Insulin-like growth factor 1 and sex hormones for assessment of anthropometric and pubertal growth of Egyptian children and adolescents with type 1 diabetes mellitus (single center study).

BACKGROUND: This study aimed to assess the anthropometric measures and pubertal growth of children and adolescents with Type 1 diabetes mellitus (T1DM) and to detect risk determinants affecting these measures and their link to glycemic control. PATIENTS AND METHODS: Two hundred children and adolescents were assessed using anthropometric measurements. Those with short stature were further evaluated using insulin-like growth factor 1 (IGF-1), bone age, and thyroid profile, while those with delayed puberty were evaluated using sex hormones and pituitary gonadotropins assay. RESULTS: We found that 12.5% of our patients were short (height SDS < -2) and IGF-1 was less than -2 SD in 72% of them. Patients with short stature had earlier age of onset of diabetes, longer duration of diabetes, higher HbA1C and urinary albumin/creatinine ratio compared to those with normal stature (p < 0.05). Additionally, patients with delayed puberty had higher HbA1c and dyslipidemia compared to those with normal puberty (p < 0.05). The regression analysis revealed that factors associated with short stature were; age at diagnosis, HbA1C > 8.2, and albumin/creatinine ratio > 8 (p < 0.05). CONCLUSION: Children with uncontrolled T1DM are at risk of short stature and delayed puberty. Diabetes duration and control seem to be independent risk factors for short stature.

Comparison of growth factor levels in injectable platelet-rich fibrin obtained from healthy individuals and patients with chronic periodontitis: a pilot study.

BACKGROUND: This study aimed to assess and compare the concentrations of growth factors, white blood cells (WBCs), and platelets in injectable platelet-rich fibrin (i-PRF) derived from people with healthy periodontal conditions and those with chronic periodontitis. METHODS: Venous blood samples were obtained from 30 patients diagnosed with chronic periodontitis (test group) and 30 participants with healthy periodontal conditions (control group). The i-PRF was then acquired from centrifuged blood. The growth factors (VEGF, IGF-1, TGF-ß1, PDGF-BB and EGF) released from the i-PRF samples were compared between groups with ELISA testing. The amounts of WBCs and platelets were also compared. RESULTS: No significant differences in the concentrations of growth factors were found between the groups (the mean values for the control and test groups were, respectively: IGF: 38.82, 42.46; PDGF: 414.25, 466.28; VEGF: 375.69, 412.18; TGF-ß1: 21.50, 26.21; EGF: 138.62, 154.82). The test group exhibited a significantly higher WBC count than the control group (8.80 vs. 6.60, respectively). However, the platelet count did not show a statistically significant difference between the groups (control group 242.0 vs. test group 262.50). No significant correlation was observed between WBC count and growth factor level in either group. CONCLUSIONS: The growth factor levels in i-PRFs did not exhibit significant difference between the two groups. This suggests that the levels of these growth factors may be unaffected by the periodontal disease.

α-Klotho levels in girls with central precocious puberty: potential as a diagnostic and monitoring marker.

Background: Recent studies suggest a link between the Klotho protein, sex hormones, and insulin-like growth factor-1 (IGF-1), indicating that α-Klotho levels may rise during puberty, including in central precocious puberty (CPP) cases. This study aimed to explore α-Klotho levels in girls with CPP to assess its potential as a diagnostic and monitoring tool for this condition. Methods: In total, 139 girls, comprising 82 patients diagnosed with CPP and 57 healthy prepubertal controls, were enrolled in this study. From March 2020 to May 2023, we assessed both α-Klotho levels and clinical parameters. α-Klotho concentrations were measured using an α-Klotho ELISA kit. For the girls with CPP, we additionally analyzed samples taken 6 months after GnRH agonist treatment. Results: α-Klotho levels were higher in the CPP group compared with the control (CPP group: 2529 ± 999 ng/mL; control group: 1802 ± 675 pg/mL) (P < 0.001), and its level modest decreased after 6 months of GnRH agonist treatment (2147± 789 pg/mL) (P < 0.001). The association between α-Klotho and IGF-1 SDS, follicular stimulating hormone and baseline luteinizing hormone was assessed by partial correlation after adjusting for age, BMI SDS (r= 0.416, p= <0.001; r= 0.261, p= 0.005; r= 0.278, p= 0.002), respectively. Receiver operating characteristic curve analysis identified an α-Klotho cut-off differentiating CPP from controls, with a cut-off of 1914 pg/mL distinguishing girls with CPP from controls with a sensitivity of 69.5% and specificity of 70.2%; the area under the curve was 0.723. Conclusion: The findings of our study are the first step towards deciphering the role of α-Klotho in puberty induction. With additional data and further research, α-Klotho could potentially be utilized as a significant diagnostic and monitoring tool for CPP.

