Insulin-like Growth factor-I Levels Research Articles

Association of an impaired GH-IGF-I axis with cardiac wasting in patients with advanced cancer.

Growth hormone (GH) resistance is characterized by high GH levels but low levels of insulin-like growth factor-I (IGF-I) and growth hormone binding protein (GHBP) and, for patients with chronic disease, is associated with the development of cachexia. We investigated whether GH resistance is associated with changes in left ventricular (LV) mass (cardiac wasting) in patients with cancer. We measured plasma IGF-I, GH, and GHBP in 159 women and 148 men with cancer (83% stage III/IV). Patients were grouped by tertile of echocardiographic LVmass/height2 (women, < 50, 50-61, > 61g/m2; men, < 60, 60-74, > 74g/m2) and by presence of wasting syndrome with unintentional weight loss (BMI < 24kg/m2 and weight loss ≥ 5% in the prior 12months). Repeat echocardiograms were obtained usually within 3-6months for 85 patients. Patients in the lowest LVmass/height2 tertile had higher plasma GH (median (IQR) for 1st, 2nd, and 3rd tertile women, 1.8 (0.9-4.2), 0.8 (0.2-2.2), 0.5 (0.3-1.6) ng/mL, p = 0.029; men, 2.1 (0.8-3.2), 0.6 (0.1-1.7), 0.7 (0.2-1.9) ng/mL, p = 0.003). Among women, lower LVmass was associated with higher plasma IGF-I (68 (48-116), 72 (48-95), 49 (35-76) ng/mL, p = 0.007), whereas such association did not exist for men. Patients with lower LVmass had lower log IGF-I/GH ratio (women, 1.60 ± 0.09, 2.02 ± 0.09, 1.88 ± 0.09, p = 0.004; men, 1.64 ± 0.09, 2.14 ± 0.11, 2.04 ± 0.11, p = 0.002). GHBP was not associated with LVmass. Patients with wasting syndrome with unintentional weight loss had higher plasma GH and GHBP, lower log IGF-I/GH ratio, and similar IGF-I. Overall, GHBP correlated inversely with log IGF-I/GH ratio (women, r = - 0.591, p < 0.001; men, r = - 0.575, p < 0.001). Additionally, higher baseline IGF-I was associated with a decline in LVmass during follow-up (r = - 0.318, p = 0.003). In advanced cancer, reduced LVmass is associated with increased plasma GH and reduced IGF-I/GH ratio, suggesting increasing GH resistance, especially for patients with wasting syndrome with unintentional weight loss. Higher baseline IGF-I was associatedwith a decrease in relative LVmass during follow-up.

Suitable dietary Myo-inositol supplementations improve growth, immunity and antioxidant properties of hybrid grouper (Epinephelus. fuscoguttatus♀ × E. lanceolatus♂) fed low-fishmeal diets

A six-week feeding trial was carried out to evaluate the effects of different dietary Myo-inositol (MI) levels on growth, feed efficiency, immunity, and antioxidant properties of juvenile hybrid grouper (Epinephelus fuscoguttatus ♀ × E. lanceolatus ♂) fed low-fishmeal diets. Seven experimental diets were made to contain 50, 100, 169, 241, 309, 386, and 459 mg/kg of MI (analyzed values, dry matter basis), being abbreviated as MI-50, MI-100, MI-169, MI-241, MI-309, MI-386, and MI-459, and each MI treatment had three replicates. Twelve fish (average initial body weight: 18.7 ± 0.1 g) were allocated to each replicate, being hand-fed their diets to apparent satiation on 8:00 am and 16:30 pm. The results indicated that within the range of 50–241 mg/kg dietary inositol, weight gain percentage (WG%), feed efficiency (FE) and protein efficiency ratio (PER) were increased with the increasing of MI, and above the 241 mg/kg, they were dropped, especially at 386 and 459 mg/kg. According to the broken-line regression analysis conducted to assess the relationship between WG% and dietary MI levels, the optimum MI dose was 267.9 mg/kg (dry weight) in the low-fishmeal diet of hybrid grouper. Condition factor (CF), viscerosomatic index (VSI), hepatosomatic index (HSI), and intestinal index (ISI) were significantly (P < 0.05) affected by dietary MI levels, varying with a similar trend as WG%. Fish fed MI-241 had the highest values of serum lysozyme (LZM), hepatic total antioxidant capacity (T-AOC) as well as the relative mRNA level of hepatic insulin-like growth factor-Ⅰ (IGF-Ⅰ) among all treatments. In conclusion, optimum dietary MI requirement for the maximal growth of hybrid grouper was 267.9 mg/kg, and suitable dietary MI supplementations improve growth, immunity, and antioxidant properties of juvenile hybrid grouper fed low-fishmeal diets.

