Mean IGF-I Levels Research Articles

RF14 | LBMON195 Once-weekly Somapacitan Is Effective And Well Tolerated In Children With GH Deficiency: A Randomized Phase 3 Trial

Abstract Growth hormone (GH) replacement therapy usually requires daily subcutaneous (s.c.) injections that can be burdensome for patients and their caregivers. Somapacitan, a long-acting reversible albumin-binding GH derivative, is in development for once-weekly s.c. administration in children with GH deficiency (GHD). REAL4 is a randomised, multi-national, open labelled, and active-controlled parallel group phase 3 trial, comprising a 52-week main phase and three-year extension period (NCT03811535). Two-hundred GH-treatment-naïve, prepubertal children with GHD (74.5% male) were randomly assigned in a 2: 1 ratio to receive 0.16 mg/kg/week s.c. somapacitan (n=132) or daily s.c. GH (0.034 mg/kg/day Norditropin®; n=68). The 52-week main trial results are presented here. The primary endpoint was annualized height velocity (HV) after 52 weeks of treatment. At week 52, the estimated mean HV was 11.2 cm/year for somapacitan compared to 11.7 cm/year for daily GH. The estimated treatment difference was -0.5 [95% CI -1.1 to 0.2] cm/year, confirming non-inferiority (non-inferiority threshold: -1.8 cm/year). Secondary height-related endpoints supported the primary endpoint. Insulin-like growth factor-I standard deviation score (IGF-I SDS) showed consistent increases for both somapacitan and daily GH over the 52 weeks, with change differences from baseline not statistically significant between treatment groups. At week 52, mean IGF-I SDS levels were similar between somapacitan (+0.28) and daily GH (+0.10) and within normal range (-2 to +2). Somapacitan was well tolerated, with no safety or local tolerability issues identified. There were no clinically relevant findings with respect to changes in glucose metabolism, no neutralizing anti-somapacitan or anti-GH antibodies were detected, and a low number of patients reported injection-site reactions, with similar proportions for somapacitan (5.3%) and daily GH (5.9%). In both treatment groups, 1.5% of patients reported injection site pain. Adherence was high for both treatments. The mean and median adherence for somapacitan treatment were 95.8% and 100%, respectively. The mean and median adherence for the daily GH group were 88.3% and 96.9%, respectively. In conclusion, once-weekly somapacitan has a similar efficacy and safety profile as daily GH with similar mean IGF-I levels in treatment-naïve children with GHD. Presentation: Sunday, June 12, 2022 1:06 p.m. - 1:11 p.m., Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Pegvisomant in combination or pegvisomant alone after failure of somatostatin analogs in acromegaly patients: an observational French ACROSTUDY cohort study

ObjectiveAfter surgery, when somatostatin analogs (SAs) do not normalise IGF-I, pegvisomant (PEG) is indicated. Our aim was to define the medical reasons for the treatment of patients with PEG as monotherapy (M) or combined with SA, either as primary bitherapy, PB (PEG is secondarily introduced after SA) or as secondary bitherapy, SB (SAs secondarily introduced after PEG).MethodsWe retrospectively analysed French data from ACROSTUDY.Results167, 88 and 57 patients were treated with M, PB or SB, respectively, during a median time of 80, 42 and 70 months. The median PEG dose was respectively 15, 10 and 20 mg. Before PEG, the mean IGF-I level did not differ between M and PB but the proportion of patients with suprasellar tumour extension was higher in PB group (67.5% vs. 44.4%, P = 0.022). SB regimen was used preferentially in patients with tumour increase and IGF-I level difficult to normalise under PEG. In both secondary regimens, the decrease of the frequency of PEG’s injections, compared to monotherapy was confirmed. However, the mean weekly dose of PEG between M and PB remained the same.ConclusionsThe medical rationale for continuing SAs rather than switching to PEG alone in patients who do not normalise IGF-I under SAs was a tumour concern with suprasellar extension and tumour shrinkage under SA. A potential explanation for introducing SA in association with PEG appears to be a tumour enlargement and difficulties to normalise IGF-I levels under PEG given alone. In both regimens, the prospect of lowering PEG injection frequency favoured the choice.

Assessment of Relationship Between Insulin-Like Growth Factor- 1 Levels And Mp3 Radiographs in Determining Skeletal Maturity

Context: The clinical importance of evaluating skeletal maturation has long been recognized by the health professions. Skeletal maturation is an integral part of individual patterns of growth and development.With many orthodontic patients, pubertal growth needs to be factored into the diagnostic equation.Accurate prediction of the timing of the pubertal growth spurt and the amount of remaining growth affects the treatment decisions in orthodontics, orthognathic surgery and dental implantology.IGF-1 mirrors growth hormone levels. Thus, IGF-I might be a good indicator of residual mandibular growth. Aims: To establish a relationship between IGF-1 levels evaluated from blood samples and MP3 stages of skeletal maturity. To investigate the relationship between the IGF-1 and the skeletal age. Methods and Material: The sample size consisted of 40 subjects between the age group of 5 – 25 including both the sexes. The periapical radiographs for MP3 and blood sample for IGF-1 was collected. Sample was sent to the lab to determine IGF-1 values. Statistical analysis used: Descriptives, ONE way ANOVA, POST HOC test, Spearman coefficient. Results: Results showed that IGF-1 levels at the peak pubertal growth were statistically higher than the start of pubertal growth, acceleration, deceleration, maturation of growth spurt and on completion of growth. There was statistically significant positive correlation between IGF-1 and MP3 stages. Conclusions: From the present study it can be concluded that IGF-1 can be successfully used as a skeletal maturity indicator. Key-words: IGF-1, MP3, GH Key Messages:The results of this study shows that mean IGF-I levels at pubertal and post pubertal stages were significantly higher than at the other stages. From the present study it can be concluded that IGF-1 can be successfully used as a skeletal

