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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 6 1752-1756
Copyright © 1997 by The Endocrine Society

Clinical Studies

Tibolone: Influence on Markers of Cardiovascular Disease

Nina Hannover Bjarnason, Ketil Bjarnason, Jens Haarbo, Herjan J.T. Coelingh Bennink and Claus Christiansen

Center for Clinical and Basic Research (N.H.B., K.B., J.H., C.C.), Ballerup Byvej 222, DK-2750 Ballerup, Denmark; and Organon (H.J.T.C.B.), 5340 BH Oss, The Netherlands

Address all correspondence and requests for reprints to: Nina Hannover Bjarnason, Center for Clinical and Basic Research, Ballerup Byvej 222, DK-2750 Ballerup, Denmark.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Tibolone, a synthetic steroid with estrogenic, androgenic, and progestogenic properties relieves climacteric symptoms and prevents postmenopausal bone loss. The influence of tibolone treatment on coagulation, fibrinolysis, and lipid metabolism was investigated in 91 healthy late postmenopausal women. They were randomly assigned in a double-blind, placebo-controlled 2-year study to receive either tibolone 1.25 mg (n = 36, 29 completed) or 2.5 mg (n = 35, 28 completed) or placebo (n = 20, 13 completed). The biochemical markers of lipid metabolism, fibrinolysis, and coagulation were measured every 3 months. In both tibolone groups a similar (~30%) decrease in high density lipoprotein cholesterol and a corresponding lowering of apolipoprotein A-1 (P < 0.001) was detected. Also serum total cholesterol and triglycerides were reduced (~15%; P < 0.01), whereas low density lipoprotein cholesterol, apolipoprotein B, and lipoprotein(a) were unaffected by tibolone. The two dose levels of tibolone resulted in a similar, marked lowering (~30%) of tissue plasminogen activator and plasminogen activator inhibitor activity as compared with placebo (P < 0.001). Plasminogen increased (~15%; P < 0.001) in both groups. Fibrinogen was lowered (P < 0.01) in the low-dose group, and antithrombin III remained unchanged. The overall effect on hemostatic factors of the present doses of tibolone in healthy, late postmenopausal women tends towards increased fibrinolysis and unchanged coagulation. This may be beneficial and might theoretically counterbalance the potentially negative effect of the decrease in high density lipoprotein cholesterol.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
ARTERIAL atherosclerosis along with imbalance in coagulation and fibrinolysis causing thrombus formation are key events in the development of cardiovascular diseases. Plasma markers of these systems are therefore important from diagnostic, prognostic, and therapeutic points of view. Thus, the inverse and independent relationship between high density lipoprotein cholesterol (HDL-C) and the risk of cardiovascular disease (CVD) is well known (1), but low density lipoprotein cholesterol (LDL-C), apolipoproteins (2), and lipoprotein(a) [Lp(a)] (3) are important also. The cascade nature of coagulation and fibrinolysis implicates that certain parameters are key regulators such as plasma fibrinogen and tissue plasminogen activator (t-PA) (4).

Besides being preventive for osteoporosis and climacteric complaints (5) hormone replacement therapy (HRT) protects against CVD as indicated by epidemiological studies (6, 7). This effect seems in part to be mediated through favorable changes in serum lipids, but hemostatic factors are among the other mechanisms that are presumably also important. The impact of HRT on hemostatic factors is, however, less well investigated. Because high-dose oral contraceptives increase the risk of thromboembolic episodes, possibly because of an adverse influence of synthetic ethinyl estradiol on hemostatic factors (8), concern about an increased thromboembolic risk for postmenopausal women receiving HRT with natural low-dose estrogens has risen. The scientific evidence for this concern is sparse; however a small group of women may be very sensitive to estrogens (8, 9).

