Download Relationships of Leptin and Sex Hormones with the Body Mass

Original Article
Relationships of Leptin and Sex Hormones
with the Body Mass Index and Waist/Hip Ratio
in Aging Taiwanese Males
Hung-En Chen, Te-Fu Tsai, Thomas I.S. Hwang
Division of Urology, Department of Surgery, Shin Kong WHS Memorial Hospital,
Taipei, Taiwan, R.O.C.
OBJECTIVE: To evaluate the relationships of leptin and sex hormones with the anthropometric parameters of general obesity (body mass index, BMI) and fat distribution (waist/ hip ratio,
WHR).
MATERIALS AND METHODS: There were 346 Taiwanese males aged 40~89 (median, 52)
2
years included in this study. The body mass index [BMI, weight (kg)/height (m )] was used as a
measure of general obesity. The waist/hip ratio [WHR, waist circumference (cm)/hip circumference
(cm)] was used to estimate fat distribution. Leptin and sex steroid levels, including total and free
testosterone, dehydroepiandrosterone sulfate (DHEAS), sex hormone-binding globulin (SHBG),
and estradiol were assessed using a radioimmunoassay. The relationships of leptin and sex hormones to age-specific ranges (in 10-year increments) were evaluated by the Mann-Whitney test,
and these to BMI, WHR, and age were evaluated by use of non-parametric statistics (Pearson coefficients).
RESULTS: Free testosterone and DHEAS levels declined with the aging process, showing
significant declines in certain age-specific ranges (p < 0.001 to p < 0.05, respectively), and were
also inversely correlated with age (r = -0.51, p < 0.001; r = -0.56, p < 0.001, respectively), while an
increase of SHBG was related to age (r = 0.38, p < 0.001) and significantly increased in
age-specific ranges. Although the BMI and WHR were generally steady among the age-specific
ranges (BMI values of between 24.1 ± 3.0 and 25.2 ± 4.4kg/m2, and WHR values of between
0.90 ± 0.04 and 0.93 ± 0.05), WHR demonstrated a significant increase with age (r = 0.28, p <
0.001). Moreover, leptin demonstrated non-significant changes in age-specific ranges, but leptin
was shown to be related to age (r = 0.10, p < 0.05) and strongly related to the BMI (r = 0.56, p <
0.001) and WHR (r = 0.28, p < 0.001).
CONCLUSIONS: In Taiwanese males, age is accompanied by reductions in sex hormone
levels, and increases in SHBG and leptin; moreover, there was no significant change in the fat
body mass, but there was a change in the body composition. Only leptin and total testosterone
demonstrated significant relationships with age-related changes in anthropometric parameters
(BMI and WHR). (JTUA 17:1-7, 2006)
Key words: leptin, sex hormone, body mass index, waist/hip ratio, age.
The distribution and growth of adipose tissue in
men are regulated by both genetic and environmental
INTRODUCTION
Received: Sep. 21, 2005
Revised: Oct. 30, 2005
Accepted: Feb. 7, 2006
Address reprint requests and correspondence to: Thomas I.S. Hwang, MD
Division of Urology, Department of Surgery, Shin Kong WHS Memorial Hospital. No. 95 Wen Chang Rd., Shih Lin District, Taipei, 111, Taiwan, R.O.C.
台灣泌尿醫誌第十七卷第一期（95 年 03 月）
1
Leptin, Sex Hormones and the BMI and WHR
Table 1. Leptin and sex-related hormones in normal Taiwanese males (N = 346).
Age
Leptin
Testosterone
Free testosterone
E2
DHEAS
(year)
(ng/ml)
(ng/ml)
(pg/ml)
(pg/ml)
(ug/dl)
27.2±5.6
179.5±64.0
3.15±1.52
4.92±1.33
40~49(n=171)
12.2±2.97
27.9±6.2
131.3±52.9***
3.38±1.83
4.66±1.32
50~59(n=103)
10.4±2.53***
3.10±1.51
4.75±1.52
27.1±6.0
85.6±43.8***
60~69(n=49)
8.6±2.44***
*
4.16±1.85
4.48±1.93
29.1±6.4
38.3±17.1*
≧ 70(n=23)
7.3±2.38
E2, estradiol; DHEAS, dehydroepiandrosterone sulfate; SHBG, sex hormone-binding globulin.
p < 0.05; ** p < 0.01; *** p < 0.001.
