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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 9 4615-4619
Copyright © 2004 by The Endocrine Society

Hormone Therapy Impairs Endothelial Function in Postmenopausal Women with Type 2 Diabetes Mellitus Treated with Rosiglitazone

Suzy Y. Honisett, Lily Stojanovska, Krishnankutty Sudhir, Bronwyn A. Kingwell, Tye Dawood and Paul A. Komesaroff

School of Life Sciences (S.Y.H., L.S.), Victoria University, Melbourne 8001, Australia; and Baker Heart Research Institute (S.Y.H., K.S., B.A.K., T.D., P.A.K.), St. Kilda Central, Melbourne 8008, Australia

Address all correspondence and requests for reprints to: Assoc. Prof. Paul Komesaroff, Department of Medicine, Monash University, The Alfred Hospital, Commercial Road, Prahran, Victoria, Australia 3181. E-mail: paul.komesaroff{at}med.monash.edu.au.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Diabetes and ovarian senescence are associated with impaired endothelial function and altered arterial mechanical properties. Alterations in normal vascular structure and functioning are the primary cause of mortality and morbidity with type 2 diabetes. Similarly, after menopause, women experience an increase in the rate of cardiovascular disease. Thiazolidinediones have exhibited a number of antiatherogenic actions in populations with type 2 diabetes. The effect of thiazolidinediones in combination with hormone therapy (HT) in postmenopausal women is, however, unknown. To assess whether HT (transdermal estradiol 50 µg and micronized progesterone (100 mg/d) affects vascular function, 21 women receiving rosiglitazone were randomly assigned to receive HT or placebo for 12 wk in a double-blind crossover design. Measures of glycemic control, lipids, blood pressure, flow-mediated dilation, and distensibility index were undertaken at baseline and after each treatment. As a result, flow-mediated dilation was significantly reduced (15.3 ± 3.8 to 6.6 ± 1.6%, P = 0.02) with HT, whereas lipids, blood pressure, and distensibility index were unchanged. Placebo had no significant affect on any variables. Thus, the addition of HT to rosiglitazone treatment attenuates endothelial function without altering other cardiovascular risk factors. Caution should, therefore, be exercised when considering combined treatment with thiazolidinedione and HT.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE THIAZOLIDINDIONE ROSIGLITAZONE improves glycemic control, indicated by reduced glycated hemoglobin, fasting glucose, and insulin levels in patients with type 2 diabetes (1, 2, 3). Good glycemic control and the subsequent amelioration of hyperinsulinemia and hyperglycemia can delay the onset of vascular complications (4). Rosiglitazone, however, also has a number of antiatherogenic effects independent of its influences on glucose and insulin metabolism (5). Rosiglitazone, therefore, provides an effective treatment for populations at high risk of developing cardiovascular disease, such as postmenopausal women with type 2 diabetes.

In healthy postmenopausal women, hormone therapy (HT) has been associated with improved vascular function (6, 7) and a reduction in cardiovascular morbidity and mortality (8, 9, 10, 11). Whether these potentially beneficial effects of HT can be extrapolated to women with endothelial dysfunction, often found with established cardiovascular disease or type 2 diabetes, has created considerable controversy. A number of investigators have shown HT reduces a number of risk factors for cardiovascular disease in postmenopausal women with type 2 diabetes, including improved glycemic control (12, 13, 14, 15), decreased circulating low-density lipoprotein (LDL), increased high-density lipoprotein (HDL) levels, and reduced soluble intercellular adhesion molecules (6). On the other hand, in vitro studies have demonstrated that hyperglycemia attenuates the ability of estrogen to stimulate nitric oxide production (16) and inhibit vascular smooth muscle cell proliferation (17). Estrogen administration has also provided neutral effects on a range of endothelial functions in vitro (18) and in postmenopausal women with type 2 diabetes (6, 19). Reducing hyperglycemia by the administration of rosiglitazone and combining this treatment with HT may provide some added benefits to cardiovascular risk in comparison with either treatment given in isolation. Previous studies have not, however, addressed this issue.