Trends of correlations between serum levels of growth hormone and insulin-like growth factor-I in general practice.

Serum levels of growth hormone (GH) and insulin-like growth factor (IGF)-I are crucial in the diagnosis and management of GH-related diseases. However, these levels are affected by nutritional and metabolic status. To elucidate the correlations between GH and IGF-I in various conditions, a retrospective analysis was performed for adult patients in which GH levels were examined by general practitioners during the period from January 2019 to December 2021. Of 642 patients, 33 patients were diagnosed with acromegaly, 21 were diagnosed with GH deficiency (GHD), and 588 were diagnosed with non-GH-related diseases (NGRD). In contrast to the positive correlations found between the levels of GH and IGF-I in patients with acromegaly (R=0.50; P<0.001) and patients with GHD (R=0.39; P=0.08), a negative correlation was found in the NGRD group (R=-0.23; P<0.001). In that group, the results of multivariable analysis showed that GH levels were predominantly influenced by gender and body mass index (BMI), whereas IGF-I levels were modulated by albumin in addition to age and GH. Of note, in the NGRD group, there was an enhanced negative correlation between GH and IGF-I under conditions of BMI < 22 and albumin < 4.0 g/dL (R=-0.45; P<0.001), and the negative correlation between GH and IGF-I was reinforced by excluding patients with other pituitary diseases and patients taking oral steroids (R=-0.51; P<0.001 and R=-0.59; P<0.001, respectively). Collectively, the results indicate that attention should be given to the presence of a negative correlation between serum levels of GH and IGF-I, especially in lean and low-nutritious conditions.

Mediating Effect of Insulin-Like Growth Factor-I Underlying the Link Between Vitamin D and Gestational Diabetes Mellitus.

Vitamin D was well-known to be associated with gestational diabetes mellitus (GDM). Insulin-like growth factor-I (IGF-I) has been linked to vitamin D and GDM, respectively. We hypothesize that changes in IGF-I metabolism induced by 25(OH)D3 might contribute to GDM. Therefore, we investigated the independent and combined relationships of serum 25(OH)D3 and IGF-I concentrations with GDM risk, and the mediation effect of IGF-I on 25(OH)D3. A total of 278 pregnant women (including 125 cases and 153 controls) were recruited in our current study. Maternal serum 25(OH)D3 and IGF-I were measured in the second trimester. Logistic regression models were used to estimate the associations of 25(OH)D3 and IGF-I concentrations with the risk of GDM. Mediation analyses were used to explore the mediation effect of IGF-I on the association between 25(OH)D3 and the risk of GDM. After adjusted for the confounded factors, both the third and fourth quartile of 25(OH)D3 decreased the risk of GDM (OR = 0.226; 95% CI, 0.103-0.494; OR = 0.109; 95% CI, 0.045-0.265, respectively) compared to the first quartile of 25(OH)D3. However, the third and fourth quartile of serum IGF-I (OR = 5.174; 95% CI, 2.287-11.705; OR = 12.784; 95% CI, 5.292-30.879, respectively) increased the risk of GDM compared to the first quartile of serum IGF-I. Mediation analyses suggested that 19.62% of the associations between 25(OH)D3 and GDM might be mediated by IGF-I. The lower concentration of serum 25(OH)D3 or higher IGF-I in the second trimester was associated with an increased risk of GDM. The serum IGF-I level might be a potential mediator between 25(OH)D3 and GDM.

Preparation of chitin/hyaluronic acid/collagen hydrogel loaded with mouse adipose-derived stem cells and its effects on wound healing of full-thickness skin defects in rats

