Cardiovascular Effects of Tibolone: A Selective Tissue Estrogenic Activity Regulator

Traditionally, it was accepted that long‐term hormone replacement therapy (HRT) has a cardiovascular beneficial effect in postmenopausal women with and without coronary artery disease (CAD). However, randomized trials in postmenopausal women have not shown any benefit in either primary or secondary prevention of cardiovascular events. Therefore, these findings have raised the question of whether traditional HRT (i.e., estrogen and progesterone) has a cardioprotective effect in women at risk for or with established CAD. Concerns about the use of conventional HRT have led to a search for alternatives. Tibolone is a synthetic compound with estrogenic, androgenic, and progestogenic properties that relieves climacteric symptoms and prevents postmenopausal bone loss. Tibolone possesses a tissue‐selective mechanism of action that differs from that of estrogen and/or progestogen. Unlike these compounds, tibolone's metabolites play a central role in its mode of action. Tibolone is widely used for HRT. However, its clinical impact on cardiovascular disease is still under study. The current review focuses on the effects of tibolone on the cardiovascular system and discusses clinical investigations with this compound in postmenopausal women.     

性激素,激素替代疗法与心血管疾病

绝经前女性的心血管疾病(CVD)风险及其发生率与同龄男性相比均较低,女性的这种性别优势却在绝经后逐渐消失,这表明,性激素,尤其是雌激素,在女性中具有心血管保护的作用。观察性研究显示女性绝经后接受激素替代疗法(HRT)可降低CVD的发病率。但是,随机前瞻性一级或二级预防试验未能证实HRT对心脏有积极影响。女性健康计划(WHI)与心脏及雌/孕激素替代研究(HERSⅠ和Ⅱ)表明,HRT使绝经后女性的CVD风险及患病率增高。HRT有利有弊的这种矛盾特性的原因尚不明确。该文重点讨论了造成这种相悖结果的可能原因,并尽可能揭示为何年青或绝经前女性CVD发病率偏低,绝经后女性并不受益于HRT。此外,在判断HRT效果时,应考虑到剂量、疗程、雌激素的类型及给药途径等因素。总之,基于年青或绝经前女性CVD发病率低,而HRT对绝经后女性并无心血管保护作用的事实,HRT已成为在女性健康方面最具有争议性的课题之一。因此,还需要进一步的研究以阐明为何HRT结果会不一致,并为提高女性生活质量提供新的治疗策略。     

Postmenopausal hypertension

Cardiovascular disease is the leading cause of death in women and claims the lives of more than half a million women every year. Hypertension is one of the most prevalent and powerful contributors to atherosclerotic cardiovascular disease. Hypertension affects more men than women until 55 years of age, but after age 55, the percentage of women is higher. Estrogen deficiency has been linked to the rapid increase in cardiovascular disease in women who have undergone natural or surgical menopause. Hormone replacement therapy (HRT) has been shown to decrease the incidence of cardiovascular disease and, in some studies, to reduce blood pressure in postmenopausal women. However, little information is available on the effects of HRT on blood pressure in hypertensive postmenopausal patients. The cardioprotective effects of estrogens are not completely understood but may involve direct effects on blood vessels through modulation of endogenous vasoconstrictors and vasodilators and through reductions in serum lipoprotein and cholesterol levels. Experimental evidence suggests that estrogen increases the biological actions of nitric oxide and decreases the actions of angiotensin. After menopause, loss of the vascular protective effects of estrogens may unmask a population of women particularly prone to hypertension who would be at higher risk for cardiovascular disease.     

