Serum Concentrations Of IGFBP-3 Research Articles

Selected Parameters of Bone Turnover in Neuroendocrine Tumors-A Potential Clinical Use?

Currently, there are no effective markers to diagnose and monitor patients with neuroendocrine tumors (NETs). The aim of this study was to assess bone metabolism based on selected markers of bone turnover: OST, OPG, and IGFBP-3, in both the group of patients with NETs and the control group. Associations with selected sociodemographic, biochemical, and clinicopathological characteristics were examined. We also evaluated any potential associations between these markers and selected biochemical markers of NETs commonly used in clinical practice. The study group included 60 patients with GEP-NETs and BP-NETs, while the control group comprised 62 healthy individuals. The serum concentrations of OST, OPG and IGFBP-3 were assessed using ELISA. OST and OPG levels were significantly higher in the study group compared to the control group. In the study group, we observed a significant correlation between OPG and the clinical stage and chromogranin A. Additionally, an association was found between OPG and histological grade, Ki-67, and metastasis in GEP-NET cases. Markers of bone turnover cannot be used in the routine diagnostics of neuroendocrine tumors. Nonetheless, these markers may help evaluate the skeletal system in patients with NETs. Further research is needed to determine the utility of osteocalcin (OST) and osteoprotegerin (OPG) as potential biomarkers for neuroendocrine tumors.

Muscle hypertrophy training does not suppress the GH/IGF axis in young adult males.

This study aimed to analyze the expression of the IGF type-1 receptor gene (IGF-1r) and IGF-I, GH, testosterone, and IGFBP-3 concentrations in young people subjected to 10weeks of muscle hypertrophy training. IGF-1r expression, serum concentrations of IGF-I, IGFBP-3, GH, and total testosterone, as well as body composition, fat percentage, and body mass index, were determined for 22 healthy young males at three moments of resistance training (first, fifth, and tenth week of training). Throughout the 10weeks of training, a reduction was observed in the relative expression of the IGF-1r gene (2-ΔΔCT) and an increase in IGF-I and GH concentrations. A reduction in total testosterone concentrations was detected during the recovery period in the fifth week. The IGFBP-3 concentrations did not change throughout the training. The resistance training protocol prescribed for muscle hypertrophy did not suppress the GH-IGF-I axis, but it did cause alterations in IGF-1r gene expression and in IGF-I kinetics compatible with increased IGF bioactivity.

Resistance training-induced improvement in physical function is not associated to changes in endocrine somatotropic activity in prefrail older adults

ContextResistance training improves muscle function in prefrail and frail elderly. The role of the somatotropic axis in this physiologic process remains unclear. Insulin-like growth factor I (IGF-I) and its associated proteins Insulin-like growth factor binding protein 3 (IGFBP3) and acid labile subunit (ALS) build a circulating ternary complex that mediates growth hormone (GH) effects on peripheral organs and can serve as a measure of endocrine somatotropic activity. ObjectiveThe aim of this study was to assess the association between resistance training-induced changes in physical performance and basal levels of IGF-I, IGFBP-3 and ALS in prefrail older adults. Methods69 prefrail community-dwelling older adults, aged 65 to 94 years, were randomly assigned to a 12-week period of strength or power training or to a control group. The study was registered at clinicaltrials.gov as NCT00783159. Serum concentrations of IGF-I, IGFBP-3 and ALS were measured at rest before and after the intervention. Hormonal differences were examined in relation to changes in physical performance assessed by the Short Physical Performance Battery (SPPB). ResultsWhile resistance training led to significant improvements in SPPB score it did not induce significant differences in somatotropic hormone concentrations. Pre- and post-intervention changes in IGF-I, IGFBP-3, ALS or IGF/IGFBP-3 molar ratio were not related to the intervention mode, even after adjustment for age, sex, nutritional status, as well as SPPB and hormone concentrations at baseline. ConclusionTraining-induced improvements in physical performance in prefrail older adults were not associated with significant changes in endocrine somatotropic activity.