OR23-07 Results From the Phase 3, Randomized, Double-Blind, Placebo-Controlled CHIASMA OPTIMAL Study of Oral Octreotide Capsules in Adult Patients with Acromegaly

Many patients taking long-acting somatostatin receptor ligand (SRL) injections as first-line medical therapy in acromegaly report limitations, including ongoing disease symptoms especially near injection cycle end and injection site pain. Oral octreotide capsules may provide an alternative to monthly injections. The phase 3 Octreotide capsules versus Placebo Treatment In MultinationAL centers (OPTIMAL) study assessed efficacy and safety of oral octreotide capsules in patients with acromegaly controlled on injectable SRLs. A multinational, randomized, placebo-controlled study was conducted in 56 adult patients with active acromegaly. Eligible patients were ≥ 18 years of age, had evidence of active disease (IGF-I ≥ 1.3 x ULN ≥3 months after last pituitary surgery), and an average IGF-I ≤ 1.0 x ULN on a stable dose of SRL injections (octreotide or lanreotide). At baseline (1 month following the last injection), patients were randomized to receive octreotide capsule or placebo (28 per group) for 36 weeks, followed by an optional open-label oral octreotide extension. The primary endpoint was proportion of patients maintaining biochemical response, defined as IGF-I ≤ 1.0 x ULN (2-value average at weeks 34 and 36). Secondary endpoints included need for rescue with injectable SRLs, GH response (GH < 2.5 ng/mL), and time to loss of IGF-I response (IGF-I >1.0 and ≥ 1.3x ULN for 2 consecutive visits). Safety and tolerability were assessed. The primary endpoint was met, as 58% of patients receiving octreotide capsules maintained IGF-I response vs 19% receiving placebo (P=0.008). Mean IGF-I levels in patients receiving octreotide capsules were within the reference range at treatment end (0.97 x ULN) vs patients receiving placebo (1.69 x ULN). All secondary endpoints were met. Of patients receiving octreotide capsules, 75% completed 36 weeks without need for rescue therapy. However, 68% of the placebo group required rescue therapy. GH response was maintained at week 36 in a significantly larger proportion of patients receiving octreotide capsules than placebo (78% vs 30%; P=0.001). Median time to loss of IGF-I response was not reached by the end of the study for patients receiving octreotide capsules vs 16 weeks for the placebo group (P <0.0001). Five patients in the placebo group had IGF-I levels in the reference range at the end of 36 weeks. Only 2 (7% of placebo group) did not meet loss of response criteria anytime throughout the study. Octreotide capsules were safe and well tolerated; no new/unexpected safety signals were observed. Most patients (55/56) experienced at least one treatment emergent adverse event; most were mild or moderate in intensity. Overall, 90% of patients who completed the trial on octreotide capsules opted to enter the open label extension phase. These phase 3 data demonstrate octreotide capsules to be potentially safe and effective for the treatment of adults with acromegaly.

MON-323 IGF-I Variability and Its Association with Demographic and Clinical Characteristics in Patients with Acromegaly Treated with Injectable Somatostatin Receptor Ligands (SRLS); Results from an International Prospective Phase III Study

Background: In clinical practice, most patients responding to injectable somatostatin receptor ligands exhibit IGF-I variability around the upper limit of normal (ULN) during long-term follow up. These fluctuations are thought to result from various factors such as assay variability, nutrition, comorbid conditions, concomitant medications and other unknown factors. The magnitude of this variability, and the factors affecting it, is not well understood in patients with acromegaly treated with injectable SRLs. Methods: IGF-I levels of patients responding to and stably treated with injectable SRLs were measured over time in the CHIASMA OPTIMAL phase III study. Two time periods were assessed - Period 1, three assessments during screening phase before randomization to octreotide capsules (N=56), and Period 2 - multiple assessments up to week 36, in patients rescued with SRL injections for at least 12 weeks (N=21). The time from the last injection to each of the 3 assessments in period 1 [Screening visits 1 and 2 (SV1 & SV2), and Baseline (BL)], was on average 6.8 ± 10.7 (SD), 15.8 ± 2.7, and 29.0 ± 1.8 days respectively. Correlation with various demographics and Baseline characteristics, including age, gender, weight, BMI and residual tumor size to IGF-I variability was assessed. Percent change for each individual patient from Minimal to Maximal IGF-I values within each period was computed and the overall population mean was calculated (lowest value was used as the denominator and all other values were expression as a positive % above this value). Results: The overall mean within-patient percent change of IGF-I levels during Period 1 was 20.48 ± 15.56 (range: 0.6-81). Mean IGF-I levels for SV1, SV2 and BL were 0.78 ± 0.18, 0.79 ± 0.18, and 0.85 ± 0.22 x ULN respectively. The overall increase in mean IGF-I levels from SV1 to BL (longest time interval) was statistically significant (p=0.0002; paired T-test). Analysis of IGF-I levels in patients during Period 2, revealed that the overall mean within-patient percent change of IGF-I levels was 15.27 ± 12.20 (range: 0-41.5). The mean duration of follow up during this period, after patients were already treated for ≥12 weeks with injectable SRL, was 1.72 (± 1.29) months. The variability observed in Period 2 was similar to that observed in the entire sample evaluated in Period 1. No significant differences were found in the mean IGF-I percent change between any demographic or baseline characteristic subgroup examined. Conclusion: IGF-I levels fluctuate in patients with acromegaly who are responsive to injectable SRLs. These fluctuations are wide and can be up to 81% higher than the lowest (most controlled) value, with an average increase of approximately 20%. Significant IGF-I increases were observed at the end of the long acting SRL injection interval.Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. s presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

