© 2000 American Heart Association, Inc.
Thrombosis |
Oral, but Not Transdermal, Administration of Estrogens Lowers Tissue-Type Plasminogen Activator Levels in Humans Without Affecting Endothelial Synthesis
From the Institute of Endocrinology, Reproduction and Metabolism (E.J.G., L.J.G.G.), the Department of Internal Medicine (C.D.A.S.), and the Institute for Cardiovascular Research (C.D.A.S.), University Hospital Vrije Universiteit, Amsterdam, and the Gaubius Laboratory (J.J.E., T.K.), The Netherlands Organization for Applied Research, Leiden, the Netherlands.
Correspondence to Dr Coen 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
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Abstract—Oral estrogen administration decreases plasma levels of tissue-type plasminogen activator (tPA), which may be explained by a decrease in endothelial tPA synthesis, an increase in its hepatic clearance, or both. In the present study, we determined (1) differences between oral (ie, via the liver) ethinyl estradiol and transdermal (ie, systemic) 17ß-estradiol administration on plasma antigen levels of tPA and plasminogen activator inhibitor type-1 before and after 4 months of hormone administration and (2) effects on endothelial tPA synthesis, by measuring the local increase in plasma tPA during venous occlusion of the upper extremity. Thirty transsexual males (median age 32 years, range 20 to 44 years ) were randomly assigned to either oral ethinyl estradiol (n=15) or transdermal 17ß-estradiol (n=15); both treatments included the antiandrogen cyproterone acetate (CA). Ten males were treated with CA alone. Seventeen transsexual females (median age 27 years, range 18 to 37 years) were treated with intramuscular testosterone esters. Only oral ethinyl estradiol plus CA but neither transdermal 17ß-estradiol plus CA, nor oral CA, nor parenteral testosterone lowered plasma tPA and plasminogen activator inhibitor-1 (P<0.001 for both). tPA release during venous occlusion was not affected by oral ethinyl estradiol plus CA in males (P=0.52) or by parenteral testosterone in females (P=0.89). These data are consistent with a previous observation, in rodents, that the decrease in tPA after oral estrogen administration can be explained by an increase in hepatic tPA clearance, leaving endothelial tPA synthesis unchanged, and suggest that these mechanisms also explain the decrease in tPA in humans.
Key Words: tissue-type plasminogen activator • sex hormones • venous occlusion • endothelium • estrogen
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Estrogens and testosterone are administered for a growing number of indications, including oral contraception and hormone replacement therapy in premenopausal and postmenopausal women and androgen substitution therapy in aging men. Their effects on the fibrinolytic system are still incompletely understood. Administration of estrogens via the oral route decreases tissue-type plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) levels in males1 2 3 and females.4 5 6 7 8 9 By contrast, transdermal administration of estrogens in females is not associated with decreases in tPA and PAI-1 antigen levels.7 8 9
Because most studies focused on changes in plasma levels, it is not clear whether the decrease in tPA levels after oral administration of estrogens reflects an increase in tPA clearance, a decrease in its synthesis, or both. Because tPA is synthesized and released by the vascular endothelium10 11 12 13 14 15 and because the continuous deposition and dissolution of fibrin along the vessel wall would be directly and locally affected if endothelial synthesis of tPA changed, the difference between the 2 possibilities is of some clinical importance.
Circulating tPA, either in the free form or complexed with PAI-1, is rapidly cleared from the circulation by the liver,10 16 resulting in a half-life of 4 to 6 minutes for tPA antigen.10 17 18 Lansink et al19 have shown, in rodents, that ethinyl estradiol increases tPA clearance through upregulation of the mannose receptor, a hepatic clearance receptor for tPA. It may be inferred that this mechanism also accounts for the decrease in tPA levels in humans, provided that endothelial synthesis of tPA is not affected by estrogens. A relatively easy way of assessing basal12 13 15 production and release of tPA by the endothelium is venous occlusion of the upper extremity, which increases tPA antigen levels by eliminating its clearance.11 12 13 14 15
To dissect the potential contributions of clearance by the liver and release by the endothelium to changes in plasma tPA, we used 2 approaches. First, the effects of transdermal administration of 17ß-estradiol were compared with those of oral ethinyl estradiol, both in combination with oral cyproterone acetate (CA). Previous studies have documented different metabolic effects, implicating hepatic mechanisms, of these 2 treatment regimens.20 21 Approximately 60% of orally administered ethinyl estradiol is inactivated by the liver via a first-pass effect through the enterohepatic circulation.22 The comparison of orally administered ethinyl estradiol (with a strong hepatic impact)23 to transdermally administered 17ß-estradiol (with less hepatic effects)20 21 would enable differentiation between hepatic and nonhepatic effects. It has been well documented that oral ethinyl estradiol does (possibly compound-specifically) affect hepatic markers, such as sex hormone–binding globulin, corticosteroid-binding globulin, growth hormone–binding protein, insulin-like growth factor-I, and angiotensinogen.24 25 26 If dissimilar effects of the 2 treatment regimens were found, this would indicate that a hepatic mechanism is likely to be involved.
