Potential Cardiovascular and Metabolic Beneficial Effects of ?-3 PUFA in Male Obesity Secondary Hypogonadism Syndrome.
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ABSTRACT:
SUBMITTER: Noce A
PROVIDER: S-EPMC7551945 | biostudies-literature | 2020 Aug
REPOSITORIES: biostudies-literature
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Potential Cardiovascular and Metabolic Beneficial Effects of ω-3 PUFA in Male Obesity Secondary Hypogonadism Syndrome.
Noce Annalisa A Marrone Giulia G Di Daniele Francesca F Di Lauro Manuela M Pietroboni Zaitseva Anna A Wilson Jones Georgia G De Lorenzo Antonino A Di Daniele Nicola N
Nutrients 20200820 9
Long-chain ω-3 polyunsaturated fatty acids (PUFAs) are fundamental biocomponents of lipids and cell membranes. They are involved in the maintenance of cellular homeostasis and they are able to exert anti-inflammatory and cardioprotective actions. Thanks to their potential beneficial effects on the cardiovascular system, metabolic axis and body composition, we have examined their action in subjects affected by male obesity secondary hypogonadism (MOSH) syndrome. MOSH syndrome is characterized by ...[more]
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Project description:Male hypogonadism associated with obesity is a very prevalent condition and is increasing in parallel with the epidemic prevalence of obesity. Low testosterone levels promote higher fat mass with reduced lean mass. Male hypogonadism is related to an increase in associated cardiometabolic complications, such as hypertension, type 2 diabetes mellitus, the metabolic syndrome, and cardiovascular disease. Its influence as a comorbidity of obesity is becoming more evident and should be evaluated and treated in at-risk patients. Mechanisms involved in this relationship include body composition changes, the presence of adipokines, insulin resistance, and other factors, some of which are still unknown. Weight loss and treatment to replace testosterone levels improve the metabolic profile and quality of life in patients with obesity and hypogonadism; these beneficial effects depend on treatment modality and duration of therapy. The use of testosterone replacement therapy may be indicated, as it has not been shown to increase cardiovascular risk, and retrospective studies suggest a reduction in events in men with metabolic syndrome and type 2 diabetes.
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Project description:Male hypogonadism is a disorder characterised by low levels of the hormone testosterone. At beginning subjects with low levels of testosterone do not show insulin resistance (insulin-sensitive patients), which develops over time (insulin-resistance patients). To analyse the metabolic alterations mainly related to decreased testosterone, we performed metabolomics investigations on the plasma of males with hypogonadism who showed normal insulin levels. Plasma from patients with low testosterone (<8?nmol/l) and homeostatic model assessment for insulin-resistance-index (HOMAi)?<?2.5, as well as matched controls, was analysed by UHPLC and mass spectrometry. Then metabolites were then subjected to multivariate statistical analysis and grouped by metabolic pathways. Glycolysis was not altered, as expected for the presence of insulin activity, but imbalances in several other pathways were found, such as the pentose phosphate pathway (PPP), glycerol shuttle, malate shuttle, Krebs cycle (TCA) and lipid metabolism. The PPP was significantly upregulated. Moreover, while the first steps of the Krebs cycle were downregulated, 2-oxoglutarate was replenished via glutaminolysis. Since glutaminolysis leads to an activation of the malate aspartate cycle, greater amounts of NADH and ATP with respect to the control were recorded. The activation of the glycerol shuttle was also recorded, with consequent lower triglyceride production and downregulation of beta-oxidation. This explained the moderately increased dyslipidaemia, as well as the mild increase in body mass index (BMI) observed in insulin-sensitive hypogonadism. Finally, a significant decrease in carnosine was recorded, explaining the muscle weakness commonly observed.
