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From the * Institute of Reproductive Medicine of
the University and Institute of Clinical
Chemistry of the University, Münster, Germany.
| Correspondence to: Prof Dr E. Nieschlag FRCP, Institute of Reproductive Medicine of the University, Domagkstr. 11, D 48149 Münster, Germany (e-mail: nieschl{at}uni-muenster.de ). |
| Received for publication August 21, 2001; accepted for publication January 3, 2002. |
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Abstract |
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2-antiplasmin-complex (PAP); and fibrinogen. NET-EN
alone led to a depletion of sexual hormones and a marked shift in hemostatic
parameters with increasing levels of FXIIc, fibrinogen, antithrombin, and
F1+2, whereas FVIIc and FVIIa levels decreased. PAP levels increased
significantly. Opposite effects were seen in the TU/placebo group, with a
significant down-regulation of fibrinolysis and the hemostatic turnover rate.
Testosterone effects were attenuated by additional administration of
gestagens. The effect of hormonal male contraception using long-acting
testosterone esters with or without gestagens was significantly measurable
within the hemostatic system. Down-regulation of the hemostatic system with
testosterone alone may indicate an antithrombotic effect, whereas clinical
consequences of an additional gestagen compound cannot be derived.
Key words: Cardiovascular risk, gestagens, hemostasis, hormonal male contraception, testosterone
Hemostatic parameters associated with cardiovascular risk include
fibrinogen factors VII and XII (FVII and FXII, respectively), antithrombin,
and prothrombin fragment F1+2 (F1+2) as substances involved in coagulation and
plasminogen activator inhibitor type 1 (PAI-1) and
plasmin-2-antiplasmin complex (PAP) as effectors of
fibrinolysis. (PAP levels serve as a terminal, summarizing marker of the
hemostatic system's turnover rate and are affected by PAI-1.)
Associations with androgen levels have been demonstrated in men for some of these parameters. Plasma levels of fibrinogen are inversely correlated with levels of endogenous and exogenous androgens in men (Glueck et al, 1993; Anderson et al, 1995; De Pergola et al, 1997). An inverse correlation is also seen between testosterone and PAI-1 as an antifibrinolytic parameter (Anderson et al, 1995; Sobel et al, 1995; Ferenchick et al, 1997; Adamkiewicz et al, 1999), although some authors have not been able to describe a relationship with androgens (De Pergola et al, 1997; van Kesteren et al, 1998). Men with hypogonadism have low baseline fibrinolytic activity, which is accounted for by increased synthesis of PAI-1 (Winkler, 1996; Bennet et al, 1987; Zollner et al, 1997). The relationship between testosterone levels and FVIIc is seen inconsistently in cross-sectional studies (Philipps et al, 1993; Yang et al, 1993; De Pergola et al, 1997). In men, the effects of androgens on levels of the activated form of coagulation factor FVIIa, for which an association with cardiovascular risk seems to be more pronounced than for FVIIc (Ruddock and Meade, 1994; Meade et al, 1993; Junker et al, 1998), have not been described. Nor is there a description of possible influences of androgens on levels of PAP as a marker of plasmin generation and fibrinolytic balance, which is positively associated with atherothrombotic events (Sakkinen et al, 1999). In addition, potential effects by androgens on other factors associated with cardiovascular risk, such as F1+2 (Rugman et al, 1994; Carr, 2001), FXII (Ishii et al, 2000; Carr, 2001), and especially FXIIa (Kohler et al, 1998; Zito et al, 2000), have not been sufficiently investigated in men.
Clinically relevant side effects of additional gestagens have been demonstrated in women. The combination of estrogens and progesterone derivatives causes an increased risk for venous thrombosis (Quehenberger et al, 1996; Helmerhorst et al, 1997; Scarabin et al, 1997; Bellinger et al, 1998; Bonduki et al, 1998; Lidegaard et al, 1998; Vandenbroucke et al, 1999; Meijers et al, 2000; Middeldorp et al, 2000; Tans et al, 2000; Winkler et al, 2000). To our knowledge, the interrelationship of gestagens and testosterone, which may have a substantial effect on hemostatic parameters involved in cardiovascular risk and atherothrombosis, has not been described.
We performed this study with healthy men to investigate the effects of a steroid combination (testosterone undecanoate [TU] with the gestagen norethisterone-enanthate [NET-EN]) on activation parameters of the hemostatic system related to cardiovascular risk, and to determine these effects using different TU combinations with placebo or the gestagen, levonorgestrel (LNG). The location of the assessed parameters within the hemostatic system is displayed in Figure 1, which represents a simplified pattern of coagulation and fibrinolysis.