The mediating role of lower body muscle strength and IGF-1 level in the relationship between age and cognition. A MIDUS substudy.

OBJECTIVE: Aging is a natural process associated with a decline in cognition. However, the mediating effect of physical function and circulating myokines on this relationship has yet to be fully clarified. This study investigated how muscle strength and circulating insulin-like growth factor-1 (IGF-1) levels mediate the relationship between age and cognitive functions. SUBJECTS AND METHODS: A total of 1255 participants aged 25-74 years included in the Midlife in the United States II study were retrospectively analyzed. In this cross-sectional analysis, we applied a serial mediation model to explore the mediating effects of muscle strength and circulating IGF-1 levels on the relationship between age and cognitive functions. We included potential confounding factors related to sociodemographics, lifestyle, and health status as covariates in the model. RESULTS: The results showed that aging had both direct and indirect effects on cognition. As predicted, muscle strength and IGF-1 levels mediated the relationship between age and specific cognitive functions. In addition, mediation analyses indicated that the association between aging and cognitive flexibility, immediate and delayed memory, and inductive reasoning were partially mediated by muscle strength and IGF-1 levels in a serial manner. CONCLUSIONS: Our study demonstrated the serial multiple mediation roles of muscle strength and IGF-1 levels on the relationship between age and specific cognitive functions. Further longitudinal research should be performed to confirm the serial mediation results.

Pseudoacromegaly-A challenging entity in the endocrine clinic: A systematic review.

OBJECTIVE: Pseudoacromegaly encompasses conditions with features of acromegaly/gigantism, but no growth hormone (GH) or insulin-like growth factor-1 (IGF-1) excess. We aimed to review published pseudoacromegaly cases evaluated due to clinical suspicion of acromegaly. DESIGN/PATIENTS: PubMed/Medline search was conducted to identify reported pseudoacromegaly cases, which were systematically reviewed to ensure they met eligibility criteria: (1) presentation suggestive of acromegaly; (2) acromegaly excluded based on normal GH, IGF-1 and/or GH suppression on oral glucose tolerance test (OGTT-GH); (3) diagnosis of the pseudoacromegaly condition was established. Data were retrieved from each case and analysed collectively. RESULTS: Of 76 cases, 47 were males, mean ages at presentation and at first acromegaloid symptoms were 28 ± 16 and 17 ± 10 years, respectively. Most common conditions were pachydermoperiostosis (47%) and insulin-mediated pseudoacromegaly (IMP) (24%). Acromegaloid facies (75%) and acral enlargement (80%) were the most common features. Measurement of random GH was reported in 65%, IGF-1 in 79%, OGTT-GH in 51%. GH excess was more frequently excluded based on two tests (53%). Magnetic resonance imaging (MRI) was performed in 30 patients, with pituitary adenoma or hyperplasia being reported in eight and three patients, respectively. Investigations differed between cases managed by endocrine and non-endocrine specialists, the former requesting more often IGF-1, OGTT-GH and pituitary MRI. CONCLUSIONS: Pseudoacromegaly is a challenging entity that may be encountered by endocrinologists. Pachydermoperiostosis and IMP are the conditions most often mimicking acromegaly. Adequate assessment of GH/IGF-1 is crucial to exclude acromegaly, which may be better performed by endocrinologists. Pituitary incidentalomas are common and require careful judgement to prevent unnecessary pituitary surgery.

Association between serum insulin-like growth factor 1 levels and the improvements of cognitive impairments in a subgroup of schizophrenia: Preliminary findings.