SHBG
(nM)
30.4±13.7
36.5±16.0**
50.9±26.3***
49.5±20.7
factors. Leptin and sex hormones are hypothesized to
significantly affect the male body composition and the
quantity of adipose tissue, as well as its distribution in
the body [1,2]. However, there are few reports related
to aging Taiwanese males [3].
Aging is associated with reductions in plasma sex
steroid hormones levels, as well as lower plasma testosterone [4]. Furthermore, a decrease in dehydroepiandrosterone sulfate (DHEAS) levels has also been reported with advancing age [5,6]. Significant changes in
body fatness and adipose tissue distribution occur with
age, and older men are generally characterized by increased body fatness and preferential accumulations of
adipose tissue. Clinically, a steady reduction in adipose
tissue found in hypogonadal men in the course of testosterone supplementation has been observed [7], but
evidence reveals that the body composition may result in
unfavorable alterations of androgen-estrogen activity,
especially in aging males [8]. However, to what extent
age-related alterations in steroid hormone profiles result
from concomitant changes in body composition and increases in adipose tissue is not well documented. Furthermore, the role of leptin, estradiol (E2), and sex hormone-binding globulin (SHBG) on body fatness and its
distribution have not been well investigated yet [9], especially in aging Taiwanese males.
This study was carried out to evaluate the relationships of leptin and sex hormones with the anthropometric parameters of general adiposity and fat dis- tribution in Taiwanese males; moreover, we compared our
data with other reports to evaluate the racial element.
were excluded). Data on the quantities of nicotine and
alcohol consumed, physical activity, nutritional factors,
level of education, profession, and financial status were
also taken into consideration.
Leptin and sex hormones including total and free
testosterone, E2, DHEAS, and sex hormone-binding
globulin (SHBG) were assessed using a radioimmunoassay (RIA). Blood samples (5 ml) were drawn after
overnight fasting at 08:00-10:00 before any other examination.
The reagents used were products of the respective
diagnostic kits, such as leptin (LINCO Research, USA),
total testosterone (Roche Elecsys, Germany), free testosterone (DSL, USA), DHEAS (Immunotech, France),
and SHBG(Immunotech, France). The intra-assay coefficient of variation ranged 4.8% to 6.1%, while the interassay coefficient of variation ranged 5.1% to 10.2%.
The BMI [weight (kg)/height (m)2] was used as a
measure of general obesity, while the WHR [waist circumference (cm)/hip circumference (cm)] was used to
estimate the fat distribution.
Among all of the men examined, relationships
among hormone levels, BMI, WHR, and age were
evaluated by use of non-parametric statistics (Pearson
coefficients). Age-specific differences in hormonal
variables were evaluated using the Mann-Whitney test.
Intergroup differences in anthropometric parameters
were evaluated using Student’s t-test. For all tests, p <
0.05 was considered significant.
MATERIALS AND METHODS
Table 2. The body mass index (BMI) and waist/hip
ratio (WHR) of normal Taiwanese males
(N = 346).
Age
BMI
WHR
(year)
(kg/m2)
(cm/cm)
24.1±3.0
0.90±0.04
40~49 (n = 171)
25.2±4.4
0.92±0.05*
50~59 (n = 103)
24.9±2.7
0.93±0.05
60~69 (n = 49)
24.3±3.1
0.92±0.04
≧ 70 (n = 23)
p < 0.05.
The study cohort was comprised of 346 healthy
men aged 40~89 years who went for a physical check-up.
The men included in the study suffered from no essential
disease (in particular, those connected with gonadal
dysfunction) and had no past history of such disease, nor
did they present any somatic pathologies on physical
examination (in particular, those with hypogonadism
2
JTUA Vol.17 No.1, March 2006
HE Chen, TF Tsai, TIS Hwang
Table 3.
Relationships of leptin and sex hormones with age, the BMI, and WHR
Age
BMI
WHR
r
p value
r
p value
r
p value
Leptin
0.10
< 0.05
0.56
< 0.001
0.27
< 0.001
Sex hormones
Total testosterone
-0.11
< 0.05
- 0.15
< 0.01
- 0.16
< 0.01
Free testosterone
-0.51
< 0.001
- 0.05
> 0.05
- 0.18
< 0.01
DHEAS
-0.557
< 0.001
0.08
> 0.05
- 0.17
< 0.01
E2
0.06
> 0.05
0.18
< 0.01
- 0.02
> 0.05
SHBG
0.38
< 0.001
- 0.20
< 0.001
- 0.05
> 0.05
BMI
0.03
> 0.05
WHR
0.28
< 0.001
BMI, body mass index; WHR, waist/hip ratio; E2, estradiol; DHEAS, dehydroepiandrosterone sulfate; SHBG, sex
hormone-binding globulin.
