Oral contraceptives, menopause hormone replacement therapy, and risk of stroke

Objectives: To review available evidence from observational and intervention studies on oral contraceptives (OC), menopause hormone replacement therapy (HRT) and stroke. Methods: Qualitative literature review. Results: High dose OC were associated to elevated risk of stroke. However, the use of low oestrogen OC preparations by non-hypertensive women not at high baseline risk is not related to an appreciable risk of stroke. With reference to HRT, randomised clinical trials showed an excess risk of stroke among users of combined therapy. Conclusions: In non-hypertensive women below age 35 stroke is not materially related to the use of low dose OC. HRT is associated to a moderate excess risk in randomised studies, and should therefore not be used for the prevention of stroke.     

The relative effects of progesterone and progestins in hormone replacement therapy

Hormone replacement therapy (HRT) was initially given to protect women against osteoporosis and alleviate menopausal symptoms, such as hot flashes, depression, sleep disturbances, and vaginal dryness. In view of the understanding of oestrogen deficiency as a major trigger for the acceleration of cardiovascular risk after menopause, HRT may also be proposed as a substantial beneficial cardioprotective agent. Progestins, which may be added to oestrogen in combined HRT to reduce the risk of uterine malignancy, have a number of potential adverse effects on the cardiovascular system which could even attenuate the benefit of unopposed oestrogen replacement therapy in post-menopausal women.     

Effects of dydrogesterone and norethisterone, in combination with oestradiol, on lipoproteins and inflammatory markers in postmenopausal women

OBJECTIVE: The lack of cardiovascular benefit from postmenopausal hormone replacement therapy (HRT) in randomised controlled trials is not readily explained. The androgenic properties of progestogens could be crucial in understanding the results of these studies, all of which employed medroxyprogesterone. We have previously reported that medroxyprogesterone has some androgenic effects intermediate between those of the more androgenic norethisterone and the less androgenic desogestrel. To examine the androgenicity of progestogens further, we compared the effects of dydrogesterone (DGT) that is even less androgenic than desogestrel, and norethisterone (NET), on lipoproteins and inflammatory markers while maintaining the same oestrogen dose. METHOD: In a crossover trial, 25 non-hysterectomised postmenopausal women were randomised to two preparations of HRT each for three 28-day treatment cycles. Both HRT regimens comprised oestradiol (1mg). One also included DGT (10mg) and the other NET (1mg). Oestradiol was taken continuously and the progestogens sequentially. Measurements were made at baseline and on the last day of the oestradiol phase and the last day of the progestogen phase in the third treatment cycle of each regimen. RESULTS: NET was more effective than DGT in significantly reducing lipoprotein (a) (p < 0.05). NET was, however, associated with significantly lower levels of high-density lipoprotein (HDL) cholesterol (p = 0.001) and triglycerides (p < 0.05). NET was less effective in opposing the oestrogen-related increase in C-reactive protein (CRP). Interleukin-6 levels did not change with either progestogen. CONCLUSION: The effect of androgenic progestogens on cardiovascular risk factors may not be as deleterious as previously assumed, especially if the lower HDL levels result from more efficient reverse cholesterol transport. The hormone related rise in C-reactive protein, without a corresponding increase in interleukin-6, may not represent a systemic inflammatory response.     

Modulation of Thrombophilia Genes by Environmental Factors

Hormone replacement therapy (HRT) is associated with reduced risk of coronary heart disease (CHD) and stroke in observational studies; however the possibility of confounding by other risk factors requires prospective assessment of its risks and benefits in randomised controlled trials. The HERS trial of oral HRT in secondary CHD prevention observed an early increased risk of myocardial infarction (MI) and venous thromboembolism (VTE) with HRT: the latter risk has been confirmed by other prospective and case-control studies, and a past history of VTE or MI is now a contraindication to oral HRT. Other prospective randomised trials of HRT, CHD and stroke are in progress. Potential prothrombotic effects of oral HRT (but probably not transdermal HRT) include increased plasma factors VII and IX, activated protein C resistance and C-reactive protein; and decreased antithrombin, protein C and S, and tissue factor pathway inhibitor. Potential protective effects of HRT include decreased blood pressure, lipids, glucose intolerance, fibrinogen, viscosity and plasminogen activator inhibitor; and increased endothelial function. The overall balance of prothrombotic and protective effects varies with HRT preparations and individual women: and may be clarified by ongoing large randomised trials and case-control studies (and substudies of trials).     

