(Hypertension. 1999;34:590-597.)
© 1999 American Heart Association, Inc.
Scientific Contributions |
Sex Steroids, Insulin, and Arterial Stiffness in Women and Men
From the Research Institute for Endocrinology, Reproduction, and Metabolism (E.J.G., L.J.G.G., J.M.H.E.), the Department of Internal Medicine (J.L., M.S., C.D.A.S.), and the Institute for Cardiovascular Research (J.L., C.D.A.S.), University Hospital Vrije Universiteit, Amsterdam, Netherlands.
Correspondence to C.D.A. Stehouwer, MD, Department of Internal Medicine, University Hospital Vrije Universiteit, PO Box 7057, 1007 MB, Amsterdam, Netherlands. E-mail cda.stehouwer{at}azvu.nl
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Abstract |
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Abstract—Arterial stiffness may be influenced by sex steroids and insulin; the association with fasting insulin level may be stronger in women than in men. Therefore, we analyzed the effects of sex steroid administration on (1) arterial stiffness and (2) the relationship between fasting insulin level and arterial stiffness. Twelve male-to-female transsexuals were treated with ethinyl estradiol and cyproterone acetate, and 18 female-to-male transsexuals were treated with testosterone esters, with assessments made at baseline and after 4 and 12 months. Changes in distensibility and compliance coefficients (DC and CC, respectively) of the common carotid artery, femoral artery (FA), and brachial artery (BA) were analyzed in relation to changes in fasting plasma levels of glucose, insulin, HDL-cholesterol, and triglycerides. After 4 months of estrogens and antiandrogens in men, significant reductions in the CC and DC of the FA (P=0.006 and P=0.04, respectively) and BA (P=0.04 and P=0.04, respectively) were observed. In women, testosterone, on average, did not affect DC or CC, but the changes in fasting insulin level were strongly negatively associated with changes in the CC and DC, especially in the FA and BA. These associations were significantly less strong in genetic men and were independent of age, mean arterial pressure, and glucose and lipid levels. This experimental study shows (1) that short-term administration of estrogens and antiandrogens increases FA and BA stiffness in men and (2) that the fasting insulin level is a stronger determinant of arterial stiffness in women than in men.
Key Words: arteries • insulin • gender • estrogen • testosterone • coefficient, distensibility • coefficient, compliance
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Introduction |
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Men are at a higher risk of developing cardiovascular disease (CVD) than women, but in non–insulin-dependent diabetes mellitus, this gender difference is much less pronounced.1 2 3 4 A core element of non–insulin-dependent diabetes mellitus is insulin resistance, and the question arises of whether insulin resistance or other elements clustered in the insulin resistance syndrome,5 such as hyperinsulinemia, glucose intolerance, dyslipidemia, abdominal obesity, and hypertension, partially negate the normal gender difference in cardiovascular risk.
Large-artery stiffening, a major determinant of cardiac workload and systolic blood pressure,6 may contribute to the development of CVD. Data on a possible gender difference in arterial stiffness are contradictory. Measurement of pulse-wave velocity, an estimate of regional arterial stiffness, indicates that arteries in men are stiffer than those in premenopausal women.7 8 9 In contrast, local arterial stiffness of the common carotid artery (CCA), measured by ultrasound,10 11 12 and global vascular stiffness, derived from pulse-pressure waveform analysis,13 occur less in men than in women. Conflicting data on the modulating effects of endogenous14 and exogenous15 16 17 18 19 20 estrogens on regional17 18 19 20 and local arterial stiffness14 15 16 in women have also been published. Currently, there is no prospective information on the effects of estrogen or testosterone administration on arterial stiffness in men or women.
Gender differences have been found in the interrelations between fasting insulin level and arterial stiffness in cross-sectional studies. A study of 4701 men and women showed that an 80% increase in fasting insulin level was associated with an increase of 5.1% in men and of 7.5% in women of Young's elastic modulus of the CCA, a measure of local arterial stiffness controlled for wall thickness.21 In a previous cross-sectional study, we found that fasting insulin level was positively and glucose utilization was negatively associated with arterial stiffness of the femoral artery (FA) in women but not in men.12 In this study, we investigated prospectively (1) the effects of cross-gender sex steroid administration on arterial stiffness indices of the CCA, FA, and brachial artery (BA) and (2) the influence of gender on the interrelationships between arterial stiffness and elements of insulin resistance syndrome.
