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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 5 2263-2268
Copyright © 2003 by The Endocrine Society

Platelet Dysfunction in Lean Women with Polycystic Ovary Syndrome and Association with Insulin Sensitivity

Didem Dereli, Gokhan Ozgen, Filiz Buyukkececi, Engin Guney and Candeger Yilmaz

Departments of Endocrinology (D.D., G.O., C.Y.) and Hematology (F.B.), Ege University Faculty of Medicine, Uckuyular/Izmir, Turkey 35350; and Department of Endocrinology (E.G.), Adnan Menderes University Faculty of Medicine, Aydin, Turkey 09110

Address all correspondence and requests for reprints to: Didem Dereli M.D., Oyak Sitesi 2/8, Sokak No. 2/13, Uckuyular/Izmir, Turkey 35350. E-mail: dtdereli{at}superonline.com.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Platelet dysfunction and its association with insulin resistance and/or hyperandrogenemia were evaluated in 50 women with polycystic ovary syndrome (PCOS), 50 women with nonclassic congenital adrenal hyperplasia (NC-CAH), and 30 women in the control group. Agonist-induced platelet aggregation was measured. Women with PCOS had significantly higher levels of platelet aggregations induced by ADP (77.4 ± 3.3 vs. 67.3 ± 2.8), collagen (79.7 ± 1.8 vs. 69.1 ± 3.9), and epinephrine (84.7 ± 2.6 vs. 67.8 ± 3.8), compared with controls. However platelet aggregations of women with NC-CAH because of ADP (68.2 ± 4.22), collagen (69.5 ± 5.4), or epinephrine (68.6 ± 4.3) were similar to those in the control group. There were negative correlations between aggregations induced by agonists and the insulin sensitivity in women with PCOS. These correlations also appeared significant after androgen levels with covariance analysis were excluded. These covariance analyses were performed because serum androgen levels might affect platelet function. Any significant correlations were not found between androgen levels and agonist-induced platelet aggregation in women with NC-CAH. We conclude that platelet dysfunction may be an important reason for the possible cardiovascular heart diseases in women with PCOS.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
POLYCYSTIC OVARY SYNDROME (PCOS) is the most common endocrine-pathological condition of reproductive system that affects nearly 5–10% of premenopausal women (1). PCOS was initially recognized as the clinical combination of anovulation and hyperandrogenism; it now appears to be a new face of the metabolic syndrome (2). PCOS is closely associated with insulin resistance (IR) and hyperinsulinemia and demonstrates an increased incidence in diabetes, hypertension, dyslipidemia, and atherosclerosis (3).

During a consensus conference on IR sponsored by the American Diabetes Association, a panel of experts defined the disorder as an impaired metabolic response to either exogenous or endogenous insulin. Additionally, their report acknowledges, "Even though the glucose-insulin relationship is clinically pertinent, conceptionally, it is also important to recognize that IR does not have to be confined just to parameters of glucose metabolism. The concept of IR should apply to any of the biological actions of insulin and might include its effect on lipid and protein metabolism, vascular endothelial function, and gene expression" (4).

IR can be associated with various features, including low birth weight, acanthosis nigricans, premature adrenarche, hyperandrogenemia, dyslipidemia, hypertension, microalbuminuria, prothrombic state, glucose intolerance, and type 2 diabetes mellitus (5, 6). The prothrombic state is more recently recognized as a component of the metabolic syndrome and is characterized by increased fibrinogen and plasminogen activator inhibitor-1 levels and unusual abnormalities in platelet functions (6).

Many women with PCOS eventually develop most of the manifestations of metabolic syndrome (3). However, one of these manifestations, platelet dysfunction, was not demonstrated in women with PCOS.

The aim of this study was to evaluate platelet function and agonist-induced aggregation in women with PCOS and the role of insulin sensitivity in such platelet activation.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Study population

Three hundred twenty women with oligomenorrhea and increased androgen levels (clinical or biochemical) were evaluated. Among them, 50 women (mean age, 21.4 ± 3.16) diagnosed with PCOS and 50 women diagnosed with nonclassic 21-hydroxylase deficiency were selected. All controls were scrutinized to exclude patients with signs and symptoms of hyperandrogenemia (clinical-biochemical). Only women whose body mass index (BMI) was less than 25 kg/m2 were included in our study to rule out the effects of obesity on IR.