Hormone replacement therapy and coronary heart disease in women: a review of the evidence

It is well documented that coronary heart disease (CHD) is the leading cause of death in women-especially postmenopausal women. The role of hormone replacement therapy (HRT) in prevention of CHD has been considered for many years. Early epidemiological studies suggested estrogen to have a potential cardioprotective role, noting that premenopausal women have a decreased risk of developing CHD compared with men. Later observational studies showed decrease of CHD risk in postmenopausal women on HRT. By 1996, estrogen (specifically Premarin) was one of the most dispensed medications in the United States. Major medical organizations such as the American College of Physicians and American College of Obstetricians and Gynecologists widely endorsed and encouraged HRT for CHD risk reduction, along with using HRT for other potential benefits (such as osteoporosis prevention). Unfortunately, recent clinical trials seem to raise more questions than provide definitive proof in the protective role of estrogen in CHD. A review of recent and ongoing observational studies and clinical trials may help guide physicians in their recommendation and discussion of the role of HRT in postmenopausal women. As this article was being prepared for publication, reports from both the Heart and Estrogen/Progestin Replacement Study Follow-up (HERS II) and the Women's Health Initiative (WHI) were published. Both studies concluded that HRT has no role in primary or secondary prevention of CHD in women.     

The effect of hormone replacement therapy on arterial blood pressure and vascular compliance in postmenopausal women with arterial hypertension

Arterial pathology is a major contributor to cardiovascular disease, morbidity and mortality. Women are at higher risk of cardiovascular disease after menopause. Arterial stiffness determined by pulse wave velocity, increases with age both in men and women, whereas arterial compliance in premenopausal women is greater than in men of similar age. This difference is lost in the postmenopausal years, with evidence of rapid decline in arterial compliance in the perimenopausal period. Loss of hormonal modulation is a likely explanation for reduced arterial compliance in postmenopausal women. Long-term treatment with hormone replacement therapy (HRT) may be expected to partially reverse the increase in arterial stiffness. The aim of the study was to analyse the effect of HRT on blood pressure and arterial compliance in postmenopausal women with arterial hypertension receiving hypotensive drugs. The results in the present study of postmenopausal women with mild to moderate arterial hypertension receiving HRT showed only a transient tendency towards lower blood pressure. In our study HRT was found to improve arterial compliance at 3 months after HRT, and the effect was maintained throughout 12 months. The increased arterial compliance in women receiving HRT was independent of blood pressure. In parallel with decreasing pulse wave velocity women receiving HRT had lower total and low-density lipoprotein cholesterol. The conclusions were that after 1 year HRT in postmenopausal women with arterial hypertension improves circadian blood pressure pattern, but it does not affect significantly blood pressure values and variability. The present study also shows that HRT significantly inhibits age-related rigidity of large arteries.     

Insulin resistance and lipids in hypertensive women on hormone replacement therapy

Hypertension, hyperinsulinaemia and dyslipidaemia are strong and independent risk factors for cardiovascular diseases. Their increasing frequency in postmenopausal women suggests that oestrogen deficiency may be a contributing factor. It is well known that oestrogen replacement therapy in postmenopausal women improves carbohydrate and lipid metabolism, but the effect of combined hormone replacement therapy (HRT) remains unclear. The purpose of the present study was to evaluate the effect of HRT on blood pressure, carbohydrate metabolism and lipid profile in postmenopausal women with primary arterial hypertension. The study population consisted of 76 postmenopausal women (mean age 51.1 ±6.8 years). Forty hypertensive women received HRT (17- β-oestradiol, norethisterone acetate, TTS, Estracomb Novartis), whereas 36 women remained without hormonal therapy. One-year combined transdermal HRT did not affect significantly blood pressure and blood pressure variability. HRT was shown to improve lipid profile with a significant decrease in total cholesterol as early as at 3 months. It does not influence carbohydrate metabolism parameters studied by glycaemia and insulinaemia in a standard oral glucose tolerance test. In conclusion, combined percutaneous HRT may reduce the lipid-depended cardiovascular risk in postmenopausal women with arterial hypertension.     

