Growth Hormone & Igf Research最新文献

The hormone secretion of GHRH-GH-IGF-1 axis in animals was decreased as aging. These hormones play an important role in maintaining bone mass and bone structure, and also affect the normal structure and function of the skin. We used plasmid-based technology to deliver growth hormone releasing hormone (GHRH) to elderly mice. In the current study, 80 and 120 μg/kg pVAX-GHRH plasmid expression plasmid were injected into old mice, the serum GHRH and insulin-like growth factor-1(IGF-1) content were increased within three weeks (P < 0.05). In the groups of 80 and 120 μg/kg plasmid, the content of procollagen type I N-terminal pro-peptide (PINP) in the serum was increased(P < 0.05), and the content of C-terminal telopeptides of type I collagen (CTX-1) in the serum was reduced significantly (P < 0.05). Furthermore, the expression of osteoprotegerin (OPG) and osteocalcin (OCN) in the femur also was increased(P < 0.05). The bone mineral density(BMD)、trabecular bone volume (BV/TV) and trabecular number(Tb.N) of mouse femur were increased significantly (P < 0.05) and trabecular separation(Tb.Sp) was decreased(P < 0.05). There were more trabecular bones in the bone marrow cavity and the trabecular bones are thicker in the groups of 80 and 120 μg/kg plasmid relative to control. The superoxide dismutase (SOD) content in the skin was increased(P < 0.05), and the malondialdehyde (MDA) content was reduced significantly (P < 0.05). Meanwhile, the skin moisture content also increased significantly(P < 0.05). Moreover, the expression of matrix metalloproteinase 3(MMP3) and matrix metalloproteinase 9(MMP9) was decreased in the skin(P < 0.05). The thickness of the dermis and epidermis of the skin had increased significantly(P < 0.05). Skin structure is more dense and complete in the two groups. These results indicate that 80 and 120 μg/kg plasmid-mediated GHRH supplementation can improve osteoporosis and skin aging in aged mice.

Objective

To ascertain the clinical magnitude of raloxifene administration on insulin-like growth factor-1 (IGF-1) and insulin-like growth factor-binding protein 3 (IGFBP-3) levels.

Methods

A systematic comprehensive search was performed without language limitation up to 14 December 2020. We included only trials that assessed the effect of raloxifene on IGF-1 and IGFBP-3 in adults. Meta-analysis was performed using the Stata software (Stata Corp. College Station, Texas, USA).

Results

Seven arms were included, encompassing postmenopausal women with type 2 diabetes mellitus, postmenopausal women with breast cancer, healthy postmenopausal women, and healthy elderly men. Raloxifene therapy significantly reduced IGF-1 levels (WMD: −2.92 nmol/L, 95% CI: −3.49, −2.35, p < 0.001) compared to placebo. Raloxifene dosage ˃60 mg/day (WMD: −3.29 ng/mL, 95% CI: −3.50 to −3.08, I² = 0.0%) decreased IGF-1 levels more than 60 mg/day (WMD: −2.29 ng/mL, 95% CI: −2.90 to −1.69, I² = 16%). Moreover, intervention duration ˃26 weeks (WMD: −3.48 ng/mL, 95% CI: −5.26 to −1.69, I² = 0.0%) reduced IGF-1 levels more than ˂26 weeks (WMD: −2.55 ng/mL, 95% CI: −3.31 to −1.79, I² = 92%). In contrast, overall results from the random-effects model did not suggest a significant change in IGFBP-3 levels upon raloxifene therapy.

Conclusion

Raloxifene therapy significantly reduced serum levels of IGF-1 levels but without changes in IGFPB-3 levels.

PAPP-A2 deficiency is a novel syndrome characterized by short stature due to low IGF bioactivity, skeletal abnormalities and decreased bone mineral density (BMD). Treatment with recombinant human IGF-1 (rhIGF-1) for 1 year demonstrated to increase growth velocity and BMD, without reported adverse effects, but data regarding the long-term efficacy and safety of rhIGF-1 administration in this entity has not yet been reported.

