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Adiponectin Levels in Women with Polycystic Ovary Syndrome

Department of Molecular and Clinical Endocrinology and Oncology (F.O., T.C., A.C., G.L.), University "Federico II," 80131 Naples; Chair of Obstetrics and Gynecology (S.P., F.Z.), University of Catanzaro, 88100 Catanzaro; and Department of Internal Medicine, Department of Medical and Surgical Sciences (G.M., R.M., C.P., R.V.), University of Padova, 35128 Padova, Italy

Address all correspondence and requests for reprints to: Dr. Francesco Orio, Jr., Via Giovanni Santoro n.14, 84123 Salerno, Italy. E-mail: f.orio{at}tin.it.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Serum adiponectin levels were evaluated in 60 women with polycystic ovary syndrome (PCOS), 30 normal-weighted and 30 obese women, and 60 healthy women age and body mass index (BMI) matched with the patients. The homeostasis model assessment (HOMA) score was also calculated. Both in PCOS and controls, serum adiponectin levels were significantly (P < 0.05) lower in obese than normal-weight women, without any difference between PCOS and controls. The HOMA score was significantly (P < 0.05) higher in obese than normal-weight women both in PCOS and controls; additionally, the HOMA score was significantly (P < 0.05) higher in normal-weight PCOS than normal-weight controls. Both in PCOS and controls, adiponectin levels were significantly correlated with BMI (r = -0.51, P < 0.01 in PCOS; r = -0.45, P < 0.01 in controls) and HOMA values (r = -0.39, P < 0.05 in PCOS; r = -0.35, P < 0.05 in controls); HOMA was correlated with BMI (r = 0.51, P < 0.01 in PCOS, r = 0.61, P < 0.001 in controls). In conclusion, our results confirm that adiponectin concentrations change according to variations of fat mass. They further suggest that insulin sensitivity per se probably does not play any pivotal role in the control of adiponectin levels in PCOS women.

	Introduction

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POLYCYSTIC OVARY SYNDROME (PCOS) is one of the most common endocrine-metabolic diseases, affecting up to 10% of women of reproductive age (1, 2). Obesity is present in approximately 44% of women with PCOS, and it is characterized by central distribution of fat. In women with PCOS, hyperinsulinemia, dyslipidemia, and/or hypertension are highly dependent on obesity, which worsens the clinical presentation of PCOS (1, 3).

The adipose tissue not only stores a large quantity of fat as an energy source (4) but also expresses a variety of genes of secretory proteins (5, 6, 7, 8, 9). The human apM1 gene has been recently discovered, and it is exclusively expressed in white adipose tissue (10). The product of this gene is called adiponectin, a 244-amino acid protein with high structural homology to collagen VIII, X, complement C1q, and TNF (11, 12). Adiponectin expression is increased by peroxisome proliferator-activated receptor agonists (13, 14).

Although the physiological role of adiponectin still has to be clarified, recent findings have indicated that it may be a kind of matrix protein with potential antiatherogenic and antiinflammatory effects (15, 16, 17, 18). Because adiponectin is a fat cell product, secreted into the circulating blood, it might be responsible for the metabolic and neuroendocrine derangements characteristic of obesity and obesity-related disease, such as PCOS.

Despite adiponectin being secreted only from adipose tissue, its plasma levels in obese subjects are, paradoxically, lower than in nonose subjects (19). Reductions of body weight increase adiponectin concentrations (20), suggesting that adiponectin expression is down-regulated by adipose tissue (21).

Moreover, serum adiponectin concentrations correlate inversely with the severity of insulin resistance (22, 23, 24) and plasma levels of low-density lipoprotein cholesterol, and triglycerides (21, 25, 26, 27, 28).

At the present no data are available on adiponectin levels in women with PCOS. In this view the aim of the present study was to evaluate serum adiponectin levels in a population of normal-weight and obese PCOS women.

	Subjects and Methods

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All the procedures used in this study were in accordance with the guidelines of the Helsinki Declaration on Human Experimentations. The study was approved by local ethical committee; the purpose of the protocol was explained to both the patients and control women, and written informed consent was obtained from them before beginning the study.