Coronary heart disease in menopausal women: implications of primary and secondary prevention trials of hormones

In direct contrast to the observational studies, both primary and secondary prevention trials of female reproductive hormones have found no benefit for coronary heart disease (CHD). Basic science studies have elucidated several mechanisms by which estrogen may improve coronary arterial physiology and prevent pathology, but have also found mechanisms by which estrogen might increase coagulation or inflammation, or might trigger coronary events in advanced lesions. Animal studies suggest that hormones may retard early atherosclerosis, while both animal studies and human angiographic trials are conclusive that hormones do not retard progression of raised lesions. Hormone use in the primary prevention observational studies would mostly have started at the age of menopause, in women whose arteries on average would be closer to normal than those of women in the clinical trials. One hypothesis worthy of further study is that estrogen may have a beneficial effect in normal or near-normal arteries, but the opposite effect in the presence of established atherosclerosis. However, at the average age of menopause, a substantial proportion of women has raised lesions, and a smaller proportion already has advanced lesions. Also, the apparent benefit of hormone use was found in secondary prevention observational studies, i.e., in women with compromised arteries. It is likely that uncorrected biases in the observational studies lead to an overestimation of any benefit of hormone use. On the other hand, endogenous estradiol may be responsible for the later onset of coronary disease in women compared to men; if so, then the appropriate test of the estrogen hypothesis would employ transdermal estradiol in a young population of menopausal women. Hormones are not indicated for the prevention of CHD, particularly in the light of the increased risk for stroke and venous thrombosis. Their use for other indications (menopausal symptoms, osteoporosis) needs to be tempered by the risk for cardiovascular disease (CVD).     

Aspects of hormone replacement therapy in the post-menopause

A review of the literature indicates that hormone replacement therapy (HRT) in post-menopausal women not only reduces the frequency of hot flushes and sweating episodes but also has a protective effect as regards the post-menopausal osteoporotic process. However, it has not yet proved possible to arrive at any conclusions concerning the overall effect of HRT on either ischaemic heart disease and other cardiovascular problems or the risk of developing malignant neoplastic disease. Nevertheless, there is evidence that oestrogen replacement in combination with a progestogen will reduce the risk of endometrial and breast cancer. There is a clear need for additional knowledge and it would therefore seem ethically appropriate to carry out an intervention study in order to determine whether women in general or specific groups in particular would benefit from long-term HRT. Such a study would seem especially urgent, since fractures of the neck of the femur and other osteoporotic manifestations are likely to be a major problem among women in the future.     

Hormone replacement therapy and the prevention of cardiovascular disease

Cardiovascular disease (CVD) is the primary killer of both men and women in Western societies. The implementation of preventive strategies has led to a fall in the rate of CVD, but there is still much to be achieved. Proven interventional strategies are largely under-utilized, and the search continues for further promising interventions. HRT appears to reduce CVD in post-menopausal women, based on observational data supported by plethora of evidence for the beneficial cardiovascular effects of estrogen. However, a recent controlled trial in post-menopausal women with established CVD has shown that a specific combined oral HRT regimen did not reduce, and may even contribute to, an early increase in cardiovascular events, suggesting that HRT is inappropriate in secondary prevention. HRT may be useful in the primary prevention of CVD, yet observational data that suggested cardiovascular benefit with HRT also suggests that 80% of CVD in women could be eliminated by lifestyle modification, without the attendant risks of HRT including thrombosis and (potentially) breast cancer. At present, it is arguable that the evidence is inadequate to recommend HRT solely for the purpose of CVD prevention, and that the challenge for the health professional should be appropriate utilization of established preventative therapies, with further research into the potential role of HRT and estrogen-receptor modulators.     