Insulin resistance and postmenopausal hormone replacement therapy

Insulin resistance causes hyperglycemia by disturbing glucose uptake in the tissues and increasing hepatic glucose production. Hyperinsulinemia has a predictive role in the generation of type 2 diabetes in nondiabetic individuals. Both insulin resistance and the associated disturbances are responsible for increased cardiovascular risk. Women of reproductive age are protected from cardiovascular disease although in the postmenopausal period the risk becomes equal to that in men and exceeds that in men later on. This observation leads us to consider the role of estrogen deficiency in the pathogenesis of cardiovascular disease. Hormone replacement therapy (HRT) is a successful method in the management of certain clinical situations in postmenopausal women. The interactions among estrogen, menopause, and cardiovascular risk bring forth the question of whether the HRT affects insulin resistance or not. The studies so far have yielded controversial results. The overall results of recent reports indicate that postmenopausal HRT improves insulin resistance. However, the available evidence is not strong enough to suggest the use of postmenopausal HRT as a first-line therapeutic measure in the management of insulin resistance.     

Hormone replacement therapy trials: An update

Recent randomized trials of hormone replacement therapy (HRT) in postmenopausal women are not consistent with the decrease in cardiovascular risk seen in observational studies of hormone therapy users compared with nonusers. Emerging evidence indicates that HRT use in some women with established coronary heart disease may be associated with prothrombotic effects or proinflammatory effects leading to adverse events. In healthy women, the decision to use HRT should be based primarily on non-cardiac factors until more data becomes available that is relevant to this population. Several alternatives to HRT, including phytoestrogens and selective estrogen receptor modulators, have favorable effects on cardiovascular risk factors, but their impact on clinical outcomes remains to be determined.     

Increased plasma concentrations of TGF-beta1 after hormone replacement therapy

OBJECTIVES AND DESIGN: Hormone replacement therapy (HRT) in postmenopausal women may reduce the cardiovascular risk. A dominant protective role of transforming growth factor beta (TGF-beta1) on coronary arteries has been proposed. Lp(a) lipoprotein may block the activation of latent TGF-beta1. Given this background, we examined the effects of HRT on TGF-beta1 and Lp(a) lipoprotein in 99 postmenopausal women. The women had angiographically documented coronary heart disease (CHD) and were randomized to either sequential transdermal 17beta-oestradiol for 14 weeks and then medroxyprogesterone (MPA) for 14 days (HRT) or to a control group (C). RESULTS: Serum levels of TGF-beta1 were increased in the HRT group compared with the C group after 3 months' treatment and this effect was sustained after 12 months. There was a significant reduction in Lp(a) lipoprotein serum levels after 3 months' treatment in the HRT group compared with the C group. However, after 12 months, no significant difference in changes in Lp(a) lipoprotein serum levels was detected between the two groups. CONCLUSION: The novel observation that transdermal 17beta-oestradiol in postmenopausal women increases levels of TGF-beta1 and lowers the concentration of Lp(a) lipoprotein suggests yet another possible mechanism for the cardioprotective effect of HRT. Whereas combination therapy of oestradiol and MPA preserves the beneficial effect on TGF-beta1, it reduces the unopposed oestradiol effects on Lp(a) lipoprotein.     

Postmenopausal Hormone Therapy: Does It Have a Role in Cardiovascular Prevention Today?

Cardiovascular disease is the leading cause of mortality in women. Results from observational studies consistently demonstrated lower heart disease rates among women who used hormone replacement therapy (HRT) compared to non-users. Data from two large randomized controlled trials showed mixed results. Subsequent post-hoc analysis found cardiovascular disease among HRT users to be lower than non-users in women 50 to 59 years of age or less than 10 years post-menopause. This has sparked much debate on the role of postmenopausal hormone therapy, especially in peri-menopausal women. Two hypotheses have been suggested to explain this divergent data: 1) HRT may be cardioprotective when introduced prior to atherosclerosis development but may be harmful in women with established CVD; or 2) HRT may be useful when started closer to menopause initiation and harmful when started later in life.     