MON-LB55 Biochemical Control of Most Patients Reverting to Injectable Long-Acting Somatostatin Receptor Ligands Is Achieved After One Dose: Results From the Phase 3, Randomized, Double Blind, Placebo-Controlled Optimal Study

Background: Injectable somatostatin receptor ligands (SRLs) are currently the most widely used medical therapy for acromegaly worldwide. Oral octreotide capsules (OOC) have been formulated as a potential therapy for this disorder and the safety and efficacy were evaluated in the CHIASMA OPTIMAL pivotal study (Samson et al. ENDO 2020). As reported, mean IGF-I levels of the OOC treatment group were maintained within normal range at the end of treatment in all patients. However, some patients may not respond to OOC treatment (25% of OOC group and 68% of placebo groups required rescue, P=0.003). This analysis describes the degree and rapidity with which patients achieve biochemical control (IGF-I ≤1.0 x ULN) when reverted to their prior injectable SRL treatment. Methods: Patients with confirmed acromegaly and receiving a stable dose of injectable SRL (≥3 months) were randomized to OOC (40mg/day; N=28) or placebo (N=28) for 36 weeks. Patients were dose titrated to 60 or 80mg of OOC (or placebo) through week 24 at investigator discretion based on increased IGF-I levels and/or worsening acromegaly signs/symptoms. Patients could be rescued via reversion to prior injectable SRL therapy if they met the predefined withdrawal criteria (i.e., IGF-I ≥1.3 x upper limit of normal [ULN] for 2 consecutive visits on the highest dose, and exacerbation of clinical signs/symptoms) or discontinued treatment early for any other reason. In the study, 7 patients in the OOC group and 19 in the placebo group required rescue. The change in IGF-I from Baseline was compared to the end of the Double-blind Placebo Controlled period. Results: In patients rescued up to week 32 and in whom there were at least 4 weeks of follow up, baseline IGF-I levels (mean of Screening Visit 2 and Baseline) were 0.80 and 0.87 x ULN in the OOC and placebo groups, respectively. In patients receiving rescue therapy, the end of study IGF-I levels (mean of week 34 and 36) were 0.80 and 0.89 x ULN in the OOC and placebo groups, respectively, virtually unchanged. The median time to return to normal baseline IGF-I values following loss of response was 4.0 weeks after discontinuing OOC and 4.0 weeks after discontinuing placebo treatment. Therefore, most patients who required rescue following a short trial of therapy with OOC returned to their baseline values following a single SRL injection. Conclusion: Most treatment failures in the CHIASMA OPTIMAL trial (on either OOC or placebo) rescued with injectable SRL re-established their baseline response levels after a single injectable SRL administration (at pre-study dose). Based on this data, patients may potentially be treated with OOC and for those not responding, either not biochemically controlled or who have adverse effects, they may be able to return to injectable SRLs with immediate IGF-I control after one SRL injection.

Acromegaly Is More Severe in Patients With AHR or AIP Gene Variants Living in Highly Polluted Areas.

An increased prevalence of acromegaly was found some years ago in a highly polluted area in North-Eastern Sicily, where high concentration of nonmethane hydrocarbons, volatile organic compounds, and cadmium was found. Aryl hydrocarbon receptor (AHR) pathway has a key role in detoxification of these compounds and in tumorigenesis. We correlated the occurrence of AHR and/or AHR-interacting protein (AIP) gene variants with acromegaly severity according to pollution exposition. This was an observational, perspective study conducted over 7 years in four Italian referral centers for pituitary diseases in which 210 patients with acromegaly were enrolled between 2008 and 2015. Genetic screening of patients for AHR and AIP variants. Clinical, biochemical, and radiological data of patients with and without AIP and/or AHR gene variants, living in polluted (high-risk for health, [HR]) or nonpolluted (NP) areas of five Italian regions were evaluated and compared. Among the 23 patients from HR areas, nine showed AHR or AIP variants. Mean IGF-I levels and pituitary tumor diameter were significantly higher in these nine patients (HR/VAR+) than in the other 14 (HR/VAR−) and in the 187 from NP areas (44 NP/VAR+). Somatostatin analogs significantly decreased mean GH and IGF-I levels in patients from NP areas and in HR/VAR− (GH P < .05; IGF-I times the upper limit of normal P < .01) but not in HR/VAR+ group. Genetic variants potentially inducing functional abnormalities of the aryl hydrocarbon receptor (AHR) pathway are associated with a more severe acromegaly, increased pituitary tumor size, and somatostatin analog resistance in patients living in HR areas.

