Hum. Reprod. Advance Access originally published online on May 4, 2006
Human Reproduction 2006 21(9):2257-2265; doi:10.1093/humrep/del146
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Adiponectin and resistin in PCOS: a clinical, biochemical and molecular genetic study
1 Department of Endocrinology and 2 Department of Molecular Genetics, Hospital Universitario Ramón y Cajal, Madrid, Spain
3 To whom correspondence should be addressed at: Department of Endocrinology, Universidad de Alcalá, Hospital Universitario Ramón y Cajal, Carretera de Colmenar Km 9’1, Madrid E-28034, Spain. E-mail: hescobarm.hrc{at}salud.madrid.org
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Abstract |
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BACKGROUND: We conducted a cross-sectional case–control study to evaluate the possible involvement of adiponectin and resistin in the pathogenesis of polycystic ovary syndrome (PCOS). METHODS: Seventy-six PCOS patients and 40 non-hyperandrogenic women matched for BMI and degree of obesity were included. Serum adiponectin and resistin levels, anthropometrical and hormonal variables, the 45 T
G and 276 GT polymorphisms in the adiponectin gene, and the –420 CG variant in the resistin gene, were analysed. RESULTS: Serum adiponectin concentrations were reduced in PCOS patients compared with controls (P = 0.038) irrespective of the degree of obesity, whereas serum resistin levels were increased in overweight and obese women compared with lean subjects (P = 0.016), irrespective of their PCOS or controls status. The adiponectin and resistin polymorphisms were not associated with PCOS and did not influence serum levels of adiponectin, resistin and other clinical and hormonal variables. In a multiple regression model, the waist-to-hip ratio, free testosterone levels and age, but not insulin resistance, were the major determinants of hypoadiponectinaemia. CONCLUSIONS: PCOS patients present with hypoadiponectinaemia, in relation with abdominal adiposity and hyperandrogenism. Our present results suggest that hyperandrogenism and abdominal obesity, by reducing the serum levels of the insulin sensitizer adipokine adiponectin, might contribute to the insulin resistance of PCOS.
Key words: adiponectin/adipokines/insulin resistance/polycystic ovary syndrome/resistin
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Introduction |
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The polycystic ovary syndrome (PCOS) can be considered a human model of insulin resistance, given that both lean and obese women presenting with PCOS are insulin resistant when compared with their non-hyperandrogenic counterparts, although insulin resistance is not a universal finding in PCOS patients (Ehrmann, 2005
). Furthermore, PCOS is frequently associated with obesity, the metabolic syndrome and disorders of glucose tolerance (Ehrmann, 2005).
Considering the frequent clustering of obesity and insulin resistance-associated disorders in PCOS patients (Ehrmann, 2005), the adipokines adiponectin and resistin, among other molecules and hormones secreted by adipose tissue, have been proposed to play a role in the pathogenesis of PCOS (Carmina et al., 2005).
Serum adiponectin levels are decreased in PCOS patients (Panidis et al., 2003; Ardawi and Rouzi, 2005; Carmina et al., 2005), yet this result may be explained by the concurrence of obesity (Orio et al., 2003), insulin resistance (Spranger et al., 2004; Sepilian and Nagamani, 2005) and/or impaired glucose tolerance (Sieminska et al., 2004) in these women. Similar considerations apply to the increase in serum resistin levels described in PCOS (Panidis et al., 2004a; Carmina et al., 2005) and to the discrepant results found regarding the possible influence of common polymorphisms in the genes encoding adiponectin and resistin in the pathogenesis of PCOS (Urbanek et al., 2003; Panidis et al., 2004b; San Millan et al., 2004; Xita et al., 2004, 2005; Haap et al., 2005), especially because the populations included in these genetic studies were not homogeneous in terms of prevalence and degree of obesity.
Because obesity possibly acted as a major confounding factor in the studies published to date, we aimed to define the influence of PCOS on the serum levels of adiponectin and resistin, and its possible association with common polymorphisms in the adiponectin and resistin genes, in a homogeneous population of PCOS patients and controls in terms of prevalence and degree of obesity.