Second, the effects of venous occlusion were examined to document whether tPA synthesis by the endothelium changes during sex hormone administration. Venous occlusion increases tPA antigen levels in the blood in the occluded arm by eliminating the clearance process11 12 13 14 15 and provides a way of assessing basal production and release of tPA by the endothelium.10 We investigated transsexual subjects receiving standard cross-gender sex hormone administration, which achieves profound changes in the hormonal milieu as well as in plasma levels of tPA.2
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Patients
We included 40 male-to-female (M
F, 39 white) and 17
female-to-male (FM, 16 white) transsexuals. Psychological criteria
for the diagnosis and treatment followed the guidelines provided by the
Harry Benjamin International Gender Dysphoria
Association.27 Thirty MF transsexuals were
open-label–randomized to receive either oral ethinyl estradiol
(Lynoral, 100 µg/d, Organon; n=15) or transdermal 17ß-estradiol
(Estraderm TTS 100, 100 µg 2x/wk, CIBA-Geigy; n=15), both in
combination with CA (Androcur, 100 mg/d, Schering), which is a
progestational compound with androgen receptor–blocking capacities.
Because the effects in males of the administration of CA alone on tPA
and PAI-1 levels are unknown, we also studied 10 MF transsexuals who
received CA alone during the first 4 months. FM transsexuals were
treated with testosterone esters (Sustanon, 250 mg/2 wk IM, Organon)
according to the standard treatment at our clinic. All FM
transsexuals had had regular menstrual cycles (28 to 31 days) before
cross-gender sex hormone administration. There was no evidence of
hypertension, cardiovascular disease, thromboembolism,
diabetes mellitus, or use of sex hormones. Lean body mass and total body fat were estimated by bioelectric impedance analysis (BIA 101/S, RJL Systems, Detroit, Michigan).28 The manufacturer’s sex-specific equations were used, corresponding to the genetic sex of subjects. Smoking status (yes or no) and body mass index (BMI, weight/height2) were also assessed. Informed consent was obtained from all subjects, and the study was conducted according to the principles of the Declaration of Helsinki and approved by the Ethical Review Committee of the University Hospital Vrije Universiteit.
Blood Sampling and Analysis
Each subject served as his or her own control, with samples
drawn before and after hormone administration. In FM transsexuals,
blood was drawn at baseline between days 5 and 9 of the follicular
phase of the menstrual cycle, because of potential fluctuations of
measurements during the cycle.29 During testosterone
treatment, blood was drawn within 5 to 9 days after the most recent
testosterone injection. An intravenous catheter was placed
in the antecubital vein of supine subjects after an overnight fast and
10 minutes of bed rest. Because of the travel time to our clinic, the
time of blood sampling was between 8:30 AM and 1:30
PM Within-subject time of sampling was, however, comparable
before and after 4 months of hormone administration (mean 10:55
AM [95% CI 10:37 to 11:12 AM] versus mean
10:37 AM [95% CI 10:19 to 10:55 AM],
respectively; P=0.10). The mean intraindividual variation
was 50 minutes (95% CI 40 to 70 minutes). Plasma tPA and PAI-1 levels
were not associated with the time of sampling before or after hormonal
treatment (data not shown). Blood was collected without a tourniquet
into evacuated tubes (Diatube H CTAD, ie, citrate, theophylline,
adenosine, and dipyridamole; Becton Dickinson).
Samples were immediately placed on ice and centrifuged at
3500g for 30 minutes at 4°C to obtain platelet-poor
plasma. 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). von Willebrand factor antigen (vWF) was measured by
an in-house enzyme immunoassay and expressed as a percentage of vWF
levels in pooled normal plasma, which contained 1.03 IU of vWF per
milliliter. 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. To test whether the oral or
transdermal estrogen administration modes differed in their effects on
peripheral androgen activity in the MF transsexuals, we
measured serum levels of 5
-androstane-3 17ß-diol
glucuronide (Adiol G)30 by a radioimmunoassay
(Diagnostic Systems Labs, Webster, Texas; reference range was 5.5 to 32
nmol/L in men and 1.3 to 6.4 nmol/L in women). Furthermore, we measured
plasma levels of HDL cholesterol by using an enzymatic
colorimetric method after phosphotungstic
acid/magnesium chloride precipitation (Boehringer-Mannheim) and
triglycerides by using an enzymatic
colorimetric method (Boehringer-Mannheim).
Changes in HDL cholesterol20 and
triglyceride21 levels may serve as markers for
the hepatic effects of oral compared with transdermal administration of
estrogens.