Hormone replacement therapy and risk for coronary heart disease. Data from the CORA-study--a case-control study on women with incident coronary heart disease

BACKGROUND: Hormone replacement therapy (HRT) has been suggested to prevent cardiovascular disease, while some intervention studies have shed doubt on this concept. Thus, uncertainty remains whether current HRT use is beneficial as to cardiovascular disease or may even be harmful. OBJECTIVES: This research investigates the association of hormone replacement therapy, risk factors and lifestyle characteristics with the manifestation of coronary heart disease in current HRT users versus never users. DESIGN: The coronary risk factors for atherosclerosis in women study (CORA-study) provide clinical and biochemical parameters and data on lifestyle in 200 consecutive pre- and postmenopausal women with incident coronary heart disease compared to 255 age-matched population-based controls, of which 87.9% were postmenopausal. RESULTS: Significantly more controls than cases used currently HRT for a median of 9.5 years (32.9% versus 20.2%), while 50.0% of cases and 42.5% of controls had never used HRT (p<0.02). Compared to women who never used HRT, current users ate less meat and sausage, had a significantly lower BMI and waist-to-hip ratio and a lower prevalence of hypertension, insulin resistance and diabetes. However, current users among cases were often smokers and smoked significantly more cigarettes than never users. In a multivariate analysis the risk of current HRT users for coronary artery disease was 57% lower than the risk of never users (odds ratio 0.428, CI 0.206-0.860, p<0.02). Adjustment for conventional and dietary risk factors revealed neither current HRT use, nor HRT use combined with smoking as independent risk factors. CONCLUSIONS: These data from the CORA-study are not compatible with an adverse impact of hormone replacement therapy on cardiovascular disease, rather support the notion of beneficial effects of HRT on weight, central adiposity, insulin sensitivity and blood pressure. Yet, the data do not support the presumption of a general healthy user effect in women on HRT either. Rather, in some women adverse lifestyle habits, especially intense smoking, appear to counteract possible beneficial effects of HRT.     

Hormone replacement therapy for African American women: missed opportunities for effective intervention.

OBJECTIVES: Because of the potential benefits and risks of hormone replacement therapy (HRT), information about the efficacy of HRT in different groups of women is important to patients and providers. The objectives of this study were to review the evidence on the benefits and risks of HRT in African American women and to present a quantitative analysis of the potential reduction in mortality from osteoporotic fractures and coronary heart disease and the potential increase in risk of breast and endometrial cancer. METHODS: A MEDLINE search of English-language observational studies and clinical trials on the effects of HRT on osteoporotic fractures and coronary heart disease (CHD) was conducted for the time period from 1966 to September 1998. Using available CHD mortality data for African American women and white women, potential reductions in mortality with HRT were explored for African American and white women. RESULTS: In the 30 studies on CHD and HRT, African American women were known to comprise only 173 (0.1%) of 148,437 participants. In 11 studies of HRT and osteoporotic fractures, only 128 (0.4%) of 40,299 participants were known to be African American women. An analysis of CHD mortality by decade intervals indicated that African American women, aged 55 to 64, are more likely to die from CHD each year than white women. Despite a lower incidence of breast and endometrial cancer among African American women, the mortality rates of African American women with these cancers is higher compared with white women. CONCLUSIONS: With the higher underlying CHD mortality rate among African American women, HRT is an important potential preventive therapy. The absence of African American women and other non-white women from clinical studies of HRT makes it difficult to fully assess the risks and benefits of HRT in this group of women.     

Controversy between estrogen replacement therapy and risk of breast cancer in menopause

At present, no information is available from controlled prospective randomized clinical trials to demonstrate a causal link between estrogen replacement therapy (HRT) and the risk of developing breast cancer. In most epidemiologic studies, HRT is not associated with an major increased risk of breast cancer; thus for women who had used estrogen for 10 years or more, the relative risk of breast cancer is 1.46 which is considered as small magnitude. Clinicians and patients are challenged with the difficult task of balancing the beneficial effects of HRT on cardiovascular and bone disease with the potential adverse effects on the breast. The analyses of the benefits and risks of HRT generally indicate that the benefits of therapy outweigh the risks. In other respect the number of survivors of breast cancer are increasing rapidly because of both early detection and the availability of more effective treatments. This effect will increase the number of hypoestrogenic survivors of breast cancer, a group that might benefit from HRT. However, the decision of using HRT has to be determined between the patient and the physician.     

HRT and heart disease: problems and prospects

The divergent findings of hormone replacement therapy (HRT) from observational and randomized clinical studies are summarized and reasons for the different results are postulated. Chronic use of HRT since menopause has no harmful effects on CHD event rate, while the initiation of therapy after a recent cardiovascular event causes an early increase in recurrent CHD events. Once endothelial dysfunction and atherosclerotic disease has developed, the starting of HRT promotes plaque instability, vascular inflammation and prothrombotic effects. The timing of HRT use since menopause is therefore crucial in the effectiveness and safety of HRT on the vascular system.     

