Normal Insulin-like Growth factor-I Research Articles

Changes in acromegaly comorbidities, treatment, and outcome over three decades: a nationwide cohort study.

To study the time-dependent changes in disease features of Danish patients with acromegaly, including treatment modalities, biochemical outcome, and comorbidities, with a particular focus on cancer and mortality. Pertinent acromegaly-related variables were collected from 739 patients diagnosed since 1990. Data are presented across three decades (1990-1999, 2000-2009, and 2010-2021) based on the year of diagnosis or treatment initiation. Adenoma size and insulin-like growth factor I (IGF-I) levels at diagnosis did not differ significantly between study periods. The risk of being diagnosed with diabetes, heart disease, sleep apnea, joint disease, and osteoporosis increased from the 1990s to the later decades, while the mortality risk declined to nearly half. The risk of cancer did not significantly change. Treatment changed toward the use of more medical therapy, and fewer patients underwent repeat surgeries or pituitary irradiation. A statistically significant increase in the proportion of patients achieving IGF-I normalization within 3-5 years was observed over time (69%, 83%, and 88%). The proportion of patients with three or more deficient pituitary hormones decreased significantly over time. Modern medical treatment regimens of acromegaly as well as increased awareness and improved diagnostics for its comorbidities have led to better disease control, fewer patients with severe hypopituitarism, and declining mortality in the Danish cohort of acromegaly patients. The risk of cancer did not increase over the study period.

Long-term Efficacy and Safety of Pasireotide in Patients With Acromegaly: 14 Years of Single-Center Real-World Experience.

Acromegaly is a rare, chronic, debilitating disorder caused by prolonged hypersecretion of growth hormone (GH) and overproduction of insulin-like growth factor I (IGF-I). Medical therapies, including the somatostatin receptor ligand (SRL) pasireotide, are frequently used to restore biochemical control. As patients often receive therapy over prolonged periods, long-term data from real-life settings are needed. A retrospective analysis was performed using a prospectively maintained database of all patients with acromegaly from our primary care center who were enrolled in clinical studies with pasireotide (first visit November 2008). The main outcome measures were safety and biochemical control (age-adjusted IGF-I ≤ upper limit of normal). Patients (n = 50) entered 4 parental studies and 30 continued in the rollover; at data cutoff (June 2022), 27 were still receiving pasireotide. Overall, median (range) exposure was 58 (3-137) months. Normal IGF-I was achieved in 54%, and acromegaly symptoms and quality of life were improved with treatment. No predictors of pasireotide response were identified; however, controlled patients had smaller tumors and lower GH at baseline. Tumor volume reduction occurred in 63% of evaluable patients (n = 10/16). Most patients presented hyperglycemic events, including 63.2% of patients with normal glucose before treatment. Older patients and those with higher IGF-I, glucose, and HbA1c at baseline had higher glucose and HbA1c during pasireotide treatment. Pasireotide provided clinical benefit and was well tolerated for more than 11 years of treatment in acromegaly patients, most of whom were resistant to first-generation SRLs.

Evaluation of Insulin-Like Growth Factor-I (IGF-I) as a Predictor of Preeclampsia

Introduction: Preeclampsia (PE) is a serious pregnancy-induced disease characterized by hypertension, proteinuria and other systemic disorders after 20 weeks of gestation and is a leading cause of maternal and fetal morbidity and mortality. The main pathological characteristics of preeclampsia are poor trophoblast cell invasion and uterine spiral artery remodeling dysfunction caused by placenta ischemia and oxidative stress. Nowadays, preeclampsia is considered to be the results of the interactions of genetic and environmental factors. However, its accurate pathogenesis remains unknown. It was considered IGF-1 might be involved in the pathogenesis of preeclampsia. As is known, the behaviors of cells, the formation of placenta and the growth of fetus are widely regulated by insulin-like growth factor 1 (IGF-1). Several studies have shown that IGF-1 was significantly reduced in preeclampsia. Objectives: To assess the role of Insulin like Growth Factor-I (IGF-I) as a Predictor of Preeclampsia. Materials and Methods: It was a prospective cohort study conducted in General Obstetrics and Gynaecology Unit OPD, Dhaka Medical College Hospital from January, 2020 to December, 2020. Pregnant women between 8 weeks to 15 weeks were enrolled for study after fulfilling selection criteria. Serum concentration of Insulin like growth factor-I (IGF-I) was assessed with cut off value of IGF-I 175.9 ng/ml. The value above 175.9 ng/ml was categorized as normal IGF-I and value below 175.9 ng/ml was categorized as low IGF-I. The patients who had value above 175.9 ng/ml were grouped as A. The value below 175.9 ng/ml was grouped as B. Then they were followed up monthly upto 28 weeks, two weekly upto 36 weeks, weekly upto delivery and puerperium for development of preeclampsia or not. All information was recorded in data collection sheet. Data were analyzed by SPSS-23. Data were compared and correlated among groups and presented by tables and figures. Result: Maternal serum concentration .....