Postmenopausal hormone replacement therapy and the vascular wall: epidemiology and clinical studies

The clinical relevance of estrogen's multiple acute and more delayed effects on vascular wall structure and function is incompletely understood. This review attempts to reevaluate epidemiological findings and clinical studies concerning the vascular actions of estrogens and gives implications for strategies in postmenopausal hormone replacement therapy (HRT). There is large evidence from observational studies that HRT reduces the risk of cardiovascular mortality and morbidity in postmenopausal women. However, according to the only large randomized, placebo-controlled, secondary prevention Heart and Estrogen/progestin Replacement Study (HERS), women with prevalent cardiovascular disease (CVD) have increased CVD events within the first year after onset of HRT. The net effects of HRT on atherosclerosis, coagulation, fibrinolysis or the inflammatory response are unproven. Randomized trials of intermediate outcomes reveal that HRT has favorable effects on isolated cardiovascular risk factors, e.g. lipoproteins, carbohydrate metabolism and vasodilatation, but the impact of this effects on clinical endpoints is still not clear. The basis of "evidenced based medicine" is currently not sufficient to provide exact recommendation who will benefit from HRT and who might not. Therefore, the decision about hormone use should consider individual benefit-risk profiles.     

Hormone Replacement Therapy and Obstructive Airway Diseases

Controversy exists as to the role of female reproductive hormones in asthma and COPD and, specifically, the effect of hormone replacement therapy (HRT) on these disorders. The differential incidence of asthma over the menstrual life cycle suggests an effect of female reproductive hormones on asthma; less data are available for COPD. Estrogen and progesterone have protean effects at the cellular level, consistent with potentially harmful and beneficial effects in lung disease. Large epidemiologic studies show an increased risk of development of asthma with the use of HRT but no consistent effects on COPD. Clinical and epidemiologic studies of exacerbations are limited, but suggest either a harmful effect or no effect of HRT on exacerbations of asthma and COPD. HRT appears to increase the risk of development of asthma but is not associated with the loss of lung function characteristic of COPD. Because the development of asthma is rare in postmenopausal women, the absolute increase in risk among women without asthma is modest. Physicians may wish to avoid HRT therapy in patients with difficult to control asthma and COPD. Clinical decisions to start or continue HRT among women without asthma or COPD should be based on the effects of HRT on more common diseases such as cardiovascular disease, breast cancer and osteoporosis, non-vertebral fractures and colon cancer.     

Fibrinolysis and lipoprotein(a) in women with coronary artery disease. Influence of hormone replacement therapy

BACKGROUND AND OBJECTIVES: The incidence of coronary artery disease (CAD) is higher in post-menopausal than in pre-menopausal women. Epidemiological studies suggest that hormone replacement therapy (HRT) decreases the risk of cardiovascular disease in post-menopausal women. HRT could modify the cardiovascular risk via several mechanisms, including modifications in the fibrinolytic system and lipoprotein (a) levels. Our study was aimed at investigating some of these modifications. DESIGN AND METHODS: In the cross-sectional part of the study we evaluated several components of the fibrinolytic system, coagulation inhibitors and lipid profile in premenopausal (n=15) and post-menopausal women (n=64) with CAD and compared these parameters with those of healthy pre-menopausal (n=31) and post-menopausal women (n=88). The prospective part of the study analyzed the effect of HRT with transdermal estrogen with or without progestogen in post-menopausal women with CAD. RESULTS: Pre- and postmenopausal women with CAD showed significant lower fibrinolytic activity and higher plasminogen activator inhibitor type 1 (PAI-1) levels than their control groups. Lp(a) levels were higher in premenopausal women with CAD than in healthy premenopausal women. In post-menopausal women with CAD, HRT induced a significant decrease in PAI-1 and Lp(a) levels. No significant differences were observed in any parameter studied between the groups treated with transdermal estrogen with and without progestogen. INTERPRETATION AND CONCLUSIONS: CAD is associated with a decrease in fibrinolytic activity, possibly due to an increase in PAI-1 levels. An increase in fibrinolytic activity and a decrease in PAI-1 and Lp(a) levels were observed in CAD women receiving transdermal HRT and these changes may have a favorable impact on the risk of new cardiovascular events in post-menopausal CAD women.     

Selective estrogen receptor modulators—A new age of estrogens in cardiovascular disease?

