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,
From the * Department of Medicine,
Veterans Affairs-Puget Sound Health Care System,
and Geriatric Research Education and Clinical
Center, University of Washington School of Medicine, Seattle, Washington; and
the Department of Medicine, Charles Drew
University, University of California at Los Angeles School of Medicine, Los
Angeles, California.
| Correspondence to: Stephanie T. Page, University of Washington Medical Center, Division of Endocrinology and Metabolism, 1959 NE Pacific, Box 357138, Seattle, WA 98195 (e-mail: page{at}u.washington.edu). |
| Received for publication June 12, 2004; accepted for publication August 17, 2004. |
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Abstract |
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Key words: Androgen, hypogonadal, leptin
Adiponectin is a recently characterized 30-kd protein secreted by adipocytes. It has sequence homology to collagen and C1q and is structurally related to the tumor necrosis factor alpha cytokine family (Haffner et al, 1996; Shapiro and Scherer, 1998; Berg et al, 2002). Adiponectin levels are almost always decreased with obesity (Rajala and Scherer, 2003), and an inverse relationship between serum adiponectin levels and body mass index (BMI) has been observed in monkeys and humans (Arita et al, 1999; Hotta et al, 2000, 2001; Berg et al, 2002). In addition, in humans, adiponectin levels correlate inversely with fat mass, particularly abdominal fat mass, in cross-sectional studies (Nishizawa et al, 2002; Cnop et al, 2003). Adiponectin appears to play a role in the regulation of insulin sensitivity (Arita et al, 1999; Hotta et al, 2000, 2001; Yang et al, 2001). Administration of recombinant adiponectin decreases plasma glucose levels in both normal and diabetic mice and improves insulin sensitivity in lipotrophic mice (Yamauchi et al, 2001). Similarly, adiponectin-deficient animals (adipo -/-) are moderately insulin resistant (Kubota et al, 2002). Although adiponectin has not yet been administered to humans, increased adiponectin levels are associated with weight loss (Hotta et al, 2000; Yang et al, 2001; Esposito et al, 2003) and thiazolidinedione treatment (Maeda et al, 2001; Yu et al, 2002), interventions that alter body composition and improve insulin sensitivity.
The relationship between adiponectin and T in humans has not been well characterized. Higher adiponectin levels are consistently found in women when compared with BMI and age-matched men (Arita et al, 1999; Nishizawa et al, 2002; Cnop et al, 2003), even when matched for intra-abdominal adiposity, a marker that negatively correlates with adiponectin levels (Cnop et al, 2003). In mice, castration increased adiponectin levels and insulin sensitivity, effects neutralized by the coadministration of T, whereas ovariectomy had no effect on female mice (Nishizawa et al, 2002), implying a role for T in adiponectin regulation in male mice. This observation is further supported by in vitro experiments, suggesting that T administration results in decreased secretion of adiponectin by 3T3-L1 adipocytes (Nishizawa et al, 2002) and the recent observation that T replacement for 6 months in young, hypogonadal men results in decreased adiponectin levels (Lanfranco et al, 2004). Together, these studies suggest that T might negatively regulate adiponectin production or serum half-life.
In this study, we hypothesized that suppression of endogenous T in normal men would result in increased serum adiponectin levels whereas administration of supraphysiologic doses of T would decrease adiponectin levels, consistent with the adiponectin data in mice (Nishizawa et al, 2002). In addition, we asked whether these changes are associated with changes in leptin, as a marker of fat mass, or BMI.
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Materials and Methods |
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Subjects
Serum adiponectin levels were retrospectively obtained from serum samples
stored at -20°C, which had not been thawed previously. Exclusion criteria
in all studies included known prostate cancer; diabetes mellitus; severe
liver, kidney, or musculoskeletal disease; substance abuse; and use of
anabolic steroids, androstenedione, dehydroepiandrosterone (DHEA), or growth
hormone.