The study was approved by the Ethics Committee and the Institutional Review Board of the Ege University Medical Faculty. All women issued an informed consent for the study. The diagnosis of PCOS was based on NICHD criteria (7): 1) hyperandrogenism and/or hyperandrogenemia; 2) oligoanovulation; and 3) exclusion of other known disorders, such as Cushing’s syndrome, hyperprolactinemia, or nonclassic congenital adrenal hyperplasia (NC-CAH). Polycystic ovary appearance at ultrasonography was not considered as a criterion for the diagnosis of the syndrome. Hyperandrogenemia was defined as serum-free testosterone (FT) greater than 3.2 pg/ml (normal range 0.8–3.2 pg/ml). Oligomenorrhea was defined as bleeding episodes occurring less than six times per year. Anovulation was confirmed in all patients with serial weekly serum progesterone levels (<2.5 ng/ml = <8.0 nmol/liter) starting on d 21 of their menstrual cycle.

Blood samples were obtained at 0730–0815 h during the early follicular phase (first through fifth days) after spontaneous or progesterone-induced menses. Medroxyprogesterone acetate (10 mg/d for 10 d, Farlutal, Deva, Istanbul) was prescribed to induce progesterone withdrawal bleeding when necessary. The tests were performed 7 d after the last dose of medroxyprogesterone acetate. Serum samples were stored at -20C until assayed.

Early follicular phase serum 17-OH progesterone (17-OHP) levels were measured in the morning to avoid diurnal variations; basal 17-OHP levels greater than 2.0 ng/ml were considered as suspected levels for NC-CAH. For the diagnosis of NC-CAH, serum 17-OHP levels were measured before and 30 and 60 min after the injection of synthetic ACTH (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24) (Synacthen, Ciba, Switzerland) administered at 0800 h during the early follicular phase. An ACTH-stimulated 17-OHP level greater than 10 ng/ml was considered as the criterion of late-onset 21-hydroxylase deficiency (8).

Diabetes mellitus, impaired glucose tolerance, thyroid dysfunction, hyperprolactinemia, and hypercortisolism were all excluded using appropriate tests. Each woman underwent a 75-g, 2-h oral glucose tolerance test to rule out diabetes mellitus or impaired glucose tolerance, and World Health Organization criteria were used for these diagnoses. Patients did not receive oral contraceptives or any medications that were known to alter hormone, lipid, or insulin metabolism 3 months prior the study. No patients or control subjects received drugs that were known to affect platelet function 4 wk before the investigations. Cigarette smoking was an exclusion criterion for this study.

Platelet functions

Chemicals. Epinephrine, ADP, collagen (soluble calfskin), and other nonspecific reagents were purchased from Bio/Data Corp. (Horsham, PA). Platelet function tests were performed with a platelet aggregation profiler (Bio/Data Corp.).

Platelet preparation and in vitro analysis of platelet aggregation. Human platelet-rich plasma (PRP) was prepared according to a method previously published elsewhere (9). Venous blood was freshly drawn from patients who had not ingested any drugs that may have an effect on platelet function during the last 4 wk. To obtain PRP, the blood was immediately mixed with 3.8% citrate (9:1 vol/vol) and then centrifuged at 150 x g for 15 min at room temperature. The top-layer PRP was collected by using a plastic Pasteur pipette and placed in a clean plastic centrifuge tube. The remaining red cells and buffy coat were centrifuged at 1500 x g for 15 min to obtain autologous platelet-poor plasma. In vitro platelet aggregation was monitored simultaneously using a Lumi-Aggregometer (Bio/DataCorp.) according to manufacturers’ instructions as previously described (10). Measurements were made for ADP, collagen, and epinephrine; the final concentrations were 10 µmol, 2 µg/liter, and 10 µmol, respectively. The aggregation responses were quantified as the maximum extent of aggregation, calculated by the maximum change in light transmission, and expressed as a percentage, considering the difference between light transmission for the platelet suspension and suspension buffer as a value of 100% (normal values -> collagen: 60–90%; epinephrine: 70–90%; ADP: 70–90%).

Methods for assay

The serum concentrations of FSH, LH, estradiol, progesterone, prolactin, and cortisol were measured by chemiluminescent enzyme immunoassay [ASC 180 (+) Ciba Diagnostics, Switzerland] with an average interassay coefficient of variation (CV) of 6% and intra-assay CV of 6.7%. The serum concentrations of dehydroepiandrosterone sulfate (DHEAS), 17-OHP, free testosterone, free T4, and TSH were measured according to standard RIAs.

