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University Department of Medicine and Therapeutics (C.J.G.K., J.M.C.C.), Gardiner Institute, Western Infirmary, Glasgow G11 6NT; Division of Biochemistry and Molecular Biology (A.S., G.W.G.), Institute of Biomedical and Life Science, University of Glasgow, Glasgow G12 8QQ; and Departments of Medicine (J.R.P.) and Obstetrics and Gynaecology (H.L.), Glasgow Royal Infirmary, Glasgow G31 2ER, United Kingdom
Address all correspondence and requests for reprints to: J. M. C. Connell, Professor of Endocrinology, University Department of Medicine and Therapeutics, Gardiner Institute, Western Infirmary, Glasgow G11 6NT, United Kingdom. E-mail: John.M.C.Connell{at}clinmed.gla.ac.uk
Abstract
Polycystic ovary syndrome (PCOS) is characterized by hyperinsulinemic insulin resistance, a metabolic disorder that in other circumstances is associated with increased cardiovascular risk. We compared macrovascular and microvascular function in 19 women with PCOS with 12 control subjects matched as a group for body mass index. Macrovascular function was assessed by recording pulse wave velocity (PWV) across the aorta and brachial artery. Microvascular function was studied by wire myography, by measuring the concentration response curve to norepinephrine (NE) before and after incubation with insulin (100 and 1,000 pM).
PWV at the level of the brachial artery was found to be significantly elevated in the PCOS group [9.08 (range, 8.34–11.15) m/sec-1 vs. 8.27 (range, 7.5–9.01) m/sec-1; P = 0.03]. In contrast, PWV measured in the aorta did not differ between the two groups [7.49 ± 1.21 vs. 7.84 ± 1.44 m/sec-1; P = 0.8].
In vessels from control subjects, insulin reduced the contraction response to NE. At an insulin concentration of 100 pM, NE negative log EC50 (pD2) was 6.2 ± 0.24 vs. 6.7 ± 0.15 (P = 0.02). At a concentration of 1,000 pM, NE pD2 was 6.4 ± 0.14 vs. 6.9 ± 0.19 (P = 0.0006). Both concentrations also caused attenuation in maximal tension developed in response to NE (insulin 100 pM, 12 ± 3%, P = 0.002; insulin 1,000 pM, 17 ± 5%, P = 0.009). In contrast, there was no change in the PCOS group with insulin at 100 pM for either pD2 (6.7 ± 0.24 vs. 6.8 ± 0.27; P = 0.3) or maximum contraction (-0.4 ± 2%; P = 0.8). At 1,000 pM, there was a change in pD2 (6.4 ± 0.2 vs. 6.8 ± 0.2; P = 0.003) but not maximum contraction (4 ± 3%; P = 0.2).
In conclusion, this study is the first to demonstrate increased vascular stiffness and a functional defect in the vascular action of insulin ex vivo in patients with PCOS. We suggest that these findings are indicative of insulin resistance at a vascular level in women without overt cardiovascular disease.
POLYCYSTIC OVARY SYNDROME (PCOS) is a common reproductive endocrine disorder that is characterized by hyperandrogenism and chronic anovulation, affecting about 5% of premenopausal women (1, 2). It is now recognized that PCOS also has a metabolic component, consisting of resistance to insulin-stimulated glucose uptake and hyperinsulinemia (3). Insulin resistance and hyperinsulinemia have been implicated not only in the development of type 2 diabetes (4), but more recently in several metabolic and hemodynamic abnormalities that predispose to cardiovascular disease (5). The precise mechanism for this is unknown. However, in hypertension and type 2 diabetes mellitus, the defect in whole-body insulin-stimulated glucose uptake correlates with decreased large vessel compliance (6) and is associated with evidence of vascular endothelial dysfunction, including reduced nitric oxide (NO) availability (7). We have hypothesized that insulin tonically maintains vascular endothelial NO synthesis (8, 9) and that impaired insulin action in vascular tissue links endothelial dysfunction (7, 10, 11), decreased arterial compliance (12, 13), and the subsequent development of cardiovascular disease (5, 11, 14). It is of relevance, therefore, that PCOS is associated with an increased lifetime risk of diabetes (15, 16, 17), hypertension (16, 18, 19), and hyperlipidemia (16, 19, 20, 21), although a recent retrospective study has indicated no increase in risk of myocardial infarction (21).
