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.
Leptin, the hormone product of the ob gene, is secreted mainly from adipocytes.1 It regulates energy balance by reducing food intake and increasing energy expenditure.2 A main function may be to initiate protective neuroendocrine responses during starvation.3 As leptin levels rise due to obesity and other factors,4 the physiological regulation including androgens5,6 present in non-obese subjects may be altered. Recent studies suggest that both hyperleptinemia per se7,8 and relative alterations in androgen levels, ie hypoandrogenicity in men and hyperandrogenicity in women, may be associated with increased risk for cardiovascular disease9,10 and glucose intolerance.11 It is thus of major interest to determine how these variables may be associated.
In humans and rodents, males have lower levels of leptin than females at any level of adiposity.12 This gender difference is evident in all age groups in humans.6,13,14 Epidemiological and experimental data support that androgens (mainly testosterone) have a negative influence on leptin levels in men.5,6 However, this association has not always been independent of adiposity,15 and no studies have so far been able to show an independent association in women.16 Tentative explanations for this conundrum include differences in the influence of androgenicity on leptin production at different body composition in males and females, and incomplete measures of biologically active testosterone levels.17,18 Our hypothesis was that the normal negative influence of androgens on leptin production is lost with increasing adiposity.
Patients and methods
The study was performed within the framework of the Northern Sweden MONICA Project, which, in turn, is part of the WHO MONICA (Monitoring of Trends and Determinants in Cardiovascular Disease) Project.19 In 1994, a population was screened for cardiovascular risk factors. A total of 2500 individuals in the 25–74 y range were invited by mail from a total population of 367 000 in this age range. Within each age group (25–34, 35–44, 45–54, 55–64, and 65–74 y) 250 men and 250 women were randomly selected from continuously updated population registers in Norrbotten and Västerbotten, the two northernmost provinces of Sweden. In total 1921 subejcts participated in the study (76.8%). Subjects were included whose blood samples were taken between 07:00 and 09:00 in order to minimize the influence of diurnal rhythm of leptin20 and androgen levels.21 Subjects who were pregnant, had diabetes or subclinical hypothyroidism, or had a history of prior myocardial infarction or stroke, or were using estrogen replacement therapy, oral contraceptives or antihypertensive agents were excluded. Furthermore, women with irregular menstruations were excluded. After an overnight fast, a 75 g oral glucose tolerance test was performed. Three subjects were found to have previously unknown diabetes and were excluded from further analysis. After these exclusions, 85 men and 73 women remained and thus formed the basis of this study. Sampling procedures have been described previously.22 This study was approved by the Research Ethics Committee of Umeå University.
Anthropometric and biochemical analyses
Body mass index (BMI) was calculated as total body weight in kilograms divided by the square of height in meters, and waist–hip ratio (WHR) was calculated as the ratio of the circumference of the narrowest part of the waist divided by the broadest part of the hip. All measurements were taken with the subject standing upright and breathing lightly. Blood pressure was measured with the subjects in the sitting position and after 5 min of rest using the random zero method.
Plasma insulin was measured by microparticle enzyme immunoassay (MEIA; Abbott Laboratories, IL, USA). The detection limit was 1.0 mU/l, and the interassay coefficient of variation (CV) was 6.7% at the level of 7.9 mU/l. Cross-reactivity with C-peptide/glucagon was non-detectable and 0.005% with proinsulin according to the manufacturer. The leptin analysis was performed using a double-antibody radioimmunoassay (RIA) with rabbit anti-human leptin antibodies, 125I-labelled human leptin as tracer and human leptin as standard (Linco Res., St Louis, MO, USA). Interassay CV was 1.9% at low levels (<5 ng/ml) and 3.2% at high levels (10–15 ng/ml).