Influence of a fermented protein-fortified dairy product on serum insulin-like growth factor-I in women with anorexia nervosa: A randomized controlled trial

Patients with anorexia nervosa (AN) have low serum IGF-I levels that may contribute to a lower bone mineral mass. We investigated the effects of a fermented, protein-fortified, dairy product on serum IGF-I levels in patients with AN during an in-hospital refeeding program. In this multicenter, randomized, double-blind, placebo-controlled, clinical trial conducted at 3 university hospitals and 3 private clinics in France and Switzerland, 62 women recently admitted with confirmed AN and with a baseline low serum IGF-I level were randomized to 2 daily isocaloric fresh cheese pots containing either 15g/150g or 3g/150g (controls) of protein for 4 weeks. The primary outcome was the change in IGF-I levels. In the primary intention-to-treat analysis, mean serum IGF-I levels increased during the intervention phase from 22.9±1.5 to 28.6±1.3nmol/L (means±SEM) (+20.2%) in the intervention group and from 20.2±1.2 to 25.7±1.5nmol/L (+16.8%) in controls. In a preplanned analysis of covariance with repeated measures, the between-group difference was close to statistical significance (P=0.071). In a post-hoc mixed-regression model analysis, the difference was statistically significant (4.9nmol/l increase; P=0.003), as was the change of the ratio IGF-I/IGF-BP3 (P=0.004). There was no between-group difference in biochemical markers of bone turnover (osteocalcin, P1NP, CTX) or in serum parathyroid hormone level. Serum calcium levels slightly increased during the intervention phase in the higher protein group (P=0.02). IGF-BP2 decreased significantly more in the intervention group during the follow up period at week 4 after supplements cessation (P=0.019). Intake of a fermented, protein-fortified, isocaloric dairy product during 4 weeks may slightly increase serum IGF-I levels in women with AN, without significant changes in bone turnover markers. NCT01823822 (www.clinicaltrials.gov).

Relationship between Foetal Growth Restriction and Maternal Nutrition Status Measured by Dual-Energy X-Ray Absorptiometry, Leptin, and Insulin-Like Growth Factor

Aims: The aim of this study was to determine if maternal nutritional status, as defined by body composition, leptin, and insulin-like growth factor (IGF)-I levels, relates to foetal growth. Methods: In this prospective study, mothers of foetuses with foetal growth restriction (FGR; cases; n = 46) and mothers of appropriate-for-gestational-age (AGA) foetuses (controls; n = 81) were consecutively recruited over a 14- month period. A maternal blood sample was obtained during the third trimester (between 32 and 34 weeks of gestation) for the assessment of IGF-I and leptin. Body composition was assessed by dual-energy X-ray absorptiometry within the first 15 days after delivery. The study used the SPSS-PC statistical package, version 19.0, and p < 0.05 was considered statistically significant. Results: Mean serum IGF-I levels were lower in the cases than in the controls (p < 0.05), whereas leptin concentrations were higher in the cases after adjusting for age, body mass index and cigarette consumption (p < 0.05). Cases had less lean and fat tissue than controls (p < 0.05) but a relatively higher fat percentage. Conclusions: The mothers of foetuses with FGR have a body composition pattern characterized by a slightly increased fraction of fat mass, lower IGF-I concentrations, and increased serum leptin levels. Optimization of maternal nutritional status should be considered, as the nutritional status may be involved in the pathogenesis of FGR.