Flow-mediated endothelium-dependent vasodilation and large arterial distensibility are accessible and reproducible parameters that measure endothelial function and arterial elasticity. These two parameters may be modifiable targets for treatment that aim to reduce cardiovascular disease risk factors associated with diabetes and menopause.

The aim of this study was to determine whether HT administered in conjunction with rosiglitazone would provide further cardioprotection in postmenopausal women with type 2 diabetes in comparison with rosiglitazone treatment alone.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Nineteen women with established type 2 diabetes, who had been taking rosiglitazone (4 mg/d) for 3 months, were recruited. All women were postmenopausal (confirmed by a serum FSH ≥ 30 IU/liter) and were between the ages of 49 and 69 yr. Subjects were excluded if they were smokers, were taking insulin, or had established cardiovascular disease or abnormalities of thyroid or hepatic function. Subjects were required to maintain their current diet and exercise habits throughout the duration of the study. All subjects gave informed consent to participate in this study, which was approved by the Alfred Hospital Human Research Ethics Committee.

The study followed a randomized, double-blind, crossover design. Subjects were currently taking rosiglitazone treatment (4 mg/d, GlaxoSmithKline, Victoria, Australia) and were randomly allocated to group 1 to receive HT [transdermal estradiol (50 µg), 3M pharmaceuticals, and oral micronized progesterone (100 mg), Iscovesco Besnins, Paris, France] or group 2 to receive placebo (patch and tablet) for a period of 12 wk, after which subjects crossed over to the alternate treatment while continuing rosiglitazone treatment. Subjects were requested to visit the Baker Medical Research Institute Menopause Clinic at baseline and after 12 wk and 24 wk of treatment. At these time points, subjects were assessed by a clinician to ensure that there were no contraindications to their involvement in the study and to monitor their diabetic control and general health. A number of measurements were also undertaken at these time points. Measurements included estradiol, FSH, LH, fasting blood glucose, insulin levels, glycated hemoglobin, total cholesterol, HDL cholesterol and LDL cholesterol, triglycerides, resting measures of blood pressure, flow-mediated dilation (FMD), and distensibility index (DI). All measurements were undertaken by trained staff and analyzed in a double-blinded fashion without reference to names, visit numbers, or treatment.

Assessment of endothelial function and large arterial compliance

FMD. This procedure was carried out in accordance with established protocols (20). Measurements were undertaken after a 12-h overnight fast, including coffee and alcohol. None of the subjects were smokers. Subjects lay supine and rested for 10–15 min before the procedure. Electrocardiograph leads attached to the ultrasound machine (Powervision 7000; Toshiba, Tokyo, Japan) were placed on the inside of both wrists and on the left side of the subject’s abdomen, and a sphygmomanometer cuff was placed on the upper right forearm. Simultaneously, a high-frequency (7.5 MHz) linear array transducer was placed longitudinally on the upper arm, 5–7 cm above the antecubital crease to obtain an image of the brachial artery. The sphygmomanometer cuff was inflated to a pressure of 250 mm Hg for 4.5 min, after which it was released abruptly and brachial artery diameter was monitored for the following 120 sec. After an additional 10–15 min, subjects received glyceryl trinitrate (300 µg) sublingually, with further monitoring of brachial artery diameter.

Mean brachial artery diameter before, during, and after reactive hyperemia and glyceryl trinitrate was calculated from three cardiac cycles synchronized with the R-wave peaks on the electrocardiograph. This technique was assessed for reproducibility in six subjects, male and female, on six occasions over 3 consecutive days, showing a coefficient of variation (CV) for brachial artery diameter of 3.4 ± 0.3%, and percentage change after reactive hyperemia of 4.6 ± 0.05%.