Venous Occlusion
Venous occlusion studies were performed at baseline and after 4
months of cross-gender sex hormone administration in 12 MF
transsexuals treated with ethinyl estradiol plus CA and in 17 FM
transsexuals treated with testosterone esters. Posttreatment
measurements were not obtained in 2 MF transsexuals for logistical
problems, and 1 MF transsexual declined participation in the venous
occlusion protocol. The venous occlusion test was performed by applying
a cuff to the upper arm for 10 minutes midway between systolic
and diastolic pressures. On the opposite arm of the
intravenous catheter, the systolic and
diastolic arterial pressures were assessed with
an automatic oscillometric device (BP-8800, Colin). These
arterial pressure measurements were repeated every 5
minutes and then averaged. The cuff pressure was maintained as exactly
as possible between the systolic and diastolic
pressures and, if necessary, adjusted according to the blood pressure
values measured at the opposite arm. Movements of the occluded arm were
avoided to prevent outflow of blood from the occluded
segment.31 Blood was sampled from venous drainage of the
occluded arm. It can be calculated that venous occlusion increases tPA
concentrations by the accumulation of basal tPA production and
release from the endothelium, without invoking an
increased rate of local tPA release.12 13 15 PAI-1 and vWF
before and after venous occlusion were used as controls. vWF is an
endothelium-derived protein, which is stored in the
endothelium in specialized storage sites (ie,
Weibel-Palade bodies). Circulating vWF, which has a plasma half-life of
12 hours,32 should not increase significantly during 10
minutes of venous occlusion in the absence of activation of the
endothelium, which has been noted
previously.33 Values of all postocclusion tPA, PAI-1, and
vWF levels were corrected for the effects of hemoconcentration by use
of the hematocrit (by automated cell counter
measurements).33 34
Statistical Analysis
Variables with distributions that were skewed to the right
(total body fat and plasma levels of HDL cholesterol,
triglycerides, tPA antigen, and PAI-1 antigen) were
logarithmically transformed before analysis to normalize their
distributions, and antilogarithms of the transformed means were used to
obtain geometric means. All data are given as (geometric) means (±SD
or 95% CI). Student t tests for independent samples or
2 tests were used to compare baseline
differences. ANCOVA was used for intergroup comparisons after adjusting
for possible confounders. Baseline values were correlated with the
Pearson correlation coefficient.
An ANOVA for repeated measurements or a Student t test for
paired samples was used to analyze the effects of cross-gender
sex hormones. An ANCOVA was used to compare effects of different
treatment regimens and to adjust for potential covariates. Proportional
changes, at 4 months, were correlated with the Spearman correlation
coefficient. If values were below the lower limit of detection, the
value of that lower limit was used for statistical analysis
(1.0 nmol/L for testosterone, 0.3 IU/L for LH, and 0.5 IU/L for FSH).
Venous occlusion data on PAI-1 levels were excluded from the
analyses for 3 FM transsexuals with levels, uncorrected for
hemoconcentration after venous occlusion, above the upper limit of
detection (ie, 96 ng/mL). One-sample t tests were used to
analyze whether increases of tPA, PAI-1, and vWF during venous
occlusion (ie, postocclusion values, adjusted for hemoconcentration,
minus preocclusion values) were significantly different from zero. A
2-tailed P<0.05 was considered statistically significant.
The software used was SPSS for Windows 8.0.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Pretreatment Values
At baseline, all subjects were eugonadal by clinical and laboratory criteria. Baseline characteristics are presented in Table 1
. Plasma PAI-1 antigen
levels were correlated with those of tPA (r=0.51,
P<0.001). In men, testosterone levels were inversely
correlated with tPA and PAI-1 antigen concentrations
(r=-0.30, P=0.06 and r=-0.28,
P=0.08, respectively).
|
Effects of Sex Steroid Administration
In MF transsexuals at baseline, there were no significant
differences between the 2 groups except for BMI, lean body mass, and
triglyceride level, which were slightly, but not
significantly, higher in males randomized to treatment with oral
ethinyl estradiol compared with males randomized to treatment with
transdermal 17ß-estradiol (Table 1
). The ethinyl estradiol
administered could not be detected by the assay used, whereas
percutaneous administration of 17ß-estradiol
increased its plasma levels up to values typical of the midfollicular
phase in women (Table 2). Oral and
transdermal estrogen administration decreased serum levels of
testosterone, Adiol G, LH, and FSH, although the suppression was more
gradual after transdermal 17ß-estradiol. Effects of oral ethinyl
estradiol compared with transdermal 17ß-estradiol are shown in Table 2 and Figure 1. tPA and PAI-1 antigen levels
decreased sharply in only the oral ethinyl estradiol group
(P<0.001 and P<0.001, respectively, compared
with the transdermal 49 7ß-estradiol group). After correction for
baseline BMI, lean body mass, and triglyceride level in an
ANCOVA for repeated measures, the 2 regimens of estrogen administration
still differed significantly in their effects on tPA and PAI-1 antigen
levels (P=0.003 and P=0.001, respectively).
|
|
|
In the oral ethinyl estradiol group, PAI-1 antigen levels showed a larger decrease than did tPA antigen levels after 2 months (72% versus 51%, P=0.001) and after 4 months (65% versus 52%, P=0.07). Proportional changes, at 4 months, of tPA and PAI-1 antigen levels were positively associated in the oral ethinyl estradiol group (r=0.51, P=0.05) and, although less strongly, in the transdermal 49 7ß-estradiol group (r=0.39, P=0.15). Proportional changes, at 4 months, of HDL cholesterol and triglycerides were not associated with proportional changes of tPA and PAI-1 antigen levels in either group (data not shown).