Abstract B78: Adiposity and the IGF-axis in girls during pubertal development

Abstract Background: Increased childhood adiposity has been associated with decreased breast cancer risk, but the biologic mechanisms underlying this association are not well understood. Pubertal growth is in part driven by the insulin-like growth factor (IGF) system and adult measures of IGF have been associated with breast cancer. We hypothesize that childhood adiposity is associated with the IGF-axis and that levels set in childhood affect later breast cancer risk. We prospectively examine associations between childhood adiposity, as measured by body mass index (BMI)-for-age percentile (BMIPCT), and serum IGF-axis biomarkers (IGF-I, IGF binding protein 1(IGFBP-1), and IGF binding protein 3 (IGFBP-3)) among girls in the Dietary Intervention Study in Children (DISC). Methods: Data are from an ancillary hormone study of 268 of the 301 girls who participated in the DISC. Girls were 8-10 years old at baseline with a median follow-up of 7 years. Data from intervention and control groups were combined and intervention status was included in adjusted analyses. Fasting blood samples (n=563) collected at baseline, years 3, 5 and last visit were available for 219 premenarcheal and 201 postmenarcheal girls. Levels of IGF-I, IGFBP-1, and IGFBP-3 were determined using radioimmunoassays. Weight and height measurements were taken at baseline and subsequent visits by trained interviewers. BMI (weight/height2)–for-age percentiles were determined using the CDC growth chart. To mitigate skewness, biomarkers were log transformed. Adjusted geometric means of IGF biomarkers were calculated by quintiles of baseline BMIPCT. All adjusted analyses included age, age2, treatment group, baseline height, and physical activity. Associations of longitudinal BMIPCT with IGF biomarkers were estimated using multivariable linear mixed-effect models, accounting for repeated BMIPCT and IGF measurements within each girl across follow-up visits. Trend tests were performed on continuous BMIPCT using adjusted mixed-effect models to estimate percentage changes in IGF biomarkers during follow-up. Results: In adjusted analyses, premenarcheal girls in the lowest quintile of baseline BMIPCT had lower geometric mean IGF-I levels than all other quintiles (Q1= 236 ng/mL (95% confidence interval (CI): 211, 264) vs. Q5 mean=271 ng/ml (95% CI: 240, 307)). Girls in the lowest quintile of BMIPCT had higher IGFBP-1 levels that decreased linearly with BMIPCT quintile (Ptrend &amp;lt;0.0001). In continuous analyses, each 10 percentile increment in baseline BMIPCT was associated with a 2.4% increase (95% CI: 0.5%, 4.2%) in IGF-I (Ptrend=0.01) and a 7.2% decrease (95% CI: 4.9%, 9.6%) in IGFBP-1 (Ptrend&amp;lt;0.0001). There was no significant association between IGFBP-3 and BMIPCT. In post-menarcheal girls, each 10 percentile increment in baseline BMIPCT was associated with a 12.0% decrease (95% CI: 8.4 %,15.6%) in IGFBP-1 (Ptrend&amp;lt;0.0001), but no significant association with IGF-I or IGFBP-3. Conclusion: This study suggests that premenarcheal girls in the lowest quintile of BMI-for-age have lower IGF-I levels than in all other quintiles. Results also show increased adiposity, as measured by BMI-for-age, is significantly associated with decreased IGFBP-1 in both pre- and postmenarcheal girls. Further research is needed to confirm these findings, as well as to explore possible associations with breast development and potentially breast cancer risk. Citation Format: Ellen M. Velie, Zhenzhen Zhang, Jean M. Kerver, Joseph C. Gardiner, Clifford J. Rosen, Joanne F. Dorgan. Adiposity and the IGF-axis in girls during pubertal development. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr B78.

Low postnatal serum IGF‐I levels are associated with bronchopulmonary dysplasia (BPD)

Aim:To characterize postnatal changes in serum insulin-like growth factor-1 (IGF-I) in relation to development of bronchopulmonary dysplasia (BPD) in very preterm infants.Methods:Longitudinal study of 108 infants with mean (SD) gestational age (GA) 27.2 (2.2) weeks. Weekly serum samples of IGF-I were analysed from birth until postmenstrual age (PMA) 36 weeks. Multivariate models were developed to identify independent predictors of BPD.Results:Postnatal mean IGF-I levels at postnatal day (PND) 3–21 were lower in infants with BPD compared with infants with no BPD (16 vs. 26 μg/L, p < 0.001). Longitudinal postnatal change in IGF-I levels (IGF-I regression coefficient (β)), PNDs 3–21, was lower in infants with BPD compared with infants with no BPD (0.28 vs. 0.97, p = 0.002) and mean IGF-I during PMA 30–33 weeks was lower in infants with BPD as compared with infants without BPD (22 vs. 29 μg/L, p < 0.001). In a binomial multiple regression model, lower GA, male gender and lower mean serum IGF-I levels during PND 3–21 were the most predictive risk factors associated with BPD (r2 = 0.634, p < 0.001).Conclusion:Lower IGF-I concentrations during the first weeks after very preterm birth are associated with later development of BPD.

Gender Difference in the Neuroendocrine Regulation of Growth Hormone Axis by Selective Estrogen Receptor Modulators

In men, GH secretion is stimulated by estradiol derived locally from aromatization of testosterone. Recently, we showed that local estrogen also plays a major role in the central regulation of GH secretion in women. Tamoxifen and raloxifene are selective estrogen receptor modulators (SERMs), drugs that block central estrogen action but exert estrogen-like effects in the liver, inhibiting hepatic IGF-I production. The relative impact of SERMs on the GH-IGF-I axis in men and women has not been investigated. The aim of the study was to determine whether there is a gender difference in the impact of SERMs on the GH-IGF-I axis. We conducted a comparative, randomized, open-label, crossover study of tamoxifen and raloxifene. Ten healthy postmenopausal women and ten healthy men were randomized to 2-wk sequential treatment with tamoxifen (10 and 20 mg/d) and raloxifene (60 and 120 mg/d) with a washout of 2 wk between treatments. The GH response to arginine, IGF-I, testosterone, and SHBG was measured. In women, but not in men, tamoxifen significantly attenuated the GH response to arginine. The GH response was not significantly blunted by raloxifene in both sexes. Both SERMs significantly reduced mean IGF-I levels to a similar degree in men and women. In men, both SERMs significantly increased LH and testosterone levels. In summary, GH secretion was blunted by tamoxifen in women in the face of reduced IGF-I feedback inhibition but not in men in whom the gonadal axis was stimulated. We conclude that potential blunting of GH secretion in men by SERMs was counteracted by concomitant central stimulation of GH secretion by testosterone. In therapeutic doses, tamoxifen may induce detrimental metabolic effects in women, but not men.