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Methods |
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We included 14 white male-to-female (M
F) transsexuals (median
age, 26 years; range, 18 to 45 years) and 18 white female-to-male
(FM) transsexuals (median age, 23 years; range, 17 to 40 years).
Baseline data of 24 of these subjects were reported
previously.12 MF transsexuals were treated with ethinyl
estradiol (100 µg/d; Lynoral, Organon) in combination with the
antiandrogen cyproterone acetate (100 mg/d; Androcur, Schering). FM
transsexuals were treated with testosterone esters (250 mg every 2
weeks IM; Sustanon, Organon). One FM transsexual reported earlier
intake of oral contraceptives; all other FM transsexuals had had
regular menstrual cycles (28 to 31 days) before cross-gender sex
hormone administration. There was no evidence of hypertension, CVD, or
use of other sex hormones. Eight MF transsexuals and 12 FM
transsexuals were smokers. Standardized radioimmunoassays were used to
measure serum levels of 17ß-estradiol and testosterone. Serum levels
of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were
measured by immunometric luminescence assays. Informed consent was
obtained from all subjects, and the study was approved by the Ethical
Review Committee of the University Hospital Vrije
Universiteit.
Hemodynamic Measurements
The distensibility coefficient (DC), reflecting
intrinsic vascular wall elasticity, and the compliance coefficient
(CC), reflecting buffering capacity of the vessel wall, were calculated
from the arterial diameter (D) and changes in
arterial diameter during the heart cycle (
D;
ie, distension) and pulse pressure (P) as follows:
DC=(2xD)/(DxP) and
CC=(
xDxD)/(2xP). All
hemodynamic measurements were performed with use of a
noninvasive ultrasound system as previously
described11 12 22 23 after at least 15 minutes of
supine rest in a temperature-controlled, quiet room. All subjects
refrained from smoking or consuming caffeine for at least 4 hours
before examination. The within-subject coefficients of variation for DC
and CC are 7.7% and 8.3%, respectively, for the CCA; 13.4% and
12.5%, respectively, for the FA; and 16.1% and 15.6%, respectively,
for the BA.22 23 The systolic,
diastolic, pulse, and mean arterial pressure
(MAP) were assessed 4 times at 5-minute intervals with an automatic
oscillometric device (BP-8800, Colin) and then averaged. Twelve-month
measurements were not obtained in 2 MF transsexuals, and some other
measurements could not be obtained successfully for practical reasons
(detailed in Tables 1 to 3).
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Elements Clustered in the Insulin Resistance Syndrome
Fasting blood samples were obtained in all subjects to
measure plasma levels of glucose, insulin (using a immunoradiometric
assay, Biosource Diagnostics), HDL cholesterol
(HDL-C), and triglycerides (using enzymatic
colorimetric methods, Boehringer Mannheim).
Body mass index was assessed
(weight/height2), and lean body mass and
total body fat were estimated using bioelectrical impedance
analysis (BIA 101/S, RJL Systems). Body circumferences were
measured in duplicate to calculate the waist-to-hip ratio. Areas of
abdominal subcutaneous and visceral fat (using a magnetic resonance
imaging technique) and glucose utilization rate (M
[expressed as mg glucose/kg lean body mass · min]; with a
2-hour hyperinsulinemic euglycemic clamp)
were assessed in 9 MF and 12 FM transsexuals at baseline and
after 12 months as previously described.12
Statistical Analysis
Variables with skewed distributions (abdominal subcutaneous
fat area and plasma levels of insulin and triglycerides)
were logarithmically transformed before analysis to normalize
their distributions. Student's t test for independent and
paired samples was used to compare differences between men and women
and between different artery sites. In the MF and the FM groups
(analyzed separately), an ANOVA for repeated measurements was
used to analyze the effects of cross-gender sex hormones.
Interaction terms were included in an ANOVA to test whether the effects
of cross-gender sex hormones on the CC and DC differed between genetic
men and women. An ANCOVA for repeated measurements was used to
analyze the influence of elements clustered in the insulin
resistance syndrome on hemodynamic measurements at the
3 time points (with 
2 as the measure of effect
size). Univariate and bivariate linear regression
analyses were used to explore interrelationships between
proportional changes, at 4 months, of hemodynamic
measurements and elements clustered in the insulin resistance syndrome.