In many circumstances, the relationship between insulin resistance and vascular dysfunction is difficult to study because subjects are affected by confounding cardiovascular problems, such as hypertension. However, this is not the case in young women with PCOS who are insulin-resistant without overt cardiovascular disturbance. Accordingly, we have assessed macrovascular and microvascular function in a group of women with PCOS and in a group of women with similar body mass index (BMI), adiposity, blood pressure (BP), lipids, and fasting glucose.
Subjects and Methods
Subjects
PCOS was defined as androgen excess (total T >3.6 nmol/liter or a free androgen index 
9%) with ovulatory dysfunction (less than six menstrual cycles per year). In all subjects, ovarian imaging was performed using ultrasound. Specific adrenal disorders were sought by biochemical testing; all subjects had normal levels of 17
hydroxyprogesterone. In no subject was the circulating level of T greater than 5 nmol/liter. Patients were recruited from the endocrine clinics of the North Glasgow Hospitals University National Health Service Trust. Patients and controls were on no medication at the time of study, and a 3-month washout was required for those on medication before the study. The control population consisted of volunteers who had regular menstrual cycles and normal androgens and were on no medication. They were recruited by a poster campaign. For each woman with PCOS, we attempted to recruit a control within 2 BMI units. This was achieved for all but seven patients. All subjects were studied within 5 d of their last menstrual period (controls), or at least 8 wk after their last menstrual period (PCOS). All subjects gave informed consent and attended fasting for all studies, which were approved by the local hospital ethical review committee.
Pulse wave velocity (PWV)
PWV was measured in a temperature-controlled room at 24 C. PWV was calculated from the measurement of pulse transit time and the distance traveled between the two recording sites [PWV = distance (m)/transit time (sec)]. A TY-306 pressure transducer (Fukuda Co., Tokyo, Japan) was used to record the pressure-flow wave. PWV was calculated using an automated device (Complior, Colson, Paris, France). Brachial artery PWV was calculated between the carotid and radial arteries of the nondominant hand, whereas aortic PWV was calculated between the carotid and femoral arteries. An average of 20 recordings were made at each site, and the average PWV was calculated. The coefficient of variation using this technique is 7.6% for brachial and 8.1% for aortic PWV.
Myography
Gluteal biopsy. With the subject lying prone, one buttock was exposed, and the area was sterilized with iodine. Lignocaine 1% was instilled sc, anesthetizing a 4- x 2-cm area. An elliptical incision was made, and a 3- x 0.75-cm segment of skin and adipose tissue was removed. Then the skin was sutured (sutures were removed 7 d later).
Acetylcholine (ACh), norepinephrine (NE) (Sigma, Poole, UK), and soluble human insulin (Actrapid, Novo Nordisk A/S, Bagsvaerd, Denmark) were prepared as fresh base solutions in physiological salt solution (PSS; composition in mM: NaCl 118.4, KCl 4.7, MgSO4H20 1.2, NaHCO3 24.9, CaCl 2.5, glucose 11.1, EDTA 0.023).
Preparation of arteries. Resistance arteries were dissected from the biopsy. Where possible, four segments of artery (diameter, 200–400 µm; length, 2 mm) were mounted as ring preparations on two 40-µm stainless steel wires in a four-channel small vessel myograph (Danish MyoTechnology, Aarhus, Denmark) and normalized, as described in detail elsewhere (22).