In the group treated with CA alone, there were significant decreases,
after 4 months, in serum levels of testosterone and 17ß-estradiol
(P=0.001 and P<0.001, respectively), a slight
suppression of FSH (P=0.07), and no change in LH
(P=0.93). Plasma tPA and PAI-1 antigen levels did not change
significantly on administration of CA alone (tPA from 5.8 ng/mL [95%
CI 3.9 to 8.7 ng/mL] to 5.4 ng m/L [95% CI 4.2 to 7.0 ng m/L],
P=0.50; PAI-1 from 14.8 ng/mL [95% CI 8.2 to 26.7 ng m/L]
to 16.3 ng m/L [95% CI 11.2 to 23.9 ng/mL], P=0.65;
Figure 1).
After testosterone administration to FM transsexuals, serum levels
of testosterone and Adiol G increased markedly, whereas serum levels of
17ß-estradiol, LH, and FSH levels decreased (Table 3). tPA and PAI-1 antigen levels did not
change significantly (Table 3 and Figure 1).
|
Venous Occlusion
Table 3 shows the effects of venous occlusion in MF and
FM transsexuals at baseline and after 4 months of cross-gender sex
hormone administration. tPA, in MF and in FM transsexuals, showed
significant increases during venous occlusion before and after hormone
administration (P<0.005 for all). In MF and in FM
transsexuals, there were positive correlations between values of tPA
before and after 10 minutes of venous occlusion; this was the case
before (r=0.66, P=0.01 and r=0.94,
P<0.001) and after (r=0.42, P=0.17
and r=0.90, P<0.001) 4 months of cross-gender
sex hormone administration.
The increase in tPA during venous occlusion did not change after 4
months of oral ethinyl estradiol in MF transsexuals
(P=0.52, Table 3 and Figure 2) or after parenteral testosterone in
FM transsexuals (P=0.89, Table 3).
Moreover, the proportional changes of tPA levels after 4 months, before
versus after venous occlusion, were not associated, either in MF or
in FM transsexuals (P=0.88 and P=0.97). Plasma
PAI-1 (Table 3) and vWF antigen levels did not change
significantly during venous occlusion either before or after 4 months
of hormone administration in either treatment group (change in vWF
[95% CI] was as follows: in MF transsexuals, baseline -4.3%
[-21.4% to 12.8%], after 4 months 1.3% [-14.5% to 17.1%]; in
FM transsexuals, baseline -0.7% [-9.0% to 7.6%], after 4
months 1.7% [-4.0% to 7.4%]; all P
0.54).
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The present study sought to clarify the mechanism by which sex steroids affect circulating levels of tPA. Two lines of evidence support the concept that the decrease of tPA antigen levels observed after oral administration of ethinyl estradiol plus CA is not related to a decreased endothelial tPA synthesis. First, tPA levels decreased after oral ethinyl estradiol (plus CA) but not after transdermal 17ß-estradiol (plus CA) administration. Second, this decrease was not accompanied by a decrease in endothelial tPA synthesis during venous occlusion.
If estrogens affected tPA levels through a decreased endothelial synthesis, one would expect oral ethinyl estradiol and transdermal 17ß-estradiol administration to have similar effects on tPA levels, but this was not found. An important difference between these 2 treatment regimens is their effect on liver metabolism,22 which is stronger with oral ethinyl estradiol24 25 than with transdermal 17ß-estradiol.20 21 One explanation for the dissimilar effects of oral ethinyl estradiol and transdermal 17ß-estradiol is the contrasting first-pass effect on the liver.22 After absorption from the intestine, estrogens enter the portal circulation and pass the hepatocyte before reaching other organs.23 Previously, it has been found that plasma levels of HDL cholesterol, triglyceride, and sex hormone–binding globulin35 increased after oral conjugated or oral natural 17ß-estradiol but not after transdermal 17ß-estradiol administration.20 21 Also, uniform and robust hepatic responses to 3 oral estrogens (ethinyl estradiol, conjugated equine estrogen, and estradiol valerate) have been reported, as measured by circulating levels of insulin-like growth factor-I, growth hormone–binding protein, and sex hormone–binding protein.26 A second explanation for a dissimilar hepatic impact may be the chemical difference between the 2 estrogenic compounds. Ethinyl estradiol may have a selectively enhanced hepatic impact,23 as evidenced by the finding that oral and transvaginal administration of ethinyl estradiol induced comparable changes in circulating levels of sex hormone–binding globulin, corticosteroid-binding globulin binding capacity, HDL cholesterol, and LDL cholesterol.36
The venous occlusion test is thought to eliminate the effects of hepatic clearance and thus provide an index of endothelial tPA synthesis.12 13 15 Previous studies using venous occlusion observed an increase in tPA antigen levels4 or no change in tPA activity37 after oral and transdermal estrogen administration, but these studies did not correct for hemoconcentration and therefore cannot be interpreted.