BACKGROUND: Numerous studies have implicated abnormal insulin-like growth factor 1 (IGF-1) in the pathophysiology of schizophrenia, but findings have been inconsistent. METHODS: We conducted a meta-analysis to compare IGF-1 levels in schizophrenia patients with healthy controls and explored factors contributing to variability between estimates. In an independent sample (58 chronic schizophrenia patients and 30 healthy controls), we investigated differences in IGF-1 levels among schizophrenia subgroups with distinct cognitive profiles, identified using k-means clustering based on five cognitive domains from The Repeatable Battery for the Assessment of Neuropsychological Status. Associations between serum IGF-1 levels and clinical and neurocognitive improvements were also examined. RESULTS: The meta-analysis revealed significantly lower serum IGF-1 levels in schizophrenia patients compared to healthy controls, albeit with high heterogeneity. Medication status, BMI, and severity of negative symptoms were identified as potential contributors to this heterogeneity. In our independent study, antipsychotic treatment led to a significant increase in IGF-1 levels, and lower pre-treatment serum IGF-1 levels correlated with greater improvement in cognitive deficits, particularly in a subgroup with more severe cognitive symptoms. CONCLUSIONS: Our findings support the "IGF-1 deficiency hypothesis" in the pathogenesis of schizophrenia. Further research is crucial to elucidate the role of IGF-1 in the cognitive impairments associated with schizophrenia.

Whether serum leptin and insulin-like growth factor-1 are predictive biomarkers for post-stroke depression: A meta-analysis and systematic review.

Leptin and insulin-like growth factor-1 (IGF-1) may play a role in clinical identification of post-stroke depression (PSD). Here, eight databases (including CNKI, Wanfang, SinoMed, VIP, PubMed, the Cochrane Library, Embase, and the Web of Science) were employed to search for studies on serum leptin and insulin-like growth factor-1 expression levels in patients with PSD. In total, 13 articles were included, of which 6 studies investigated the expression level of serum leptin in patients with PSD, 7 studies explored the serum IGF-1 in PSD patients. Then, the RevMan 5.4 software was used for meta-analysis. The results showed that serum leptin levels were significantly higher in PSD patients than in patients without PSD (SMD = 1.54, 95% CI: 0.84, 2.23; P = 0.006). The result of subgroup analysis showed that the serum leptin levels in PSD patients were significantly higher than those without PSD in acute phase (SMD = 1.38, 95% CI: 0.04, 2.71; P = 0.04), subacute phase (SMD = 2.31, 95% CI: 0.88, 3.73; P = 0.001), and chronic phase (SMD = 1.02, 95% CI: 0.43, 1.60; P = 0.0007); There was no significant difference in serum IGF-1 level between PSD patients and patients without PSD (SMD = 0.49, 95% CI: -0.55, 1.52; P = 0.36). Moreover, the subgroup analysis also showed that there was no statistical difference in acute stage (SMD = 0.36, 95% CI: 0.89, 1.60; P = 0.57). Our study provides evidence to prove that serum leptin level has potential clinical application value as biomarkers for identifying PSD.

Estimation of the reference values and decision limits for growth hormone in newborns using dried blood spots.

OBJECTIVES: Severe deficiency of growth hormone (GHD) of the newborn is a rare but potentially life-threatening disease. GH measured during the first week of life, using dried blood spots (DBS), may offer several advantages. Aim of the study was to estimate the reference values for GH in newborns by a new analytical method using DBS. METHODS: Using a new developed analytical method, GH was estimated from DBS of 1,036 healthy newborns attending the Neonatology Unit of Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico of Milan in the period July-October 2021. Reference values for GH deficiency were estimated by the Harrell-Davis bootstrap method, with 90 %CI calculated by the bias-corrected and accelerated bootstrap method. RESULTS: All GH measurements required 33 analytical sessions (8 months) with a CV% for calibration curve slopes equal to 6.9 %. Intermediate precision evaluated by measurement of low (3 µg/L) and high (10 µg/L) quality controls was, respectively, 14 and 6.5 %. GH reference values, estimated at percentiles 1.0st, 2.5th and 5.0th, and their 90 %CI, were, respectively, 4.5 µg/L (90 %CI 3.8-5.1), 5.9 µg/L (90 %CI 5.4-6.4) and 7.0 µg/L (90 %CI 6.7-7.3). GH levels were not associated with sex, standard deviation scores, birth weight, gestational age, type of delivery or mother's variables (age, smoking habit, gestational diabetes). CONCLUSIONS: Validation data suggest that this method can be used to measured GH in newborns using DBS. The reference values estimated in this study are in accordance with previous published works using ELISA and may help confirming the clinical suspicion of neonatal GHD.

[Predictors of postoperative remission of acromegaly. (Experience of the Burdenko Neurosurgical Center)]. / Prediktory posleoperatsionnoi remissii akromegalii. (Opyt FGAU «NMITs neirokhirurgii im. akad. N.N. Burdenko¼).

