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A strong association between biologically active testosterone and leptin in non-obese men and women is lost with increasing (central) adiposity

Abstract

OBJECTIVE: In both humans and rodents, males have lower levels of leptin than females at any level of adiposity. Experimental data support the idea that testosterone exerts a negative influence on leptin levels. There are, however, major inconsistencies in available data concerning the possible association between androgenicity and leptin in humans. Reasons could be the influence of androgenicity on leptin production being dependent on body composition, and incomplete measures of biologically active testosterone levels. In the present study we have characterized the relationship between biologically active testosterone and leptin after careful stratification for gender and adiposity.

DESIGN AND SUBJECTS: Healthy subjects (n=158; 85 men and 73 pre- and postmenopausal women) from the Northern Sweden MONICA (Monitoring of Trends and Determinants in Cardiovascular Disease) population were studied with a cross-sectional design.

MEASUREMENTS: Anthropometric measurements (body mass index (BMI) and waist circumference) and oral glucose tolerance tests were performed. Circulating levels of leptin, insulin, testosterone, androstenedione, sex hormone-binding globulin (SHBG) and insulin-like growth factor-1 (IGF-1) were measured by radioimmunoassays or microparticle enzyme immunoassays. Apparent concentrations of free testosterone and non-SHBG-bound testosterone were calculated.

RESULTS: After adjustments for age, BMI and insulin, leptin levels were inversely correlated to testosterone levels in non-obese men (r=−0.56, P<0.01) and obese women (r=−0.48, P<0.05). In contrast, leptin and testosterone correlated in a positive manner in non-obese women (r=0.59, P<0.01). Levels of SHBG were negatively associated with leptin in men with low waist circumference (r=−0.59, P<0.01). The following factors were associated with leptin in a multivariate model: low levels of biologically active testosterone and SHBG in men with low and medium waist circumference, insulin in men with high waist circumference, high levels of testosterone and insulin in non-obese women, and BMI in obese women.

CONCLUSION: We conclude that low leptin levels are associated with androgenicity in non-obese men and women and that the direction of this association is dependent on gender and body fat distribution. Based on these results we suggest that the relation between testosterone and leptin contributes to the gender difference in circulating leptin levels.

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References

  1. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM . Positional cloning of the mouse obese gene and its human homologue Nature 1994 372: 425–432.

    Article  CAS  Google Scholar 

  2. Bray GA, York DA . Leptin and clinical medicine: a new piece in the puzzle of obesity J Clin Endocrinol Metab 1997 82: 2771–2776.

    Article  CAS  PubMed  Google Scholar 

  3. Ahima RS, Prabakaran D, Mantzoros C, Qu D, Lowell B, Maratos-Flier E, Flier JS . Role of leptin in the neuroendocrine response to fasting Nature 1996 382: 259–252.

    Article  Google Scholar 

  4. Considine RV, Sinha MK, Heiman ML, Kriauciunas A, Stephens TW, Nyce MR, Ohannesian JP, Marco CC, McKee LJ, Bauer TL et al. Serum immunoreactive-leptin concentrations in normal-weight and obese humans New Engl J Med 1996 334: 292–295.

    Article  CAS  PubMed  Google Scholar 

  5. Wabitsch M, Blum WF, Muche R, Braun M, Hube F, Rascher W, Heinze E, Teller W, Hauner H . Contribution of androgens to the gender difference in leptin production in obese children and adolescents J Clin Invest 1997 100: 808–813.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Blum WF, Englaro P, Hanitsch S, Juul A, Hertel NT, Muller J, Skakkebaek NE, Heiman ML, Birkett M, Attanasio AM, Kiess W, Rascher W . Plasma leptin levels in healthy children and adolescents: dependence on body mass index, body fat mass, gender, pubertal stage, and testosterone J Clin Endocrinol Metab 1997 82: 2904–2910.

    CAS  PubMed  Google Scholar 

  7. Söderberg S, Ahren B, Jansson JH, Johnson O, Hallmans G, Asplund K, Olsson T . Leptin is associated with increased risk of myocardial infarction J Intern Med 1999 246: 409–418.

    Article  PubMed  Google Scholar 

  8. Söderberg S, Ahrén B, Stegmayr B, Johnson O, Wiklund PG, Weinehall L, Hallmans G, Olsson T . Leptin is a risk marker for first-ever hemorrhagic stroke in a population-based cohort Stroke 1999 30: 328–337.

    Article  PubMed  Google Scholar 

  9. Phillips GB, Pinkernell BH, Jing TY . The association of hypotestosteronemia with coronary artery disease in men Arterioscler Thromb 1994 14: 701–706.