The fact that we found no change in tPA concentrations after administration of CA alone, together with the differential effects of oral ethinyl estradiol versus transdermal 17ß-estradiol administration (both plus CA), suggests that ethinyl estradiol, and not CA, was the cause of the decreased tPA level. Together, our findings indicate that a decreased tPA synthetic rate is an unlikely explanation for the decreased plasma tPA levels after oral administration of ethinyl estradiol. In line with this are the observations that incubation of human endothelial cells with ethinyl estradiol as well as testosterone in vitro did not affect the synthesis of tPA38 and, conversely, that subcutaneous injection of ethinyl estradiol in vivo in rodents19 did increase the plasma clearance rate of tPA via upregulation of the mannose receptor on liver endothelial cells. Thus, an increased hepatic clearance rate,19 combined with the lack of effect on endothelial release found in the present study, strongly supports the concept that oral ethinyl estradiol affects circulating levels of tPA through an enhanced hepatic clearance.
The exact source of PAI-1 is unknown, but there is evidence that circulating PAI-1 in vivo originates from hepatocytes10 39 or adipocytes,1 40 41 although endothelial cells are also capable of producing PAI-1, at least in vitro.38 42 Circulating PAI-1, like tPA, is rapidly cleared from the circulation by the liver,10 16 resulting in a half-life of 10 to 15 minutes for PAI-1 antigen,42 which would enable the venous occlusion test to differentiate between endothelial and alternative sources for PAI-1 release in vivo. We found no evidence of substantial PAI-1 secretion by endothelium of the upper extremity in males and females, both before or after hormone administration, in accordance with previous data.13 14 33 The differential effects of oral versus transdermal administration of estrogen-CA combinations on PAI-1 antigen levels may also point to an increased hepatic PAI-1 clearance, as found for tPA, although, alternatively, they may result from a decreased nonendothelial (possibly hepatic)10 39 PAI-1 production after oral estrogen administration.
In MF transsexuals, before estrogen administration, PAI-1 and tPA
antigen levels correlated inversely with testosterone levels, whereas
in previous studies, testosterone levels correlated positively with tPA
activity43 and inversely with PAI
activity43 44 45 in men. Interestingly, oral administration
of the androgenic steroid stanozolol has been shown to decrease tPA and
PAI-1 antigen levels.46 This contrasts with the lack of
effect of parenteral administration of testosterone esters in
males47 and in females in our present and previous
studies.1 2 This raises the possibility that distinct
androgenic compounds have different effects on tPA and PAI-1 levels;
alternatively, the route of administration of androgens may be
relevant.
Prospective epidemiological data support the notion that estrogen replacement therapy alone or in combination with progestogen protects postmenopausal women against cardiovascular disease.48 49 50 Alterations in the fibrinolytic system, such as the decrease in plasma PAI-1 concentrations with oral, but not transdermal,7 8 9 administration of estrogens in postmenopausal women, are thought to contribute to this reduced cardiovascular risk. The effects of oral estrogens on plasma tPA and PAI-1 antigen levels are independent of the chemical compounds used: oral conjugated equine,6 7 9 natural,3 8 and synthetic1 2 4 5 estrogens all had similar effects, which suggests that a similar mechanism regulates these changes. Our finding of a lack of effect on the local tPA release by the endothelium may indicate that tPA and PAI-1 antigen alterations do not necessarily translate into an improved local fibrinolytic potential on oral estrogen administration.
In conclusion, the hepatic impact of orally administered ethinyl estradiol appears to be responsible for an enhanced hepatic clearance of tPA, which consequently decreases plasma levels of tPA antigen. Thus, an increased fibrinolytic potential after oral estrogen administration does not necessarily represent an improved endothelial function.
|
Acknowledgments |
|---|
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 Dr Henk Asscheman, MD, for help in the design of this study, to Jos A.J. Megens for assistance in the logistics, to the staff of the Endocrinology Laboratory (head, Dr Corrie Popp-Snijders) for performing endocrine measurements, and to Prof John S. Yudkin, MD (University College London) for critically reviewing the manuscript.
Received May 10, 1999; accepted October 21, 1999.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Giltay EJ, Elbers JMH, Gooren LJG, Emeis JJ, Kooistra T, Asscheman H, Stehouwer CDA. Visceral fat accumulation is an important determinant of plasminogen activator inhibitor-1 levels in young, non-obese men and women: modulation by cross-sex hormone administration. Arterioscler Thromb Vasc Biol. 1998;18:1716–1722.
2. Van Kesteren PJM, Kooistra T, Lansink M, Van Kamp GJ, Asscheman H, Gooren LJG, Emeis JJ, Vischer UM, Stehouwer CDA. The effects of sex steroids on plasma levels of marker proteins of endothelial cell functioning. Thromb Haemost. 1998;79:1029–1033.[Medline] [Order article via Infotrieve]
3. Giri S, Thompson PD, Taxel P, Contois JH, Otvos J, Allen R, Ens G, Wu AHW, Waters DD. Oral estrogen improves serum lipids, homocysteine and fibrinolysis in elderly men. Atherosclerosis. 1998;137:359–366.[Medline] [Order article via Infotrieve]
4. Siegbahn A, Ruusuvaara L. Age dependence of blood fibrinolytic components and the effects of low-dose oral contraceptives on coagulation and fibrinolysis in teenagers. Thromb Haemost. 1988;60:361–364.[Medline] [Order article via Infotrieve]
5. Gevers Leuven JA, Kluft C, Bertina RM, Hessel LW. Effects of two low-dose oral contraceptives on circulating components of the coagulation and fibrinolytic systems. J Lab Clin Med. 1987;109:631–636.[Medline] [Order article via Infotrieve]
6.