A systematic literature review to evaluate extended dosing intervals in the pharmacological management of acromegaly

PurposeThis systematic literature review investigated whether extended dosing intervals (EDIs) of pharmacological acromegaly treatments reduce patient burden and costs compared with standard dosing, while maintaining effectiveness.MethodsMEDLINE/Embase/the Cochrane Library (2001–June 2021) and key congresses (2018–2021) were searched and identified systematic literature review bibliographies reviewed. Included publications reported on efficacy/effectiveness, safety and tolerability, health-related quality of life (HRQoL), and patient-reported and economic outcomes in longitudinal/cross-sectional studies in adults with acromegaly. Interventions included EDIs of pegvisomant, cabergoline, and somatostatin receptor ligands (SRLs): lanreotide autogel/depot (LAN), octreotide long-acting release (OCT), pasireotide long-acting release (PAS), and oral octreotide; no comparator was required.ResultsIn total, 35 publications reported on 27 studies: 3 pegvisomant monotherapy, 11 pegvisomant combination therapy with SRLs, 9 LAN, and 4 OCT; no studies reported on cabergoline, PAS, or oral octreotide at EDIs. Maintenance of normal insulin-like growth factor I (IGF-I) was observed in ≥ 70% of patients with LAN (1 study), OCT (1 study), and pegvisomant monotherapy (1 study). Achievement of normal IGF-I was observed in ≥ 70% of patients with LAN (3 studies) and pegvisomant in combination with SRLs (4 studies). Safety profiles were similar across EDI and standard regimens. Patients preferred and were satisfied with EDIs. HRQoL was maintained and cost savings were provided with EDIs versus standard regimens.ConclusionsClinical efficacy/effectiveness, safety, and HRQoL outcomes in adults with acromegaly were similar and costs lower with EDIs versus standard regimens. Physicians may consider acromegaly treatment at EDIs, especially for patients with good disease control.

Treatment of acromegaly has substantial effects on body composition: a long-term follow-up study.

Acromegaly is associated with changes in body composition. Long-term changes following acromegaly treatment and the impact of different treatments have been less investigated. We performed a retrospective study in 201 patients with acromegaly. Body composition was assessed by dual-energy X-ray absorptiometry. To investigate the specific effects of treatment vs aging, changes in body composition were compared in one group of patients evaluated both at the time of active and controlled disease (active-to-controlled (A>C); n = 31) and in another group of patients evaluated two times while the disease was controlled (controlled-to-controlled (C>C); n = 32). In the whole cohort, insulin-like growth factor I (IGF-I) was correlated with fat (r = -0.369; P < 0.001) and lean mass (r = 0.383; P < 0.001). Patients from A>C and C>C groups were comparable for age, sex, BMI and follow-up duration (P = n.s.). Reduction in IGF-I levels was associated with an increase in fat mass and a decrease in lean mass in the A>C group, which was four and eight times more pronounced compared to the C>C group (fat mass: +39 ± 34% vs +10 ± 15%, P < 0.001; lean mass: -8 ± 8% vs -0.2 ± 6%, P < 0.001, respectively). Changes in fat mass were negatively associated with IGF-I (r = -0.450; P = 0.011) and independent of the individual therapy. The daily dose of pegvisomant correlated with fat mass (r = 0.421; P = 0.002) and insulin sensitivity index (r = -0.466; P < 0.001). Treatment of acromegaly strongly impacts body composition until biochemical disease remission, characterized by an increase in fat mass and a decrease in lean mass. These changes are closely associated with the normalization of IGF-I. Thereafter, body composition changes are similar to what is observed with aging.