Abstract P1-10-02: Effect of metformin on metabolic markers associated with breast cancer risk in a phase II clinical trial in overweight/obese premenopausal women

Abstract Background: The increasing rate of obesity in the United States is accompanied by serious health concerns. Obesity increases breast cancer burden and is associated with increased risk of triple-negative breast cancer in premenopausal women and overall poor prognosis in breast cancer patients. There is a need for intervention strategies aiming to reduce obesity-associated dysregulation to attenuate breast cancer risk.Methods: We conducted a Phase II, double-blind, randomized, placebo-controlled clinical trial in overweight/obese premenopausal women with elements of metabolic syndrome to assess the potential of metformin to reduce obesity-associated breast cancer risk. Study participants received metformin (850 mg BID, n = 76) or placebo (n = 75) for 12 months. Fasting blood samples were collected at baseline, 6-months and 12-months from each participant. We analyzed the effects of metformin on circulating levels of insulin/IGF axis, adipokines, and neutrophil-to-lymphocyte ratio in samples collected from this trial. Serum concentrations of insulin, IGF-1, IGFBP-3, leptin and high-molecular weight adiponectin were measured using ELISA immunoassays. Results: The study population included 151 women and had a mean age of 39.5 years, mean body mass index (BMI) was 37.8 and study participants had a large waist and at least one other component of metabolic syndrome. Metformin treatment did not result in significant changes in members of the insulin/IGF axis compared to the placebo group, however, limiting the analysis to participants with detectable metformin in the blood serum resulted in favorable changes in insulin (p=0.0215), HOMA-IR (p<0.001) and a significant increase in IGFBP-3 (p=0.0176) in the metformin group after the intervention. We observed significant decreases in leptin (p=0.0018) and the leptin-to-adiponectin ratio (p=0.0036) in the metformin arm longitudinally. Additionally, we observed a significant reduction in the neutrophil-to-lymphocyte ratio (NLR), a systemic inflammation marker, in the metformin group compared to the placebo group (p=0.0170). Conclusions: We conclude that metformin led to favorable changes in metabolic markers associated with breast cancer risk in the metformin treated participants, however, the changes were not significantly different from the placebo group. The NLR was significantly reduced after metformin intervention compared to the placebo group. More research is needed to understand the effects of metformin on the insulin/IGF axis and adipokines in overweight/obese premenopausal women. Citation Format: Edgar Tapia, Diana Villa-Guilen, Pavani Chalasani, Sara Centuori, Denise J. Roe, Jose Guillen, Catherine Cordova, Liane Pinto, Sherry Chow. Effect of metformin on metabolic markers associated with breast cancer risk in a phase II clinical trial in overweight/obese premenopausal women [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-10-02.

Energy homeostasis genes modify the association between serum concentrations of IGF-1 and IGFBP-3 and breast cancer risk

Breast cancer is a multifactorial disease in which the interplay among multiple risk factors remains unclear. Energy homeostasis genes play an important role in carcinogenesis and their interactions with the serum concentrations of IGF-1 and IGFBP-3 on the risk of breast cancer have not yet been investigated. The aim of this study was to assess the modifying effect of the genetic variation in some energy homeostasis genes on the association of serum concentrations of IGF-1 and IGFBP-3 with breast cancer risk. We analyzed 78 SNPs from 10 energy homeostasis genes in premenopausal women from the 4-Corner’s Breast Cancer Study (61 cases and 155 controls) and the Mexico Breast Cancer Study (204 cases and 282 controls). After data harmonization, 71 SNPs in HWE were included for interaction analysis. Two SNPs in two genes (MBOAT rs13272159 and NPY rs16131) showed an effect modification on the association between IGF-1 serum concentration and breast cancer risk (Pinteraction < 0.05, adjusted Pinteraction < 0.20). In addition, five SNPs in three genes (ADIPOQ rs182052, rs822391 and rs7649121, CARTPT rs3846659, and LEPR rs12059300) had an effect modification on the association between IGFBP-3 serum concentration and breast cancer risk (Pinteraction < 0.05, adjusted Pinteraction < 0.20). Our findings showed that variants of energy homeostasis genes modified the association between the IGF-1 or IGFBP-3 serum concentration and breast cancer risk in premenopausal women. These findings contribute to a better understanding of this multifactorial pathology.

Serum IGF-I concentrations are low in female bodybuilders in the pre-contest phase

Bodybuilding involves athletes performing a series of poses/postures on the stage so that they can be classified according to their best esthetic and physical appearance during the competition. In the weeks prior to the target competition, the athletes subject themselves to restrictive diets and different physical training methods, as well as using dietary supplementation and, in some cases, anabolic steroids, to reduce body fat to low levels and maintain or increase muscle mass. On the other hand, it is known that physical training is a potent stimulator for releasing the components of the GH/IGF-I axis that are directly linked to the anabolic process. Based on these assumptions, this study aimed to verify the kinetics of IGF-I and of its binding protein IGFBP-3 in female bodybuilders. Serum IGF-I and IGFBP-3 concentrations were recorded before and after standardized training sessions at two different times: in the initial phase (phase 1) and in the final phase of the pre-contest (phase 2) of a 12-week training season. It was possible to conclude that there was a significant reduction in serum IGF-I values at the end of the pre-contest phase that preceded the athletes' participation in a competition. With relation to the serum IGF-I and IGFBP-3 values measured before and after the standardized training session, it was only possible to verify significant changes in the IGF-I values in the initial phase of the pre-contest. It seems reasonable to suggest that the caloric restriction used by bodybuilders may be related to the decrease in IGF-I values verified at the end of the pre-contest phase.