Plasma concentrations of testosterone and of sex hormone-binding globulin (SHBG) were determined by RIA in untreated plasma using commercial kits obtained from Diagnostic Products Corp., Los Angeles, CA (‘Coat-a-Count®’ Testosterone) and from Eurodiagnostics AB, Malmö, Sweden (SHBG). Plasma concentrations of 4-androstene-3,17-dione (A-4) were determined after extraction with diethyl ether by RIA as described by Brody and co-workers23 with minor modifications.24 In the modified method the sample volume was increased to 100 μl, the original anti-body was substituted by anti-4-androstene-3,17-dione-7-carboxyethyl thioether-bovine serum albumin (Bio-Clin Ltd, Cardiff, UK) and the incubation volume and amount of dextrane-coated charcoal were changed according to the suggestions by the manufacturer of the antibody. Detection limits and intra- and interassay CV were for testosterone 0.1 nmol/l, 6% and 10%; for SHBG 0.05 nmol/l, 4% and 8%; and for A-4 0.6 nmol/l, 6% and 10%, respectively.
Apparent concentrations of free testosterone (FT) and non-SHBG-bound testosterone (NST) were calculated from values for total testosterone (TT), SHBG and a fixed albumin concentration of 40 g/l for women and 42 g/l for men, by successive approximation using a computer program based upon an equation system derived from the law of mass actions.25 Insulin-like growth factor-1 (IGF-1) was determined by RIA after separation of IGFs from IGF-binding proteins (IGFBPs) by acid-ethanol extraction and cryoprecipitation. To minimize interference of the remaining IGFBPs, des(1-3)-IGF-1 was used as radioligand.26 The intra- and interassay CVs were 4 and 11%, respectively.
All the main study variables were positively skewed and, therefore, (ln) transformed values were used. Means (geometric for transformed values) with 95% CI are presented. Bivariate (Pearson's) and partial correlation coefficients were calculated, adjusted for age, BMI and (fasting) insulin. One-way analysis of variance (ANOVA) with adjustments for covariates were used, and significant differences between factor levels were evaluated after Bonferroni correction. Multiple linear regression analysis was performed with fixed entries. Two-tailed tests were used and a P-value <0.05 was considered significant. All calculations were made with the statistical program SPSS (Chicago, IL), version 6.1, on a Macintosh computer.
Baseline characteristics of the study population are shown in Table 1. Men had higher waist circumference, WHR, and testosterone levels (FT, NST and TT) in combination with lower SHBG and leptin concentrations vs both pre- and postmenopausal women. Furthermore, men were more obese (BMI) compared with premenopausal women. Pre-menopausal women had higher levels of A-4 compared to postmenopausal women, whereas testosterone (FT, NST and TT) and leptin levels did not differ between pre- and postmenopausal women. IFG-1 levels were highest in premenopausal women followed by men, who had higher levels than postmenopausal women.
Men and women were divided into three groups according to tertiles of waist circumference. Separate cut-offs for pre- and postmenopausal women were used in order to stratify for menstrual status resulting in an equal proportion of menstruating and postmenopausal women in each tertile (approximately 60% menstruating women in each tertile). Table 2 shows cut-off levels for tertiles and means for study variables within each tertile of waist circumference. (Tertiles of BMI and tertiles of waist circumference without stratification for menstrual status were analysed with virtually identical results, data not shown.)
In summary, higher waist circumference was associated with increasing levels of insulin and leptin in both men and women. In contrast, the relation between waist circumference and levels of testosterone (FT and NST) was different between genders: high waist circumference was associated with low testosterone in men, whereas in women, high waist circumference was associated with high testosterone. Furthermore, high waist circumference was associated with low levels of IGF-1 and increasing age in men, while in women abdominal obesity was linked to low levels of SHBG. The difference in testosterone levels between men with high vs low waist circumference became non-significant once adjusted for age (data not shown). Further adjustment for BMI in combination with age rendered all remaining differences in both men and women non-significant.
