Cardiovascular disease and hormone replacement therapy
Ali Baziad (1) and Thierry Pache (2)
(1) Department of Obstetrics and Gynaecology, University of Indonesia, Jakarta, and Dr Cipto Mangunkusumo General Hospital, Jakarta, Indonesia; (2) Department of Obstetrics and Gynaecology, University Hospital, Geneva, Switzerland
Life expectancy is increasing steadily throughout both the developed and developing world, leading to an increase in the elderly population worldwide. The number of women of menopausal age and their concomitant health problems are increasing accordingly. Longer life expectancy does not necessarily mean a better quality of life, and many elderly women are suffering the consequences of a lack of ovarian oestrogen production. Almost all of the clinical signs and symptoms they develop in later life are due to a basic lack of oestrogen.
One of the most important health problems is the increase in the incidence of coronary heart disease (CHD) in menopausal women. CHD is the major cause of death in women over the age of 50 years in the industrialized West. The incidence of ischaemic heart disease (IHD) in postmenopausal women in the USA is twice that of osteoporosis (1000 and 530 per 100,000 population, respectively), and the death rate from IHD is more than 10-fold higher. Breast cancer is numerically less important, with an incidence of 310 per 100,000 population and a death rate of 100 per 100,000 population. The mortality rates from breast cancer in Eastern and Central Europe are now the world’s highest, and are continuing to rise in countries such as Bulgaria and Hungary, in both women and men. In the near future cardiovascular disease (CVD) will also become a significant health problem in some developing countries due to changes in life style in which populations are adopting the unhealthy habits and behaviour of those in the industrialized countries.
Throughout the world the increasing cost of medical consultations for CVD has been accompanied by a steady increase in the cost of treatment. The cost of drugs in many countries has risen with the number of prescriptions. Hospital admissions and coronary bypass graft surgery have increased fourfold in the same period. Hospital stays for elderly people are often longer than those for younger people due to their slower recovery time and consequent need for more planned community support before discharge home. Hospitalization for non-infectious diseases needs to be supported by sophisticated and expensive equipment.
Oestrogen deficiency is a well-recognized and important factor responsible for the marked increase in the incidence of myocardial infarction, stroke and dementia after the menopause. The role of oestrogen is further supported by evidence from a number of epidemiological studies that have shown a substantial reduction in CVD among women receiving oestrogen replacement therapy (ERT). A recent review of the data suggests a reduction in risk of CVD of 40% or more among women who have ever taken oestrogen. Although many doctors and women are aware that oestrogen replacement can have positive effects, only a small number of menopausal women take advantage of oestrogen therapy. One of the reasons for this is the belief that the oestrogen used in ERT has the same properties as that used in oral contraceptives. People are wary of the adverse effects of oral contraceptives, such as hypertension, thromboembolism and myocardial infarction. If only they realized that the oestrogen used in ERT is natural oestrogen which has a much lower potency than that which effects the physiological menstrual cycle, they would be more willing to accept the benefits of therapy.
Risk factors for coronary heart disease in menopausal women
The term ‘risk factor’ was first coined in relation to CHD. This disease, as well as other CVDs, is multifactorial in origin. The major risk factors for CHD are high blood pressure, cigarette smoking, dietary habits, elevated blood cholesterol, lack of physical activity, obesity, and diabetes . Women with premature menopause (as a result of surgery, chemotherapy or premature failure) and menopausal women are also at risk for CVD .
Mechanism of hormonal effects
Hormone replacement therapy (HRT) could modify the cardiovascular risk by several mechanisms, including modifications in the plasma concentration of lipoprotein, glucose, insulin, and in blood pressure and the haemostatic system .
The incidence of CHD is also related to the serum levels of high-density lipoprotein (HDL) and low-density lipoprotein (LDL). Women aged 20–50 years have a more favourable lipid profile than men of a similar age (lower plasma LDL and very-low-density lipoprotein, and higher plasma HDL). However, at the menopause there is a detrimental change in lipid profile, namely an increase in LDL and a decrease in HDL . A high level of HDL has been shown to reduce the risk of CHD . On the other hand, a 1% rise in LDL increases the risk of CHD by up to 2% within 6 years, and a 1% decrease in HDL increases the risk of CHD by up to 34% [6–8]. Recently, increased lipoprotein (a) (Lp[a]) has also been found in postmenopausal women .
