1 INSERM Research Unit 403 and Synarc, Lyon, 2 Gynecology Department Bichat Hospital, Paris, 3 INSERM ERIT-M0101, Porte-Madeleine Hospital, Orléans, 4 Hotel Dieu Hospital, Paris and 5 Rheumatology Department, Cochin Hospital René-Descartes University, Paris, France
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Abstract |
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Key words: cardiovascular disease/C-reactive protein/estradiol/inflammation/tibolone
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Introduction |
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Tibolone is a synthetic tissue-specific steroid [(7, 17
)-17-hydroxy-7-methyl-19-norpregn-5(10)-en-20-yn-3-one: Org OD 14, Livial; Organon, Oss, The Netherlands] with estrogenic, androgenic, and progestogenic properties depending of the tissue. Tibolone has been shown to be effective in relieving climacteric symptoms (Punnonen et al., 1984
; Crona et al., 1988
) and to prevent post-menopausal bone loss (Rymer et al., 1994
; Bjarnason et al., 1996
). In addition this compound has effects on some cardiovascular risk factors including lipoprotein (a), triglycerides, cholesterol fractions, and leukocytes adhesion molecule expression in endothelial cells (Milner et al., 1996
; Cagnacci et al., 1997
; Doren et al., 2000
; Mendoza et al., 2000
; Simoncini and Genazzani, 2000
). However, the effects of tibolone on serum CRP have not yet been investigated.
The aim of this study was to compare the effects of a 2 year treatment with tibolone or a combined E2 and norethisterone acetate (NETA) on serum CRP in a randomized study of healthy post-menopausal women.
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Materials and methods |
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Participants were randomized (block size 6) to one of the three treatment groups, masked for treatment by means of the double-dummy method: (i) tibolone 1.25 mg/day, (ii) tibolone 2.5 mg/day and (iii) E2 2 mg/day plus NETA 1 mg/day (E2 + NETA; Novo Nordisk A/S, Bagsvaerd, Denmark) at bedtime. At the same time, each subject took one tablet of calcium 500 mg supplement daily with a meal. The subjects adherence to study therapy was assessed by counting tablets. Duration of follow-up was 2 years. Among the 163 women who completed the 2 year study, we considered patients followed in a single centre; serum samples were available at each time point in the 139 patients included in the present study.
Serum CRP measurements
Fasting morning blood samples were obtained in all subjects at all time points: all serum samples were kept frozen at 70°C until assayed. Serum C-reactive protein (CRP) was assayed using an ultrasensitive clinically validated immunonephelometry method (Roberts et al., 2001) on a BNA Behring nephelometer (N Latex CRP mono; Behringwerke AG, Marburg, Germany). The intra- and inter-assay variations were <5% and the detection limit was 0.2 mg/l. To reduce inter-assay variability, all samples for each individual patient were analysed in the same assay run and a single lot of reagent was used for all measurements.
Statistical analysis
Between-group differences in baseline age, weight, height and BMI were assessed by analysis of variance. As the distribution of serum CRP levels and their changes from baseline were skewed, serum CRP results were shown as the median and the interquartile range. Changes of serum CRP from baseline in each group and at each time point were assessed by the non-parametric Wilcoxon test. Comparison of percentage changes of serum CRP between groups was assessed by non-parametric MannWhitney or KruskalWallis tests. Correlation between serum CRP, age, weight or BMI was assessed by the non-parametric Spearman test.
Because CRP is an acute phase reactant protein, its level is highly sensitive to presence of acute infections and other inflammatory conditions. Therefore, in addition to the analysis on the whole population, we also performed a subsequent analysis after excluding subjects who reported infections requiring antibiotic therapy or surgery and also women with baseline levels of CRP >10 mg/l, which is considered as the threshold level for the existence of marked acute inflammatory condition (Macy et al., 1997).