SAT-435 Optimization of Pharmacological Treatment of Acromegaly: Impact on IGF-1 Levels Comparing Isolated Octreotide LAR and Combined Pharmacological Therapy

Background:Transphenoidal surgery remains the best treatment for acromegaly, although the disease is unlikely to be controlled with surgery in approximately half of macroadenomas. Unfortunately, invasive macroadenomas represents over than 65% of GH-secreting adenomas (1-4). Somatostatin analogues (SSAs) are widely recognized as the first choice of primary and postsurgical pharmacological therapy in patients with acromegaly. However, more than one third of the patients fail to control insulin-like growth factor I (IGF-I) and growth hormone (GH) levels. Previous studies have shown benefits arising from the combination of SSAs, cabergoline and even estrogen therapy in mild activity of disease. Objectives:The aim of this study was to compare the efficacy in decrease and normalization of IGF-I values, of Octreotide LAR treatment isolated compared to associated with cabergoline and or cabergoline and estrogen in patients that have not undergone any other pharmacological treatment. Patients and Methods: Case series studythat enrolled 54 patients, divided in two groups, receiving OCT-LAR initially administrated a dose of 20 mg/month (IM), adjusted individually, after 3 months, with the goal of achieving normal age-matched IGF-I values, reaching the maximum dose of 30 mg/month. The second group received OC-LAR 30 mg/month associated with CBG 2 mg per week.The third group received in combination estrogen therapy Results and Discussion:The baseline mean serum IGF-I was significantly higher than after 6 months of treatment with OCT-LAR (p=0,020) and OCT-LAR+CBG (p=0,004) but no significant difference was shown for the comparison of IGF-I after 6 and 12 months in OC-LAR group (p=0,960) or OC-LAR+CBG group (p=0,929). After de adjustment of IGF-1 levels for age, the data showed a significant reduction in ULNV% comparing the basal and 6 months values in OCT-LAR (p=0,013) and OCT-LAR+CBG (p=0,004). In group OCT-LAR, the best reduction of IGF-1 was obtained after 12 months of treatment. In the group OCT-LAR-CBG, the best control was achieved at six months and was not statistically different from 12 months (p=0,047). In multitreated patients, estrogen therapy benefited IGF-1 reduction. Conclusion: The percentage of patients that reached normalization of serum IGF-I was significantly higher in the OC-LAR + CBG group at 6 months. There was no statistically significant difference at 12 months post treatment .

Correlation analysis between short-term insulin-like growth factor-I and glucose intolerance status after transsphenoidal adenomectomy in acromegalic patients: a large retrospective study from a single center in China.

Our study aimed to investigate the associations of glucose tolerance status with insulin-like growth factor-I (IGF-I) and other clinical laboratory parameters of acromegalic patients before and after the patients underwent transsphenoidal adenomectomy (TSA) by conducting a single-center, retrospective study. A total of 218 patients with acromegaly who had undergone TSA as the first treatment were retrospectively analyzed. Serum IGF-I, growth hormone (GH) and glucose levels were measured before and after surgery. The follow-up levels for random GH, GH nadir, and the percentage of the upper limit of normal IGF-I (%ULN IGF-I) were decreased significantly. The percentages of normal (39.0%), early carbohydrate metabolism disorders (33.0%) and diabetes mellitus (28.0%) changed to 70.2%, 16.5% and 13.3%, respectively, after TSA. %ULN IGF-I at baseline was higher in the diabetes mellitus (DM) group than in the normal glucose tolerance group and impaired glucose tolerance (IGT) /impaired fasting glucose (IFG) groups before TSA, and the DM group exhibited a greater reduction in %ULN IGF-I value after surgery. The follow-up %ULN IGF-I value after surgery was significantly lower in the improved group, and Pearson's correlation analysis revealed that the reductions in %ULN IGF-I corresponded with the reductions in glucose level. This study examined the largest reported sample with complete preoperative and follow-up data. The results suggest that the age- and sex-adjusted IGF-I level, which reflects altered glucose metabolism, and the change of it are associated with improved glucose tolerance in acromegalic patients both before and after TSA.

A multivariable prediction model for pegvisomant dosing: monotherapy and in combination with long-acting somatostatin analogues.