Objective: To prepare the chitin/hyaluronic acid/collagen hydrogel loaded with mouse adipose-derived stem cells and to explore its effects on wound healing of full-thickness skin defects in rats. Methods: The research was an experimental research. Chitin nanofibers were prepared by acid hydrolysis and alkaline extraction method, and then mixed with hyaluronic acid and collagen to prepare chitin/hyaluronic acid/collagen hydrogels (hereinafter referred to as hydrogels). Besides, the hydrogels loaded with mouse adipose-derived stem cells were prepared. Thirty male 12-week-old guinea pigs were divided into negative control group, positive control group, and hydrogel group according to the random number table, with 10 guinea pigs in each group. Ethanol, 4-aminobenzoic acid ethyl ester, or the aforementioned prepared hydrogels without cells were topically applied on both sides of back of guinea pigs respectively for induced contact and stimulated contact, and skin edema and erythema formation were observed at 24 and 48 h after stimulated contact. Adipose-derived stem cells from mice were divided into normal control group cultured routinely and hydrogel group cultured with the aforementioned prepared hydrogels without cells. After 3 d of culture, protein expressions of platelet-derived growth factor-D (PDGF-D), insulin-like growth factor-Ⅰ (IGF-Ⅰ), and transforming growth factor β1 (TGF-β1) were detected by Western blotting (n=3). Eight male 8-week-old Sprague-Dawley rats were taken and a circular full-thickness skin defect wound was created on each side of the back. The wounds were divided into blank control group without any treatment and hydrogel group with the aforementioned prepared hydrogels loaded with adipose-derived stem cells applied. Wound healing was observed at 0 (immediately), 2, 4, 8, and 10 d after injury, and the wound healing rate was calculated at 2, 4, 8, and 10 d after injury. Wound tissue samples at 10 d after injury were collected, the new tissue formation was observed by hematoxylin-eosin staining; the concentrations of interleukin-1α (IL-1α), IL-6, IL-4, and IL-10 were detected by enzyme-linked immunosorbent assay method; the expressions of CD16 and CD206 positive cells were observed by immunohistochemical staining and the percentages of positive cells were calculated. The sample numbers in animal experiment were all 8. Results: At 24 h after stimulated contact, no skin edema was observed in the three groups of guinea pigs, and only mild skin erythema was observed in 7 guinea pigs in positive control group. At 48 h after stimulated contact, skin erythema was observed in 8 guinea pigs and skin edema was observed in 4 guinea pigs in positive control group, while no obvious skin erythema or edema was observed in guinea pigs in the other two groups. After 3 d of culture, the protein expression levels of PDGF-D, IGF-I, and TGF-β1 in adipose-derived stem cells in hydrogel group were significantly higher than those in normal control group (with t values of 12.91, 11.83, and 7.92, respectively, P<0.05). From 0 to 10 d after injury, the wound areas in both groups gradually decreased, and the wounds in hydrogel group were almost completely healed at 10 d after injury. At 4, 8, and 10 d after injury, the wound healing rates in hydrogel group were (38±4)%, (54±5)%, and (69±6)%, respectively, which were significantly higher than (21±6)%, (29±7)%, and (31±7)% in blank control group (with t values of 3.82, 3.97, and 4.05, respectively, Pvalues all <0.05). At 10 d after injury, compared with those in blank control group, the epidermis in wound in hydrogel group was more intact, and there were increases in hair follicles, blood vessels, and other skin appendages. At 10 d after injury, the concentrations of IL-1α and IL-6 in wound tissue in hydrogel group were significantly lower than those in blank control group (with tvalues of 8.21 and 7.99, respectively, P<0.05), while the concentrations of IL-4 and IL-10 were significantly higher than those in blank control group (with tvalues of 6.57 and 9.03, respectively, P<0.05). The percentage of CD16 positive cells in wound tissue in hydrogel group was significantly lower than that in blank control group (t=8.02, P<0.05), while the percentage of CD206 positive cells was significantly higher than that in blank control group (t=7.21, P<0.05). Conclusions: The hydrogel loaded with mouse adipose-derived stem cells is non-allergenic, can promote the secretion of growth factors in adipose-derived stem cells, promote the polarization of macrophages to M2 phenotype in wound tissue in rats with full-thickness skin defects, and alleviate inflammatory reaction, thereby promoting wound healing.

Sugar sweetened beverages, natural fruit juices, and cancer: what we know and what still needs to be assessed.

Cancer is known as one of the leading causes of death in the world. In addition to early mortality, cancer is associated with disability in affected patients. Among environmental risk factors, special attention has been paid to the role of dietary factors. In recent decades, the consumption of sugar-sweetened beverages (SSBs) and natural fruit juices has increased. Several studies have assessed the effects of these beverages on human health and found that a higher intake of SSBs is associated with a greater risk of obesity, diabetes, cardiovascular diseases, hypertension, and non-alcoholic fatty liver disease. However, current evidence for cancer incidence and mortality is not conclusive. In the current review, we concluded that SSBs intake might be positively associated with cancer incidence/mortality through their increasing effects on obesity, inflammatory biomarkers, serum levels of insulin-like growth factor-I (IGF-I), and advanced glycation end-products. Such a positive association was also seen for natural fruit juices. However, types of natural fruit juices were not considered in most previous studies. In addition, some types of cancer including brain, lung, and renal cancers were not assessed in relation to SSBs and natural fruit juices. Therefore, further studies are needed in this regard.

