The role of SHBG and LPL gene polymorphism in the development of age-related hypogonadism in overweight men: Literature review

Merkhat Akkaliyev 1 * , Nurlan Aukenov 2, Meruyert Massabayeva 3, Bakytbek Apsalikov 4, Saule Rakhyzhanova 5, Muratkhan Kuderbaev 1
More Detail
1 Department of Surgery Disciplines, Semey Medical University, Semey, Kazakhstan
2 Department of Health and Human Resources, Ministry of Health of the Republic of Kazakhstan, Semey, Kazakhstan
3 Scientific-Research Laboratory Center, Semey Medical University, Semey, Kazakhstan
4 Department of Family Medicine, Semey Medical University, Semey, Kazakhstan
5 Department of Normal Physiology, Semey Medical University, Semey, Kazakhstan
* Corresponding Author
J CLIN MED KAZ, Volume 18, Issue 5, pp. 11-17.
OPEN ACCESS 1010 Views 586 Downloads
Download Full Text (PDF)


Testosterone is the main male hormone responsible for the formation and maintenance of male sex characteristics and the sexual performance of men. With age testosterone levels decrease which is a natural physiological process. But the timing of age-related hypogonadism progress has individual differences. Physiological processes occurring in the body of an aging man are due to genetic, population and individual features of genes and their mutations leading to genetic polymorphism. Gene polymorphism is represented mainly by single nucleotide substitutions that are SNP (single nucleotide polymorphism). Genes SHBG and LPL are important links in the synthesis and transport of testosterone in male body as well as in the development of androgen deficiency. This review discusses the role of polymorphic variants of SHBG and LPL genes in the early development of age-related hypogonadism in overweight men.


Akkaliyev M, Aukenov N, Massabayeva M, Apsalikov B, Rakhyzhanova S, Kuderbaev M. The role of SHBG and LPL gene polymorphism in the development of age-related hypogonadism in overweight men: Literature review. J CLIN MED KAZ. 2021;18(5):11-7.


  • Nassar, G. N., & Leslie, S. W. Physiology, Testosterone. StatPearls. 2019; 95(1): 122-131.
  • Pashkova E. YU., Rozhdestvenskaya O,A. Vozrastnoy androgennyi deficit u mujchin: etiologia, klinika, diagnostic, lechenie. Andrologia I genitalnaya hirurgia. Age-related androgenic deficiency in men: etiology, clinical presentation, diagnosis, treatment. Andrology and genital surgery. 2015;16(1): 95-101.
  • Tyuzikov I.A., Kalinchenko S.Yu., Vorslov L.O., Tishova Yu.A. Mesto androgenogo defisita v klinişeskom portrete sovremenogo urologişeskogo pasienta. Andrologia i genitalnaya hirurgia. The place of androgen deficiency in the clinical portrait of a modern urological patient. Andrology and Genital Surgery. 2013;14(3):48-57.
  • Lunenfeld, B., Mskhalaya, G., Zitzmann, M., Arver, S., Kalinchenko, S., Tishova, Y., & Morgentaler, A. Recommendations on the diagnosis, treatment and monitoring of hypogonadism in men. The Aging Male. 2015; 18(1): 5–15.
  • Venkatesan R, Viswanathan M. Obesity – Are we continuing to play the genetic “blame game”?. Advances in Genomics and Genetics. 2016; 6: 11-23
  • Beck, T., Shorter, T., & Brookes, A. J. GWAS Central: A comprehensive resource for the discovery and comparison of genotype and phenotype data from genome-wide association studies. Nucleic Acids Research. 2020; 48(D1): D933–D940
  • Avvakumov, G. V., Cherkasov, A., Muller, Y. A., & Hammond, G. L. Structural analyses of sex hormone-binding globulin reveal novel ligands and function. Molecular and Cellular Endocrinology . 2010; 1(16): 13–23.
  • Hammond, G. L. Diverse Roles for Sex Hormone-Binding Globulin in Reproduction. BIOLOGY OF REPRODUCTION. 2011; 85: 431–441.
  • Li, H., Pham, T., Mcwhinney, B. C., Ungerer, J. P., Pretorius, C. J., Richard, D. J., Mortimer, R. H., D’emden, M. C., & Richard, K. Sex Hormone Binding Globulin Modifies Testosterone Action and Metabolism in Prostate Cancer Cells. International Journal of Endocrinology. 2016; 10: 1-10.