The effect of oestrogen and progesterone on lipid metabolism is greatly dependent on their nature, i.e. natural oestrogen and progesterone are considered to have a more beneficial effect compared with synthetic hormones. Commonly used forms and doses of natural oestrogen (0.625 mg of oral conjugated oestrogen or 1.5–2.0 mg of oral oestradiol) result in significant decreases in total and LDL cholesterol and apolipoprotein B concentration, with a concomitant increase in HDL cholesterol [10, 11].
The effect of progestogens on the lipoprotein pattern is largely dependent on the type and dose. The 19-norethisterone compounds have marked androgenic properties with pronounced HDL cholesterol-lowering activity. Either levonorgestrel 1.25–2.50 mg or norethisterone 5 mg daily, when added for 10–14 days per month to the oestrogen regimen, may reduce HDL cholesterol to below baseline levels .
The 17a-hydroxyprogesterone-derived progestogens have little or no effect on lipoprotein pattern. A study in 1990 on postmenopausal women  made the following findings: the HDL levels of women who received conjugated natural oestrogen and natural progesterone (medroxyprogesterone acetate [MPA]) increased from 64.5 mg% to 193.6 mg%. On the other hand, women who received norethisterone derivatives instead of MPA did not show a significant rise in HDL (i.e. from 50.6 mg% to 66 mg%). It is, however, worth noting that only a small number of patients were recruited to this study.
Continuous regimens consisting of both oestrogen and progestogen given daily, appear to attenuate the expected reduction in LDL cholesterol and the increase in HDL cholesterol .
Modification of the haemostatic system may play a role in the pathogenesis of CHD. A fibrinolytic hypofunction caused by an increase in plasminogen activator inhibitor-1 (PAI-1) has been detected in IHD . An increase in factor VII, fibrinogen and PAI-1 activity has been reported in postmenopausal women . In both ovariectomized and postmenopausal women an increase in factor VII (10%), fibrinogen (10–40%) and serum fibrinogen activity (20–30%) was found. On the other hand, there were no changes observed in factor V and VIII, platelet count or prothrombin time . The effects of HRT on the haemostatic system have not been extensively studied, but some researchers have speculated that ERT could decrease CVD by modifying the haemostatic parameters. Although some reports suggest that HRT induces a hypercoagulable state by increasing factor VII , other studies have reported a decrease in factor VII and fibrinogen and no modification of prothrombin fragment 1 + 2 and the thrombin/antithrombin III complex in HRT . Some studies looking at the influence of HRT on the fibrinolytic system have found a decrease in PAI-1 activity and a variation in tissue type plasminogen activator levels . A raised level of Lp(a) interferes with the fibrinolytic system because of its structural similarity to plasminogen. Lp(a) could be the link between impaired fibrinolysis and atherosclerosis .
The results of studies of hormonal effects on clotting factors differ, depending on the dose and type of oestrogen and on whether or not a progestogen was added. In some studies, oestrogen appears to lower the concentration of fibrinogen . Antithrombin III activity was lowered by giving ethinyloestradiol . Oral oestrogen plus a progestogen given for 1 year to 60 postmenopausal women caused a decrease in factor VII [18, 19]. Oestradiol or oestradiol valerate 1–2 mg produces no effect on haemostatic parameters . Addition of 0.5 mg norethisterone or 5 mg norgestrel given cyclically or continuously produces no effect on coagulation and thrombocyte aggregation [24, 25]. An increase in fibrinolytic activity and a decrease in Lp(a) have been found in women receiving HRT .