Stunting and wasting in neurological Wilson disease: Role of copper, zinc, and insulin-like growth factor-I.

Copper (Cu) and zinc (Zn) are important trace elements for the growth and development of children. In Wilson disease (WD), impaired Cu metabolism may affect growth. This study was conducted to evaluate the height and weight of children with neurological WD and correlate these with serum Cu, Zn, and insulin-like growth factor-I (IGF-I). This prospective cohort study was conducted in a tertiary care teaching institute. Children with neurologic WD were included. The height, weight, and body-mass index of each child were measured and categorized according to the revised national growth chart. Serum Cu, Zn, calcium, alkaline phosphatase, albumin, thyroid-stimulating hormone, and urinary-Cu were measured. Serum IGF-1 was measured by enzyme-linked immunosorbent assay. The relationship between height and weight with trace elements and IGF was analyzed using parametric or non-parametric tests. There were 52 children (5-18 years) with neurologic WD. Thirty-six (69.2%) children had normal height, 12 (23.1%) were tall, and 4 (7.7%) were stunted. Forty-six (88.5%) children had normal weight and six (11.5%) children were underweight. IGF-1 correlated with height, weight, duration of treatment, and serum Zn level. About 15.4% of children had stunting and/or wasting, which was associated with low levels of serum IGF-I, Zn, and calcium. Stunting and/or wasting occurs in 15.4% of children with neurologic WD and is associated with reduced serum IGF-I, Zn, and calcium concentration. Adjunctive Zn and calcium treatment may help in achieving normal growth.

Somatropin for Turner Syndrome

&#x0D; Early initiation of growth hormone therapy is recommended in children with Turner syndrome if the child already has growth failure or has a high chance of short stature (1 guideline).&#x0D; Growth hormone treatment can be started at 45 mcg/kg/day to 50 mcg/kg/day (1 guideline).&#x0D; Monitor treatment by regular height measurements and assessment of levels of insulin-like growth factor-I (1 guideline).&#x0D; Continue treatment until the desired height is achieved or when no more growth potential remains (1 guideline).&#x0D;

Long-term, real-world experience of pasireotide dose reduction in patients with acromegaly.

Pasireotide long-acting release is effective in achieving biochemical control and reducing tumour volume in patients with acromegaly inadequately controlled by first-line therapy. As part of a long-term, real-world study at our centre, 20 of 50 patients receiving pasireotide benefited from a reduction in pasireotide dose. Pasireotide reduced insulin-like growth factor I (IGF-I) levels to below the upper limit of the normal range, with some patients responding within 1-3 months of treatment (n=11) and others after ≥4 months (n=9). Following pasireotide dose reduction, IGF-I levels showed a mild increase but remained within the normal range after a median of 39 months in the early responders and 17 months in the late responders. Glucose and glycated haemoglobin levels decreased following dose reduction. Identifying patients who may benefit from a reduction in pasireotide dose warrants further research as it may improve the management of pasireotide-associated hyperglycaemia in susceptible patients.

Early Neuromuscular Electrical Stimulation Preserves Muscle Size and Quality and Maintains Systemic Levels of Signaling Mediators of Muscle Growth and Inflammation in Patients with Traumatic Brain Injury: A Randomized Clinical Trial.

To investigate the effects of an early neuromuscular electrical stimulation (NMES) protocol on muscle quality and size as well as signaling mediators of muscle growth and systemic inflammation in patients with traumatic brain injury (TBI). Two-arm, single-blinded, parallel-group, randomized, controlled trial with a blinded assessment. Setting. Trauma intensive care unit at a university hospital. Participants. Forty consecutive patients on mechanical ventilation (MV) secondary to TBI were prospectively recruited within the first 24 hours following admission. Interventions. The intervention group (NMES; n = 20) received a daily session of NMES on the rectus femoris muscle for five consecutive days (55 min/each session). The control group (n = 20) received usual care. Main Outcome Measures. Muscle echogenicity and thickness were evaluated by ultrasonography. A daily blood sample was collected to assess circulating levels of insulin-like growth factor I (IGF-I), inflammatory cytokines, and matrix metalloproteinases (MMP). Both groups were similar at baseline. A smaller change in muscle echogenicity and thickness (difference between Day 1 and Day 7) was found in the control group compared to the NMES group (29.9 ± 2.1 vs. 3.0 ± 1.2, p < 0.001; -0.79 ± 0.12 vs. -0.01 ± 0.06, p < 0.001, respectively). Circulating levels of IGF-I, pro-inflammatory cytokines (IFN-y), and MMP were similar between groups. An early NMES protocol can preserve muscle size and quality and maintain systemic levels of signaling mediators of muscle growth and inflammation in patients with TBI. This trial is registered with https://www.ensaiosclinicos.gov.br under number RBR-2db.