Assessment of large arterial compliance. DI estimates the underlying mechanical (as opposed to functional) properties of the large arteries and is independent of vessel size. DI was determined using calculations based on the area method of Liu et al. (21), as described previously (22). Briefly, this method requires measurement of central arterial pressure using carotid tonometry (SPT-301; Millar Instruments, Houston, TX), and blood flow using continuous wave Doppler velocimetry (Multi-Dopplex MD1; Huntleigh Technology, Cardiff, UK). The carotid arterial waveform was calibrated using brachial mean and diastolic blood pressure (DBP) (Dinamap vital signs monitor, 1846 SX, Critikon), to derive carotid systolic blood pressure (SBP) as previously described (22, 23).

Biochemical assays. Venous blood samples were obtained from subjects for the determination of sex hormones. FSH was measured using a two-site chemiluminescent (sandwich) immunoassay (Ciba-Corning, Medfield, MA). Insulin assays used a commercial RIA kit (Pharmacia and Upjohn, Stockholm, Sweden) (CV, 2.83%). Glycated hemoglobin was measured using a Borate affinity chromatography (in-house method at Alfred Pathology; within run CV, 0.82–0.46%; run-to-run CV, 2.91–1.09%). Total cholesterol (CV, 2.4%), HDL (CV, 4.8%), LDL (CV, 3.8%), triglycerides (CV, 3.6%), and glucose (CV, 4.5%) were measured using Cholestec L.D.X Lipid Profile plus Glucose (Cholestec, Hayward, CA).

Statistical analysis

Data were analyzed using Sigma Stat 2.0 (Jandell, San Rafael, CA). Data reported are mean ± SEM. An unpaired t test was undertaken at baseline between groups 1 and 2. Statistical analysis was undertaken by a two-way ANOVA with repeated measures comparing the effects of placebo and hormonal therapy. This statistical method incorporated an analysis of treatment order between groups 1 and 2 as a between-subjects factor and also tested any carryover effects of treatment. This statistical method has previously been described and validated (24). Significance was reported at P < 0.05.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The age range of women was 58 ± 3 yr. There were no significant differences between baseline values for any variables measured for women allocated hormonal therapy first (group 1) as opposed to women allocated placebo treatment first (group 2) (Table 1Go).


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  		TABLE 1. Baseline characteristics between groups prior to treatment

 
Body mass index (BMI) was significantly higher after treatment with HT in comparison with placebo (P = 0.04) (Table 2Go). Serum estradiol levels were higher (P = 0.03), whereas circulating FSH (P = 0.001) and LH (P = 0.04) were reduced after the administration of HT, in comparison with placebo treatment (Table 2Go).


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  		TABLE 2. Group characteristics after treatment

 
There were no significant alterations to total cholesterol, HDL cholesterol, LDL cholesterol, or triglycerides with either HT or placebo treatment (Table 2Go), nor were there any changes in fasting glucose, insulin, or glycated hemoglobin with treatment (Table 2Go).

There were no significant differences in DI, central SBP, brachial SBP, DBP, or mean arterial pressure (MAP) between HT or placebo treatment (Table 2Go). FMD was significantly reduced (P = 0.02) in response to 12 wk of HT treatment in comparison with placebo treatment (Fig. 1Go).



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  		FIG. 1. FMD of brachial artery, after 12 wk of placebo and after 12 wk of HT (n = 19). *, Significant (P = 0.02) difference between treatment groups.

 
There was no significant effect of the order of treatment given on any of the variables measured, indicating that there were no significant carryover effects between treatments.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The main findings of this study were that the addition of HT to rosiglitazone treatment attenuated endothelial function as measured by the change in brachial artery diameter in response to ischemia in postmenopausal women with type 2 diabetes. This response was observed in the absence of changes to other cardiovascular risk factors such as lipoprotein levels or arterial stiffness. The addition of HT to rosiglitazone treatment did not adversely affect glycemic control.