Tibolone [(7{alpha}, 17{alpha})-17-hydroxy-7-methyl-19-norpregn-5(10)-en-20-yn-3-one, Org OD 14; Livial] is a synthetic steroid with estrogenic, androgenic, and progestogenic properties and is used to prevent climacteric symptoms (10) and postmenopausal bone loss (11, 12, 13). As a frequently used hormone-like alternative to traditional HRT, it is valuable to determine the influence of tibolone on the risk factors of CVD.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Ninety-one healthy women were enrolled in a randomized, placebo-controlled, double-blind study to investigate the effect on bone of tibolone (protocol 32910; Organon, Oss, The Netherlands) (11). They were not treated with any medication known to affect coagulation, fibrinolysis, lipid or bone metabolism, and at least 10 yr had passed since spontaneous menopause. They were randomly assigned to receive daily treatment with either 2.5 mg tibolone (n = 35), 1.25 mg tibolone (n = 36), or placebo (n = 20). Twenty-one women did not complete the study, seven from each treatment group. The study period was 24 months, with examinations at baseline and every 3 months. Blood samples were drawn after an overnight fast and tobacco abstinence.

Serum total cholesterol, HDL-C [after precipitation (14)], and triglycerides were determined enzymatically by an autoanalyzer (Cobas Mira Plus, Roche Diagnostic Systems, Basel, Switzerland). The intraassay precision errors of HDL-C, total cholesterol, and triglycerides are 0.9%, 2.0%, and 2.3%, respectively. The interassay precision errors of the same parameters are 3.4%, 2.0%, and 2.3%, respectively. LDL-C was estimated as described by Friedewald et al. (15). Apolipoprotein A1 (ApoA1) and apolipoprotein B (ApoB) were measured by immunoturbidimetric methods (16). The intraassay precision error is below 4%, and the interassay precision error is below 3% for ApoA1 and ApoB at the center. Lp(a) was measured turbidimetrically (17); intra- and interassay precision errors were <6% and <3%, respectively.

Fibrinogen was analyzed photometrically just after sampling (18). Antithrombin III, plasminogen, t-PA, plasminogen activator inhibitor antigen (PAI-1), and plasminogen activator inhibitor activity (PAI activity) were sampled after 10 min of supine rest with minimal stasis and collected in citrate tubes. For determinations of fibrinolysis parameters, the tubes were stored on ice after sampling and were spun cooled within 30 min of sampling. Tubes for coagulation assays were kept at room temperature. The specimens were stored immediately after sampling at -20 C, and all measurements were determined using the same batch of assay reagents for each individual. Antithrombin III and plasminogen were determined spectophotometrically (19, 20); t-PA, PAI-1, and PAI activity were measured by ELISA (21, 22, 23). Intra- and interassay precision errors of these analyses were: fibrinogen, 5.6% and 10.6%, respectively; antithrombin III, 1.8% and 4.9%, respectively; plasminogen, 1.5% and 2.7%, respectively; t-PA, 4.8% and 6.3%, respectively; PAI-1, 4.3% and 8.5%; and PAI activity, 11.0% and 14.0%, respectively.

Hematology parameters were determined automatically (Sysmex, TOA Medical Electronics Co., Ltd., Kobe, Japan) and serum glucose was determined by an enzymatic principle using Cobas Mira Plus. Blood pressure was measured after 10 min of supine rest at all visits using a digital device (UA-731, Takeda Medical, Takeda Medical, Inc., Japan). To eliminate interindividual variance, values were expressed as percentages of initial values. All longitudinal analyses was performed as completers analysis using Statistical Analyzing System (SAS Institute, Cary, NC). The cumulated response for each variable was calculated as the average change (mean of individual response) of the variable in each group during the study period. The independent effects of treatment, time, age, years since menopause, and body weight on serum parameters were analyzed by two-way ANOVA (general linear models procedure).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Baseline values demonstrated comparability of the three groups (Table 1Go). Each tibolone dose induced a major and similar decrease (~30%) in serum HDL-C as compared with placebo (P < 0.001) (Fig. 1Go). This decrease seemed to diminish during the study, because a slight but significant increase in HDL-C (on average (0.21% ± 0.1%/month, P < 0.05) was detected in both treatment groups, resulting in an increase of 5% after 2 yr. The average change in HDL-C was not correlated to baseline values of weight, height, blood pressure, age, and number of years since menopause. Corresponding to the reduction in HDL-C, ApoA1 was lowered (P < 0.001), and the changes in HDL-C were mirrored in decreased levels of total cholesterol (P < 0.001), whereas no change was observed in LDL-C and ApoB (Fig. 1Go). Serum triglycerides were lowered (~15%) (P < 0.01) (Fig. 1Go).