BACKGROUND: Treatment of acromegaly is still an unresolved problem. Overall postoperative remission rate ranges from 34 to 85%. These values are better for microadenomas (75-90%) and worse for macroadenomas (45-70%). Identification of predictors of acromegaly remission after surgical treatment is an urgent objective to improve the quality of medical care for these patients. OBJECTIVE: To analyze postoperative freedom from acromegaly and predictors of remission. MATERIAL AND METHODS: A retrospective single-center study included 227 patients with acromegaly who underwent resection of pituitary adenoma between August 2018 and August 2021. RESULTS: Remission (normalization of serum IGF-1) was achieved in 65 (55%) patients. Growth hormone and IGF-1 index decreased after surgery in all patients. Mean preoperative serum growth hormone was 12.45 [6.88, 29.85] ng/ml, early postoperative concentration - 1.54 [0.80, 3.38] ng/ml, in delayed period - 1.15 [0.57, 3.80] ng/ml. Mean IGF-1 index was 2.18 [1.69, 2.71], 1.47 [0.99, 1.90] and 0.99 [0.74, 1.43], respectively. CONCLUSION: Significant predictors of acromegaly remission after neurosurgical treatment were age, preoperative level of growth hormone, tumor size and location, growth hormone and IGF-1 index in early postoperative period and residual tumor after surgery. Multivariate analysis revealed a significant association of acromegaly remission with small tumor size, low postoperative level of growth hormone and no residual tumor within 3-6 month after surgery.

[Effect of recombinant human growth hormone on serum Klotho and fibroblast growth factor 23 in children with idiopathic short stature]. / é‡ç»„äººç”Ÿé•¿æ¿€ç´ æ²»ç–—å¯¹ç‰¹å‘æ€§çŸ®å°ç—‡å„¿ç«¥è¡€æ¸ Klothoå’Œæˆçº¤ç»´ç»†èƒžç”Ÿé•¿å› å­23的影响.

OBJECTIVES: To investigate the changes in the serum levels of Klotho, fibroblast growth factor 23 (FGF23), and insulin-like growth factor-1 (IGF-1) in children with idiopathic short stature (ISS) before and after recombinant human growth hormone (rhGH) treatment, as well as the correlation of Klotho and FGF23 with the growth hormone (GH)/IGF-1 growth axis in these children. METHODS: A prospective study was conducted on 33 children who were diagnosed with ISS in the Department of Pediatrics, Hebei Provincial People's Hospital, from March 10, 2021 to December 1, 2022 (ISS group). Twenty-nine healthy children, matched for age and sex, who attended the Department of Child Healthcare during the same period, were enrolled as the healthy control group. The children in the ISS group were treated with rhGH, and the serum levels of Klotho, FGF23, and IGF-1 were measured before treatment and after 3, 6, and 9 months of treatment. A correlation analysis was conducted on these indexes. RESULTS: There were no significant differences in the serum levels of IGF-1, Klotho, and FGF23 between the ISS and healthy control groups (P>0.05). The serum levels of Klotho, FGF23, and IGF-1 increased significantly in the ISS group after 3, 6, and 9 months of rhGH treatment (P<0.05). In the ISS group, Klotho and FGF23 levels were positively correlated with the phosphate level before treatment (P<0.05). Before treatment and after 3, 6, and 9 months of rhGH treatment, the Klotho level was positively correlated with the IGF-1 level (P<0.05), the FGF23 level was positively correlated with the IGF-1 level (P<0.05), and the Klotho level was positively correlated with the FGF23 level (P<0.05), while Klotho and FGF23 levels were not correlated with the height standard deviation of point (P>0.05). CONCLUSIONS: The rhGH treatment can upregulate the levels of Klotho, FGF23, and IGF-1 and realize the catch-up growth in children with ISS. Klotho and FGF23 may not directly promote the linear growth of children with ISS, but may have indirect effects through the pathways such as IGF-1 and phosphate metabolism. The consistent changes in Klotho, FGF23 and IGF-1 levels show that there is a synergistic relationship among them in regulating the linear growth of ISS children.

Circulating hormones in biopsy-proven steatotic liver disease and steatohepatitis: A Multicenter Observational Study.

