Cardiovascular Effects of Growth Hormone: Preliminary Study on Oxidative Stress in Adults with Growth Hormone Deficiency

Cardiovascular Effects of Growth Hormone: Preliminary Study on Oxidative Stress in Adults with Growth Hormone Deficiency | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Cardiovascular Effects of Growth Hormone: Preliminary Study on Oxidative Stress in Adults with Growth Hormone Deficiency Maria Kościuszko, Angelika Buczyńska, Aleksandra Wiatr, Dorota Jankowska, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4883080/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Adult growth hormone deficiency (AO-GHD) is associated with increased mortality due to a higher risk of cardiovascular complications. Oxidative stress (OS) diminishes antioxidant capacity, leading to endothelial dysfunction and promoting thrombotic and inflammatory mechanisms. This increases the risk of cardiovascular diseases and metabolic disorders. Imbalances in the synthesis or signaling of endothelin-1 (ET-1) and nitric oxide (NO) are linked to hypertension, atherosclerosis, and heart failure. Additionally, elevated levels of asymmetric dimethylarginine (ADMA), an inhibitor of nitric oxide synthase, contribute to vascular endothelial dysfunction, increased vascular tension, higher blood pressure, and the activation of pro-atherogenic mechanisms. This preliminary study aims to investigate the cardiovascular effects of recombinant human growth hormone (rhGH) therapy in AO-GHD. The findings of this research suggest a potential association between rhGH replacement therapy in AO-GHD patients and a reduction in cardiovascular risk through its impact on ET-1, NO, ADMA concentrations, and OS status markers. These results have the potential to inform the optimization of rhGH replacement therapy protocols, thereby exerting a broader influence on the cardiovascular well-being of individuals undergoing such interventions. Health sciences/Cardiology Health sciences/Endocrinology Health sciences/Health care growth hormone growth hormone deficiency endothelin-1 oxidative stress asymmetric dimethyl arginine Introduction Growth hormone (GH) exerts a multifaceted physiological influence, impacting growth, metabolism, and overall health well-being. Insulin-like growth factor I (IGF-I) functions as a peripheral mediator of GH action, with its synthesis regulated by GH ( 1 ). Growth hormone deficiency (GHD) observed in adults can either manifest in childhood and continue into adulthood (childhood-onset GHD - CO-GHD) or develop in adulthood (adult-onset GHD -AO-GHD) ( 2 , 3 ). It is estimated that GHD occurs with a frequency of 2–3 cases per 10 000 individuals ( 4 ). The causes of pituitary somatotropin deficiency can include congenital and genetically determined mutations in POUF1 (Pit-1), PROP-1, HESX-1, LHX-3 and LHX-4 genes. Additionally, it may result from mutations leading to isolated GHD or arise from brain development disorders. Acquired GHD can be caused by pituitary-hypothalamic region tumors, which are statistically the most significant cause. Other causes encompass Langerhans cell histiocytosis, head trauma leading to pituitary damage, hydrocephalus, empty sella syndrome, and unspecified or unknown diagnoses ( 2 , 5 ). Over 60 years ago, recombinant human growth hormone (rhGH) treatment began in a patient with GHD. Recent advancements have highlighted GH's vital role, not only in stimulating growth but also in modulating lipid, carbohydrate, and protein metabolism ( 6 – 9 ). GHD is linked to increased cardiovascular risk and mortality, but rhGH therapy has shown improvements in cardiometabolic factors, including lipid profiles, endothelial function, and markers of cardiovascular inflammation like adipokines and oxidative stress (OS) ( 10 – 12 ). Elevated OS plays a significant role in cardiovascular disorders, primarily through oxidative damage to macromolecules and the oxidation of plasma lipoproteins, which contributes to atherosclerosis ( 12 – 17 ). Understanding these mechanisms is crucial for developing effective cardiovascular prevention and treatment strategies. Endothelin-1 (ET-1), nitric oxide (NO), and IGF-I are key in cardiovascular health, with IGF-I enhancing NO synthesis and improving cardiac function ( 18 – 20 ). Furthermore, a critical non-traditional cardiovascular risk factor is the elevated concentration of asymmetric dimethylarginine (ADMA), a potent inhibitor of NO synthase that contributes to vascular endothelial dysfunction. Increased ADMA levels coincide with heightened vascular tension, elevated blood pressure, and the activation of numerous pro-atherogenic mechanisms ( 21 , 22 ). The imbalance between important opposing macromolecules, ET-1, NO, and ADMA, plays a key role in vascular tone regulation and maintaining vascular homeostasis, which can lead to various cardiovascular disorders ( 21 – 23 ). Additionally, GHD may contribute to increased fat storage, especially within visceral adipose tissue, ultimately leading to obesity. Moreover, the presence of obesity-related insulin resistance (IR) further complicates the interaction between GH and metabolic processes. IR not only affects the body's sensitivity to insulin but also disrupts the normal functions of GH ( 24 ). A commonly used measure to evaluate IR is the Visceral Adiposity Index (VAI), which utilizes lipid profile data to assess visceral fat distribution and its relationship with IR. Studies have demonstrated that this marker is associated with increased risk of cardiovascular diseases and is inversely correlated with tissue insulin sensitivity ( 25 – 27 ). The objective of this study was to investigate the cardiovascular and metabolic effects by evaluating the concentrations of ET-1, ADMA, NO, and OS parameters, including total oxidative capacity (TOC) and total antioxidant capacity (TAC), in correlation with changes in lipid profile, body composition and IR, among AO-GHD patients before and during treatment with rhGH. The future application of measuring the above parameters in everyday practice for patients undergoing substitution therapy with rhGH could potentially be used to monitor the effectiveness of treatment in terms of both cardiovascular risk prevention and IR. Material and methods Studied population The study was conducted at the Department of Endocrinology, Diabetology, and Internal Medicine, Medical University of Białystok, Poland, under grant APK.002.393.2021. It involved 15 participants (4 females, 11 males), aged 18 to 60, all diagnosed with AO-GHD. Severe AO-GHD was diagnosed based on clinical symptoms, IGF-1 levels below age- and sex-specific references, and GH secretion under 3 ng/ml in hypoglycemic stimulation tests after correcting cortisol, thyroxine, and sex steroid deficiencies. Fourteen patients had multiple pituitary hormone deficiencies, while one had isolated GH deficiency (Table 1). Exclusion criteria included severe general condition, uncontrolled metabolic diabetes (HbA1c > 7%), pre- or proliferative diabetic retinopathy, pregnancy, and a history of cancer. After informed consent and meeting inclusion criteria, patients began rhGH therapy (Omnitrope 5 mg/1.5 ml, Sandoz GmbH) at 0.2 mg/day for males and 0.3 mg/day for females. Doses were adjusted based on IGF-1 levels 30 days after initiation and then every 180 days. The average daily dose was 0.5 mg/day for females and 0.4 mg/day for males. Anthropometric measurements, including height and weight, were meticulously conducted using standardized instruments. Subsequently, body mass index (BMI) was calculated by dividing body weight (in kilograms) by the square of height (in square meters). Moreover, IR was estimated using VAI, calculated as follows for women: (waist circumference/36.58 + [1.89 × BMI]) × (TG/0.81) × (1.52/HDL), and for men: (waist circumference/39.68 + [1.88 × BMI]) × (TG/1.03) × (1.31/HDL). Furthermore, a thorough evaluation of bone mineral density and body composition was performed utilizing the dual-energy X-ray absorptiometry (DEXA) method. The patients did not smoke cigarettes, did not abuse alcohol and did not have any other conditions that could have affected peripheral OS or similar criteria. The above information was obtained based on the medical history, physical examination and medical documentation provided by the patients. Venous blood samples (5.5 mL) were collected fasting, centrifuged, and serum stored at -80°C. Table 1. Clinical characteristics in the AO-GHD group. Patients (n=15) Sex Age (years) Treatment (before rhGH) Dose of rhGH Etiology GHD IGF-1 (ng/ml) initially BMI (kg/m2) initially CO-GHD in history P1 F 41 HCT, L, D, Es/Pg 0.5 mg CPGP 68.6 30.9 + P2 M 25 L,T 0.5 mg NFPM 62.8 24.8 + P3 M 18 T 0.4 mg CPH 27.3 22.8 + P4 F 26 HCT, L, Es/Pg 0.6 mg CPH 40.1 29.0 + P5 M 19 D, L, T, HCT 0.3 mg CPGP 74.8 34.9 + P6 F 60 HCT, L 0.4 mg ES 15.11 24.3 - P7 M 20 L, HCT, T 0.3 mg CPH 91.8 28.1 + P8 M 23 - 0.3 mg I 138.8 25.9 - P9 F 38 L, HCT, Es/Pg 0.5 mg NFPM 47.07 24.9 - P10 M 18 T 0.2 mg I 120.2 20.4 + P11 M 28 L, HCT, T, D 0.3 mg CPGP 22.6 27.1 + P12 M 42 L, T, D 0.3 mg CPGP 63.0 54.1 + P13 M 36 HCT, L, T 0.5 mg CPGP 48.9 21.5 + P14 M 18 L, HCT, D, T 0.7 mg CPGP 54.4 24.4 + P15 M 25 L, HCT, T 0.5 mg CPGP 8.6 35.8 + Abbreviations: GHD : growth hormone deficiency; rhGH : recombinant human growth hormone; P : patient; F : female; M : male; HCT : hydrocortisone; L : levothyroxine; Es/Pg : estrogen/progesterone; D : desmopressin; T : testosterone; CPH : congenital pituitary hypoplasia; CPGP : craniopharyngioma postsurgical; ES : empty sella; NFPM : non-functioning pituitary macroadenoma; FPM : functioning pituitary macroadenoma; CO-GHD - childhood-onset growth hormone deficiency; I : idiopathic; IGF-1 : insulin like growth factor type 1; BMI : body mass index. Biochemical measurement Measurements of TOC, TAC, NO, IGF-1, ET-1 and ADMA levels were taken prior to the commencement of the therapy, at the 6-month mark, and at the conclusion of the 12-month period. To assess oxidative status, the study relied on the quantification of total oxidative capacity (TOC) and total antioxidant capacity (TAC). Specifically, the TOC status was determined through a photometric immunodiagnostic assay employing the PerOx (TOS/TAC) kit sourced from Immunodiagnostic KC 5100 and Immunodiagnostic KC 5200. To precisely quantitate DNA Damage serum concentrations were measured using the electrochemiluminescence (ECLIA) method on DNA/RNA Oxidative Damage Elisa Kit Cayman 589320. For the quantitative determination of asymmetric dimethylarginine (ADMA) in serum, the ADMA Xpress ELISA Immunodiagnostic K 7890 kit was used. Nitric Oxide (NO) was determined using the colorimetric method with the Colorimetric Assay Kit Elabscience E-BC-K035-H. Moreover endothelin -1 (ET-1) was tested on Kit Elabscience E-EL-H0064, which uses ELISA method. The ECLIA method was utilized to assay concentrations of N‑terminal pro‑brain natriuretic peptide in serum (Elecsys proBNP II Roche 09315268190 Cobas e411). Statistical analysis Statistical analyses were performed using GraphPad Prism 9.0 software. Data distribution was assessed with the Shapiro-Wilk test, indicating non-normal distribution. Consequently, nonparametric tests, including the Mann-Whitney (**) and Kruskal-Wallis (*) tests, were used for inter-group comparisons. Statistical significance was set at p<0.05. Spearman correlation analysis was conducted to evaluate relationships between parameters. Odds ratios (ORs) and logistic regressions were computed using GraphPad Prism v. 9.0.. Statistical analysis involved repeated-measures ANOVA and post hoc tests with Bonferroni corrections. Bioelectrical impedance analysis The Bioelectrical Impedance Analysis (BIA) method was employed to assess body composition using the medical body analyzer INBODY 220 (Biospace, Korea). This device enables the measurement of bone mineral density, bone mineral content (BMC), body mass, total body water (TBW), fat mass, lean mass and BMI. Results Measurement analysis The correlations indicate the relationships between VAI and various metabolic parameters. A strong negative correlation between VAI and HDL suggests that as VAI increases (indicating higher visceral adiposity), HDL levels tend to decrease. Conversely, a strong positive correlation between VAI and TG implies that as VAI increases, TG levels also tend to increase, indicating a higher risk of dyslipidemia. The negative correlation between VAI and Ca indicates that higher VAI is associated with lower levels of calcium. Lastly, the moderate positive correlation between VAI and HOMA suggests that as VAI increases, IR (as measured by HOMA) tends to rise, indicating a greater risk of metabolic dysfunction. Biochemical analysis IGF-1 measurements and Ca 2+ In the group AO-GHD patients, statistically significant higher concentration of IGF-1 after 6 and 12 months therapy were observed compering to baseline value (p=0.0003; p=0.0001; respectively). We did not observe statistically significant differences in the concentrations of IGF-1 at 6 months of therapy compared to 12 months (p=0.15). Moreover we note significant higher concentrations of calcium (Ca 2+ ) after 12 months compare to baseline (p=0.01) (Table 2.). Endothelin-1 In the AO-GHD group, statistically significant lower concentration of ET-1 after 12 months therapy were observed compering to baseline value (p=0.007). We did not observe significant differences in ET-1 concentrations after 6 months of therapy, as shown in Table 2. Asymmetric dimethylarginine In the group AO-GHD patients, statistically significant lower concentration of ADMA after 6 and 12 months therapy were observed compering to baseline value (p=0.01) (Table 2.). Nitric oxide No statistically significant changes in the concentration of NO were observed (Table 2.). Oxidative stress measurement In the AO-GHD group exhibited significantly lower concentrations of TOS/TOC after 6 and 12 months (p=0.02 vs p=0.04; respectively) and higher concentrations of TAS/TAC after 12 months compared to baseline value were observed (p=0.02) (Table 2.). Lipid profile No statistically significant changes in the lipid profile were observed (Table2.). Table 2. The investigated biochemical parameters in the AO-GHD group. Parameters AO-GHD group (n=15) Initially After 6 mth After 12 mth p value (0 vs 6 mth) p* value (0 vs 12 mth) IGF-1 (ng/ml) 47.07 (8.57-138.8) 122.8 (44.1-278.1) 155.1 (36.04-265.1) 0.0003 0.0001 ET-1 (pg/ml) 8.67 (0.18-40.09) 8.4 (0.03-28.89) 5.93 (0.18-20.44) 0.24 0.007 ADMA (umol/ml) 0.5 (0.31-0.75) 0.43 (0.25-0.67) 0.38 (0.29-0.59) 0.01 0.01 NO (umol/ml) 23.54 (7.57-58.52) 30.79 (5.63-55.94) 31.11 (7.57-82.06) 1.0 0.73 TAS/TAC (umol/l) 258.6 (241.8-276.7) 258.3 (244.3-291.9) 271.1 (248.4-392.1) 0.22 0.02 TOS/TOC (umol/l) 457.3 (32.12-1655) 394.4 (171.9-1391) 589.5 (47.24-1514) 0.02 0.04 Cholesterol (mg/dl) 201 (114-302) 188 (87-296) 199 (114-295) 0.28 0.69 LDL (mg/dl) 126 (65-219) 121.5 (48-173) 131 (58-216) 0.85 0.20 HDL (mg/dl) 43 (24-85) 45 (26-76) 50 (27-80) 0.41 0.20 TG (mg/dl) 120 (51-684) 125 (55-259) 120.5 (45-326) 0.91 0.67 NT-proBNP (pg/ml) 45.13 (10-2025) 35.71 (10-1546) 27.16 (10-1325) 0.38 0.23 Ca (mmol/l) 2.31 (2.03-2.8) 2.32 (2.02-2.44) 2,37 (2.17-3.02) 0.18 0.01 Glucose (mg/dl) 89 (80-180) 90 (75-172) 86 (75-147) 0.19 0.15 Vitamin D (ng/ml) 27.7 (9.6-70.7) 30.5 (18.7-51.4) 27.7 (9.5-51.2) 0.73 0.45 Abbreviations: AO-GHD : adult-onset growth hormone deficiency; IGF-1 : insulin like growth factor type 1; ET-1 : endothelin 1; ADMA : asymmetric dimethylarginine; NO : nitric oxide; TAS : total antioxidant status; TAC : total antioxidant capacity; TOS : total oxidant status; TOC : total oxidant capacity; NT-pro-BNP : N-terminal fragment of the pro brain natriuretic peptide Ca : calcium. DXA and body composition In the AO-GHD group, we observed statistically significant differences in fat tissue mass after 6 and 12 months of therapy compared to the baseline value (p=0.006; p=0.04; respectively). However, we did not observe statistically significant differences in tissue, bone mineral content (BMC), total mass, L1-L4 density, and femoral neck density (Table 3.). Table 3. The investigated bioimpedance parameters in the AO-GHD group. Parameters AO-GHD group (n=15) Initially After 6 mth After 12 mth p value (0 vs 6mth) p* value (0 vs 12 mth) Total mass (kg) 78.6 (39.6-167.3) 85.8 (67.6-122.3) 78.0 (62.3-156) 0.72 0.51 Tissue fat % 37.5 (27.4-50.4) 36.3 (30.6-48.8) 38.4 (26.7-48.7) 0.006 0.04 Fat tissue (g) 28434 (13891-82462) 30931 (19970-52232) 29937 (16939-67385) 0.23 0.08 Lean mass (g) 48646 (23996-81228) 52144 (36852-73131) 45550 (36530-84977) 0.08 0.49 BMC 2547 (1261-3778) 2637 (2149-3829) 2568 (1770-3650) 0.77 0.42 L1-L4 BMD 1.09 (0.8-1.6) 1.08 (0.9-1.6) 1.1 (0.9-1.5) 1.0 0.73 L1-L4 T score -1.1 (-3.4-3.2) -1.0 (-2.1-2.8) -0.3 (-2.0-2.4) 0.56 0.17 L1-L4 Z score -1.1 (-3.7-3.0) -0.7 (-2.3-2.7) -0.9 (-2.3-2.0) 0.20 0.73 Neck BMD 0.95 (0.7-1.4) 0.97 (0.78-1,4) 0.96 (0.77-1.5) 0.30 0.29 Neck T score -0.8 (-2.1-2.3) -0.7 (-1.9-2.0) -0.6 (-1.9-2.5) 0.58 0.79 Neck Z score -0.9 (-2.2-2.0) -1.1 (-2.2-1.6) -1.0 (-2.0-2.3) 0.59 0.72 VAI 4.31 (1.56-11.77) 4.23 (1.58-7.03) 3.58 (1.34-9.05) 0.59 0.69 Abbreviations: AO-GHD : adult-onset growth hormone deficiency; BMC : bone mineral content; BMD : bone mineral density; VAI : visceral adiposity index. Correlations In the study group, we observed statistical significant negative correlation between IGF-1 concentration and TOS/TOC capacity after 6 and 12 months of therapy (p<0.006; R=-0.73, p<0.01, R=-0.69, respectively). Moreover we note a positive correlation between IGF-1 and TAS/TAC capacity after 6 and 12 months (p<0.001; R=0.83, p<0.01; R=0.69, respectively). Moreover, in AO-GHD group IGF-1 demonstrated a moderate negative correlation with ADMA (p<0.01; R=-0.65) and NO (p<0.03, R=-0.67) after 12 months of therapy. Furthermore, in the treated group, we observed initially statistically significant negative correlation between IGF-1 and NT-pro-BNP concentration (p<0.02; R= -0.62). After 6 months we note positive correlation between TOS/TOC capacity and NT-pro-BNP concentration (p<0.04; R=0.56). Additionally we note moderate negative correlation between TOS/TOC and lean mass initially (p<0.03; R= -0.52). Moreover HDL concentration note positive correlation with TOS/TOC initially (p<0.04; R= 0.49) and negative with TAS/TAC after 12 months treatment (p<0.01; R= -0.72). In the conducted