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.     

Postmenopausal hormone therapy: new questions and the case for new clinical trials

Observational studies suggest that postmenopausal hormone therapy (HT) prevents coronary heart disease, whereas randomized clinical trials have not confirmed a cardioprotective effect. Although observational studies may have overestimated the coronary benefit conferred by postmenopausal hormone use, there are other plausible explanations for the apparent discrepancy between previous results and the less favorable findings from clinical trials such as the large Women's Health Initiative. There is now a critical mass of data to support the hypothesis that age or time since menopause may importantly influence the benefit-risk ratio associated with HT, especially with respect to cardiovascular outcomes, and that the method of administration, dose, and formulation of exogenous hormones may also be relevant. Although the weight of the evidence indicates that older women and those with subclinical or overt coronary heart disease should not take HT, estrogen remains the most effective treatment currently available for vasomotor symptoms, and its effects on the development of coronary disease in newly postmenopausal women remain unclear. Moreover, effects of HT on quality of life and cognitive function in recently postmenopausal women merit further study. These unresolved clinical issues provide the rationale for the design of the Kronos Early Estrogen Prevention Study, a 5-year randomized trial that will evaluate the effectiveness of low-dose oral estrogen and transdermal estradiol in preventing progression of atherosclerosis in recently postmenopausal women.     

Progestogens and venous thromboembolism among postmenopausal women using hormone therapy

Hormone therapy (HT) is the most effective treatment for correcting menopausal symptoms after menopause. HT initially consisted of estrogens alone and progestogens were secondly added to estrogens for preventing the risk of endometrial cancer associated to estrogens use. Venous thromboembolism (VTE), including deep vein thrombosis and pulmonary embolism, is a major harmful effect of HT. It is now well known that oral and transdermal estrogens are differentially associated with VTE risk but progestogens may be another important determinant of the thrombotic risk among HT users. Both randomized controlled trials and meta-analysis of observational studies suggested that the VTE risk was higher among users of estrogens plus progestogens than among users of estrogens alone. With respect to the different pharmacological classes of progestogens, there is evidence for a deleterious effect of medroxyprogesterone acetate on VTE risk. In addition, observational studies showed that norpregnane derivatives were significantly associated with an increased VTE risk whereas micronized progesterone could be safe with respect to thrombotic risk. The effect of tibolone on VTE risk remains uncertain. In conclusion, progestogens may have differential effects on VTE risk according to the molecules and therefore represent an important potential determinant of the thrombotic risk among postmenopausal women using estrogens.     

Postmenopausal status and early menopause as independent risk factors for cardiovascular disease: a meta-analysis

OBJECTIVE: Loss of ovarian function and subsequent deficiency of endogenous estrogens is suggested to enhance cardiovascular disease risk and related death after menopause. The aim was to obtain valid estimates of the cardiovascular disease risk associated with postmenopausal status and early menopause. DESIGN: A literature search of observational studies was performed using PubMed and EMBASE (1966 to May 1, 2004). Eighteen studies on postmenopausal status and age at menopause in relation to cardiovascular disease were selected. Six studies investigated menopausal status, nine studies investigated menopausal age, and three studied both. General variance-based methods were used to pool relative risk estimates and corresponding 95% confidence intervals. Stratification was performed for study design, type of menopause, outcome, and adjustment for age and smoking. RESULTS: The pooled relative risk estimate for postmenopausal versus premenopausal status and cardiovascular disease was 1.36 (95% CI, 1.15-1.60). In the stratified analysis, the pooled effect was 0.96 (95% CI, 0.77-1.21) after controlling for age and smoking. The pooled effect of bilateral oophorectomy on cardiovascular disease was 2.62 (95% CI, 2.05-3.35). For early menopause and cardiovascular disease, with the menopausal age category containing 50 years as a reference, the pooled relative risk estimate was 1.25 (95% CI, 1.15-1.35). In the stratified analysis, the pooled effect was 1.38 (95% CI, 1.21-1.58) after controlling for age and smoking. The pooled effect of bilateral oophorectomy on cardiovascular disease was 4.55 (95% CI, 2.56-8.01). CONCLUSIONS: Overall, there was no convincing relationship between postmenopausal status and cardiovascular disease. However, there was a modest effect of early menopause on cardiovascular disease. The effect was more pronounced for women with an artificial menopause than for women with a natural menopause.     