Two Spanish siblings with short stature due to a homozygous loss-of-function mutation in the PAPP-A2 gene (p.D643fs25*) were treated with rhIGF-1 twice daily for six years. Growth velocity continued to increase and both patients achieved their target height. Free IGF-1 concentrations increased notably after rhIGF-1 administration, with serum IGFBP-3, IGFBP-5 and ALS levels also being higher during treatment. BMD was progressively normalized and an increase in lean mass was also noted during treatment. No episodes of hypoglycemia or any other adverse effects were documented. An increase in the growth of kidney and spleen length was observed in one of the patients.

Objective: Milk protein may stimulate linear growth through insulin-like growth factor-1 (IGF-1). However, the effect of plant proteins on growth factors is largely unknown. This study assesses the effect of combinations of milk and rapeseed protein versus milk protein alone on growth factors in children.

Design: An exploratory 3-armed randomized, double-blind, controlled trial was conducted in 129 healthy 7–8 year-old Danish children. Children received 35 g milk and rapeseed protein (ratio 54:46 or 30:70) or 35 g milk protein per day for 4 weeks. The primary outcome was difference in IGF-1 changes between intervention groups after 4 weeks. Secondary outcomes included changes in IGF-1 after 1 week and changes in insulin-like growth factor binding protein-3 (IGFBP-3), IGF-1/IGFBP-3, insulin, height, weight and body composition after 1 and 4 weeks. Results were analysed by multiple linear mixed-effect models.

Results: There were no differences in changes of plasma IGF-1, insulin-like growth factor binding protein-3 (IGFBP-3), IGF-1/IGFBP-3 ratio or insulin between groups after 1 or 4 weeks based on 89 complete cases (P > 0.10). IGF-1 increased by 13.7 (95% CI 9.7;17.7) ng/mL and 18.0 (14.0;22.0) ng/mL from baseline to week 1 and 4, respectively, a 16% increase during the intervention. Similarly, insulin increased by 31% (14; 50) and 33% (16; 53) from baseline to week 1 and 4. Fat-free mass index (FFMI) increments were higher with milk alone than rapeseed blends (P < 0.05), coinciding with a trend towards a lower height increment. Body mass index increased within all groups (P < 0.05), mainly due to an increase in FFMI (P < 0.01).

Conclusion: There were no differences in changes of growth factors between the combinations of milk and rapeseed protein and milk protein alone in healthy, well-nourished children with a habitual intake of milk. Within groups, growth factors increased considerably. Future studies are needed to investigate how intakes of plant and animal proteins affect childhood growth.

Background

Isolated growth hormone deficiency (IGHD) due to mutations in GH1 gene is a rare disease caused by deficient production of endogenous growth hormone (GH).

Methods

We reported the clinical manifestation and genetic diagnosis (whole exome sequencing [WES], nested PCR Sanger sequencing, and rtPCR) of a family with two children with IGHD type I. We conducted a systematic review of cases with IGHD and compared height, and treatment outcomes in subtypes of IGHD.

Results

The patients were siblings born of nonconsanguineous parents from the Chinese Han population. The siblings both presented significantly short stature without other apparent abnormalities. The patients carry compound heterozygous mutations in GH1: a deletion and c.456 + 1G > A mutation that led to abnormal splicing. The systematic review identified 365 IGHD cases with GH1 mutations. Among these patients, their body height was most severely impaired in patients with IGHD type Ia, and the height standard deviation score decreased with the age of diagnosis in IGHD type Ia. Patients with IGHD type II had the longest duration of rhGH treatment, while patients with IGHD type Ib had the highest relative height improvement.

Conclusion

We identified two patients with IGHD type I caused by compound heterozygotic GH1 deletion and splicing mutation. The analysis of previously published IGHD patients suggests differences in linear growth among subtypes of IGHD.

Background

Current guidelines indiscriminately recommend magnetic resonance imaging (MRI) of the pituitary gland in pediatric growth hormone deficiency (GHD). The relationship between abnormal MRI, most importantly a tumor, and peak GH levels is not well known.

Methods

In this retrospective chart review, pituitary MRI results of children, ages of 3–16 years with GHD were collected and divided into 3 groups according to peak stimulated GH levels; ≤5, 5–7.4 and 7.5–10 ng/mL, Groups A, B & C respectively. Clinical and MRI findings were compared between the groups.