Walsh BW, Kuller LH, Wild RA, Paul S, Farmer M,
Lawrence JB, Shah AS, Anderson PW. Effects of raloxifene on serum
lipids and coagulation factors in healthy postmenopausal women.
JAMA. 1998;279:1445–1451.
7. Kroon U-B, Silfverstolpe G, Tengborn L. The effects of transdermal estradiol and oral conjugated estrogens on haemostasis variables. Thromb Haemost. 1994;71:420–423.[Medline] [Order article via Infotrieve]
8.
Scarabin P-Y, Alhenc-Gelas M, Plu-Bureau G, Taisne P,
Agher R, Aiach M. Effects of oral and transdermal estrogen/progesterone
regimens on blood coagulation and fibrinolysis in
postmenopausal women: a randomized controlled trial. Arterioscler
Thromb Vasc Biol. 1997;17:3071–3078.
9.
Kon Koh K, Mincemoyer R, Bui MN, Csako G, Pucino F,
Guetta V, Waclawiw M, Cannon RO. Effects of hormone-replacement therapy
on fibrinolysis in postmenopausal women. N
Engl J Med. 1997;336:683–690.
10. Brommer EJP, Derkx FHM, Schalekamp MADH, Dooijewaard G, Van Der Klaauw MM. Renal and hepatic handling of endogenous tissue-type plasminogen activator (t-PA) and its inhibitor in man. Thromb Haemost. 1988;59:404–411.[Medline] [Order article via Infotrieve]
11.
Kruithof EKO, Nicolosa G, Bachmann F.
Plasminogen activator inhibitor 1:
development of a radioimmunoassay and observations on its plasma
concentration during venous occlusion and after platelet
aggregation. Blood. 1987;70:1645–1653.
12. Keber D. Mechanism of tissue plasminogen activator release during venous occlusion. Fibrinolysis. 1988;2(suppl 2):96–103.
13. Keber D, Blinc A, Fettich J. Increase of tissue plasminogen activator in limbs during venous occlusion: a simple haemodynamic model. Thromb Haemost. 1990;64:433–437.[Medline] [Order article via Infotrieve]
14. Koh SCL, Yuen R, Viegas OAC, Chua SE, Ng BL, Sen DK, Ratman SS. Plasminogen activators t-PA, u-PA and its inhibitor (PAI) in normal males and females. Thromb Haemost. 1991;66:581–585.[Medline] [Order article via Infotrieve]
15. Emeis JJ. Normal and abnormal endothelial release of tissue-type plasminogen activator. In: Glas-Greenwalt P, ed. Fibrinolysis in Disease: Molecular and Hemovascular Aspects of Fibrinolysis. Boca Raton, Fla; CRC Press; 1995:55–64.
16.
Bu G, Willams S, Strickland DK, Schwartz AI. Low
density lipoprotein receptor-related protein/alpha 2-macroglobulin
receptor is an hepatic receptor for tissue-type plasminogen
activator. Proc Natl Acad Sci U S A. 1992;89:7427–7431.
17. Verstraete M, Su CA, Tandwell P, Feuerer W, Collen D. Pharmacokinetics and effects on fibrinolytic and coagulation parameters of two doses of recombinant tissue-type plasminogen activator in healthy volunteers. Thromb Haemost. 1986;56:1–5.[Medline] [Order article via Infotrieve]
18.
Chandler WL, Alessi MC, Aillaud MF, Henderson P, Vague
P, Juhan-Vague I. Clearance of tissue plasminogen
activator (TPA) and TPA/plasminogen
activator inhibitor type 1 (PAI-1) complex:
relationship to elevated TPA antigen in patients with high PAI-1
activity levels. Circulation. 1997;96:761–768.
19.
Lansink M, Jong M, Bijsterbosch M, Bekkers M, Toet K,
Havekes L, Emeis J, Kooistra T. Increased clearance explains lower
plasma levels of tissue-type plasminogen
activator by estradiol: evidence for potently enhanced
mannose receptor expression in mice. Blood. 1999;94:1330–1336.
20. Chetkowski RJ, Meldrum DR, Steingold KA, Randle D, Lu JK, Eggena P, Hershman JM, Alkjaersig NK, Fletcher AP, Judd HL. Biologic effects of transdermal estradiol. N Engl J Med. 1986;314:1615–1620.[Abstract]
21.
De Lignieres B, Basdevant A, Thomas G, Thalabard
J-C, Mercier-Bodard C, Conard J, Guyene T-T, Mairon N, Corvol P,
Guy-Grand B, Mauvais-Jarvis P, Sitruk-Ware R. Biological effects of
estradiol-17ß in postmenopausal women: oral versus
percutaneous administration. J Clin
Endocrinol Metab. 1986;62:536–541.
22. Goldzieher JW. Pharmacology of contraceptive steroids: a brief review. Am J Obstet Gynecol. 1989;160:1260–1264.[Medline] [Order article via Infotrieve]
23. Judd H. Efficacy of transdermal estradiol. Am J Obstet Gynecol. 1987;156:1326–1331.[Medline] [Order article via Infotrieve]
24. Mashchak CA, Lobo RA, Dozono-Takano R, Eggena P, Nakamura RM, Brenner PF, Mishell DR Jr. Comparison of pharmacodynamic properties of various estrogen formulations. Am J Obstet Gynecol. 1982;144:511–518.[Medline] [Order article via Infotrieve]
25.
