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Original Studies |
Departments of Pharmacology and Clinical Pharmacology (V.L., U.P., M.K., R.H.) and Physiology (I.H.), University of Turku, and the Department of Internal Medicine, Turku Municipal Hospital (A.L.), Turku; and the Department of Internal Medicine, University of Helsinki (R.T.), and Diabetes and Genetic Epidemiology Unit, Department of Epidemiology and Health Promotion, National Public Health Institute (J.T.), Helsinki, Finland
Address all correspondence and requests for reprints to: Dr. Virve Luukkaa, M.D., University of Turku, Department of Pharmacology and Clinical Pharmacology, Kiinamyllynkatu 10, FIN-20520 Turku, Finland. E-mail: virve.luukkaa{at}utu.fi
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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In both humans and rodents, males have lower plasma leptin concentrations than their female counterparts at any level of adiposity (6, 7). Leptin messenger ribonucleic acid expression is lower in obese men than in obese women (8) and is lower in obese boys than in obese girls (9). The gender difference in serum leptin concentration is well established (10, 11, 12), and in vitro results suggest that gonadal hormones, such as testosterone, may be important regulators of leptin secretion. A strong inverse association between serum levels of leptin and testosterone was recently reported in untreated and testosterone-treated hypogonadal men (13, 14). The effect of testosterone treatment on circulating leptin has been studied previously in adolescents with delayed puberty (15), but to date has not been examined in eugonadal men. To further elucidate the role of androgens on leptin production, we performed two studies in men. First, the relationship between circulating testosterone and serum leptin was studied in a cross-sectional survey of elderly nondiabetic men. Second, the effect of testosterone treatment on serum leptin was determined in a longitudinal study in eugonadal young men.
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Subjects and Methods |
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A total of 269 men participated in a cross-sectional study investigating the health of elderly inhabitants of the city of Turku, Finland. Subjects were a representative 73% cohort of 71- to 72-yr-old men living in this area. The subjects visited local health care centers for routine medical examination and an oral glucose tolerance test and provided serum samples. At the time of the visit, the mean age of the men was 71.3 ± 0.5 yr (range, 71–72 yr). Their mean weight was 78.2 ± 10.7 kg, mean height was 1.75 ± 0.05 m, and mean body mass index (BMI) was 25.9 ± 3.6 kg/m2. A 75-g oral glucose tolerance test was performed according to the WHO criteria on the morning after an overnight fast. Blood samples were collected at 0 and 120 min for the determination of plasma glucose and insulin concentrations. Men in the survey with diabetes mellitus or with an abnormal glucose tolerance test according to the WHO criteria were excluded from the present study. The study was approved by the local institutional ethical review committee.
Testosterone treatment in young men
The serum samples of 10 men participating in the WHO Task Force
on Methods for the Regulation of Male Fertility were used to study the
effect of exogenous testosterone on serum leptin levels (16). The mean
age was 31.3 ± 7.7 yr (range, 25–41 yr), the mean weight was
75.2 ± 10.7 kg, the mean height was 1.81 ± 0.06 m, and
the mean BMI was 22.8 ± 2.1 kg/m2. The participants
had no concomitant diseases. Routine medical examinations were
performed, and the men provided blood samples for testosterone, LH, and
FSH measurements. The samples were also used for leptin and insulin
determinations. The subjects received weekly injections of testosterone
enanthate (200 mg, im, as 0.8 mL Testoviron-Depot 250, Schering,
Berlin, Germany). Testosterone injections continued for 12 months after
the subjects had become azoospermic, which usually occurred within 2–4
months. Before the treatment and every 3 months after the initiation of
the testosterone injections, the participants were examined by a
physician. Blood samples were taken twice before treatment (
1 month
apart), every 3 months during treatment, and once after treatment. The
protocol was approved by the WHO Toxicology Group, scientific and
ethical review group, and the Secretariat committee on research
involving human subjects. The study was also approved by the joint
ethical committee of the University of Turku and Turku University
Hospital. The men and their partners provided witnessed written
informed consent.