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Results |
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Discussion |
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Several studies have reported that HRT in the form of unopposed oral E2, conjugated equine estrogens or combined estrogen and progestin therapy increases serum CRP in post-menopausal women (Cushman et al., 1999a,b
; Ridker et al., 1999
; van Baal et al., 1999a
; Walsh et al., 2000
). It has been shown that micronized progesterone and trimegestone do not influence the magnitude of CRP changes during HRT (Cushman et al., 1999a
; van Baal et al., 1999b
), suggesting that the effect of HRT on this inflammation marker is mainly mediated through activation of the estradiol receptor and is not altered by progestins. The effect of the addition of medroxyprogesterone acetate is still under discussion: in some studies it is without influence, in others it decreases the elevation induced by estrogens (Wakatsuki et al., 2002
). It is not excluded that some progestins could have an effect per se. In this study we found for the first time that the combination of oral E2 at a dose of 2 mg and NETAa 19-nortestosterone-derived progestogen which, in contrast to other progestins, has an effect on bone turnover (Christiansen et al., 1985
)increased serum CRP levels with a magnitude similar to that previously reported for other HRT regimens.
Tibolone is a steroid with estrogen, progestin and androgen activities depending on the tissue (tissue specific steroid). Like the selective estrogen receptor modulator raloxifene, it demonstrates estrogenic activity on bone (Ederveen and Kloosterboer, 2001), but no stimulating effects on the endometrium and the breast (Punnonen et al., 1984
). On the liver, tibolone has a mild androgenic effect as shown by the decrease of high-density-lipoprotein cholesterol, triglycerides and mainly testosterone estradiol-binding globulin. There is no available marker which can assess the liver estrogenic effect of tibolone. The tibolone-induced increase of serum CRP was of similar magnitude to the one observed in this study with the combined E2 + NETA regimen and with the results previously reported for unopposed or combined 2 mg E2 or 0.625 mg conjugated equine estrogens (Cushman et al., 1999a
; Ridker et al., 1999
; van Baal et al., 1999b
; Walsh et al., 2000
). Tibolone at the two doses induced a similar increase of serum CRP suggesting that the 1.25 mg dose is already large enough to fully express the effect of tibolone on that biochemical parameter.
The mechanisms by which HRT and tibolone increase serum CRP in post-menopausal women are unclear. CRP is produced by the liver and the main regulators of its synthesis are inflammatory cytokines such as interleukin (IL)-6, tumour necrosis factor- and IL-1ß (de Maat et al., 1996
). Thus, one could speculate that administration of estrogens and androgens increases the activity of inflammatory cytokines (Pfeilschifter et al., 2002
). A small study (van Baal et al., 1999b
) of post-menopausal women did not find any significant effect of unopposed or combined E2 on serum IL-6 and fibrinogen levels, the latter being like CRP synthesized by the liver under the control of pro-inflammatory cytokines. However, because in that study only IL-6 was investigated and because serum levels of cytokines may not represent a sensitive index of overall cytokine activity, we cannot exclude that HRT has some pro-inflammatory effects. In accordance with this latter hypothesis, it was reported that HRT increases both IL-6 and CRP in post-menopausal women with coronary artery disease (Zanger et al., 2000
). In a controlled study of 160 post-menopausal women aged 50 years on average, it has been shown that treatment with E2 2 mg and NETA 1 mg leads to a small but significant increase in IL-6, and IL-1 receptor antagonist, but not IL-1 (Abrahamsen et al., 2000
). This contrasts with reductions of IL-6 production by estrogens in vitro, and one could speculate on the effect of the androgenic/progestogen component of the treatment on this slight increase in pro-inflammatory cytokines, although it has been suggested that androgens and progestogens may have some anti-inflammatory effects (Sitteri et al., 1997; Parkar et al., 1998
; Pfeilschifter et al., 2002
). Alternatively, because of the first pass effects of orally administered estrogens, it may be possible that estrogens increase serum CRP by a direct action on gene regulation. In this context, it is of interest to note that transdermal E2which avoids the first pass hepatic effectdoes not lead to an increase of serum CRP (Sattar et al., 1999
; Giltay et al., 2000
; Lowe et al., 2001
; Vehkavaara et al., 2001
). Actually it has been reported that in healthy post-menopausal women oral and non-oral E2 have different effects on serum insulin-like growth factor I, which, like CRP, is mainly synthesized by the liver (Weissberger et al., 1991
; Garnero et al., 1999
). It should be mentioned, however, that the administration of a small dose (1 mg) of oral E2 may have no effect on CRP level (van Baal et al., 1999a
). There are very few studies on the effect of androgen administration on CRP level. Parenteral administration of testosterone increases CRP levels in transexual women by 141% (Giltay et al., 2000
). In animal models, Achatina fulica (Bose and Battacharya, 2000
) and a mouse transgenic of the human CRP (Szalai et al., 1998
), it has been shown that the synthesis of CRP is under androgen influence. Therefore it may be possible that the effect of tibolone on serum CRP is due to a hepatic androgenic effect and additional studies are required to explore this hypothesis.