Myograph protocol. Following the normalization procedure described above, vessels were maintained in PSS at 37 C for an additional 60 min. Then they were exposed twice to KPSS (PSS solution with KCl substituted for NaCl on an equimolar basis) and subsequently incubated with PSS for 30 min before a cumulative concentration response curve (CRC) to NE (10-9 M to 3 x 10-5 M). After a further 30-min incubation, a plateau contraction was obtained (10-6 M NE) before a CRC to ACh (10-9 M to 3 x 10-5 M). If vessels did not contract to KPSS or NE or if they showed no relaxation to ACh, they were excluded from the study.
Vessels were incubated with insulin as previously described, but using physiological concentrations of insulin. Vessels were incubated for 30 min with PSS alone (control) or with insulin (100 pM or 1,000 pM) before a further NE CRC. Responses are expressed as a percentage of the maximum contraction to NE or as the negative log EC50 (pD2) (23).
Whole-body insulin sensitivity. Subjects attended after an overnight fast. Baseline BP and heart rate were recorded after 20 min of supine rest, before the insertion of indwelling cannulae into the left antecubital vein for administration of glucose and insulin and retrogradely into the right dorsal hand vein for blood sampling. To arterialize the blood, the right hand was placed in a heated box for the duration of the experiment (60 C; Department of Physiology, University of Nottingham, Nottingham, UK). Insulin sensitivity was assessed using a modified version of the hyperinsulinemic euglycemic clamp as described by DeFronzo et al.(23a) In brief, a primed, constant rate infusion of soluble insulin (1.5 mU/kg·min) was administered for 180 min, and a variable rate infusion of 20% glucose was administered to maintain euglycemia (5.2 mmol/liter). The insulin was prepared in 45 ml of 0.9% NaCl, and 5 ml of the subject’s own blood were added to prevent adsorption of insulin to plastic surfaces. The infusion was administered using a Braun Perfusor pump (Braun, Melsungen, Germany). Glucose (20%) was infused from 4–180 min using an IVAC IV infusion system (Basingstoke, UK); glucose infusion rate was adjusted manually according to the glucose concentration measured at 5-min intervals in 2-ml blood samples collected from the dorsal right hand. Under steady-state conditions, whole-body glucose disposal rate was calculated from the glucose infusion rate and the serum glucose concentration by applying De Fronzo’s space correction (mg/kg·min). At 60-min intervals from baseline to 180 min, blood samples were also collected for the measurement of serum insulin concentrations. Measurement of BP and heart rate were recorded every 30 min using a semiautomatic sphygmomanometer (Dinamap, Bracknell, UK) (24).
Clinical measures
Ovarian morphology was assessed by the same operator (H. Lyall) in each subject, using either trans-abdominal or trans-vaginal ultrasound.
BP and pulse were recorded by an oscillometric technique using a Dinamap Critikon (Johnson \|[amp ]\| Johnson, Maidenhead, UK). Waist to hip ratios (WHRs) were measured in the standard fashion by a single observer (C. J. G. Kelly).
Biochemistry
Routine biochemical analysis on all subjects was performed using an Olympus AU5200 autoanalyzer. Baseline hormonal profiles (T, progesterone, PRL 17-hydroxyprogesterone, and FSH/LH) were measured using a Bayer Corp. (Elkhart, IN) Immuno 1 autoanalyser, and sex hormone binding globulin was measured using the DPC Immulite 2000. The free androgen index was calculated by total T (nmol/liter)/sex hormone binding globulin (nmol/liter) x 100. Fasting lipids were measured on a Beckman Coulter, Inc. (Fullerton, CA), Syncron CX4.
Statistics
Statistical analysis was performed using Minitab 13.1 (State College, PA). Data are expressed as mean ± SD or as the median (Q1, Q3) if not normally distributed. Differences between the groups were assessed using the two-sample t test (normally distributed data) or a Mann-Whitney U test (nonparametric data) with P less than 0.05 being considered statistically significant.