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Materials and Methods |
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In a single-dose pharmacokinetic study (phase 1), 7 healthy white men, aged 28-38 years with no previous history of androgen preparation use, received a single intramuscular injection of 200 mg NET-EN at day 0 (Kamischke et al, 2000a).
The phase 2 study consisted of 3 hormonal regimens, each comprising 14 healthy white men aged 18-45 years with no previous history of androgen preparation use. Every volunteer received intramuscular injections of 1000 mg TU in study weeks 0, 6, 12, and 18 plus either daily oral placebo treatment, daily oral LNG (250 µg), or intramuscular injections of NET-EN (200 mg) in study weeks 0, 6, 12, and 18. The total treatment phase lasted 24 weeks, and oral medication was administered accordingly. The last follow-up visit was scheduled for week 52 (Kamischke et al, 2000b,c). Groups did not differ in age, body mass index, or smoking habits. Subjects did not experience severe infections or inflammatory disease throughout the trial (C-reactive protein [CRP] levels are provided in Table 1). The study was approved by the ethics committee of the university and the State Medical Board, Münster, Germany. All participants volunteered for the study and provided written informed consent.
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Testosterone Undecanoate
This substance has not yet been introduced to the market. With an injection
volume of 4 mL, the dose of 1000 mg TU in castor oil leads to maximal
concentrations of 19.3 ± 2.1 nmol/L after 11.4 ± 1.5 days. The
terminal half-life was determined as 33.9 ± 4.9 days. The optimal
injection interval was set between 6 and 8 weeks
(Nieschlag et al, 1999;
Zitzmann and Nieschlag,
2000).
Levonorgestrel and Norethisterone-Enanthate
Both substances were supplied by Schering, Berlin, Germany. LNG is
currently marketed by Schering as Microlut. NET-EN is marketed by Schering
under the name of Noristerat.
Collection and Processing of Plasma Samples
All venous blood samples (9 parts blood in 1 part 0.13 M sodium citrate pH
7.8) were obtained after a fasting state in standardized conditions between
0800 and 1200 hours after a 30-minute rest. Plasma was separated at 800
x g on study days 0, 14, 41, and 84 (phase 1) or during study
weeks 0, 16, 24, and 52 (phase 2). Samples were immediately stored at
-80°C for a maximum of 12 months. The cooling device we used is equipped
with an alarm system and provided temperature continuity during the time when
samples were stored. Assays are not affected under these conditions. All
assays were performed in one batch.
Laboratory Methods
Prothrombin time (normal range, 70%-130%), activated partial thromboplastin
time (normal range, 24-35 seconds), FVIIc (normal range, 70%-120%), and FXIIc
(normal range, 70%-150%) were measured using a Behring BCS coagulation
analyzer and Thromborel S or Pathromtin SL, respectively, and a specific
deficient plasma for FVIIc and FXIIc (all from Behring Diagnostics, Marburg,
Germany). Using data provided by Clauss
(1957), fibrinogen (normal
range, 180-350 mg/dL) and antithrombin activity (normal range, 80%-120%) were
determined using the BCS analyzer and Multifibren U (Behring Diagnostics) or a
chromogenic substrate (Berichrom ATIII, Behring Diagnostics). FVIIa (normal
range, 15.5-238.7 mU/mL) was also determined using the BCS analyzer and a
clotting assay kit (Roche, Mannheim, Germany). PAP (normal range, 120-700
µg/L) was measured with a commercially available enzyme-linked
immunosorbent assay (ELISA) kit (WAK Chemie, Schwalbach, Germany) in the same
method used to measure F1+2 (normal range, 0.4-1.1 nmol/L). Hematocrit (normal
range, 42%-52%) and platelet count (normal range, 150-350 x
106/mL) were determined using the automated hematology analyzer
Technicon H3 (Bayer, Fernwald, Germany). FXIIa was measured with an ELISA kit
(Shield Diagnostic, Dundee, United Kingdom). The reference range was 1.0-3.0
ng/mL. C-reactive protein was determined nephelometrically on a BNII analyzer
(Dade Bering, Schwalbach, Germany). The lower detection limit was 0.08 mg/L,
the upper normal value was 0.5 mg/L.