A large body of evidence suggests hormone replacement therapy (HRT) reduces cardiovascular risk in postmenopausal women. It is, however, associated with serious side effects, such as increased risk of breast and endometrial cancer. This has likely caused uneasiness among both women and health care providers. A new class of compounds, called selective estrogen receptor modulators (SERMs), have emerged. Through their interactions at the estrogen receptor level they have become a class of compounds distinct from estrogen. While they share similar effects with estrogen on such factors as lipid profile and bone density, they affect other tissues differently. Specifically, they do not induce endometrial hyperplasia and are therefore not associated with endometrial cancer. In vitro studies have also shown that they inhibit lipoprotein oxidation and vascular smooth muscle cell proliferation. The cumulative effects of these compounds may prove quite beneficial in reducing cardiovascular risk in postmenopausal women while avoiding serious side effects. This may, in turn, ease much of the anxiety surrounding the issue of HRT. Clinical trials are presently being conducted to evaluate the effectiveness of raloxifene, a SERM, on cardiovascular risk reduction in postmenopausal women.     

Hormone Replacement Therapy,Selective Estrogen Receptor Modulators,and Tissue-Specific Compounds

In industrialized countries, coronary heart disease (CHD) is not only the leading cause of death in women but of disability as well. Menopause, regardless of age at onset, is associated with a marked increase in CHD risk. Based on epidemiologic studies demonstrating mainly positive biologic effects of hormone replacement therapy (HRT) on CHD risk factors and outcomes, earlier recommendations decreed that most, if not all, postmenopausal women should be treated with long-term HRT. Recent randomized controlled trials with clinical CHD endpoints have shown that previously held dicta may not be accurate. Selective estrogen receptor modulators (SERMs) such as tamoxifen and raloxifene are alternatives to HRT. SERMs represent a growing class of compounds that act as either estrogen receptor agonists or antagonists in a tissue-selective manner. This pharmacologic profile may offer the opportunity to dissociate favorable cardiovascular effects of estrogen from unfavorable stimulatory effects on the breast and endometrium. The only data available regarding the effects of tamoxifen on cardiovascular events in postmenopausal women are from breast cancer trials. They showed fewer fatal myocardial events in women randomly assigned to tamoxifen compared with women assigned to placebo. Raloxifene is a so-called second-generation SERM. It seems clear that raloxifene increases bone mineral density, has no effect on the endometrium, and holds high promise for the prevention of breast cancer. The effect of raloxifene on cardiovascular disease is uncertain. On the basis of the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, raloxifene may offer some protection to women with cardiovascular disease or to those who are at high risk. Proof that raloxifene reduces the risk of CHD requires a clinical trial with hard clinical endpoints. Such a study is currently underway. Clinical trials have demonstrated that the synthetic 19-nortestosterone derivative tibolone reduces climacteric complaints and prevent osteoporosis without causing menstrual bleeding. Tibolone lowers lipoprotein(a), fibrinogen, and plasminogen activator inhibitor-1 levels and improves glucose tolerance, insulin sensitivity, and endothelial function; however, it also lowers high-density lipoprotein cholesterol by >20%. The long-term impact of tibolone on the risk of CHD is not known and needs to be studied.     

Hormone replacement therapy

Hormone Replacement Therapy (HRT) is replacement of depleted endogenous estrogen for postmenopausal women. Usually progestin is used in combination to avoid endometrial proliferation. As for bone metabolism, estrogens exert bone protective effect through inhibition of bone absorption. HRT has been shown to improve bone mineral density and to lower the risk of osteoporotic bone fracture. However, the results of recent large scale clinical studies in the U.S. indicate that HRT not only raise the risk of breast cancer, but also increase the incidence of atherosclerotic cardiovascular diseases. According to these studies, the benefit of HRT does not outweigh its risk except the treatment of postmenopausal vasomotor symptoms. To resolve this problem, low dose HRT and SERM (selective estrogen receptor modulator) regimens are under investigation.     