  • Tint, A. N., Hoermann, R., Wong, H., Ekinci, E. I., MacIsaac, R. J., Jerums, G., Zajac, J. D., & Grossmann, M. Association of sex hormone-binding globulin and free testosterone with mortality in men with type 2 diabetes mellitus. European Journal of Endocrinology. 2016; 174(1): 59–68.
  • Firtser, S., Juonala, M., Magnussen, C. G., Jula, A., Loo, B. M., Marniemi, J. et al. Relation of total and free testosterone and sex hormone-binding globulin with cardiovascular risk factors in men aged 24-45 years. The Cardiovascular Risk in Young Finns Study. Atherosclerosis. 2012; 222(1): 257–262.
  • Xita, N., & Tsatsoulis, A. Genetic variants of sex hormone-binding globulin and their biological consequences. Mol. Cell. Endocrinol. 2010; 316( 1): 60–65.
  • Fui, M. N. T., Dupuis, P., & Grossmann, M. Lowered testosterone in male obesity: Mechanisms, morbidity and management. Asian J Androl. 2014; 16( 2): 223–231.
  • Carrageta, D. F., Oliveira, P. F., Alves, M. G., & Monteiro, M. P. Obesity and male hypogonadism: Tales of a vicious cycle. Obesity Reviews. 2019; 20(8): 1148–1158.
  • Kelly D.M., Jones T.H. Testosterone and obesity. Obesity Reviews. 2015; 16(7): 581-606 doi: 10.1111/obr.12282 PMID: 25982085
  • Fernandez, C. J., Chacko, E. C., & Pappachan, J. M. Male obesity-related secondary hypogonadism – pathophysiology, clinical implications and Management. In European Endocrinology . 2019; 15( 2): 83–90.
  • Aguirre, L. E., Colleluori, G., Fowler, K. E., Jan, I. Z., Villareal, K., Qualls, C., Robbins, D., Villareal, D. T., & Armamento-Villareal, R. High aromatase activity in hypogonadal men is associated with higher spine bone mineral density, increased truncal fat and reduced lean mass. European Journal of Endocrinology. 2015; 173(2): 167–174.
  • Merlotti, D., Gennari, L., Stolakis, K., & Nuti, R. (2011). Aromatase Activity and Bone Loss in Men. Journal of Osteoporosis. 2011; 1–11.
  • Colleluori, G., Chen, R., Turin, C. G., Vigevano, F. et al. Aromatase Inhibitors Plus Weight Loss Improves the Hormonal Profile of Obese Hypogonadal Men Without Causing Major Side Effects. Frontiers in Endocrinology. 2020; 11: 277.
  • Haring, R., Baumeister, S. E., Völzke, H., Dörr, M., Felix, S. B., Kroemer, H. K., Nauck, M., & Wallaschofski, H. Prospective association of low total testosterone concentrations with an adverse lipid profile and increased incident dyslipidemia. European Journal of Preventive Cardiology. 2011; 18(1): 86–96.
  • Kersten Sander. Physiological regulation of lipoprotein lipase. Biochim Biophys Acta. 2014; 1841(7): 919-933. doi: 10.1016/j.bbalip.2014.03.013.
  • Andrade Junior, M. C. de. Lipoprotein Lipase: A General Review. Insights in Enzyme Research. 2018; 02(01): 1-13.
  • Davies, B. S. J., Beigneux, A. P., Fong, L. G., & Young, S. G. (2012). New wrinkles in lipoprotein lipase biology. Current Opinion in Lipidology. 2012; 23( 1): 35–42). NIH Public Access.
  • Fui, M. N. T., Dupuis, P., & Grossmann, M. Lowered testosterone in male obesity: Mechanisms, morbidity and management. Asian J Androl. 2014; 16( 2): 223–231).
  • Lee, M. J., Chien, K. L., Chen, M. F., Stephenson, D. A., & Su, T. C. Overweight modulates APOE and APOA5 alleles on the risk of severe hypertriglyceridemia. Clinica Chimica Acta. 2013; 416: 31–35.
  • Adieva M.K., Aukenov N.E., Kazymov M.S., Nurzhanova A.E., Slamkhanova N.S., Masabaeva M.R. Influence of LPL gene polymorphism on insulin resistance among adolescents from Semey, East Kazakhstan region. VESTNİK KAZAHSKOGO NASİONALNOGO MEDİSİNSKOGO UNİVERSİTETA. 2021; 2–1: 372–376.
