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The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 2 614-618
Copyright © 2000 by The Endocrine Society

Original Studies

The Effect of Hormone Replacement Therapy on Cardiovascular Hemodynamics in Women with Turner’s Syndrome

M. Elsheikh, R. Bird, B. Casadei, G. S. Conway and J. A. H. Wass

Department of Endocrinology, Radcliffe Infirmary (M.E., J.A.H.W.), Oxford, United Kingdom OX2 6HE; and the Department of Cardiovascular Medicine, John Radcliffe Hospital (R.B., B.C.), Headington, Oxford, United Kingdom; and the Department of Endocrinology, Middlesex Hospital, London, United Kingdom OX3 7XP

Address all correspondence and requests for reprints to: Prof. John A. H. Wass, Department of Endocrinology, Radcliffe Infirmary, Woodstock Road, Oxford, United Kingdom OX2 6HE. E-mail: john.wass{at}noc.anglox.nhs.uk


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Women with Turner’s syndrome, the majority of whom are estrogen deficient, have an increased incidence of coronary artery disease. The aim of this study was to assess the effects of hormone replacement therapy (HRT) on central arterial hemodynamics, insulin sensitivity, and lipids in adults with Turner’s syndrome. Twenty-one women with Turner’s syndrome were studied prospectively, on and off 3 months of estradiol valerate in combination with levonorgestrel. The following measurements were made: body mass index, waist/hip ratio, serum lipids, fasting insulin and glucose, and mean arterial blood pressure. Aortic root pressure and waveforms were estimated noninvasively and the augmentation index (AI), a measure of aortic stiffness, was calculated. The AI was significantly lower during estrogen therapy (22% vs. 15%; P = 0.008), suggesting a reduction in central arterial stiffness. Fasting insulin and glucose concentrations were also significantly lower during HRT (P = 0.01 and P = 0.0004, respectively). There was no difference in body mass index, serum lipids, or brachial and aortic blood pressures on and off treatment. Total cholesterol was correlated with the AI (r = 0.4; P = 0.03).

These results suggest that HRT in women with Turner’s syndrome has a favorable effect on central arterial hemodynamics and insulin sensitivity. The lack of effect on serum lipids suggests that the effects of HRT on aortic compliance may be mediated by an improvement in endothelial function.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
IN 1938, HENRY Turner (1), and before him Ullrich, described the clinical features of Turner’s syndrome (TS), of which the most consistent are short stature and ovarian dysgenesis. It affects approximately 1 in 2500 live female births (2), corresponding to 1.5 million women worldwide. TS is a result of the complete or partial absence of an X chromosome. Women with Turner’s syndrome have a 3-fold increase in mortality, primarily as a result of cardiovascular complications (3, 4). A recent study suggests that these women have an incidence of coronary heart disease twice that of the general population (5). Women with TS have several risk factors for ischemic heart disease (IHD), including hypertension (6, 7), insulin resistance (8), hyperlipidemia (9, 10), and estrogen deficiency (2).

Over the past decade there have been several studies examining the effect of hormone replacement therapy (HRT) on the primary prevention of IHD in postmenopausal women. A recent meta-analysis of these studies shows an average 50% reduction in risk of IHD in women receiving HRT (11). The mechanisms are not completely understood, but include a favorable effect on blood lipids and insulin sensitivity as well as beneficial effects on endothelial and vascular smooth muscle function (12). There is accumulating evidence that estrogen receptors are present in vascular smooth muscle and endothelial cells, and as a result, estrogens may directly influence vascular compliance (13). However, recently, optimism about the beneficial cardiovascular effects of HRT has been tempered by the results of the HERS study (14). This study, the first randomized controlled trial assessing the effect of HRT on the development of cardiovascular disease, failed to show any benefit from the ingestion of conjugated equine estrogens in combination with medroxyprogesterone acetate in the secondary prevention of coronary artery disease. Studies examining the use of estrogens in women with TS have concentrated on the effects on bone density and final height; as a result, the cardioprotective efficacy of HRT in women with TS is unknown.

Increased arterial stiffness or reduced aortic compliance is now recognized as being a risk factor for the development of cardiovascular disease (15). Until recently, this could only be measured by direct intraarterial recording. However, noninvasive methods have now been devised that can accurately derive aortic pressure waveform from that measured at the radial artery by applanation tonometry.

The aim of this study was to assess the degree to which HRT may be protective against IHD in women with TS by measuring arterial stiffness, blood pressure, insulin sensitivity, and lipids.


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

Women with TS were recruited from the adult Turner clinics at the Radcliffe Infirmary (Oxford, UK) and the Middlesex Hospital (London, UK). The diagnosis of TS was based on peripheral leukocyte karyotype analysis. Women with preexisting renal disease, cardiovascular disease, or diabetes mellitus were excluded from the study.