Interaction terms of genetic gender and insulin changes were included
in linear regression analyses to test whether the associations
of the proportional changes of hemodynamic measurements
and fasting insulin levels differed between genetic men and women. If a
value was below the lower limit of detection, that value was used for
statistical calculations (for LH, 0.3 IU/L; FSH, 0.5 IU/L;
17ß-estradiol, 90 pmol/L; and testosterone, 1.0 nmol/L).
P<0.05 (2-way) was considered statistically significant.
The software used was SPSS for Windows, version 8.0.
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Results |
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Pretreatment Values
All subjects were eugonadal at baseline according to clinical and laboratory criteria. D and CC of the BA were statistically significantly larger in men than in women (P=0.009 and P=0.001, respectively). No significant gender differences were found in other hemodynamic measurements, nor in smoking status, body mass index, and plasma levels of glucose, insulin, triglyceride, and HDL-C (Tables 1 and 2).
Effects of Cross-Gender Sex Hormone Administration
After estrogen and antiandrogen administration to MF
transsexuals, serum levels of testosterone, LH, and FSH decreased
(Table 1). In MF transsexuals, 4 months of administration of
estrogens and antiandrogens, as compared with baseline, was associated
with significant reductions of D, CC, and DC of the FA
(P=0.02, P=0.006, and P=0.04,
respectively) and BA (P=0.01, P=0.04, and
P=0.04, respectively; Figure 1) and a significant increase in heart
rate (P=0.005; Table 1). The proportional changes, at
4 months, in D of the FA and BA were significantly
different than the change in D of the CCA
(P=0.047 and P=0.01, respectively), whereas
changes in D were similar for the FA and BA
(P=0.85). The proportional changes, at 4 months, in heart
rate were not significantly associated with any proportional change of
the DC or CC of the CCA, FA, and BA, except for the DC of the FA (ß=
-0.64, P=0.04). After 12 months, the CC of the FA remained
significantly decreased (P=0.03; Figure 1) and heart
rate remained significantly increased (P=0.02) as compared
with baseline values. No significant changes were seen in D
values (Table 1).
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P<0.05 (ANOVA for
repeated measurements comparing baseline and 4- and 12-month
values).
After testosterone administration to FM transsexuals, the serum
testosterone level increased markedly, whereas serum levels of
17ß-estradiol, LH, and FSH decreased only slightly (Table 2).
The CC and DC of the CCA, FA, and BA did not change significantly over
time (Figure 1). The D values of the FA and BA
increased significantly after 4 and 12 months of androgen
administration in an ANOVA for repeated measurements (Table 2).
Interaction terms in an ANOVA for repeated measurements showed that the
effects on CC and DC did not differ significantly between
administration of estrogens+antiandrogens or androgens (for all,
P
0.23; Figure 1), except for the CC of the FA, which tended to
decrease in genetic men as compared with genetic women
(P=0.07).
Associations With Elements Clustered in the Insulin Resistance
Syndrome
Table 3 shows the associations
between proportional changes, at 4 months, of D, CC, and DC
with proportional changes of elements clustered in the insulin
resistance syndrome. The proportional change of fasting insulin level
was the most robust determinant of the proportional changes of
D, CC, and DC, with positive associations in MF
transsexuals and negative associations in FM transsexuals (Table 3 and Figure 2). Interaction
analysis showed that these associations differed significantly
between the genetic sexes (Figure 2). Associations of
proportional changes of insulin level with those of the CC and DC of
the FA in MF transsexuals and with those of the CC and DC of the FA
and the CC of the BA in FM transsexuals were independent of smoking
status, age, and proportional changes of MAP, body mass index, and
glucose, HDL-C, and triglyceride levels. To establish this,
several bivariate regression analyses were performed with
proportional changes of the CC or DC as the dependent variable and
with proportional changes of fasting insulin level combined with each
of the possible confounding variables as the 2 independent
variables.
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When both the MF and FM transsexuals with a proportional change
in fasting insulin level >50% (Figure 2) were excluded from
the analyses, the results were similar: Proportional changes in
fasting insulin level were still positively associated with those of
the CC of the FA (ß=0.64, P=0.048) in MF transsexuals
and negatively associated with those of the CC and DC of the FA
(ß=-0.72, P=0.001 and ß=-0.64, P=0.006,
respectively) and of the CC of the BA (ß=-0.56, P=0.02)
in FM transsexuals.
ANCOVA of values at baseline and after 4 and 12 months of cross-gender
sex hormone administration was used to analyze the variability
in DC and CC explained by the fasting insulin level. In MF
transsexuals, fasting insulin level significantly determined the
variability of the CC and DC of the CCA
(2=0.25, P=0.04 and
2=0.35, P=0.003, respectively). In
FM transsexuals, fasting insulin level significantly determined the
variability of the CC of the CCA (2=0.15,
P=0.02), CC and DC of the FA
(2=0.27, P=0.002 and
2=0.15, P=0.03, respectively), and
CC and DC of the BA (2=0.35,
P<0.001 and 2=0.29,
P=0.001, respectively). Visual interpretation of
relationships between fasting insulin level and the CC and DC indicated
that these were largely positively related in genetic men and inversely
related in genetic women, both before and during hormone administration
(data not shown).
With the use of ANCOVA, we also analyzed whether the variability of D, DC, or CC could be explained by glucose utilization, the abdominal subcutaneous fat area, or the visceral fat area. None of these covariables could significantly explain the variability of the hemodynamic measurements of the CCA, FA, or BA (data not shown).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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We prospectively studied the effects of cross-gender sex steroid administration on arterial stiffness indices in healthy women and men. Because of the heterogeneity of the arterial tree, we studied 3 sites. On the basis of the elastin, collagen, and smooth muscle content in the vessel wall, the CCA is regarded as an elastic vessel, whereas the FA and BA are regarded as muscular vessels.6 Our findings suggest that administration of high-dose estrogens and antiandrogens to young men may have short-term deteriorating effects on FA and BA compliance and distensibility. Estrogenic effects on arterial stiffness may partly account for the somewhat increased short-term risk of CVD associated with relatively high-dose estrogen administration in men with prostate cancer24 or myocardial infarction.25 In addition, administration of estrogens and progestogens to postmenopausal women with26 or without27 coronary disease does not decrease and may even increase the short-term risk of CVD, which contradicts epidemiological data.28 In genetic women, we found that androgen administration did not affect arterial stiffness, whereas the D of the FA and BA increased, which may be an adaptation to increased water retention29 and muscle mass. An increased muscle mass might affect the D of the FA and BA more than that of the CCA, because the FA and BA supply blood to muscular territories.
In previous cross-sectional studies, postmenopausal estrogen replacement therapy was associated with higher CCA distensibility15 16 and lower aortofemoral and leg pulse-wave velocity,18 whereas no differences were found in brachial and aortodorsalis pulse-wave velocity19 and CCA distensibility16 with estrogen-progesterone combination therapy. Furthermore, natural fluctuations of estrogen levels during the menstrual cycle did not influence the CC and DC of the CCA and FA,14 and long-term use of the synthetic steroid tibolone did not influence aortic pulse-wave velocity.17 A longitudinal study showed that short-term withdrawal of estrogen-containing therapy, either alone or combined with progesterone, in postmenopausal women decreased systemic arterial compliance and increased leg pulse-wave velocity, both of which were restored to baseline values after reinstitution of therapy.20
At baseline, we found a higher CC in men than in women, which was significant for the BA and nonsignificant for the FA and CCA (48%, 27%, and 13%, respectively) and which may have been due to the relatively larger D that is part of the numerator of the equation for CC (Tables 1 and 2). Larger artery calibers and a lower heart rate13 in men as compared with women may be related to the greater body height of men.12 30
Possible Determinants of Changes in Arterial Stiffness
The mechanism of action of sex steroids on arterial
stiffness is not well understood. First, estrogens could act directly
on vascular smooth muscle and endothelial cells, which
contain estrogen receptors.31 32 Second,
estrogens,33 like androgens,29 increase body
water retention. Estrogens also increase arginine vasopressin
release,33 myocardial contractility, and
stroke volume34 and, in our subjects, increased heart
rate. This possibly reduced stroke volume as well as the time interval
in which the pulsatile pressure expands the arterial wall.
Because of the dynamic viscoelastic properties of the vessel wall, the
maximum increase in D falls as a consequence of increased
heart rate. This could have led to a decreased D value at
4 months, as was found in the FA and BA. In anesthetized rats,
it has been shown that acute increases in heart rate are accompanied by
reductions in arterial compliance and
distensibility.35
Third, the effects may be mediated by an action on insulin sensitivity or circulating insulin. Estrogens may induce insulin resistance36 and, in our subjects, increased the fasting insulin level, which is a fair marker of insulin resistance among subjects with normal glucose tolerance.37 We previously concluded that arterial stiffening in women is positively associated with fasting insulin levels or insulin resistance,12 which is supported by the present experimental data. Insulin resistance may lead to a disturbance of cellular cation transport (or be a marker thereof), which may promote vasoconstriction and arterial stiffening,38 affecting the muscular FA and BA more than the elastic CCA. However, insulin may also directly affect the vessel wall. Insulin induces hypertrophy of vascular smooth muscle in vitro39 ; insulin receptors have been found in the arterial wall40 ; and CCA wall thickness, which is inversely associated with CCA distensibility,16 is positively related to insulin level in vivo.41
The contrasting associations in men and women between fasting insulin level and arterial stiffness suggest that being a genetic woman (ie, the presence of 2 X chromosomes) determines the relationship between fasting insulin level and arterial stiffness. Alternatively, the presence of circulating estrogens, which were not substantially reduced in genetic women (cf Table 2), may be the basis for the stronger relationship between fasting insulin level and arterial stiffness in women than in men. Our findings may be relevant to the observation that diabetic women, as compared with diabetic men, are at a relatively higher risk of developing CVD1 2 and have a worse prognosis after myocardial infarction.3 4
Limitations and Strengths of Study
Our analyses were limited by the fact that because of the
nature of the treatment indication, we could include only relatively
small numbers of subjects, did not include a control group, and used an
open study design. However, a regression toward the mean effect seems
unlikely with regard to the effects on FA and BA stiffness in men
treated with estrogens and antiandrogens, because shifts in FA and BA
distension differed significantly from those of the CCA. Local pulse
pressure was not measured, but BA pulse pressure did not appear to
modulate the association between fasting insulin level and
arterial stiffness, as illustrated by the significantly
stronger associations in women than in men between shifts of fasting
insulin level and locally measured D (not corrected for
P and D). We applied statistical
analyses many times by including several covariates, without
correcting for their multiplicity. However, our main finding, the
association between fasting insulin level and arterial
stiffness, was strong, consistent in the 2 muscular arteries,
robust during and after sex steroid challenges, and significantly
different between the genetic sexes. Moreover, this is, to the best of
our knowledge, the first report from an experimental study of the
stronger association in women than in men between muscular artery
stiffness and fasting insulin level, which has been reported in
cross-sectional studies.12 21
Conclusions
Estrogen and antiandrogen administration for 4 months increases FA
and BA stiffness in men, whereas the effects wear off somewhat after 12
months. In women, testosterone administration did not affect CC or DC,
but the proportional changes of fasting insulin level were strongly
negatively associated with the proportional changes of CC and DC. These
associations were consistent in the FA and BA, were
significantly less strong in genetic men, and were independent of age,
MAP, and glucose and lipid levels. Fasting insulin level in the
presence of estrogens may be a stronger determinant of
arterial stiffness in women than in men.
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Acknowledgments |
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We are indebted to Jos A.J. Megens for assistance in the logistics of this study. C.D.A.S. is supported by a Clinical Research Fellowship from the Diabetes Fonds Nederland and the Netherlands Organization for Scientific Research.
Received March 4, 1999; first decision April 6, 1999; accepted June 8, 1999.
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E. Moore, A. Wisniewski, and A. Dobs Endocrine Treatment of Transsexual People: A Review of Treatment Regimens, Outcomes, and Adverse Effects J. Clin. Endocrinol. Metab., August 1, 2003; 88(8): 3467 - 3473. [Abstract] [Full Text] [PDF]
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R. Tatchum-Talom, C. Martel, and A. Marette Influence of estrogen on aortic stiffness and endothelial function in female rats Am J Physiol Heart Circ Physiol, February 1, 2002; 282(2): H491 - H498. [Abstract] [Full Text] [PDF]
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F. P. M. Kruijver, A. Fernández-Guasti, M. Fodor, E. M. Kraan, and D. F. Swaab Sex Differences in Androgen Receptors of the Human Mamillary Bodies Are Related to Endocrine Status Rather Than to Sexual Orientation or Transsexuality J. Clin. Endocrinol. Metab., February 1, 2001; 86(2): 818 - 827. [Abstract] [Full Text]
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