For testosterone measurements, samples from the NET-EN single-dose study group, the TU/placebo group, and the TU/LNG group were measured using a commercial fluoroimmunoassay (Autodelfia, Wallac, Turku, Finland). Serum testosterone levels of the TU/NET-EN group were measured after changing to another commercial ELISA kit (DRG Instruments GmbH, Marburg, Germany). Levels of sex hormone binding globulin (SHBG) and estradiol were determined by highly specific timeresolved fluoroimmunoassays (Autodelfia). In our laboratory, the normal range for serum levels of total testosterone is 12-35 nmol/L, the upper normal limit for estradiol is 250 pmol/L, and the normal range for SHBG is 11-71 nmol/L. To maintain these parameters, our laboratory participates in a quality control scheme and regularly passes requirements. Levels of free testosterone were calculated from levels of SHBG and total serum testosterone according to the law of mass action, using 3.6 x 104 M-1 as the association constant of testosterone with albumin and 1 x 109 mol/L with SHBG. Calculation with this method yields highly reliable values of levels of free testosterone (Vermeleulen et al, 1999). The laboratory staff was unaware of the patients' treatment schedules.
Statistical Analysis
All variables were checked for normal distribution by the
Kolmogorov-Smirnov one-sample test for goodness of fit by applying the
modified calculation of statistical significance according to the Lilliefors
test (stricter criteria). Due the small number (n = 7) of subjects in the
NET-EN single-dose group, putative changes from baseline in this part of the
study were calculated using the Friedman nonparametric test for repeated
measurements (ie, the Dunn post hoc test for comparison with baseline values).
To compare differences between the groups of the second, larger phase of the
study, instead of using analysis of covariance on changes from baseline (by
incorporating baseline values as covariates), values were transformed within
each group to homogenous, dimensionless baseline values of 100. Thus, without
impairing statistical power, variations between study groups were evaluated by
two-way analysis of variance (ANOVA) because all parameters followed a
gaussian distribution. Because this is not always the case for F1+2 and PAP,
these values were logarithmically transformed for analysis as well (different
results were not observed). Changes from baseline for each specific group were
calculated by ANOVA for repeated measurements; overall, when P
<.05, the Dunnett post hoc test for changes from baseline values was
performed. The influence of changing levels of sexual hormones on the
described parameters was evaluated with time-series analyses using
cross-correlations. Fibrinogen is an inflammation marker and was positively
associated with CRP. Aside from analysis of uncorrected values of fibrinogen
levels and in order to exclude influences from minor viral infections, which
occurred in some subjects, fibrinogen levels were adjusted for CRP to properly
determine the effect of the study drugs (also see CRP levels in
Table 1).
Computations were performed using a statistical software package from SPSS (Chicago, Ill; release 9.0.1.). Unless otherwise stated, results are given as means ± SEM in tables and figures. Two-sided P values <.05 were considered significant. For ANOVA results, levels of statistical significance are followed by asterisks (*,**,***) representing P values less than.05,.01, and.001, respectively.
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Results |
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Phase 2
Total testosterone levels increased with high significance in the
TU/placebo group; changes in comparison to baseline were not significant in
either gestagen treatment group. Due to a significant decrease in SHBG levels,
concentrations of free testosterone increased in both gestagen treatment
groups; there also was high significance in the TU/placebo treatment group
(Table 4). In the TU/placebo
group, significantly decreasing levels of FXIIc and PAP were observed, and
antithrombin levels decreased significantly as well. The TU/LNG group
demonstrated significantly decreasing levels of FVIIa and FXIIc; in the
TU/NET-EN group, significantly decreasing levels of FVIIc and fibrinogen were
observed (Table 5,
Figure 3). Significant
differences with two-way ANOVA between the TU/gestagen treatment group and the
TU/placebo treatment group are displayed in
Table 6. For the hemostatic
turnover rate, a highly significant difference between the TU/gestagen group
and the TU/placebo group was observed; a significant down-regulation occurred
in the latter group, whereas stable conditions were maintained in the groups
that received an additional gestagen.
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Other Parameters
Other parameters were assessed in samples of the contraceptive trial; all
values remained within normal ranges for all groups. A significant increase in
platelet count was observed for the TU/LNG group. Hematocrit levels increased
significantly in both gestagen treatment groups but remained unchanged in the
TU/placebo group (Table 7).
Coagulation times remained within normal limits and were not significantly
altered.
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Relationship of Hemostatic Parameters to Sexual Hormone Levels
For results in the TU/placebo group, time series—dependent
cross-correlations revealed that serum levels of estradiol were positively
associated with FVIIa levels (r =.32, P =.019), although
this model accounts for only 9.8% of the variance. Serum levels of
testosterone predicted negative levels of FXIIc with high significance
(r = -.41, P =.002); this model accounts for 16.6% of the
variance. This observation, albeit weaker, was discernable for FXIIa as well.
Serum levels of total testosterone also predicted negative antithrombin levels
with high significance (r = -.41, P =.001). Testosterone
levels accounted for 17.2% of the variance in antithrombin levels.