Effective treatment of acromegaly with pegvisomant (PEGV), a growth hormone receptor antagonist, requires an appropriate dose titration. PEGV doses vary widely among individual patients, and various covariates may affect its dosing and pharmacokinetics. To identify predictors of the PEGV dose required to normalize insulin-like growth factor I (IGF-I) levels during PEGV monotherapy and in combination with long-acting somatostatin analogues (LA-SSAs). Two retrospective cohorts (Rotterdam + Liège Acromegaly Survey (LAS), total n = 188) were meta-analyzed as a form of external replication to study the predictors of PEGV dosing in addition to LA-SSA, the LAS (n = 83) was used to study the predictors of PEGV monotherapy dosing. Multivariable regression models were used to identify predictors of the PEGV dose required to normalize IGF-I levels. For PEGV dosing in combination with LA-SSA, IGF-I levels, weight, height and age, were associated with the PEGV normalization dosage (P ≤ 0.001, P ≤ 0.001, P = 0.028 and P = 0.047 respectively). Taken together, these characteristics predicted the PEGV normalization dose correctly in 63.3% of all patients within a range of ±60 mg/week (21.3% within a range of ±20 mg/week). For monotherapy, only weight was associated with the PEGV normalization dose (P ≤ 0.001) and predicted this dosage correctly in 77.1% of all patients within a range of ±60 mg/week (31.3% within a range of ±20 mg/week). In this study, we show that IGF-I levels, weight, height and age can contribute to define the optimal PEGV dose to normalize IGF-I levels in addition to LA-SSA. For PEGV monotherapy, only the patient's weight was associated with the IGF-I normalization PEGV dosage.

Somatostatin Receptor Expression in GH-Secreting Pituitary Adenomas Treated with Long-Acting Somatostatin Analogues in Combination with Pegvisomant

Background: Growth hormone-secreting pituitary adenomas (somatotroph adenoma) predominantly express somatostatin receptors (SSTRs) subtypes 2 and 5. Higher SSTR2 expression on somatotroph adenomas results in a better response to somatostatin analogues (SSAs), which preferentially bind, but also downregulate, SSTR2. The effect of the combined treatment with SSAs and the GH receptor antagonist pegvisomant (PEGV) on SSTR expression in somatotroph adenomas is currently unknown. Aim of the Study: To assess SSTR2 and SSTR5 expression in three groups of somatotroph adenomas: drug-naive, treated with long-acting (LA) SSA monotherapy, or LA-SSA/PEGV combination therapy before surgery. Additionally, we evaluated the required PEGV dose to achieve insulin-like growth factor I (IGF-I) normalization in relation to the SSTR expression. Materials and Methods: At our Pituitary Center Rotterdam, we selected acromegalic patients who underwent transsphenoidal neurosurgery. All patients were eventually treated with LA-SSA/PEGV combination therapy during their medical history. SSTR2 and SSTR5 expression in somatotroph adenoma tissues was determined using immunohistochemistry. Results: Out of 39 somatotroph adenoma tissue samples, 23 were drug-naive, 9 received pretreatment with LA-SSA and 7 LA-SSA/PEGV combined treatment. SSTR2 expression was significantly higher in treatment-naive compared to combined treatment somatotroph adenomas (p = 0.048), while SSTR5 expression did not differ. Noteworthy, SSTR2 expression in naive somatotroph adenoma tissues was inversely correlated with the required PEGV dose to achieve IGF-I normalization during postsurgical medical treatment (ρ = -0.538, p = 0.024). Conclusion: In our specific cohort, the SSTR2 expression was lower in patients pretreated with LA-SSA/PEGV compared to the drug-naive acromegalic patients. Additionally, the SSTR2 expression in treatment-naive somatotroph adenoma tissues was inversely correlated with the required PEGV dose to achieve IGF-I normalization.

The Modern Criteria for Medical Management of Acromegaly.

Acromegaly is an insidious disorder characterized by excess secretion of growth hormone (GH) and elevated circulating levels of insulin-like growth factor-I (IGF-I), generally caused by a pituitary adenoma. It is a rare disease associated with an average 10-year reduction in life expectancy due to metabolic, cardiovascular, and cerebrovascular comorbidities and reduced quality of life caused by paresthesias, fatigue, osteoarthralgia, or bone fractures. In 2000, Cortina Consensus Conference established general criteria for diagnosis and biochemical control of acromegaly, which have been revised in recent years, adapting them to emerging clinical evidences as well as the evolving assay techniques. Authors have proposed a binary definition of cure for acromegaly, where both GH and IGF-I are important determinants: the former is more linked to the presence of residual adenomatous tissue, while the latter to the peripheral activity of the disease. Control of tumor growth and complications is also an essential goal of treatment. Surgical, medical, and radiotherapy approaches are all valid alternatives. The surgical option is, however, unsuccessful in about 50% of patients. Somatostatin analogs (SRLs), octreotide LAR, and lanreotide ATG can inhibit cell growth, besides their beneficial effects on GH hypersecretion and on most comorbidities. Pasireotide is a new multireceptor-targeted SRL with reported superior biochemical efficacy to octreotide, due to higher affinity for SSTR-5, but potentially causing detrimental effects on glucose homeostasis. Pegvisomant could be a valid choice in all patients resistant to SRLs. It is a competitive GH antagonist, which efficaciously blocks IGF-I production, inhibiting the dimerization of GH receptor. Normal IGF-I levels represent, therefore, its only relevant efficacy endpoint, while only few cases of tumor growth on pegvisomant have been reported, so far.