A path model of chronic stress,the metabolic syndrome,and coronary heart disease

OBJECTIVE: We tested a theoretical stress model cross-sectionally and prospectively that examined whether relationships of chronic stress, psychophysiology, and coronary heart disease (CHD) varied in older adult men (N = 47), older adult women not using hormone replacement therapy (HRT) (N = 64), and older adult women using HRT (N = 41). METHOD: Structural equations examined relationships of CHD with 1) chronic stress (caring for a spouse with Alzheimer's disease and patient functioning), 2) vulnerability (anger and hostility), 3) social resources (supports), 4) psychological distress (burden, sleep problems, and low uplifts), 5) poor health habits (high-caloric, high-fat diet and limited exercise), and 6) the metabolic syndrome (MS) (blood pressure, obesity, insulin, glucose, and lipids). RESULTS: Caregiver men had a greater prevalence of CHD (13/24) than did noncaregiver men (6/23) (p <.05) 27 to 30 months after study entry. This was influenced by pathways from caregiving to distress, distress to the MS, and the MS to CHD. In men, poor health habits predicted the MS 15 to 18 months later, and the MS predicted new CHD cases over 27 to 30 months. In women, no "caregiving-CHD" relationship occurred; however, 15 to 18 months after study entry women not using HRT showed "distress-MS" and "MS-CHD" relationships. In women using HRT, associations did not occur among distress, the MS, and CHD, but poor health habits and the MS were related. CONCLUSIONS: In older men, pathways occurred from chronic stress to distress to the metabolic syndrome, which in turn predicted CHD. Older women not using HRT showed fewer pathways than men; however, over time, distress, the MS, and CHD were related. No psychophysiological pathways occurred in older women using HRT.     

Prevention of postmenopausal osteoporosis with oestrogen replacement therapy and associated compounds: update on clinical trials since 1995

Hormonal replacement therapy (HRT) is generally regarded as first choice for pharmacological prevention of osteoporosis in women. We reviewed recent studies of HRT regimens and selective oestrogen receptor modulators (SERMs), including controlled trials of at least one-year duration published since 1995 until February 2000 providing data on bone mineral density (BMD) or fractures. Natural and synthetic oestrogens exert a continuum of positive effects on BMD in a dose-dependent, though non-proportional, fashion independent of age and mode of administration. Bone loss may be largely prevented by 25 microg transdermal patch oestradiol, 0.3 mg conjugated equine or 0.3 mg esterified oestrogens. Progestogens neither attenuate nor augment the effect of oestrogens; sole use of tibolone prevents bone loss. Both the SERMs, tamoxifen and raloxifene, slightly increase BMD. There are no adequately powered fracture trials for any HRT regimen. Raloxifene 60 mg daily decreases the relative risk of vertebral fractures by at least 30%, as demonstrated by one 3-year fracture study of osteoporotic women. In conclusion, the recommendation to use oestrogen for postmenopausal osteoporosis, given both the lack of fracture trials and the rare trials on long-term use of HRT in (late) postmenopausal women, is not well supported. Fracture trials could overcome shortcomings of the current level of evidence.     

Diabetes and the menopause

Diabetes mellitus is the commonest chronic disease in post-menopausal women and is a predisposing factor for cardiovascular disease, which is the leading cause of death in this cohort in Western societies. Diabetes and the menopause are two independent risk factors for development of cardiovascular disease. Risk factor modification in terms of diabetes appears straightforward; however, correction of oestrogen deficiency which hallmarks the menopause appears complex. Our aim is to discuss this question based on the evidence available. Co-morbid diseases are common in post-menopausal diabetics. Hence, it not easy to either conduct or establish clear causal relationships in randomised controlled trials. Consequently, making decisions about treatment becomes difficult. However, it is important adopt strategies to help post-menopausal diabetic women alleviate their menopausal symptoms and to minimise the adverse consequences of their condition. We conclude that the low-risk diabetic post-menopausal women should be offered appropriate hormone replacement therapy, whereas non-oestrogen-based treatments should be the treatment of choice for high-risk women.     