Sex Hormones, Insulin, and Insulin-like Growth Factors in Recurrence of High-Stage Endometrial Cancer.

The influence of sex hormone and insulin/insulin-like growth factor (IGF) axis signaling on endometrial cancer recurrence is unknown. We evaluated these pathways in a prospective cohort of Gynecologic Oncology Group (GOG)0210 trial endometrial adenocarcinoma patients. Stage II-IV patients (N = 816) were included in this study. Pretreatment specimens were tested for tumor mRNA and protein expression of IGF1, IGF2, IGF-binding proteins (IGFBP)-1 and -3, insulin (IR) and IGF-I receptors (IGF1R), phosphorylated IR/IGF1R (pIGF1R/pIR), and estrogen (ER) and progesterone receptors (PR) using qPCR and IHC. Serum concentrations of insulin, IGF-I, IGFBP-3, estradiol, estrone, and sex hormone binding globulin were measured. HRs and 95% confidence intervals (CI) for progression-free survival were calculated from Cox models adjusting for age, stage, and grade. Recurrence occurred in 280 (34%) cases during a median of 4.6 years of follow-up. ER positivity (HR, 0.67; 95% CI, 0.47-0.95), IR positivity (HR, 0.53; 95% CI, 0.29-0.98), and circulating IGF-I (highest vs. lowest quartile: HR, 0.66; 95% CI, 0.47-0.92) were inversely associated with recurrence risk. Circulating estradiol (highest vs. lowest tertile: HR, 1.55; 95% CI, 1.02-2.36) and pIGF1R/pIR positivity (HR, 1.40; 95% CI, 1.02-1.92) were associated with increased recurrence risk. Circulating estradiol and tumor tissue phosphorylated (activated) IGR1R/IR were independently associated with higher risk of recurrence in patients with endometrial cancer. This study may inform future clinical trials of endocrine-targeted adjuvant therapies in patients with endometrial cancer that could include baseline assessment of serum and tissue biomarkers of estradiol and insulin signaling pathways.

Transition from gynaecomastia to lipomastia in pubertal boys.

Gynaecomastia is frequent in pubertal boys and is regarded as a self-limiting abnormality. However, longitudinal studies proving this hypothesis are scarce. Longitudinal follow-up study (median 2.4, range 1.0-4.8years). The regression of breast diameter was analysed in 31 pubertal boys aged 11.7-16.1 (median 13.2)years with gynaecomastia. Furthermore, weight changes (as BMI-SDS) and pubertal stage, oestradiol [E2], oestriol, oestrone, androstenedione, testosterone [T], dihydrotestosterone, gonadotropins, IGF-1, and IGFBP-3 serum concentrations determined at first clinical presentation were related to breast diameter regression determined by palpation and disappearance of breast glandular tissue in ultrasound in follow-up to identify possible predictors of breast regression. During the observation period, the breast diameter decreased (in median -1 (interquartile range [IQR] -5 to +1) cm). At follow-up, 6% of boys had no breast enlargement any more, and 65% developed lipomastia. Gynaecomastia was still present in 29%. None of the analysed hormones was related significantly to breast diameter regression or disappearance of breast glandular tissue. In multiple linear regression analyses adjusted for observational period, as well as age and BMI-SDS at first presentation, changes in BMI-SDS (β-coefficient 6.0±2.3, p=.015) but not the E2/T ratio or any other hormone determined at baseline was related to changes in breast diameter. Breast diameter regression seems not to be predictable by a hormone profile in pubertal boys with gynaecomastia. In pubertal boys presenting with gynaecomastia, conversion to lipomastia of smaller volume is common. The reduction of weight status was the best predictor of breast diameter regression.

Kinetics of cytokines IL-6, IL-10 and TNF-α and their relationship with serum IGF-I and IGFBP-3 concentrations in adolescent swimmers throughout a training season

Aim: The objective of this study was to analyze the kinetics of the IL-6, IL-10, and TNF-α cytokines and their relationship with the serum IGF-I and IGFBP-3 levels of adolescent swimmers throughout a training season.