Acromegaly treatment in Romania. How close are we to disease control?

In Romania, no nationwide data for acromegaly treatment and control rate are available. Our objective was to assess the acromegaly control rate in a tertiary referral centre, which covers an important part of Romanian territory and population of patients with acromegaly. We reviewed the records of all 164 patients (49 males and 115 females; median age 55 [47, 63.5] years) with newly or previously diagnosed acromegaly, who have been assessed at least once in our tertiary referral centre between January 1, 2012 and March 31, 2016. This sample represents 13.6% of the total expected 1200 Romanian patients with acromegaly and covers 82.9% of the counties in Romania. Control of acromegaly was defined as a random serum growth hormone (GH) < 1 ng/mL and an age-normalised serum insulin-like growth factor-I (IGF-I) value. The GH and IGF-I values used for calculation of the control rate were those at the last evaluation. The same assays for GH and IGF-I measurement were used in all patients. There were 147 treated and 17 untreated patients. Of the 147 patients assessed after therapy, 137 (93.2%) had pituitary surgery, 116 (78.9%) were on medical treatment at the last evaluation, and 67 (45.5%) had radiotherapy. Seventy-one (48.3%) had a random GH < 1 ng/mL, 54 (36.7%) had a normalised, age-adjusted IGF-I, and 42 (28.6%) had both normal random serum GH and IGF-I. In Romania, acromegaly benefits from the whole spectrum of therapeutic interventions. However, the control rate remains disappointing.

Endoscopic endonasal transsphenoidal treatment for acromegaly: 2010 consensus criteria for remission and predictors of outcomes.

Acromegaly is a chronic disorder characterized by enhanced growth hormone (GH) secretion and elevated insulin-like growth factor-I (IGF-I) levels, usually caused by pituitary adenomas. In this retrospective study, we reviewed our experience with endoscopic endonasal transsphenoidal surgery (EETS) with in remission rates using the 2010 consensus criteria, predictors of remission and associated complications. The authors retrospectively analyzed data from 56 acromegalic patients who underwent pure EETS. Tumors were classified according to size and suprasellar/parasellar extension. The criteria of remission were GH levels < 1 ng/mL randomly, < 0.4 ng/mL after oral glucose tolerance test and normal IGF-I levels for age and sex within the first 3 and 6 months after surgery. Biochemical remission was achieved in 4 of 5 microadenomas (80%) and in 33 of 51 macroadenomas (64.7%). The total remission rate was 66.1% (37 of 56 adenomas). Age, gender and suprasellar extension did not affect the remission rate. However, cavernous sinus invasion, sphenoid sinus invasion and history of prior surgery were associated with lower rates of disease control. EETS represents an effective and safe option for the treatment of patients with acromegaly. High disease control rates and a small number of complications are some of the most important points related to the technique.

Measurement of free GH and bioactive IGF-I in non-diabetic haemodialysis patients treated with GH for 7 days

End-stage renal failure (ESRF) patients demonstrate augmented growth hormone (GH) secretion, but normal insulin-like growth factor-I (IGF-I) concentrations, indicating a state of GH resistance. To test this hypothesis, we compared the IGF-I response with exogenous GH in haemodialysis patients and healthy controls, with special focus on free GH and bioactive IGF-I. Ultrafiltered free GH and total GH were measured in serum collected hourly for 24 h at baseline and after 7 days of recombinant human (rh) GH (50 µg/kg/day) treatment in 11 non-diabetic haemodialysis patients and 10 matched controls. Serum levels of bioactive IGF-I (determined by cell-based IGF-I receptor activation assay), total IGF-I and the GH-binding protein (GHBP) were assayed twice daily. At baseline, patients showed elevated total GH (24 ± 5 versus 9 ± 1 µg/L × h, P < 0.02), free GH (21 ± 5 versus 7 ± 1 µg/L × h, P < 0.02), reduced GHBP (1.5 ± 0.3 versus 2.5 ± 0.2 nmol/L, P < 0.01), high-normal total IGF-I (173 ± 18 versus 135 ± 14 µg/L, P = 0.12) and subnormal bioactive IGF-I (2.1 ± 0.3 versus 2.8 ± 0.2 µg/L, P < 0.05) when compared with controls. After 7 days of rhGH treatment, there was a greater GH increase in the non-diabetic haemodialysis patients than in controls (total GH: 293 ± 33 versus 166 ± 13 µg/L × h, P < 0.001; free GH: 284 ± 40 versus 126 ± 15 µg/L × h, P < 0.001). GHB remained unaffected and total IGF-I increased to the same extent in patients and controls (701 ± 87 versus 572 ± 33 µg/L, P = 0.17), whereas bioactive IGF-I tended to be lower in patients (5.37 ± 0.55 versus 6.63 ± 0.25 µg/L, P < 0.10). When adjusting for the actual increments in plasma GH, the ability of exogenous GH to stimulate bioactive IGF-I levels was reduced by ~50% in ESRF (P < 0.02), whereas the response of total IGF-I remained normal (74%; P= 0.18) The study demonstrates that ESRF is associated with markedly elevated serum levels of free GH. Furthermore changes in bioactive, but not immunoreactive, IGF-I indicated that the hepatic sensitivity to GH was reduced by 50% in ESRF patients. Clearly, the physiological importance of our observations awaits further studies, but they suggest that changes in total IGF-I may not necessarily reflect changes in the endogenous activity of IGF-I in ESRF patients on GH treatment.