It is well known that diabetes is strongly associated with CHD, diabetic women having a higher incidence of CHD compared with diabetic men . Insulin resistance can be defined as a relative decrease in sensitivity of the target tissue to the action of insulin, with an associated increase in circulating insulin concentration. Hyperinsulinaemia resulting from insulin resistance increases CHD risk. Oestrogen administration increases insulin secretion and improves insulin sensitivity. Progestogens increase pancreatic insulin secretion but, unlike oestrogens, they increase insulin resistance. The effect of progestogens may partly depend on the androgenicity of the steroid used. Treatment with either oral conjugated equine oestrogen 0.625 mg daily and cyclic norethisterone 0.5 mg, or cyclic transdermal norethisterone 0.5 mg, produced no change in glucose tolerance and a reduction in insulin resistance after 1 year of treatment .
An increase in central (upper) body fat (android fat) is associated with an increased risk of CHD, unlike fat in the lower body segment (gynoid fat). The proportion of android fat correlates positively with insulin resistance. The menopause is associated with a significant increase in the proportion of android fat and significant reduction in the proportion of gynoid fat . HRT prevents increases in abdominal fat, favouring redistribution to gynoid fat independent of serum lipids or lipoprotein, with little effect on total body fat . This beneficial effect in redistribution of body fat has been shown to be associated with a decreased risk of CHD.
Hypertension is one of the most powerful and prevalent known cardiovascular risk factors. Early menopause is associated with a relatively selective increase in diastolic blood pressure. Oral or vaginal oestriol treatment does not increase blood pressure . Furthermore, administration of 0.625 mg and 2.5 mg piperazine oestrone sulphate with or without addition of progestogen reduced diastolic and systolic blood pressure significantly . Administration of 2–4 mg oestradiol valerate with or without progestogen does not generally affect blood pressure .
Blood vessel endothelial cells produce certain materials such as anti-platelet aggregation substance, prostacyclin, a vasodilator, and endothelin which is a muscle relaxant . In an experimental animal study, oestrogen prevented smooth muscle proliferation, inhibited platelet aggregation, and increased prostacyclin and elastic collagen fibre production by arterial smooth muscle cells .
Several investigations in animal models and humans have demonstrated increased uterine blood flow after oestrogen and progesterone administration and a decrease after progesterone only . In postmenopausal women, oestrogen increases vulvar blood flow by up to 50%, while 10 mg MPA decreases it . Uterine blood flow increased when HRT was applied to postmenopausal women using conjugated natural oestrogen and the natural progesterone dydrogesterone for 3 consecutive months . The increased blood flow is believed to be due to reduced vascular resistance. Long-term treatment with 17a-oestradiol (22 weeks) in normotensive postmenopausal women results in a decrease in pulsatility index of the carotid artery, thought to represent impedance to blood flow .
A calcium antagonistic property of oestrogen has been observed in the uterine arteries. Oestradiol decreases calcium entry into uterine vascular smooth muscle cells . It has been hypothesized that some cardiovascular benefits of ERT may be due to a calcium antagonist effect of oestrogen . Long-term calcium antagonist treatment is known to decrease the progression of atheroma when given to patients with established CHD . Oestrogen may therefore be cardioprotective via a beneficial effect on atheroma progression due to its calcium antagonistic properties in a way similar to that of nifedipine and nicardipine.
Routes of administration
Oral administration of HRT is generally suggested since it most effectively prevents CVD and osteoporosis. Oral administration triggers HDL production in the liver. In addition, oral administration triggers somatomedin secretion needed to enhance calcium absorption in the intestine.
It remains controversial whether or not transdermal oestrogen is effective in preventing CVD. In a randomized, comparative study, a sequentially combined oral HRT regimen consisting of oestradiol valerate (2 mg daily on days 1–21) and cyproterone acetate (1 mg daily on days 12–21) induced a lipid pattern, and probably also a change in lipoprotein levels, that is generally considered to be more beneficial with regard to the prevention of CVD than that induced by a sequentially combined regimen of transdermal oestradiol (50 µg applied twice weekly for 3 weeks) and oral dydrogesterone (20 mg daily on days 12–21) . Besides, a natural progestogen like cyproterone acetate (even with a marked antiandrogenic effect) has little or no effect on the lipid and lipoprotein profile. The half-life of cyproterone acetate is longer than that of other progestogens, justifying a shorter course of sequential treatment (10 days).