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Materials and methods |
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Subjects
Seventy-six consecutive PCOS patients and 40 non-hyperandrogenic women were included in the study. The PCOS and control groups were matched for BMI, degree of obesity [lean, BMI < 25 kg/m2; overweight, BMI 25–29.9 kg/m2; obese, BMI
30 kg/m2 (National Institutes of Health Consensus Development Panel, 1998)] and prevalence of smoking. The control group was composed of lean female volunteers and consecutive patients reporting to the endocrinology outpatient clinic for dietary treatment of obesity. Hyperandrogenic disorders were ruled out thoroughly in all the controls. All the women were Caucasian, and none had a history of disorders of glucose tolerance or hypertension or had taken hormonal medications for the last 6 months. The ethics committee of the Hospital Ramón y Cajal approved the study, and informed consent was obtained from each patient and control.
The diagnosis of PCOS was based on endocrine criteria (Zawadzki and Dunaif, 1992; The Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group, 2004): clinical and/or biochemical hyperandrogenism, ovulatory dysfunction, and exclusion of hyperprolactinaemia, nonclassic congenital adrenal hyperplasia and androgen-secreting tumours. Ovarian ultrasound examination was not performed, and no patients with the new criteria added by the ESHRE/ASRM consensus meeting were studied here. The methods used to define hyperandrogenism and ovulatory dysfunction and to exclude secondary aetiologies have been detailed earlier (Villuendas et al., 2005).
Protocol
Clinical and anthropometrical variables, including hirsutism score, clinical blood pressure, BMI and waist-to-hip ratio (WHR), were determined in all the subjects. Serum and plasma sampling and an oral glucose tolerance test (OGTT) were performed as previously reported (Villuendas et al., 2005). Samples were used for measurement of adiponectin, resistin, total testosterone, androstenedione, dehydroepiandrosterone sulphate (DHEA-S), sex hormone-binding globulin (SHBG), a complete lipid profile and basal and post-OGTT insulin and glucose levels.
Adiponectin and resistin were measured by commercial immunoassays (Human Adiponectin RIA Kit and Human Resistin ELISA Kit, Linco Research, St. Charles, MO, USA) with intra- and inter-assay coefficients of variation below 10%. The technical characteristics of the assays employed for plasma glucose, lipid profiles and serum hormone measurements have been reported elsewhere (Escobar-Morreale et al., 1997, 2000; San Millán et al., 2001). The free testosterone concentration was calculated from total testosterone and SHBG concentrations (Vermeulen et al., 1999). The composite insulin sensitivity index (ISI) was calculated from the circulating glucose and insulin concentrations during the OGTT (Matsuda and DeFronzo, 1999), and beta-cell function was estimated from fasting insulin and glucose levels by the homeostasis model assessment (HOMA-
) (Matthews et al., 1985).
Genotype analysis
DNA was extracted from lymphocytes by the salting-out method. Genotyping of polymorphisms 45 TG and 276 GT in the adiponectin gene (Hara et al., 2002) was performed by PCR–RFLP using endonucleases AvaI and BsmI, respectively. Primers were designed from contig NT005962 (www.ncbi.nlm.nih.gov) to amplify a 439-bp fragment (from nucleotide 2301053 to nucleotide 2301491) that includes both polymorphisms (San Millan et al., 2004). A CG variation located 420 bp upstream to the initiation codon in the putative promoter region of human resistin gene was studied as previously described (Mattevi et al., 2004).
Statistical analysis
Data are represented as mean ± SD unless otherwise stated. The primary end-point of the study was to evaluate the influence of PCOS on serum adipokines while considering the possible influences of obesity and of the polymorphisms in adiponectin and resistin genes described earlier on these hormones. A multivariate general linear model (GLM) was used to analyse the influence of having PCOS, degree of obesity, adiponectin and resistin genotypes, and the interaction between all these factors, on serum adipokines and clinical and biochemical variables. Because the adiponectin 45 TG and 276 GT polymorphisms are in linkage disequilibrium (Xita et al., 2005), only the 45 TG variant was included in the model to fulfil the GLM prerequisite of actual independence between independent variables. Age was introduced as a covariate, because controls were older compared with PCOS patients. The GLM calculated also the univariate influences of independent variables only when supported by a significant multivariate result. Before GLM analysis, the dependent variables were tested for normality using the Kolmogorov–Smirnov statistic, logarithmic or square root transformations applied as needed to ensure a normal distribution.