Utility of Serum Ferritin for Predicting Myalgic Encephalomyelitis/Chronic Fatigue Syndrome in Patients with Long COVID.

The most common symptom of post-acute coronavirus disease 2019 (COVID-19) is fatigue, and it potentially leads to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS); however, a specific prognosticator is lacking. We aimed to elucidate the clinical characteristics of patients who developed ME/CFS after COVID-19. In this retrospective observational study, patients who visited Okayama University Hospital for long COVID between February 2021 and March 2022 were investigated. Of the 234 patients, 139 (59.4%) had fatigue symptoms. Fifty patients with fatigue symptoms (21.4%) met the criteria for ME/CFS (ME/CFS group), while the other 89 patients did not (non-ME/CFS group); 95 patients had no fatigue complaints (no-fatigue group). Although the patients' backgrounds were not significantly different between the three groups, the ME/CFS group presented the highest scores on the self-rating symptom scales, including the Fatigue Assessment Scale (FAS), EuroQol, and the Self-Rating Depression Scale (SDS). Furthermore, serum ferritin levels, which were correlated with FAS and SDS scores, were significantly higher in the ME/CFS group (193.0 μg/L, interquartile range (IQR): 58.8-353.8) than in the non-ME/CFS group (98.2 μg/L, 40.4-251.5) and no-fatigue group (86.7 μg/L, 37.5-209.0), and a high serum ferritin level was prominent in female patients. Endocrine workup further showed that the ME/CFS group had higher thyrotropin levels but lower growth hormone levels in serum and that insulin-like growth factor-I levels were inversely correlated with ferritin levels (R = -0.328, p < 0.05). Serum ferritin level is a possible predictor of the development of ME/CFS related to long COVID, especially in female patients.

Effects of age and seasonal temperatures on cortisol levels and GHR, IGF-I, and IGF-II expressions in rainbow trout (Oncorhynchus mykiss)

The growth hormone (GH)/insulin-like growth factor (IGF) endocrine axis regulates the cellular growth and organ development in related to changing environmental conditions and age. The aim of this study is to determine growth factor genes, which are biological markers of growth in muscle and liver of rainbow trout (Oncorhynchus mykiss) in different seasonal temperatures and age ranges and the reveal of the relationship between serum cortisol (COR) levels from stress parameters. No difference was found in serum COR levels between the groups with respect to temperature and age. Serum GH levels were found to be higher in the summer juvenile trout compared to the winter juvenile and adult trouts. There was no difference in liver growth hormone receptor (GHR) mRNA levels of juvenile and adult trouts in winter while insulin-like growth factor-I (IGF-I) and insulin-like growth factor-II (IGF-II) mRNA levels in liver and muscle tissues were found to be higher in juvenile trout compared to adults. Among trout of different ages, GHR, IGF-I and IGF-II mRNA levels in liver in summer were higher for juvenile trout compared to adults. Muscle IGF-I mRNA levels in summer were higher in adult trout compared to juveniles. IGF-II mRNA levels in liver and muscle tissues of juvenile trout showed an increase in winter compared to in summer. While the GHR and IGF-II mRNA levels in the liver tissue of adult trout were observed to higher in winter compared to summer, IGF-I mRNA levels were found to be higher in summer. GHR, IGF-I and IGF-II mRNA levels in muscle tissue of adult trout were found to be higher in summer than in winter. This study indicated that juvenile and adult rainbow trout (Oncorhynchus mykiss) are adapted to both winter and summer temperature and that GHR, IGF-I and IGF-II genes are highly expressed.

Bone-Derived IGF-I Regulates Radial Bone Growth in Adult Male Mice.