Body mass index trajectories and age at menopause in a British birth cohort

OBJECTIVE: This study investigates the influence of body mass index (BMI) at ages 15, 20, 26, 36, and 43, and of BMI trajectories from 20 to 36 years on the timing of menopause and hormone therapy (HT) use until age 57 years. METHODS: A nationally representative British cohort of 1583 women born in March 1946 with prospective data across the life course. RESULTS: By age 57, a total of 695 women had experienced natural menopause while 431 women had started HT prior to menopause. Cox regression models indicated no significant associations between BMI at any age, or BMI trajectory, and timing of natural menopause. At every age BMI was strongly (p< or =0.01) and linearly associated with age at HT use and BMI from 26 years onwards was associated with age at first event (menopause or HT use). Decreasing BMI was associated with earlier HT use at all ages. These associations were not accounted for by parity, cigarette smoking or childhood and adult social class. CONCLUSION: BMI across the reproductive lifespan did not influence age at menopause to an extent that would be clinically relevant for postmenopausal health. Lower BMI at all ages and underweight trajectory were related to an earlier start of HT. Further studies are required to understand whether such relationships are due to underweight women experiencing menopause earlier (and because of menopausal symptoms starting HT earlier) than heavier women, or having behavioural characteristics related to earlier HT use, independent of menopause.     

Early postmenopausal hormone therapy improves postural balance

OBJECTIVE: Postmenopausal hormone therapy (HT) results in more substantial reductions in the risk of hip fracture when initiated sooner rather than later after menopause. We studied the effects of postmenopausal HT on the postural balance of postmenopausal women, with further assessment according to the time since they achieved menopause. DESIGN: One hundred women with a mean age of 52.5 years (91 evaluable) were randomly and blindly assigned to either a sequential estradiol-norethisterone acetate regimen or placebo for 3 months, after which all participants received open HT for a further 3 months. Postural balance was assessed as sway velocity using a force platform. RESULTS: After 3 months of HT, sway velocity had improved (decreased) from baseline by 7.0% (P = 0.007 vs baseline and P = 0.038 vs placebo). Continued HT for 6 months further improved sway velocity by 12% from baseline (P < 0.0001) to reach values similar to those historically found in younger women or in postmenopausal women after long-term HT. Closer proximity to menopause and more pronounced increases in serum estradiol values were associated with stronger improvements in sway velocity (P = 0.018 for interaction). HT also improved dizziness (P = 0.016 vs baseline and 0.022 vs placebo). (Nonparametric statistics are used throughout, except for analyses of interaction and dizziness.) CONCLUSIONS: Initiation of HT soon after menopause rapidly improved postural balance to levels normally seen in young women. We suggest that improved postural balance can contribute to the protection against fractures associated with HT and explain the more substantial reduction in hip fracture risk after HT initiated sooner, compared with later, after menopause. Further study is required to confirm these results.     

Various actions of oestrogens on the vascular system

Epidemiological studies show a reduction in cardiovascular disease with postmenopausal oestrogen use. Oestrogens have been shown to have both metabolic effects and direct effects on the vasculature, both of which may improve arterial function and reduce or reverse atheroma formation. The metabolic effects include changes in lipids and lipoproteins, glucose and insulin metabolism, coagulation and fibrinolysis. The direct arterial effects include changes in endothelium-dependent processes, ion channels, renin–angiotensin system and remodelling processes. The various actions of oestrogens on the vascular system are reviewed. It is clearly important to understand the biological basis of these effects of oestrogen on the cardiovascular system in order to optimize current and future hormone-replacement therapy in women after natural or surgical menopause.     

Recent reversal of trends in hormone therapy use in a European population

OBJECTIVE: The impact of the Women's Health Initiative (WHI) randomized trial results published in July 2002 indicating that hormone therapy (HT) is potentially harmful for the heart and the mammary gland of naturally postmenopausal women was assessed for the first time in a European population. DESIGN: This study continuously monitored HT use from 1994 through 2003 in a population-based random sample of 5,758 women aged 35 to 74 years residing in Geneva (city and canton), Switzerland, yielding 1,938 naturally postmenopausal women with an intact uterus and 206 artificially postmenopausal women. Women in the former subgroup weighed substantially less than their WHI trial counterparts but were not otherwise at lower risk for cardiovascular disease. RESULTS: Among the naturally postmenopausal women with an intact uterus, current HT use increased from 29% to 46% (P < 0.0001) through July 2002 and then decreased abruptly to 31% in 2003. Current HT use remained stable (range, 38%-46%; trend P = 0.92) among the artificially postmenopausal women. CONCLUSIONS: Successive annual increases from 1994 through 2001 in the prevalence of current HT use by postmenopausal women living in Geneva were dramatically reversed to the level in 1994 just after the results of the WHI trial were published, but only for naturally postmenopausal women with an intact uterus. Approximately one in three of the latter women who stopped using HT may also have lost its beneficial effects on bone health.     