observation, a statistically significant correlation between NO concentration and baseline fat tissue was demonstrated (p<0.04; R=0.51). Moreover, NT-pro-BNP value showed a statistically significant negative correlation with total cholesterol and LDL levels after 6 months of therapy (p<0.01; R=-0.70, p<0.01; R=-0.84; respectively). Furthermore, a statistically significant negative correlation was demonstrated at baseline between ET-1 concentration and total mass, tissue mass, lean mass, BMC, BMD, and Ca. Moreover, a negative correlation was also observed after 12 months between ET-1 concentration and lean mass (p<0.001; R=-0.81) and BMC (p<0.0001; R=-0.84). ADMA initially corelated positive with total mass, tissue mass, lean mass and fat tissue. Moreover significant positive correlation between ADMA and BMI were observed after 12 months of therapy (p<0.02; R-0.64). All correlations are presented in Table 4. Table 4. Spearman`s correlation coefficients between OS parameters and other metabolic markers in AO-GHD group initially and during the treatment. Parameters Initially After 6 months After 12 months IGF-1 vs TOS/TOC p<0.006; R= -0.73 NS p<0.01; R= -0.69 IGF-1 vs TAS/TAC p<0.001; R=0.83 NS p<0.01; R=0.69 IGF -1 vs ADMA NS NS p<0.01; R= -0.65 IGF-1 vs NO NS NS p<0.03; R= -0.67 IGF-1 vs NT-pro-BNP p<0.02; R= -0.62 NS NS TOS/TOC vs NT-pro-BNP NS p<0.04; R=0.56 NS TOS/TOC vs Lean mass p<0.035; R= -0.52 NS NS TOS/TOC vs HDL p<0.04; R= 0.49 NS NS TAS/TAC vs HDL NS NS p<0.01; R= -0.72 TAS/TAC vs DNA/RNA NS p<0.02; R=0.49 NO vs Fat tissue p<0.04; R=0.51 NS NS NO vs TG NS NS p<0.004; R=0.67 NT-pro-BNP vs cholesterol NS p<0.01; R= -0.70 NS NT-pro-BNP vs LDL NS p<0.001; R= -0.84 NS ET-1 vs Total mass p<0.05; R= -0.53 NS NS ET-1 vs Tissue mass p<0.05; R= -0.51 NS NS ET-1 vs Lean mass p<0.05; R= -0.55 NS p<0.001; R= -0.81 ET-1 vs BMC p<0.01; R= -0.51 NS p<0.0001; R= -0.84 ET-1 vs BMD p<0.01; R= -0.61 NS NS ET-1 vs Ca p<0.03; R= -0.65 NS NS ADMA vs Total mass p<0.02; R=0.54 NS NS ADMA vs Tissue mass p<0.02; R=0.53 NS NS ADMA vs Lean mass p<0.04; R=0.49 NS NS ADMA vs Fat tissue p<0.03; R=0.52 NS NS ADMA vs BMI NS NS p<0.02; R=0.64 Abbreviations: IGF-1 : insulin like growth factor type 1; ET-1 : endothelin 1; ADMA : asymmetric dimethylarginine; NO : nitric oxide; TAS : total antioxidant status; TAC : total antioxidant capacity; TOS : total oxidant status; TOC : total oxidant capacity; NT-pro-BNP : N-terminal fragment of the pro brain natriuretic peptide; Ca : calcium; HDL : high density lipoprotein; DNA : deoxyribonucleic acid ; RNA: ribonucleic acid; TG : triglycerides; BMC : bone mineral content; BMD : bone mineral density; BMI : body mass index. Discussion Previous observations have indicated that untreated AO-GHD is associated with increased mortality among patients with pituitary insufficiency compared to the general population. This increased mortality is particularly notable in female patients and is predominantly due to cardiovascular diseases (28). Nonetheless, it has been noted that rhGH therapy ameliorates multiple cardiometabolic risk factors, encompassing lipid abnormalities, endothelial dysfunction, atherosclerosis and indicators of cardiovascular inflammation such as adipokine profile or OS status (29,30). Furthermore, patients with GHD present a clinical phenotype that is characterized by increased fat mass, predominantly visceral fat, and reduced lean body mass, what is connected to higher cardiovascular risk (31,32). Fat tissue is commonly linked to a persistent, low-level inflammation marked by increased concentrations of inflammatory markers and cytokines (33). Due to this inflammation, adipocytes secrete ROS, exacerbating the inflammatory condition. This interaction between ROS and inflammation elevates OS levels and amplifies the risk of cardiovascular diseases (34). Accordingly, OS plays a crucial role in the development of cardiovascular diseases and its related complications (35).OS arises through the increased generation of ROS, including free radicals, surpassing its antioxidant capacity (36). Moreover, an important, unconventional cardiovascular risk factor involves high levels of ADMA, a strong inhibitor of NO synthase leading to dysfunction of the vascular endothelium (22). Elevated concentrations of ADMA concentrations are associated with increased vascular resistance, higher blood pressure, and the initiation of several mechanisms that promote atherosclerosis (37-39). Following rhGH therapy in the study group, a clinically significant increase in IGF-1 concentration was observed after 6 and 12 months compared to the baseline value (p=0.0003, p=0.000; respectively). There were no significant differences in IGF-1 concentrations observed at 6 months compared to 12 months of therapy (p=0.15). The statistically significant increase in IGF-1 concentration observed during the therapy were attributed to the individual adjustment of rhGH dosage aimed at achieving optimal treatment outcomes. The initial assessment occurred 30 days after initiating the starting dose, followed by subsequent assessments every 6 months. In the opposition to our study, other researchers have observed higher IGF-1 concentrations in individuals with GHD only after one year (40,41). The study results indicate that IGF-1 plays a specialized role in the complex mechanisms underlying cardiovascular function. The rhGH treatment, through its increase in IGF-1 levels, has the potential to influence the reduction of cardiovascular risk and, consequently, mortality. Emerging evidence suggests that ET-1 and related peptides play a significant prognostic role in coronary artery disease, hypertension, and heart failure (18,42,43). Furthermore, ET-1 has been investigated as both a predictor and prognostic marker in cardiovascular events, often associated with cardiac remodeling such as increased left atrial diameter and left ventricular mass (44). Additionally, NO functions as a crucial vasodilator, promoting blood vessel dilation by relaxing smooth muscle cells in the vessel walls (45). The balance between ET-1 and NO is crucial for regulating vascular tone and maintaining vascular stability. Any disruption in this balance can lead to various cardiovascular conditions (42,46). Research has also explored the relationship between ET-1 levels and mortality in the general population (47). Additionally, there are reports indicating that intravenously administered ET-1 in healthy men inhibits the increase in GH levels stimulated by growth hormone-releasing hormone (48). Our study results unequivocally demonstrated a significantly lower concentration of ET-1 after 12 months of therapy in the GHD group compared to baseline values (p=0.0007). This finding suggests a potential link to reduced cardiovascular risk in these patients. We didn’t note significant differences of ET-1 concentrations after six months therapy, what may be associated with individualizing the dosage of the medication. ADMA arises from the irreversible methylation of arginine residues and acts as an independent risk factor for cardiovascular diseases (49,50). ADMA has the ability to act as a competitive inhibitor of NO synthase enzymes and contributes to the development and advancement of microvascular complications by impacting endothelial cell function, OS induced damage, inflammation, and fibrosis (51,52). In the examined group of AO-GHD, we observed a statistically significant lower concentration of ADMA after just 6 months, with a declining trend persisting at the 12-month mark of therapy compared to the baseline value (p=0.01; p=0.01 respectively). Our study results contradict previous observations, which showed a significant reduction in endothelial damage marker concentrations only after 12 months of therapy in both children and adults (53). The pathogenesis of circulatory diseases is increasingly being attributed to OS, particularly as cardiovascular risk factors can also trigger redox imbalance. Experimental study conducted in both the CO-GHD and AO-GHD groups indicate a close association between pituitary somatotropin deficiency and increased OS status (54). OS occurs when the body produces more ROS, such as free radicals, than it can neutralize with its antioxidant system (55,56). This imbalance can manifest through processes such as lipid peroxidation, oxidation of protein thiol and amino groups, and the production of superoxide anions. These mechanisms trigger the activation of blood platelets and can result in thrombosis, vascular remodeling, vasoconstriction, and inflammatory responses (57). Patients diagnosed with AO-GHD are characterized by elevated OS (58). In our study group, we observed significantly decreased TOC concentrations after 6 and 12 months of therapy (p=0.2 vs p=0.04, respectively). Furthermore, in the AO-GHD group, IGF-1 demonstrated a negative correlation with TOS/TOC (p<0.006; R=-0.73), as well as with NT-pro-BNP concentration (p<0.02; R=-0.62) initially. IGF-1 can influence this process through various mechanisms, including the regulation of antioxidant enzyme expression such as superoxide dismutase and catalase, which help mitigate OS by neutralizing ROS (59,60). Concurrently, GHD can decrease the activity of the antioxidant system, impairing the ability to neutralize ROS (61). This decline may be due to reduced levels of antioxidants or diminished antioxidant effectiveness. In the AO-GHD group, IGF-1 initially showed a moderate positive correlation with TAS/TAC (p<0.001; R=0.83). Our findings align with those of Mohn et al., who reported an increase in TAC after one year of rhGH therapy (62). These findings suggest that rhGH treatment, and consequently the normalization of IGF-1 levels, may have a beneficial effect in reducing OS by enhancing antioxidant levels, potentially lowering cardiovascular risk. The connections between ADMA and TAS capacity is intricate and multifaceted. ADMA-induced endothelial dysfunction and OS can diminish TAS capacity by impairing the activity of antioxidant enzymes and depleting non-enzymatic antioxidants. Conversely, antioxidants can mitigate ADMA's detrimental effects by scavenging ROS and restoring endothelial function (63). In the treated group, we observed a positive correlation between ADMA and TAS capacity (p=0.02; R= 0.5). Furthermore, there was a moderate negative correlation between IGF-1 levels and ADMA concentration after 12 months of rhGH therapy (p<0.01; R=-0.65). Additionally, we noted a moderate positive correlation between IGF-1 and HDL concentration (p<0.01, R=0.77), as well as between TOS and HDL concentration (p=0.04; R=0.49). High-density lipoprotein particles contribute to reducing OS, which partially supports their role in preventing atherosclerosis (64). HDL contains enzymes such as paraoxonase-1 (PON1), which help break down lipid peroxides, thereby protecting lipids from oxidation (65). However, levels of HDL cholesterol and its functional effectiveness can differ substantially, so that raising HDL cholesterol levels might not improve its functional capabilities, particularly in scenarios where oxidative changes to HDL cause it to dysfunction (66). Studies have shown that there is an inverse correlation between HDL levels and TOS/TOC. Higher HDL levels are typically associated with lower TOS levels, indicating better protection against OS (67). However, in pathological conditions such as atherosclerosis, diabetes or chronic inflammatory states, this correlation may be disrupted (68-70). Oxidative modifications in HDL molecules can lead to the loss of their protective properties and even result in pro-inflammatory and pro-atherogenic effects. In the conducted study, a statistically significant positive correlation was observed between the baseline concentration of HDL and TOS/TOC (p<0.04, R=0.49). Additionally, a statistically significant negative correlation was observed between the concentration of HDL and TAS/TAC after 12 months of rhGH substitution therapy (p<0.01; R=-0.72). The obtained research results suggest that in the examined group of patients with AO-GHD in a state of elevated OS due to GHD, the observed increased levels of HDL do not fulfill their protective function. Moreover, our study results suggest that rhGH substitution therapy may influence the oxidative balance of the body, leading to a reduction in the TAS/TAC status. As a result, lower TAS/TAC levels may be associated with elevated levels of HDL. This could arise from various mechanisms, such as changes in lipid metabolism, action on oxidative signaling pathways, or other biological interactions that affect HDL levels. Levels of HDL cholesterol do not forecast the composition or function, hence evaluating the quality rather than merely the quantity of HDL cholesterol is crucial for assessing the risk of cardiovascular diseases, especially in the AO-GHD patients group. The relationship between NO and GHD is complex and multifaceted, given their significant roles in diverse physiological functions. In individuals with GHD, alterations in NO levels or pathways may influence vascular function, potentially heightening cardiovascular risk. Conversely, GHD can result in decreased NO production, affecting endothelial function (71). In our study, a statistically significant negative correlation between IGF-1 and NO was observed after 12 months of treatment (p<0.03; R= -0.67). Our findings suggest that rhGH replacement therapy in GHD patients has improved endothelial function and NO levels, potentially reducing cardiovascular risk. GH significantly influences the structure, proportions, and composition of body tissues (31). GH affects body composition primarily through its lipolytic and protein synthesis-enhancing actions, with its anti-natriuretic function also being significant. Growth hormone exhibits both direct and indirect lipolytic effects, including increased sensitivity to other hormones such as adrenaline or testosterone Most data indicate that this activity plays a crucial role in reducing fat tissue during GH replacement therapy (72-74). Another important effect of GH action is the increase in protein synthesis (75). In adults with a GHD, attention is primarily drawn to increased fat tissue mass, mainly visceral fat, and a decrease in fat-free mass (76,77). Changes in body composition can therefore lead to reduced physical performance, worsened well-being, as well as being a significant risk factor for cardiovascular diseases. Currently, it is believed that GH replacement therapy leads to beneficial changes in body composition. The most commonly described outcomes include a reduction in fat tissue mass, particularly visceral fat, an increase in fat-free mass, muscle mass and total mass. For example, studies by Gertner et al. showed an increase in fat-free mass and a decrease in fat tissue mass by several kilograms on average after 12 months of GH therapy (78). Long-term analysis of the consequences of GH administration indicates that changes in fat tissue and fat-free mass occur within the first 6 months of replacement therapy and persist during further treatment (79,80). Johansson et al. have noted a slight increase in fat tissue mass after a longer period of rhGH use compared to the first 6 months, but its total mass remained significantly lower after 2 and 3 years of treatment compared to baseline values (81). Generally, during rhGH substitution, the average body mass does not deviate significantly from the pre-treatment body mass, as the increase in fat-free mass is accompanied by a decrease in fat tissue mass, as well demonstrated in our study based on the evaluation of weight at baseline and after 6 and 12 months of therapy (p=0.72, p=0.51, respectively) (81, 82). The beneficial effects of GH on total body fat and its distribution have been examined in our study by means of DEXA. In the examined group of patients, we observed a statistically significant decrease in fat tissue content after just 6 months of rhGH replacement therapy, with this trend persisting after 12 months, consistent with previous observations (p=0.006; p=0.04; respectively). Furthermore, ET-1 displayed a moderate negative correlation with tissue mass (p<0.05; R=-0.51), BMC ( p<0.01; R=-0.51), total mass ( p<0.05; R=-0.53) and lean mass (p<0.05; R=-0.55). The observed correlations above suggest that under the influence of rhGH treatment and consequently the increase in IGF-1 and its positive correlation with tissue mass, total mass, and lean mass, there is a reduction in cardiovascular risk expressed by a decrease in ET-1 levels. Moreover, previous observation indicate that the increase in BMD under the influence of ongoing rhGH replacement therapy occurs after approximately 18 months and is initially preceded by a decrease in BMD, attributed to an increase in the bone remodeling process (83). This could potentially explain why we did not observe statistically significant changes in BMD values in the study group. However, we demonstrated a negative correlation between BMD and ET-1 concentration (p<0.01; R=-0.61). Our results suggesting a direct relationship between ET-1, not only on cardiovascular risk, but also on bone metabolism. GH directly regulates glucose homeostasis by inducing glycogenolysis, gluconeogenesis, and lipolysis, and by promoting IR, while indirectly through the production of IGF-I (84). Moreover, its primary function involves stimulating lipolysis, supplying free fatty acids to shift metabolism from glucose and proteins to lipid utilization (85). Additionally, it's commonly observed that individuals who suffer from GHD are prone to low blood sugar levels, a condition known as hypoglycemia, which is notably prevalent during their early years (86). However, GH also plays a role in fat metabolism by encouraging the breakdown of fat stores. First 6 months of GH replacement is connected with decreases insulin sensitivity, and after this time insulin sensitivity returns toward baseline values (87). Following decreased insulin sensitivity, a compensatory increase in insulin secretion is typically observed. Additionally, GH also acts as a potent growth factor for β-cell proliferation and insulin secretion (88). Consequently, people with GHD often accumulate higher amounts of body fat, leading to obesity. Normally, obesity is linked to an increased risk of developing IR, a precursor to diabetes type 2 (86). A multitude of studies, encompassing cross-sectional and prospective