To examine the relationship between leptin and testosterone, bivariate and partial correlations between leptin levels and the determined variables were performed (Table 3). In these analyses, adjustments were made for age, BMI and insulin after stratification for gender, menstrual status and waist circumference. Further adjustments for waist circumference, smoking habits and levels of IGF-1 did not add any additional information (data are not shown). Before adjustments and stratification, leptin correlated significantly with BMI, waist circumference and fasting insulin in both men and women. Furthermore, a significant negative correlation was seen between leptin and testosterone (FT, NST and TT) in men, whereas a significant positive correlation was seen between leptin and testosterone (FT and NST) in women.
After stratification for waist circumference, a significant negative correlation between leptin levels and testosterone (FT, NST and TT) in men remained in the middle tertile of waist circumference. These correlations remained markedly significant even after adjustments. In addition, leptin levels correlated substantially and inversely with SHBG in the low tertile of waist circumference. Furthermore, fasting insulin correlated strongly to leptin in men from the middle and high tertiles of waist circumference. In contrast, leptin did not correlate with testosterone or SHBG in men after stratification for BMI (data not shown).
In women, there was a strong and positive correlation between leptin and testosterone (FT, NST and TT) in the low tertile of waist circumference. In contrast, the association between leptin and TT was inverse among women from the middle and high BMI tertiles (r=−0.48; P<0.05, and r=−0.52; P<0.05, respectively). Leptin and insulin correlated in women from the high BMI tertile (r=0.49; P<0.05), but not in women from the middle and the low BMI tertiles.
Adjustment for circulating SHBG levels did not influence the association between biological active testosterone (FT and NST) and leptin in men and in women. However, the association between TT and leptin was no longer significant in non-obese men after this adjustment.
Levels of A-4 did not correlate significantly with leptin concentrations after adjustments. The direction of the correlations were, however, similar to that between leptin and testosterone in the corresponding tertile. Levels of IGF-1 were not associated with leptin and biologically active testosterone in men and women after adjustments (data not shown).
Table 4 shows the results from a multiple linear regression analysis with leptin concentrations as the dependent variable. Factors that have been shown to correlate significantly to leptin in this and other studies were introduced in the model. Data for FT are presented but nearly identical results were obtained with NST and TT (data not shown).
In summary, high levels of insulin and a high waist circumference were significant predictors for high leptin concentrations among males. After stratification, the main associations to leptin were high waist circumference in the low waist tertile; low levels of FT and high levels of insulin in combination with low age in the middle waist tertile; and high levels of insulin in the high waist tertile.
In women, high levels of insulin in combination with high BMI were significantly associated with high leptin levels. High levels of FT and insulin in combination with high BMI in the low waist tertile, and BMI in the middle and high waist tertiles were significantly associated with leptin levels.
The combination term waist circumference by FT was strongly associated with high leptin levels in women (P=0.0005), but not in men, suggesting a significant interaction between androgenicity and body composition among females.
When SHBG was added to the model in a final step, it was found to be inversely associated with leptin levels in non-obese men (data not shown). In fact, the addition of SHBG to the model improved the explanatory level from 46 to 60% in the low waist tertile. The addition of SHBG did not add any further information in women or in the upper two waist tertiles in men.
This cross-sectional study strongly supports an association between levels of androgens and leptin in both men and women. Importantly, there is a clear gender difference in the direction of the correlation. The association between androgen levels and leptin seems to be dependent of fat distribution in men. Specifically, measures of androgenicity were inversely associated with leptin levels in men in the lower two tertiles of waist circumference. In contrast, this association was strongly positive in low weight women in the lowest tertile. These results may explain some of the contradictory results in earlier reports and suggest that testosterone contributes to the gender difference in leptin levels.