Epidemiological data has revealed that women with diabetes have a cardiovascular risk similar to that of nondiabetic men (25); suggesting that women with diabetes are denied the vascular protection afforded by estrogen. This has been demonstrated in animal models; aortic rings of ovariectomized streptozotocin mice treated with 17ß-estradiol showed an attenuation in norepinephrine-induced contractile response, in comparison with nondiabetic controls treated with estradiol (18). Similar findings have been demonstrated in humans; nondiabetic postmenopausal women using HT had greater endothelium-dependent dilation as opposed to postmenopausal women with type 2 diabetes using HT (6). Considerable controversy remains regarding the effects of estrogen in a population that is likely to have endothelial dysfunction, such as diabetic subjects. Further research is warranted to determine the mechanism associated with this apparent paradoxical effect. The abolition of the vascular protective effects of estrogen with diabetes does not, however, explain the reduction in brachial FMD with the combination of rosiglitazone and HT.

A possible molecular mechanism accounting for this attenuation in endothelial function may be that estrogen antagonizes rosiglitazone binding to PPAR{gamma} in estrogen target tissue such as the endothelium. Estrogen alone does not function effectively as a ligand for the PPAR{gamma} (26), nor do PPAR and estrogen receptors form a heterodimer in vivo (27); therefore, the relationship between estrogen and PPARs may involve indirect mechanisms. PPAR{gamma} is selectively activated by prostaglandins, specifically from the J2 series (28). Estrogen can regulate prostaglandin production in target tissue such as the uterus (29, 30, 31, 32, 33, 34), such that estradiol increases the release of arachidonate, a precursor of prostaglandins (35). These prostaglandins may compete for PPAR{gamma} binding with thiazolidinediones. Estradiol treatment in ducks causes a decrease in prostaglandin D2 levels due to an increased conversion to a metabolite, which appears to be extremely similar in structure and behavior to prostaglandin ligands for PPAR{gamma} ({Delta}12-prostaglandin J2) (26). It is possible that this prostaglandin metabolite competitively binds to PPAR{gamma} and reduces the ligand binding of rosiglitazone, subsequently reducing endothelial function.

Another interpretation of these results may involve estrogen receptors, which are up-regulated with estrogen administration, negatively regulating PPAR action on peroxisome proliferator response elements (PPRE) through competition for DNA binding. A similar molecular occurrence was apparent with thyroid hormone receptor {alpha} competitively binding with PPAR to PPREs; however, only PPAR mediated a transcriptional activation via PPRE (36). Thyroid hormone and estrogens are both members of the steroid thyroid nuclear receptor superfamily, which form heterodimers with retinoid X receptors to bind to hormone response elements; therefore, a similarity may exist in the relationship of these hormone receptors, with a reduction in PPAR activation and the subsequent impairment of endothelial function, as indicated by reduced brachial artery FMD.

Neither of these interpretations takes into account the maintenance of glycemic control and lack of differences in other cardiovascular risk factors, such as DI, blood pressure, and lipoproteins, in the HT group compared with placebo. Further comprehensive in vitro investigations are required to substantiate these interpretations.

It is important to note that FMD measures conduit artery response as a measure of endothelial function; this correlates well with invasive testing of coronary endothelial function (37, 38). DI, on the other hand, examines properties of large proximal arteries. The effects of combined rosiglitazone and HT treatment were apparent on peripheral conduit vessels; however, these effects were not seen in large proximal arteries. Although there is no evidence, PPAR{gamma} receptor concentrations may vary between tissues, thus explaining a significant effect of treatment on peripheral arteries but not on larger proximal arteries.

The effect of progesterone on rosiglitazone action has not been investigated. It is possible that progesterone negatively influences FMD in postmenopausal women with type 2 diabetes.

In our investigation, women taking rosiglitazone at the commencement of the study recorded circulating glucose levels greater than 7 mmol/liter, a level still regarded as high in comparison with recommended healthy ranges (4–7 mmol/liter). Alternate to the previous two interpretations of the reduced FMD results is a hypothesis that proposes, in a postmenopausal type 2 diabetes population experiencing hyperglycemia, that estrogen may impair endothelial function, therefore negating the beneficial cardiovascular effects of rosiglitazone. High glucose concentrations have been shown in vitro to attenuate the antiproliferative effect of estrogen on human vascular smooth muscle cell proliferation (39), suggesting an interaction between estrogen and hyperglycemia at the vascular level.