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Project description:Abstract Introduction: Excess aromatase activity in adipose tissue has been linked to increased conversion of testosterone (T) to estradiol, resulting in high estradiol levels and suppressing gonadotropins. In obese men, this can cause obesity-associated hypogonadotropic hypogonadism (OHH) with decreased fertility. T replacement therapies frequently result in negative feedback suppression of follicle stimulating hormone (FSH) and luteinizing hormone (LH), further impairing semen fertility. Aromatase inhibition avoids this complication, restoring T without impairing fertility parameters, by reducing inhibitory effects of excess estradiol on LH and FSH. We report the impact of a weekly (QW) oral aromatase inhibitor on hormone levels and semen parameters in patients with OHH. Methods: A 24-wk, multicenter, randomized, double-blind, placebo (PBO)-controlled phase IIb trial (NCT02730169) of 3 doses of leflutrozole QW in obese adult males (BMI 30-50 kg/m2) with morning serum T <300 ng/dL. Exclusion criteria: Type 1 or uncontrolled type 2 diabetes; clinically significant endocrinopathy; prostate disease; recently diagnosed cardiovascular conditions; treatment with confounding medications (including those affecting gonadotropin or T levels). Primary endpoint: normalization (300-1000 ng/dL) of serum T in >75% of patients by end of treatment (EOT) at Wk 24. Secondary endpoints included gonadotropin and estradiol levels; a substudy assessed change in semen parameters. Safety was monitored from 1st dose to 90 days after EOT. Results: 271 patients (means: age 50.9 (±8.7) yrs, BMI 38.1 (±5.3) kg/m2, T 231.1 (±54.6) ng/dL) were randomized to 3 doses of leflutrozole or PBO. All 3 leflutrozole-treated arms met the primary endpoint with normalized T levels by EOT in >75% of patients vs 10% for PBO (p<0.001). Dose-dependent elevations in FSH and LH (p<0.001) and dose-dependent reductions in estradiol were observed at EOT. At Wks 12 and 20, numerical increases in sperm counts were observed in all 3 leflutrozole groups vs PBO, with statistically significant improvements (LS mean difference [95% CI]) in semen volume (1.37 [0.41, 2.34] ml, p=0.006, n=24), spermatozoa (270.084 [65.007, 475.161] x106/ejaculate, p=0.011, n=23), and total motile sperm count (127.711 [12.602, 242.819] 106/ejaculate, p=0.030, n=22) in leflutrozole highest dose group vs PBO. Leflutrozole was generally well tolerated; 24.7% of patients experienced related treatment-emergent adverse events (AEs). Of these, 3.0-7.5% of patients in the 3 leflutrozole dose groups experienced serious AEs, vs 5.2% of patients receiving PBO. Conclusions: In contrast to suppression of spermatogenesis seen with exogenous T therapy, leflutrozole restores normal endogenous physiologic T levels whilst increasing FSH/LH, with positive effects on semen fertility parameters in men with OHH. A 24-wk, blinded extension study is currently ongoing.
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Project description:Background and objectivesObesity and metabolic syndrome (MS) increase the risk of cardiovascular disease (CVD), chronic kidney disease (CKD), and all-cause mortality. Serum cystatin C (S-CysC), a marker of GFR, has been shown to be associated with CVD and CKD. This study was designed to elucidate the association of urinary CysC (U-CysC), a marker of renal tubular dysfunction, with CVD and CKD risk factors in patients with obesity and MS.Design, setting, participants, & measurementsThe U-CysC-creatinine ratio (UCCR) was examined in 343 Japanese obese outpatients enrolled in the multi-centered Japan Obesity and Metabolic Syndrome Study.ResultsUCCR was positively correlated with urine albumin-creatinine ratio (UACR) and S-CysC and negatively correlated with estimated GFR (eGFR). Among obese patients, UCCR was significantly higher in MS patients than in non-MS patients. UCCR had significant correlations with the number of components of MS and arterial stiffness, all of which are CVD predictors, similarly to UACR (P<0.05). Interestingly, diet- and exercise-induced weight reduction for 3 months significantly decreased only UCCR among all of the renal markers examined (P<0.01), in parallel with the decrease in BMI, HbA1c, and arterial stiffness, suggesting the beneficial effect of weight reduction on renal tubular dysfunction.ConclusionsThis study demonstrates that UCCR is significantly associated with renal dysfunction, the severity of MS, arterial stiffness, and weight change in obese patients. The data of this study suggest that U-CysC could serve as a CVD and CKD risk factor in patients with obesity and MS.
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Project description:Idiopathic hypogonadotropic hypogonadism (IHH) patients are characterized by the absence of puberty and varying degrees of deteriorated metabolic conditions. Osteocalcin (OC) could regulate testosterone secretion and energy metabolism, but it remains unknown whether such an effect exists in IHH patients. Our study is aimed to examine the relationship between serum OC levels with testosterone and its responsiveness to gonadotropin stimulation and metabolic profiles in male IHH patients. A total of 99 male patients aged 18-37 years and diagnosed with IHH were enrolled in the current study, and the relationships between OC and testicular volume, baseline total testosterone (TT), free testosterone (FT), and peak TT (Tmax) levels after human chorionic gonadotropin (hCG) stimulation, gonadotropin responsiveness index (GRI), which is calculated by dividing Tmax by testicular volume, as well as metabolic profiles, such as 2-h post-challenge glucose (2hPG) and fat percentage (fat%), were analyzed. The results showed that OC had an independent negative relationship with testicular volume (r = -0.253, P = 0.012) and a positive association with Tmax (r = 0.262, P = 0.014) after adjusting for confounders. In addition, OC was a major determinant of GRI (adjusted R 2 for the model = 0.164, P = 0.012), fat% (adjusted R 2 for the model = 0.100, P = 0.004), and 2hPG (adjusted R 2 for the model = 0.054, P = 0.013) in IHH patients. In conclusion, OC is associated with testosterone secretion upon gonadotropin stimulation, glucose metabolism, and fat mass variations in IHH. This study was registered at clinicaltrials.gov (NCT02310074).
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