Is there a role for the IGF system and epidermal growth factor (EGF) in the pathogenesis of adrenocortical adenomas? A preliminary case-control study.

Adrenal incidentalomas (AI) are very common and mostly they are non-functioning adenomas (NFA). NFAs are often associated with insulin resistance and metabolic syndrome. Several biomarkers, including certain growth factors, may participatein the pathogenesis ofmetabolic changes in patients with adrenal adenomas.Patients with NFA and age-matched control subjects were enrolled in the study. Data on age, gender, presence of metabolic syndrome or its components were obtained for each subject. Blood samples were obtained and glycemia, insulinemia, lipid profile, and selected growth factor levels were measured. Forty-three patients with NFA and 40 controls were included in the study. Differences were not found in the metabolic syndrome and its components prevalence or in the biochemical profile between patients and the control group. Significant differences were noticed in the levels of IGF1, IGF2, and IGFBP3 (p=0.016, p=0.005, p=0.004, respectively), but there were no differences in VEGF or EGF concentrations. In NFA patients, an association between glycemia and EGF levels was present (p=0.026). No significant correlations between tumor size and insulin or growth factor concentrations were present in AI patients. Significantly higher serum IGF1, IGF2, and IGFBP3 concentrations in NFA patients may support the role of the IGF axis in the pathogenesis of adrenocortical lesions.No correlation between IGFs or IGFBP3 and parameters of glucose or lipid metabolism was found. Present results may support the role of the growth hormone axis rather than hyperinsulinemia and insulin resistance in the pathogenesis of adrenocortical adenomas.

Development of a novel assay for IGFBP-2 complexed with IGF-I and-II in human serum

BackgroundInsulin-like growth factor binding-protein 2 (IGFBP-2) was originally identified as an IGF-carrier, governing IGF half-life, tissue accessibility and biological effects. Later, IGFBP-2 was discovered to possess IGF-independent effects. IGFBP-2 circulates in several forms, as free protein, complexed with IGF-I or IGF-II, or as IGFBP-2 fragments. The various IGFBP-2 forms are all included when measuring serum IGFBP-2 concentrations by immunoassay (i.e., immunoreactive (ir-)IGFBP-2). In this study, we describe a novel method to measure the amount of IGF that circulates bound to IGFBP-2. MethodIGFBP-2 was immunoprecipitated from human serum using magnetic beads, which were subsequently eluted by acidification. After neutralization, eluates were assayed for ir-IGFBP-2, IGF-I and IGF-II and compared to serum concentrations. This allowed measurement of IGFBP-2-compexed IGF-I and IGF-II, respectively. To test the method clinically, serum from 146 patients with lung cancer, 151 patients with non-cancer pulmonary diseases and 28 healthy controls were analyzed. ResultsWe immuno-precipitated 97 ± 3.3% of serum IGFBP-2 and recovered > 75% of IGFBP-2-complexed IGFs, with intra- and inter-assay coefficient of variations (CVs) averaging < 5% and < 13%, respectively. No co-precipitation with IGFBP-1, −3 or − 4 was detected.Serum levels of ir-IGFBP-2 (median [25;75%]) differed between groups (cancer patients vs. non-cancer patients vs. healthy controls): 342 [260;480] vs. 262 [189;388] vs. 190 [141;269] μg/l (p < .0001). In parallel with this, concentrations of IGF-II carried by IGFBP-2 averaged: 45.0 [33.3;52.5] vs. 34.2 [25.4;46.1] vs. 19.8 [14.1;26.0] μg/l (p < .0001), and concentrations of IGF-I 8.0 [5.2;11.8] vs. 5.4 [3.6;7.3] vs. 7.0 [3.8;13.0] μg/l (p < .0001). Thus, IGFBP-2 carried more IGF-II than IGF-I in all groups (p < .0001). When expressed relative to IGF-concentrations, IGFBP-2 carried 9.0 [5.3;15.5] % of the IGF-I and 4.8 [2.9;5.8] % of the IGF-II in serum from healthy subjects. Notably, in patients, IGFBP-2 carried relatively less IGF-I, but more IGF-II (p < .0001). ConclusionUsing our novel assay, we demonstrate: that IGFBP-2 carries ≈10% of circulating IGF-I and ≈5% of circulating IGF-II in healthy subjects; that IGF-II is the primary ligand for IGFBP-2; and that IGFBP-2 carries even more IGF-II in patients than in healthy subjects. Thus, our assay may provide information on IGFBP-2 beyond what is achievable by simply measuring ir-IGFBP-2.