Subjects

Sixty women with PCOS, 30 normal-weight [body mass index (BMI), 18–25 kg/m²], and 30 obese (BMI, >30 kg/m²) were enrolled for the study. The diagnosis of PCOS was made using the following criteria: 1) anovulatory infertility and normal serum FSH levels (normal range, 1.0–10.0 IU/liter), and 2) at least two of the following features: hirsutism (Ferriman and Gallwey score, >8); elevated serum androgen levels [total testosterone (T), >2 nmol/liter], and/or androstenedione (A) greater than 15 nmol/liter, and/or dehydroepiandrosterone sulfate (DHEA-S) greater than 10 µmol/liter); LH/FSH ratio above 2; and polycystic ovaries identified by transvaginal ultrasonography (TV-USG) examination (29, 30).

Sixty healthy women matched for age and BMI with the patients agreed to participate to this study as controls. All controls were evaluated by a medical history, physical and pelvic examination, and complete blood chemistry. Women with a menstrual cycle less than 26 d or more than 30 d were excluded. The normal ovulatory state was confirmed by TV-USG and plasma progesterone (P) assay during the luteal phase of the cycle.

Exclusion criteria for all subjects were pregnancy, hypothyroidism, hyperprolactinemia, Cushing’s syndrome, congenital adrenal hyperplasia, current or previous (within the last 6 months) use of oral contraceptives, glucocorticoids, antiandrogens, ovulation induction agents, antidiabetic and antiobesity drugs, or other hormonal drugs. None of the patients was affected by neoplastic, metabolic, and cardiovascular disorder or other concurrent relevant medical illness. All subjects were nonsmokers, and none drank alcoholic beverages.

Study protocol

Patients were studied during early follicular phase (second to fifth day) of the spontaneous or P-induced menstrual cycle. Blood samples were collected after an overnight fasting from all subjects for biochemical and hormonal determinations.

All subjects underwent TV-USG and anthropometric measurements. In particular, in each woman weight and height were measured to calculate BMI. Waist to hip circumference ratio was also measured (29).

Biochemical and hormonal analysis

Plasma LH, FSH, 17ß-estradiol (E₂), P, 17OH-progesterone (17OH-P), T, A, DHEA-S, prolactin (PRL), SHBG, glucose, insulin, and adiponectin levels were evaluated in each subjects in duplicate. LH, FSH, E₂, P, T, A, DHEA-S, 17OH-P, and PRL were measured by specific RIA as previously described (30, 31). SHBG was measured using an immunoradiometric assay (30). Plasma glucose was determined by the glucose oxidase method (30), and serum insulin was measured by a solid-phase chemiluminescent enzyme immunoassay (30). Adiponectin was measured in serum using a commercially available RIA kit (Linco Research, Inc., St. Charles, MO) in which ¹²⁵I-labeled murine adiponectin and a multispecies adiponectin rabbit antiserum was used to determine the level of adiponectin in serum by the double-antibody/PEG. Adiponectin standards were prepared using recombinant human adiponectin with a sensitivity of 1 ng/ml and intraassay and interassay coefficient of variation of 3.1% and 5%, respectively. The free androgen index was calculated using the following formula: T (nmol/liter)/SHBG (nmol/liter) x 100 (32). The estimate of insulin resistance by homeostasis model assessment (HOMA) score was also calculated in all subjects as described by Matthews et al. (33).

Statistical analysis

The statistical analysis was performed using the SPSS 9.0 (SPSS, Inc., Chicago, IL) package by the unpaired t test. The Pearson’s correlation coefficients were calculated. Data are presented as mean ± SE. Statistical significance was set at 5%.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Table 1 shows anthropometric, biochemical, and endocrine data in PCOS and control women, according to BMI. As expected, LH, P, 17OH-P, T, A, DHEA-S, SHBG, and insulin differ in PCOS, compared with controls (Table 1). Additionally, insulin levels were lower (P < 0.05) in normal-weight than obese women of both groups (Table 1).

View larger version (11K): [in this window] [in a new window]   Figure 1. Adiponectin levels in 60 PCOS and 60 healthy women, grouped according to BMI in 30 subjects/group.