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  		Table 1. Pretreatment clinical and biochemical data [Mean (SD)]. Blood pressure reported as [meansystolic/meandiastolic (SDsystolic/SDdiastolic)]. Lp(a), PAI, and PAI-activity are given as [med(25–75%)]

 


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  		Figure 1. Serum HDL, ApoA1, LDL-C, ApoB, total cholesterol, and triglycerides at 3-month intervals expressed as percentages of initial values. Average changes (mean of individual response) are shown on right. Placebo, {blacksquare}; tibolone 1.25 mg, •; tibolone 2.5 mg, {circ}.

 
There were no significant differences between groups for Lp(a), but a slight decrease was seen in all groups over time (Fig. 2Go). In both tibolone groups, an equal increase in plasminogen (~15%) and a decrease in t-PA and PAI activity (~30–40%) was detected when compared with placebo (P < 0.001) (Fig. 2Go). Also, PAI-1 antigen was lowered as compared with placebo (P < 0.001). Fibrinogen decreased in the low-dose group, whereas antithrombin III was unchanged by tibolone treatment (Table 2Go). Neither height nor blood pressure were significantly affected by tibolone.



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  		Figure 2. Serum plasminogen, t-PA, PAI activity, and Lp(a) at 3-month intervals expressed as percentages of initial values (mean ± SEM). Average changes are shown on right. Placebo, {blacktriangleup}; tibolone 1.25 mg, •; tibolone 2.5 mg, {blacksquare}.

 

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  		Table 2. Average response to treatment during study [mean (SEM)]

 
Initial values of weight were significantly correlated with baseline values of PAI-1 (r = 0.37; P < 0.001), PAI activity (r = 0.41; P < 0.001), and t-PA (r = 0.30; P < 0.01). Prestudy t-PA was significantly correlated to age (r = 0.23; P < 0.05) and to number of years since menopause (r = 0.23; P < 0.05), whereas baseline fibrinogen was correlated significantly to age (r = 0.27; P < 0.01). However, the changes in these biochemical parameters were still significant when correcting for age, years since menopause, and weight. Pretreatment values of t-PA and PAI-1 were highly correlated (n = 70; r = 0.72; P < 0.001), as well as the average change of t-PA and PAI-1 during tibolone treatment (n = 57; r = 0.44; P < 0.001).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
This study was carried out on a representative sample of healthy postmenopausal women. The double-blind, randomized design provided well-matched study groups, and all data were analyzed blindly, supporting the validity of the results. The incidence of vaginal bleeding was 20%, but the drug was otherwise well tolerated (11).

The lipid analyses revealed two principal findings, namely a significant reduction in HDL-C and ApoA1, as well as an equal response in all parameters of the two dose levels. A lowering of HDL-C of comparable magnitude has been described earlier in studies of shorter duration (24, 25, 26), in which the response was also obvious within the first months of treatment. It has been suggested in studies of longer duration that the HDL-C lowering effect of tibolone is only transient (27, 28). However, from our data, the increase with time seems to be small. The reduction in total cholesterol and ApoA1 (24, 25, 26, 27, 28, 29) and the lack of effect on LDL-C (26, 27) are all largely in agreement with earlier findings. In a cross-sectional study, ApoB was found to increase during tibolone treatment (30), however our longitudinal data on ApoB, which were consistent with the course of LDL-C, do not confirm this finding. Lp(a) has previously been found to be lowered by tibolone in small cross-sectional, short-term, and uncontrolled studies (30, 31, 32). In fact, we found a slight decrease in Lp(a) in all groups including the placebo group over time. With a lack of adequate control, this finding could have been misinterpreted as drug related.