Blood samples for hormonal tests were collected after 16 h of fasting; after collected, blood samples were immediately placed on ice and then centrifuged at 3500 x g for 30 min at +4 C. The plasma was separated within 1 h and then stored at -70 C.

Plasma glucose was measured by the glucose oxidase technique (Biobak Laboratory Supplies Trade, Ankara, Turkey) with an interassay CV of 1.7% and intra-assay CV of 0.8%. Insulin levels were measured by microparticle enzyme immunoassay (Abbott, Wesbaden-Delkenheim, Germany) with intra-assay and interassay CV of 2.4%.

Homeostasis model assessment (HOMA)-IR was calculated according to the following formula:

where FIRI is fasting plasma insulin level (microunits per milliliters), and FPG is fasting plasma glucose level (nanomoles per liter) (11).

BMI was calculated according to the following formula:

Statistical analysis

The Statistical Package for the Social Sciences (version 10.0 for Windows; SPSS, Inc., Chicago, IL) was used for statistical analyses. The characteristic of distribution was tested with the Kolmogorov-Smirnov test. Results were expressed as mean ± SD. Differences between means were analyzed by unpaired t test using two-tailed tests for significance. Because of differing numbers of subjects in some groups, the Tukey-Kramer multiple comparison procedure was used for post hoc comparisons. Correlations between agonist-induced platelet aggregation rate and IR were evaluated again after excluding FT with analysis of covariance, whereas it might affect insulin sensitivity. P values smaller than 0.05 were regarded as statistically significant.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The mean demographic, endocrinological, and metabolic characteristics of the three groups are given in Table 1Go. Age, BMI, and waist to hip ratios did not differ significantly between the patients and controls. The mean levels of serum FSH, prolactin, and estradiol were comparable among the three groups. The LH levels in PCOS women were significantly higher than the other two groups’ LH levels (P < 0.01); serum DHEAS levels in patients with NC-CAH were significantly higher than the other two groups’ DHEAS levels (P < 0.01). However, serum FT levels were higher in both patients with PCOS and NC-CAH, compared with the control group (P < 0.01). There were no differences in FT levels between the PCOS and NC-CAH groups (P > 0.05).


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  		Table 1. Clinical and metabolic parameters of our patients

 
Serum mean fasting glucose and insulin levels from patients with PCOS were significantly higher than the NC-CAH and control groups (P < 0.05, P < 0.01, respectively). The HOMA-IR was significantly higher in the PCOS group and indicated an IR in these patients (Table 2Go).


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  		Table 2. Glucose metabolism and hematologic parameters of our patients

 
The mean serum levels of cholesterol, low-density lipoprotein, and lipoprotein (a) were comparable among the groups. However, the mean triglyceride concentration was higher, and the mean high-density lipoprotein concentration was significantly lower in the PCOS group, compared with the other two groups (P < 0.01).

None of the subjects documented cardiovascular or any other thromboembolic diseases. The leukocytes, hematocrit, and platelet counts were comparable among the groups.

Women with PCOS displayed a significantly increased platelet aggregation induced by ADP (77.4 ± 3.3 vs. 67.3 ± 2.8, P = 0.007; 77.4 ± 3.3 vs. 68.2 ± 4.22, P = 0.006), collagen (79.7 ± 1.8 vs. 69.1 ± 3.9, P = 0.003; 79.7 ± 1.8 vs. 69.5 ± 5.4, P = 0.003) and epinephrine (84.7 ± 2.6 vs. 67.8 ± 3.8, P < 0.001; 84.7 ± 2.6 vs. 68.6 ± 4.3, P < 0.001), compared with the control group and patients with NC-CAH, respectively. The highest aggregation responses were observed with epinephrine in all subjects with PCOS.

There were negative correlations between each agonist-induced aggregation response and insulin sensitivity in women with PCOS (ADP P < 0.01, r = -0.68; collagen, P < 0.01, r = -0.72). The strongest correlation was observed between epinephrine and insulin sensitivity (P < 0.01, r = -0.76). These correlations were significant after excluding androgen levels with analysis of covariance, as serum androgens might affect platelet function (ADP, P < 0.01, r = -0.68; collagen, P < 0.01, r = -0.72; epinephrine, P < 0.01, r = -0.76) (Figs. 1–3GoGoGo).