The effects of transdermal estradiol alone or with cyclical dydrogesterone on markers of cardiovascular disease risk in postmenopausal women with type 2 diabetes: a pilot study

The objective of this open, longitudinal, controlled study was to assess the effect of transdermal estradiol alone or combined with cyclical dydrogesterone on the markers of cardiovascular disease (CVD) risk in postmenopausal women with type 2 diabetes. The control group consisted of postmenopausal diabetic women who declined menopausal hormone replacement therapy (HRT). Twenty-eight postmenopausal women (19 on HRT and 9 controls) with type 2 diabetes were followed up for 12 months. From the active treatment group 14 women with a uterus in situ had 80 microg/24 hr transdermal estradiol (Fematrix 80; Solvay Healthcare Ltd, Southampton, UK) and oral dydrogesterone 10 mg daily for the first 12 days of the calendar month, whereas 5 women with previous hysterectomy had 80 microg/24 hr transdermal estradiol (Fematrix 80) alone. CVD risk markers were measured before and at regular intervals after starting HRT. The main outcome measures were weight, systolic and diastolic blood pressure, fasting plasma glucose, glycated hemoglobin (HbA1c), glucose/insulin ratio, total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, lipoprotein (a), high-sensitivity C-reactive protein (hs-CRP), fibrinogen, and endothelin-1. Transdermal estradiol with or without dydrogesterone in women with type 2 diabetes did not adversely affect any of the measured markers of cardiovascular risk. There was a significant decrease in HbA1c, total cholesterol, and LDL cholesterol at 6 months in women receiving HRT. Some of the cardiovascular disease risk markers may improve in postmenopausal women with type 2 diabetes with transdermal estradiol. This effect may have important clinical implications and it deserves further investigation in appropriately designed trials.     

Hormone replacement therapy and cardiovascular risk in menopausal women

The incidence of cardiovascular disease (CVD) differs markedly with regard to gender and age. Women have CVD 10 years later than men. Estrogen seems to play a key role in mediating the risk of CVD in women. The relative risk of CVD is lower in women before menopause and equals that of men between the 6th and 7th decade. However the effects of hormone replacement therapy (HRT) on cardiovascular morbidity and/or mortality in postmenopausal women remain controversial. The results of observational studies and randomized trials in post menopausal women are reviewed in this article. They point out the absolute need of large scale prospective randomized clinical studies to quantify the effects of HRT for primary and secondary prevention of cardiovascular disease in particular in non American countries.     

The effects of hormone replacement therapy and raloxifene on C-reactive protein and homocysteine in healthy postmenopausal women: a randomized, controlled trial

C-Reactive protein and homocysteine are independent risk factors for the development of cardiovascular disease. This study compared the effects of hormone replacement therapy (HRT) and raloxifene on serum C-reactive protein and homocysteine levels as markers of cardiovascular risk in healthy postmenopausal women. Healthy postmenopausal women (n = 390) were enrolled in a double blind, randomized, placebo-controlled, 6-month trial at eight out-patient sites in the United States. Women were randomly assigned to receive continuous combined HRT (0.625 mg/day conjugated equine estrogen and 2.5 mg/day medroxyprogesterone acetate), raloxifene (60 or 120 mg/day), or placebo for 6 months. C-Reactive protein and homocysteine were measured in baseline and 6-month serum samples. HRT increased C-reactive protein levels by 84% (P<0.001), whereas raloxifene (60 and 120 mg/day) had no significant effect (-6% and -4%;, respectively; P>0.2). Raloxifene (60 and 120 mg/day) significantly lowered serum levels ofhomocysteine by 8% (P = 0.014) and 6% (P = 0.024), respectively, similar to the 7% (P = 0.014) reduction obtained with HRT. We conclude that HRT and raloxifene lower serum homocysteine levels to a comparable extent in postmenopausal women. Whereas cardiovascular risk predicted by C-reactive protein in healthy postmenopausal women is not influenced by raloxifene, the relationship between elevated C-reactive protein levels with HRT and cardiovascular disease events requires further study.