlled acromegaly groupswere compared in terms of alkaline phosphatase (ALP), calcium, magnesium, phosphorus, parathormone (PTH) and 25-OH Vitamin D (25[OH]D), and C-terminal telopeptide of type 1 collagen (CTX). Patients with hypogonadism and normal gonadal status were also compared in terms of these parameters among patients with acromegaly.Results:The calcium, phosphorus, and CTX were increased in the acromegaly group compared to the control group (p=0.04, p=0.006, and p<0.001, respectively). Age, estimated glomerular filtration rate (eGFR), PTH, and 25(OH)D levels were similar in the acromegaly group and the control group. The ALP, calcium, phosphorus, and CTX were increased in patients with active acromegaly compared to those in remission (p=0.03, p=0.001, p=0.03, and p=0.017, respectively). Age, eGFR, ALP, calcium, and CTX were increased in acromegalic patients with hypogonadism compared in those without hypogonadism (p<0.001, p=0.004, p=0.003, p=0.001, and p=0.009, respectively) while phosphorus, PTH, and 25(OH)D levels were similar between the two groups.Conclusion:Growth hormone (GH) and insulin-like growth factor 1 (IGF-1) levels, as well as concomitant hypogonadism, play an active role in calcium and CTX levels, while phosphorus levels are associated only with IGF-1 and GH rather than hypogonadism.

Low Dose Growth Hormone Adjuvant Treatment With Ultra-Long Ovarian Stimulation Protocol in Poor Responders Showed Non-inferior Pregnancy Outcome Compared With Normal Responders.

Background: Growth hormone (GH) has long been used as adjuvant treatment in ovarian stimulation for in vitro fertilization (IVF), especially in poor responder (PR) patients. However, its clinical efficacy remains unclear, and most studies are underpowered owing to their small sample size with different regimens.Methods: Our study was divided into two parts. The first part was a parallel randomized, observational study in which 184 patients who fulfilled the criteria of poor ovarian response (POR) were enrolled and received ultra-long ovarian stimulation protocol with or without GH adjuvant therapy. For the second part, clinical data were retrospectively extracted from 163 patients classified as PRs who received 10 IU GH adjuvant therapy and 157 patients classified as normal responders (NRs) who received the same IVF protocol treatment without GH adjuvant therapy.Results: For the first part of the study, the ovarian response, the number of oocytes retrieved, and the number of available embryos transferred were all significantly higher in the GH (+) group than in the GH (–) group. The clinical pregnancy rate was significantly higher in the GH (+) group (31.9 vs. 16.7%, p = 0.0168). The miscarriage rate did not differ significantly between the groups. The ongoing pregnancy rate was also significantly higher in the GH (+) group than in the GH (–) group (26.6 vs. 14.4%, p = 0.0418). Logistic regression revealed that the chance of clinical pregnancy in the GH (+) group significant increased 2.34-fold in comparison with the GH (–) group (p = 0.018). Subgroup analysis showed that the chance of clinical pregnancy in the GH (+) group significantly increased 2.38-fold (p = 0.034). The second part of the study showed no statistical difference between the PR with GH and the NR without GH groups regarding the implantation rate (15.6 vs. 19.8%, p = 0.3254) and the clinical pregnancy rate (31.9 vs. 39.5%, p = 0.1565). The NR without GH group showed insignificantly higher chance of clinical pregnancy (OR = 1.39, p = 0.157) compared with the PR with GH group.Conclusion: Our results suggested that low-dose GH supplementation may improve ovarian response and pregnancy outcome in POR patients, particularly in patients younger than 40 years old. Moreover, the low-dose GH effect in POR patients resulted in non-inferior clinical pregnancy outcome compared with NRs.

Growth Hormone Promotes in vitro Maturation of Human Oocytes.

Increasing the success rate of in vitro maturation (IVM) for human oocytes has a major clinical significance. Previous studies have shown that growth hormone (GH) added into IVM medium could promote IVM of oocytes from non-human beings. However, few studies on systematic IVM for human oocytes with GH have been reported. Human germinal vesicle (GV) oocytes collected for IVM were cultured with different concentrations of GH to optimize the concentration. Metaphase II (MII) stage oocytes obtained from IVM were fertilized by intracytoplasmic sperm injection (ICSI). Maturation rate, fertilization rate, and blastocyst rate were assessed after IVM with or without GH. Furthermore, gene expression profiles were compared in oocytes between the two groups using single-cell RNA-seq. The optimal concentration of GH for IVM was 200 ng/ml, and the maturation rate of this group reached 70% which was double that of the control group (35%, P = 0.004). The fertilization rate (73.1 vs. 60.3%) and blastocyst rate (25.0 vs. 15.5%) both had an increasing trend in the GH group compared to controls. Single-cell RNA-Seq and real-time PCR data showed that GH could significantly enhance the expression of genes associated with meiotic progression and embryo development, such as AURKA (aurora kinase A, P = 0.007), PDIA6 (protein disulfide isomerase family A member 6, P = 0.007), LINGO2 (leucine rich repeat and Ig domain containing 2, P = 0.007), and CENPJ (centromere protein J, P = 0.039). Taken together, GH could promote maturation of human oocytes, probably through accelerating meiotic progression, balancing redox homeostasis of cellular environment, and promoting oocyte developmental competence.