Insulin-like growth factor I (IGF-I) and its present significance in digestive system diseases

Insulin-like growth factor I (IGF-I) is a main mediator of growth hormone’s (GH) action. Under physiological conditions, IGF-I is responsible for growth and development of organism through influence on proliferation and differentiation of cells. IGF-I is produced in almost all tissues of organism and its activity is determined by interaction with specific receptors (IGF-IR, IGF-IIR) and IGF-binding proteins (IGFBP-1 - IGFBP-6), and by proteases hydrolyzing IGFBPs as well. Currently, a surge of interest on insulin-like growth factor I as a potential factor contributing to the development of neoplasms, including neoplasms of digestive system, is observed. IGFBPs and IGF-IR may also be of importance in etiology and pathogenesis of cancer. It is assumed that high serum concentration of IGF-I may increase the risk of cancer development whereas high serum concentration of IGFBP-3 may inhibit the progression of the disease. Until recently, attempts of modulating the concentration of IGF-I with the use of pharmacological agents of diverse mechanisms of action under innovative anti-cancer therapies, have been made. Lately, it is pointed to the possibility of application of IGF-I in the management of certain diseases of digestive system. It was observed that IGF-I not only contributes to the maintenance of normal structure and function of epithelium in the gastrointestinal tract but also stimulates repair processes in damaged mucosa. Results of preliminary studies on the treatment of short bowel syndrome, gastric ulcer disease, enteritis induced by chemo- and radiotherapy, and inflammatory bowel disease with the use of exogenous IGF-I are encouraging.

IGF-1 and IGFBP-3 in cancer patients

Growth factors called somatomedins have been isolated from human plasma and described in the seventies of the last centry. Insulin-like growth factors and their binding proteins are synthesized mainly in the liver, this process is regulated by the growth hormone. Insulin-like effects of IGF-1 are primarily stimulating the uptake of glucose by adipocytes and muscle cells. Moreover, IGF-1 stimulates cell division, plays a significant role in the processes of differentiation, maturation, repair of damaged DNA and apoptosis. Insulin-like growth factor binding proteins by binding IGF-1 modulate its biological activity, counteract the potentially carcinogenic activity of unbound IGF-1. Furthermore, IGFBPs, especially IGFBP-3, have independent effects on cell growth, for example, IGFPB-3 has proapoptotic activities. Elevated level of IGF-1 with simultaneously reduced concentration of its binding protein are considered risk factors for the development of a number of diseases, including neoplastic diseases. High serum concentrations of IGF-1 and low levels of IGFBP-3 are associated with increased risks of lung, breast, prostate, and colorectal cancers.

IGF-1 and IGFBP-3 serum concentrations in patients undergoing programmed frozen-thawed embryo transfer of euploid PGT-A embryos

IGF-1 has been shown to induce embryonic development in vitro, but at high concentrations exhibits toxic effects by decreasing embryonic glucose uptake. IGFBP-3 binds IGF-1, modulating its bioavailability and is essential to its function. Prior reports have associated elevated follicular phase IGF-1 with pregnancy loss in frozen-thawed embryo transfer in natural cycles (n-FET), but an association in programmed (p-FET) cycles or in the luteal phase has not been analyzed. We sought to determine whether serum levels of IGF-1 and IGFBP-3 correlate with the outcome of p-FET cycles. Retrospective cohort study. Patients who underwent p-FET of single, good quality (Grade ≥2BB), PGT-normal embryos were included in the study. GnRH-agonist suppression was started in the preceding luteal phase, overlapped with estradiol patches, and stopped with the start of progesterone. Serum samples were collected on cycle day 2 (CD2), the day of progesterone start (CDP4), and cycle days 28 (CD28) and 30 (CD30). Embryo transfer occurred on the 7th day of P4 administration. Serum levels of IGF-1 and IGFBP-3 were compared between those who did not achieve pregnancy, those who had a live birth, and those who had a pregnancy loss. Serum IGF-1 and IGFBP-3 levels were measured by chemiluminescent immunoassays using the Immulite 2000 XPi. Statistical analysis was performed using Chi-square and Fisher’s exact test. P<0.05 was deemed statistically significant. A total of 102 patients who underwent p-FET of single euploid embryos over 2 years were analyzed. The mean age at retrieval was 35.7 ± 4.1 years, BMI 24.2 ± 4.8 kg/m2, gravity 1.8 ± 1.6, parity 0.4 ± 0.6 and peak endometrial thickness 9.7 ± 2.0 mm. 76.5% of patients were pregnant and 78.2% of those had a live birth. Among women who conceived, those who had a subsequent pregnancy loss had significantly higher serum IGF-1 levels on CDP4 and CD28 compared to those who achieved live birth when analyzing patients whose serum IGF-1 levels were above the mean value of IGF-1 level on CDP4 (136 ng/ml, p= 0.044) and CD28 (138 ng/ml, p=0.007), and between patients with CD28 IGF-1 levels one standard deviation above the mean (≥160 ng/ml, p=0.007). There was no significant difference in the serum levels of IGFBP-3 in any of the treatment cycle days.Tabled 1p-FET, Deliveredp-FET, Pregnancy losspIGF-1 CDP4 (≥ mean value)63.6%33%0.044IGF-1 CD 28(≥ mean value)58%14%0.044IGF-1 CD28 (≥ 160 ng/ml)70.8%14%0.007 Open table in a new tab In p-FET cycles with transfer of a single, euploid, high quality embryo, IGF-1 serum levels on day of progesterone start and CD28 are significantly higher in patients who subsequently had a pregnancy loss compared to those who had a live birth. This is in contrast to the findings of prior studies in n-FET.