The clinical implications of elevated CRP with tibolone and more broadly estrogens remain uncertain. Spontaneous increased CRP levels, even within the normal range, are associated with increased risk of cardiovascular events in apparently healthy women (Ridker et al., 1997). In addition, HRT is associated with an increased risk of cardiovascular events in women with coronary heart disease (Hulley et al., 1998
). However, the consequences of pharmacological increase of CRP may be different than those of a spontaneously high level of CRP. Statinswhich are effective in reducing the risk of stroke (Byington et al., 2001
)reduce serum CRP levels in healthy subjects and in patients with cardiovascular diseases (Albert et al., 2001
). Furthermore, statins attenuate CRP increase during estrogen replacement therapy in post-menopausal women (Koh et al., 2002
). Thus, it could be inferred that increased CRP with HRT and tibolone may lead to an increased risk of cardiovascular events. However, HRT and tibolone may have different effects on the vascular inflammatory response which has also been suggested to be associated with increased risk of cardiovascular diseases. In-vitro systems using human endothelial cells from umbilical vein have shown conflicting results. It has been shown that E2 transiently increases TNF-induced expression of E-selectin, vascular cell adhesion molecule type 1 (VCAM-1) and intercellular adhesion molecule type I (ICAM-1) (Cid et al., 1994
; Aziz and Wakefiled, 1996; Zhang et al., 2002
). In the same model, however, E2 has been reported to decrease IL-1 (Caulin-Glaser et al., 1996
)- or lipopolysaccharide (Simoncini et al., 1999
)-mediated induction of E-selectin and VCAM-1, with a similar effect for tibolone in this latter situation (Simoncini and Genazzani, 2000
). Randomized clinical studies have however found that E2, combined E2 + progestin and conjugated equine estrogens consistently decreasedslightly but significantlythe serum levels of E-selectin, VCAM-1 and ICAM-1 in both healthy post-menopausal women (Koh et al., 1997
, 1999
; Guzic-Salobir et al., 2001
; Wakatsuki et al., 2002
) and in women with coronary artery disease (Sbarouni et al., 2000
; Zanger et al., 2000
). In addition, no study has assessed the impact of tibolone on serum CRP in patients with coronary heart disease, nor directly the relationships between tibolone treatment and the risk of coronary heart disease. The treatment of post-menopausal monkeys with tibolone does not lead to an increase in coronary atherosclerosis, despite a strong decrease in high-density lipoproteins (Clarkson et al., 2001
). Finally, it is of interest to note that in our study we found sustained increased serum CRP levels with combined E2 + NETA and tibolone over 2 years, whereas in the HERS study cardiovascular events peaked during the first year of HRT and then decreased (Hulley et al., 1998
), although a time-dependent decrease was not observed for the risk of deep venous thrombosis (Grady et al., 2000
). Together these data suggest that the increase of CRP levels with estrogen and tibolone does not demonstrate that CRP elevation per se will necessarily lead to increased risk of cardiovascular disease.
Our study has some limitations. The study did not include a placebo group and one may speculate on the significance of the serum CRP changes with tibolone and combined E2 + NETA. However, all serum CRP measurements for each individual were performed in a single assay run and previous studies performed in similar populations of healthy post-menopausal women did not show any significant changes of serum CRP over periods of 312 months when treated with placebo (van Baal et al., 1999a; Walsh et al., 2000
). We did not measure other parameters reflecting vascular inflammatory response such as E-selectin, VCAM-1 and ICAM-1 which may react differently than CRP to HRT (Zanger et al., 2000
). In conclusion, in this randomized study in healthy post-menopausal women, we found that tibolone and combined E2 + NETA increased serum CRP levels to a comparable extent. Additional studies are required to investigate the mechanisms by which these treatments increase serum CRP. More importantly, trials are needed to test directly whether increased serum CRP with HRT and tibolone would influence the risk of cardiovascular events in post-menopausal women with or without coronary heart disease.
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Notes |
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References |
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Submitted on February 26, 2002; accepted on June 13, 2002.