Acromegaly and Pregnancy: A Retrospective Multicenter Study of 59 Pregnancies in 46 Women

Few data are available on pregnancy outcomes in women with acromegaly. This was a retrospective multicenter study. The study included 46 women with GH-secreting pituitary microadenomas (n = 7) or macroadenomas (n = 39). Their mean age was 31.7 yr (±4.5 yr). Incomplete transsphenoidal surgical resection (n = 39) and pituitary radiation (n = 14) had been performed, respectively, 2.9 ± 2.6 and 7.3 ± 4.2 yr before pregnancy. The patients were receiving dopamine agonists (n = 25) and/or somatostatin analogs (n = 14), and GH/IGF-I hypersecretion was controlled and uncontrolled in, respectively, 23 and 34 cases. Five pregnancies followed the fertility treatment. Fifty-nine pregnancies resulted in 64 healthy babies. Gestational diabetes and gravid hypertension occurred in four (6.8%) and eight (13.6%) pregnancies, respectively, and both were more frequent when GH/IGF-I hypersecretion was not controlled before pregnancy. Visual field defects were diagnosed during pregnancy in four women, three of whom were diagnosed with acromegaly during the pregnancy. Seven women had isolated headache. Magnetic resonance imaging performed 3.9 ± 0.3 months after delivery showed that the size of the adenoma had increased in three cases, decreased in two cases, and remained stable in 22 cases. Seventeen women breast-fed with no complications. Four women gave birth to a small-for-gestational-age infant; all had received somatostatin analogs, alone or in combination with dopamine agonists, during pregnancy. The mean IGF-I level fell significantly during the first trimester in 12 cases (before conception 588 ± 207 ng/ml, first trimester 319 ± 126 ng/ml, P = 0.002), whereas the GH concentration did not change significantly. The following conclusions were reached: 1) pregnancy in women with active or uncontrolled acromegaly may be associated with an increased risk of gestational diabetes and gravid hypertension; 2) pregnancy is occasionally associated with symptomatic enlargement of GH-secreting pituitary macroadenomas; 3) changes in serum GH and IGF-I concentrations are variable during pregnancy, indicating that routine monitoring is not mandatory if the pregnancy is uneventful; and 4) GH-suppressive treatment can be safely withdrawn after conception in most acromegalic women.

The IGF-I Response to Growth Hormone Is Related to Body Mass Index in Short Children with Normal Weight

Aim: We investigated whether the insulin-like growth factor (IGF)-I response to growth hormone (GH) is regulated by body mass index (BMI) in short children with normal weight. Methods: We studied 37 prepubertal children with idiopathic short stature (ISS), comparing children with high-normal BMI (standard deviation scores, SDS 1.23 ± 0.11, n = 20) and low-normal BMI (SDS –0.93 ± 0.12, n = 17). The IGF-I response to GH was determined with an abbreviated IGF-I generation test, by measuring serum IGF-I concentrations at baseline and 24 h after the administration of GH (0.033 mg/kg). Results: Children with high- and low-normal BMI had similar age (8.5 ± 0.7 vs. 8.7 ± 0.7 years) and height (–2.0 ± 0.1 vs. –2.2 ± 0.2 SDS). However, children with high-normal BMI exhibited higher mean basal IGF-I (191 ± 15 vs. 139 ± 11 ng/ml, p < 0.05), higher mean IGF-I levels 24 h after GH administration (261 ± 22 vs. 164 ± 14 ng/ml, p < 0.05) and a higher IGF-I percent increase after GH administration (37 ± 5 vs. 17 ± 4%, p < 0.05) compared with children with normal-low BMI. Conclusion: BMI modulates the IGF-I response to GH, suggesting that GH sensitivity may be influenced by the nutritional status in children with ISS and normal body weight.

Optimizing Medical Therapy of Acromegaly: Beneficial Effects of Cabergoline in Patients Uncontrolled with Long-Acting Release Octreotide