Twenty-one women with TS (mean age, 32 yr; range, 17–47 yr) were studied prospectively, on and off HRT (2 mg estradiol valerate daily/75 µg levonorgestrel for 12 of 28 days). Twelve women were studied first on treatment and then 3 months after stopping HRT, and 9 were first studied off HRT and then after 3 months of treatment. They were all studied during the estrogen phase of treatment. Their karyotypes were as follows: 45,X, 57% (n = 12); 45,X/46,XX, 24% (n = 5); 45,X/46,XY, 14% (n = 3); and 45,X/46,Xi(Xq), 5% (n = 1). All subjects were biochemically euthyroid, as defined by a normal TSH throughout the study, although 3 (14%) were receiving T4 replacement therapy. Four subjects (19%) were taking antihypertensive medication but were normotensive on investigation. None was a smoker or received lipid-lowering medication. Significant structural cardiac defects were excluded by Doppler echocardiography in all subjects. Three subjects had a bicuspid aortic valve but normal valvular and ventricular function.

Measurements

Subjects were assessed after a 12-h overnight fast. They were studied in the sitting position after a rest of at least 15 min in a quiet, temperature-controlled room. Body habitus was evaluated by body mass index (weight/height2) and waist/hip ratio.

Laboratory evaluation included determination of total serum cholesterol, high density lipoprotein (HDL), and triglyceride levels by standard enzymatic methods. Fasting plasma glucose was measured using a Randox hexakinase-based method (Randox, Belfast, Northern Ireland), and serum insulin was measured using a double antibody RIA (Pharmacia & Upjohn, Inc., Milton Keynes, UK). Blood pressure was measured in the sitting position by brachial sphygmomanometry. The average of three recordings for each subject was calculated.

Central arterial hemodynamics were assessed noninvasively using applanation tonometry (16). A pencil-shaped probe incorporating a transducer was put over the radial artery and allowed direct measurement of arterial pressure pulse (Sphygmocor BPAS-1 PWV Medical Pty. Ltd., Sidney, Australia). The principle is similar to that used in measuring intraocular pressure. That is, flattening the curved surface of the artery allows accurate registration of intraarterial pressure. Data are acquired directly into a computer, and waveforms are analyzed. The aortic pulse waveform was derived from the radial pulse waveform by using a validated transfer function (17) implemented in the Sphygmocor software. Measurements using this method have been shown to correspond closely to intraarterially recorded waves (16, 17, 18). All measurements were performed by the same investigators. Ten consecutive pulse waves were analyzed and averaged to obtain a representative waveform for each subject. These were further analyzed, and the following parameters were derived: aortic blood pressure, ejection duration, and augmentation index. The pressure waveform is determined by both a forward wave and a reflected wave, returning toward the heart. The reflected wave is superimposed onto the forward wave, increasing systolic blood pressure. The augmentation index (AI) is defined as the pressure wave above its systolic shoulder divided by pulse pressure (Fig. 1Go). The augmentation index is a measure of central arterial stiffness. Decreasing arterial compliance, for example as a result of aging or atherosclerosis, results in an increase in the augmentation index (19, 20). Additionally, the augmentation index is closely linked to left ventricular mass (21).



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  		Figure 1. The effect of HRT on aortic pulse waveform. AI = P2 - P1/pulse pressure.

 
Statistical analysis

Statistical analysis was performed using C-Stat for windows version 1.5 (Cherwell Scientific Publishing Ltd., Oxford, UK). The variables, with the exception of insulin and glucose levels, were normally distributed, so the effects of HRT on body habitus, serum lipids, central and peripheral blood pressure, and arterial hemodynamics were assessed by Student’s paired t test. The effects of HRT on fasting insulin and glucose concentrations were assessed using the Wilcoxon matched pairs test. Comparison between more than two groups was performed using ANOVA. Pearson’s correlation coefficient was used to assess the association between the variables. Results were considered significant if P < 0.05. All data are reported as the mean ± SEM.

The study was approved by the Central Oxford Research ethics committee, and all participants gave written informed consent.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Table 1Go summarizes the characteristics of subjects on and off HRT. Waist/hip ratio was significantly reduced during HRT (P = 0.04) despite no change in BMI. Fasting insulin and glucose levels were also significantly lower during HRT (P = 0.03 and P = 0.0004, respectively). There was no change in total cholesterol, HDL cholesterol, or triglyceride concentrations with treatment. Additionally, HRT had no significant effect on brachial or aortic blood pressures or resting heart rate.


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  		Table 1. Subjects characteristics (n = 21)

 
The AI was significantly lower during sex hormone replacement therapy (22% vs. 15%; P = 0.008), indicating a reduction in central arterial stiffness (Fig. 2Go). In two subjects, the AI increased during HRT. However, in these subjects, there was a significant reduction in heart rate after HRT. This may explain the paradoxical effect of HRT on the AI in these subjects, as it is well established that AI and heart rate are inversely related (16, 17, 18).



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  		Figure 2. The effect of HRT on the AI in women with TS. Squares represent the mean AI.

 
Figure 3Go shows the correlation between total cholesterol and AI (r = 0.4; P = 0.03). There was no significant correlation between AI and body composition, HDL cholesterol, triglycerides, or brachial and central blood pressures. Additionally, there was no correlation between insulin levels and central arterial hemodynamics.