  • Das, B., Pawar, N., Saini, D., & Seshadri M. Genetic association study of selected candidate genes (ApoB, LPL, Leptin) and telomere length in obese and hypertensive individuals. BMC Medical Genetics. 2009; 10(1): 99.
  • Hamosh, M., & Hamosh, P. Lipoproteins and Lipoprotein Lipase. Comprehensive Physiology . 2011; pp. 387–418. John Wiley & Sons, Inc.
  • Ohlsson, C., Wallaschofski, H., Lunetta, K. L., Stolk, L., Perry, J. R. B., Koster, A. et al. Genetic Determinants of Serum Testosterone Concentrations in Men. PLoS Genetics. 2011; 7(10): e1002313.
  • Coviello, A. D., Haring, R., Wellons, M., Vaidya, D., Lehtimäki, T., Keildson, S. et al. A genome-wide association meta-analysis of circulating sex hormone-binding globulin reveals multiple loci implicated in sex steroid hormone regulation. PLoS Genetics. 2012; 8(7): 1-12.
  • Yassin, D. J., Doros, G., Hammerer, P. G., & Yassin, A. A. Long-term testosterone treatment in elderly men with hypogonadism and erectile dysfunction reduces obesity parameters and improves metabolic syndrome and health-related quality of life. Journal of Sexual Medicine. 2014; 11(6): 1567–1576.
  • Vandenput, L., & Ohlsson, C. Genome-wide association studies on serum sex steroid levels. Molecular and Cellular Endocrinology. 2014; 382(1): 758–766.
  • Chen, Y. P., Nie, L. L., Li, H. G., Liu, T. H., Fang, F., Zhao, K. et al. The rs5934505 single nucleotide polymorphism (SNP) is associated with low testosterone and late-onset hypogonadism, but the rs10822184 SNP is associated with overweight and obesity in a Chinese Han population: A case-control study. Andrology. 2016; 4(1): 68–74.
  • Castellano-Castillo, D., Royo, J. L., Martínez-Escribano, A., Sánchez-Alcoholado, L., Molina-Vega, M., Queipo-Ortuño, M. I. et al. Effects of SHBG rs1799941 Polymorphism on Free Testosterone Levels and Hypogonadism Risk in Young Non-Diabetic Obese Males. Journal of Clinical Medicine. 2019; 8(8), 1136.
  • Jin, G., Sun, J., Kim, S. T., Feng, J., Wang, Z., Tao, S., Chen, Z., Purcell, L. et al. Genome-wide association study identifies a new locus JMJD1C at 10q21 that may influence serum androgen levels in men. Human Molecular Genetics. 2012; 21(23): 5222–5228.
  • Grigorova, M., Punab, M., Poolamets, O., Adler, M., Vihljajev, V., & Laan, M. Genetics of sex hormone-binding globulin and testosterone levels in fertile and infertile men of reproductive age. Journal of the Endocrine Society. 2017; 1(6): 560–576.
  • Goto, A., Morita, A., Goto, M., Sasaki, S., Miyachi, M., Aiba, N., Terauchi, Y., Noda, M., & Watanabe, S. Associations of sex hormone-binding globulin and testosterone with diabetes among men and women (the Saku Diabetes study): A case control study. Cardiovascular Diabetology. 2012; 11.
  • Shakhanova, A., Aukenov, N., Nurtazina, A., Massabayeva, M., Babenko, D., Adiyeva, M., & Shaimardonov, N. Association of polymorphism genes LPL, ADRB 2, agt and agtr1 with risk of hyperinsulinism and insulin resistance in the kazakh population. Biomedical Reports. 2020; 13(5): 1–10.
  • Shaw, J. E., Sicree, R. A., & Zimmet, P. Z. Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Research and Clinical Practice . 2010; 87( 1): 4–14.
  • Perry, J. R. B., Weedon, M. N., Langenberg, C., Jackson, A. U., Lyssenko, V. et al. Genetic evidence that raised sex hormone binding globulin (SHBG) levels reduce the risk of type 2 diabetes. Human Molecular Genetics. 2010; 19(3): 535–544.
  • Herder, C., & Roden, M. Genetics of type 2 diabetes: Pathophysiologic and clinical relevance. Eur J Clin. 2011; 41( 6 ): 679–692).