Study 1— Twenty-one normal, healthy, eugonadal volunteers ages 18-50 years were randomized to treatment with acyline in various doses (Herbst et al, 2004). Seven eugonadal men who received T in addition to acyline in a separate study described elsewhere (Coviello et al, submitted) were included in the analyses to examine BMI and adipokines. There were no subjects lost to treatment once drug administration was initiated.
Study 2— Twenty-nine men aged 55-85 years were recruited and randomized to testosterone enanthate (TE; Schein Pharmaceuticals, Florham Park, NJ; n = 13) or placebo (n = 12) administration prior to knee or hip replacement as previously described (Amory et al, 2002; Herbst et al, 2003a). Samples were obtained in these outpatients 3 weeks (baseline) and 1 day prior to undergoing elective joint replacement; postoperative samples were not included in the analyses. Four subjects were excluded from the analyses on the basis of established diabetes mellitus managed with oral hypoglycemics (although inclusion of their values in the analyses did not change any of the significant results).
Protocols
Study 1—
Subjects were treated with various doses of acyline (300 µg/kg once, 75
µg/kg every 4 days x 3, or 75 µg/kg every other day x 5 for
a total dose of 225-375 µg/kg; Acyline, n = 21) or, in a separate study,
with acyline 300 µg/kg on day 0 + TE 100 mg/wk on days 0, 7, 14, and 21 as
described elsewhere (Acyline + TE, n = 7; Herbst et al, 2004; Coviello et al,
submitted). Subjects receiving Acyline alone were combined into a single group
because all dosage groups produced a similar decline in serum T to castrate
levels with similar kinetics (within 24 hours of acyline administration;
Herbst et al, submitted). Blood sampling was performed on days 0, 2-3, 4, 6-7,
14-15, 21, and 28-30.
Study 2— Participants were randomized to receive either TE 600 mg in 3 mL of sterile sesame oil intramuscularly (IM) every week (n = 13) or a placebo of 3 mL of sterile sesame oil IM every week (n = 12) on days 0, 7, and 14 as previously described (Amory et al, 2002). Blood samples were collected before injections on days 0, 7, 14 (baseline), and 21 in all subjects except a subset of men (n = 9) for which all 4 blood samples were collected after a 12-hour overnight fast (Herbst et al, 2003a).
The Institutional Review Board of the University of Washington and the Veterans Affairs Research and Development Committee approved the studies, and subjects gave written informed consent prior to screening in all cases.
Measurements
Testosterone—
T levels were measured by immunofluorometric assay (Delfia, Wallac Oy,
Turku, Finland, for subjects receiving Acyline alone or high-dose T;
Diagnostic Products Corporation [DPC], Los Angles, Calif, for subjects
receiving Acyline + T). All samples from a given individual were included in
duplicate in a single assay. The Delfia assay sensitivity was 0.5 nmol/L. For
low, mid, and high pooled values of 3.8, 10.6, and 24.4 nmol/L, respectively,
the intra-assay coefficients of variation were 9.6%, 5.2%, and 6.1% and the
interassay coefficients of variation were 12%, 8.2%, and 6.7%, respectively.
The DPC assay sensitivity was 0.35 nmol/L. For low, mid, and high pooled
values, the intra-assay coefficients of variation were 10.0%, 5.3%, and 6.6%
and the interassay coefficients of variation were 13.6%, 6.1%, and 6.8%
respectively.
Adiponectin— For all samples, adiponectin was measured by radioimmunoassay (Linco Research Inc, St Charles, Mo). All samples from each individual were measured in duplicate in one assay. The assay sensitivity for adiponectin was 1.56 µg/mL. Intra-assay and interassay coefficients of variation were 3.9% and 6.6%, respectively.
Leptin— For all samples, leptin was measured by radioimmunoassay (Linco Research). All samples from each individual were measured in duplicate in one assay. The assay sensitivity for leptin was 0.5 ng/mL. Intra-assay and interassay coefficients of variation were 5% and 7.1%, respectively.