research, meta-analyses, and systematic reviews, provide strong evidence that IR alone is a cardiovascular risk factor across diverse population groups (89,90). On the other hand, IR can impact the secretion of GH as well (91). Elevated insulin levels, typically linked to IR, may suppress GH release from the pituitary gland (92). This suppression could play a role in the emergence of GHD in certain individuals experiencing IR. The rhGH replacement therapy in individuals with GHD has been shown to improve insulin sensitivity and glucose metabolism (93). In our study, the VAI index was used to assess IR. The observations conducted did not show any statistically significant differences in the outcomes of rhGH treatment after 6 and 12 months. Furthermore, in the examined group of patients, a statistically significant negative correlation was found between the VAI value and the HDL concentration, which may indicate the adverse effect of abdominal obesity on HDL cholesterol levels, potentially increasing the risk of cardiovascular diseases in patients with AO-GHD. The diversity within the patients cohorts, varying doses of rhGH, comorbidities and short duration of observation may be account for the obtained research findings. Long-term longitudinal studies, focusing on glucose homeostasis as the primary outcome, are still necessary to better elucidate the true metabolic impact of rhGH replacement therapy in AO-GHD. Despite taking various precautions, our study may still be influenced by certain biases, and we acknowledge several key limitations. The sample size of the study group is relatively small, limiting the statistical power of our findings. Therefore, it is important to replicate our results in a larger and more diverse population to better understand the roles of ET-1, ADMA and OS in AO-GHD and their potential impact on the development of cardiovascular complications. Moreover, further research is needed to explore the relationships between markers such as ET-1, ADMA, OS and cardiovascular risk in adults with GHD. This will enable the development of personalized therapeutic approaches, potentially including long-term GH replacement therapy. Conclusions Our study highlights the potential benefits of individually dosed rhGH therapy in individuals with AO-GHD. After six months of treatment, patients experienced a reduction in the risk of cardiovascular diseases and mortality, suggesting a positive impact on overall health outcomes. Furthermore, our findings underscore the utility of measuring ET-1, ADMA and OS levels in serum as potential indicators of treatment efficacy in AO-GHD patients. These biomarkers could aid in the development of personalized treatment regimens and the identification of individuals who may benefit from primary prevention strategies. Declarations Funding This research was funded by internal financing of the Medical University of Bialystok, grand number (APK.002.393.2021). Author Contributions Conceptualization, M.K., A.B., A.W., D.J., A.PK., and A.J.K.; methodology, M.K., M.Z., A.W., A.PK., K.S., A.A., and A.B.; software, A.B., A.W., D.J. and M.K.; validation, M.K., A.PK., M.Z. and A.B.; formal analysis, M.K., A.B. and A.PK.; investigation, M.K. and A.PK.; resources, M.K., A.B., A.W., and M.Z.; data curation, M.K., K.S., A.A., D.J., A.B., and A.PK.; writing—original draft preparation, M.K., A.B., and A.PK.; writing—review and editing, M.K., A.B., A.A., K.S., A.W., and A.J.K.; visualization, M.K. and A.B.; supervision, A.W., M.K., A.J.K., and A.PK.; project administration, M.K. and A.B.; funding acquisition, M.K., A.J.K., and A.P-K. Disclosures The authors have nothing to disclose. Data Availability I kindly inform you that the datasets analyzed during the current study are available from the corresponding author upon reasonable request. I hereby confirm that all research was conducted in accordance with the relevant guidelines and regulations. I declare that informed consent was obtained from all participants and/or their legal guardians. The study was carried out in compliance with the Declaration of Helsinki. Furthermore, pursuant to Article 29(2) and (14) of the Act of December 5, 1996, on the Professions of Doctor and Dentist (Journal of Laws of 2020, item 514, as amended), I confirm that the experimental protocol was approved by the designated institution—the Bioethics Committee of the Medical University of Bialystok (Resolution No: APK.O 02.393.2021). References Aguiar-Oliveira, M. H., & Bartke, A. (2019). Growth Hormone Deficiency: Health and Longevity. 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Short-term, low-dose GH therapy improves insulin sensitivity without modifying cortisol metabolism and ectopic fat accumulation in adults with GH deficiency. The Journal of clinical endocrinology and metabolism, 99(10), E1862–E1869. https://doi.org/10.1210/jc.2014-1532 Yuen, K. C., & Dunger, D. B. (2007). Therapeutic aspects of growth hormone and insulin-like growth factor-I treatment on visceral fat and insulin sensitivity in adults. Diabetes, obesity & metabolism, 9(1), 11–22. https://doi.org/10.1111/j.1463-1326.2006.00591.x Münzer, T., et al. (2001). Effects of GH and/or sex steroid administration on abdominal subcutaneous and visceral fat in healthy aged women and men. The Journal of clinical endocrinology and metabolism, 86(8), 3604–3610. https://doi.org/10.1210/jcem.86.8.7773 Carrel, A. L., & Allen, D. B. (2000). Effects of growth hormone on adipose tissue. Journal of pediatric endocrinology & metabolism: JPEM, 13 Suppl 2, 1003–1009. Rosenberg, A. G. W., et al. (2021). Growth Hormone Treatment for Adults With Prader-Willi Syndrome: A Meta-Analysis. The Journal of clinical endocrinology and metabolism, 106(10), 3068–3091. https://doi.org/10.1210/clinem/dgab406 Gomes-Santos, E., et al. (2014). Increased visceral adiposity and cortisol to cortisone ratio in adults with congenital lifetime isolated GH deficiency. The Journal of clinical endocrinology and metabolism, 99(9), 3285–3289. https://doi.org/10.1210/jc.2014-2132 Gertner J. M. (1993). Effects of growth hormone on body fat in adults. Hormone research, 40(1–3), 10–15. https://doi.org/10.1159/000183761 Modesto, M.deJ., et al. (2014). Muscle strength and body composition during the transition phase in patients treated with recombinant GH to final height. Journal of pediatric endocrinology & metabolism: JPEM, 27(9–10), 813–820. https://doi.org/10.1515/jpem-2013-0317 Weaver, J. U., et al. (1995). The effect of low dose recombinant human growth hormone replacement on regional fat distribution, insulin sensitivity, and cardiovascular risk factors in hypopituitary adults. The Journal of clinical endocrinology and metabolism, 80(1), 153–159. https://doi.org/10.1210/jcem.80.1.7829604 Johansson, J. O., Wirén, L., Oscarsson, J., Bengtsson, B. A., & Johannsson, G. (2003). Growth hormone (GH) replacement in GH-deficient adults: a crossover trial comparing the effect on metabolic control, well-being and compliance of three injections per week versus daily injections. Growth hormone & IGF research: official journal of the Growth Hormone Research Society and the International IGF Research Society, 13(6), 306–315. https://doi.org/10.1016/s1096-6374(03)00041-8 Carroll, P. V., et al. (2004). Comparison of continuation or cessation of growth hormone (GH) therapy on body composition and metabolic status in adolescents with severe GH deficiency at completion of linear growth. The Journal of clinical endocrinology and metabolism, 89(8), 3890–3895. https://doi.org/10.1210/jc.2003-031588 Sneppen, S. B., et al. (2002). Bone mineral content and bone metabolism during physiological GH treatment in GH-deficient adults–an 18-month randomised, placebo-controlled, double blinded trial. European journal of endocrinology, 146(2), 187–195. https://doi.org/10.1530/eje.0.1460187 Sharma V. M. (2019). Emerging Mechanisms of GH-Induced Lipolysis and Insulin Resistance. Pediatric endocrinology reviews: PER, 17(1), 4–16. https://doi.org/10.17458/per.vol17.2019.s.ghlipolysisandinsulinresistance Møller, N., & Jørgensen, J. O. (2009). Effects of growth hormone on glucose, lipid, and protein metabolism in human subjects. Endocrine reviews, 30(2), 152–177. https://doi.org/10.1210/er.2008-0027 Garmes, H. M., & Castillo, A. R. (2019). Insulin signaling in the whole spectrum of GH deficiency. Archives of endocrinology and metabolism, 63(6), 582–591. https://doi.org/10.20945/2359-3997000000188 Fowelin, J., Attvall, S., Lager, I., & Bengtsson, B. A. (1993). Effects of treatment with recombinant human growth hormone on insulin sensitivity and glucose metabolism in adults with growth hormone deficiency. Metabolism: clinical and experimental, 42(11), 1443–1447. https://doi.org/10.1016/0026-0495(93)90197-v Qiu, H., Yang, J. K., & Chen, C. (2017). Influence of insulin on growth hormone secretion, level and growth hormone signalling. Sheng li xue bao: [Acta physiologica Sinica], 69(5), 541–556. Adeva-Andany, M. M., Martínez-Rodríguez, J., González-Lucán, M., Fernández-Fernández, C., & Castro-Quintela, E. (2019). Insulin resistance is a cardiovascular risk factor in humans. Diabetes & metabolic syndrome, 13(2), 1449–1455. https://doi.org/10.1016/j.dsx.2019.02.023 Neeland, I. J., et al., International Atherosclerosis Society, & International Chair on Cardiometabolic Risk Working Group on Visceral Obesity (2019). Visceral and ectopic fat, atherosclerosis, and cardiometabolic disease: a position statement. The lancet. Diabetes & endocrinology, 7(9), 715–725. https://doi.org/10.1016/S2213-8587(19)30084-1 Dong, X., Su, L., & Patti, M. E. (2022). Growth Hormone and Counterregulation in the Pathogenesis of Diabetes. Current diabetes reports, 22(10), 511–524. https://doi.org/10.1007/s11892-022-01488-7 Kim SH, Park MJ. Effects of growth hormone on glucose metabolism and insulin resistance in human. Ann Pediatr Endocrinol Metab. 2017;22(3):145–152. doi: 10.6065/apem.2017.22.3.145 . Epub 2017 Sep 28. PMID: 29025199; PMCID: PMC5642081. Pellegrin, M. C., et al. (2019). Glucose Metabolism Evaluated by Glycated Hemoglobin and Insulin Sensitivity Indices in Children Treated with Recombinant Human Growth Hormone. Journal of clinical research in pediatric endocrinology, 11(4), 350–357. https://doi.org/10.4274/jcrpe.galenos.2019.2019.0281 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4883080","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":354082413,"identity":"7e9f0c0d-78b4-423f-bcd1-b80486cb5548","order_by":0,"name":"Maria Kościuszko","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABE0lEQVRIie2QvUrEQBCAJwibZvDaCTniEwgLARH0YRKEtVnBSlIeCJvCs7fzFfIIewS0yXGVkHCN18TmGrsUKdzEQsTk5DqR/ZqZgfmYHwCL5Y+iASITnBl0CXO7yE/3UA5Rdwr9Nij6SgLqi3HlOF1udAMiOEpz5TWtCJj39pI11wST9C4aUk6KS76Ygwx5ESsfUYbMlzfV3CxGxTIbVLQAjZDEGTnKB0qMKEWJRuF0Naysali0Rnl8cMxi3CheIap2l1IKyBFkPCsdRRjJWJH7tN45pawhn3LR3XJ7hlqEDCVbTznh6C0rcfC+TS7Mx543VdP2SV1t2/Ngkt4PKp/wbxX2JY63/8R93afbYrFY/j8fOdVglMsBbTgAAAAASUVORK5CYII=","orcid":"","institution":"Medical University of Bialystok","correspondingAuthor":true,"prefix":"","firstName":"Maria","middleName":"","lastName":"Kościuszko","suffix":""},{"id":354082414,"identity":"bbf86e59-2776-4c72-a7ce-8b70849f1415","order_by":1,"name":"Angelika Buczyńska","email":"","orcid":"","institution":"Medical University of Bialystok","correspondingAuthor":false,"prefix":"","firstName":"Angelika","middleName":"","lastName":"Buczyńska","suffix":""},{"id":354082416,"identity":"770fdd57-1d14-45b6-a127-ac37634a6313","order_by":2,"name":"Aleksandra Wiatr","email":"","orcid":"","institution":"Medical University of Bialystok","correspondingAuthor":false,"prefix":"","firstName":"Aleksandra","middleName":"","lastName":"Wiatr","suffix":""},{"id":354082417,"identity":"67635bc6-cdc7-456a-8057-c8f8a046c16f","order_by":3,"name":"Dorota Jankowska","email":"","orcid":"","institution":"Medical University of Bialystok","correspondingAuthor":false,"prefix":"","firstName":"Dorota","middleName":"","lastName":"Jankowska","suffix":""},{"id":354082418,"identity":"c68e8506-74de-410f-86fb-bd02319c5181","order_by":4,"name":"Agnieszka Adamska","email":"","orcid":"","institution":"Medical University of Bialystok","correspondingAuthor":false,"prefix":"","firstName":"Agnieszka","middleName":"","lastName":"Adamska","suffix":""},{"id":354082420,"identity":"519ab0fa-5f93-4e84-a32e-30df771d3b0f","order_by":5,"name":"Katarzyna Siewko","email":"","orcid":"","institution":"Medical University of Bialystok","correspondingAuthor":false,"prefix":"","firstName":"Katarzyna","middleName":"","lastName":"Siewko","suffix":""},{"id":354082421,"identity":"fff3c7b3-ced3-471d-81e2-5ee31160a6b6","order_by":6,"name":"Marcin Zaniuk","email":"","orcid":"","institution":"Medical University of Bialystok","correspondingAuthor":false,"prefix":"","firstName":"Marcin","middleName":"","lastName":"Zaniuk","suffix":""},{"id":354082422,"identity":"f96a83d7-2b51-4ce7-9fa8-33f48b23af0b","order_by":7,"name":"Adam Jacek Krętowski","email":"","orcid":"","institution":"Medical University of Bialystok","correspondingAuthor":false,"prefix":"","firstName":"Adam","middleName":"Jacek","lastName":"Krętowski","suffix":""},{"id":354082426,"identity":"9d07628f-36d5-41a2-a6b9-b05f9abd1645","order_by":8,"name":"Anna Popławska-Kita","email":"","orcid":"","institution":"Medical University of Bialystok","correspondingAuthor":false,"prefix":"","firstName":"Anna","middleName":"","lastName":"Popławska-Kita","suffix":""}],"badges":[],"createdAt":"2024-08-08 20:07:46","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4883080/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4883080/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":71484209,"identity":"eb1ee933-eba8-4c13-a0c1-b28286afdf0e","added_by":"auto","created_at":"2024-12-16 06:25:08","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1144521,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4883080/v1/d043b02e-3a09-4912-bb92-45345fbb80bc.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Cardiovascular Effects of Growth Hormone: Preliminary Study on Oxidative Stress in Adults with Growth Hormone Deficiency","fulltext":[{"header":"Introduction","content":"\u003cp\u003eGrowth hormone (GH) exerts a multifaceted physiological influence, impacting growth, metabolism, and overall health well-being. Insulin-like growth factor I (IGF-I) functions as a peripheral mediator of GH action, with its synthesis regulated by GH (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). Growth hormone deficiency (GHD) observed in adults can either manifest in childhood and continue into adulthood (childhood-onset GHD - CO-GHD) or develop in adulthood (adult-onset GHD -AO-GHD) (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). It is estimated that GHD occurs with a frequency of 2\u0026ndash;3 cases per 10 000 individuals (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). The causes of pituitary somatotropin deficiency can include congenital and genetically determined mutations in POUF1 (Pit-1), PROP-1, HESX-1, LHX-3 and LHX-4 genes. Additionally, it may result from mutations leading to isolated GHD or arise from brain development disorders. Acquired GHD can be caused by pituitary-hypothalamic region tumors, which are statistically the most significant cause. Other causes encompass Langerhans cell histiocytosis, head trauma leading to pituitary damage, hydrocephalus, empty sella syndrome, and unspecified or unknown diagnoses (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eOver 60 years ago, recombinant human growth hormone (rhGH) treatment began in a patient with GHD. Recent advancements have highlighted GH's vital role, not only in stimulating growth but also in modulating lipid, carbohydrate, and protein metabolism (\u003cspan additionalcitationids=\"CR7 CR8\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). GHD is linked to increased cardiovascular risk and mortality, but rhGH therapy has shown improvements in cardiometabolic factors, including lipid profiles, endothelial function, and markers of cardiovascular inflammation like adipokines and oxidative stress (OS) (\u003cspan additionalcitationids=\"CR11\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). Elevated OS plays a significant role in cardiovascular disorders, primarily through oxidative damage to macromolecules and the oxidation of plasma lipoproteins, which contributes to atherosclerosis (\u003cspan additionalcitationids=\"CR13 CR14 CR15 CR16\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). Understanding these mechanisms is crucial for developing effective cardiovascular prevention and treatment strategies. Endothelin-1 (ET-1), nitric oxide (NO), and IGF-I are key in cardiovascular health, with IGF-I enhancing NO synthesis and improving cardiac function (\u003cspan additionalcitationids=\"CR19\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). Furthermore, a critical non-traditional cardiovascular risk factor is the elevated concentration of asymmetric dimethylarginine (ADMA), a potent inhibitor of NO synthase that contributes to vascular endothelial dysfunction. Increased ADMA levels coincide with heightened vascular tension, elevated blood pressure, and the activation of numerous pro-atherogenic mechanisms (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). The imbalance between important opposing macromolecules, ET-1, NO, and ADMA, plays a key role in vascular tone regulation and maintaining vascular homeostasis, which can lead to various cardiovascular disorders (\u003cspan additionalcitationids=\"CR22\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAdditionally, GHD may contribute to increased fat storage, especially within visceral adipose tissue, ultimately leading to obesity. Moreover, the presence of obesity-related insulin resistance (IR) further complicates the interaction between GH and metabolic processes. IR not only affects the body's sensitivity to insulin but also disrupts the normal functions of GH (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). A commonly used measure to evaluate IR is the Visceral Adiposity Index (VAI), which utilizes lipid profile data to assess visceral fat distribution and its relationship with IR. Studies have demonstrated that this marker is associated with increased risk of cardiovascular diseases and is inversely correlated with tissue insulin sensitivity (\u003cspan additionalcitationids=\"CR26\" citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe objective of this study was to investigate the cardiovascular and metabolic effects by evaluating the concentrations of ET-1, ADMA, NO, and OS parameters, including total oxidative capacity (TOC) and total antioxidant capacity (TAC), in correlation with changes in lipid profile, body composition and IR, among AO-GHD patients before and during treatment with rhGH. The future application of measuring the above parameters in everyday practice for patients undergoing substitution therapy with rhGH could potentially be used to monitor the effectiveness of treatment in terms of both cardiovascular risk prevention and IR.