Cardiovascular Health and Disease
There is biologic plausibility supporting the role of endogenous estrogen and the maintenance of premenopausal cardiovascular health. This is mediated through the expression of ERalpha and ERbeta in different vascular beds, including the vascular endothelium and smooth muscle cells. This is especially true for ERalpha, although ERbeta is present in myocardial cells where it regulates the expression of nitric oxide synthases. Of significance is the reduction of ERalpha in women with atherosclerotic coronary arteries. This may be relevant to the discordant positive CVD benefit of ET in surgically menopausal and recently menopausal women and the potential harm of HT in older postmenopausal women. The same may be true for the use of tibolone in older women.
The presence and control of modified risk factors for CVD are distinct from factors that influence the stability of plaque formation in established atherosclerotic disease. Early risk factors include abnormalities in lipid-lipoprotein metabolism, insulin resistance, disorders of hemostasis, and increasing blood pressure. These menopausal/age-related changes must be clearly differentiated from diseases that require specific therapy, such as diabetes, dyslipidemia, and hypertension. Tibolone improves insulin sensitivity in women with insulin resistance; does not have an adverse effect on blood pressure including women with hypertension; has a minimal effect on various hemostatic factors with a trend toward increased fibrinolysis; and lowers plasma levels of total cholesterol, LDL-cholesterol and LDL-cell size, triglycerides, and lipoprotein Lp(a).[87,90] Tibolone does, however, reduce circulating levels of HDL-cholesterol, a putative cardioprotective lipoprotein.
Epidemiologic studies demonstrate a clear and inverse correlation between HDL-cholesterol levels and the risk of CVD. HDL-cholesterol is a complex moiety with numerous subfractions and dependence on enzymes, receptors, and transfer proteins that will either retard or enhance the major function of HDL: to remove excess cholesterol from peripheral tissues for uptake and metabolism by the liver and excretion as bile acids (Figure 3). The reason for low HDL-cholesterol plasma levels is key to its association with enhanced risk for atherosclerosis: this relationship is true for low HDL-cholesterol secondary to its reduced synthesis; a reduction in HDL-C following enhanced clearance does not appear to increase atherosclerosis.[92,93]
The HDL lipoprotein-mediated reverse cholesterol transport mechanism is complex. In brief, there are 5 clearly defined steps in the process (Figure 3): (1) Apolipoprotein A-1 is synthesized in the liver after interacting with binding transporter (ABCA1) to form lipid poor apolipoprotein A-1; (2) The latter combines with ABCA-1 in peripheral tissues (eg, vascular endothelium) and removes cholesterol by forming nascent pre-beta HDL; (3) Nascent pre-beta is converted to mature alpha HDL by the enzyme LCAT. HDL-cholesterol is now returned to the liver via 2 pathways: by binding to the hepatic scavenger receptor class B type 1 (4); and/or by the cholesterol transfer protein CETP to VLDL and via lipoprotein lipase metabolism to LDL-cholesterol and subsequent uptake by the liver through the hepatic LDL receptor (5); HDL also decreases atherosclerosis by protecting LDL from oxidation and its attachment to scavenger receptor SR-A and foam cell formation (6).
Studies in monkeys and in women using skin fibroblasts and Fu5AH cells have shown that tibolone maintains cholesterol efflux in doses equivalent to 1.25 mg to 2.5 mg of tibolone daily.
Despite a mean reduction of 30% in the HDL-cholesterol of monkeys treated with the equivalent of 1.25 mg daily tibolone, there was no increase in coronary atherosclerosis of the sacrificed animals. The Fu5AH cells serve as a model of cholesterol diffusion mediated by the scavenger receptor-B1 [Figure 3; (4)]; the skin fibroblasts represent a lipid-free-A1-mediated mechanism [Figure 3; (1)]. A recent study using plasma from postmenopausal women taking tibolone showed a 22%-32% decrease in HDL-cholesterol but no change in the cholesterol efflux from skin fibroblasts and from Fu5AH cells. In the latter study, tibolone did increase hepatic lipase activity by 25%. Since other HDL-converting plasma enzymes and transfer proteins (eg, LCAT and CETP [Figure 3; (3)] were not affected, the lowering of HDL may be partly accounted for by reduced hepatic synthesis of HDL precursors. In summary, these researchers concluded that conservation of CETP activity [Figure 3; (5)] is an important contributor to stable cholesterol efflux from fibroblasts into the plasma of tibolone-treated women. Tibolone does not reduce the activity of the antioxidant enzyme paraoxonase/arylesterase [Figure 3; (6)].
Clinical implications: The conclusions of the reverse cholesterol transport studies from human[92,96] and monkey[93,95] plasma following exposure to similar doses of tibolone were the same. Given the absence of an increase in the degree of atherosclerosis in the monkeys, it is biologically plausible to assume that a 20%-30% decrease in plasma HDL-cholesterol in women after tibolone therapy -- although statistically significant -- is unlikely to increase the risk of atherosclerosis. This is consistent with the long-term follow-up (7.5 years) of women treated with tibolone who had no increase in carotid artery intima-media thickness or number of atherosclerosis plaques. The lowering of plasma HDL-cholesterol in response to tibolone therapy may, however, depend on the subject's initial HDL-cholesterol value.
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Cite this: Postmenopausal Tibolone Therapy: Biologic Principles and Applied Clinical Practice - Medscape - Jan 03, 2007.