  • Wallace, I. R., McKinley, M. C., Bell, P. M., & Hunter, S. J. Sex hormone binding globulin and insulin resistance. Clin. Endocrinology . 2013; 78( 3): 321–329).
  • El Tarhouny, S., Zakaria, S., Abdu-Allah, A., Hadhoud, K., Hanafi, M., & Al Nozha ArBIM, O. Sex Hormone Binding Globulin Gene Polymorphism and Risk of Type 2 Diabetes Mellitus in Egyptian Men. West Indian Med J. 2015; 64(4):338-343. doi: 10.7727/wimj.2014.088.
  • Völzke, H., Aumann, N., Krebs, A., Nauck, M., Steveling, A., Lerch, M. M., Rosskopf, D., & Wallaschofski, H. Hepatic steatosis is associated with low serum testosterone and high serum DHEAS levels in men. International Journal of Andrology. 2010; 33(1): 45–53.
  • Wang, Q., Kangas, A. J., Soininen, P., Tiainen, M., Tynkkynen, T. et al. Sex hormone-binding globulin associations with circulating lipids and metabolites and the risk for type 2 diabetes: observational and causal effect estimates. International Journal of Epidemiology.2015; 44(2): 623–637.
  • Le, T. N., Nestler, J. E., Strauss, J. F., & Wickham, E. P. Sex hormone-binding globulin and type 2 diabetes mellitus. Trends in Endocrinology and Metabolism. 2012; 23( 1 ): 32–40.
  • Yeap, B. B., Beilin, J., Shi, Z., Knuiman, M. W., Olynyk, J. K., Chubb, S. A. P., Bruce, D. G., & Milward, E. A. The C282Y polymorphism of the hereditary hemochromatosis gene is associated with increased sex hormone-binding globulin and normal testosterone levels in men. Journal of Endocrinological Investigation. 2010; 33(8): 544–548.
  • Ramachandran, S., Hackett, G. I., & Strange, R. C. Sex Hormone Binding Globulin: A Review of its Interactions With Testosterone and Age, and its Impact on Mortality in Men With Type 2 Diabetes. Sexual Medicine Reviews. 2019; 7( 4 ): 669–678).
  • Shahid, S. U., Shabana, & Rehman, A. Predictive value of plasma lipid levels for coronary artery disease (CAD). Biologia. 2020; 75(9): 1455–1463.
  • Topolyanskaya, S. V., Vakulenko, O. N., Eliseeva, T. A., Balyasnikova, N. A., Kalinin, G. A., Kupina, L. M., & Strizhova, N. V. Lipid blood profile in old patients with ischemic heart disease. Kardiologiya. 2018; 58(3): 28–36.
  • Dedov I.I., Tyulpakov A.N., Chekhonin V.P., Baklaushev V.P., Archakov A.I., Moshkovsky S.A. Personalized medicine: current state and prospects. Bulletin of the RAMS.2012; 67(12): 4-12.
  • Sentsova T.B., Kirillova O.O., Tutelyan V.A., Vorozhko I.V., Revyakina V.A., Gapparova K.M. Immunology. 2014; 5 ( 35): 241-244.
  • Sentsova T.B., Chernyak O.O., Vorozhko I.V., Gapparova K.M., Grigoryan O.N., Chekhonina Yu.G., Churicheva A.M. Genetic predictors of the effectiveness of standard low-calorie diet therapy in obese patients. Obesity and Metabolism. 2016;13(3):45-48.
  • Pyun, J.-A., Kim, S., Park, K., Baik, I., Cho, N. H., Koh, I. et al. Interaction Effects of Lipoprotein Lipase Polymorphisms with Lifestyle on Lipid Levels in a Korean Population: A Cross-sectional Study. Genomics & Informatics. 2012; 10(2): 88-98.
  • Baik, I., Lee, S. K., Kim, S. H., & Shin, C. A lipoprotein lipase gene polymorphism interacts with consumption of alcohol and unsaturated fatto modulate serum hdl-cholesterol concentrations. Journal of Nutrition. 2013; 143(10): 1618–1625.
  • Han, P., Wei, G., Cai, K., Xiang, X., Deng, W. P., Li, Y. B., Kuang, S. et al. Identification and functional characterization of mutations in LPL gene causing severe hypertriglyceridaemia and acute pancreatitis. Journal of Cellular and Molecular Medicine. 2020; 24(2): 1286–1299.