\u003c/p\u003e"},{"header":"Material and methods","content":"\u003cp\u003e\u003cstrong\u003eStudied population\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was conducted at the Department of Endocrinology, Diabetology, and Internal Medicine, Medical University of Białystok, Poland, under grant APK.002.393.2021. It involved 15 participants (4 females, 11 males), aged 18 to 60, all diagnosed with AO-GHD. Severe AO-GHD was diagnosed based on clinical symptoms, IGF-1 levels below age- and sex-specific references, and GH secretion under 3 ng/ml in hypoglycemic stimulation tests after correcting cortisol, thyroxine, and sex steroid deficiencies. Fourteen patients had multiple pituitary hormone deficiencies, while one had isolated GH deficiency (Table 1). Exclusion criteria included severe general condition, uncontrolled metabolic diabetes (HbA1c \u0026gt; 7%), pre- or proliferative diabetic retinopathy, pregnancy, and a history of cancer. After informed consent and meeting inclusion criteria, patients began rhGH therapy (Omnitrope 5 mg/1.5 ml, Sandoz GmbH) at 0.2 mg/day for males and 0.3 mg/day for females. Doses were adjusted based on IGF-1 levels 30 days after initiation and then every 180 days. The average daily dose was 0.5 mg/day for females and 0.4 mg/day for males.\u003c/p\u003e\n\u003cp\u003eAnthropometric measurements, including height and weight, were meticulously conducted using standardized instruments. Subsequently, body mass index (BMI) was calculated by dividing body weight (in kilograms) by the square of height (in square meters).\u0026nbsp;Moreover, IR was estimated using VAI, calculated as follows for women: (waist circumference/36.58 + [1.89 \u0026times; BMI]) \u0026times; (TG/0.81) \u0026times; (1.52/HDL), and for men: (waist circumference/39.68 + [1.88 \u0026times; BMI]) \u0026times; (TG/1.03) \u0026times; (1.31/HDL). Furthermore, a thorough evaluation of bone mineral density and body composition was performed utilizing the dual-energy X-ray absorptiometry (DEXA) method. The patients did not smoke cigarettes, did not abuse alcohol and did not have any other conditions that could have affected peripheral OS or similar criteria. The above information was obtained based on the medical history, physical examination and medical documentation provided by the patients. Venous blood samples (5.5 mL) were collected fasting, centrifuged, and serum stored at -80\u0026deg;C.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1.\u003c/strong\u003e Clinical characteristics in the AO-GHD group.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" align=\"\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"11.458333333333334%\" valign=\"top\"\u003e\n \u003cp\u003ePatients (n=15)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.25%\" valign=\"top\"\u003e\n \u003cp\u003eSex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.416666666666666%\" valign=\"top\"\u003e\n \u003cp\u003eAge (years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.541666666666666%\" valign=\"top\"\u003e\n \u003cp\u003eTreatment\u003c/p\u003e\n \u003cp\u003e(before rhGH)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.375%\" valign=\"top\"\u003e\n \u003cp\u003eDose of rhGH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.5%\" valign=\"top\"\u003e\n \u003cp\u003eEtiology GHD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.541666666666666%\" valign=\"top\"\u003e\n \u003cp\u003eIGF-1 (ng/ml) initially\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\" valign=\"top\"\u003e\n \u003cp\u003eBMI (kg/m2)\u003c/p\u003e\n \u003cp\u003einitially\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\" valign=\"top\"\u003e\n \u003cp\u003eCO-GHD in history\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"11.458333333333334%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eP1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.25%\" valign=\"top\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.416666666666666%\" valign=\"top\"\u003e\n \u003cp\u003e41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.541666666666666%\" valign=\"top\"\u003e\n \u003cp\u003eHCT, L, D, Es/Pg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.375%\" valign=\"top\"\u003e\n \u003cp\u003e0.5 mg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.5%\" valign=\"top\"\u003e\n \u003cp\u003eCPGP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.541666666666666%\" valign=\"top\"\u003e\n \u003cp\u003e68.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\" valign=\"top\"\u003e\n \u003cp\u003e30.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\" valign=\"top\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"11.458333333333334%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eP2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.25%\" valign=\"top\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.416666666666666%\" valign=\"top\"\u003e\n \u003cp\u003e25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.541666666666666%\" valign=\"top\"\u003e\n \u003cp\u003eL,T\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.375%\" valign=\"top\"\u003e\n \u003cp\u003e0.5 mg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.5%\" valign=\"top\"\u003e\n \u003cp\u003eNFPM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.541666666666666%\" valign=\"top\"\u003e\n \u003cp\u003e62.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\" valign=\"top\"\u003e\n \u003cp\u003e24.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\" valign=\"top\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"11.458333333333334%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eP3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.25%\" valign=\"top\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.416666666666666%\" valign=\"top\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.541666666666666%\" valign=\"top\"\u003e\n \u003cp\u003eT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.375%\" valign=\"top\"\u003e\n \u003cp\u003e0.4 mg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.5%\" valign=\"top\"\u003e\n \u003cp\u003eCPH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.541666666666666%\" valign=\"top\"\u003e\n \u003cp\u003e27.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\" valign=\"top\"\u003e\n \u003cp\u003e22.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\" valign=\"top\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"11.458333333333334%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eP4\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.25%\" valign=\"top\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.416666666666666%\" valign=\"top\"\u003e\n \u003cp\u003e26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.541666666666666%\" valign=\"top\"\u003e\n \u003cp\u003eHCT, L, Es/Pg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.375%\" valign=\"top\"\u003e\n \u003cp\u003e0.6 mg\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.5%\" valign=\"top\"\u003e\n \u003cp\u003eCPH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.541666666666666%\" valign=\"top\"\u003e\n \u003cp\u003e40.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\" valign=\"top\"\u003e\n \u003cp\u003e29.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\" valign=\"top\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"11.458333333333334%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eP5\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.25%\" valign=\"top\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.416666666666666%\" valign=\"top\"\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.541666666666666%\" valign=\"top\"\u003e\n \u003cp\u003eD, L, T, HCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.375%\" valign=\"top\"\u003e\n \u003cp\u003e0.3 mg\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.5%\" valign=\"top\"\u003e\n \u003cp\u003eCPGP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.541666666666666%\" valign=\"top\"\u003e\n \u003cp\u003e74.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\" valign=\"top\"\u003e\n \u003cp\u003e34.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\" valign=\"top\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"11.458333333333334%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eP6\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.25%\" valign=\"top\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.416666666666666%\" valign=\"top\"\u003e\n \u003cp\u003e60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.541666666666666%\" valign=\"top\"\u003e\n \u003cp\u003eHCT, L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.375%\" valign=\"top\"\u003e\n \u003cp\u003e0.4 mg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.5%\" valign=\"top\"\u003e\n \u003cp\u003eES\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.541666666666666%\" valign=\"top\"\u003e\n \u003cp\u003e15.11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\" valign=\"top\"\u003e\n \u003cp\u003e24.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"11.458333333333334%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eP7\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.25%\" valign=\"top\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.416666666666666%\" valign=\"top\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.541666666666666%\" valign=\"top\"\u003e\n \u003cp\u003eL, HCT, T\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.375%\" valign=\"top\"\u003e\n \u003cp\u003e0.3 mg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.5%\" valign=\"top\"\u003e\n \u003cp\u003eCPH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.541666666666666%\" valign=\"top\"\u003e\n \u003cp\u003e91.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\" valign=\"top\"\u003e\n \u003cp\u003e28.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\" valign=\"top\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"11.458333333333334%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eP8\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.25%\" valign=\"top\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.416666666666666%\" valign=\"top\"\u003e\n \u003cp\u003e23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.541666666666666%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.375%\" valign=\"top\"\u003e\n \u003cp\u003e0.3 mg\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.5%\" valign=\"top\"\u003e\n \u003cp\u003eI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.541666666666666%\" valign=\"top\"\u003e\n \u003cp\u003e138.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\" valign=\"top\"\u003e\n \u003cp\u003e25.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"11.458333333333334%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eP9\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.25%\" valign=\"top\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.416666666666666%\" valign=\"top\"\u003e\n \u003cp\u003e38\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.541666666666666%\" valign=\"top\"\u003e\n \u003cp\u003eL, HCT, Es/Pg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.375%\" valign=\"top\"\u003e\n \u003cp\u003e0.5 mg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.5%\" valign=\"top\"\u003e\n \u003cp\u003eNFPM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.541666666666666%\" valign=\"top\"\u003e\n \u003cp\u003e47.07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\" valign=\"top\"\u003e\n \u003cp\u003e24.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"11.458333333333334%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eP10\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.25%\" valign=\"top\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.416666666666666%\" valign=\"top\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.541666666666666%\" valign=\"top\"\u003e\n \u003cp\u003eT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.375%\" valign=\"top\"\u003e\n \u003cp\u003e0.2 mg\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.5%\" valign=\"top\"\u003e\n \u003cp\u003eI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.541666666666666%\" valign=\"top\"\u003e\n \u003cp\u003e120.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\" valign=\"top\"\u003e\n \u003cp\u003e20.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\" valign=\"top\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"11.458333333333334%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eP11\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.25%\" valign=\"top\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.416666666666666%\" valign=\"top\"\u003e\n \u003cp\u003e28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.541666666666666%\" valign=\"top\"\u003e\n \u003cp\u003eL, HCT, T, D\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.375%\" valign=\"top\"\u003e\n \u003cp\u003e0.3 mg\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.5%\" valign=\"top\"\u003e\n \u003cp\u003eCPGP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.541666666666666%\" valign=\"top\"\u003e\n \u003cp\u003e22.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\" valign=\"top\"\u003e\n \u003cp\u003e27.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\" valign=\"top\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"11.458333333333334%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eP12\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.25%\" valign=\"top\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.416666666666666%\" valign=\"top\"\u003e\n \u003cp\u003e42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.541666666666666%\" valign=\"top\"\u003e\n \u003cp\u003eL, T, D\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.375%\" valign=\"top\"\u003e\n \u003cp\u003e0.3 mg\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.5%\" valign=\"top\"\u003e\n \u003cp\u003eCPGP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.541666666666666%\" valign=\"top\"\u003e\n \u003cp\u003e63.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\" valign=\"top\"\u003e\n \u003cp\u003e54.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\" valign=\"top\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"11.458333333333334%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eP13\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.25%\" valign=\"top\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.416666666666666%\" valign=\"top\"\u003e\n \u003cp\u003e36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.541666666666666%\" valign=\"top\"\u003e\n \u003cp\u003eHCT, L, T\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.375%\" valign=\"top\"\u003e\n \u003cp\u003e0.5 mg\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.5%\" valign=\"top\"\u003e\n \u003cp\u003eCPGP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.541666666666666%\" valign=\"top\"\u003e\n \u003cp\u003e48.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\" valign=\"top\"\u003e\n \u003cp\u003e21.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\" valign=\"top\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"11.458333333333334%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eP14\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.25%\" valign=\"top\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.416666666666666%\" valign=\"top\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.541666666666666%\" valign=\"top\"\u003e\n \u003cp\u003eL, HCT, D, T\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.375%\" valign=\"top\"\u003e\n \u003cp\u003e0.7 mg\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.5%\" valign=\"top\"\u003e\n \u003cp\u003eCPGP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.541666666666666%\" valign=\"top\"\u003e\n \u003cp\u003e54.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\" valign=\"top\"\u003e\n \u003cp\u003e24.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\" valign=\"top\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"11.458333333333334%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eP15\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.25%\" valign=\"top\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.416666666666666%\" valign=\"top\"\u003e\n \u003cp\u003e25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.541666666666666%\" valign=\"top\"\u003e\n \u003cp\u003eL, HCT, T\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.375%\" valign=\"top\"\u003e\n \u003cp\u003e0.5 mg\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.5%\" valign=\"top\"\u003e\n \u003cp\u003eCPGP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.541666666666666%\" valign=\"top\"\u003e\n \u003cp\u003e8.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\" valign=\"top\"\u003e\n \u003cp\u003e35.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\" valign=\"top\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations: \u003cstrong\u003eGHD\u003c/strong\u003e: growth hormone deficiency; \u003cstrong\u003erhGH\u003c/strong\u003e: recombinant human growth hormone; \u003cstrong\u003eP\u003c/strong\u003e: patient; \u003cstrong\u003eF\u003c/strong\u003e: female; \u003cstrong\u003eM\u003c/strong\u003e: male; \u003cstrong\u003eHCT\u003c/strong\u003e: hydrocortisone; \u003cstrong\u003eL\u003c/strong\u003e: levothyroxine; \u003cstrong\u003eEs/Pg\u003c/strong\u003e: estrogen/progesterone; \u003cstrong\u003eD\u003c/strong\u003e: desmopressin; \u003cstrong\u003eT\u003c/strong\u003e: testosterone; \u003cstrong\u003eCPH\u003c/strong\u003e: congenital pituitary hypoplasia; \u003cstrong\u003eCPGP\u003c/strong\u003e: craniopharyngioma postsurgical; \u003cstrong\u003eES\u003c/strong\u003e: empty sella;\u003cstrong\u003e\u0026nbsp;NFPM\u003c/strong\u003e: non-functioning pituitary macroadenoma; \u003cstrong\u003eFPM\u003c/strong\u003e: functioning pituitary macroadenoma; \u003cstrong\u003eCO-GHD\u003c/strong\u003e -\u0026nbsp;childhood-onset growth hormone deficiency; \u003cstrong\u003eI\u003c/strong\u003e: idiopathic; \u003cstrong\u003eIGF-1\u003c/strong\u003e: insulin like \u0026nbsp; growth factor type 1; \u003cstrong\u003eBMI\u003c/strong\u003e: body mass index.