Statistical Analysis
For statistical analyses and graphing of data from study 1, data from days
2-3 were labeled day 3; from days 6-7, day 7; from days 14-15, day 15; and
from days 28-30, day 30. All results are expressed as means ± SEM
unless otherwise indicated. A paired t test with a Bonferroni
correction was used to determine differences between treatment and baseline
values within a group. Changes over time between groups were assessed by a
2-way analysis of variance of hormone levels, with time and group as factors,
and were verified with a Tukey's honestly significant difference post hoc
test. In addition, differences between groups at a given time point were
verified by 2-sample Student's t tests. For all comparisons,
P 
.05 was considered statistically significant.
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Results |
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Study 1: Testosterone Deficiency and Adiponectin
Acyline is a potent GnRH antagonist that, as we have previously reported
(Herbst et al, 2002), renders
normal young men acutely hypogonadal with serum T in the castrate range; in
this study, we found that all dosage regimens of acyline resulted in nearly
undetectable serum gonadotropins within 24 hours after a single dose or
multiple doses. This effect persisted for at least 15 days after a dose of 300
µg/kg (Herbst et al, 2004); thereafter, T levels slowly rose back to
baseline levels by day 30 post-injection
(Figure 1A). Adiponectin was
significantly increased above baseline within 7 days of acyline
administration, an effect that persisted as long as 30 days following single
or multiple doses of acyline (Figure
1B). A maximal increase in adiponectin of 49% ± 5.5% was
seen at day 21 following acyline administration (maximum adiponectin at day 21
of 12.2 ± 1.0 compared with 8.6 ± 0.9 µg/mL at baseline;
Figure 1B).
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To determine whether the effect of acyline on adiponectin was specifically attributable to the resultant decrease in serum testosterone levels, we measured adiponectin levels in subjects who received TE 100 mg IM/wk for 4 weeks in addition to 300 µg/kg of acyline starting on day 0. In these subjects, serum testosterone levels were maintained within the normal range throughout the treatment period (Figure 1A), and serum adiponectin (Figure 1B) did not change significantly.
Because adiponectin might be affected by changes in body composition, we examined leptin, as a biochemical marker of fat mass, and BMI in subjects receiving acyline. Leptin levels increased significantly in subjects receiving Acyline alone by day 15 (data not shown), an effect that persisted through day 30 (Table 3). Changes in leptin in subjects receiving both acyline and T (Table 3) were not significant. BMI was unchanged in subjects receiving Acyline or Acyline + TE (Table 3), and baseline BMI and change in adiponectin were not correlated.
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Study 2: Adiponectin and Supraphysiologic Testosterone
Because adiponectin levels were sensitive to a rapid decrease in serum T,
we examined whether increases in serum T above the normal range would affect
adiponectin levels. Elderly men received 600 mg of TE or placebo IM for 3
weeks, and adiponectin levels were measured at baseline and 21 days later. As
reported previously (Amory et al,
2002), serum T in the group receiving exogenous T was
significantly increased above baseline, whereas in the placebo group, T levels
were unchanged (Figure 2A).
Adiponectin significantly decreased from baseline in subjects receiving
exogenous T for 21 days, (baseline 14.3 ± 1.9 compared with 10.8
± 1.5 µg/mL on day 21, P < .05 vs baseline and placebo),
whereas it was unchanged in the placebo group (baseline 12.9 ± 1.4
compared with 12.6 ± 1.3 µg/mL on day 21;
Figure 2B).
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Because adiponectin can be affected by changes in body composition, we examined leptin as a marker of fat mass and BMI in subjects receiving 600 mg TE/wk IM. Leptin levels decreased in the subjects receiving T compared with both baseline and placebo, whereas in the placebo group, leptin increased slightly compared with baseline (Table 3). BMI increased significantly over baseline and when compared with the placebo group in subjects receiving 600 mg TE/wk IM (Table 3). There was no correlation between baseline BMI and change in adiponectin.