Evaluation of IGF1/IGFBP3 Molar Ratio as an Effective Tool for Assessing the Safety of Growth Hormone Therapy in Small-for-gestational-age, Growth Hormone-Deficient and Prader-Willi Children

Objective:IGF1 concentration is the most widely used parameter for the monitoring and therapeutic adaptation of recombinant human growth hormone (rGH) treatment. However, more than half the variation of the therapeutic response is accounted for by variability in the serum concentrations of IGF1 and IGFBP3. We therefore compared the use of IGF1/IGFBP3 molar ratio with that of IGF1 concentration alone.Methods:We selected 92 children on rGH for this study and assigned them to three groups on the basis of growth deficiency etiology: small for gestational age (SGA), GH deficiency (GHD) and Prader-Willi syndrome (PWS). Plasma IGF1 and IGFBP3 concentrations and their molar ratio were determined.Results:Before rGH treatment, mean IGF1/IGFBP3 molar ratio in the SGA, GHD and PWS groups was 0.14±0.04, 0.07±0.01 and 0.12±0.02, respectively. After the initiation of rGH treatment, these averages were 0.19±0.07, 0.20±0.08 and 0.19±0.09, within the normal range for most children, even at puberty and despite some significant increases in serum IGF1 levels.Conclusion:We consider IGF1/IGFBP3 molar ratio to be a useful additional parameter for assessing therapeutic safety in patients on rGH, and for maintaning the values within the normal range for age and pubertal stage.

Association of Muscle Mass with Survival after Radical Prostatectomy in Patients with Prostate Cancer.

Although muscle mass has been associated with survival in patients with various types of solid tumors, the relationship between muscle mass and survival in patients with prostate cancer remains unclear. We retrospectively investigated the association of muscle mass with survival after radical prostatectomy in patients with prostate cancer. We reviewed the records of 2,042 patients who underwent radical prostatectomy of prostate cancer between 1998 and 2013. Muscle mass was evaluated by measuring the psoas muscle index on preoperative computerized tomography images. In the lowest, second, third and highest psoas muscle index quartiles the 10-year distant metastasis-free survival rate was 72.5%, 83.8%, 92.3% and 93.7% (p <0.001), the 10-year cancer specific survival rate was 85.7%, 92.1%, 96.8% and 97.6%, and the 10-year overall survival rate was 74.5%, 79.6%, 89.8% and 90.6%, respectively (each p <0.001). The psoas muscle index positively correlated with the body mass index, serum concentrations of IGFBP-3 and bioavailable testosterone, and inversely correlated with patient age, the serum SHBG concentration and the neutrophil-to-lymphocyte ratio. On multivariable analysis the psoas muscle index was independently associated with increased risks of biochemical recurrence, distant metastasis, and cancer specific and overall death. Low muscle mass may be associated with increased risks of recurrence and mortality in patients who undergo radical prostatectomy of prostate cancer regardless of the body mass index. Large-scale prospective studies are warranted.