Weissberger AJ, Ho KK, Lazarus L. Contrasting effects
of oral and transdermal routes of estrogen replacement therapy on
24-hour growth hormone (GH) secretion, insulin-like growth factor I,
and GH-binding protein in postmenopausal women. J Clin
Endocrinol Metab. 1991;72:374–381.
26. Kelly JJ, Rajkovic IA, O’Sullivan AJ, Sernia C, Ho KKY. Effects of different oral oestrogen formulations on insulin-like growth factor-I, growth hormone and growth hormone binding protein in post-menopausal women. Clin Endocrinol. 1993;39:561–567.[Medline] [Order article via Infotrieve]
27. Walker PA, Berger JC, Green R, Laub DR, Reynolds CL, Wollman L. Standards of care: the hormonal and surgical sex reassignment of gender dysphoric persons. Arch Sex Behav. 1985;14:79–90.[Medline] [Order article via Infotrieve]
28.
Segal KR, Van Loan M, Fitzgerald PI, Hodgdon JA, Van
Itallie TB. Lean body mass estimation by bioelectrical impedance
analysis: a four-site cross-validation study. Am J
Clin Nutr. 1988;47:7–14.
29. Jespersen J, Kluft C. Inhibition of tissue-type plasminogen activator in plasma of women using oral contraceptives and in normal women during a menstrual cycle. Thromb Haemost. 1986;55:388–389.[Medline] [Order article via Infotrieve]
30.
Rittmaster RS. Androgen conjugates: physiology and
clinical significance. Endocr Rev. 1993;14:121–132.
31. Stegnar M, Mavri A. Reproducibility of fibrinolytic response to venous occlusion in healthy subjects. Thromb Haemost. 1995;73:453–457.[Medline] [Order article via Infotrieve]
32. Van Genderen PJJ, Prins FJ, Lucas IS, Van de Moesdijk D, Van Vliet HHDM, Van Strik R, Michiels JJ. Decreased half-life time of plasma von Willebrand factor collagen binding activity in essential thrombocythaemia: normalization after cytoreduction of the increased platelet count. Br J Haematol. 1997;99:832–836.[Medline] [Order article via Infotrieve]
33. Wieczorek I, Ludlam CA, MacGregor I. Venous occlusion does not release von Willebrand factor, factor VIII or PAI-1 from endothelial cells: the importance of consensus on the use of correction factors for haemoconcentration. Thromb Haemost. 1993;69:91–93.[Medline] [Order article via Infotrieve]
34. Keber D. On the use of different correction factors for hemoconcentration. Thromb Haemost. 1983;49:245–245.[Medline] [Order article via Infotrieve]
35. Anderson DC. Sex-hormone binding globulin. Clin Endocrinol. 1974;3:69–96.[Medline] [Order article via Infotrieve]
36. Goebelsmann U, Mashchak CA, Mishell DR. Comparison of hepatic impact of oral and vaginal administration of ethinyl estradiol. Am J Obstet Gynecol. 1985;151:868–877.[Medline] [Order article via Infotrieve]
37. Boschetti C, Cortellaro M, Nencioni T, Bertolli V, Della Volpe A, Zanussi C. Short- and long-term effects of hormone replacement therapy (transdermal vs oral conjugated equine estrogens, combined with medroxyprogesterone acetate) on blood coagulation factors in postmenopausal women. Thromb Res. 1991;62:1–8.[Medline] [Order article via Infotrieve]
38. Kooistra T, Bosma PJ, Jespersen J, Kluft C. Studies on the mechanism of action of oral contraceptives with regard to fibrinolytic variables. Am J Obstet Gynecol. 1990;163:404–412.[Medline] [Order article via Infotrieve]
39. Kooistra T, Bosma P, Tons H, Van Den Ende A, Meyer P, Princen H. Plasminogen activator inhibitor 1: biosynthesis and mRNA levels are increased by insulin in cultured human hepatocytes. Thromb Haemost. 1989;62:723–728.[Medline] [Order article via Infotrieve]
40. Shimomura I, Funahashi T, Takahashi M, Maeda K, Kotani K, Nakamura T, Yamashita S, Miura M, Fukuda Y, Takemura K, Tokunaga K, Matsuzawa Y. Enhanced expression of PAI-1 in visceral fat: possible contributor to vascular disease in obesity. Nat Med. 1996;2:800–803.[Medline] [Order article via Infotrieve]
41. Alessi MC, Peiretti F, Morage P, Henry M, Nalbone G, Juhan-Vague I. Production of plasminogen activator inhibitor 1 by human adipose tissue: possible link between visceral fat accumulation and vascular disease. Diabetes. 1997;46:860–867.[Abstract]
42. Lijnen HR, Collen D. Mechanism of physiological fibrinolysis. Baillieres Clin Haematol. 1995;8:277–290.[Medline] [Order article via Infotrieve]
43. Glueck CJ, Glueck HI, Stroop D, Hamer T, Tracey T. Endogenous testosterone, fibrinolysis, and coronary heart disease in hyperlipidaemic men. J Lab Clin Med. 1993;122:412–420.[Medline] [Order article via Infotrieve]
