Does tibolone exacerbate atherosclerosis?

Tibolone is widely used in many countries (though not in the USA) for the treatment of post-menopausal symptoms and to inhibit post-menopausal bone loss. Tibolone’s popularity likely reflects the observation that it equals traditional hormone therapy in the relief of hot flushes, vaginal dryness, and the prevention of bone loss and, in addition, appears to increase libido. The post-menopausal benefits of tibolone relate to the uniqueness of the metabolism of the parent molecule. In human and non-human primates, tibolone is converted to three metabolites. Two are weak estrogen agonists (the 3-alpha and 3-beta hydroxy metabolites). The third metabolite, the delta-4 isomer, is a molecule that binds both to the progesterone receptor and to the androgen receptor with progestogenic and androgenic effects. Although tibolone has numerous benefits for postmenopausal women, it markedly lowers plasma concentrations of the HDL with consistent reductions of HDL cholesterol (HDLC) and ApoA1. The magnitude of the reductions is generally 20–30%. Because there is a strong inverse relationship between both HDLC and ApoA1 and the occurrence of coronary heart disease (CHD) among women not taking hormones, there has been concern that tibolone-induced reductions in HDLC and ApoA1 might increase risk for CHD. However, recent studies have shown in women and monkeys that hormone-therapy-induced alterations in HDLC or ApoA1 do not easily translate into changes in CHD risk. For example, in such studies, only 25–30% of the ability of estrogens to inhibit progression of atherosclerosis relates to changes in plasma lipids/lipoproteins; whereas 70–75% relates to their direct effects on arteries. Those estimates, which are based on estradiol and conjugated equine estrogens (CEEs), may not extend to weaker estrogens, such as the 3-alpha and 3-beta hydroxyl metabolites of tibolone. It has thus been uncertain whether tibolone’s adverse HDLC effects should be expected to accelerate atherosclerosis and thereby increase CHD risk. Bots et al. report the effect of tibolone on the progression of carotid artery atherosclerosis, using carotid artery intima–media thickness as the indicator of progression or regression. The comparator group in that trial was CEE plus medroxyprogesterone acetate (MPA), both given continuously. Unfortunately, because of unexplained inconsistencies in the trial outcomes, there remains uncertainty about whether and to what extent tibolone affects atherosclerosis in post-menopausal women. Before commenting on OPAL, it is helpful to consider the comparative and experimental evidence that tibolone is neutral in its effects on atherosclerosis and weigh that evidence in light of the OPAL trial outcomes. That estrogen administration results in a ‘disconnect’ in the usual relationship between plasma lipid/lipoprotein concentrations and atherosclerosis progression was first shown in pre-menopausal monkeys treated with an oral contraceptive containing ethinyl estradiol and a progestin. This hormonal exposure, which markedly reduced HDLC, should have exacerbated atherogenesis but instead reduced lesion extent by 88%. It appeared that the estrogen benefits to arterial metabolism offset the deleterious effects of the reduced HDLC. Additional evidence for a ‘disconnect’ between the plasma lipid concentrations and the progression of coronary artery atherosclerosis came from a study of surgically post-menopausal monkeys that were administered estradiol by way of a silastic implant. Estradiol resulted in a 50% reduction in coronary artery atherosclerosis extent without any significant changes in the plasma lipid/lipoprotein profiles. Recently, studies of women have confirmed our findings in the monkey. The well-known Estrogen in the Prevention of Atherosclerosis Trial (EPAT) found that only 30% of the beneficial effect of estradiol on carotid artery intima–media thickness progression was due to alterations in HDLC and LDLC. Studies of surgically post-menopausal cynomolgus monkeys have added to understanding of the effects of tibolone-induced perturbations of plasma lipoproteins on the progression of coronary artery atherosclerosis. Although female monkeys are not women, they closely resemble women in reproductive characteristics and vulnerability to chronic disease. Moreover, using the monkey model, it is possible to obtain direct pathological measurements of extent of coronary artery atherosclerosis. In