Cardiovascular disease and hormone replacement therapy in Asia
Although a high incidence and prevalence of CVD have been documented in elderly women worldwide, there are no accurate data available specifically for Asian women. The incidence of CVD in Asian women is thought to be currently lower than that in their Western counterparts, but is nevertheless steadily increasing.
CVD is the leading cause of death in Asian/Pacific Island females (36.2%) [American Heart Association. Biostatistical fact sheet — population. Asian/Pacific Islanders and cardiovascular diseases. Internet communication, 1991], whilst in Western Asia and South-East Asia, an estimated 20 million deaths (15–20%) annually are due to CVD. In the Eastern Mediterranean (Iran, Iraq, Kuwait, Oman, Qatar), the proportion of deaths from CVD ranges from 25 to 45%. CHD seems to be the predominant type of cardiopathy encountered in many countries, and hospital data indicate rising trends [American Heart Association. Biostatistical fact sheet — population. International cardiovascular disease statistics. Internet communication, 1990].
Several countries have experienced rapid socioeconomic changes over the last two decades. Daily caloric intake has increased. In China and India alone (accounting for about half the total population of the developing world), 4.5–5 million people die each year from CVD. In China, the mortality rate attributable to CVD increased from 86.2 per 100,000 in 1957 (12.1% of total deaths) to 214.3 per 100,000 in 1990 (35.8% of total deaths) in urban areas [American Heart Association. Biostatistical fact sheet — population. International cardiovascular disease statistics. Internet communication, 1990].
In Japan, the incidences of breast cancer and CVD are very low . The traditional Asian diet is low in fat and high in fibre and is also rich in phyto-oestrogens. Soya is consumed in large quantities in Japan and contains precursors of the weakly oestrogenic isoflavones, genistein and daidzein. The Japanese daily diet contains about 80 mg of genistein, which is about 80 times greater than that in the typical daily American diet. Women who consume at least 30 mg soya per day reduce their cholesterol level by up to 9% and the probability of CHD declines to about 18–28%. Studies in rodents, non-human primates and women strongly suggest that dietary oestrogenic soy isoflavones may provide cardioprotective benefits without increasing the risk of endometrial and breast cancer in menopausal women .
— The most important cause of death among postmenopausal women is CHD, especially in the West.
— Oestrogen deficiency is the major cause of CVD. The administration of oestrogen with or without progestogen is expected to reduce CVD.
— Continuous or cyclic oestrogen therapy increases HDL cholesterol and decreases LDL cholesterol. The effect of additional progestogen to the oestrogen regimen on serum lipids is type- and dose-dependent, i.e. 19-norethisterone has pronounced HDL-lowering properties, while 17a-hydroxyprogesterone and the newer generation nandrolone derivatives have little effect on lipid profile.
— HRT appears to have a beneficial effect on the coagulation/fibrinolytic balance, including fibrinolytic activity, without affecting coagulation factors, and lowers Lp(a) levels.
— Oestrogen treatment favours a gynoid fat distribution pattern which has been found to decrease the risk of CVD.
— Oestrogen administration with or without progestogen does not generally increase blood pressure.
— Endothelium-dependent vasodilatation is enhanced by oestrogen therapy, and acute or chronic oestrogen administration increases peripheral blood flow and decreases peripheral vascular resistance.
— Limited studies to date have suggested antagonistic properties of oestrogen.
— The incidence of CVD in Asian women is currently lower than that in the Western population but is steadily increasing; this is partly due to the adoption of an unfavourable life style prevalent in Western societies.
— Studies are needed to identify the relative importance of the different cardiovascular risk factors and the incidence of CVD in postmenopausal Asian women.
— Both short- and long-term trials are needed to examine the effect of HRT on lipid and non-lipid risk factors such as coagulation profile, glucose, blood flow and blood pressure in postmenopausal Asian women.
— Studies are needed to determine the optimal dose of oestrogen and progestogen in postmenopausal Asian women as well as into the different routes of administration of both oestrogen and progestogens.
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