Laboratory methods
Blood samples were collected after an overnight fast, and serum was separated after centrifugation and stored at -20 C until analyzed. In the study of the elderly men, blood glucose was determined by the hexokinase method. Serum leptin was measured with a human leptin RIA kit (Linco Research, St. Charles, MO), using a polyclonal antibody raised in rabbits against highly purified human leptin. The assay had a sensitivity of 0.5 µg/L. The interassay coefficient of variation (CV) was 6.5% at a mean leptin concentration of 2.9 µg/L and 9.9% at a mean concentration of 14.5 µg/L. Serum insulin was determined with a Phadeseph insulin RIA kit (Pharmacia, Uppsala, Sweden), with a detection limit of 2.5 mU/L. The intraassay CV was 0.5% at a serum insulin concentration of 13.3 mU/L, and the interassay CV was 6.4% at an insulin concentration of 20.1 mU/L. The assay procedures for the immunofluorometric assays of LH and FSH were performed as previously described (16). Testosterone was measured as previously described by Huhtaniemi et al. (17).
Statistical analyses
In the study of the elderly men, Pearson correlation coefficients and multiple linear regression analysis were used. In the study of young men, the statistical comparisons were performed with one-way ANOVA for repeated measurements and with Student’s t test. P < 0.05 was considered statistically significant. The values given below are means with SDs. BMI was calculated by dividing body weight (kilograms) by square height (meters). Statistical analyses were performed with Statistical Analysis System software (SAS version 6.12, SAS Institute, Cary, NC).
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The mean serum leptin, testosterone, and insulin concentrations in
the study population were 8.5 ± 5.5 µg/L, 20.7 ± 8.0
nmol/L, and 11.1 ± 6.8 IU/L, respectively. Pearson correlation
coefficients among serum leptin, testosterone, insulin, and BMI are
presented in Table 1
. A significant
inverse correlation was found between leptin and testosterone (r =
-0.39; P < 0.001; Fig. 1). There were significant positive
correlations between leptin and insulin and between leptin and BMI
(r = 0.60; P < 0.001 and r = 0.50;
P < 0.01, respectively). Furthermore, significant
correlations were found between insulin and testosterone and between
insulin and BMI (Table 1). To determine the independent contributions
of testosterone, insulin, and BMI to the serum leptin concentration,
they all were included in multiple linear regression analysis. These
variables jointly explained a very high proportion (85%) of the total
variability in serum leptin concentrations. Testosterone had a
significant inverse (r = -0.176; SE = 0.034;
P < 0.001), and both insulin and BMI had a significant
positive effect on serum leptin (r = 0.389; SE =
0.054; P < 0.001 and r = 0.318; SE =
0.040; P < 0.001, respectively). A similar conclusion
was reached when the partial correlation between testosterone and
leptin concentrations, adjusted for insulin concentration or BMI, was
calculated (r = -0.27; P < 0.0001 and r =
-0.33; P < 0.001, respectively).
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There was a significant correlation between serum leptin and
testosterone concentrations (r = -0.48; P <
0.001; Fig. 2). Testosterone injections
significantly reduced serum leptin (P = 0.002, by ANOVA
for repeated measurements), LH (P < 0.001), and FSH
(P < 0.001) concentrations, whereas BMI
(P = 0.071) and serum insulin (P =
0.195) remained unchanged (Fig. 2 and Table 2). There was a 44% decrease in the mean
serum leptin concentration from 3.4 ± 1.4 µg/L before treatment
to 1.9 ± 0.6 µg/L during testosterone treatment
(P < 0.005, by paired t test). Three months
after the cessation of testosterone treatment, plasma leptin levels had
returned to the basal level. There was a 2.7-fold increase in the mean
serum testosterone concentration from 25.1 ± 7.9 to 67.0 ±
18.4 nmol/L during treatment (P < 0.001). Pretreatment
concentrations of serum testosterone were also reached 3 months after
discontinuing testosterone injections. Reduced serum LH and FSH
concentrations were only partially normalized, especially in the case
of LH, after the cessation of therapy.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The existence of such a relationship between testosterone and leptin was further strengthened by the prospective study in young males in whom serum leptin was reduced after testosterone injections and increased again after the discontinuation of the treatment. Our findings suggest that testosterone, either directly or indirectly, suppresses serum leptin in the normal male population.