Pearson’s 
2 and Fisher’s exact tests were used to test the association between discontinuous variables and to test the genomic variants for deviation from the Hardy–Weinberg equilibrium. P < 0.05 was considered statistically significant.
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Results |
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Effect of PCOS, degree of obesity, and adiponectin and resistin genotypes on serum adipokines, and clinical and biochemical variables related to hyperandrogenism
Patients and controls were equally distributed according to BMI and the degree of obesity (Table I). Controls were older than PCOS patients (31 ± 8 versus 26 ± 6 years, P < 0.001).
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The GLM included serum levels of adiponectin and resistin, systolic and diastolic blood pressure, the hirsutism score, WHR, ISI, fasting insulin and glucose levels, beta-cell function, lipid profiles and hormone concentrations as dependent variables, and PCOS or control status, degree of obesity and carrying variant alleles of the adiponectin 45 T
G polymorphism and of the resistin –420 CG polymorphism were introduced as independent variables.
The results of the multivariate analysis are summarized in Table II. Because age was introduced as a covariate, all analyses were corrected for the difference of age between PCOS patients and healthy controls. Regarding the main effects, only PCOS or control status and the degree of obesity influenced significantly the dependent variables, whereas the adiponectin 45 TG polymorphism and the resistin –420 CG polymorphism did not show significant effects.
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Importantly, there was no interaction between PCOS or control status and degree of obesity, indicating that the influence of PCOS on the variables studied here was not different in lean women compared with overweight and obese women and that the influence of the degree of obesity on the dependent variables was the same in the PCOS and control groups.
The results of the univariate analysis of the effects of PCOS or control status and of the degree of obesity are shown in Figure 1 for serum adiponectin and resistin levels, and in Tables III and IV for the other clinical and biochemical variables.
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P = 0.016 between obese, overweight and lean women. Adipokine data were analysed by a general linear model introducing PCOS status and degree of obesity as independent variables, and introducing age as a covariate. No statistically significant interaction between PCOS and the degree of obesity was observed, indicating that the influence of PCOS on serum adipokine concentrations studied here was not different in lean women compared with overweight and obese women, and that the influence of obesity on serum adipokine concentrations was the same in the PCOS and control groups.
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PCOS patients presented with reduced serum adiponectin levels compared with healthy controls (9.1 ± 3.5 versus 11.8 ± 5.5 µg/ml, P = 0.038), which were independent of the degree of obesity (Figure 1), whereas serum resistin levels were similar in both groups (Figure 1). PCOS patients also had increased hirsutism scores, WHR, serum fasting insulin and HOMA-
values, serum triglycerides, total testosterone, free testosterone, androstenedione and DHEA-S concentrations, and reduced SHBG levels, and ISI values, compared with that of controls (Table III).
Although defining the influences of obesity on the dependent variables was not the primary end-point of the study, we found that overweight and obesity resulted in an increase in serum resistin concentrations (lean: 14.7 ± 7.1, overweight: 19.4 ± 9.2, obese: 16.5 ± 6.7 ng/ml, P = 0.016), systolic blood pressure, fasting glucose and insulin levels, HOMA- and serum triglycerides and free testosterone concentrations, and a decrease in SHBG levels and in ISI values (Figure 1 and Table IV). Of note, serum adiponectin concentrations were not affected by the degree of obesity (Figure 1).
The only influences of the adiponectin and resistin polymorphisms studied here on dependent variables arose from interactions (Table II). Carrying variant alleles of the adiponectin 45 TG polymorphism interacted with the degree of obesity, resulting in an increase in SHBG levels in the 12 lean carriers of 45 G adiponectin alleles compared with the 22 lean women homozygous for wild-type alleles (504 ± 325 versus 360 ± 118 µg/dl, respectively, F = 4.784, P = 0.011). This was not found in overweight and obese women. Also, there were complex interactions of PCOS or control status, the degree of obesity and carrying variant alleles of the adiponectin 45 TG polymorphism and of the resistin –420 CG polymorphism on serum resistin (F = 7.241, P = 0.001), triglycerides (F = 4.878, P = 0.010) and SHBG (F = 4.638, P = 0.012) which were caused by differences between very small subgroups of women that did not follow any discernible pattern of changes, and possibly resulted from outlier values in some of these individuals (data not shown).