Results

A total of 399 children were included. Abnormal MRI was found in 36.9% of group A subjects, compared to group B (16.7%) and group C (17.0%), both p values =0.0002. Children with multiple pituitary hormonal deficiencies (MPHD) had a higher rate of abnormalities than those with isolated GHD. Children with isolated GHD were more likely to have abnormal MRI with peak GH level < 5 ng/mL compared to those with levels, 5–7.4 & 7.5–10 ng/mL. 4 children in group A had a craniopharyngioma. ROC analysis comparing peak GH levels with abnormal MRI findings showed an area under the curve (AUC) of 0.614 and 0.728 for IGHD and MPHD, respectively.

Conclusion

Although abnormal MRI was found in all 3 study groups, it was more likely at GH level < 5 ng/mL and in children with MPHD. To avoid missing a tumor, the importance of imaging in children with GHD and peak GH levels <5 ng/mL cannot be overemphasized.

Objective

To analyze pregnancy course and outcomes in women treated for acromegaly and compare outcomes based on disease activity at the time of conception.

Design

Retrospective study.

Patients

Women with acromegaly diagnosed prior to or during pregnancy from 2010 to 2019, representing cases (14 pregnancies in 12 cases), were later stratified based on active (n = 5) or controlled disease (n = 9) at time of conception. Female acromegalic patients over the same period constituted the ‘acromegaly cohort’ (AC) (n = 75).

Results

All cases had macroadenomas with nadir GH of 15.06 ng/ml (IQR 9–30), IGF-I index of 3.04 (1.96–3.82), for which they had undergone pituitary surgery; except two patients diagnosed during pregnancy, who received pharmacotherapy followed by surgery 4 months postpartum. Adjuvant pharmacotherapy was required in 71.4% patients and radiotherapy in 35.7%. Pregnancy occurred at a median of 2 (0.8–5.1) years after surgery and 21.4% required assisted reproduction. All had term delivery with normal APGAR except one case with gestational hypertension, who delivered a preterm baby. None had congenital malformations. Despite higher baseline IGF-I, GH and tumor volume in those with pre-conceptional active acromegaly, materno-fetal outcomes were not different from those with controlled disease (p > 0.05). Similar or greater proportion of cases had normal GH and no residual tumor postpartum, even in those with pre-conceptional active acromegaly.

Conclusion

The current study showed conducive outcomes of gestation in women treated for acromegaly and no higher rates of pregnancy parameters or complications than non-acromegaly pregnancies in the same population. Active acromegaly does not seem to have an adverse bearing on outcomes.

Aims

The aim of the study was to evaluate the prevalence and predictors of abnormal glucose tolerance (Diabetes + Prediabetes) and its resolution in Acromegaly.

Settings and design

Retrospective observational study.

Methods and material

Ninety patients with acromegaly and followed up post operatively for 1 year were included. The study cohort was divided into two groups: Group A: abnormal glucose tolerance [AGT: Diabetes + prediabetes (n = 40)] and Group B: normal glucose tolerance (NGT) (n = 50).The impact of the following parameters: age, sex, Waist Circumference(WC), Body Mass Index (BMI), duration of acromegaly, Growth Hormone (GH) levels, Insulin like Growth Factor 1 (IGF1) levels, pituitary tumour size, hypertension, and family history of diabetes as predictors for diabetes were studied pre surgery and post-surgery at 3 months and 1 year affecting glycaemia. Unpaired t-test, chi-square test and binary logistic regression analysis were used for statistical analysis.

Results

The prevalence of AGT in our cohort was 44.44% (Diabetes 37.77%, prediabetes 6.66%).Patients with AGT were older (44.2 ± 12.21 years vs. 34.92 ± 11.62 years; p = 0.00040) and had higher WC (in cm) (91.35 ± 7.87 vs.87.12 ± 6.07; p = 0.005) than NGT. Hypertension and family history of diabetes were significantly more frequent in patients with AGT. GH and IGF1 levels were not significantly different between the groups. On binary logistic regression, Sex (p = 0.0105) (OR = 6.0985), waist circumference (p = 0.0023) (OR = 1.2276) and hypertension (p = 0.0236) (OR = 1.632) were found to be significant predictors of AGT in acromegaly. After surgery 42.5% and 62.5% patients became normoglycemic at 3 months and 1 year respectively. On binary logistic regression there were no predictors for achieving normoglycemia at 3 months or 1 year, however the delta change in GH, BMI and tumour size were significant.