This is in keeping with earlier findings in subgroups of male patients. Intramuscular testosterone treatment decreased plasma leptin levels in female to male transsexuals (18). Testosterone supplementation has been reported to normalize otherwise elevated plasma leptin levels in both young and old hypogonadal men (19, 20) without concomitant changes in body habitus, body fat content, or BMI (20). An inverse association of leptin and testosterone has also been reported in both untreated and testosterone-treated hypogonadal men (14) and in young men with insulin-dependent diabetes mellitus (21). Similarly, besides confirming a strong correlation between leptin and BMI and a gender difference in the levels of leptin, a recent population-based study reported an inverse correlation between leptin and testosterone that was independent of BMI (22).
Significant correlations between serum testosterone and leptin have not been found in all published studies. After adjusting for BMI, Haffner et al. found no correlation between leptin and sex hormones in a cross-sectional study of middle-aged normoglycemic men with asymptomatic atherosclerosis (23). In a study of elderly hypogonadal men, circulating leptin levels correlated strongly with BMI and body fat, but not with age, testosterone, or bioavailable testosterone (20). The reason for the diverging results is not known, but considering the complexity of factors affecting the regulation of leptin secretion, the heterogeneity of the populations studied may be a contributing factor.
One confounding factor in determining the testosterone-leptin
relationship is the concentration of sex hormone binding globulin
(SHBG), which may influence both total and free testosterone levels.
SHBG increases with age (24). In our study, the effect of age has been
controlled by using subjects in a narrow age range. As SHBG is reduced
in obese individuals (24, 25), obese men with the highest leptin levels
may also have relatively low SHBG concentrations. SHBG is known to be
positively correlated with total testosterone and inversely correlated
with the percent free testosterone (24). Therefore, the fraction of
free testosterone might have been greater than anticipated in obese
subjects, and the correlation between testosterone and leptin might be
even steeper than that presented in Fig. 1
.
Old age in men is accompanied by a decrease in the testosterone concentration (26) and changes in body composition. Therefore, age might also be an important secondary regulator of plasma leptin. In rats, leptin gene expression increases with age, independently of increasing adiposity (27). In humans, there are contradicting results of age dependence of the plasma leptin concentration. Ostlund et al. reported circulating leptin to be inversely related to age even after adjustment for percent body fat and gender (28). In contrast, Roberts et al. found no effect of age on the relationship between circulating leptin and body fat mass in weight-stable nonobese men and women aged 18–81 yr (29). It is noteworthy that any possible effect of age was eliminated in our study due to the narrow age range of the elderly subjects.
In our study, neither BMI nor serum insulin changed in testosterone-treated young men. As BMI does not discriminate between fat-free and fat mass, it cannot separate a muscular person from a fatty one. Nevertheless, BMI is easy to measure, it is usually also available retrospectively, and it is the most precise measure of short term longitudinal changes in body fat in a single person. In an earlier study in which weekly testosterone injections were used for contraceptive purposes in young men, fat mass decreased by 16% after 6 months of treatment (30). Therefore, the decline in serum leptin levels observed after repeated testosterone injections in our study could also be a phenomenon secondary to a decrease in body fat.
Adipocytes specifically bind androgens (31) and appear to carry androgen receptors (32). Administration of testosterone increases lipolysis and the number of ß-adrenoceptors in male rat adipocytes (33). Recently, it was reported that testosterone and its active metabolite dihydrotestosterone were able to suppress leptin secretion and leptin messenger ribonucleic acid in primary culture of human adipocytes, suggesting a direct effect of testosterone at the level of adipocytes (9). The mechanism by which testosterone exerts this negative effect is currently unclear.
In summary, we found an inverse association between leptin and testosterone both in a population-based study of elderly men and in young eugonadal men. Furthermore, the plasma leptin concentration was clearly suppressed during testosterone treatment and returned to the pretreatment level after cessation of testosterone treatment without concomitant changes in either BMI or serum insulin. The association between serum testosterone and leptin was still significant after adjusting for BMI and insulin. The mechanism underlying this effect of testosterone remains to be elucidated. Testosterone is probably one of the most important factors contributing to the lower serum leptin levels in men compared with women.
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Acknowledgments |
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Footnotes |
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Received February 26, 1998.
Revised June 3, 1998.
Accepted June 12, 1998.
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)
concentrations during testosterone treatment in young men. The first
measurements were performed at admission, 3 wk before the basal samples
(time zero) were collected. The error bars present the
SD.