Insulin-like growth factor-I correlates more closely than growth hormone with insulin resistance and glucose intolerance in patients with acromegaly

In normal subjects growth hormone (GH) and insulin-like growth factor-I (IGF-I) have opposing effects on glucose metabolism. Active acromegaly is associated with insulin resistance (IR) and glucose intolerance although both GH and IGF-I are elevated. Our objective was to compare whether GH or IGF-I correlates more closely with IR and glucose intolerance in acromegaly. Basal serum IGF-I and GH, glucose and insulin during an oral glucose tolerance test were measured in 70 normoglycemic and 44 hyperglycemic acromegalic patients (21 impaired fasting glucose, 11 impaired glucose tolerance and 12 diabetes mellitus) according to American Diabetes Association criteria. 55 patients were assessed before any treatment for acromegaly and 59 after surgery and/or radiotherapy (15 patients had normal IGF-I after treatment). Patients treated with somatostatin analogs, GH-receptor antagonists or antidiabetic drugs were excluded. IR was assessed by various basal and stimulated indices. Homeostatic Model Assessment 2-Insulin Resistance (HOMA2-IR) index correlated more closely with IGF-I (r=0.65, p<0.0001) than nadir (r=0.23, p=0.008) or random GH (r=0.26, p=0.002). HOMA2-IR correlated better with IGF-I than nadir or random GH also in normoglycemic (n=70; r=0.74, p<0.0001 vs. r=0.36, p=0.001 vs. r=0.39, p<0.001) and hyperglycemic patients (n=44; r=0.54, p=0.0002 vs. r=0.09, p=0.4 vs. r=0.14, p=0.26). In multivariate logistic regression analysis IGF-I but not GH was a significant risk factor for glucose intolerance after adjusting for age, sex, weight and acromegaly duration (OR=1.56, p=0.01). In acromegaly IGF-I correlates more closely than GH with IR. IGF-I levels but not GH are associated with glucose intolerance.

Effects of insulin‐like growth factor‐I administration on in vivo regulation of urea synthesis in normal subjects and patients with cirrhosis

The anabolic effects of insulin-like growth factor-I (IGF-I) may involve a decrease of hepatic nitrogen (N) clearance, but this has never been studied in humans. Patients with cirrhosis have low levels of IGF-I and might benefit from IGF-I therapy. Conversely, a possible decrease in hepatic N clearance by IGF-I could increase the risk of hepatic encephalopathy. To examine the effects of 1-week IGF-I administration on the functional hepatic N clearance (FHNC), viz. the linear slope of the relationship between blood-α-amino-N concentration and urea-N synthesis rate as controlled by an infusion of alanine. A randomized sequence-crossover placebo-controlled study. Eight healthy volunteers and eight patients with alcoholic cirrhosis received injections of saline or IGF-I twice daily (50 μg/kg) for 7 days. IGF-I levels at baseline were lower in the patients than those in the controls. The IGF-I treatment normalized patient levels and caused an increase in the controls to supra-physiological levels. FHNC was lower in patients compared with healthy subjects (23.0 vs 36.5 L/h, P=0.03). IGF-I treatment reduced FHNC by 30% in healthy subjects (from 36.5 to 25.7 L/h, P = 0.02), whereas no effect was found in the patients. IGF-I downregulates urea synthesis in normal subjects. This may be part of the explanation behind the anabolic effects of IGF-I. The normalization of IGF-I in cirrhosis patients without an effect on urea synthesis implies that the patients were resistant to IGF-I with regard to reduction of hepatic amino-N elimination. IGF-I treatment of cirrhosis patients evidently carries no risk of N accumulation.