Insulin-like growth factor-I (IGF-I) levels, which are reduced by age, and cortical bone dimensions are major determinants of fracture risk in elderly subjects. Inactivation of liver-derived circulating IGF-I results in reduced periosteal bone expansion in young and older mice. In mice with lifelong depletion of IGF-I in osteoblast lineage cells, the long bones display reduced cortical bone width. However, it has not previously been investigated whether inducible inactivation of IGF-I locally in bone in adult/old mice affects the bone phenotype. Adult tamoxifen-inducible inactivation of IGF-I using a CAGG-CreER mouse model (inducible IGF-IKO mice) substantially reduced IGF-I expression in bone (-55%) but not in liver. Serum IGF-I and body weight were unchanged. We used this inducible mouse model to assess the effect of local IGF-I on the skeleton in adult male mice, avoiding confounding developmental effects. After tamoxifen-induced inactivation of the IGF-I gene at 9 months of age, the skeletal phenotype was determined at 14 months of age. Computed tomography analyses of tibia revealed that the mid-diaphyseal cortical periosteal and endosteal circumferences and calculated bone strength parameters were decreased in inducible IGF-IKO mice compared with controls. Furthermore, 3-point bending showed reduced tibia cortical bone stiffness in inducible IGF-IKO mice. In contrast, the tibia and vertebral trabecular bone volume fraction was unchanged. In conclusion, inactivation of IGF-I in cortical bone with unchanged liver-derived IGF-I in older male mice resulted in reduced radial growth of cortical bone. This suggests that not only circulating IGF-I but also locally derived IGF-I regulates the cortical bone phenotype in older mice.

Effect of body condition loss in early lactation Holstein cows on plasma IGF-I, prolactin and NEFA during breeding period and its association with some reproductive indices.

The associations between early lactation changes of the body condition score (BCS) and mid-lactation levels of blood insulin like Growth Factor-I (IGF-1), prolactin, insulin, non-esterified fatty acids (NEFA), milk production and some reproductive indices were investigated. Monthly milk yield and BCS were recorded. Blood samples were collected on days 60, 90 and 120 (±5 days) of lactation. Twelve and 17 cows showed BCS losses ≤0.75 and >0.75 on day 60, respectively. BCS losses ≤0.75 till d60 after calving enhanced the IGF-I concentration on d90 (57.8±10.7 vs 35.6±17.8 ng/ml; P=0.001). The differences of blood metabolites were prominent on d90. Trends of insulin changes between d60 BCS (P=0.04) groups were different. Inverse correlations were detected between IGF-I and NEFA (-0.6, P=0.001), IGF-I and milk production (-0.4, P=0.05), NEFA and prolactin (-0.8, P<0.001) on d90. Higher percentages of cows with BCS loss >0.75 (d60) showed their first heat after d40 postpartum. In conclusion, irrespective of BCS at the time of breeding, the level of BCS loss during the first 60 days of lactation may affect further reproductive performance due to prolonged alterations of IGF-I, NEFA, prolactin and insulin levels. The extent of postpartum BCS loss may be a predictor of metabolic status of cows during mid-lactation.

Feeding after spawning and energy balance at spawning are associated with repeat spawning interval in steelhead trout

Consecutive and skip repeat spawning (1- or ≥2-year spawning interval) life histories commonly occur in seasonally breeding iteroparous fishes. Spawning interval variation is driven by energetic status and impacts fisheries management. In salmonids, energetic status (either absolute level of energy reserves or the rate of change of energy reserves, i.e., energy balance) is thought to determine reproductive trajectory during a critical period ∼1 year prior to initial spawning. However, information on repeat spawners is lacking. To examine the timing and the aspects of energetic status that regulate repeat spawning interval, female steelhead trout (Oncorhynchus mykiss) were fasted for 10 weeks after spawning and then fed ad libitum and compared to ad libitum fed controls. Plasma growth hormone (GH) and insulin-like growth factor-I (IGF-I) levels were measured to assess long-term energy balance. Plasma estradiol levels showed that some fish in both groups initiated a consecutive spawning cycle. In fasted fish, GH was lower at spawning in consecutive versus skip spawners. In consecutive spawners, GH was higher at spawning in fed versus fasted fish. These results suggest that fish with a less negative energy balance at spawning initiated reproductive development in the absence of feeding, but that feeding during the post-spawning period enabled initiation of reproduction in some fish with a more negative energy balance at spawning. Thus, both energy balance at spawning and feeding after spawning regulated reproductive schedules. These results show that the critical period model of salmonid maturation applies to regulation of repeat spawning, and that the reproductive decision window extends into the first 10 weeks after spawning.