There is a growing bulk of evidence suggesting that testosterone may influence leptin levels. Testosterone administration reduces leptin levels in hypogonadal27,28 and eugonadal men,29 in adolescents with delayed puberty,30 and in female to male transsexuals.31 Furthermore, increasing levels of testosterone parallels a decline in leptin levels during puberty.32,33 Conversely, testosterone suppression by GnRH agonist treatment of central precocious puberty in boys increases leptin levels.34 Since testosterone is involved in the regulation of fat mass, it may be speculated that the relation between testosterone and leptin is indirect. However, experimental data support the idea that testosterone acts directly on the adipocyte as expression and secretion of leptin is reduced in cultured adipocytes after coincubation with testosterone or dihydrotestosterone,5 suggesting a direct effect as well.
An inverse association between androgens and leptin has been shown repeatedly in healthy middle-aged15,35,36 and in older men.29,37,38 However, some studies have failed to show any significant correlation after adjustments for BMI,15,37,38 whilst others do so.16,36 Interestingly, the men included in studies which fail to report a significant association between androgenicity and leptin after adjustments have in common mean BMI levels corresponding to the more obese males in our study.15,37,38 In contrast, Paolisso et al reported a significant negative testosterone-leptin association in subjects with a mean BMI level corresponding to our males in the low waist tertile.16 Therefore, the varying results in the literature may be explained by an important effect of fat mass/distribution on the testosterone–leptin association, as shown in the present study.
A crude positive correlation association between testosterone and leptin in women has been reported by some,6,36,39,40,41 but not other investigators.16,37 It has also been a matter of controversy whether a positive correlation between leptin and various measures of androgenicity is present among women with the polycystic ovary syndrome (PCO).40,42 We found a positive association between measures of biologically active testosterone (FT and NST) among women in the crude analysis, which was lost after adjustment for covariates. However, a positive association was present only in non-obese women, which may explain why previous reports have failed to establish this association after adjustment for adiposity.
We found a strong inverse association between leptin and SHBG in men with low waist circumference. The SHBG-leptin association has been evaluated earlier, but with conflicting results, mostly due to the effects of adiposity.35,36
Testosterone levels decreased with increasing central obesity in healthy men, while they increase with increasing obesity in healthy women, the latter irrespective of menstrual status. This association is suggestive of a relative hypoandrogenicity in obese men, and a relative hyperandrogenicity in obese women, which is in alignment with earlier reports.43,44,45 In men, this could be due to obesity-related hyperleptinemia that inhibits testosterone secretion at the testicular level.46,47 These changes, which are proposed to be components of the insulin resistance syndrome,48 are associated with increased risk for cardiovascular disease in both men and women.9,49
One interesting finding in this study is the absence of association between leptin levels on one hand and testosterone and SHBG levels on the other in more obese persons. This could be explained by a dual influence of leptin and testosterone on the secretion of each other. In moderately obese subjects, testosterone might inhibit leptin secretion, explaining the negative relation in the middle tertile of waist circumference in men between the two variables. However, in the more obese subjects, the higher leptin levels due to increased adiposity might reduce secretion of testosterone,46,47 thereby explaining that the association between the two variables is lost in obese subjects. More obese persons (centrally obese men) are thus, in addition to disturbances in androgen levels, characterized by hyperleptinemia and hyperinsulinemia, which are possible risk factors for cardiovascular disease.7,50 This would add a link between abdominal obesity, androgen abnormalities, hyperleptinemia and future risk for cardiovascular disease, although more studies using more direct measurements of adiposity than BMI and waist circumference need to be undertaken to further explore this possibility.
A threshold effect of androgens on leptin production may thus explain these results, as recently suggested.51 Androgens may regulate leptin production and secretion within certain degrees of adiposity associated with a hormonal milieu favoring this association, whereas the hormonal milieu associated with obesity favors regulators as insulin. This is not apparent unless the effects of adiposity are carefully handled in the statistical analysis.