Fig.1a
Free testosterone vs. Age
25
Free testosterone (pg/mL)
Coefficient of regression determination: R2 = 0.260 (p < 0.001)
Pearson correlation coefficient: r = - 0.51
20
15
10
5
0
40
50
60
70
Fig.1b
In this study of 346 Taiwanese middle-aged and
elderly males, we found that the aging process had relatively strong inverse relationships with free test- osterone and DHEAS and a positive correlation with SHBG,
whereas modest relationships were found with total tes台灣泌尿醫誌第十七卷第一期（95 年 03 月）
90
Leptin vs.
vs. Age
waist-hip ratio (WHR)
DHEAS
10
Coefficient of regression determination: R2 = 0.073 (p < 0.001)
9
correlation
coefficient: r = 0.27
Coefficient
of regression determination:Pearson
R2 = 0.3211
(p < 0.001)
8
Pearson correlation coefficient: r = - 0.557
7
6
5
4
3
2
1
0
400
350
300
250
200
150
100
50
0
40
0.80
50
0.85
60
Age (years)
DISCUSSION
80
Age (years)
Leptin (ng/mL)
Serum levels of leptin and sex-related hormones of
essentially normal Taiwanese males in age-specific
ranges are listed in Table 1, which reveals the influence
of age. Generally, declines in free testosterone and
DHEAS with age and a rise in SHBG with age were
observed and significantly differed among each 10-year
range. No significant changes were found in total testosterone, leptin, or E2 levels among the age-specific
ranges.
The BMI and WHR of normal Taiwanese males are
shown in Table 2. Generally no significant differences
between age groups were found for BMI and WHR. The
relationships of leptin and sex hormones to age, BMI, or
WHR are shown in Table 3. Trends of reduced total testosterone (r = -0.11, p < 0.05), free testosterone (r =
-0.51, p < 0.001) and DHEAS (r = -0.56, p < 0.001) levels were found with age (Fig. 1a, b), while trends of increased SHBG (r = 0.38, p < 0.001) and leptin (r = 0.10,
p< 0.05) levels were related to age. The WHR was related to age (r = 0.28, p < 0.001), while the BMI was
not.
Moreover, only leptin was shown simultaneously to
be strongly related to the BMI (r = 0.56, p < 0.001) and
WHR (r = 0.27, p < 0.001) (Fig. 2a, b), while total testosterone was inversely and modestly related to the BMI
and WHR (r = -0.15, p < 0.01, r = -0.16, p < 0.01, respectively) (Table 3).
tosterone and leptin, but no relation was found with E2.
Our results support most studies which have reported an
aging influence on sex hormones in healthy males
[1,4,10].
DHEAS (ug/dL)
RESULTS
0.90
70
0.95
80
1.00
90
WHR (cm/cm)
Fig 1. Relationships of free testosterone and dehydroepiandrosterone sulfate (DHEAS) with age.
The curves reveal that free testosterone and
DHEAS decline with age (1a, r= -0.51, p < 0.001;
1b, r = -0.557, p < 0.001).
Leptin is a protein hormone produced by adipose
3
1.05
Leptin, Sex Hormones and the BMI and WHR
4
Fig.2a
12
Leptin vs. body-mass index (BMI)
Coefficient of regression determination: R2 = 0.304 (p < 0.001)
Pearson correlation coefficient: r = 0.56
10
Leptin (ng/mL)
cells, and it modulates food intake and the metabolic
rate [1]. Leptin predominately influences human energy
balance through neuronal pathways by regulating food
intake and may interact with other hormones, such as
testosterone, ghrelin, and adeponectin, in regulating energy expenditures, although the exact mechanism is still
unclear [11,12].Leptin levels significantly increased
with age in Taiwanese middle-aged and elderly males in
this study as has been reported in Caucasian males
[11,13], while Perry et al. reported that leptin levels
tended to be inversely correlated with age (r = -0.228, p
= 0.09) in African-American men [10]. In most studies,
leptin is highly correlated with body fat and the BMI
[10,14,15]. In this study, leptin levels were found to be
strongly correlated with the BMI and WHR among Taiwanese males, although there are fewer obviously and
extremely obese individuals among Taiwanese compared to Western people who maintain much higher
BMI and WHR values [10,15].