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBiochemical measurement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMeasurements of TOC, TAC, NO, IGF-1, ET-1 and ADMA levels were taken prior to the commencement of the therapy, at the 6-month mark, and at the conclusion of the 12-month period. To assess oxidative status, the study relied on the quantification of total oxidative capacity (TOC) and total antioxidant capacity (TAC). Specifically, the TOC status was determined through a photometric immunodiagnostic assay employing the PerOx (TOS/TAC) kit sourced from Immunodiagnostic KC 5100 and Immunodiagnostic KC 5200. To precisely quantitate DNA Damage serum concentrations were measured using the electrochemiluminescence (ECLIA) method on DNA/RNA Oxidative Damage Elisa Kit Cayman 589320. For the quantitative determination of asymmetric dimethylarginine (ADMA) in serum, the ADMA Xpress ELISA Immunodiagnostic K 7890 kit was used. Nitric Oxide (NO) was determined using the colorimetric method with the Colorimetric Assay Kit Elabscience E-BC-K035-H. Moreover endothelin -1 (ET-1) was tested on Kit Elabscience \u0026nbsp; E-EL-H0064, which uses ELISA method. The ECLIA method was utilized to assay concentrations of N‑terminal pro‑brain natriuretic peptide in serum (Elecsys proBNP II Roche 09315268190 Cobas e411).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStatistical analyses were performed using GraphPad Prism 9.0 software. Data distribution was assessed with the Shapiro-Wilk test, indicating non-normal distribution. Consequently, nonparametric tests, including the Mann-Whitney (**) and Kruskal-Wallis (*) tests, were used for inter-group comparisons. Statistical significance was set at p\u0026lt;0.05. Spearman correlation analysis was conducted to evaluate relationships between parameters. Odds ratios (ORs) and logistic regressions were computed using GraphPad Prism v. 9.0.. Statistical analysis involved repeated-measures ANOVA and post hoc tests with Bonferroni corrections.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBioelectrical impedance analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe Bioelectrical Impedance Analysis (BIA) method was employed to assess body composition using the medical body analyzer INBODY 220 (Biospace, Korea). This device enables the measurement of bone mineral density, bone mineral content (BMC), body mass, total body water (TBW), fat mass, lean mass and BMI.\u0026nbsp;\u003c/p\u003e"},{"header":"Results ","content":"\u003cp\u003e\u003cstrong\u003eMeasurement analysis \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe correlations indicate the relationships between VAI and various metabolic parameters. A strong negative correlation between VAI and HDL suggests that as VAI increases (indicating higher visceral adiposity), HDL levels tend to decrease. Conversely, a strong positive correlation between VAI and TG implies that as VAI increases, TG levels also tend to increase, indicating a higher risk of dyslipidemia. The negative correlation between VAI and Ca indicates that higher VAI is associated with lower levels of calcium. Lastly, the moderate positive correlation between VAI and HOMA suggests that as VAI increases, IR (as measured by HOMA) tends to rise, indicating a greater risk of metabolic dysfunction.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBiochemical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIGF-1 measurements and Ca\u003csup\u003e2+\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn the group AO-GHD patients, statistically significant higher concentration of IGF-1 after 6 and 12 months therapy were observed compering to baseline value (p=0.0003; p=0.0001; respectively). We\u0026nbsp;did not observe statistically significant differences in the concentrations of IGF-1 at 6 months of therapy compared to 12 months (p=0.15). Moreover we note significant higher concentrations of calcium (Ca\u003csup\u003e2+\u003c/sup\u003e) after 12 months compare to baseline (p=0.01) (Table 2.).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEndothelin-1\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn the AO-GHD group, statistically significant lower concentration of ET-1 after 12 months therapy were observed compering to baseline value (p=0.007). We did not observe significant differences in ET-1 concentrations after 6 months of therapy, as shown in Table 2.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAsymmetric dimethylarginine\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn the group AO-GHD patients, statistically significant lower concentration of ADMA after 6 and 12 months therapy were observed compering to baseline value (p=0.01) (Table 2.).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eNitric oxide\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo statistically significant changes in the concentration of NO were observed (Table 2.).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOxidative stress measurement\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn the AO-GHD group exhibited significantly lower concentrations of TOS/TOC after 6 and 12 months (p=0.02 vs p=0.04; respectively) \u0026nbsp;and higher concentrations of TAS/TAC after 12 months compared to baseline value were observed (p=0.02) (Table 2.).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLipid profile\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo statistically significant changes in the lipid profile were observed (Table2.).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2.\u003c/strong\u003e The investigated biochemical parameters in the AO-GHD group.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"661\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.363636363636363%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eParameters\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.515151515151516%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.757575757575758%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAO-GHD group (n=15)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.12121212121212%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.12121212121212%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.12121212121212%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.363636363636363%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.515151515151516%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eInitially\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.757575757575758%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAfter 6 mth\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.12121212121212%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAfter 12 mth\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.12121212121212%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ep value\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(0 vs 6 mth)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.12121212121212%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ep* value\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(0 vs 12 mth)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.363636363636363%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eIGF-1 (ng/ml)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.515151515151516%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e47.07\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(8.57-138.8)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.757575757575758%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e122.8\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(44.1-278.1)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.12121212121212%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e155.1\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(36.04-265.1)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.12121212121212%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.0003\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.12121212121212%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.0001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.363636363636363%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eET-1 (pg/ml)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.515151515151516%\" valign=\"top\"\u003e\n \u003cp\u003e8.67\u003c/p\u003e\n \u003cp\u003e(0.18-40.09)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.757575757575758%\" valign=\"top\"\u003e\n \u003cp\u003e8.4\u003c/p\u003e\n \u003cp\u003e(0.03-28.89)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.12121212121212%\" valign=\"top\"\u003e\n \u003cp\u003e5.93\u003c/p\u003e\n \u003cp\u003e(0.18-20.44)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.12121212121212%\" valign=\"top\"\u003e\n \u003cp\u003e0.24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.12121212121212%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.007\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.363636363636363%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eADMA (umol/ml)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.515151515151516%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.5\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(0.31-0.75)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.757575757575758%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.43\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(0.25-0.67)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.12121212121212%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.38\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(0.29-0.59)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.12121212121212%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.01\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.12121212121212%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.01\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.363636363636363%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eNO (umol/ml)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.515151515151516%\" valign=\"top\"\u003e\n \u003cp\u003e23.54\u003c/p\u003e\n \u003cp\u003e(7.57-58.52)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.757575757575758%\" valign=\"top\"\u003e\n \u003cp\u003e30.79\u003c/p\u003e\n \u003cp\u003e(5.63-55.94)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.12121212121212%\" valign=\"top\"\u003e\n \u003cp\u003e31.11\u003c/p\u003e\n \u003cp\u003e(7.57-82.06)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.12121212121212%\" valign=\"top\"\u003e\n \u003cp\u003e1.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.12121212121212%\" valign=\"top\"\u003e\n \u003cp\u003e0.73\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.363636363636363%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eTAS/TAC\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(umol/l)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.515151515151516%\" valign=\"top\"\u003e\n \u003cp\u003e258.6\u003c/p\u003e\n \u003cp\u003e(241.8-276.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.757575757575758%\" valign=\"top\"\u003e\n \u003cp\u003e258.3\u003c/p\u003e\n \u003cp\u003e(244.3-291.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.12121212121212%\" valign=\"top\"\u003e\n \u003cp\u003e271.1\u003c/p\u003e\n \u003cp\u003e(248.4-392.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.12121212121212%\" valign=\"top\"\u003e\n \u003cp\u003e0.22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.12121212121212%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.02\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.363636363636363%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eTOS/TOC\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(umol/l)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.515151515151516%\" valign=\"top\"\u003e\n \u003cp\u003e457.3\u003c/p\u003e\n \u003cp\u003e(32.12-1655)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.757575757575758%\" valign=\"top\"\u003e\n \u003cp\u003e394.4\u003c/p\u003e\n \u003cp\u003e(171.9-1391)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.12121212121212%\" valign=\"top\"\u003e\n \u003cp\u003e589.5\u003c/p\u003e\n \u003cp\u003e(47.24-1514)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.12121212121212%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.02\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.12121212121212%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.04\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.363636363636363%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCholesterol\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(mg/dl)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.515151515151516%\" valign=\"top\"\u003e\n \u003cp\u003e201\u003c/p\u003e\n \u003cp\u003e(114-302)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.757575757575758%\" valign=\"top\"\u003e\n \u003cp\u003e188\u003c/p\u003e\n \u003cp\u003e(87-296)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.12121212121212%\" valign=\"top\"\u003e\n \u003cp\u003e199\u003c/p\u003e\n \u003cp\u003e(114-295)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.12121212121212%\" valign=\"top\"\u003e\n \u003cp\u003e0.28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.12121212121212%\" valign=\"top\"\u003e\n \u003cp\u003e0.69\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.363636363636363%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eLDL\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(mg/dl)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.515151515151516%\" valign=\"top\"\u003e\n \u003cp\u003e126\u003c/p\u003e\n \u003cp\u003e(65-219)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.757575757575758%\" valign=\"top\"\u003e\n \u003cp\u003e121.5\u003c/p\u003e\n \u003cp\u003e(48-173)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.12121212121212%\" valign=\"top\"\u003e\n \u003cp\u003e131\u003c/p\u003e\n \u003cp\u003e(58-216)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.12121212121212%\" valign=\"top\"\u003e\n \u003cp\u003e0.85\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.12121212121212%\" valign=\"top\"\u003e\n \u003cp\u003e0.20\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.363636363636363%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eHDL\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(mg/dl)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.515151515151516%\" valign=\"top\"\u003e\n \u003cp\u003e43\u003c/p\u003e\n \u003cp\u003e(24-85)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.757575757575758%\" valign=\"top\"\u003e\n \u003cp\u003e45\u003c/p\u003e\n \u003cp\u003e(26-76)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.12121212121212%\" valign=\"top\"\u003e\n \u003cp\u003e50\u003c/p\u003e\n \u003cp\u003e(27-80)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.12121212121212%\" valign=\"top\"\u003e\n \u003cp\u003e0.41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.12121212121212%\" valign=\"top\"\u003e\n \u003cp\u003e0.20\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.363636363636363%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eTG\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(mg/dl)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.515151515151516%\" valign=\"top\"\u003e\n \u003cp\u003e120\u003c/p\u003e\n \u003cp\u003e(51-684)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.757575757575758%\" valign=\"top\"\u003e\n \u003cp\u003e125\u003c/p\u003e\n \u003cp\u003e(55-259)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.12121212121212%\" valign=\"top\"\u003e\n \u003cp\u003e120.5\u003c/p\u003e\n \u003cp\u003e(45-326)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.12121212121212%\" valign=\"top\"\u003e\n \u003cp\u003e0.91\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.12121212121212%\" valign=\"top\"\u003e\n \u003cp\u003e0.67\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.363636363636363%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eNT-proBNP (pg/ml)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.515151515151516%\" valign=\"top\"\u003e\n \u003cp\u003e45.13\u003c/p\u003e\n \u003cp\u003e(10-2025)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.757575757575758%\" valign=\"top\"\u003e\n \u003cp\u003e35.71\u003c/p\u003e\n \u003cp\u003e(10-1546)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.12121212121212%\" valign=\"top\"\u003e\n \u003cp\u003e27.16\u003c/p\u003e\n \u003cp\u003e(10-1325)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.12121212121212%\" valign=\"top\"\u003e\n \u003cp\u003e0.38\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.12121212121212%\" valign=\"top\"\u003e\n \u003cp\u003e0.23\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.363636363636363%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCa (mmol/l)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.515151515151516%\" valign=\"top\"\u003e\n \u003cp\u003e2.31\u003c/p\u003e\n \u003cp\u003e(2.03-2.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.757575757575758%\" valign=\"top\"\u003e\n \u003cp\u003e2.32\u003c/p\u003e\n \u003cp\u003e(2.02-2.44)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.12121212121212%\" valign=\"top\"\u003e\n \u003cp\u003e2,37\u003c/p\u003e\n \u003cp\u003e(2.17-3.02)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.12121212121212%\" valign=\"top\"\u003e\n \u003cp\u003e0.18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.12121212121212%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.01\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.363636363636363%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eGlucose\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(mg/dl)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.515151515151516%\" valign=\"top\"\u003e\n \u003cp\u003e89\u003c/p\u003e\n \u003cp\u003e(80-180)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.757575757575758%\" valign=\"top\"\u003e\n \u003cp\u003e90\u003c/p\u003e\n \u003cp\u003e(75-172)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.12121212121212%\" valign=\"top\"\u003e\n \u003cp\u003e86\u003c/p\u003e\n \u003cp\u003e(75-147)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.12121212121212%\" valign=\"top\"\u003e\n \u003cp\u003e0.19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.12121212121212%\" valign=\"top\"\u003e\n \u003cp\u003e0.15\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.363636363636363%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eVitamin D\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(ng/ml)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.515151515151516%\" valign=\"top\"\u003e\n \u003cp\u003e27.7\u003c/p\u003e\n \u003cp\u003e(9.6-70.