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Discussion |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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PAP levels as the terminal marker of fibrinolysis were affected by both testosterone depletion and testosterone administration, but because levels of direct products of fibrin formation, PAI-1, or the effects of factor XI (Bouma and Meijers, 2000) or thrombin-activated fibrinolysis inhibitor, which is not directly associated with cardiovascular risk factors (Juhan-Vague et al, 2000a), were not assessed during this study, it remains to be speculated how this effect was generated. Cytokine-induced production of FXII, which consequently activates the fibrinolytic system via the urokinase-plasminogen pathway, is a possible mediator of this effect, as levels of FXIIc and FXIIa were significantly positively correlated with PAP levels and showed a negative association with those of testosterone. An activation of fibrinolysis by decreased levels of PAI-1 is unlikely because this protein is known to be increased in hypogonadism (Bennet et al, 1987; Winkler, 1996).
According to our observations, the additional administration of progestins
can partly influence these effects. Significant differences were seen for
FVIIa, FXIIa, FXIIc, antithrombin, fibrinogen, and especially PAP. The
gestagens seem to mitigate testosterone-induced influence on the hemostatic
system. Both LNG (which is 18-methyl-NET) and NET-EN have androgenic activity,
whereas their proper antiandrogenic activity is scarce or even debatable
(Lobo, 1988; Neumann et al, 1988;
Deckers et al, 2000).
Antiandrogenic effects could rather be exerted by their 5-reduced
metabolites, which possess high androgen receptor binding capacities but
diminished androgenic activity
(Perez-Palacios et al, 1992).
Compared to NET-EN, LNG has a higher affinity to the androgen receptor and
exerts stronger androgenic effects. This also applies to the progesterone
receptor; the affinity of LNG to the progesterone receptor is about 2-3 times
stronger than that of NET-EN and may explain the differential influences
(Bergink et al, 1983;
Hoppen and Hammann 1987;
Lobo, 1988; Perez-Palacios et al, 1992;
Deckers et al, 2000). Both
substances do not bind to the estrogen receptor in a measurable amount
(Bergink et al, 1983; Hoppen and Hammann, 1987). It
must be considered that gestagens can bind to SHBG and displace testosterone,
and can decrease levels of SHBG, thus increasing free testosterone levels
(Nilsson and von Schoultz,
1989; Van der Vange et al,
1990; Raudaskoski et al,
1998).
Changes in hemostatic parameters must be discussed from the perspective of lipid parameters as well. During the NET-EN single-dose study, levels of high-density lipoprotein cholesterol (HDL-C) and lipoprotein(a) decreased significantly, whereas levels of low-density lipoprotein cholesterol (LDL-C) increased (Kamischke et al, 2000a). During the contraceptive trials, LDL-C levels increased significantly in the TU/NET-EN group, whereas levels in the TU/placebo and TU/LNG groups decreased slightly, but not significantly. HDL-C levels decreased significantly in all 3 groups. Levels of antifibrinolytic lipoprotein(a) were lower in both groups that received gestagens but remained unchanged in the TU/placebo group (Kamischke et al, 2000b, c). Decreasing levels of PAP can therefore not be attributed to changes in lipoprotein(a).
Testosterone given as single substance in the form of a long-acting ester leads to a lower turnover rate in the hemostatic system, which is mirrored by decreasing PAP levels. PAP reflects reactive fibrinolysis and is associated with subclinical atherosclerosis, especially in the presence of concomitantly increased levels of fibrinogen (Stein et al, 1997; Sakkinen et al, 1999). In persons with subclinical insulin resistance and obesity, however, hypofibrinolysis due to increased levels of PAI-1 and consequent depressed plasmin generation may enhance the progression of atherosclerosis (Meade et al, 1993; Juhan-Vague et al, 2000b). Thus, the observed effects of testosterone need to be regarded differentially for cardiovascular risk and atherothrombosis; the effects may benefit healthy persons, but they could have an adverse influence in those afflicted with insulin resistance.
In conclusion, single-dose NET-EN or TU alone exhibit prothrombotic and antithrombotic effects, respectively, which may exert clinical adverse or beneficial effects. Hormonal male contraception by a combined regimen of longacting testosterone esters and progestins shows, in summary, few effects within the hemostatic system of healthy men, and absolute values remained within normal ranges. Nevertheless, testosterone and gestagen effects are detectable and demonstrate the necessity for further long-term investigations to determine a clinical meaningfulness.
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Acknowledgments |
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Footnotes |
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, full line), TU/LNG ([UNK], dashed line), and
TU/NET-EN (
, dashed line). Results of two-way ANOVA (difference of
curves) are shown with asterisks (* and **, representing
P <.05 and.01 respectively). For TU/placebo, significant changes
from baseline are displayed as asterisks according to ANOVA for repeated
measurements.