What is the significance of the strong correlation
of leptin with the BMI and WHR? After cloning of the
ob gene, the severely obese leptin-deficient ob/ob mice
were injected with leptin, which led to weight loss [16].
These findings support the initial concept that leptin’s
function is to control weight gain by reducing food intake and increasing energy expenditure, and that human
obesity might also be a leptin-deficient state. However,
obese homozygous individuals with a leptin deficiency
state have only rarely been found, and several demographic studies have failed to demonstrate a mutation in
the human gene coding for leptin. In contrast, elevated
serum levels of leptin in obese individuals have been
found [17]. It is clear now that the vast majority of human obesity is associated with increased levels of leptin.
A similar result was found in our study. Although the
exact mechanism is not clear, a hypothesis of leptin resistance or reduced sensitivity to leptin associated with
human obesity is suggested by these findings.
The BMI is used as a reliable measure of general
obesity and has been strongly related to a variety of
measures of fatness [18], especially among middle-aged
adults. Obesity is a heterogeneous condition, and not
every obese patient is at an increased risk of cardiovascular disease; only an unfavorable fat distribution
(such as visceral obesity) is a critical complication of
obesity [6]. The WHR was used to estimate visceral
obesity, which is considered an increased risk for cardiovascular complications [6]. Moreover, this type of
obesity is associated with several hormonal and
metabolic aberrations, as well as increased risks of developing cardiocerebrovascular disease and non– insulin
-dependent diabetes mellitus [18].
In men, testosterone is the main testicular androgen
8
6
4
2
0
15
20
25
30
35
BMI (kg/m2)
Fig.2b
Fig 2. Relationships of leptin with the body mass
index (BMI) and waist/hip ratio (WHR). The
curves reveal that leptin is positively correlated with both the BMI (2a, r = 0.56, p <
0.001) and WHR ( 2b, r = 0.27, p < 0.001).
[19], E2 is the main circulating estrogen, and DHEAS is
the main adrenal androgen [6,19], whereas SHBG is a
binding protein which regulates the tissue availability of
free androgens and estrogens [20]. In most populations
of elderly men, BMI has been associated with decreases
in SHBG [18,20], DHEAS [4,6,14], total testosterone
and, free testosterone [4,20], and increases in E2 [10,13].
However, only modest inverse correlations of total testosterone and the BMI (r = -0.15, p < 0.01), and SHBG
and the BMI (r = -0.20, p < 0.001), and a positive correlation of E2 and the BMI (r = 0.18, p < 0.01) were found
in Taiwanese males in this study, while no correlations
were demonstrated for free testosterone or DHEAS with
the BMI.
Visceral adiposity has been generally linked to adrenal and gonadal hypoandrogenicity in men[7]. Some
studies have confirmed an inverse association of the
WHR with total and free testosterone levels as well as
with DHEAS [15], as did this study (Table 3). However,
another study found no correlation with testosterone and
JTUA Vol.17 No.1, March 2006
HE Chen, TF Tsai, TIS Hwang
DHEAS [4], in healthy or in obese men, suggesting the
extent of decline in sex hormones mainly depends on the
degree of obesity.
8.
CONCLUSIONS
Significant correlations of leptin with the BMI as
well as with the WHR were demonstrated in Taiwanese
males, while only a modest inverse correlation of total
testosterone to BMI and inverse correlations of total and
free testosterone to WHR were shown. This study suggests that androgen decline caused by normal aging is
not obviously related to general obesity or body composition in older Taiwanese males. Therefore, androgen
supplementation in hypogonadal older men is not expected to influence body composition to the same extent.
ACKNOWLEDGEMENTS
This study was supported by a research grant
(8302-90-1601-01) from Shin Kong WHS Memorial
Hospital; technical assistance by Ms. Karen Zu-Hwa
Cheng is gratefully acknowledged.
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5
Original Article
Received: Sep. 21, 2005
Revised: Oct. 30, 2005
Accepted: Feb. 7, 2006
Address reprint requests and correspondence to: Thomas I.S. Hwang, MD
Division of Urology, Department of Surgery, Shin Kong WHS Memorial Hospital. No. 95 Wen Chang Rd., Shih Lin District, Taipei, 111, Taiwan, R.O.C.
台灣泌尿醫誌第十七卷第一期（95 年 03 月）
1