    Article  CAS  PubMed  Google Scholar 

  10. Phillips GB, Pinkernell BH, Jing TY . Relationship between serum sex hormones and coronary artery disease in postmenopausal women Arterioscler Thromb Vasc Biol 1997 17: 695–701.

    Article  CAS  PubMed  Google Scholar 

  11. Larsson H, Ahrén B . Androgen activity as a risk factor for impaired glucose tolerance in postmenopausal women Diabetes Care 1996 19: 1399–1403.

    Article  CAS  PubMed  Google Scholar 

  12. Rosenbaum M, Leibel RL . Clinical review 107: Role of gonadal steroids in the sexual dimorphisms in body composition and circulating concentrations of leptin J Clin Endocrinol Metab 1999 84: 1784–1789.

    CAS  PubMed  Google Scholar 

  13. Matsuda J, Yokota I, Iida M, Murakami T, Naito E, Ito M, Shima K, Kuroda Y . Serum leptin concentration in cord blood: relationship to birth weight and gender J Clin Endocrinol Metab 1997 82: 1642–1644.

    Article  CAS  PubMed  Google Scholar 

  14. Havel PJ, Kasim-Karakas S, Dubuc GR, Mueller W, Phinney SD . Gender differences in plasma leptin concentrations Nature Med 1996 2: 949–950.

    Article  CAS  PubMed  Google Scholar 

  15. Haffner SM, Miettinen H, Karhapaa P, Mykkanen L, Laakso M . Leptin concentrations, sex hormones, and cortisol in nondiabetic men J Clin Endocrinol Metab 1997 82: 1807–1809.

    CAS  PubMed  Google Scholar 

  16. Paolisso G, Rizzo MR, Mone CM, Tagliamonte MR, Gambardella A, Riondino M, Carella C, Varricchio M, D'Onofrio F . Plasma sex hormones are significantly associated with plasma leptin concentration in healthy subjects Clin Endocrinol (Oxf) 1998 48: 291–297.

    Article  CAS  Google Scholar 

  17. Vermeulen A, Verdonck L, Kaufman JM . A critical evaluation of simple methods for the estimation of free testosterone in serum J Clin Endocrinol Metab 1999 84: 3666–3672.

    Article  CAS  PubMed  Google Scholar 

  18. Rosner W . Letters to the editor: Errors in the measurement of plasma free testosterone J Clin Endocrinol Metab 1997 82: 2014–2015.

    Article  CAS  PubMed  Google Scholar 

  19. WHO MONICA project principal investigators (Prepared by H. Tunstall Pedoe) . The World Health Organization MONICA Project (Monitoring Trends and Determinants in Cardiovascular Disease): a major international collaboration J Clin Epidemiol 1988 41: 105–114.

    Article  Google Scholar 

  20. Sinha MK, Ohannesian JP, Heiman ML, Kriauciunas A, Stephens TW, Magosin S, Marco C, Caro JF . Nocturnal rise of leptin in lean, obese, and non-insulin-dependent diabetes mellitus subjects J Clin Invest 1996 97: 1344–1347.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Dabbs JM Jr . Salivary testosterone measurements: reliability across hours, days, and weeks Physiol Behav 1990 48: 83–86.

    Article  PubMed  Google Scholar 

  22. Söderberg S, Olsson T, Eliasson M, Johnson O, Ahrén B . Plasma leptin levels are associated with abnormal fibrinolysis in men and postmenopausal women J Intern Med 1999 245: 533–543.

    Article  PubMed  Google Scholar 

  23. Brody S, Carlstrom K, Lagrelius A, Lunell NO, Rosenborg L . Serum levels of 4-androstene-3,17-dione in menstruating and post-menopausal women. Evaluation of a radioimmunoassay and correlation with bone mineral content and endometrial pathology Acta Obstet Gynecol Scand 1983 62: 531–534.

    Article  CAS  PubMed  Google Scholar 

  24. Stege R, Eriksson A, Henriksson P, Carlstrom K . Orchidectomy or oestrogen treatment in prostatic cancer: effects on serum levels of adrenal androgens and related steroids Int J Androl 1987 10: 581–587.

    Article  CAS  PubMed  Google Scholar 

  25. Sodergard R, Backstrom T, Shanbhag V, Carstensen H . Calculation of free and bound fractions of testosterone and estradiol-17 beta to human plasma proteins at body temperature J Steroid Biochem 1982 16: 801–810.