PMON166 Safety Comparison of 40- vs 60-mg/day Doses of Oral Octreotide Capsules for Treatment of Acromegaly in the CHIASMA OPTIMAL Trial

Abstract Background Oral octreotide capsules (OOC) are a treatment option for patients with acromegaly in the United States who have previously responded to injectable somatostatin receptor ligands (iSRLs, octreotide or lanreotide). In previous phase 3 studies, the safety of OOC was shown to be consistent with iSRLs, without dose-dependent adverse reactions. In the double-blind, placebo-controlled period (DPC) of the CHIASMA OPTIMAL trial (NCT03252353), patients were randomized to twice-daily OOC at 40-mg/day, with the option for up-titration to 80-mg/day. In contrast, patients entered the open-label extension (OLE) at a 60-mg/day dose. Objective Examine the safety of 40-mg/day versus 60-mg/day OOC doses. Methods Eligible patients had the option to enroll in the OLE following the core trial. All patients received OOC 60-mg/day upon entering the OLE regardless of prior treatment in the DPC, including patients who received placebo in the DPC. OOC doses were up- or down-titrated based on insulin-like growth factor I (IGF-I) level and/or acromegaly signs or symptoms. The current analysis compared the incidence of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), TEAE-related study drug discontinuation, and acromegaly-related TEAEs (defined as new or worsening signs or symptoms of acromegaly). Results Twenty-eight patients randomized to OOC in the DPC (40-mg/day dose) and 19 who were originally randomized to placebo and continued into the OLE (60-mg/day dose) were included in the analysis. Biochemical control was similar in both groups as demonstrated by mean IGF-I levels over the respective periods. Ninety-six percent of patients on 40-mg/day and 57.9% on 60-mg/day experienced ≥1 TEAEs. Two patients on 60-mg/day reported a total of 2 SAEs, both deemed unrelated to study drug. Two patients on 40-mg/day experienced TEAEs leading to study drug discontinuation (headache and gastrointestinal symptoms). The incidence of acromegaly-related TEAEs was generally lower in those on 60-mg/day versus 40-mg/day. Conclusions This is the first analysis exploring differences in OOC doses. The nature and incidence of TEAEs occurring with an OOC dose of 60-mg/day versus 40-mg/day were similar, though this analysis was limited by differences in TEAE reporting across sequential phases of a lengthy trial. A trend was observed for decreased incidence of acromegaly-related TEAEs with the 60-mg/day dose. This finding is in line with previous analyses showing no dose-related TEAEs with OOC. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Tracking and Cumulative Lifetime Exposure to IGF-I in 6459 Healthy Individuals and in SGA Children Treated With GH.

Supraphysiological serum insulin-like growth factor-I (IGF-I) concentrations have been a matter of concern in children treated with GH because high IGF-I levels were associated with risk of later disease in former epidemiological studies. To determine whether a single IGF-I measurement reliably reflects lifetime IGF-I exposure we evaluated intraindividual longitudinal tracking of IGF-I and IGF-binding protein-3 (IGFBP-3) levels and we estimated cumulative lifetime exposure to IGF-I in healthy and GH-treated individuals. We included 6459 healthy participants (cross-sectional = 5326; longitudinal = 1133) aged 0-76 years (9963 serum samples) and 9 patients born small-for-gestational-age (SGA) with 238 serum samples during GH treatment. Intraindividual tracking of IGF-I and IGFBP-3 (SD score [SDS]) was determined by intraclass correlation coefficients (ICCs). Cumulative lifetime IGF-I exposure was estimated by area under the curve of the predicted SDS trajectory from 0 to 76 years. For IGF-I (SDS), ICCs were 0.50 (95% CI, 0.47-0.53) for male and 0.53 (0.50-0.56) for female participants. Lifetime IGF-I exposure was significantly higher in female (mean 12 723 ± 3691 SD) than in male participants (12 563 ± 3393); P = 0.02. In SGA children, treatment with GH increased the lifetime exposure to IGF-I from 9512 ± 1889 to 11 271 ± 1689, corresponding to an increase in lifetime IGF-I trajectory from -0.89 SD ± 0.57 to -0.35 SD ± 0.49. Because IGF-I and IGFBP-3 levels track throughout life, a single measurement reliably reflects lifetime exposure. GH therapy increased the lifetime exposure to IGF-I only slightly and it remained below the average lifetime exposure in the reference population.