Effects of the estrogen replacement therapy on different biochemical markers of endothelial reactivity in recent postmenopausal healthy women

The risk of cardiovascular disease significantly increases after menopause. Accordingly, many evidences suggest that estrogens may positively affect the production of different vasoactive factors, such as nitric oxide, prostacyclin, endothelin-1 and catecholamines and induce favourable changes in lipid profile. However, although observational data indicate that hormone replacement therapy (HRT) reduces significantly the cardiovascular risk, recent results have added controversial data to the institution of HRT in postmenopausal women. These last studies present numerous bias, related to inclusion of a single combination HRT regimen, recruitment women of older age groups who began treatment years after menopause and generally with pre-existing coronary artery disease. In fact, it is known that aging and atherosclerotic injury may induce estrogen receptors depletion, endothelial dysfunction and thrombosis, thus potentially decreasing HRT efficacy. Therefore, particular attention must be paid to the age of the woman and the complexity of atheroscleriotic lesions as determinants of the response to HRT for each patient. Moreover, the maintenance of an healthy and normal functioning endothelium after menopause emerges as a major target to retain maximal cardiovascular benefit from this treatment.     

Women's hearts need special treatment

Coronary heart disease (CHD) is the leading cause of death for both men and women in the Western world. Some studies show that the observed decline in cardiovascular mortality is not as pronounced among women as among men. There is a growing awareness that most earlier studies both on primary and secondary risk factors, diagnosis, prognosis, and rehabilitation have focused mainly on men. Thus, there is a need to develop knowledge about women with CHD and to address gender issues in treatment and rehabilitation strategies. Negative affect and emotions increase risk and may interfere with effective cardiac rehabilitation. Therefore, methods for coping with emotional stress need to be included in treatment regimens after a coronary event. The feasibility of a stress management program for women with CHD was assessed in a pilot study. The program consisted of twenty 2-hr group sessions during 1 year, with 5 to 9 participants per group. The pilot study showed that this treatment program had a low dropout rate and resulted in improvement in quality of life and reduction in stress and symptoms. Further work to optimize psychosocial interventions for women with CHD is needed. This research was funded by the National Board of Health and Welfare in Sweden.     

Issues to debate on the Women's Health Initiative (WHI) study. Epidemiology or randomized clinical trials--time out for hormone replacement therapy studies?

Over the last 40 years, there has been increasing epidemiological evidence that post-menopausal treatment with sex steroids in physiological doses may reduce the relative risk of cardiovascular disease (CVD). These findings have been supported by biological studies showing favourable changes in cardiovascular risk factors with estrogen supplementation. The impact of the so-called 'healthy user' bias has been eagerly debated, and the results of the first and only randomized long-term clinical trial of HRT for primary prevention have therefore been long awaited. The dramatic decision to halt the Women's Health Initiative (WHI) study before completion came unexpectedly as the consequence of not only an increased risk of breast cancer but also increased occurrence of cardiovascular events with HRT. Due to the superior design of the study, the results from the WHI study have had an enormous impact on the clinical recommendations of HRT to post-menopausal women, concurrent with a degradation of evidence from observational studies. It is not very likely that other long-term randomized clinical trials (RCTs) will be completed and epidemiology has certainly been disreputed-so is this 'time out' for HRT studies?     

Opinion survey towards hormone replacement therapy in the prevention of coronary heart disease

Background: Observational and experimental data underscore the cardioprotective effects of hormone replacement therapy (HRT). On the other hand, the randomised trial available, the ‘Heart and Estrogen/Progestin Replacement Study (HERS)’, showed no reduced risk of coronary heart disease (CHD), using HRT. Aim: Opinion survey on the effect of HRT on CHD risk. Setting: Identification of articles on the related topic using a Medline search. Written survey of the authors’ opinion towards HRT in relation to CHD. Results: Thirty-seven of the 108 principal authors responded. Among them, respectively, 16 (43%) and seven (19%) found that HRT has favourable effects on primary and secondary prevention, two (5%) and five (14%) that it had no effect, none (0%) and four ( 11%) that it had an unfavourable effect, seven (19%) and nine (25%) that it had both favourable and unfavourable effects, and nine (25%) and ten (27%), thought that there are not enough data. Considering a risk modification superior to 20% as clinically relevant, then 57% thought that HRT has a beneficial effect of on primary prevention and 30% on secondary prevention, while none of the responders considered that HRT has unfavourable effects on primary prevention and only 2% on secondary prevention of CHD. Conclusion: Despite the negative results of the HERS study, about one-half of the responders still think that HRT has a beneficial effect on primary prevention of CHD and almost one-third on secondary prevention.