    Article  CAS  PubMed  Google Scholar 

  26. Bang P, Eriksson U, Sara V, Wivall IL, Hall K . Comparison of acid ethanol extraction and acid gel filtration prior to IGF-I and IGF-II radioimmunoassays: improvement of determinations in acid ethanol extracts by use of truncated IGF-I as radioligand Acta Endocrinol (Copenh) 1991 124: 620–629.

    Article  CAS  Google Scholar 

  27. Jockenhovel F, Blum WF, Vogel E, Englaro P, Muller-Wieland D, Reinwein D, Rascher W, Krone W . Testosterone substitution normalizes elevated serum leptin levels in hypogonadal men J Clin Endocrinol Metab 1997 82: 2510–2513.

    Article  CAS  PubMed  Google Scholar 

  28. Sih R, Morley JE, Kaiser FE, Perry HM, 3rd, Patrick P, Ross C . Testosterone replacement in older hypogonadal men: a 12-month randomized controlled trial J Clin Endocrinol Metab 1997 82: 1661–1667.

    Article  CAS  PubMed  Google Scholar 

  29. Luukkaa V, Pesonen U, Huhtaniemi I, Lehtonen A, Tilvis R, Tuomilehto J, Koulu M, Huupponen R . Inverse correlation between serum testosterone and leptin in men J Clin Endocrinol Metab 1998 83: 3243–3246.

    CAS  PubMed  Google Scholar 

  30. Arslanian S, Suprasongsin C . Testosterone treatment in adolescents with delayed puberty: changes in body composition, protein, fat, and glucose metabolism J Clin Endocrinol Metab 1997 82: 3213–3220.

    CAS  PubMed  Google Scholar 

  31. Elbers JM, Asscheman H, Seidell JC, Frolich M, Meinders AE, Gooren LJ . Reversal of the sex difference in serum leptin levels upon cross-sex hormone administration in transsexuals J Clin Endocrinol Metab 1997 82: 3267–3270.

    CAS  PubMed  Google Scholar 

  32. Garcia-Mayor RV, Andrade MA, Rios M, Lage M, Dieguez C, Casanueva FF . Serum leptin levels in normal children: relationship to age, gender, body mass index, pituitary–gonadal hormones, and pubertal stage J Clin Endocrinol Metab 1997 82: 2849–2855.

    CAS  PubMed  Google Scholar 

  33. Mantzoros CS, Flier JS, Rogol AD . A longitudinal assessment of hormonal and physical alterations during normal puberty in boys. V. Rising leptin levels may signal the onset of puberty J Clin Endocrinol Metab 1997 82: 1066–1070.

    CAS  PubMed  Google Scholar 

  34. Palmert MR, Radovick S, Boepple PA . The impact of reversible gonadal sex steroid suppression on serum leptin concentrations in children with central precocious puberty J Clin Endocrinol Metab 1998 83: 1091–1096.

    CAS  PubMed  Google Scholar 

  35. Nyström F, Ekman B, Österlund M, Lindström T, Öhman KP, Arnqvist HJ . Serum leptin concentrations in a normal population and in GH deficiency: negative correlation with testosterone in men and effects of GH treatment Clin Endocrinol (Oxf) 1997 47: 191–198.

    Article  Google Scholar 

  36. Vettor R, De Pergola G, Pagano C, Englaro P, Laudadio E, Giorgino F, Blum WF, Giorgino R, Federspil G . Gender differences in serum leptin in obese people: relationships with testosterone, body fat distribution and insulin sensitivity Eur J Clin Invest 1997 27: 1016–1024.

    Article  CAS  PubMed  Google Scholar 

  37. Janssen JA, Huizenga NA, Stolk RP, Grobbee DE, Pols HA, de Jong FH, Attanasio AM, Blum WF, Lamberts SW . The acute effect of dexamethasone on plasma leptin concentrations and the relationships between fasting leptin, the IGF-I/IGFBP system, dehydroepiandrosterone, androstenedione and testosterone in an elderly population Clin Endocrinol (Oxf) 1998 48: 621–626.

    Article  CAS  Google Scholar 

  38. Lagiou P, Signorello LB, Trichopoulos D, Tzonou A, Trichopoulou A, Mantzoros CS . Leptin in relation to prostate cancer and benign prostatic hyperplasia Int J Cancer 1998 76: 25–28.

    Article  CAS  PubMed  Google Scholar 

  39. Ambrosius WT, Compton JA, Bowsher RR, Pratt JH . Relation of race, age, and sex hormone differences to serum leptin concentrations in children and adolescents Horm Res 1998 49: 240–246.