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.757575757575758%\" valign=\"top\"\u003e\n \u003cp\u003e30.5\u003c/p\u003e\n \u003cp\u003e(18.7-51.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.12121212121212%\" valign=\"top\"\u003e\n \u003cp\u003e27.7\u003c/p\u003e\n \u003cp\u003e(9.5-51.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.12121212121212%\" valign=\"top\"\u003e\n \u003cp\u003e0.73\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.12121212121212%\" valign=\"top\"\u003e\n \u003cp\u003e0.45\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations: \u003cstrong\u003eAO-GHD\u003c/strong\u003e: adult-onset growth hormone deficiency;\u0026nbsp;\u003cstrong\u003eIGF-1\u003c/strong\u003e: insulin like \u0026nbsp;growth factor type 1; \u003cstrong\u003eET-1\u003c/strong\u003e: endothelin 1; \u003cstrong\u003eADMA\u003c/strong\u003e: asymmetric dimethylarginine;\u0026nbsp;\u003cstrong\u003eNO\u003c/strong\u003e: nitric oxide;\u0026nbsp;\u003cstrong\u003eTAS\u003c/strong\u003e: total antioxidant status;\u0026nbsp;\u003cstrong\u003eTAC\u003c/strong\u003e: total antioxidant capacity;\u0026nbsp;\u003cstrong\u003eTOS\u003c/strong\u003e: total oxidant status;\u0026nbsp;\u003cstrong\u003eTOC\u003c/strong\u003e: total oxidant capacity;\u0026nbsp;\u003cstrong\u003eNT-pro-BNP\u003c/strong\u003e: N-terminal fragment of the pro brain natriuretic peptide\u0026nbsp;\u003cstrong\u003eCa\u003c/strong\u003e: calcium.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDXA and body composition\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn the AO-GHD group, we observed statistically significant differences in fat tissue mass after 6 and 12 months of therapy compared to the baseline value (p=0.006; p=0.04; respectively). However, we did not observe statistically significant differences in tissue, bone mineral content (BMC), total mass, L1-L4 density, and femoral neck density (Table 3.).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3.\u003c/strong\u003e The investigated bioimpedance parameters in the AO-GHD group.\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"661\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.095310136157337%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eParameters\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.969742813918305%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.733736762481088%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAO-GHD group (n=15) \u0026nbsp;\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.733736762481088%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.733736762481088%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.733736762481088%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.095310136157337%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.969742813918305%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eInitially\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.733736762481088%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAfter 6 mth\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.733736762481088%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAfter 12 mth\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.733736762481088%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ep value\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(0 vs 6mth)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.733736762481088%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ep* value\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(0 vs 12 mth)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.095310136157337%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;Total mass (kg)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.969742813918305%\" valign=\"top\"\u003e\n \u003cp\u003e78.6\u003c/p\u003e\n \u003cp\u003e(39.6-167.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.733736762481088%\" valign=\"top\"\u003e\n \u003cp\u003e85.8\u003c/p\u003e\n \u003cp\u003e(67.6-122.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.733736762481088%\" valign=\"top\"\u003e\n \u003cp\u003e78.0\u003c/p\u003e\n \u003cp\u003e(62.3-156)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.733736762481088%\" valign=\"top\"\u003e\n \u003cp\u003e0.72\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.733736762481088%\" valign=\"top\"\u003e\n \u003cp\u003e0.51\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.095310136157337%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eTissue fat %\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.969742813918305%\" valign=\"top\"\u003e\n \u003cp\u003e37.5\u003c/p\u003e\n \u003cp\u003e(27.4-50.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.733736762481088%\" valign=\"top\"\u003e\n \u003cp\u003e36.3\u003c/p\u003e\n \u003cp\u003e(30.6-48.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.733736762481088%\" valign=\"top\"\u003e\n \u003cp\u003e38.4\u003c/p\u003e\n \u003cp\u003e(26.7-48.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.733736762481088%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.006\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.733736762481088%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.04\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.095310136157337%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eFat tissue (g)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.969742813918305%\" valign=\"top\"\u003e\n \u003cp\u003e28434\u003c/p\u003e\n \u003cp\u003e(13891-82462)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.733736762481088%\" valign=\"top\"\u003e\n \u003cp\u003e30931\u003c/p\u003e\n \u003cp\u003e(19970-52232)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.733736762481088%\" valign=\"top\"\u003e\n \u003cp\u003e29937\u003c/p\u003e\n \u003cp\u003e(16939-67385)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.733736762481088%\" valign=\"top\"\u003e\n \u003cp\u003e0.23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.733736762481088%\" valign=\"top\"\u003e\n \u003cp\u003e0.08\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.095310136157337%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eLean mass (g)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.969742813918305%\" valign=\"top\"\u003e\n \u003cp\u003e48646\u003c/p\u003e\n \u003cp\u003e(23996-81228)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.733736762481088%\" valign=\"top\"\u003e\n \u003cp\u003e52144\u003c/p\u003e\n \u003cp\u003e(36852-73131)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.733736762481088%\" valign=\"top\"\u003e\n \u003cp\u003e45550\u003c/p\u003e\n \u003cp\u003e(36530-84977)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.733736762481088%\" valign=\"top\"\u003e\n \u003cp\u003e0.08\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.733736762481088%\" valign=\"top\"\u003e\n \u003cp\u003e0.49\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.095310136157337%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eBMC\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.969742813918305%\" valign=\"top\"\u003e\n \u003cp\u003e2547\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(1261-3778)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.733736762481088%\" valign=\"top\"\u003e\n \u003cp\u003e2637\u003c/p\u003e\n \u003cp\u003e(2149-3829)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.733736762481088%\" valign=\"top\"\u003e\n \u003cp\u003e2568\u003c/p\u003e\n \u003cp\u003e(1770-3650)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.733736762481088%\" valign=\"top\"\u003e\n \u003cp\u003e0.77\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.733736762481088%\" valign=\"top\"\u003e\n \u003cp\u003e0.42\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.095310136157337%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eL1-L4 BMD\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.969742813918305%\" valign=\"top\"\u003e\n \u003cp\u003e1.09\u003c/p\u003e\n \u003cp\u003e(0.8-1.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.733736762481088%\" valign=\"top\"\u003e\n \u003cp\u003e1.08\u003c/p\u003e\n \u003cp\u003e(0.9-1.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.733736762481088%\" valign=\"top\"\u003e\n \u003cp\u003e1.1\u003c/p\u003e\n \u003cp\u003e(0.9-1.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.733736762481088%\" valign=\"top\"\u003e\n \u003cp\u003e1.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.733736762481088%\" valign=\"top\"\u003e\n \u003cp\u003e0.73\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.095310136157337%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eL1-L4 T score\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.969742813918305%\" valign=\"top\"\u003e\n \u003cp\u003e-1.1\u003c/p\u003e\n \u003cp\u003e(-3.4-3.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.733736762481088%\" valign=\"top\"\u003e\n \u003cp\u003e-1.0\u003c/p\u003e\n \u003cp\u003e(-2.1-2.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.733736762481088%\" valign=\"top\"\u003e\n \u003cp\u003e-0.3\u003c/p\u003e\n \u003cp\u003e(-2.0-2.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.733736762481088%\" valign=\"top\"\u003e\n \u003cp\u003e0.56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.733736762481088%\" valign=\"top\"\u003e\n \u003cp\u003e0.17\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.095310136157337%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eL1-L4 Z score\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.969742813918305%\" valign=\"top\"\u003e\n \u003cp\u003e-1.1\u003c/p\u003e\n \u003cp\u003e(-3.7-3.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.733736762481088%\" valign=\"top\"\u003e\n \u003cp\u003e-0.7\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(-2.3-2.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.733736762481088%\" valign=\"top\"\u003e\n \u003cp\u003e-0.9\u003c/p\u003e\n \u003cp\u003e(-2.3-2.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.733736762481088%\" valign=\"top\"\u003e\n \u003cp\u003e0.20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.733736762481088%\" valign=\"top\"\u003e\n \u003cp\u003e0.73\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.095310136157337%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eNeck BMD\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.969742813918305%\" valign=\"top\"\u003e\n \u003cp\u003e0.95\u003c/p\u003e\n \u003cp\u003e(0.7-1.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.733736762481088%\" valign=\"top\"\u003e\n \u003cp\u003e0.97\u003c/p\u003e\n \u003cp\u003e(0.78-1,4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.733736762481088%\" valign=\"top\"\u003e\n \u003cp\u003e0.96\u003c/p\u003e\n \u003cp\u003e(0.77-1.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.733736762481088%\" valign=\"top\"\u003e\n \u003cp\u003e0.30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.733736762481088%\" valign=\"top\"\u003e\n \u003cp\u003e0.29\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.095310136157337%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eNeck T score\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.969742813918305%\" valign=\"top\"\u003e\n \u003cp\u003e-0.8\u003c/p\u003e\n \u003cp\u003e(-2.1-2.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.733736762481088%\" valign=\"top\"\u003e\n \u003cp\u003e-0.7\u003c/p\u003e\n \u003cp\u003e(-1.9-2.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.733736762481088%\" valign=\"top\"\u003e\n \u003cp\u003e-0.6\u003c/p\u003e\n \u003cp\u003e(-1.9-2.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.733736762481088%\" valign=\"top\"\u003e\n \u003cp\u003e0.58\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.733736762481088%\" valign=\"top\"\u003e\n \u003cp\u003e0.79\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.095310136157337%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eNeck Z score\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.969742813918305%\" valign=\"top\"\u003e\n \u003cp\u003e-0.9\u003c/p\u003e\n \u003cp\u003e(-2.2-2.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.733736762481088%\" valign=\"top\"\u003e\n \u003cp\u003e-1.1\u003c/p\u003e\n \u003cp\u003e(-2.2-1.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.733736762481088%\" valign=\"top\"\u003e\n \u003cp\u003e-1.0\u003c/p\u003e\n \u003cp\u003e(-2.0-2.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.733736762481088%\" valign=\"top\"\u003e\n \u003cp\u003e0.59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.733736762481088%\" valign=\"top\"\u003e\n \u003cp\u003e0.72\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.095310136157337%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eVAI\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.969742813918305%\" valign=\"top\"\u003e\n \u003cp\u003e4.31\u003c/p\u003e\n \u003cp\u003e(1.56-11.77)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.733736762481088%\" valign=\"top\"\u003e\n \u003cp\u003e4.23\u003c/p\u003e\n \u003cp\u003e(1.58-7.03)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.733736762481088%\" valign=\"top\"\u003e\n \u003cp\u003e3.58\u003c/p\u003e\n \u003cp\u003e(1.34-9.05)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.733736762481088%\" valign=\"top\"\u003e\n \u003cp\u003e0.59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.733736762481088%\" valign=\"top\"\u003e\n \u003cp\u003e0.69\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations: \u003cstrong\u003eAO-GHD\u003c/strong\u003e: adult-onset growth hormone deficiency; \u003cstrong\u003eBMC\u003c/strong\u003e: bone mineral content; \u003cstrong\u003eBMD\u003c/strong\u003e: bone mineral density;\u003cstrong\u003e\u0026nbsp;VAI\u003c/strong\u003e: visceral adiposity index.\u0026nbsp;\u003c/p\u003e\n\u003ch3\u003eCorrelations\u003c/h3\u003e\n\u003cp\u003eIn the study group, we observed statistical significant negative correlation between IGF-1 concentration and TOS/TOC capacity after 6 and 12 months of therapy (p\u0026lt;0.006; R=-0.73, p\u0026lt;0.01, R=-0.69, respectively). Moreover we note a positive correlation between IGF-1 and TAS/TAC capacity after 6 and 12 months (p\u0026lt;0.001; R=0.83, p\u0026lt;0.01; R=0.69, respectively). Moreover, in AO-GHD group IGF-1 demonstrated a moderate negative correlation with ADMA (p\u0026lt;0.01; R=-0.65) and NO (p\u0026lt;0.03, R=-0.67) after 12 months of therapy. Furthermore, in the treated group, we observed initially statistically significant negative correlation between IGF-1 and NT-pro-BNP concentration (p\u0026lt;0.02; R= -0.62). After 6 months we note positive correlation between TOS/TOC capacity and NT-pro-BNP concentration \u0026nbsp;(p\u0026lt;0.04; R=0.56). Additionally we note moderate negative correlation between TOS/TOC and lean mass initially (p\u0026lt;0.03; R= -0.52). Moreover HDL concentration note positive correlation with TOS/TOC initially (p\u0026lt;0.04; R= 0.49) and negative with TAS/TAC after 12 months treatment (p\u0026lt;0.01; R= -0.72). In the conducted observation, a statistically significant correlation between NO concentration and baseline fat tissue was demonstrated (p\u0026lt;0.04; R=0.51). Moreover, NT-pro-BNP value showed a statistically significant negative correlation with total cholesterol and LDL levels after 6 months of therapy (p\u0026lt;0.01; R=-0.70, p\u0026lt;0.01; R=-0.84; respectively). Furthermore, a statistically significant negative correlation was demonstrated at baseline between ET-1 concentration and total mass, tissue mass, lean mass, BMC, BMD, and Ca. Moreover, a negative correlation was also observed after 12 months between ET-1 concentration and lean mass (p\u0026lt;0.001; R=-0.81) and BMC (p\u0026lt;0.0001; R=-0.84). ADMA initially corelated positive with total mass, tissue mass, lean mass and fat tissue. Moreover significant positive correlation between ADMA and BMI were observed after 12 months of therapy (p\u0026lt;0.02; R-0.64). All correlations are presented in Table 4.\u003cstrong\u003e\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 4.\u003c/strong\u003e Spearman`s correlation coefficients between OS parameters and other metabolic markers in AO-GHD group initially and during the treatment.