To determine the time course of adiponectin changes in the setting of supraphysiologic T levels, weekly adiponectin levels were measured in a subgroup of the subjects receiving TE 600 mg/wk IM (n = 4) or placebo (n = 5) who had participated in a substudy of acute lipid effects of high-dose T (Herbst et al, 2003a). A trend toward a decrease in adiponectin by day 14 after testosterone administration persisted at day 21 (Figure 3). However in this small subgroup, the differences compared with baseline and placebo did not reach statistical significance. Leptin decreased by 36.3% ± 3.1% on day 14 and 29.4% ± 9.9% on day 21 with T and increased by 24.7% ± 18.3% on day 14 and 20.3% ± 7.9% on day 21 in the placebo group (P < .05) in the subgroup analyses, but either group compared with baseline was not significantly different.
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Discussion |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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-reduction to
dihydrotestosterone) regulate adiponectin levels in men. Our data demonstrate the marked effect of T, its active metabolites (estradiol and dihydrotestosterone), or both on adiponectin in vivo. Even though these analyses used stored serum, the differences we observed are not likely attributable to the instability of adiponectin in stored samples because measurements of adiponectin by radioimmunoassay have been shown to be reproducible in samples stored up to 1 year at -20°C (Pischon et al, 2003). We cannot exclude the possibility that our results are influenced by baseline differences between the study subjects in each group (Tables 1 and 2). Of note, higher baseline adiponectin levels were observed in the older men despite their higher BMI (Table 2). This is likely a function of age because a recent analysis found age to be more strongly related to adiponectin than any other variable analyzed, including BMI and intra-abdominal fat (Cnop et al, 2003). Similar studies in age- and BMI-matched groups would further validate our observations, but we saw changes in adiponectin with T manipulation in both young and older men, suggesting that the regulatory effect of T on adiponectin is not age dependent
The mechanism by which T influences adiponectin is not clear from these studies. It is possible that the effect of T on adiponectin is mediated through its effects on body composition. T has been shown to increase lean body mass and decrease fat mass as soon as 4 weeks after administration (Herbst et al, 2003). Similar changes in body composition with administration of supraphysiologic doses of TE are likely to have occurred in this study because we observed a decrease in leptin and an increase in BMI within 21 days (Table 2). Conversely, hypogonadism is associated with increased fat mass and BMI (Smith et al, 2001; Basaria et al, 2002). Consistent with these results, in our study, leptin increased within 30 days of acute hypogonadism. These changes in leptin, and by inference fat mass, were both temporally and positively associated with changes in adiponectin in both of our studies. It is possible that decreases in fat mass result acutely in decreased secretion of adiponectin by adipocytes and, conversely, that acute increases in fat mass result in increases in adiponectin levels. This would be in contrast to cross-sectional studies wherein adiponectin levels correlate inversely with fat mass, abdominal fat mass in particular (Cnop et al, 2003; Ducluzeau et al, 2003), and weight loss is associated with increases in serum adiponectin (Yang et al, 2001). Future studies that include detailed body composition by dual x-ray absorptiometry (DEXA) or computed tomography scan in the setting of androgen manipulation are warranted in determining the mechanism through which T regulates adiponectin.
Whether sex steroids have a direct effect on adiponectin metabolism,
cellular trafficking, or expression by adipocytes is not known. It is possible
that androgens decrease adiponectin expression by sequestering ARA70, a
coactivator common to both the androgen receptor (AR) and peroxisome
proliferator-activated receptor gamma 1 (PPAR
;
Heinlein et al, 1999).