Conclusions

The prevalence of AGT was 44.44%. Female sex, WC and hypertension were found to be significant predictors of AGT in acromegaly. Post-surgery normoglycemia was achieved in 42.5% at 3 months and 62.5% at 1 year with no predictors for normalisation of AGT.

Objective

IGF-I and branched-chain amino acids have been reported to promote muscle hypertrophy via the stimulation of protein synthesis. Sestrin2, the function of which is regulated by leucine, has been reported to attenuate the activity of the mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) that stimulates protein synthesis. The objective of this study was to examine whether IGF-I modulates Sestrin2 abundance and to clarify the involvement of Sestrin2 in the effect of IGF-I and leucine on mTROC1.

Design

C2C12 and L6 myocytes were stimulated by leucine (1 mM) with or without pretreatment with IGF-I (100 ng/mL). Phosphorylation of p70 S6 kinase (S6K) and 4E-binding protein 1 (4E-BP1), both of which are targets of the mTORC1, was examined by western blotting. Effects of Sestrin2 small interfering RNA (siRNA) on the actions of leucine and IGF-I were examined. Sestrin2 mRNA and protein levels were also determined after Sestrin2 siRNA.

Results

Leucine increased the phosphorylation of S6K and 4E-BP1 in a dose-dependent manner. Pretreatment with IGF-I for 5 h further increased the stimulatory effect of leucine on the phosphorylation of S6K and 4E-BP1 in C2C12 cells. IGF-I increased Sestrin2 protein and messenger RNA levels. Sestrin2 siRNA increased or tended to increase basal phosphorylation of 4E-BP1 and decreased the leucine-induced phosphorylation in C2C12 and L6 cells, in particular after IGF-I treatment, suggesting the involvement of Sestrin2 in the action of leucine and IGF-I. The net increase in leucine-induced 4E-BP1 phosphorylation appeared to be attenuated by Sestrin2 siRNA. Likewise, Sestrin2 siRNA attenuated leucine-induced S6K phosphorylation in L6 cells. However, Sestrin2 siRNA did not influence leucine-induced S6K phosphorylation in C2C12 cells.

Conclusions

IGF-I and leucine cooperatively increased mTORC1 activity in C2C12 cells. IGF-I increased Sestrin2. Sestrin2 siRNA experiments showed that Sestrin2 was involved in the effect of leucine and IGF-I on mTORC1 activity in C2C12 and L6 cells, and suggested that increased Sestrin2 by IGF-I pretreatment might play a role in enhancing the effect of leucine on mTORC1.

Purpose

Evaluation of the lacrimal gland volume (LGV) and its correlation with tear film functions, serum growth hormone (GH) and insulin-like growth factor-1 (IGF-1) levels in acromegaly patients compared to a control group was aimed.

Methods

This prospective case-control study included the eyes of 38 patients with uncontrolled (UA) and 48 patients with controlled acromegaly (CA) and 44 patients with nonfunctioning pituitary adenoma. LGV of the patients was evaluated at the baseline, 3rd, and 6th-month visits with magnetic resonance imaging. Schirmer's test, tear breakup time (TBUT), and ocular surface disease index (OSDI) scores were evaluated at the same visits. Their correlation with serum IGF-1 and GH was investigated. Main outcome measure was the difference in mean LGV.

Results

The mean LGV of the acromegaly patients at the baseline visit (116.0 ± 33.2 mm³) and the 3rd-month visit (119.5 ± 36.4 mm³) was higher than the control group (65.2 ± 22.3 mm³ and 63.2 ± 22.3 mm³, respectively; p < 0.001) without any significant difference between the UA and CA patients in the LGV in three consecutive visits (p > 0.05). Among all patients, IGF-1 and GH levels showed a positive correlation with the LGV (p < 0.001; r = 0.52; r = 0.6, respectively). However, Schirmer, TBUT, and OSDI scores did not show any difference among the three groups at each visit (p > 0.05).

Conclusion

Acromegaly patients may have larger lacrimal glands compared to the controls and this increase correlated with the increased IGF-1 and GH levels. Lacrimal gland volume may have no effect on its tear film related functions.