BACKGROUND: The role of metabolic/inflammatory hormonal systems in metabolic dysfunction associated steatotic liver disease (MASLD) remains to be fully elucidated. PURPOSE: To report the levels of the novel total and H-specific growth differentiation factor-15 (GDF-15) and other established hormonal systems and to describe hormonal patterns in controls and patients with MASLD and its stages. METHODS: This is a multicenter study from two Gastroenterology-Hepatology Departments (Greece and Australia) and one Bariatric-Metabolic Surgery Department (Italy). Overall, n = 455 serum samples of patients with biopsy-proven MASLD (n = 374) and Controls (n = 81) were recruited. RESULTS: We report for the first time that total and H-specific GDF-15 levels are higher in MASLD, at-risk metabolic dysfunction associated steatohepatitis (MASH), and severe fibrosis than in Controls. In addition, follistatin-like-3 (FSTL-3), free insulin-like growth factor-1 (IGF-1), leptin, and insulin levels were higher in MASLD patients than in Controls, while adiponectin levels were lower in MASLD subjects than in Controls. Activin-A, follistatin (FST), FSTL-3, and insulin levels significantly increased in severe fibrosis compared to no/mild fibrosis, while free IGF-1 decreased. In addition, adiponectin levels were lower in subjects without fibrosis vs. any fibrosis. Moreover, GDF-15 presented a strong positive association for the likelihood of having MASLD and at-risk MASH, while in adjusted analyses, FST and adiponectin showed inverse associations. Two different patterns of at-risk MASH were revealed through unsupervised analysis (total variation explained=54%). The most frequent pattern met in our sample (34.3%) was characterized by higher levels of total and H-specific GDF-15, follistatins, and activins, as well as low adiponectin levels. The second pattern revealed was characterized by high levels of free IGF-1, insulin, and leptin, with low levels of activin-A and adiponectin. Similar patterns were also generated in the case of overall MASLD. CONCLUSIONS: Total and H-specific GDF-15 levels increase as MASLD severity progresses. FSTL-3, free IGF-1, leptin, and insulin are also higher, whereas adiponectin and activin-A levels are lower in the MASLD group than in Controls. Hormonal systems, including GDF-15, may not only be involved in the pathophysiology but could also prove useful for the diagnostic workup of MASLD and its stages and may potentially be of therapeutic value.

Proposed reference intervals of serum insulin-like growth factor-1 (IGF-1) levels in older Japanese populations.

Measurements of serum insulin-like growth factor 1 (IGF-1) levels are useful surrogate markers for the diagnosis and management of patients with growth hormone-related disorders. We have previously published normative data of serum IGF-1 levels for the Japanese population aged 0-77 years by combining and analyzing previously reported references, which were separately and independently constructed, to properly reflect data in the transition period. Although the reference is widely used in both clinical and research settings, the reference did not include data for those aged >77 years, raising the question of how we would evaluate patients over those ages. In this study, we extended the age- and sex-specific reference ranges of serum IGF-1 levels to the age of 80 years by reanalyzing combined data on serum IGF-1 levels from previously published references. Based on our results, we proposed that individuals aged >80 years can be evaluated using the references set at the age of 80 years. However, our proposal was based on a very limited number of participants. Therefore, physicians should exercise caution when interpreting IGF-1 standard deviation scores for those aged >80 years because they are not exactly correct but acceptable.

Short Stature due to Bioinactive Growth Hormone (Kowarski Syndrome).

OBJECTIVE: Bioinactive growth hormone (BGH) is a structurally abnormal, biologically inactive, but immunoreactive form of growth hormone encoded by pathogenic growth hormone 1 gene variants. The underlying cause of the defective physiology is decreased BGH binding affinity to both growth hormone binding proteins and growth hormone receptors (GHRs). GHR cannot dimerize when it is in a quiescent state because BGH cannot activate it. Nondimerized GHR is unable to activate intracytoplasmic signaling pathway molecules such as Janus kinase 2 and signal transducer and activator of transcription, which initiate insulin-like growth factor-1 (IGF-1) transcription. IGF-1 cannot therefore be synthesized and IGF-1 levels in the circulation decrease. In contrast to children with growth hormone insensitivity, children with short stature due to BGH, known as Kowarski syndrome, exhibit an outstanding linear growth response to recombinant growth hormone therapy. For a number of reasons, differential diagnosis presents some difficulties. Similar diseases caused by genetic abnormalities that cause short stature range in severity from minor to severe clinical spectrum. Furthermore, some patients with Kowarski syndrome have previously been diagnosed with familial short stature, constitutional delayed puberty, and idiopathic short stature. This paper aims to review the particular clinical and laboratory findings of BGH. METHODS: This study collected clinical and laboratory data from KS cases reported in the literature. RESULTS: This review reports that KS cases have lower SDSs for height and IGF-1 compared to growth hormone deficiency. CONCLUSION: The diversity of genetic defects underlying Kowarski syndrome (KS) will provide new insights into growth hormone insensitivity. As the availability of genetic analysis, including functional investigations expands, researchers will identify new underlying genetic pathways.