44. Caron P, Bennet A, Camare R, Louvet JP, Boneu B, Sié P. Plasminogen activator inhibitor in plasma is related to testosterone in men. Metabolism. 1989;38:1010–1015.[Medline] [Order article via Infotrieve]
45. Marques-Vidal P, Sié P, Cambou J-P, Chap H, Perret B. Relationships of plasminogen activator inhibitor activity and lipoprotein(a) with insulin, testosterone, 17ß-estradiol, and testosterone binding globulin in myocardial infarction patients and healthy controls. J Clin Endocrinol Metab. 1995;80:1794–1798.[Abstract]
46. Verheijen JH, Rijken DC, Chang GTG, Preston FE, Kluft C. Modulation of rapid plasminogen activator inhibitor in plasma by stanozolol. Thromb Haemost. 1984;51:396–397.[Medline] [Order article via Infotrieve]
47. Anderson RA, Ludlam CA, Wu FCW. Haemostatic effects of supraphysiological levels of testosterone in normal men. Thromb Haemost. 1995;74:693–697.[Medline] [Order article via Infotrieve]
48. Grady D, Rubin SM, Pettiti DB, Fox CS, Black D, Ettinger B, Ernster VL, Cummings SR. Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern Med. 1992;117:1016–1037.
49.
Barrett-Connor E, Bush TL. Estrogen and
coronary heart disease in women. JAMA. 1991;265:1861–1867.
50.
Grodstein F, Stampfer MJ, Manson JE, Colditz GA,
Willett WC, Rosner B, Speizer FE, Hennekens CH. Postmenopausal estrogen
and progestin use and the risk of cardiovascular
disease. N Engl J Med. 1996;335:453–461.
This article has been cited by other articles:
 |
|
 |
|
  L. J. Gooren, E. J. Giltay, and M. C. Bunck Long-Term Treatment of Transsexuals with Cross-Sex Hormones: Extensive Personal Experience J. Clin. Endocrinol. Metab., January 1, 2008; 93(1): 19 - 25. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. H Bisschop, A. W Toorians, E. Endert, W. M Wiersinga, L. J Gooren, and E. Fliers The effects of sex-steroid administration on the pituitary-thyroid axis in transsexuals. Eur. J. Endocrinol., July 1, 2006; 155(1): 11 - 16. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Pretorius, J. M. Luther, L. J. Murphey, D. E. Vaughan, and N. J. Brown Angiotensin-Converting Enzyme Inhibition Increases Basal Vascular Tissue Plasminogen Activator Release in Women But Not in Men Arterioscler Thromb Vasc Biol, November 1, 2005; 25(11): 2435 - 2440. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. J Giltay, K. H Kho, B. A Blansjaar, M. M Verbeek, P B. H Geurtz, J. M Geleijnse, and L. J G Gooren The sex difference of plasma homovanillic acid is unaffected by cross-sex hormone administration in transsexual subjects J. Endocrinol., October 1, 2005; 187(1): 109 - 116. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. G T'Sjoen, Y. Beguin, E. Feyen, R. Rubens, J.-M. Kaufman, and L. Gooren Influence of exogenous oestrogen or (anti-) androgen administration on soluble transferrin receptor in human plasma J. Endocrinol., July 1, 2005; 186(1): 61 - 67. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. H. Smith, S. R. Coats, H. Qin, M. S. Petrie, J. W. Covington, M. Su, M. Eren, and D. E. Vaughan Differential and Opposing Regulation of PAI-1 Promoter Activity by Estrogen Receptor {alpha} and Estrogen Receptor {beta} in Endothelial Cells Circ. Res., August 6, 2004; 95(3): 269 - 275. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. W. F. T. Toorians, M. C. L. G. D. Thomassen, S. Zweegman, E. J. P. Magdeleyns, G. Tans, L. J. G. Gooren, and J. Rosing Venous Thrombosis and Changes of Hemostatic Variables during Cross-Sex Hormone Treatment in Transsexual People J. Clin. Endocrinol. Metab., December 1, 2003; 88(12): 5723 - 5729. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. L Hoetzer, B. L Stauffer, H. M Irmiger, M. Ng, D. T Smith, and C. A DeSouza Acute and chronic effects of oestrogen on endothelial tissue-type plasminogen activator release in postmenopausal women J. Physiol., September 1, 2003; 551(2): 721 - 728. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 K. H. Humphries and S. Gill Risks and benefits of hormone replacement therapy: The evidence speaks Can. Med. Assoc. J., April 15, 2003; 168(8): 1001 - 1010. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. J. Brown, A. Abbas, D. Byrne, J. A. Schoenhard, and D. E. Vaughan Comparative Effects of Estrogen and Angiotensin-Converting Enzyme Inhibition on Plasminogen Activator Inhibitor-1 in Healthy Postmenopausal Women Circulation, January 22, 2002; 105(3): 304 - 309. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||