Comparison of the Efficacy of Octreotide Long-acting Repeatable and Lanreotide Autogel in Acromegalic Patients

Background: Somatostatin analogues have been used as the first-line medical therapy for active acromegaly that is not completely cured, or which recurs after surgery. The aim of this study was to compare the effects of octreotide long-acting repeatable (LAR) and lanreotide Autogel. Such a comparison has not been reported in Korea. Methods: Twenty-seven patients who had previously undergone surgery for acromegaly from December 2003 to March 2005 were included. We retrospectively investigated eight patients who underwent operation only and 19 patients who additionally received medical treatment after surgery (octreotide LAR, n = 5; lanreotide Autogel, n = 5). Growth hormone (GH) and insulin-like growth factor-I (IGF-I) levels were measured. Results: The mean pre-operative and post-operative levels of GH were lower in patients who underwent surgery only than in those who received adjuvant therapy, but IGF-I levels were not significantly different. In the 19 patients receiving medical treatment after unsuccessful surgery, the mean baseline GH levels were 24.2 g/L for octreotide LAR and 22.8 g/L for lanreotide Autogel (P = 0.711), and the mean GH levels 36 months post-treatment were 4.1 g/L and 2.5 g/L, respectively (P = 0.794). GH g/L represented 30% of octreotide LAR patients and 33.3% of lanreotide Autogel patients (P = 0.91). Patients with normal IGF-I levels represented 54.5% and 66.7%, respectively (P = 0.71). Conclusion: No significant difference in therapeutic effect of octreotide LAR and lanreotide Autogel was evident in 19 Korean acromegalic patients who were not completely cured by surgery and radiation therapy.

Sustained Maintenance of Normal Insulin-like Growth Factor-I during Pregnancy and Successful Delivery in an Acromegalic Patient with Octreotide-LAR® Treatment

was discontinued when the patient was found to be at the 12th week of pregnancy. During pregnancy, the patient experienced clinical well-being and she maintained her IGF-I levels within the normal range for her age-matched despite discontinuation of Octreotide-LAR ® treatment at early gestation. She delivered a full-term healthy male infant. The serum IGF-I levels of the patient in - creased progressively increased after delivery. This report describes a successful pregnancy in an acromegalic woman who was ex - posed to Octreotide-LAR ® during the early gestational period. She and who showed an unexpected pattern of persistently normal IGF-I levels through the pregnancy despite discontinuation of Octreotide-LAR ® therapy. (Endocrinol Metab 25:213-216, 2010)

A Canadian multi-centre, open-label long-term study of Pegvisomant treatment in refractory acromegaly

Acromegaly is a rarely diagnosed condition with potentially serious complications including accelerated heart disease and reduced survival. After a mean interval of nearly 9 years from onset of disease, a significant proportion of patients are diagnosed with invasive adenomas precluding complete surgical resection. Furthermore, strict normalization of the growth hormone (GH) target insulin-like growth factor I (IGF-I) cannot always be achieved by adjunctive medical therapy with somatostatin analogues. Here we report the results of a Canadian multi-centre study open-label, dose-titrated long-term study examining safety and efficacy outcomes of a growth hormone receptor antagonist, pegvisomant in 19 patients with refractory acromegaly. Previously pegvisomant-treated and treatment-naïve refractory acromegalic patients at least 18 yr of age were eligible (n=19). Patients received open-label daily subcutaneous injections of pegvisomant adjusted according to IGF-I levels. Safety and IGF-I levels were assessed every 4 to 6 wk. Baseline and follow-up visits at 3-month intervals also included administration of the Signs and Symptoms of Acromegaly Questionnaire. This study is registered with ClinicalTrials.gov, NCT00151437. We show that, in escalating doses, pegvisomant results in age-adjusted normalization of IGF-I in nearly all such patients. This IGF-I normalization occurred early on and was maintained throughout the study period of 27 months (IGF-I standard deviation score (SDS), mean +/- SE: 1.66 +/- 0.36, P=0.0003 vs baseline), with a nadir at 18 months (IGF-I SDS, mean +/- SE: 1.50 +/- 0.38, P=0.0010 vs baseline). IGF-I control was also accompanied by measurable improvements in disease-associated symptoms and without radiographic evidence of pituitary tumour progression. Overall, the safety profile of pegvisomant therapy in this patient population was found to be satisfactory and suitable for a long-term treatment. Our findings provide support for the long-term safety and efficacy of the GH receptor antagonist pegvisomant in achieving IGF-I control in patients with refractory acromegaly.