Background: Previous data indicate a beneficial effect of cabergoline (CAB) association to somatostatin analogs (SA) in acromegalics resistant to SA monotherapy. Objective: To assess the efficacy of CAB association on acromegalics with high IGF-I on stable long-acting release octreotide (OCT-LAR) (30 mg/28 days). Design, Subjects and Methods: 34 patients (17 male, 25–85 years, 33 macroadenomas) were enrolled in this prospective study. OCT-LAR was administered as primary (n = 4) and as secondary (n = 30) treatment: after surgery (n = 16), after surgery + radiotherapy (RT) (n = 11), and after RT only (n = 3). Duration of OCT-LAR therapy prior to CAB was 24 ± 12 months. The immunohistochemical features of the tumors disclosed GH/PRL co-secretion in 11/21 patients. 13 patients had high PRL levels prior to CAB. The initial CAB dose was 1.5 mg/week. No IGF-I normalization led to a dose increase to 3.5 mg/week. The OCT-LAR dose was kept stable during treatment. IGF-I, GH and PRL levels were compared before and after CAB association. OCT-LAR was withdrawn in patients who achieved IGF-I normalization, in order to assess the influence of CAB. Results: Comparing OCT-LAR to OCT-LAR/CAB treatment, there was a significant decrease in mean GH, IGF-I, %ULNR-IGF-I and PRL levels. During OCT-LAR/CAB treatment, IGF-I normalized in 19 patients (56%). IGF-I normalization was correlated to lowest IGF-I levels on OCT-LAR monotherapy, but not to baseline PRL levels or GH/PRL co-expression. OCT-LAR withdrawn in all who had achieved IGF-I normalization on combined therapy resulted in IGF-I elevation to abnormal levels in all patients. Gastrointestinal symptoms were reported by 12 patients. Conclusion: OCT-LAR and CAB association has been shown to be an effective alternative therapy for those acromegalics who still have active acromegaly despite monotherapy with SA, mainly for those with lower pretreatment IGF-I concentrations. According to previous studies, the beneficial effects of CAB occur even when pretreatment PRL is normal and/or there is no tumor GH/PRL co-expression.

Comparison between weight-based and IGF-I-based growth hormone (GH) dosing in the treatment of children with GH deficiency and influence of exon 3 deleted GH receptor variant

Objective Compare the most frequently used weight-based GH dosing with an IGF-I level-based strategy in the treatment of children with severe GH deficiency. Additionally, analyse the influence of the GH receptor exon 3 polymorphism on IGF-I levels during GH therapy. Design Thirty children with GH deficiency on treatment with GH for 4.3 ± 3.2 yr in a single University Hospital were divided in group W (weight-based GH dosing) and group I (IGF-I-based dosing). In group I, GH doses were changed by 8.3 μg/kg d to maintain IGF-I levels between 0 and +2 SDS, whereas in group W the dose was fixed at 30 μg/kg d in prepubertal and 50 μg/kg d in pubertal patients. Growth velocity was measured after 1 yr, IGF-I and IGFBP3 levels quarterly. GH receptor exon 3 was genotyped by PCR. Results Most patients in Group I reached target IGF-I levels after 6 months with a GH dose ranging between 25 and 66 μg/kg d (mean ± SD, 38 ± 8). Each change of 8.3 μg/kg d of GH dose, resulted in change of 1.17 ± 0.6 SDS of IGF-I levels. Mean IGF-I levels were higher in Group I 0.8 ± 0.5 SDS than in Group W −0.3 ± 1.9 SDS ( p < 0.05), but growth velocities were similar, 6.8 ± 2.6 cm/yr and 6.9 ± 2.6 cm/yr ( p = NS), respectively. Serum IGFBP3 levels were similar in both groups and were less useful to individualize GH therapy. Even treated with a similar mean GH dose, patients carrying at least one GH receptor d3-allele reached higher IGF-I levels (0.7 ± 1.2 SDS) than those homozygous for the full-length allele (−0.3 ± 1.2 SDS; p < 0.05), however, growth velocities were not different. Conclusions By adjusting the GH dose, it was feasible to maintain IGF-I in the desired range (0–+2 SDS). Patients carrying at least one GH receptor d3-allele reached higher circulating IGF-I levels than those homozygous for the full-length allele. A multiple regression analysis failed to demonstrate an independent influence of IGF-I levels on GV during the 12 months of observation.

Androgens May Mediate a Relative Preservation of IGF-I Levels in Overweight and Obese Women Despite Reduced Growth Hormone Secretion

Obesity is characterized by reduced GH secretion, but data regarding IGF-I levels and their determinants are conflicting. The objectives were to determine whether IGF-I levels are reduced and to investigate determinants of GH and IGF-I in healthy overweight and obese women. A cross-sectional study was performed. The study was conducted at a General Clinical Research Center. Thirty-four healthy women without pituitary/hypothalamic disease participated, including 11 lean [body mass index (BMI) <25 kg/m(2)], 12 overweight (BMI > or =25 kg/m(2) and <30 kg/m(2)), and 11 obese (BMI > or =30 kg/m(2)) women of comparable age (overall mean age, 30.7 +/- 7.8 yr). There was no intervention. The main outcome measures were frequent sampling (every 10 min for 24 h) for GH, peak GH after GHRH-arginine stimulation, IGF-I, IGF binding protein-3, estrone, estradiol, testosterone, free testosterone, SHBG, homeostasis model assessment of insulin resistance, and abdominal fat. Mean 24-h GH and peak stimulated GH were lower in overweight than lean women and lowest in obese women. Mean IGF-I levels trended lower in obese, but not overweight, compared with lean women. Free testosterone was positively associated with IGF-I (R = 0.36, P = 0.04) but not with GH measures. Visceral fat was the only determinant of mean 24-h GH (R(2) = 0.66, P < 0.0001) and of peak stimulated GH (R(2) = 0.63, P < 0.0001), and mean 24-h GH accounted for 39% of the variability of IGF-I (P = 0.0002), with an additional 28% (P < 0.0001) attributable to free testosterone levels. Despite a linear decrease in GH secretion and peak stimulated GH levels with increasing BMI in healthy overweight and obese women, IGF-I levels were not commensurately reduced. Androgens may contribute to this relative preservation of IGF-I secretion in overweight and obese women despite reduced GH secretion.