View larger version (11K): [in this window] [in a new window]   Figure 2. HOMA values in 60 PCOS and 60 healthy women, grouped according to BMI in 30 subjects/group.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Adiponectin is probably one of the most important adipocytokines of the adipose tissue (25). It is highly expressed and actively secreted by adipocytes (34); it is abundantly present in the human circulation and displays a variety of functions, including antiatherogenic, antiinflammatory, and insulin-sensitizing properties (15, 35, 36).

This is the first study evaluating serum adiponectin concentrations in obese and normal-weight PCOS women. Our data confirm that obese women have adiponectin levels significantly lower than normal-weight healthy controls (37, 38). In addition, fasting serum adiponectin levels in patients with PCOS were comparable to those observed in control women matched for age and BMI. Obese PCOS women also exhibit reduced adiponectin levels when compared with normal-weight women with PCOS. Lastly, adiponectin levels were inversely correlated with BMI both in PCOS and healthy women.

Plasma adiponectin concentrations were decreased in insulin-resistant obese (19) and type 2 diabetic patients (39). PCOS is characterized by insulin resistance, which may lead to major metabolic consequences with an increased risk of developing type 2 diabetes in respect to the general female population (40). PCOS patients often display an increased basal insulin level, likely caused by an increased insulin secretion and a reduced hepatic insulin clearance (40); impairment of peripheral insulin-stimulated glucose utilization is also present. It has been shown that these abnormalities are independent of obesity, which, when present, displays a further worsening effect on insulin sensitivity (41).

In the present study, insulin levels were higher and insulin sensitivity, as assessed by HOMA, lower in normal-weight PCOS group than in controls; serum adiponectin concentrations did not differ between the two groups. Therefore, the high degree of insulin resistance in women with PCOS (42) does not influence (is unlikely to modify) adiponectin levels, despite the evidence that adiponectin levels have been widely recognized to be decreased in an insulin resistant state (22). The link between adiponectin and insulin sensitivity was further enforced by the observation that this adipocytokine is able to stimulate glucose utilization (43) and reduce the hepatic glucose production (44). Furthermore, adiponectin expression in rodents was shown to be highly affected by changes in adiposity and insulin sensitivity (45).

The low adiponectin level in obesity probably is due to its down-regulation by the increased adipose tissue. An amelioration of insulin sensitivity, which occurs during reduction of body weight (46), is likely linked to this phenomenon because the increase of insulin sensitivity could be associated with the increase of adiponectin levels. In fact, adiponectin has been shown to be suppressed in states of insulin resistance, such as type 2 diabetes (22) and obesity (47). Additionally, in a large series of Japanese subjects (48) and adult Pima Indians (22), adiponectin levels were negatively related to the indices of insulin resistance even after the adjustment for age and BMI; in Pima Indian children, these levels decreased with increasing adiposity, without any correlation with obesity-induced insulin resistance (36).

It is worth noting, however, that normal-weight PCOS women, who have increased insulin secretion, compared with normal-weight controls, have normal adiponectin levels, ruling out a relevant role of insulin on adiponectin secretion. Thus, our data suggest that adiponectin variations result mainly by changes in the adipose tissue more than by changes of insulin levels and/or insulin sensitivity.

As further support of our clinical data, recent studies in adiponectin knockout mice report a substantial lack of effects on insulin sensitivity, measured by a hyperinsulinemic-euglycemic clamp (49). However, when adiponectin knockout mice were infected with adenovirus producing full-length adiponectin, insulin sensitivity increased (50). All these data taken together suggest that the complex puzzle of adiponectin regulation at the adipose tissue is still to be fully elucidated.

In conclusion, our results further confirm that adiponectin concentrations change according to variations of fat mass in healthy women as well as women with PCOS. They also suggest that insulin sensitivity per se is unlikely to play a pivotal role in the control of adiponectin levels in PCOS women.

	Footnotes

 
Abbreviations: 17OH-P, 17OH-progesterone; A, androstenedione; BMI, body mass index; DHEA-S, dehydroepiandrosterone sulfate; E₂, 17ß-estradiol; HOMA, homeostasis model assessment; P, progesterone; PCOS, polycystic ovary syndrome; PRL, prolactin; T, testosterone; TV-USG, transvaginal ultrasonography.

Received December 26, 2002.

Accepted February 24, 2003.

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