  • Lun, Y., Sun, X., Wang, P., Chi, J., Hou, X., & Wang, Y. Severe hypertriglyceridemia due to two novel loss-of-function lipoprotein lipase gene mutations (C310R/E396V) in a Chinese family associated with recurrent acute pancreatitis. Oncotarget. 2017; 8(29): 47741–47754.
  • Pingitore, P., Lepore, S. M., Pirazzi, C., Mancina, R. M., Motta, B. M., Valenti, L., Berge, K. E., Retterstøl, K., Leren, T. P., Wiklund, O., & Romeo, S. Identification and characterization of two novel mutations in the LPL gene causing type I hyperlipoproteinemia. Journal of Clinical Lipidology. 2016; 10(4): 816–823.
  • Xie, S.-L., Chen, T.-Z., Huang, X.-L., Chen, C., Jin, R., Huang, Z.-M., & Zhou, M.-T. Genetic Variants Associated with Gestational Hypertriglyceridemia and Pancreatitis. PLoS ONE. 2015; 10(6): e0129488.
  • Chen, T. Z., Xie, S. L., Jin, R., & Huang, Z. M. A novel lipoprotein lipase gene missense mutation in Chinese patients with severe hypertriglyceridemia and pancreatitis. Lipids in Health and Disease. 2014; 13(1): 52.
  • Richards, S., Aziz, N., Bale, S., Bick, D., Das, S., Gastier-Foster, J., Grody, W. W., Hegde, M., Lyon, E., Spector, E., Voelkerding, K., & Rehm, H. L. Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genetics in Medicine. 2015; 17(5): 405–424.
  • Johansen, C. T., & Hegele, R. A. Genetic bases of hypertriglyceridemic phenotypes. In Current Opinion in Lipidology . 2011; 22 ( 4): 247–253.
  • Khovidhunkit, W., Charoen, S., Kiateprungvej, A., Chartyingcharoen, P., Muanpetch, S., & Plengpanich, W. Rare and common variants in LPL and APOA5 in thai subjects with severe hypertriglyceridemia: A resequencing approach. Journal of Clinical Lipidology. 2016; 10(3): 505-511.e1.
  • Gaudet, D., Méthot, J., & Kastelein, J. Gene therapy for lipoprotein lipase deficiency. In Current Opinion in Lipidology . 2012; 23( 4): 310–320.
  • Rebhi, L., Kchok, K., Omezzine, A., Kacem, S., Rejeb, J. et al. Six lipoprotein lipase gene polymorphisms, lipid profile and coronary stenosis in a Tunisian population. Molecular Biology Reports. 2012; 39(11): 9893–9901.
  • DAOUD, M. S., ATAYA, F. S., FOUAD, D., ALHAZZANI, A., SHEHATA, A. I., & AL-JAFARI, A. A. Associations of three lipoprotein lipase gene polymorphisms, lipid profiles and coronary artery disease. Biomedical Reports.2013; 1(4): 573–582.
  • Sarzynski, M. A., Jacobson, P., Rankinen, T., Carlsson, B., Sjöström, L., Carlsson, L. M. S., & Bouchard, C. Association of GWAS-Based Candidate Genes with HDL-Cholesterol Levels before and after Bariatric Surgery in the Swedish Obese Subjects Study. The Journal of Clinical Endocrinology & Metabolism. 2011; 96(6): E953–E957.
  • Božina, T., Sertić, J., Lovrić, J., Jelaković, B., Šimić, I., & Reiner, Ž. Interaction of genetic risk factors confers increased risk for metabolic syndrome: The role of peroxisome proliferator-Activated receptor γ. Genetic Testing and Molecular Biomarkers. 2014; 18(1): 32–40.
  • Kim, Y., Lee, M., Lim, Y., Jang, Y., Park, H. K., & Lee, Y. (2013). The gene-diet interaction, LPL PvuII and HindIII and carbohydrate, on the criteria of metabolic syndrome: KMSRI-Seoul Study. Nutrition. 2013; 29(9): 1115–1121.
  • Gao, R. R., Wang, M., Hu, Y., Xu, C. Y., Li, Y. C., Zhang, Z. Y., Chen, S. Y., & Mao, X. Y. Impact of LPL gene rs283 polymorphism on exercise-induced changes in metabolism of obese adolescents and the regulatory mechanisms behind it. Experimental Physiology. 2015; 100(6): 698–707.