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  		Figure 1. Correlation of epinephrine and HOMA-IR F. Testosterone as covariant. Epineph, Epinephrine.

 


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  		Figure 2. Correlation of ADP and HOMA-IR F. Testosterone as covariant.

 


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  		Figure 3. Correlation of collagen and HOMA-IR F. Testosterone as covariant.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
This report indicates the hyperaggregable state and its dependence on IR in patients with PCOS. We demonstrated an enhanced platelet response to various agonists (ADP, collagen, and epinephrine) in women with PCOS. There was a negative correlation between the hyperaggregability of platelets and the insulin sensitivity.

Type 2 diabetes mellitus and obesity are two common endocrinopathies that are associated with IR and increased risk of coronary heart disease. Platelet dysfunction was demonstrated both in diabetic and obese patients. It was reported that the response to epinephrine, ADP, collagen, and thrombin was enhanced in type 2 diabetes and obesity (12, 13, 14).

Although we need long-term event studies to determine whether PCOS is an independent risk factor for cardiovascular disease, several cardiovascular risk factors (including increased waist to hip ratio, obesity, diabetes, hypertension, and lipid abnormalities) are more prevalent among women with PCOS (15, 16, 17). Endothelial injury or plaque rupture accompanied by platelet adhesion and aggregation at the site of injury may be a critical event, which may cause mortality and morbidity due to atherogenesis as most coronary events occur with less than one third narrowing of the vessel lumen (18). Therefore, platelet dysfunction may assume an important role in the signal event in the possible atherosclerosis in women with PCOS. This thesis is substantiated by results in studies in which antiplatelet drugs such as aspirin and dipyridamole protected individuals against stroke and myocardial infarction, both in diabetic and nondiabetic individuals (19).

Bach and Dunaif (20) reported selective defects in some of the insulin actions: The effects of insulin on carbohydrate metabolism were impaired in patients with PCOS, but the mitogenic actions were preserved. Ciaraldi et al. (21) also demonstrated a tissue selective insulin resistance in patients with PCOS. For these reasons, insulin actions on platelets might be affected or preserved in this group of women.

In our study, we demonstrated an increased response to various platelet aggregation agonists. The response to ADP, collagen, and epinephrine were higher in patients with PCOS than the other groups, and these responses were negatively correlated with insulin sensitivity.

Such findings, especially the exaggerated response to epinephrine, are important because they provide strong evidence for the effect of insulin action on platelets in women with PCOS. Platelets are sites of insulin action and can be subject to variation in insulin sensitivity (22). Insulin is generally thought to reduce platelet responses to agonists ADP, collagen, thrombin, and platelet-activating factor (22, 23).

A clue to this action of insulin is the finding that insulin down-regulates the number of {alpha}2 adrenergic receptors on platelets (24, 25). Epinephrine potentiates the effects of other aggregating agents and stimulates Gi-mediated inhibition of adenylate-cyclase (6). It is clear that an effect of insulin to modify the action of epinephrine would attenuate platelet responses to other aggregates. For these reasons, our findings indicate that insulin action is defective on platelets in women with PCOS.

Serum androgen levels affect platelet aggregation (26, 27). The hyperaggregability of the platelets in women with PCOS might also be dependent on the hyperandrogenic state but not IR. For this purpose, we also investigated a group of women with NC-CAH. Women with NC-CAH and PCOS have similar clinical and laboratory findings with respect to the hyperandrogenic state, but IR is not a regular component of the former disease (8). We did not demonstrate platelet hyperaggregation in patients with NC-CAH. This finding suggests that the hyperaggregation in PCOS is dependent to IR.

We conclude that platelet dysfunction may be an additional mechanism (beyond effects of other recognized coronary risk factors) by which cardiovascular risk might be increased in PCOS (28). Further studies are needed to investigate the long-time benefits of using antiplatelet agents such as aspirin and dipyridamole on cardiovascular events and investigate whether insulin sensitizer agents such as metformin and glitazones have any benefits on platelet dysfunction.


   Footnotes
 
Abbreviations: 17-OHP, 17-OH progesterone; BMI, body mass index; CV, coefficient of variation; DHEAS, dehydroepiandrosterone sulfate; FT, free testosterone; HOMA, homeostasis model assessment; IR, insulin resistance; NC-CAH, nonclassic congenital adrenal hyperplasia; PCOS, polycystic ovary syndrome; PRP, platelet-rich plasma.

Received August 30, 2002.

Accepted February 14, 2003.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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