Association of adiponectin and resistin polymorphisms with PCOS
None of the polymorphisms studied here was associated with PCOS or with the degree of obesity (Table V). Although G alleles of the resistin –420 CG polymorphism showed a near-significant tendency towards an increased frequency in PCOS patients, the resistin –420 CG genotypes were not differentially represented in PCOS patients and in controls (Table V). The adiponectin 45 TG and 276 GT polymorphisms were in linkage disequilibrium (2 = 11.650, P = 0.020) also in our population.
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Hypoadiponectinaemia of PCOS: relationships with hyperandrogenism, body composition and insulin resistance
Considering that PCOS patients and controls differed in hyperandrogenism, body fat disposition, insulin resistance, beta-cell function and age, the decrease in serum adiponectin levels observed in PCOS patients may be related to any of these variables. To further explore these influences, we applied multivariate linear regression analysis, considering PCOS patients and controls as a whole, with serum adiponectin concentrations as the dependent variable, and stepwise (probability of F to enter
0.05; probability of F to remove 0.10) introduction of free testosterone, WHR, ISI, HOMA- and age as independent variables. Of note, given the similar BMI values of PCOS patients and controls, the BMI was not included as an independent variable in the model.
Adiponectin concentrations were log-transformed to coax to linearity the non-linear relationship with the independent variables. The model explained 27.5% of the variance in serum adiponectin levels (adjusted R2 = 0.275, F = 15.5, P < 0.0001) and retained only the WHR ( = –1.033, 95% CI: –1.456 to –0.609, P < 0.001), the free testosterone levels ( = –0.002, 95% CI: –0.004 to –0.001, P = 0.003) and age ( = 0.005, 95% CI: 0.000–0.010, P = 0.036) in the equation, whereas ISI and HOMA- values were excluded (P > 0.200 for both). Tolerance analysis ruled out a strong colinearity between the independent variables included in the multiple regression model. Therefore, both hyperandrogenism and the predominantly abdominal deposition of body fat, and to a lesser extent a younger age, contributed to the decrease in serum adiponectin levels observed in our series.
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Discussion |
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Our present results demonstrate that PCOS patients from Spain have hypoadiponectinaemia and that this finding is completely independent of the degree of obesity. On the contrary, serum resistin levels are not different in PCOS patients and non-hyperandrogenic controls, but increased in overweight and obese women compared with lean subjects irrespective of PCOS. Furthermore, the genomic variants in the adiponectin and resistin genes studied here do not play a role in the changes in serum adiponectin and resistin concentrations described above, nor are their allelic and genotype frequencies different in PCOS patients compared with non-hyperandrogenic controls.
Our experimental approach, by comparing homogeneous groups of women in terms of prevalence and degree of obesity, and applying a very strict yet powerful multivariate GLM analysis, may contribute to explain some of the controversies between previous studies. The use of a multivariate GLM analysis corrected the results for the difference in age between PCOS patients in controls and assured that positive findings did not arise from type I statistical errors—finding a difference that is not actually present in the population—derived from the multiple comparisons performed, as might occur if separate univariate analyses were used for each dependent variable.
Also, the use of multivariate GLM analysis provided a detailed evaluation of the individual influences of PCOS and of the degree of obesity on serum adipokines and ruled out a significant interaction of PCOS and degree of obesity on these influences. The latter indicates that the decrease in serum adiponectin levels in PCOS patients was present for each level of obesity and was significant in lean, overweight and obese women.
Similarly, the increase in serum resistin concentrations in overweight and obese women compared with lean women was present in PCOS patients and in controls. However, we raise a cautionary note against the extrapolation to the general population of our present finding of increased serum resistin levels in overweight and obese women. Our study was not designed to evaluate the influence of obesity on adipokines, and the prevalence of overweight and obesity in our population was very large. Therefore, it is possible that the influence of obesity on serum adipokines in the general population is different, explaining the discordance between our present findings and previous results showing no increase in serum resistin levels in obese subjects (Lee et al., 2003).
Moreover, the GLM analysis indicated that the adiponectin gene 45 TG and resistin –420 CG polymorphisms did not have an independent influence on any of the clinical and biochemical variables studied here, including the serum concentrations of the proteins encoded by these genes, when also considering the stronger influences of PCOS and degree of obesity on them.