Evaluation of cognitive performance by using P300 auditory event related potentials (ERPs) in patients with growth hormone (GH) deficiency and acromegaly

Context Impaired cognitive performance has been demonstrated in adults with GH deficiency and acromegaly by using different neuropsychological tests. P300 event related potential (ERP) application is a well established neurophysiological approach in the assessment of cognitive performance. Objectives Evaluation of cognitive performance by using P300 ERPs has not been reported in acromegaly, and the comparisons of the P300 ERPs between the patients with GH deficiency and GH excess have not been done yet. Therefore present study was designed to investigate the effects of GH deficiency and GH excess on cognitive performance by using P300 ERPs. Design and Methods The study comprised 19 patients with severe GH deficiency, 18 acromegalic patients and 16 age, education and sex matched healthy controls. Baseline auditory ERPs were obtained at Fz (frontal), Cz (central), Pz (parietal) and Oz (occipital) electrode sites in GH deficient group, GH excess group and control group. Results There was a significant difference between mean serum IGF-I levels in the GH deficient and acromegalic patients (48 ± 38 ng/ml and 742 ± 272 ng/ml, respectively) ( P = 0.01). The mean P300 latency of the patients with GH deficiency was significantly ( P = 0.0001) prolonged when compared with that of normal controls and acromegalic patients at all electrode sites. The mean P300 amplitude of the patients with acromegaly was significantly ( P = 0.005) lower when compared with that of normal controls and GH deficient patients at all electrode sites. Conclusions Using ERPs recordings, the present study indicates the prolongation of P300 latencies in patients with severe GH deficiency and reduction of P300 amplitudes in patients with acromegaly. This study provides the electrophysiological evidence for the presence of cognitive dysfunction in both GH deficiency and GH excess, and different components of the cognitive performance are impaired in these conditions.

Evaluation of insulin-like growth factor-I in postmenopausal women with breast cancer treated with raloxifene

BackgroundThe objective of this study was to evaluate serum IGF-I levels in postmenopausal women with breast cancer treated primarily with raloxifene.MethodsTwenty-two postmenopausal patients with operable, stage I or II, estrogen receptor-positive carcinomas participated in this study. Following confirmation of diagnosis, the patients received 60 mg of raloxifene for 28 days prior to definitive surgery. Blood samples were collected for evaluation of serum IGF-I levels prior to initiating medication and following a 28-day treatment course. Student's t-test for paired samples was used in the statistical analysis. Significance was established at p < 0.05.ResultsMean serum IGF-I levels pre- and post-raloxifene treatment were 143.7 ± 9.7 ng/ml and 94.8 ± 7.6 ng/ml, respectively. This reduction in serum IGF-I levels following treatment with raloxifene was statistically significant (p < 0.001).ConclusionRaloxifene significantly reduced serum IGF-I levels in postmenopausal women with breast cancer.

Genetic Determinants of Circulating Insulin-Like Growth Factor (IGF)-I, IGF Binding Protein (BP)-1, and IGFBP-3 Levels in a Multiethnic Population

Both circulating levels and genetic variation of IGFs have been associated with cancer risk, yet the relationship between the two is not well understood. To investigate whether common genetic variation in IGF1, IGF binding protein 1 (IGFBP1), and IGFBP3 influences circulating levels of IGF-I, IGFBP-1, and IGFBP-3, we conducted a cross-sectional study of African-American, Native Hawaiian, Japanese-American, Latino, and white men and women in the Multiethnic Cohort. Plasma levels of IGF-I, IGFBP-1, and IGBFP-3 were measured by ELISA in a random sample of 837 Multiethnic Cohort participants. Previously identified tag single nucleotide polymorphisms (SNPs) for IGF1 (29 tag SNPs) and IGFBP1/IGFBP3 (23 tag SNPs) were genotyped among the 837 participants. Analysis of covariance was conducted to test for differences in mean IGF-I, IGFBP-1, and IGFBP-3 levels across respective IGF1, IGFBP1, and IGFBP3 genotypes, adjusting for previously identified dietary and lifestyle correlates. Five highly correlated IGFBP3 SNPs (rs3110697, rs2854747, rs2854746, rs2854744, and rs2132570) demonstrated strongly significant associations with IGFBP-3 levels when conservatively adjusted for multiple hypothesis testing (Bonferroni adjusted P trends = 7.75 x 10(-8) to 1.44 x 10(-5)). Patterns of associations were consistent across the five racial/ethnic groups. In summary, our study suggests that common genetic variation in IGFBP3 influences circulating levels of IGFBP-3 among African-Americans, Native Hawaiians, Japanese-Americans, Latinos, and whites.