Changes in Cross-Sectional Area of the Median Nerve and Body Composition Parameters after Treatment of Acromegaly: 1 year Follow-Up.

Objective Median neuropathy is a common manifestation of acromegaly, although its pathology is uncertain. Changes in levels of growth hormone (GH) and insulin-like growth factor I (IGF-I) and body composition are potential parameters in pathology of median neuropathy in acromegaly. We aimed to assess changes in the cross-sectional area (CSA) of the median nerve and body composition in newly diagnosed acromegalic patients 1 year after treatment and to determine their mutual relationships. Design This prospective study included 30 patients with newly diagnosed acromegaly and 30 healthy controls matched for age, gender, and body mass index. Physical and laboratory examinations, dual-energy X-ray absorptiometry (DXA), and ultrasound evaluations were performed at baseline and 1 year after initial treatment. Results The CSA of the median nerve was increased in acromegalic patients compared with controls (13.1 mm2 [12.2–14.9] vs 7.5 mm2 [6.4–8.4], P < 0.001). One year after treatment of acromegaly, GH and IGF-I levels decreased significantly. The median nerve CSA was significantly reduced after treatment (11.6 mm2 [10.2–13.1], P < 0.001). Reduction of IGF-I levels correlated with a decrease in lean mass and increase in fat mass. The median nerve CSA positively correlated with IGF-I levels (R = 0.492, P=0.006) and lean mass (R = 0.419, P=0.021) in acromegalic patients before treatment. Conclusion This study demonstrates a reduction in the median nerve CSA 1 year after treatment of acromegaly. These changes are closely associated with a reduction in IGF- I levels and in lean body mass. The enlargement of the median nerve in acromegaly can be reversed with adequate treatment.

Alterations in insulin-like growth factor system in spinal muscular atrophy.

Spinal muscular atrophy (SMA) is an inherited neuromuscular disease caused by survival motor neuron (SMN) protein deficiency. Insulin-like growth factor-I (IGF-I) is a myotrophic and neurotrophic factor that has been reported to be dysregulated in in vivo SMA model systems. However, detailed analyses of the IGF-I system in SMA patients are missing. In this study, we analyzed the components of the IGF-I system in serum and archived skeletal muscle biopsies of SMA patients. Serum IGF-I, IGF binding protein (IGFBP)-3, and IGFBP-5 levels were analyzed in 11 SMA patients and 13 healthy children by immunoradiometric and enzyme-linked immunosorbent assays. The expression of IGF-I, IGF-I receptor, and IGFBP-5 proteins was investigated by immunofluorescence analysis in the archived skeletal muscle biopsies of nine SMA patients, six patients with non-SMA-related neuromuscular disease and atrophic fibers in muscle biopsy, and four controls. A significant decrease in IGF-I levels (mean ± SD: -1.39 ± 1.46 vs. 0.017 ± 0.83, p=.02) and increase in IGFBP-5 levels (mean ± SD: 2358.5 ± 1617.4ng/mL vs. 1003.4 ± 274.3ng/mL, p=.03) were detected in serum samples of SMA patients compared to healthy controls. Increased expression of IGF-I, IGF-I receptor, and IGFBP-5 was detected in skeletal muscle biopsies of SMA patients and non-SMA neuromuscular diseases, indicating atrophy-specific alterations in the pathway. Our findings suggested that the components of the IGF-I system are altered in SMA patients at both the systemic and tissue-specific levels.

Ghrelin, growth hormone and insulin-like growth Factor-I levels in people with protein C deficiency

The primary objective of this study was to examine if people with protein C deficiency, which is a natural anticoagulant and also an endogenous acyl ghrelin peptidase, have elevated circulating levels of acyl ghrelin. The clinical trial was conducted in a university hospital setting. People with protein C deficiency were identified and invited to participate by a specialized coagulation outpatient clinic. People with protein C deficiency were examined and compared to age, sex, and body mass index matched healthy controls with regards to acyl ghrelin, unacylated ghrelin, growth hormone (GH) and insulin-like growth-factor I (IGF-I) in a cross-sectional case-control study. Systemic levels of acyl ghrelin, desacyl ghrelin, acyl-to-desacyl ghrelin ratio, GH and IGF-I were similar in people with protein C deficiency and healthy controls. Despite a significant reduction of protein C in people with protein C deficiency, there was no difference in acyl ghrelin or the secondary end points unacylated ghrelin, GH, or IGF-I in people with protein C deficiency.