Detection of synthetic analogues of insulin-like growth factor 1 in different biological fluids by liquid chromatography quadrupole time-of-flight mass spectrometry: comparison of different immunoaffinity protocols.

Insulin-like growth factor 1 analogues are prohibited in sport for their ability to enhance athletic performance in several sport disciplines. Their detection presents several analytical challenges, mainly due to the minimum required performance limits fixed by the World Anti-Doping Agency. Here, we are presenting analytical workflows to detect IGF-1 and its analogues in different biological matrices. Several off-line immunocapture techniques and protocols were comparatively evaluated. Separation and detection were performed by using standard flow reverse-phase liquid chromatography coupled to a time-of-flight mass spectrometer. The best recoveries were obtained using magnetic beads or pipette tips functionalized with protein A. The analytical workflows were fully validated for qualitative determinations: all the target analytes were clearly distinguishable from the interference of the matrices, with limits of detection and identification in the range of 0.05-0.30 ng/mL in urine and 0.5-2.0 ng/mL in serum/plasma. The extraction efficiency proved to be repeatable (CV% < 10) with recoveries higher than 50%. Intra- and inter-day precision were found to be smaller than 10 and 15%, respectively. The method was successfully applied to the analysis of authentic matrix samples containing the target peptides at the minimum required performance limits, proving that the method developed can be successfully applied to detect and identify IGF-1 analogues for doping control purposes in all the matrices selected. The analytical workflow developed here to detect the target peptides in different matrices can be readily implemented in anti-doping laboratories and has the potential to be adapted for the simultaneous analysis of different similarly sized peptide hormones of doping relevance.

Insulin-like growth factor-1 and retinopathy of prematurity: A systemic review and meta-analysis.

The prevalence of retinopathy of prematurity (ROP) is rapidly increasing worldwide. Many researchers have explored the relationship between insulin-like growth factor-1 (IGF-1) and ROP; however, the results are controversial. This meta-analysis evaluates the correlation between IGF-1 and ROP systematically. We searched for PubMed, Web of Science, Embase, the Cochrane Central Register of Controlled Trials, Ovid MEDLINE, SinoMed, ClinicalTrials.gov, and 3 Chinese databases up to June 2022. Then, the meta-regression and subgroup analysis were carried out. Twelve articles with 912 neonates were included in this meta-analysis. The results revealed that 4 of 7 covariates account for significant heterogeneity: location, measurement method of IGF-1 levels, collection time of blood sample, and the severity of ROP. The pooled analysis showed that low IGF-1 levels could serve as a risk factor associated with the development and severity of ROP. Serum IGF-1 monitoring in preterm infants after birth will be helpful in the diagnosis and treatment of ROP, and the reference value of IGF-1 should be standardized according to the measurement of IGF-1 and the region, as well as the postmenstrual age of prematurity.

Dehydroepiandrosterone supplementation and the impact of follicular fluid metabolome and cytokinome profiles in poor ovarian responders.