    CAS  PubMed  Google Scholar 

  40. Brzechffa PR, Jakimiuk AJ, Agarwal SK, Weitsman SR, Buyalos RP, Magoffin DA . Serum immunoreactive leptin concentrations in women with polycystic ovary syndrome J Clin Endocrinol Metab 1996 81: 4166–4169.

    CAS  PubMed  Google Scholar 

  41. Perry HM III, Morley JE, Horowitz M, Kaiser FE, Miller DK, Wittert G . Body composition and age in African-American and Caucasian women: relationship to plasma leptin levels Metabolism 1997 46: 1399–1405.

    Article  PubMed  Google Scholar 

  42. Rouru J, Anttila L, Koskinen P, Penttila TA, Irjala K, Huupponen R, Koulu M . Serum leptin concentrations in women with polycystic ovary syndrome J Clin Endocrinol Metab 1997 82: 1697–1700.

    Article  CAS  PubMed  Google Scholar 

  43. Haffner SM, Karhapaa P, Mykkanen L, Laakso M . Insulin resistance, body fat distribution, and sex hormones in men Diabetes 1994 43: 212–219.

    Article  CAS  Google Scholar 

  44. Pedersen SB, Borglum JD, Brixen K, Richelsen B . Relationship between sex hormones, body composition and metabolic risk parameters in premenopausal women Eur J Endocrinol 1995 133: 200–206.

    Article  CAS  PubMed  Google Scholar 

  45. Zumoff B, Strain GW, Miller LK, Rosner W, Senie R, Seres DS, Rosenfeld RS . Plasma free and non-sex-hormone-binding-globulin-bound testosterone are decreased in obese men in proportion to their degree of obesity J Clin Endocrinol Metab 1990 71: 929–931.

    Article  CAS  PubMed  Google Scholar 

  46. Caprio M, Isidori AM, Carta AR, Moretti C, Dufau ML, Fabbri A . Expression of functional leptin receptors in rodent Leydig cells Endocrinology 1999 140: 4939–4947.

    Article  CAS  PubMed  Google Scholar 

  47. Tena-Sempere M, Pinilla L, Gonzalez LC, Dieguez C, Casanueva FF, Aguilar E . Leptin inhibits testosterone secretion from adult rat testis in vitro J Endocrinol 1999 161: 211–218.

    Article  CAS  PubMed  Google Scholar 

  48. Björntorp P . Androgens, the metabolic syndrome, and non-insulin-dependent diabetes mellitus Ann NY Acad Sci 1993 676: 242–252.

    Article  PubMed  Google Scholar 

  49. Dunaif A . Insulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis Endocr Rev 1997 18: 774–800.

    CAS  Google Scholar 

  50. Fontbonne A . Why can high insulin levels indicate a risk for coronary heart disease Diabetologia 1994 37: 953–955.

    Article  CAS  PubMed  Google Scholar 

  51. Van Den Saffele JK, Goemaere S, De Bacquer D, Kaufman JM . Serum leptin levels in healthy ageing men: are decreased serum testosterone and increased adiposity in elderly men the consequence of leptin deficiency Clin Endocrinol (Oxf) 1999 51: 81–88.

    Article  CAS  Google Scholar 

  52. Mantzoros CS, Dunaif A, Flier JS . Leptin concentrations in the polycystic ovary syndrome J Clin Endocrinol Metab 1997 82: 1687–1691.

    CAS  PubMed  Google Scholar 

  53. Thorén M, Hilding A, Baxter RC, Degerblad M, Wivall-Helleryd IL, Hall K . Serum insulin-like growth factor I (IGF-I), IGF-binding protein-1 and -3, and the acid-labile subunit as serum markers of body composition during growth hormone (GH) therapy in adults with GH deficiency J Clin Endocrinol Metab 1997 82: 223–228.

    PubMed  Google Scholar 

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Acknowledgements

We are indebted to the Northern Swedish MONICA Project and the grants supporting it. This study was also supported by grants from the Swedish Medical Research Council (grants no. 71P-11769 to TO and no.14X-6834 to BA), the Swedish Public Institute of Health, the Swedish Heart and Lung Foundation, Ernhold Lundström, and Novo Nordic Foundations, Swedish Diabetes Association, the country councils of Northern Sweden (Visare Norr), and the Faculties of Medicine, Umeå and Lund Universities. The authors are grateful to Lilian Bengtsson and Hans Stenlund for assistance in technical and statistical matters.

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Söderberg, S., Olsson, T., Eliasson, M. et al. A strong association between biologically active testosterone and leptin in non-obese men and women is lost with increasing (central) adiposity. Int J Obes 25, 98–105 (2001). https://doi.org/10.1038/sj.ijo.0801467

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