Results
Clinical features
The groups were well matched for BP, pulse, BMI, WHR, fasting plasma glucose, and lipids (Table 1
). The control group was, however, significantly older than the PCOS group (P = 0.001). As expected, there was a significant increase in the biochemical markers of PCOS free androgen index (P < 0.0001) and polycystic ovary morphology (P < 0.0001) in the affected group. There was a nonsignificant trend toward a lower insulin-mediated glucose disposal rate in women with PCOS (5.9 ± 2.79 vs. 7.5 ± 1.82; P = 0.07).
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Myography was completed in 11 women with PCOS and 10 controls. The subgroups maintained similar characteristics to those described above (Table 2).
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PWV at the level of the brachial artery was found to be significantly elevated in the PCOS group when compared with controls [9.08 (range, 8.34–11.15) m/sec-1 vs. 8.27 (7.5, 9.01) m/sec-1; P = 0.03] (Fig. 1). In contrast, PWV measured in the aorta did not differ between the two groups (7.49 ± 1.21 m/sec-1 vs. 7.84 ± 1.44 m/sec-1; P = 0.8).
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General responses. The diameter of vessels from women with PCOS and control subjects was not different (323.6 ± 16.2 vs. 315.4 ± 18.1 µm; P = 0.4). Both groups also exhibited similar endothelium-dependent relaxation to ACh (maximum relaxation, PCOS 88 ± 4.2% vs. control 86 ± 5.1%; P = 0.4). Vessels from both groups displayed the characteristic sigmoid relationship to increasing concentrations of NE. There was no evidence of tachyphylaxis in response to NE in vessels used as controls for time of study, which were exposed to NE, and no differences were observed between groups in baseline responses to NE.
Insulin responses.
In vessels from control subjects, insulin at both concentrations caused a right shift in the CRC (Fig. 2A) [NE pD2, 6.2 ± 0.24 (100 pM) vs. 6.7 ± 0.15 (vehicle), P = 0.02; 6.4 ± 0.14 (1,000 pM) vs. 6.9 ± 0.19 (vehicle); P = 0.0006]. Both concentrations also caused attenuation in maximal tension developed in response to NE (insulin 100 pM, 12 ± 3%, P = 0.002; insulin 1,000 pM, 17 ± 5%, P = 0.009).
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) [pD2, 6.7 ± 0.24 (100 pM) to 6.8 ± 0.27 (vehicle), P = 0.3; or maximum contraction (-0.4 ± 2%; P = 0.8]. At 1,000 pM, there was a change in pD2 (6.4 ± 0.2 to 6.8 ± 0.2; P = 0.003) but not maximum contraction (4 ± 3%; P = 0.2). Discussion
PCOS is associated with an increased lifetime risk of hypertension (16, 18, 20, 21), dyslipidemia (16, 20, 21), type 2 diabetes (15, 16, 17, 21), and possibly cardiovascular disease (25, 26, 27). Similarly, premenopausal women with PCOS have an increased prevalence of impaired carbohydrate metabolism; up to 40% of women with PCOS have either impaired glucose tolerance or type 2 diabetes (15, 17).
The mechanism of the link between PCOS and increased cardiovascular risk is not well understood. In the present study, we have demonstrated that women with PCOS exhibit evidence of impaired macrovascular and microvascular function when compared with a matched control group of subjects. First, we found evidence of reduced vascular compliance (increased PWV) in brachial arteries of women with PCOS. PWV is known to increase with age (28) and hypertension (28, 29, 30), and several studies have reported increased PWV in diabetic (31, 32, 33, 34, 35) and hyperlipidemic patients (30, 36). Although our control subjects were older than the patients (potentially masking any difference), they were well matched for other factors known to influence PWV. These data may, therefore, have implications for the long-term cardiovascular health of women with PCOS (29, 36, 37).
We hypothesized that insulin resistance might underlie vascular dysfunction in PCOS (6, 8, 13). Previous studies have provided evidence to link metabolic insulin resistance with the influence of insulin on vascular compliance. For example, Westerbacka et al. (39) demonstrated that insulin infused at physiological levels failed to reduce aortic stiffness in a group of obese, insulin-resistant subjects using augmentation index as a measure of arterial stiffness; this defect correlated closely with whole-body insulin resistance. Thus, insulin-resistant subjects seem to have an impaired large (conduit) artery response to insulin, implying that metabolic insulin resistance is accompanied by abnormal vascular function. The present data suggest that arterial consequences of metabolic dysregulation also occur in PCOS.