When evaluating the variables associated with the decrease in serum adiponectin concentrations in PCOS patients, abdominal adiposity and hyperandrogenism contributed significantly to the variance in adiponectin levels, whereas the ISI did not. This particular result reproduces, in a much larger population of Spaniards, the results by Ducluzeau et al. (2003) in the French. By applying euglycaemic hyperinsulinaemic clamps to 16 PCOS patients, these authors demonstrated that plasma adiponectin levels correlated negatively with WHR and directly with the glucose disposal rate, suggesting a role for adiponectin in the regulation of the latter (Ducluzeau et al., 2003). Ducluzeau et al. (2003) concluded that serum adiponectin levels were a better indicator for abdominal fat mass than for insulin sensitivity in PCOS. Similarly, Sieminska et al. (2004) recently reported that serum adiponectin levels are reduced in Polish PCOS patients, and that serum adiponectin concentrations were best predicted by the WHR, free androgen index and presence of impaired glucose tolerance in a multiple regression analysis. As occurred in our series, it was an estimation of the free testosterone concentration and not total testosterone, the androgenic parameter that determined serum adiponectin concentrations (Sieminska et al., 2004). The presence of hypoadiponectinaemia in PCOS is also supported by reports in American (Sepilian and Nagamani, 2005), Arabian (Ardawi and Rouzi, 2005) and Italian populations (Carmina et al., 2005).
Hypoadiponectinaemia may contribute to insulin resistance in PCOS women, because adiponectin normally reduces the triglyceride content of muscle, up-regulating insulin signalling, and activates PPAR
, increasing fatty acid combustion and energy combustion, and by activating AMP-activated protein kinase, adiponectin enhances muscle fat oxidation and transport and inhibits the expression of gluconeogenic enzymes, reducing hepatic glucose production (Kadowaki and Yamauchi, 2005).
According to our present results, the abdominal deposition of fat is characteristically associated with hypoadiponectinaemia. Therefore, we speculate that abdominal adiposity, by means of hypoadiponectinaemia, may contribute to the reduced insulin sensitivity of PCOS independently of the degree of obesity.
Androgen excess favours abdominal adiposity in women (Lovejoy et al., 1996; Elbers et al., 1997; Nilsson et al., 1998), an effect that can be reversed by treatment with the antiandrogen drug flutamide (Gambineri et al., 2004). Furthermore, prenatal androgen exposure leading to abdominal adiposity (Eisner et al., 2003) and insulin resistance (Bruns et al., 2004) during adult life has been proposed recently to play a role in the pathogenesis of PCOS (Franks et al., 2006; Xita and Tsatsoulis, 2006). Therefore, hyperandrogenism might indirectly favour insulin resistance in PCOS, by inducing abdominal adiposity and a decrease in the insulin sensitizer adipokine adiponectin.
Considering that insulin resistance and hyperinsulinism are established pathogenic mechanisms for hyperandrogenism in PCOS (Dunaif, 1997), the facilitation of insulin resistance by androgen excess through the induction of abdominal adiposity and hypoadiponectinaemia would close the vicious circle of insulin resistance, hyperinsulinism and hyperandrogenism in PCOS patients. However, because a great overlap exists between PCOS patients and non-hyperandrogenic controls in serum adiponectin levels, it is also probable that this mechanism is restricted to a subset of PCOS patients, possibly those with a more android distribution of body fat and higher androgen levels.
But our present results are discordant with respect to some previous studies. Orio et al. (2003) found a decrease in serum adiponectin levels in obese PCOS and control women compared with lean PCOS and control women. However, they did not evaluate the interaction between PCOS and obesity on serum adiponectin levels, missing a decrease in serum adiponectin levels in PCOS women compared with controls which was apparent by visual inspection of their data. Of note, a more recent paper of the same authors concluded that serum adiponectin levels were actually reduced in PCOS patients even after controlling for BMI (Carmina et al., 2005). Furthermore, it is possible that the presumed lack of effect of PCOS on serum adiponectin levels (Orio et al., 2003) derived from the absence of differences in the distribution of body fat in the groups of women compared in their study, given that all these groups, including even the lean healthy controls, had a mean WHR above 0.85.