We did not find any adiposity-independent associations between A-4 and leptin levels. This is in accordance with earlier studies of A-4 vs leptin in healthy postmenopausal women,37 and in PCO women,42 and of dehydroepiandrostenedionesulfate vs leptin in healthy adults,15 in PCO women,52 and in children.39
It is notable that measures of biologically active testosterone (FT and NST) associate with leptin in a nearly identical pattern in both men and women, supporting the view that free and albumin-bound testosterone fractions have the same biological role.45 In contrast, the pattern of associations between leptin and TT, which includes non-biologically active testosterone bound to SHBG, resembles both the associations between biologically active testosterone and leptin, and the association between SHBG and leptin, especially in men. These different patterns should be taken into consideration when evaluating earlier reports. The influence of androgenicity on leptin levels should be evaluated via levels of the biologically active testosterone fraction calculated by validated techniques.
We did not find any association between levels of IGF-1 on one hand and levels of leptin and biologically active testosterone on the other in this population of healthy subjects. One reason could be that leptin and androgens are associated with fat metabolism, whilst IGF-1 is more associated to protein synthesis.53 Leptin levels are, however, associated with the growth hormone (GH)/IGF-1 axis, as it has been shown that GH treatment lowered leptin levels in GH-deficient subjects.35 Whether this association is indirect through altered body composition, or direct through hypothalamic effects remains to be established. Furthermore, it is of interest to include studies of IGF-1 binding proteins in the further evaluation of associations between IGF-1, adiposity and leptin.37
Our analysis was not performed in pre- and postmenopausal women separately due to few individuals in each tertile. However, no major differences were observed in means between pre- and postmenopausal women, neither between the entire groups nor in each tertile, except for A-4 and IGF-1. Furthermore, results of separate correlation and regression analyses for pre- and postmenopausal women were concordant, although not always significant (data not shown). The MONICA study is a strictly population-based study,19 thus minimizing selection bias. All possible care has been taken to exclude persons whose leptin or testosterone levels could be influenced by various diseases. Therefore, it is likely that our conclusions for women are valid in spite of being based on combined analysis of pre- and postmenopausal women.
In conclusion, we demonstrate that leptin levels are associated to androgenicity in middle–low weight men and women and the direction of this association is dependent on gender and fat mass distribution. A loss of regulation of leptin by testosterone in obese men and women could be an important feature of the insulin resistance syndrome.
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.
Bray GA, York DA . Leptin and clinical medicine: a new piece in the puzzle of obesity J Clin Endocrinol Metab 1997 82: 2771–2776.
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.
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.
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.
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.
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.
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.
Phillips GB, Pinkernell BH, Jing TY . The association of hypotestosteronemia with coronary artery disease in men Arterioscler Thromb 1994 14: 701–706.
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.
Larsson H, Ahrén B . Androgen activity as a risk factor for impaired glucose tolerance in postmenopausal women Diabetes Care 1996 19: 1399–1403.
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.
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.
Havel PJ, Kasim-Karakas S, Dubuc GR, Mueller W, Phinney SD . Gender differences in plasma leptin concentrations Nature Med 1996 2: 949–950.
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.
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.
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.
Rosner W . Letters to the editor: Errors in the measurement of plasma free testosterone J Clin Endocrinol Metab 1997 82: 2014–2015.
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.
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.
Dabbs JM Jr . Salivary testosterone measurements: reliability across hours, days, and weeks Physiol Behav 1990 48: 83–86.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Haffner SM, Karhapaa P, Mykkanen L, Laakso M . Insulin resistance, body fat distribution, and sex hormones in men Diabetes 1994 43: 212–219.
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.
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.
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.
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.
Björntorp P . Androgens, the metabolic syndrome, and non-insulin-dependent diabetes mellitus Ann NY Acad Sci 1993 676: 242–252.
Dunaif A . Insulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis Endocr Rev 1997 18: 774–800.
Fontbonne A . Why can high insulin levels indicate a risk for coronary heart disease Diabetologia 1994 37: 953–955.
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.
Mantzoros CS, Dunaif A, Flier JS . Leptin concentrations in the polycystic ovary syndrome J Clin Endocrinol Metab 1997 82: 1687–1691.
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.
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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