PPAR1,2, the AR, and ARA70 are all expressed in human adipocytes
(Dieudonne et al, 1998), and
ARA70 is upregulated during adipocyte differentiation, a PPAR-mediated
process (Yeh and Chang, 1996;
Nishizuka et al, 2002). PPAR agonists, thiazolidinediones, have been shown to increase
adiponectin expression (Maeda et al,
2001), likely through a functional PPAR-responsive element in the
human adiponectin promoter (Iwaki et al,
2003). In vitro activation of the AR reduces ARA70-dependent
expression of a PPAR reporter gene, suggesting that cross talk might
exist between the AR and PPAR via sequestration of ARA70 within tissues
that coexpress both AR and PPAR
(Heinlein et al, 1999). In
this model, interaction of the AR with T might compete with PPAR for
ARA70, resulting in reduced expression of PPAR-regulated genes such as
adiponectin. Validation of such a model will require further molecular
analyses.
The effects of androgens on insulin sensitivity are not well understood. Three months of androgen deprivation mediated by a GnRH agonist in elderly men with prostate cancer increases serum insulin levels (Smith et al, 2001; Dockery et al, 2003), whereas oral T undecanoate increased insulin sensitivity in obese, middle-aged men (Marin et al, 1992a,b). However, studies of androgen supplementation in elderly hypogonadal and eugonadal men have not verified these findings (Friedl et al, 1989; Singh et al, 2002; Liu et al, 2003; Schroeder et al, 2003), and supraphysiologic doses of TE in young healthy subjects do not appear to improve insulin sensitivity (Friedl et al, 1989; Singh et al, 2002). It is possible that although androgens decrease adiponectin, which might decrease insulin sensitivity, the favorable affects of androgens on body composition neutralize this effect with no net change in insulin sensitivity.
We have demonstrated that experimentally induced T deficiency increases circulating adiponectin, whereas supraphysiologic T suppresses adiponectin in normal men. We conclude that T, its active metabolites, or both suppress circulating adiponectin concentrations and also that androgen administration reduces basal adiponectin concentrations. Whether or not these changes persist long term and what effect they have on insulin sensitivity will be the subject of future research.
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Acknowledgments |
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Footnotes |
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S.T.P. and K.L.H. contributed equally to this work and should both be considered first authors.
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R. B. S. Harris, T. J. Bartness, and H. J. Grill Leptin Responsiveness in Chronically Decerebrate Rats Endocrinology, October 1, 2007; 148(10): 4623 - 4633. [Abstract] [Full Text] [PDF]
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 D. Barb, C. J Williams, A. K Neuwirth, and C. S Mantzoros Adiponectin in relation to malignancies: a review of existing basic research and clinical evidence Am. J. Clinical Nutrition, September 1, 2007; 86(3): 858S - 866S. [Abstract] [Full Text] [PDF]
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D. Glintborg, M. Andersen, C. Hagen, J. Frystyk, V. Hulstrom, A. Flyvbjerg, and A. P. Hermann Evaluation of metabolic risk markers in polycystic ovary syndrome (PCOS). Adiponectin, ghrelin, leptin and body composition in hirsute PCOS patients and controls. Eur. J. Endocrinol., August 1, 2006; 155(2): 337 - 345. [Abstract] [Full Text] [PDF]
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M.-H. Gannage-Yared, S. Khalife, M. Semaan, F. Fares, S. Jambart, and G. Halaby Serum adiponectin and leptin levels in relation to the metabolic syndrome, androgenic profile and somatotropic axis in healthy non-diabetic elderly men. Eur. J. Endocrinol., July 1, 2006; 155(1): 167 - 176. [Abstract] [Full Text] [PDF]
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A. Bojesen, K. Kristensen, N. H. Birkebaek, J. Fedder, L. Mosekilde, P. Bennett, P. Laurberg, J. Frystyk, A. Flyvbjerg, J. S. Christiansen, et al. The Metabolic Syndrome Is Frequent in Klinefelter's Syndrome and Is Associated With Abdominal Obesity and Hypogonadism Diabetes Care, July 1, 2006; 29(7): 1591 - 1598. [Abstract] [Full Text] [PDF]
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 M Mitchell, D T Armstrong, R L Robker, and R J Norman Adipokines: implications for female fertility and obesity Reproduction, November 1, 2005; 130(5): 583 - 597. [Abstract] [Full Text] [PDF]
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