Similar methodological concerns might apply to the report by Panidis et al. (2003) in Greek women, who found reduced serum adiponectin levels in obese PCOS patients when compared with lean PCOS patients and lean non-hyperandrogenic controls, but did not include for comparison a group of obese non-hyperandrogenic controls, essential for unravelling the intricate relationships between adiponectin, insulin resistance and obesity (Orio et al., 2004). Furthermore, in the study of Spranger et al. (2004) in the German population that showed no differences in serum adiponectin levels between PCOS patients and controls, these groups were grossly mismatched for BMI, and the possible interaction of obesity with PCOS on serum adiponectin levels was not studied.
In contrast with these negative results, Ardawi and Rouzi (2005) recently reported that hypoadiponectinaemia is evident in obese and lean women with PCOS. Finally, other recent studies in Czech and Polish patients did not include non-hyperandrogenic controls (Lewandowski et al., 2005; Vrbikova et al., 2005) and focused on the relationship of serum adiponectin with indexes of insulin resistance and with serum testosterone (Vrbikova et al., 2005) and with the response of serum adipokines to an oral glucose load (Lewandowski et al., 2005). These studies were relatively limited in their conclusions, because the distribution of body fat, which according to our present results is a major determinant of serum adiponectin levels, was not considered.
Regarding serum resistin levels, our present results are in agreement with most previous studies showing no significant increase in serum resistin levels in PCOS patients (Panidis et al., 2004a; Seow et al., 2004, 2005; Carmina et al., 2005; Lu et al., 2005) and an increase of the serum concentrations of this hormone only in obese subjects (Panidis et al., 2004a; Carmina et al., 2005). However, considering that in one of these studies, the expression of resistin mRNA by adipocytes was increased in PCOS patients (Seow et al., 2004), and that in cultured human theca cells, resistin enhanced 17alpha-hydroxylase activity (Munir et al., 2005)—a marker of ovarian hyperandrogenism in PCOS women—it is also possible that resistin might play local roles in the pathogenesis of PCOS.
Finally, our data presented here do not support any role for the adiponectin 45 TG and 276 GT variants and for the resistin –420 CG polymorphisms in the pathogenesis of PCOS. The genotype frequencies of these polymorphisms were not distributed differently in PCOS and control subjects, in conceptual agreement with previous studies regarding these adiponectin (Panidis et al., 2004b; Xita et al., 2005) and resistin (Urbanek et al., 2003; Xita et al., 2004) variants. It should be mentioned that in one of these studies, the adiponectin 45 TG genotype was associated in a dominant-only fashion with a subset of PCOS patients presenting with increased serum androstenedione levels, but this association was not apparent when considering the raw genotype frequencies or in patients with lower levels of this androgen (Panidis et al., 2004b).
And although these adiponectin and resistin variants have been proposed to act as modifiers of the PCOS insulin-resistant phenotype by influencing proxies for insulin resistance (Xita et al., 2004) and the BMI (Xita et al., 2005), our present data indicate that these influences are not important when considering the major effects of PCOS and of overweight and obesity on them by a more strict statistical approach such as the multivariate GLM applied to our series, because only minor interactions on a few biochemical and hormonal variables remained significant when also considering the major impact of PCOS and obesity.
In summary, we here demonstrate that women with PCOS present with hypoadiponectinaemia irrespective of the degree of obesity, whereas overweight and obesity might be determinant for increased resisting levels in premenopausal women, and that these findings are not related to the adiponectin 45 TG and 276 GT variants and to the resistin –420 CG polymorphisms. Furthermore, hyperandrogenism and abdominal adiposity appear to be the major determinants of hypoadiponectinaemia in PCOS, leading to the possibility that decreased serum levels of adiponectin is one of the links between hyperandrogenism and abdominal obesity, and insulin resistance, in some PCOS patients.
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Acknowledgements |
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The authors thank Ms. Genoveva González, Laboratorio de Endocrinología, Hospital Ramón y Cajal, for excellent technical help. This work was supported by Grants FIS PI020741, PI050341, PI 050551 and RGDMG03/212 from the Fondo de Investigación Sanitaria, Instituto de Salud Carlos III and by Grant GR/SAL/0137/2004 from the Consejería de Educación, Comunidad de Madrid.
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Submitted on February 11, 2006; resubmitted on April 1, 2006; accepted on April 7, 2006.
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