The fibrinolysis and coagulation analyses revealed a marked and similar decrease in PAI activity and t-PA of the two dose levels. Previously in an unblinded study, tibolone was found to lower t-PA and PAI-1 as compared with baseline and to a combined HRT regimen, whereas coagulation parameters were unaffected (33). In two placebo-controlled, 12-week studies, tibolone increased plasminogen and lowered fibrinogen but an increase in antithrombin III was also seen (34, 35). In a cross-sectional study after 5–6 yr of treatment, tibolone was found to increase antithrombin III as compared with placebo (36). Generally, our data on fibrinolysis and coagulation support these results from studies in early postmenopausal women, although the increase in antithrombin III (34, 35, 36) were not supported by our data.

With our current knowledge, the changes in HDL-C and ApoA1 in the present study may be unfavorable in terms of cardiovascular disease, but the clinical significance of pharmacologically reduced HDL-C circulating levels and its possible association with increased risk of cardiovascular disease remains to be fully clarified. The role of serum triglycerides as a risk factor of cardiovascular disease is still unclear (37). It has been suggested that elevated levels of serum triglyceride predicts cardiovascular disease in postmenopausal women but not in men (38). Because conventional HRT has been reported to be neutral or to slightly elevate serum triglycerides (especially conjugated equine estrogens) (39, 40), the lowering effect of tibolone on triglycerides could theoretically be an advantage as compared with conventional HRT.

The lowering effect on fibrinogen and t-PA seems to be favorable because these markers have been found to independently predict the risk of ischemic events (4, 41, 42), but intervention studies have not been conducted yet. The same implications concerns the lowering effect on PAI activity and PAI-1. The strong correlation between t-PA and PAI-1 has been described previously and may show that these factors are circulating as inactive complexes (4). Thus, elevated values of t-PA and PAI-1 in plasma seem to reflect decreased rather than enhanced fibrinolysis. The mixed hormonal properties of tibolone suggest a mechanism of action resembling the mechanisms of estrogens, progestogens, androgens, or a combination of these. These effects are complex even within hormone groups. However, the tendency towards increased fibrinolysis of tibolone found in our data may at least partly be attributed to the androgenic effect.

In conclusion, the present dose levels of tibolone seem to be disadvantageous on HDL-C and ApoA1 but potentially beneficial on triglycerides. The effects of tibolone on markers of hemostasis might be beneficial and may theoretically counterbalance the potentially adverse influence on HDL-C. Our results suggest that even lower tibolone doses might be advantageous, but the clinical significance of these pharmacologically induced changes on athero- and thrombogenesis are still not clear, and further studies are needed to evaluate the effects of tibolone in this respect.


   Acknowledgments
 
We thank nurse Lone Petersen for assisting in data collection.

Received November 20, 1996.

Revised February 7, 1997.

Accepted February 14, 1997.


   References
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 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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J. C. Gallagher, D. J. Baylink, R. Freeman, and M. McClung
Prevention of Bone Loss with Tibolone in Postmenopausal Women: Results of Two Randomized, Double-Blind, Placebo-Controlled, Dose-Finding Studies
J. Clin. Endocrinol. Metab., October 1, 2001; 86(10): 4717 - 4726.
[Abstract] [Full Text] [PDF]

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S. Palacios
Tibolone: a tissue-specific approach to the menopause
Eur. Heart J. Suppl., October 1, 2001; 3(suppl_M): M12 - M16.
[Abstract] [PDF]

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G. Jackson
Tibolone and the cardiovascular system
Eur. Heart J. Suppl., October 1, 2001; 3(suppl_M): M17 - M21.
[Abstract] [PDF]

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