\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.113671274961597%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eParameters\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.113671274961597%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eInitially\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.73425499231951%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAfter 6 months\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.038402457757297%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAfter 12 months\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.113671274961597%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eIGF-1 vs TOS/TOC\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.113671274961597%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ep\u0026lt;0.006; R= -0.73\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.73425499231951%\" valign=\"top\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.038402457757297%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ep\u0026lt;0.01; R= -0.69\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.113671274961597%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eIGF-1 vs TAS/TAC\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.113671274961597%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ep\u0026lt;0.001; R=0.83\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.73425499231951%\" valign=\"top\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.038402457757297%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ep\u0026lt;0.01; R=0.69\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.113671274961597%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eIGF -1 vs ADMA\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.113671274961597%\" valign=\"top\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.73425499231951%\" valign=\"top\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.038402457757297%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ep\u0026lt;0.01; R= -0.65\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.113671274961597%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eIGF-1 vs NO\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.113671274961597%\" valign=\"top\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.73425499231951%\" valign=\"top\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.038402457757297%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ep\u0026lt;0.03; R= -0.67\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.113671274961597%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eIGF-1 vs NT-pro-BNP\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.113671274961597%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ep\u0026lt;0.02; R= -0.62\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.73425499231951%\" valign=\"top\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.038402457757297%\" valign=\"top\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.113671274961597%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eTOS/TOC vs NT-pro-BNP\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.113671274961597%\" valign=\"top\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.73425499231951%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ep\u0026lt;0.04; R=0.56\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.038402457757297%\" valign=\"top\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.113671274961597%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eTOS/TOC vs Lean mass\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.113671274961597%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ep\u0026lt;0.035; R= -0.52\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.73425499231951%\" valign=\"top\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.038402457757297%\" valign=\"top\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.113671274961597%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eTOS/TOC vs HDL\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.113671274961597%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ep\u0026lt;0.04; R= 0.49\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.73425499231951%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eNS\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.038402457757297%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eNS\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.113671274961597%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eTAS/TAC vs HDL\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.113671274961597%\" valign=\"top\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.73425499231951%\" valign=\"top\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.038402457757297%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ep\u0026lt;0.01; R= -0.72\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.113671274961597%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eTAS/TAC vs DNA/RNA\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.113671274961597%\" valign=\"top\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.73425499231951%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ep\u0026lt;0.02; R=0.49\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.038402457757297%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.113671274961597%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eNO vs Fat tissue\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.113671274961597%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ep\u0026lt;0.04; R=0.51\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.73425499231951%\" valign=\"top\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.038402457757297%\" valign=\"top\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.113671274961597%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eNO vs TG\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.113671274961597%\" valign=\"top\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.73425499231951%\" valign=\"top\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.038402457757297%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ep\u0026lt;0.004; R=0.67\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.113671274961597%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eNT-pro-BNP vs cholesterol\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.113671274961597%\" valign=\"top\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.73425499231951%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ep\u0026lt;0.01; R= -0.70\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.038402457757297%\" valign=\"top\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.113671274961597%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eNT-pro-BNP vs LDL\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.113671274961597%\" valign=\"top\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.73425499231951%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ep\u0026lt;0.001; R= -0.84\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.038402457757297%\" valign=\"top\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.113671274961597%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eET-1 vs Total mass\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.113671274961597%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ep\u0026lt;0.05; R= -0.53\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.73425499231951%\" valign=\"top\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.038402457757297%\" valign=\"top\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.113671274961597%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eET-1 vs Tissue mass\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.113671274961597%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ep\u0026lt;0.05; R= -0.51\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.73425499231951%\" valign=\"top\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.038402457757297%\" valign=\"top\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.113671274961597%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eET-1 vs Lean mass\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.113671274961597%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ep\u0026lt;0.05; R= -0.55\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.73425499231951%\" valign=\"top\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.038402457757297%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ep\u0026lt;0.001; R= -0.81\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.113671274961597%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eET-1 vs BMC\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.113671274961597%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ep\u0026lt;0.01; R= -0.51\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.73425499231951%\" valign=\"top\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.038402457757297%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ep\u0026lt;0.0001; R= -0.84\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.113671274961597%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eET-1 vs BMD\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.113671274961597%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ep\u0026lt;0.01; R= -0.61\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.73425499231951%\" valign=\"top\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.038402457757297%\" valign=\"top\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.113671274961597%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eET-1 vs Ca\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.113671274961597%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ep\u0026lt;0.03; R= -0.65\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.73425499231951%\" valign=\"top\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.038402457757297%\" valign=\"top\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.113671274961597%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eADMA vs Total mass\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.113671274961597%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ep\u0026lt;0.02; R=0.54\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.73425499231951%\" valign=\"top\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.038402457757297%\" valign=\"top\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.113671274961597%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eADMA vs Tissue mass\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.113671274961597%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ep\u0026lt;0.02; R=0.53\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.73425499231951%\" valign=\"top\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.038402457757297%\" valign=\"top\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.113671274961597%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eADMA vs Lean mass\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.113671274961597%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ep\u0026lt;0.04; R=0.49\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.73425499231951%\" valign=\"top\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.038402457757297%\" valign=\"top\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.113671274961597%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eADMA vs Fat tissue\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.113671274961597%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ep\u0026lt;0.03; R=0.52\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.73425499231951%\" valign=\"top\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.038402457757297%\" valign=\"top\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.113671274961597%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eADMA vs BMI\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.113671274961597%\" valign=\"top\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.73425499231951%\" valign=\"top\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.038402457757297%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ep\u0026lt;0.02; R=0.64\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations:\u0026nbsp;\u003cstrong\u003eIGF-1\u003c/strong\u003e: insulin like growth factor type 1; \u003cstrong\u003eET-1\u003c/strong\u003e: endothelin 1; \u003cstrong\u003eADMA\u003c/strong\u003e: asymmetric dimethylarginine;\u0026nbsp;\u003cstrong\u003eNO\u003c/strong\u003e: nitric oxide;\u0026nbsp;\u003cstrong\u003eTAS\u003c/strong\u003e: total antioxidant status;\u0026nbsp;\u003cstrong\u003eTAC\u003c/strong\u003e: total antioxidant capacity;\u0026nbsp;\u003cstrong\u003eTOS\u003c/strong\u003e: total oxidant status;\u0026nbsp;\u003cstrong\u003eTOC\u003c/strong\u003e: total oxidant capacity;\u0026nbsp;\u003cstrong\u003eNT-pro-BNP\u003c/strong\u003e: N-terminal fragment of the pro brain natriuretic peptide;\u0026nbsp;\u003cstrong\u003eCa\u003c/strong\u003e: calcium;\u0026nbsp;\u003cstrong\u003eHDL\u003c/strong\u003e: high density lipoprotein;\u0026nbsp;\u003cstrong\u003eDNA\u003c/strong\u003e:\u0026nbsp;deoxyribonucleic acid\u003cstrong\u003e; RNA:\u0026nbsp;\u003c/strong\u003eribonucleic acid; \u003cstrong\u003eTG\u003c/strong\u003e:\u0026nbsp;triglycerides; \u003cstrong\u003eBMC\u003c/strong\u003e:\u0026nbsp;bone mineral content;\u0026nbsp;\u003cstrong\u003eBMD\u003c/strong\u003e:\u0026nbsp;bone mineral density;\u0026nbsp;\u003cstrong\u003eBMI\u003c/strong\u003e: body mass index.\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion ","content":"\u003cp\u003ePrevious observations have indicated that untreated AO-GHD is associated with increased mortality among patients with pituitary insufficiency compared to the general population. This increased mortality is particularly notable in female patients and is predominantly due to cardiovascular diseases (28). Nonetheless, it has been noted that rhGH therapy ameliorates multiple cardiometabolic risk factors, encompassing lipid abnormalities, endothelial dysfunction, atherosclerosis and indicators of cardiovascular inflammation such as adipokine profile or OS status (29,30). Furthermore, patients with GHD present a clinical phenotype that is characterized by increased fat mass, predominantly visceral fat, and reduced lean body mass, what is connected to higher cardiovascular risk (31,32). Fat tissue is commonly linked to a persistent, low-level inflammation marked by increased concentrations of inflammatory markers and cytokines (33). Due to this inflammation, adipocytes secrete ROS, exacerbating the inflammatory condition. This interaction between ROS and inflammation elevates OS levels and amplifies the risk of cardiovascular diseases (34). Accordingly, OS plays a crucial role in the development of cardiovascular diseases and its related complications (35).OS arises through the increased generation of ROS, including free radicals, surpassing its antioxidant capacity (36). Moreover, an important, unconventional cardiovascular risk factor involves high levels of ADMA, a strong inhibitor of NO synthase leading to dysfunction of the vascular endothelium (22). Elevated concentrations of ADMA concentrations are associated with increased vascular resistance, higher blood pressure, and the initiation of several mechanisms that promote atherosclerosis (37-39).\u003c/p\u003e\n\u003cp\u003eFollowing rhGH therapy in the study group, a clinically significant increase in IGF-1 concentration was observed after 6 and 12 months compared to the baseline value (p=0.0003, p=0.000; respectively). There were no significant differences in IGF-1 concentrations observed at 6 months compared to 12 months of therapy (p=0.15). The statistically significant increase in IGF-1 concentration observed during the therapy were attributed to the individual adjustment of rhGH dosage aimed at achieving optimal treatment outcomes. The initial assessment occurred 30 days after initiating the starting dose, followed by subsequent assessments every 6 months. In the opposition to our study, other researchers have observed higher IGF-1 concentrations in individuals with GHD only after one year (40,41). The study results indicate that IGF-1 plays a specialized role in the complex mechanisms underlying cardiovascular function. The rhGH treatment, through its increase in IGF-1 levels, has the potential to influence the reduction of cardiovascular risk and, consequently, mortality.\u003c/p\u003e\n\u003cp\u003eEmerging evidence suggests that ET-1 and related peptides play a significant prognostic role in coronary artery disease, hypertension, and heart failure (18,42,43). Furthermore, ET-1 has been investigated as both a predictor and prognostic marker in cardiovascular events, often associated with cardiac remodeling such as increased left atrial diameter and left ventricular mass (44). Additionally, NO functions as a crucial vasodilator, promoting blood vessel dilation by relaxing smooth muscle cells in the vessel walls (45). The balance between ET-1 and NO is crucial for regulating vascular tone and maintaining vascular stability. Any disruption in this balance can lead to various cardiovascular conditions (42,46). Research has also explored the relationship between ET-1 levels and mortality in the general population (47). Additionally, there are reports indicating that intravenously administered ET-1 in healthy men inhibits the increase in GH levels stimulated by growth hormone-releasing hormone (48). Our study results unequivocally demonstrated a significantly lower concentration of ET-1 after 12 months of therapy in the GHD group compared to baseline values (p=0.0007). This finding suggests a potential link to reduced cardiovascular risk in these patients. We didn’t note significant differences of ET-1 concentrations after six months therapy, what may be associated with individualizing the dosage of the medication. \u003c/p\u003e\n\u003cp\u003eADMA arises from the irreversible methylation of arginine residues and acts as an independent risk factor for cardiovascular diseases (49,50). ADMA has the ability to act as a competitive inhibitor of NO synthase enzymes and contributes to the development and advancement of microvascular complications by impacting endothelial cell function, OS induced damage, inflammation, and fibrosis (51,52). In the examined group of AO-GHD, we observed a statistically significant lower concentration of ADMA after just 6 months, with a declining trend persisting at the 12-month mark of therapy compared to the baseline value (p=0.01; p=0.01 respectively). Our study results contradict previous observations, which showed a significant reduction in endothelial damage marker concentrations only after 12 months of therapy in both children and adults (53). \u003c/p\u003e\n\u003cp\u003eThe pathogenesis of circulatory diseases is increasingly being attributed to OS, particularly as cardiovascular risk factors can also trigger redox imbalance. Experimental study conducted in both the CO-GHD and AO-GHD groups indicate a close association between pituitary somatotropin deficiency and increased OS status (54). OS occurs when the body produces more ROS, such as free radicals, than it can neutralize with its antioxidant system (55,56). This imbalance can manifest through processes such as lipid peroxidation, oxidation of protein thiol and amino groups, and the production of superoxide anions. These mechanisms trigger the activation of blood platelets and can result in thrombosis, vascular remodeling, vasoconstriction, and inflammatory responses (57). \u003c/p\u003e\n\u003cp\u003ePatients diagnosed with AO-GHD are characterized by elevated OS (58). In our study group, we observed significantly decreased TOC concentrations after 6 and 12 months of therapy (p=0.2 vs p=0.04, respectively). Furthermore, in the AO-GHD group, IGF-1 demonstrated a negative correlation with TOS/TOC (p\u0026lt;0.006; R=-0.73), as well as with NT-pro-BNP concentration (p\u0026lt;0.02; R=-0.62) initially. IGF-1 can influence this process through various mechanisms, including the regulation of antioxidant enzyme expression such as superoxide dismutase and catalase, which help mitigate OS by neutralizing ROS (59,60).