Lean body mass accretion is elevated in response to dietary vitamin D: A dose–response study in female weanling rats

Vitamin D status positively relates to lean body mass in infants. This study tested the effect of vitamin D on body composition and growth-related hormones. It was hypothesized that low vitamin D status programs for higher fat mass accretion. Female weanling Sprague–Dawley rats (4 weeks; n = 6/diet) were randomized to AIN-93G diets with modified vitamin D contents for 8 weeks: group 1 (1 IU vitamin D3/g diet), group 2 (2 IU vitamin D3/g diet), and group 3 (4 IU vitamin D3/g diet). At week 0, 4, and 8 of study, measurements included: serum 25(OH)D3, IGF-1, IGFBP3, leptin, and whole body composition assessed with DXA. Differences among groups were tested using mixed model ANOVA with Tukey's post hoc t-tests. No differences were observed in baseline body composition and biomarkers, nor did body weight and food intake differ over the study. At week 8, serum 25(OH)D3 in group 3 was higher (P < .0001) compared to groups 1 and 2. At 8 weeks, lean mass (P < .05) and lean mass accretion (P < .05) were significantly higher in groups 2 and 3 compared to group 1. Serum IGF-1 concentration declined over time (P < .001) with smaller declines at week 8 in group 3 (P < .05). Serum IGFBP3 concentration was lower at week 4 in group 2 compared to groups 1 and 3. Serum leptin concentration and fat mass were not affected by diet. These results suggested that the achievement of higher vitamin D status may support a lean body phenotype without altering weight gain.

The levonorgestrel-releasing intrauterine device induces endometrial decidualisation in women on tamoxifen

There is conflicting literature on whether the levonorgestrel-releasing intrauterine system (LNG-IUS; Mirena®) induces decidualisation in the tamoxifen-treated endometrium. The expression of the decidualisation marker IGFBP-1 was measured using immunohistochemistry in endometrial biopsies and in serum (using ELISA) of 20 postmenopausal women at the start of tamoxifen-treatment for breast cancer. Ten women were then fitted with LNG-IUS and the other ten received tamoxifen-treatment only and acted as controls. Samples were taken at baseline and after 12 months. At baseline, all endometrial samples were negative for IGFBP-1 and at 12 months, IGFBP-1 was only expressed in the endometria of women fitted with the LNG-IUS, confirming the observed histological features of decidualisation. By contrast, serum IGFBP-1 concentrations were increased by tamoxifen, but not in the group receiving LNG-IUS. In conclusion, tamoxifen induces a rise in serum IGFBP-1 suggesting a systemic, possibly hepatic effect, whilst LNG abrogates this in both the liver and endometrium.Impact statementWhat is already known on this subject? Previous reports of the use of LNG-IUS in women on tamoxifen have provided conflicting evidence as to whether the endometrium exhibited decidualisation or not. These reports were however based solely on histological examination and lacked supporting biochemical data.What do the results of this study add? After 12 months of treatment with LNG-IUS, the endometria of women on tamoxifen show histological features of decidualisation and the presence of the decidualisation marker IGFBP-1, suggesting that levonorgestrel protects the tamoxifen-treated uterus from additional pathology by causing decidualisation. Serum levels of IGFBP-1 were expected to be a reflection of uterine production, but contrary to expectations, higher levels were identified in women on tamoxifen alone. These data suggest that an inhibition of tamoxifen-induced serum IGFBP-1 production (possibly from a hepatic source) by LNG-IUS occurred and indicates independent systemic effects of both drugs in post menopausal breast cancer patients.What are the implications of these findings for clinical practice and/or further research? This research demonstrated a mechanism for endometrial protection in women on tamoxifen. It also alerts clinicians to the fact that both tamoxifen and LNG-IUS exert systemic effects in this patient group.

Sex hormone, insulin, and insulin-like growth factor signaling in recurrence of high stage endometrial cancer: Results from the NRG Oncology/Gynecologic Oncology Group 210 trial.