BACKGROUND: Poor ovarian responders (POR) are women undergoing in-vitro fertilization who respond poorly to ovarian stimulation, resulting in the retrieval of lower number of oocytes, and subsequently lower pregnancy rates. The follicular fluid (FF) provides a crucial microenvironment for the proper development of follicles and oocytes through tightly controlled metabolism and cell signaling. Androgens such as dehydroepiandrosterone (DHEA) have been proposed to alter the POR follicular microenvironment, but the impact DHEA imposes on the FF metabolome and cytokine profiles is unknown. Therefore, the objective of this study is to profile and identify metabolomic changes in the FF with DHEA supplementation in POR patients. METHODS: FF samples collected from 52 POR patients who underwent IVF with DHEA supplementation (DHEA +) and without (DHEA-; controls) were analyzed using untargeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) metabolomics and a large-scale multiplex suspension immunoassay covering 65 cytokines, chemokines and growth factors. Multivariate statistical modelling by partial least squares-discriminant regression (PLSR) analysis was performed for revealing metabolome-scale differences. Further, differential metabolite analysis between the two groups was performed by PLSR ß-coefficient regression analysis and Student's t-test. RESULTS: Untargeted metabolomics identified 118 FF metabolites of diverse chemistries and concentrations which spanned three orders of magnitude. They include metabolic products highly associated with ovarian function - amino acids for regulating pH and osmolarity, lipids such fatty acids and cholesterols for oocyte maturation, and glucocorticoids for ovarian steroidogenesis. Four metabolites, namely, glycerophosphocholine, linoleic acid, progesterone, and valine were significantly lower in DHEA + relative to DHEA- (p < 0.05-0.005). The area under the curves of progesterone glycerophosphocholine, linoleic acid and valine are 0.711, 0.730, 0.785 and 0.818 (p < 0.05-0.01). In DHEA + patients, progesterone positively correlated with IGF-1 (Pearson r: 0.6757, p < 0.01); glycerophosphocholine negatively correlated with AMH (Pearson r: -0.5815; p < 0.05); linoleic acid correlated with estradiol and IGF-1 (Pearson r: 0.7016 and 0.8203, respectively; p < 0.01 for both). In DHEA- patients, valine negatively correlated with serum-free testosterone (Pearson r: -0.8774; p < 0.0001). Using the large-scale immunoassay of 45 cytokines, we observed significantly lower MCP1, IFNγ, LIF and VEGF-D levels in DHEA + relative to DHEA. CONCLUSIONS: In POR patients, DHEA supplementation altered the FF metabolome and cytokine profile. The identified four FF metabolites that significantly changed with DHEA may provide information for titrating and monitoring individual DHEA supplementation.

Endoscopic endonasal approach for acromegaly: surgical outcomes using 2018 consensus criteria for remission.

Objective: The primary aim is to analyze the endoscopic endonasal surgical results in short-term and two-year follow-ups according to the 11th Acromegaly Consensus statement (2018). Indeed, prognostic factors and complications were analyzed. Subjects and methods: 40 patients who underwent endoscopic endonasal surgery by acromegaly between 2013 to 2020 was analyzed. Patients were considered in remission if an upper limit of normal (ULN) IGF-1 was less than 1.0 at the six-month and two-year follow-ups. Moreover, we assessed the Knosp grade, tumor volumetry, ULN, T2 signal in MRI, reoperation, and complications. Results: The mean age of admission was 46.7 years. Thirty-two patients were in remission after six months of surgery (80%), decreasing to 76.32% at the two-year follow-up. All microadenomas presented remission (n = 6). Regarding the complications, three patients had permanent panhypopituitarism (7.5%); postoperative cerebrospinal fluid (CSF) leaks did not occur in this series. The hyperintense signal on the T2 MRI and a higher tumor volumetry were the single predictor's factors of non-emission in a multivariate regression logistic analysis (p < 0.05). Preoperative hormone levels (GH and IGF-1) were not a prognostic factor for remission. The re-operated patients who presented hypersignal already had a high predictor of clinical-operative failure. Conclusion: The endoscopic endonasal surgery promotes high short-term and two-year remission rates in acromegaly; the tumor's volumetry and the T2 hypersignal were statistically significant prognostic factors in non-remission - the complications presented at similar rates in comparison to the literature. In invasive GH-secreting tumors, we should offer these patients a multi-disciplinary approach to improve acromegalic patients' remission rates.

Association, diagnostic accuracy and optimal threshold of salivary IGF-1 and vitamin DBP levels for estimation of pubertal growth spurt: A cross sectional study.