\u003c/p\u003e\n\u003cp\u003eConcurrently, GHD can decrease the activity of the antioxidant system, impairing the ability to neutralize ROS (61). This decline may be due to reduced levels of antioxidants or diminished antioxidant effectiveness. In the AO-GHD group, IGF-1 initially showed a moderate positive correlation with TAS/TAC (p\u0026lt;0.001; R=0.83). Our findings align with those of Mohn et al., who reported an increase in TAC after one year of rhGH therapy (62). These findings suggest that rhGH treatment, and consequently the normalization of IGF-1 levels, may have a beneficial effect in reducing OS by enhancing antioxidant levels, potentially lowering cardiovascular risk. \u003c/p\u003e\n\u003cp\u003eThe connections between ADMA and TAS capacity is intricate and multifaceted. ADMA-induced endothelial dysfunction and OS can diminish TAS capacity by impairing the activity of antioxidant enzymes and depleting non-enzymatic antioxidants. Conversely, antioxidants can mitigate ADMA's detrimental effects by scavenging ROS and restoring endothelial function (63). In the treated group, we observed a positive correlation between ADMA and TAS capacity (p=0.02; R= 0.5). Furthermore, there was a moderate negative correlation between IGF-1 levels and ADMA concentration after 12 months of rhGH therapy (p\u0026lt;0.01; R=-0.65). Additionally, we noted a moderate positive correlation between IGF-1 and HDL concentration (p\u0026lt;0.01, R=0.77), as well as between TOS and HDL concentration (p=0.04; R=0.49).\u003c/p\u003e\n\u003cp\u003eHigh-density lipoprotein particles contribute to reducing OS, which partially supports their role in preventing atherosclerosis (64). HDL contains enzymes such as paraoxonase-1 (PON1), which help break down lipid peroxides, thereby protecting lipids from oxidation (65). However, levels of HDL cholesterol and its functional effectiveness can differ substantially, so that raising HDL cholesterol levels might not improve its functional capabilities, particularly in scenarios where oxidative changes to HDL cause it to dysfunction (66). Studies have shown that there is an inverse correlation between HDL levels and TOS/TOC. Higher HDL levels are typically associated with lower TOS levels, indicating better protection against OS (67). However, in pathological conditions such as atherosclerosis, diabetes or chronic inflammatory states, this correlation may be disrupted (68-70). Oxidative modifications in HDL molecules can lead to the loss of their protective properties and even result in pro-inflammatory and pro-atherogenic effects. In the conducted study, a statistically significant positive correlation was observed between the baseline concentration of HDL and TOS/TOC (p\u0026lt;0.04, R=0.49). Additionally, a statistically significant negative correlation was observed between the concentration of HDL and TAS/TAC after 12 months of rhGH substitution therapy (p\u0026lt;0.01; R=-0.72). The obtained research results suggest that in the examined group of patients with AO-GHD in a state of elevated OS due to GHD, the observed increased levels of HDL do not fulfill their protective function. Moreover, our study results suggest that rhGH substitution therapy may influence the oxidative balance of the body, leading to a reduction in the TAS/TAC status. As a result, lower TAS/TAC levels may be associated with elevated levels of HDL. This could arise from various mechanisms, such as changes in lipid metabolism, action on oxidative signaling pathways, or other biological interactions that affect HDL levels. Levels of HDL cholesterol do not forecast the composition or function, hence evaluating the quality rather than merely the quantity of HDL cholesterol is crucial for assessing the risk of cardiovascular diseases, especially in the AO-GHD patients group. \u003c/p\u003e\n\u003cp\u003eThe relationship between NO and GHD is complex and multifaceted, given their significant roles in diverse physiological functions. In individuals with GHD, alterations in NO levels or pathways may influence vascular function, potentially heightening cardiovascular risk. Conversely, GHD can result in decreased NO production, affecting endothelial function (71). In our study, a statistically significant negative correlation between IGF-1 and NO was observed after 12 months of treatment (p\u0026lt;0.03; R= -0.67). Our findings suggest that rhGH replacement therapy in GHD patients has improved endothelial function and NO levels, potentially reducing cardiovascular risk.\u003c/p\u003e\n\u003cp\u003eGH significantly influences the structure, proportions, and composition of body tissues (31). GH affects body composition primarily through its lipolytic and protein synthesis-enhancing actions, with its anti-natriuretic function also being significant. Growth hormone exhibits both direct and indirect lipolytic effects, including increased sensitivity to other hormones such as adrenaline or testosterone Most data indicate that this activity plays a crucial role in reducing fat tissue during GH replacement therapy (72-74). Another important effect of GH action is the increase in protein synthesis (75). In adults with a GHD, attention is primarily drawn to increased fat tissue mass, mainly visceral fat, and a decrease in fat-free mass (76,77). Changes in body composition can therefore lead to reduced physical performance, worsened well-being, as well as being a significant risk factor for cardiovascular diseases. Currently, it is believed that GH replacement therapy leads to beneficial changes in body composition. The most commonly described outcomes include a reduction in fat tissue mass, particularly visceral fat, an increase in fat-free mass, muscle mass and total mass. For example, studies by Gertner et al. showed an increase in fat-free mass and a decrease in fat tissue mass by several kilograms on average after 12 months of GH therapy (78). Long-term analysis of the consequences of GH administration indicates that changes in fat tissue and fat-free mass occur within the first 6 months of replacement therapy and persist during further treatment (79,80). Johansson et al. have noted a slight increase in fat tissue mass after a longer period of rhGH use compared to the first 6 months, but its total mass remained significantly lower after 2 and 3 years of treatment compared to baseline values (81). Generally, during rhGH substitution, the average body mass does not deviate significantly from the pre-treatment body mass, as the increase in fat-free mass is accompanied by a decrease in fat tissue mass, as well demonstrated in our study based on the evaluation of weight at baseline and after 6 and 12 months of therapy (p=0.72, p=0.51, respectively) (81, 82). The beneficial effects of GH on total body fat and its distribution have been examined in our study by means of DEXA. In the examined group of patients, we observed a statistically significant decrease in fat tissue content after just 6 months of rhGH replacement therapy, with this trend persisting after 12 months, consistent with previous observations (p=0.006; p=0.04; respectively). Furthermore, ET-1 displayed a moderate negative correlation with tissue mass (p\u0026lt;0.05; R=-0.51), BMC ( p\u0026lt;0.01; R=-0.51), total mass ( p\u0026lt;0.05; R=-0.53) and lean mass (p\u0026lt;0.05; R=-0.55). The observed correlations above suggest that under the influence of rhGH treatment and consequently the increase in IGF-1 and its positive correlation with tissue mass, total mass, and lean mass, there is a reduction in cardiovascular risk expressed by a decrease in ET-1 levels. Moreover, previous observation indicate that the increase in BMD under the influence of ongoing rhGH replacement therapy occurs after approximately 18 months and is initially preceded by a decrease in BMD, attributed to an increase in the bone remodeling process (83). This could potentially explain why we did not observe statistically significant changes in BMD values in the study group. However, we demonstrated a negative correlation between BMD and ET-1 concentration (p\u0026lt;0.01; R=-0.61). Our results suggesting a direct relationship between ET-1, not only on cardiovascular risk, but also on bone metabolism.\u003c/p\u003e\n\u003cp\u003eGH directly regulates glucose homeostasis by inducing glycogenolysis, gluconeogenesis, and lipolysis, and by promoting IR, while indirectly through the production of IGF-I (84). Moreover, its primary function involves stimulating lipolysis, supplying free fatty acids to shift metabolism from glucose and proteins to lipid utilization (85). Additionally, it's commonly observed that individuals who suffer from GHD are prone to low blood sugar levels, a condition known as hypoglycemia, which is notably prevalent during their early years (86). However, GH also plays a role in fat metabolism by encouraging the breakdown of fat stores. First 6 months of GH replacement is connected with decreases insulin sensitivity, and after this time insulin sensitivity returns toward baseline values (87). Following decreased insulin sensitivity, a compensatory increase in insulin secretion is typically observed. Additionally, GH also acts as a potent growth factor for β-cell proliferation and insulin secretion (88). Consequently, people with GHD often accumulate higher amounts of body fat, leading to obesity. Normally, obesity is linked to an increased risk of developing IR, a precursor to diabetes type 2 (86). A multitude of studies, encompassing cross-sectional and prospective research, meta-analyses, and systematic reviews, provide strong evidence that IR alone is a cardiovascular risk factor across diverse population groups (89,90). On the other hand, IR can impact the secretion of GH as well (91). Elevated insulin levels, typically linked to IR, may suppress GH release from the pituitary gland (92). This suppression could play a role in the emergence of GHD in certain individuals experiencing IR. The rhGH replacement therapy in individuals with GHD has been shown to improve insulin sensitivity and glucose metabolism (93). In our study, the VAI index was used to assess IR. The observations conducted did not show any statistically significant differences in the outcomes of rhGH treatment after 6 and 12 months. Furthermore, in the examined group of patients, a statistically significant negative correlation was found between the VAI value and the HDL concentration, which may indicate the adverse effect of abdominal obesity on HDL cholesterol levels, potentially increasing the risk of cardiovascular diseases in patients with AO-GHD. The diversity within the patients cohorts, varying doses of rhGH, comorbidities and short duration of observation may be account for the obtained research findings. Long-term longitudinal studies, focusing on glucose homeostasis as the primary outcome, are still necessary to better elucidate the true metabolic impact of rhGH replacement therapy in AO-GHD. Despite taking various precautions, our study may still be influenced by certain biases, and we acknowledge several key limitations. The sample size of the study group is relatively small, limiting the statistical power of our findings. Therefore, it is important to replicate our results in a larger and more diverse population to better understand the roles of ET-1, ADMA and OS in AO-GHD and their potential impact on the development of cardiovascular complications. Moreover, further research is needed to explore the relationships between markers such as ET-1, ADMA, OS and cardiovascular risk in adults with GHD. This will enable the development of personalized therapeutic approaches, potentially including long-term GH replacement therapy.\u003c/p\u003e"},{"header":"Conclusions ","content":"\u003cp\u003eOur study highlights the potential benefits of individually dosed rhGH therapy in individuals with AO-GHD. After six months of treatment, patients experienced a reduction in the risk of cardiovascular diseases and mortality, suggesting a positive impact on overall health outcomes. Furthermore, our findings underscore the utility of measuring ET-1, ADMA and OS levels in serum as potential indicators of treatment efficacy in AO-GHD patients. These biomarkers could aid in the development of personalized treatment regimens and the identification of individuals who may benefit from primary prevention strategies.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research was funded by internal financing of the Medical University of Bialystok, grand number (APK.002.393.2021).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConceptualization, M.K., A.B., A.W., D.J., A.PK., and A.J.K.; methodology, M.K., M.Z., A.W., A.PK., K.S., A.A., and A.B.; software, A.B., A.W., D.J. and M.K.; validation, M.K., A.PK., M.Z. and A.B.; formal analysis, M.K., A.B. and A.PK.; investigation, M.K. and A.PK.; resources, M.K., A.B., A.W., and M.Z.; data curation, M.K., K.S., A.A., D.J., A.B., and A.PK.; writing\u0026mdash;original draft preparation, M.K., A.B., and A.PK.; writing\u0026mdash;review and editing, M.K., A.B., A.A., K.S., A.W., and A.J.K.; visualization, M.K. and A.B.; supervision, A.W., M.K., A.J.K., and A.PK.; project administration, M.K. and A.B.; funding acquisition, M.K., A.J.K., and A.P-K.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDisclosures\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have nothing to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eI kindly inform you that the datasets analyzed during the current study are available from the corresponding author upon reasonable request.\u003c/p\u003e\u003cp\u003eI hereby confirm that all research was conducted in accordance with the relevant guidelines and regulations. I declare that informed consent was obtained from all participants and/or their legal guardians.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe study was carried out in compliance with the Declaration of Helsinki.\u003c/p\u003e\n\u003cp\u003eFurthermore, pursuant to Article 29(2) and (14) of the Act of December 5, 1996, on the Professions of Doctor and Dentist (Journal of Laws of 2020, item 514, as amended), I confirm that the experimental protocol was approved by the designated institution\u0026mdash;the Bioethics Committee of the Medical University of Bialystok (Resolution No: APK.O 02.393.2021).\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eAguiar-Oliveira, M. H., \u0026amp; Bartke, A. (2019). Growth Hormone Deficiency: Health and Longevity. 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Ann Pediatr Endocrinol Metab. 2017;22(3):145\u0026ndash;152. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.6065/apem.2017.22.3.145\u003c/span\u003e\u003cspan address=\"10.6065/apem.2017.22.3.145\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Epub 2017 Sep 28. PMID: 29025199; PMCID: PMC5642081.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePellegrin, M. C., et al. (2019). Glucose Metabolism Evaluated by Glycated Hemoglobin and Insulin Sensitivity Indices in Children Treated with Recombinant Human Growth Hormone. Journal of clinical research in pediatric endocrinology, 11(4), 350\u0026ndash;357. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.4274/jcrpe.galenos.2019.2019.0281\u003c/span\u003e\u003cspan address=\"10.4274/jcrpe.galenos.2019.2019.0281\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"growth hormone, growth hormone deficiency, endothelin-1, oxidative stress, asymmetric dimethyl arginine","lastPublishedDoi":"10.21203/rs.3.rs-4883080/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4883080/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eAdult growth hormone deficiency (AO-GHD) is associated with increased mortality due to a higher risk of cardiovascular complications. Oxidative stress (OS) diminishes antioxidant capacity, leading to endothelial dysfunction and promoting thrombotic and inflammatory mechanisms. This increases the risk of cardiovascular diseases and metabolic disorders. Imbalances in the synthesis or signaling of endothelin-1 (ET-1) and nitric oxide (NO) are linked to hypertension, atherosclerosis, and heart failure. Additionally, elevated levels of asymmetric dimethylarginine (ADMA), an inhibitor of nitric oxide synthase, contribute to vascular endothelial dysfunction, increased vascular tension, higher blood pressure, and the activation of pro-atherogenic mechanisms. This preliminary study aims to investigate the cardiovascular effects of recombinant human growth hormone (rhGH) therapy in AO-GHD. The findings of this research suggest a potential association between rhGH replacement therapy in AO-GHD patients and a reduction in cardiovascular risk through its impact on ET-1, NO, ADMA concentrations, and OS status markers. These results have the potential to inform the optimization of rhGH replacement therapy protocols, thereby exerting a broader influence on the cardiovascular well-being of individuals undergoing such interventions.\u003c/p\u003e","manuscriptTitle":"Cardiovascular Effects of Growth Hormone: Preliminary Study on Oxidative Stress in Adults with Growth Hormone Deficiency","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-09-16 12:57:47","doi":"10.21203/rs.3.rs-4883080/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"eb4f8345-0f4f-48b2-a24a-3f58397b60c7","owner":[],"postedDate":"September 16th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":37631258,"name":"Health sciences/Cardiology"},{"id":37631259,"name":"Health sciences/Endocrinology"},{"id":37631260,"name":"Health sciences/Health care"}],"tags":[],"updatedAt":"2024-12-16T06:24:31+00:00","versionOfRecord":[],"versionCreatedAt":"2024-09-16 12:57:47","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4883080","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4883080","identity":"rs-4883080","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}