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  		Figure 3. The association between cholesterol and AI in women with TS.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
This is the first study to show that sex hormone replacement therapy in women with TS has a significant favorable effect on central arterial hemodynamics. In particular, it reduces arterial stiffness, as evidenced by a reduction in the augmentation index. The beneficial hemodynamic effect of HRT demonstrated in this study was independent of blood pressure and serum lipids. In addition, we have demonstrated an association between plasma cholesterol levels and arterial stiffness. Finally, we have shown that HRT reduces fasting insulin and glucose levels in TS women.

Our findings are in keeping with those of Hayward and colleagues (22), who have demonstrated a reduction in the AI in older postmenopausal women receiving HRT independent of blood pressure changes. However, this was not found by other investigators (23). It is interesting to note that the effects of HRT on arterial hemodynamics are rapid, but may be reversed by even short term withdrawal of therapy. This is in keeping with other studies looking at the effects of estrogen administration on vascular endothelial function (13, 24, 25). As all of our study participants received an estrogen/progestagen preparation, our data suggest that either levonorgestrel does not negate the beneficial effects of estrogen on arterial stiffness or that levonorgestrel itself may improve arterial compliance in women with TS. We did not detect changes in lipid metabolism after short term HRT withdrawal, suggesting that the beneficial effects of HRT on aortic compliance may be mediated by an improvement in endothelial function. Certainly, there are considerable data showing that estrogens induce vasodilatation by stimulating the release of nitric oxide by vascular endothelial cells (13, 26) in addition to preventing vascular smooth muscle proliferation (27). Nitric oxide has been shown to attenuate atherosclerosis by inhibiting platelet aggregation and monocyte adhesion to the vascular wall in addition to inhibiting vascular smooth muscle proliferation (28). The antiatherogenic effects of estrogens may, therefore, be at least in part explained by its stimulatory effects on nitric oxide production in addition to its inhibitory effects on smooth muscle growth (12).

The association between central aortic pressure waveforms and cardiovascular risk factors has been studied extensively. Up until recently, the only method of assessing arterial pressure waves was directly, using invasive techniques. Over the past decade, applanation tonometry has been developed as a noninvasive method of studying central arterial hemodynamics. Its accuracy has been validated in both animal and human studies (16, 17, 18). An association between arterial stiffness and left ventricular hypertrophy has been shown by some investigators (21, 29). Others have reported an association between increased arterial stiffness and ischemic heart disease (15, 30, 31, 32). These results in TS, therefore, suggest that one mechanism by which the administration of HRT may reduce their risk of developing ischemic heart disease is by improving aortic compliance.

An association between systolic blood pressure and arterial stiffness has been demonstrated by some (23), but not all (33), investigators. We were unable to demonstrate an association between blood pressure and AI, as a measure of arterial stiffness in our study group. Additionally, we did not show an association between insulin levels and aortic compliance, which is in keeping with previous work (33). The lack of effect of HRT on peripheral and central blood pressure is consistent with other studies in postmenopausal women (34, 35) as well as in women with TS (36). Gravholt and colleagues, however, showed a small, but significant, fall in mean diastolic blood pressure using ambulatory blood pressure monitoring in women with TS receiving HRT. Our inability to confirm this may be due to the fact that we measured blood pressure over 1 h rather than 24-h readings.

The direct association between total cholesterol levels and arterial stiffness in women with TS is in keeping with earlier work in postmenopausal women (23) and in patients with newly diagnosed IHD (32). We did not detect a significant change in serum lipids after estrogen withdrawal. Longer term studies may be necessary to assess the effects of estrogen replacement on serum lipids in women with TS. In contrast to Gravholt and colleagues (36), we demonstrated an improvement in insulin sensitivity in women with TS by the administration of HRT. Our findings are consistent with those of several large randomized studies in postmenopausal women showing a reduction in insulin levels with HRT (35, 37).

Coronary heart disease is the most common cause of death in both women and men, and adults with TS seem to have several risk factors for its early development. Hypertension is prevalent in women with TS (6, 7). In addition, women with TS have been shown to be insulin resistant (8, 36), which in itself has been implicated in the development of coronary artery disease (38, 39). Type 2 diabetes mellitus occurs with an increased frequency in TS (5, 40, 41), and this has been shown to adversely affect cardiovascular risk in females. Hypercholesterolemia has been shown by some (9, 10), but not all (7, 36, 42), investigators.

Long term prospective studies are required to assess the effect of HRT on cardiovascular risk factors in women with TS. Additionally, there are few data on the optimal mode of estrogen replacement in women with TS. Further studies of this aspect of therapy would help to optimize the care of these women and potentially decrease cardiovascular risk.

In conclusion, our findings suggest that HRT improves body habitus, arterial stiffness, and insulin sensitivity in women with TS and, in doing so, may reduce the risk of cardiovascular morbidity.

Received June 7, 1999.

Revised October 12, 1999.

Accepted October 25, 1999.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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