AIM: To determine the association of salivary IGF-1 and vitamin D Binding Protein with cervical vertebral maturation index (CVMI) across the pubertal stages and to determine the diagnostic accuracy and optimal threshold of these biomarkers for estimation of pubertal growth. DESIGN: Cross-sectional observational study. SETTING: Material and methods. All patients in the age group of 8-23 years from the Outpatient Department of Orthodontics and Dentofacial orthopaedics, between the period of July 2020 to December 2020 meeting the eligibility criteria were included. Lateral cephalograms obtained from the patients were divided into pre pubertal, pubertal & post pubertal groups based on CVMI by Baccetti et al. Unstimulated whole saliva was collected by a swab-based method & analyzed with ELISA. RESULTS: Ninety-four participants were divided in three stages: prebubertal (30), pubertal (33), post pubertal (31). A significant difference was observed in the salivary IGF-1 & DBP across the three stages. Post-hoc test revealed significantly higher mean salivary IGF-1 & DBP in pubertal group than in pre & post-pubertal group. Receiver operator characteristic curve revealed excellent diagnostic accuracy for salivary IGF-1with areas under the curve (AUC) of 0.962, satisfactory for vitamin DBP with AUC of 0.831 and poor diagnostic accuracy for age with AUC of 0.536. Youden index revealed the optimal threshold to be 3.96ng/ml and 124.13pg/ml for salivary IGF-1 and vitamin DBP respectively. CONCLUSION: The levels of Salivary IGF-1 and Vitamin DBP increased during C3 and C4 stages. Compared to vitamin DBP diagnostic accuracy of salivary IGF-1 was excellent and an optimal threshold of 3.96ng/ml can be utilized to distinguish pubertal & non-pubertal participants.

Macro-GH - A clinical entity causing a diagnostic challenge - A case report.

AIM: Presentation of a new case of a patient with macro-GH, that may interfere with different GH assays leading to false-positive results in serum samples. CASE PRESENTATION: A 61-year-old female was referred with a pituitary macroadenoma and elevated growth hormone levels. The laboratory tests showed increased fasting GH level, measured by a sandwich chemiluminescence immunoassay (LIAISON® XL) without suppression on oral glucose tolerance test and normal IGF-1. The patient did not have the typical signs and symptoms of acromegaly. The patient underwent a transsphenoidal resection of a pituitary tumor, showing only α-subunit immunostaining. Postoperative GH levels remained elevated. An interference in the determination of GH level was suspected. GH was analyzed by three different immunoassays, UniCel DxI 600, Cobas e411 and hGH-IRMA. Heterophilic antibodies and rheumatoid factor were not detected in serum sample. GH recovery after precipitation with 25 % polyethylene glycol (PEG) was 12 %. Size-exclusion chromatography confirmed the presence of macro-GH in serum sample. CONCLUSION: If results of laboratory tests are not consistent with the clinical findings, the presence of an interference within immunochemical assays could be suspected. To identify interference caused by the macro-GH, the PEG method and size-exclusion chromatography should be used.

[Effect of Interactions Among Obesity-Related Proteins on Breast Cancer Risk: A Preliminary Study].

Objective: To explore the potential interactions among obesity-related proteins in the pathogenic process of breast cancer (BC) in women. Methods: We conducted a case-control study, enrolling 279 primary breast cancer cases and 260 age-frequency-matched healthy women between April 2014 and May 2015. Based on the evidence of previous published literature on obesity-related proteins and BC risks, we selected proteins that received more attention and measured the plasma levels of these proteins by enzyme-linked immunosorbent assay (ELISA). After stratification of the subjects according to their menopausal status, an analytic strategy combining multivariate logistic regression and generalized multifactor dimensionality reduction (GMDR) was used to explore the effect of the possible interactions of these proteins on BC risk. Results: There were marginal high-order interactions among insulin-like growth factor 1 (IGF-1), insulin-like growth factor binding protein 3 (IGFBP-3), C-reactive protein (CRP), resistin (RETN), soluble leptin receptor (sOB-R), and adiponectin (ADP) in premenopausal women (with the balanced accuracy for the testing set being 59.01%, cross-validation consistency being 10/10, and permutation test P=0.05). There were high-order interactions among leptin (LEP), sOB-R, ADP, CRP, IGFBP3 and visfatin (VF) in postmenopausal women (with the balanced accuracy for the testing set being 67.31%, cross-validation consistency being 10/10, and permutation test P=0.01). Along with an increase in the number of obesity-related proteins to which the subjects were exposed, the risk of developing breast cancer gradually increased in both pre- and postmenopausal women ( OR pre =2.18, 95% CI: 1.69-2.82; OR post =2.41, 95% CI: 1.75-3.32). Conclusions: This preliminary study suggested high-order interactions among obesity-related proteins on BC risk in both pre- and postmenopausal women. In future studies, close attention should be given to these potential interactions when these proteins are used jointly as predictors, as well as in developing a comprehensive risk scoring system for BC.