To test this relationship further, we examined the vasorelaxant effects of insulin on resistance arterioles. In resistance arteries from healthy control women, insulin caused a dose-dependent attenuation of NE action. Both the maximum response and sensitivity (pD2) to NE were reduced after exposure to physiological 100 pM and supraphysiological 1,000 pM insulin concentrations for 30 min. In contrast, no response was seen at 100 pM in the PCOS vessels, whereas at 1,000 pM sensitivity but not maximum response was altered. Thus, women with PCOS have an abnormal resistance artery response to insulin, even in the absence of any other risk factors.
The present study is the first to our knowledge to demonstrate a functional defect in the vascular action of insulin ex vivo in resistance arteries from women with an insulin-resistant metabolic disorder without overt cardiovascular disease. The defect in the resistance arterioles appears to be specific to the action of insulin in that constriction to NE and relaxation to ACh were not different between the PCOS subjects and controls.
Taken in the context of previous reports on the vascular actions of insulin, it is tempting to speculate that the defect we have demonstrated in vessels from women with PCOS reflects abnormal regulation of endothelial NO synthesis by the hormone. There is good evidence that insulin regulates blood vessel tone via its actions on endothelial NO synthesis (7, 40, 41, 42, 43, 44). Indeed, we have previously reported a positive correlation between insulin sensitivity and endothelial NO production in normal subjects (40) and patients with hypertension and type 2 diabetes (7). Although insulin sensitivity and endothelial NO synthesis are positively related in healthy humans (40), insulin resistant states such as obesity (45), gestational diabetes, hypertension (7), and type 2 diabetes (46) are all associated with impaired insulin-mediated nitric oxide-dependent vasodilatation. Indeed, Paradisi et al. (47) measuring leg blood flow recently described decreased insulin-mediated vasodilatation and endothelial dysfunction in a group of insulin-resistant women with PCOS compared with controls. Thus, our current data in large and small blood vessels in women with PCOS, a condition in which reduced insulin sensitivity is common, are consistent with these earlier reports.
The mechanism for the defective vascular action of insulin remains unclear. Human endothelial cells possess insulin receptors, and insulin has been shown to increase NO release from cultured endothelial cells via a phosphatidylinositol-3 (PI-3) kinase pathway (48). Studies of insulin signaling in women with PCOS suggest a defect in the PI-3 kinase pathway; Dunaif and Thomas (49) demonstrated signaling defects in both skin and muscle fibroblasts resulting in down-regulation of the PI-3 kinase pathway. This raises the possibility that there is a defect of insulin signaling in PCOS manifested by reduced glucose transport in skeletal muscle and adipose tissue and by abnormal insulin-regulated vascular endothelial NO production in the vasculature.
In summary, therefore, abnormal vascular compliance and altered reactivity of resistance arteries are new findings in PCOS that may provide further evidence of the general nature of the risk associated with insulin resistance. These vascular changes may be the forerunners of more overt cardiovascular abnormalities such as high BP in older women with PCOS. The putative mechanism of altered insulin regulation of endothelial NO identifies a new therapeutic target that merits further investigation.
Footnotes
This work was supported by Grant 1459 from the Scottish Hospitals Endowment Research Trust (to H.L., G.W.G., and J.M.C.C.).
Abbreviations: ACh, Acetylcholine; BMI, body mass index; BP, blood pressure; CRC, concentration response curve; NE, norepinephrine; NO, nitric oxide; PCOS, polycystic ovary syndrome; pD2, negative log EC50; PI-3, phosphatidylinositol-3; PSS, physiological salt solution; PWV, pulse wave velocity; WHR, waist to hip ratio.
Received May 1, 2001.
Accepted October 17, 2001.
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