Oxidative Stress Inhibits Insulin-like Growth Factor-I Induction of Chondrocyte Proteoglycan Synthesis through Differential Regulation of Phosphatidylinositol 3-Kinase-Akt and MEK-ERK MAPK Signaling Pathways

The ability of insulin-like growth factor I (IGF-I) to stimulate cartilage matrix synthesis is reduced in aged and osteoarthritic cartilage. Aging and osteoarthritis are associated with an increase in reactive oxygen species, which we hypothesized would interfere with normal IGF-I signaling. We compared IGF-I signaling in normal and osteoarthritic human articular chondrocytes and investigated the effects of oxidative stress induced by tert-butylhydroperoxide (tBHP). In normal human chondrocytes, IGF-I initiated a strong and sustained phosphorylation of IRS-1 (Tyr-612) and Akt (Ser-473) and transient ERK phosphorylation. In contrast, in osteoarthritic chondrocytes, which possessed elevated basal IRS-1 (Ser-312) and ERK phosphorylation, IGF-I failed to stimulate IRS-1 (Tyr-612) or Akt phosphorylation. In normal human chondrocytes, tBHP triggered strong IRS-1 (Ser-312 and Ser-616) and ERK phosphorylation and inhibited IGF-I-induced IRS-1 (Tyr-612) and Akt phosphorylation. Lentivirus-mediated overexpression of constitutively active (CA) Akt significantly enhanced proteoglycan synthesis, whereas both dominant negative Akt and CA MEK inhibited proteoglycan synthesis. CA Akt also promoted type II collagen and Sox9 expression, whereas tBHP treatment and CA MEK inhibited aggrecan, collagen II, and Sox9 mRNA expression. In osteoarthritic chondrocytes, the antioxidants Mn(III) tetrakis(4-benzoic acid)porphyrin and N-acetylcysteine increased the ratio of Akt to ERK phosphorylation and promoted IGF-I-mediated proteoglycan synthesis. Chemical inhibition of ERK significantly enhanced IGF-I phosphorylation of Akt and alleviated tBHP inhibition of Akt phosphorylation. These results demonstrate opposing roles for phosphatidylinositol 3-kinase-Akt and MEK-ERK in cartilage matrix synthesis and suggest that elevated levels of reactive oxygen species cause chondrocyte IGF-I resistance by altering the balance of Akt to ERK activity.

Alterations of growth plate and abnormal insulin-like growth factor I metabolism in growth-retarded hypokalemic rats: effect of growth hormone treatment

Hypokalemic tubular disorders may lead to growth retardation which is resistant to growth hormone (GH) treatment. The mechanism of these alterations is unknown. Weaning female rats were grouped (n = 10) in control, potassium-depleted (KD), KD treated with intraperitoneal GH at 3.3 mg x kg(-1) x day(-1) during the last week (KDGH), and control pair-fed with KD (CPF). After 2 wk, KD rats were growth retarded compared with CPF rats, the osseous front advance (+/-SD) being 67.07 +/- 10.44 and 81.56 +/- 12.70 microm/day, respectively. GH treatment did not accelerate growth rate. The tibial growth plate of KD rats had marked morphological alterations: lower heights of growth cartilage (228.26 +/- 23.58 microm), hypertrophic zone (123.68 +/- 13.49 microm), and terminal chondrocytes (20.8 +/- 2.39 microm) than normokalemic CPF (264.21 +/- 21.77, 153.18 +/- 15.80, and 24.21 +/- 5.86 microm). GH administration normalized these changes except for the distal chondrocyte height. Quantitative PCR of insulin-like growth factor I (IGF-I), IGF-I receptor, and GH receptor genes in KD growth plates showed downregulation of IGF-I and upregulation of IGF-I receptor mRNAs, without changes in their distribution as analyzed by immunohistochemistry and in situ hybridization. GH did not further modify IGF-I mRNA expression. KD rats had normal hepatic IGF-I mRNA levels and low serum IGF-I values. GH increased liver IGF-I mRNA, but circulating IGF-I levels remained reduced. This study discloses the structural and molecular alterations induced by potassium depletion on the growth plate and shows that the lack of response to GH administration is associated with persistence of the disturbed process of chondrocyte hypertrophy and depressed mRNA expression of local IGF-I in the growth plate.