5509 Background: Sex hormone and insulin/insulin-like growth factor (IGF) axis signaling pathways play an important role in endometrial cancer development but their role in endometrial cancer recurrence is unknown. In this study GOG-8015 we evaluated these pathways in a prospective cohort of patients diagnosed with the most common type of endometrial cancer, endometrioid adenocarcinoma. Methods: Stage II-IV endometrioid endometrial adenocarcinoma patients (N = 816) enrolled in the GOG-210 study with pre-treatment specimens were tested for tumor mRNA and protein expression levels of IGF1, IGF2, IGF binding proteins ( IGFBP) -1and -3, the insulin (IR) and IGF-I receptors (IGF1R), and phosphorylated (activated) IR/IGF1R as well as estrogen (ER) and progesterone receptors (PR) using quantitative PCR and immunohistochemistry (IHC). Serum concentrations of insulin, IGF-I, IGFBP-3, estradiol, estrone and sex hormone binding globulin were measured using ELISAs. Hazard ratios (HR) and 95% confidence intervals (CI) for risk of recurrence were obtained from multivariable Cox proportional hazard’s models with adjustment for age, stage and grade. Results: Recurrence occurred in 280 (34%) cases during a mean of 5.4 years of follow-up. ER-positivity (HR 0.67, 95% CI 0.47-0.95), IR-positivity (HR 0.53, 95% CI 0.29-0.98) and serum IGF-I levels (highest versus lowest quartile, HR 0.66, 95% CI 0.47-0.92) were inversely associated with recurrence risk. Conversely, circulating estradiol (highest versus lowest tertile, HR 1.55, 95% CI 1.02-2.36) and insulin (per 10 uU/ml, HR 1.52, 95% CI 1.12-2.06) and phosphorylated IGF1R/pIR expression (HR 1.40, 95% CI 1.02-1.92) were associated with increased risk of recurrence. Conclusions: We identified novel sex hormone and insulin/IGF axis tissue and circulating biomarkers of recurrence in a prospective study of high stage endometrioid endometrial cancer. Circulating insulin and estradiol, and tissue phosphorylated (activated) IGR1R/IR were independently associated with recurrence. These findings support prioritizing studies to establish their clinical utility as prognostic biomarkers and to investigate new strategies that target these pathways for prevention and treatment of endometrial cancer recurrence.

OR07-5 A Cross-Sectional Study of IGF-I Bioavailability through Childhood: Associations with PAPP-A2 and Anthropometric Data

Insulin-like growth factor I (IGF-I) is one of the essential hormonal mediators of human growth. Circulating IGF-I exists in a ternary complex bound to the acid-labile subunit (ALS) and an IGF binding protein, predominantly IGFBP-3. Pregnancy Associated Plasma Protein-A2 (PAPP-A2), which cleaves intact IGFBP-3, liberates IGF-I from the ternary complex to interact with cell surface receptors. Genome-wide association studies have linked PAPPA2 to adult stature, and mutations in PAPPA2 cause short stature with decreased IGF-I bioavailability. As little is known about PAPP-A2 concentrations throughout childhood and its association with IGF-I bioavailability, we evaluated normal serum concentrations of free IGF-I, intact IGFBP-3, and PAPP-A2 throughout childhood and their relationship with anthropometry. We assessed serum samples from 838 individuals (Age: 3-18, Male: 48%, Caucasian: 83%) who participated in the Cincinnati Genomic Control Cohort, a population-based study of generally healthy children. Patients on medications known to affect growth or with significant medical comorbidities were excluded. Subjects were evaluated at a single visit. Height and weight were measured and a blood sample was drawn. Serum samples were aliquoted and stored at −80 ° C without thawing until the current assays were performed. Total and free IGF-I, total and intact IGFBP-3 and PAPP-A2 were measured using ELISA kits developed by Ansh Laboratories. Age-specific reference interval curves were generated by sex. Correlation and regression analyses were used to examine relationships among analytes and association between each analyte and age, sex, race, height, and BMI. Statistical analyses were performed using SAS®, version 9.4. Free IGF-I increased with age. Serum PAPP-A2 consistently decreased throughout childhood. Serum intact IGFBP-3 increased from early childhood into adolescence with a more marked rise than total IGFBP-3. In multiple regression analysis, height Z-score was positively associated with free and total IGF-I (P=0.01; P<0.0001). Free IGF-I was positively associated with total IGF-I (M; F, r=0.32; r=0.39, P<0.0001). Intact IGFBP-3 was negatively associated with PAPP-A2 (M; F, r=−0.58; r=−0.65, P<0.0001) and the percentage of free to total IGF-I in both sexes (r=−0.53, P<0.0001). PAPP-A2 was positively associated with the percentage of free to total IGF-I (M; F, r=0.18; r=0.38, P<0.001) but not with absolute free IGF-I levels. In conclusion, this is the first study describing PAPP-A2 and intact IGFBP-3 concentrations throughout childhood. Surprisingly, PAPP-A2, a positive modulator of IGF-I bioavailability, decreased with age, but was not positively associated with absolute levels of free IGF-I. Higher levels of PAPP-A2 led to more cleavage of intact IGFBP-3 and thus increased the percentage of free to total IGF-I in this population.