Relationship between sex hormones, markers of adiposity and inflammation in male patients with severe obesity undergoing bariatric surgery

Abstract

Aim: In males, obesity is characterized by features resembling those observed during aging, such as hypogonadism and cytokines imbalance, yet at an early age. A direct connection between the low-grade inflammatory state and sex steroid abnormalities has been proposed to explain the development of these conditions in obesity.

Methods: We evaluated the relationship between sex hormones plasma levels and metabolic and inflammatory parameters in a cohort of patients with grade III obesity (n = 24, BMI 43.4 ± 8.5 kg/m²) undergoing bariatric surgery. Furthermore, we assessed the in vitro effects of testosterone exposure on the expression of markers of adiposity such as FABP-4, PPARγ, leptin, and adiponectin in human-derived adipocytes.

Results: A direct correlation was observed between BMI and hsCRP (P < 0.05), while testosterone plasma levels showed a statistically significant inverse correlation with hsCRP, but also with HOMA index, leptin, and von Willebrand factor concentrations (P < 0.05). In human-derived adipocytes, testosterone exposure promotes a reduction in the gene expression of adiposity markers, which is inhibited by co-exposure with the antiandrogen flutamide.

Conclusion: Our study shows a relationship between testosterone plasma levels and markers of inflammation in severe obesity, with testosterone exposure affecting adiposity biomarkers expression in humans. In light of these results, hypogonadism should be promptly identified in male patients with obesity and timely treated to reduce the burden of the disease.

Keywords

Obesity / testosterone / inflammation / hsCRP / adipocyte / cytokines

References

[1] Dandona P.Update: hypogonadotropic hypogonadism in type 2 diabetes and obesity.J Clin Endocrinol Metab2011;96:2643-51 PMCID:PMC3167667

[2] Di Vincenzo A,Vettor R.Obesity, male reproductive function and bariatric surgery.Front Endocrinol2018;9:769 PMCID:PMC6305362

[3] Di Vincenzo A,Bertoli E.Short-term effects of surgical weight loss after sleeve gastrectomy on sex steroids plasma levels and PSA concentration in men with severe obesity.Aging Male2020;23:464-8

[4] Bélanger C,Dupont P.Adipose tissue intracrinology: potential importance of local androgen/estrogen metabolism in the regulation of adiposity.Horm Metab Res2002;34:737-45

[5] Dhindsa S,Vora M,Chaudhuri A.Low estradiol concentrations in men with subnormal testosterone concentrations and type 2 diabetes.Diabetes Care2011;34:1854-9 PMCID:PMC3142021

[6] Yudkin JS,Emeis JJ.C-reactive protein in healthy subjects: associations with obesity, insulin resistance, and endothelial dysfunction: a potential role for cytokines originating from adipose tissue?.Arterioscler Thromb Vasc Biol1999;19:972-8

[7] Hotamisligil GS,Caro JF,Spiegelman BM.Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance.J Clin Invest1995;95:2409-15 PMCID:PMC295872

[8] Vettor R,Rossato M.Review article: adipocytokines and insulin resistance.Aliment Pharmacol Ther2005;22 Suppl 2:3-10

[9] Bobjer J,Tsatsanis C,Giwercman A.Negative association between testosterone concentration and inflammatory markers in young men: a nested cross-sectional study.PLoS One2013;8:e61466 PMCID:PMC3630214

[10] Maggio M,Ble A.Correlation between testosterone and the inflammatory marker soluble interleukin-6 receptor in older men.J Clin Endocrinol Metab2006;91:345-7

[11] Furuhashi M,Shimamoto K.Fatty acid-binding protein 4 (FABP4): pathophysiological insights and potent clinical biomarker of metabolic and cardiovascular diseases.Clin Med Insights Cardiol2014;8:23-33 PMCID:PMC4315049

[12] Ivanova EA,Melnichenko AA.Peroxisome proliferator-activated receptor (PPAR) gamma agonists as therapeutic agents for cardiovascular disorders: focus on atherosclerosis.Curr Pharm Des2017;23:1119-24

[13] Keating NL,Smith MR.Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer.J Clin Oncol2006;24:4448-56

[14] Vikan T,Njølstad I.Endogenous sex hormones and the prospective association with cardiovascular disease and mortality in men: the Tromsø Study.Eur J Endocrinol2009;161:435-42

[15] Di Lorenzo N,Batterham RL.Clinical practice guidelines of the European Association for Endoscopic Surgery (EAES) on bariatric surgery: update 2020 endorsed by IFSO-EC, EASO and ESPCOP.Surg Endosc2020;34:2332-58 PMCID:PMC7214495