FMD is significantly associated with the extent of coronary artery disease (CAD) (40). Therefore, FMD is an effective noninvasive measure of endothelial dysfunction, which may be used as a surrogate marker to determine changes in coronary circulation. The clinical significance of changes in FMD has been demonstrated in a previous study which compared patients with CAD and healthy control subjects (40). This study demonstrated that patients with CAD had approximately half the brachial artery vasodilation, in response to reactive hyperemia, in comparison with healthy controls. The FMD values of the healthy control patients in this previous study were very similar to our baseline figures (12.6 ± 6.7 vs. 12.8 ± 3.7%, respectively), and the values of the CAD patients were very similar to the FMD values of patients in the current study after hormonal therapy treatment (5.7 ± 4.8 vs. 6.5 ± 2.5%, respectively) (39). However, there are no data, to the best of our knowledge, that quantify FMD values in relation to the risk of CAD. Long-term studies are required to determine whether the combination of rosiglitazone and hormonal therapy affects the rate of cardiovascular events in patients with type 2 diabetes.

In the current study, women experienced a small (0.4%), but significant, increase in BMI while taking hormonal therapy. The cause for this increase is unknown. In view of previous large clinical trial data (41), it is unlikely to be caused by HT alone; however, the possibility of an interaction between HT and weight gain cannot be excluded. Women were required to maintain constant diet and exercise habits throughout the duration of this study. The consistency of these lifestyle factors was, however, not verified. Therefore, it is difficult to ascertain what caused this small, but significant, increase in BMI with hormonal therapy treatment. It is possible that neurohumoral changes associated with the increase in BMI may have contributed to the reduction in FMD.

The current study looked at combined HT and rosiglitazone. The lack of change in blood biochemistry levels, as a result of HT in this study, varies from previous studies that have demonstrated significant alterations in HT alone (42, 43, 44). The magnitudes of changes in these previous studies were variable and may be dependent on the type of hormones used. In addition, the types of estrogens used by women in these studies varied considerably and included conjugated equine estrogens, 17ß-estradiol, and estradiol valerate, in both opposed and unopposed regimens. In contrast, in our study, a homogenous regimen of HT, consisting of transdermal estradiol and micronized progesterone, was administered.

This is the first study to investigate the effects of combined rosiglitazone and HT in vitro or in vivo. Accordingly, the mechanisms underlying the clinical outcomes that we have demonstrated are unknown. A limitation of this study is that it cannot provide information regarding the underlying mechanisms of the effects we have demonstrated.

Further studies are required to examine the underlying mechanisms of these results; in particular, in vitro studies examining the effects of sex hormones, thiazolidinediones, and varying glucose concentrations in endothelial cells may shed light on possible interactions. It would also be of interest to ascertain whether the observed interaction between hormonal therapy and rosiglitazone is specific to thiazolidinediones or whether this is generalizable to other hypoglycemic agents. This cannot be ascertained within the current study and would require further studies that employ other agents that lower hyperglycemia.

This is the first study to investigate the effects of combined rosiglitazone and HT in a clinical setting. Our findings suggest that HT should be administered with caution to postmenopausal women with type 2 diabetes who are using thiazolidinedione therapy.


   Footnotes
 
Abbreviations: BMI, Body mass index; CAD, coronary artery disease; CV, coefficient of variation; DBP, diastolic blood pressure; DI, distensibility index; FMD, flow-mediated dilation; HDL, high-density lipoprotein; HT, hormone therapy; LDL, low-density lipoprotein; MAP, mean arterial pressure; PPRE, peroxisome proliferator response elements; SBP, systolic blood pressure.

Received September 15, 2003.

Accepted May 26, 2004.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals