© 1998 American Heart Association, Inc.
Original Contributions |
Visceral Fat Accumulation Is an Important Determinant of PAI-1 Levels in Young, Nonobese Men and Women
Modulation by Cross-Sex Hormone Administration
From the Institute of Endocrinology, Reproduction and Metabolism (E.J.G., J.M.H.E., L.J.G.G., H.A.), the Department of Internal Medicine (C.D.A.S.), and the Institute for Cardiovascular Research (C.D.A.S.), Hospital Vrije Universiteit, Amsterdam, and the Gaubius Laboratory (J.J.E., T.K.), TNO-PG, Leiden, The Netherlands.
Correspondence to Prof Dr Louis J.G. Gooren, MD, Department of Endocrinology, Division of Andrology, Hospital Vrije Universiteit, PO Box 7057, 1007 MB, Amsterdam, Netherlands. E-mail l.gooren{at}inter.nl.net
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Abstract |
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Abstract—Increased plasminogen activator inhibitor type-1 (PAI-1) levels, leading to impaired fibrinolysis, are associated with increased visceral fat in middle-aged and obese subjects. It is unknown, however, whether this association is independent of other disturbances clustered in the insulin resistance syndrome. We analyzed this association in young, nonobese transsexual men and women before and after administration of cross-sex steroids, which potentially influence many elements of the insulin resistance syndrome, including PAI-1 levels and visceral fat accumulation. We assessed the visceral fat area (by MRI); total body fat; insulin sensitivity (with a glucose clamp technique); and plasma levels of PAI-1, insulin, and triglycerides in young (<37 years old), nonobese (body mass index <28 kg/m2), healthy men (n=18) and women (n=15) before and after 12 months of cross-sex hormone administration. Men were treated with ethinyl estradiol 100 µg/d plus cyproterone acetate 100 mg/d, and women were treated with testosterone esters 250 mg IM every 2 weeks. At baseline, only visceral fat area was significantly correlated with plasma PAI-1 levels in both men (r=0.57, P=0.03) and women (r=0.59, P=0.03). In multivariate linear regression analysis, this association was independent of total body fat, insulin sensitivity, and plasma levels of triglycerides and insulin. After 12 months of cross-sex hormone administration, the plasma PAI-1 levels were no longer correlated with visceral fat (which had increased).We conclude that in young, nonobese men and women, visceral fat area is an important determinant of plasma PAI-1 levels. After cross-sex hormone administration, this association was no longer demonstrable.
Key Words: plasminogen activator inhibitor type-1 • visceral fat accumulation • insulin sensitivity • sex hormones
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Introduction |
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Impaired fibrinolysis is a risk factor for cardiovascular disease (CVD).1 2 3 Fibrinolysis is activated by tissue plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA).4 Plasmatic type 1 plasminogen activator inhibitor (PAI-1) inhibits the action of both tPA and uPA.4 The exact origin of plasmatic PAI-1 is unknown, but in vitro studies show that it is produced by a wide variety of cell types,4 including endothelial cells, vascular smooth muscle cells, hepatocytes,5 and adipocytes.6 7 8 Correlations have been found between plasma PAI-1 levels and visceral fat accumulation measured by means of the waist-to-hip ratio (WHR),9 10 11 12 13 14 ultrasonographic techniques,15 or CT.7 16 It is unknown, however, whether this association already exists in young, nonobese subjects, since previous studies included middle-aged subjects,7 9 10 11 12 13 14 15 16 obese subjects,9 10 11 12 13 14 15 16 or subjects with essential hypertension.14 Associations of plasma PAI-1 levels have also been described with other disturbances that are clustered in the insulin resistance syndrome, ie, insulin resistance, hyperinsulinemia, glucose intolerance, dyslipidemia, and hypertension.17 Therefore, it is unknown whether the association between plasma PAI-1 levels and visceral fat accumulation is independent of these disturbances.18 Previous studies either did not include all of these elements of the insulin resistance syndrome in one statistical model7 9 10 or used indirect or crude estimates, such as WHR, to estimate fat distribution,9 11 12 13 14 19 and insulin levels after a glucose tolerance test,12 15 16 the minimal-model method,11 13 or a hyperglycemic clamp14 to estimate insulin sensitivity.
Sex differences have been found in the interrelations between fibrinolytic variables and elements of the insulin resistance syndrome,14 many of which are influenced by administration of sex steroids. Oral estrogen administration increases triglyceride and HDL cholesterol levels20 and decreases insulin sensitivity.21 22 Exogenous estrogens are also known to reduce plasma PAI-1 levels.23 24 25 Testosterone administration has no effect on triglyceride26 27 28 and insulin28 levels but decreases HDL cholesterol levels,26 27 decreases22 29 or has no effect28 on insulin sensitivity, reduces total body fat28 and abdominal subcutaneous fat depots,30 31 and increases visceral fat depots.30 31 It is unknown whether the shifts in PAI-1 levels during sex-steroid administration are partly mediated by quantitative changes in visceral fat accumulation or by other elements of the insulin resistance syndrome.
The aim of this study was to examine the association between plasma PAI-1 levels and visceral fat accumulation in young, nonobese subjects. We aimed particularly to examine whether this association was independent of other variables clustered in the insulin resistance syndrome. Furthermore, because we selected transsexual subjects for these studies, we were able to reassess this association after 12 months of cross-sex hormone administration, which is known to influence many elements of the insulin resistance syndrome, including PAI-1 levels and visceral fat accumulation. Transsexuals, being no different from members of their own genital sex from an endocrine32 33 34 or metabolic22 27 31 viewpoint, provide us with the opportunity to study the effects of high-dose sex steroid administration in young, nonobese subjects. We therefore consider transsexuals as a valid model for a study of the regulation of PAI-1 levels.
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Methods |
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Patients
Eighteen male-to-female (M
F) transsexuals with a median age
of 27 years (range, 18 to 37) and 15 female-to-male (FM)
transsexuals with a median age of 23 years (range, 16 to 33) were
recruited between October 1993 and April 1996 and agreed to participate
in the study. Subjects with a body mass index (BMI)
(weight/height2) >28 kg/m2
were excluded. All subjects were judged to be clinically healthy on the
basis of medical history, physical examination, and routine laboratory
tests. In particular, hypertension, diabetes mellitus, and evidence of
cardiovascular, liver, or endocrine diseases were not
noted. None reported intake of hormones (such as oral contraceptives)
or medications known to affect sex-steroid or lipid
metabolism or insulin sensitivity. Ten MF transsexuals
and 7 FM transsexuals were smokers. Before the start of hormone
therapy, all FM transsexuals had regular menstrual cycles (28 to
31 days).
We measured the variables reflecting insulin resistance (glucose
and insulin levels and glucose utilization), plasma lipids
(triglyceride and HDL cholesterol levels), fat
distribution (BMI, WHR, total body fat, abdominal subcutaneous fat, and
visceral fat area), and mean arterial pressure at baseline
and again after 12 months of cross-sex hormone administration. For
logistical reasons, some measurements were not obtained in all
subjects. Mean arterial pressure was measured directly, not
calculated, with an automatic device (BP-8800, Colin) at baseline and
after 12 months of cross-sex hormone administration after the patient
had rested for at least 15 minutes (mean of 4 recordings
repeated every 3 minutes). MF transsexuals were treated with ethinyl
estradiol 100 µg/d (Lynoral, Organon) in combination with the
antiandrogen cyproterone acetate 100 mg/d (Androcur, Schering) to
counteract the effects of testosterone. FM transsexuals were treated
with testosterone esters (Sustanon, Organon) 250 mg every 2 weeks
intramuscularly. Informed consent was obtained from all subjects, and
the study was approved by the Ethical Review Board of the Hospital
Vrije Universiteit.
Blood Sampling and Analysis
In FM transsexuals, blood was drawn at baseline between days
3 and 9 of the menstrual cycle during the follicular phase, and during
hormone treatment, within 5 to 9 days after the most recent
testosterone injection. Blood samples were obtained between 9:30 and
10:30 AM after a 12-hour fast. 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. Immunoradiometric assays were used to measure
serum levels of sex hormone–binding globulin (SHBG) and insulin
(Biosource Diagnostics). Plasma levels of glucose,
triglycerides, and HDL cholesterol were
measured by using standard laboratory methods. Blood was also collected
into evacuated tubes (Diatube H CTAD, Becton Dickinson). Samples were
immediately placed on ice and centrifuged at 3500g
for 30 minutes at 4°C. Plasma was separated and snap-frozen within 1
hour and stored at -70°C until analysis. Plasma levels of
tPA and PAI-1 antigen were measured by using commercially available
enzyme immunoassay kits (Thrombonostika tPA and Thrombonostika PAI-1,
Organon Teknika), and uPA antigen was evaluated by using an in-house
enzyme immunoassay.35
Measurement of Fat Distribution
The lean body mass (LBM) and the total body fat were estimated
at baseline and after 12 months of cross-sex hormone treatment by
bioelectrical impedance analysis (BIA 101/S, RJL
Systems).36 In addition, body circumferences were
measured in duplicate with a flexible plastic tape at the level of the
abdomen (midway between the lower rib margin and the iliac crest) and
the hip (over the greater trochanters) to calculate the WHR. Areas of
abdominal subcutaneous and visceral fat depots were assessed by MRI
technique in 15 MF and 14 FM transsexuals. The procedure of image
analysis has been described in detail
elsewhere.31 Repeated measurements were obtained
by using the same MRI and scanning parameters. An inversion
recovery pulse sequence was used, and appropriate scanning
parameters were chosen to obtain good image contrast
between adipose and other tissues. Three transverse images were taken
at the abdominal level: 1 at the anatomic marker (lower edge of the
umbilicus) and 1 above and 1 below this position (slice thickness, 10
or 12 mm, depending on the imager used). The image-analyzing
computer program (developed by our Department of Biomedical
Engineering) is based on a "seed-growing" procedure. In short,
after a seed point is placed in the abdominal subcutaneous or the
visceral fat depot, it can be circumscribed by selection of a pixel
intensity range. The intensity range is selected for each image
separately according to the pixel intensity histogram. The areas of the
circumscribed abdominal subcutaneous and visceral fat depots were
calculated by converting the number of pixels to square centimeters,
and the mean of the 3 abdominal images was taken. To reduce
variability, all measurements were performed by a single experienced
observer. The intraobserver coefficients of variation were 2.3% for
abdominal subcutaneous fat and 9.8% for visceral fat.
Hyperinsulinemic Euglycemic Clamp
Insulin sensitivity was measured at baseline and after 12 months
of cross-sex hormone treatment by using a glucose clamp
technique.37 Two intravenous
catheters were placed in contralateral antecubital or antebrachial
veins of each arm, 1 for blood withdrawal and the other for insulin and
glucose infusion. The insulin solution for intravenous
infusion was prepared by adding 0.5 mL human insulin (100 IU/mL;
Velosulin, Novo Nordisk A/S) and 4.5 mL human albumin (20%)
(Central Blood Transfusion Laboratory, Amsterdam, Netherlands) to 45 mL
of 0.9% NaCl to a final insulin concentration of 1 IU/mL. The insulin
infusion rate was calculated per kilogram of LBM. The procedure
consisted of a 2-hour period with the insulin infusion rate at 62.5
mU/kg LBM per hour. The clamp procedure was started 30 minutes after
cannulation (0 minutes). After the start of the insulin infusion,
arterial blood glucose levels were measured every 5 minutes
with the use of a Yellow Springs Instruments glucose analyzer
(glucose oxidase method), and the 20% glucose infusion rate was
adjusted to maintain blood glucose concentration at the fasting level
(ie, mean blood glucose level from -30 to 0 minutes). Blood samples
for the determination of insulin levels were collected every half hour.
In the second hour, the glucose disposal rate was calculated from the
steady-state glucose infusion rate, the LBM, and the mean insulin
level, ie, M/I value=(100xmg glucose/kg LBM per min per pmol insulin
per L).
Statistical Analysis
Data are given as mean±SD. Variables with a skewed
distribution (abdominal subcutaneous fat area, total body fat, and
plasma levels of PAI-1, uPA, and triglycerides) were
logarithmically transformed before analysis to normalize their
distributions. Student's t test for independent samples and
an ANCOVA was used to compare baseline differences between men and
women. In the MF and FM groups separately, the ANOVA test for
repeated measurements or the t test for paired samples were
used to explore the effects of cross-sex hormones on plasma PAI-1
levels and other variables of interest. Baseline values, values
after 12 months of treatment, and proportional changes between baseline
and 12 months were correlated by using Spearman's correlation
coefficient. Both groups were pooled in a multiple linear regression
analysis to further explore interrelationships between the
logarithmically transformed plasma PAI-1 level and elements of the
insulin resistance syndrome. Interaction terms were included to test
whether the associations of the plasma PAI-1 level and the visceral fat
area differed between men and women or before and after cross-sex
hormone administration. When endocrine measurements were below the
lower limit of detection, the value of that lower limit was used for
statistical calculations (for LH 0.3 IU/L, for FSH 0.5 IU/L, for
17ß-estradiol 90 pmol/L, and for testosterone 1.0 nmol/L). Two-sided
P<0.05 was considered statistically significant. The
software used was SPSS for Windows 7.0.
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Results |
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Determinants of PAI-1 Levels at Baseline
All subjects were eugonadal at baseline by clinical and laboratory criteria. Baseline characteristics are presented in Table 1
. Plasma PAI-1 levels were
statistically significantly higher in women than in men
(P=0.049), a difference that disappeared (P=0.93)
after controlling for total body fat (higher in women) in an ANCOVA.
Plasma tPA and uPA levels were not statistically significantly
different between men and women (P=0.63 and
P=0.50). Plasma PAI-1 levels were positively and
significantly correlated with plasma tPA levels in men
(r=0.72, P=0.001) and women (r=0.63,
P=0.01), negatively with serum SHBG levels in men
(r=-0.50, P=0.05), and negatively with serum
17ß-estradiol levels in women (r=-0.55,
P=0.03).
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The PAI-I level was correlated significantly with the visceral fat area
in men (r=0.57, P=0.03) and with the visceral fat
area and total body fat in women (r=0.59, P=0.03
and r=0.70, P=0.006) but not with WHR or insulin
sensitivity (Figure 1). Also, no
significant correlations were found with levels of glucose, insulin,
triglycerides, HDL cholesterol, BMI, abdominal
subcutaneous fat area, and mean arterial pressure (data not
shown).
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A multiple linear regression analysis was performed on pooled
data from all subjects, with the plasma PAI-1 level as the dependent
variable and biological sex, age, total body fat, and the visceral
fat area forced into the model. The visceral fat area was the only
variable that added significantly to the model (ß=0.53,
P=0.02). Interaction analysis showed that the
relationship of plasma PAI-1 level and the visceral fat area was not
significantly different between men and women (P=0.84). To
further analyze the relationship between plasma PAI-1 level and
the visceral fat area, the biological sex, insulin level, insulin
sensitivity, triglyceride levels, total body fat, and the
visceral fat area were forced into the model. The visceral fat area
maintained a positive, independent association with plasma PAI-1 levels
after controlling for these possible confounding variables (Table 2). The use of the M value
instead of the M/I value did not lead to different conclusions in any
of the analyses (data not shown).
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Effects of Cross-Sex Hormone Administration
After estrogen and antiandrogen administration to MF
transsexuals, serum levels of testosterone decreased to undetectable
levels. The ethinyl estradiol administered could not be detected by the
assay used, but the biological effects of estrogens were reflected in a
large increase of serum levels of SHBG. After testosterone
administration to FM transsexuals, serum levels of testosterone
increased markedly while serum 17ß-estradiol levels decreased. In 2
FM subjects the serum 17ß-estradiol levels decreased to below the
lower limit of detection. The serum level of SHBG decreased, reflecting
the biological effects of androgens. Serum levels of LH and FSH were
not significantly suppressed (Table 3).
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Ethinyl estradiol plus cyproterone acetate administration to men during
a 12-month period was associated with decreases in plasma levels of
PAI-1 by 62% (Figure 2), tPA by 53%,
and uPA by 37% (Table 3
). Testosterone treatment of women during the
same 12 months was not associated with changes in PAI-1 (Figure 2) or
tPA levels; however, uPA levels increased by 28% (Table 3). This
increase in uPA level was only apparent after 12 months. There was a
positive correlation between the proportional changes in plasma levels
of PAI-1 and tPA in the men (r=0.77, P<0.001)
and in the women (r=0.70, P=0.004). After 12
months of treatment, the plasma levels of PAI-1 and tPA were
significantly correlated in MF (r=0.58,
P=0.01) and FM (r=0.69, P=0.005)
transsexuals, similar to the situation before hormone
administration.
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) and 15 F
) at baseline, after 4 months, and after 12 months of
cross-sex hormone administration. P values
were assessed by ANOVA for repeated measurements.In men treated with ethinyl estradiol plus cyproterone acetate, significant increases were found in the fasting insulin levels (by 38%), the triglyceride levels (by 88%), the HDL cholesterol level (by 18%), the BMI (by 5%), the WHR (by 1%), the total body fat (by 38%), the abdominal subcutaneous fat area (by 54%), and the visceral fat area (by 17%). Insulin sensitivity (M/I value) and mean arterial pressure did not change significantly. In women treated with testosterone, plasma levels of glucose, insulin, and triglycerides; insulin sensitivity; and mean arterial pressure did not change significantly. The HDL cholesterol level decreased by 23%. The BMI did not change significantly, but the LBM increased by 9%, the WHR increased by 3%, the total body fat decreased by 24%, the abdominal subcutaneous fat area decreased by 18%, and the visceral fat area increased by 18%, all significantly.
Proportional changes in plasma PAI-1 levels were not correlated with
any of the proportional changes of the elements of the insulin
resistance syndrome, including visceral fat area. For values obtained
after 12 months of cross-sex hormone treatment, plasma PAI-1
levels were not correlated with any of these variables except for
mean arterial pressure, which was correlated positively
with plasma PAI-1 levels in MF transsexuals (r=0.70,
P=0.004). A multiple linear regression analysis in
data pooled from all subjects with the plasma PAI-1 level as the
dependent variable and the biological sex and the visceral fat area
forced into the model showed that the visceral fat area had lost the
association with the plasma PAI-1 (ß=0.16, P=0.13). When
12-month values were compared with baseline values in a linear
regression analysis, the association between the plasma PAI-1
level and the visceral fat area was weakened significantly in MF
(P<0.001) and nonsignificantly in FM (P=0.16;
Figure 3) transsexuals.
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Discussion |
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An increased plasma PAI-1 level, an important cause of impaired fibrinolysis, is a risk factor for CVD.1 2 3 We studied the relation between plasma PAI-1 levels and the visceral fat area. The strengths of our study are the inclusion of only healthy, nonobese men and women under the age of 37 years and the use of "gold standard" techniques to assess the visceral fat mass and insulin sensitivity. In previous studies, correlations have been found between plasma PAI-1 levels and the visceral fat area measured by means of CT in middle-aged men and women7 and in middle-aged men including obese subjects.16 Our findings show this association to exist even in healthy, young, nonobese subjects by the use of an accurate MRI technique. This raises the possibility that visceral fat accumulation is directly connected to CVD through increased PAI-1 levels.1 2 3 Indeed, increasing mortality due to CVD is already apparent with increasing BMI in nonobese and mildly overweight women (BMI <29 kg/m2 )38 and is also apparent in obesity, especially if the depot of fat is visceral.38 39 40 41 42
The insulin resistance syndrome includes a cluster of metabolic and hemodynamic disturbances, ie, insulin resistance, hyperinsulinemia, glucose intolerance, dyslipidemia including hypertriglyceridemia, visceral fat accumulation, hypertension, and hypofibrinolysis, which increase the risk of CVD.17 Many studies in healthy subjects have suggested that beside visceral fat accumulation, other elements of the insulin resistance syndrome are associated with increased plasma PAI-1 levels. PAI-1 levels were reported to be positively correlated with increased insulin levels,9 10 12 13 14 16 43 decreased insulin sensitivity,10 13 14 19 43 increased plasma triglyceride levels,11 12 14 15 43 and increased blood pressure.16 43 However, these associations could well be indirect and, at least in part, depend on the relationship between PAI-1 and visceral fat, because visceral fat is associated with insulin resistance44 and increased glucose, insulin, and triglyceride levels.40 41 This concept is supported by our data showing that the association between plasma PAI-1 levels and visceral fat area was independent of insulin sensitivity and plasma levels of insulin and triglycerides. Moreover, some previous studies may have lacked sufficient sensitivity to show the influence of visceral fat, because WHR or BMI was used in multivariate analysis as an estimate of intra-abdominal fat.9 11 12 13 14 19 These measures are reasonable but imprecise estimates of visceral fat, as illustrated by our finding of no relation between PAI-1 and WHR or BMI in the face of a strong relation between PAI-1 and MRI-estimated visceral fat mass.
In our young, nonobese subjects, PAI-1 levels were higher in women than in men. However, this sex difference disappeared after adjustment for total body fat. Previous large population-based studies in healthy men and premenopausal women found similar PAI-1 activity levels45 and higher PAI-1 levels in men versus women.46 The assumption, based on previous studies,23 24 25 47 48 that oral estrogen plus antiandrogen administration would decrease PAI-1 levels and that testosterone administration would not change PAI-1, was indeed confirmed by our data. Furthermore, uPA levels had increased after 12, but not after 4, months of testosterone administration in women.
In both groups, the correlation between the visceral fat area and
plasma PAI-1 level at baseline had disappeared after 12 months of
sex-steroid hormone administration. This was especially clear in MF
transsexuals, but in this group the administered sex steroids had a
substantially larger effect. What might explain this dissociation?
First, sex steroid–induced shifts in metabolic
variables that are included in the insulin resistance syndrome
could be involved in PAI-1 metabolism. This concept is not
supported by our data, because proportional changes in PAI-1 levels
were not correlated with proportional changes in insulin sensitivity or
plasma levels of insulin, glucose, triglycerides, and HDL
cholesterol. Second, changes in hepatic clearance might be
relevant. The parallel decrease in PAI-1, tPA, and uPA in MF
transsexuals is consistent with a clearance effect, because
PAI-1, tPA, and uPA share a major hepatic clearance
pathway.49 50 This idea is further supported by
the observation that oral, but not transdermal, administration of
estrogens reduces plasma PAI-1 levels.24 25 A
clearance effect, however, appears less likely to explain the changes
in the testosterone-treated FM transsexuals. Third, sex steroids
could have altered adipocyte
metabolism.51 PAI-1 synthesis can
take place in hepatocytes5 and
adipocytes.6 7 8 Therefore, shifts could have
occurred directly in the secretion of PAI-1 by adipocytes or indirectly
in the secretion of substances influencing the hepatic secretion of
PAI-1.8 52 In this respect, it is noteworthy that
the cytokines interleukin-6 and tumor necrosis factor-
and
the acute-phase reactant C-reactive protein were not associated with
plasma PAI-1 levels either before or after 12 months of hormone
administration (data not shown). We have, however, not studied portal
concentrations of these cytokines or free fatty acids, because
the topography of the portal vein makes these studies
difficult.40
Our data indicate that in young, nonobese men and women, the visceral fat area is an important determinant of plasma PAI-1 level, independent of insulin sensitivity and plasma levels of insulin and triglycerides. Visceral fat may be directly linked to a low fibrinolytic activity and thereby to an increased risk of CVD. After oral estrogen and antiandrogen administration to men, plasma levels of PAI-1, tPA, and uPA decreased substantially, and after testosterone administration to women, only plasma uPA levels increased. After administration of cross-sex hormones, the association between plasma PAI-1 and the ensuing increases in visceral fat area was no longer demonstrable. This dissociation could not be explained by changes in elements of the insulin resistance syndrome, but whether it should be ascribed to changes in hepatic clearance of PAI-1 or changes in adipocyte metabolism directly or indirectly involved in PAI-1 synthesis remains to be elucidated.
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Acknowledgments |
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Dr Stehouwer is supported by a Clinical Research Fellowship from the Diabetes Fonds Nederland and the Netherlands Organization for Scientific Research (NWO). We are indebted to J.A.J. Megens and Dr P.J.M. van Kesteren for assistance in the logistics of this study.
Received February 26, 1998; accepted April 24, 1998.
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