[16] Di Vincenzo A,Crescenzi M,Vettor R.Dihydrotestosterone, and not testosterone, enhances the LPS-induced inflammatory cytokine gene expression in human adipocytes.Biomedicines2023;11:1194 PMCID:PMC10135847

[17] Sirdah MM,Al Laham NA.The reliability of the National Cholesterol Education Program's Adult Treatment Panel III (NCEP/ATP III) and the International Diabetes Federation (IDF) definitions in diagnosing metabolic syndrome (MetS) among Gaza Strip Palestinians.Diabetes Metab Syndr2012;6:4-8

[18] Woodhouse LJ,Bhasin M.Dose-dependent effects of testosterone on regional adipose tissue distribution in healthy young men.J Clin Endocrinol Metab2004;89:718-26

[19] Haider A,Doros G.Hypogonadal obese men with and without diabetes mellitus type 2 lose weight and show improvement in cardiovascular risk factors when treated with testosterone: an observational study.Obes Res Clin Pract2014;8:e339-49

[20] Yassin A,Haider KS.Testosterone therapy in men with hypogonadism prevents progression from prediabetes to type 2 diabetes: eight-year data from a registry study.Diabetes Care2019;42:1104-11

[21] Wittert G,Robledo KP.Testosterone treatment to prevent or revert type 2 diabetes in men enrolled in a lifestyle programme (T4DM): a randomised, double-blind, placebo-controlled, 2-year, phase 3b trial.Lancet Diabetes Endocrinol2021;9:32-45

[22] Haider KS,Saad F.Remission of type 2 diabetes following long-term treatment with injectable testosterone undecanoate in patients with hypogonadism and type 2 diabetes: 11-year data from a real-world registry study.Diabetes Obes Metab2020;22:2055-68 PMCID:PMC7689919

[23] Isidori AM,Strollo F.Leptin and androgens in male obesity: evidence for leptin contribution to reduced androgen levels.J Clin Endocrinol Metab1999;84:3673-80

[24] Jockenhövel F,Vogel E.Testosterone substitution normalizes elevated serum leptin levels in hypogonadal men.J Clin Endocrinol Metab1997;82:2510-3

[25] Zhang YX,Schoefl GI.Coronary C-reactive protein distribution: its relation to development of atherosclerosis.Atherosclerosis1999;145:375-9

[26] Kupelian V,Araujo AB,Clark RV.Association of sex hormones and C-reactive protein levels in men.Clin Endocrinol2010;72:527-33 PMCID:PMC2866020

[27] Kaplan SA,Lin J,Meehan AG.Elevated high sensitivity C-reactive protein levels in aging men with low testosterone.Aging Male2010;13:108-12

[28] Kalinchenko SY,Mskhalaya GJ,Giltay EJ.Effects of testosterone supplementation on markers of the metabolic syndrome and inflammation in hypogonadal men with the metabolic syndrome: the double-blinded placebo-controlled Moscow study.Clin Endocrinol2010;73:602-12.

[29] Saad F,Gooren L.Hypogonadal men with psoriasis benefit from long-term testosterone replacement therapy - a series of 15 case reports.Andrologia2016;48:341-6

[30] Nasser M,Saad F.Testosterone therapy in men with Crohn's disease improves the clinical course of the disease: data from long-term observational registry study.Horm Mol Biol Clin Investig2015;22:111-7.

[31] Spiel AO,Jilma B.von willebrand factor in cardiovascular disease: focus on acute coronary syndromes.Circulation2008;117:1449-59

[32] Michels A,Mewburn J.von willebrand factor is a critical mediator of deep vein thrombosis in a mouse model of diet-induced obesity.Arterioscler Thromb Vasc Biol2020;40:2860-74

[33] van Kesteren PJM,Lansink M.The effects of sex steroids on plasma levels of marker proteins of endothelial cell functioning.Thromb Haemost1998;79:1029-33.

[34] Alqahtani SA.Administration of testosterone improves the prothrombotic and antifibrinolytic parameters associated with its deficiency in an orchidectiomized rat model.Platelets2019;30:624-30

[35] Garvey WT,Brett EM.Reviewers of the AACE/ACE Obesity Clinical Practice GuidelinesAmerican association of clinical endocrinologists and american college of endocrinology comprehensive clinical practice guidelines for medical care of patients with obesity..Endocr Pract2016;22 Suppl 3:1-203

[36] Blonde L,Reddy SS.American association of clinical endocrinology clinical practice guideline: developing a diabetes mellitus comprehensive care plan-2022 update.Endocr Pract2022;28:923-1049 PMCID:PMC10200071