Plasma adiponectin levels in postmenopausal women with or without long-term hormone therapy

OBJECTIVE: Recent large, prospective, randomized studies show that hormone therapy (HT) does not confer a protective effect against cardiovascular disease (CVD) but may in fact increase cardiovascular events. Low plasma adiponectin levels are considered to be related to the development of atherosclerosis and CVD. The purpose of this study was to determine the effect of long-term hormone therapy on plasma adiponectin levels in postmenopausal women. METHODS: We recruited a total of 88 postmenopausal women aged 55-69 years old. Our sample consisted of 44 women who had undergone estrogen plus progestogen therapy (EPT) for more than 5 years and 44 age-matched women who had not received HT. We measured plasma adiponectin levels, the serum levels of their lipid profiles, high-sensitivity C-reactive protein (hs-CRP), fasting glucose levels, fasting insulin levels and estradiol levels. Their medical histories including their age at menopause, vitamin use, exercise, alcohol ingestion and cigarette smoking were also assessed by a questionnaire. RESULTS: The mean duration (mean+/-S.D.) of HT was 8.4+/-2.4 years. The mean serum estradiol level (mean+/-S.D.) of the HT group was 47.9+/-36.8 pg/L, significantly higher than that of the non-HT group (p<0.01). Plasma adiponectin levels were significantly lower in the HT group than in the non-HT group (p<0.05). Plasma adiponectin levels were inversely correlated to cholesterol, triglycerides and HOMA-IR (r=-0.33, p<0.05; r=-0.40, p<0.01 and r=-0.30, p<0.05, respectively) in the non-HRT group, but such correlations were not seen in the HT group. In the multivariate analysis, hormone therapy and serum estradiol levels were the independent factors associated with plasma adiponectin levels after adjustments were made for potential confounders. CONCLUSION: Plasma adiponectin levels were significantly lower in postmenopausal women with long-term HT than in those without HT, suggesting that long-term HT may modulate plasma adiponectin level in postmenopausal women.     

B-type natriuretic peptide after hormone therapy in postmenopausal women with chest pain and normal coronary angiogram

OBJECTIVES: Coronary heart disease is relatively uncommon in premenopausal women but shows a sharp increase after menopause. The decline of endogenous ovarian hormones is commonly assumed to be a major component of this phenomenon. The effects of estrogens on the vasculature have been investigated extensively in previous studies. However, the effects of estrogens on myocardial function have not been evaluated in humans. We sought to examine the effects of hormone therapy (HT) on myocardial function and cardiac natriuretic peptides in postmenopausal women with chest pain and a normal coronary angiogram. DESIGN: Transdermal HT (estradiol: 0.72 mg/2 d) was administered to 15 postmenopausal women with chest pain and a normal coronary angiogram (mean age, 53 y) for 12 weeks, and oral HT (conjugated equine estrogens: 0.625 mg/d) was administered to another 15 postmenopausal women (mean age, 54 y) for 12 weeks. Echocardiography or cardiac catheterization showed no cardiac dysfunction in any woman at baseline. Cardiac function was evaluated by echocardiography, and plasma B-type natriuretic peptide was measured every 4 weeks. RESULTS: B-type natriuretic peptide levels increased after transdermal HT (baseline: 13.1 +/- 3.1, 4 wk: 22.1 +/- 2.9, 8 wk: 33.2 +/- 3.1, 12 wk: 38.4 +/- 3.3 pg/mL; P < 0.01 vs baseline). The levels were also augmented after oral HT (baseline: 14.1 +/- 3.8, 4 wk: 23.2 +/- 3.3, 8 wk: 35.6 +/- 3.9, 12 wk: 39.6 +/- 3.5 pg/mL; P < 0.01 vs baseline). Serial echocardiography showed no changes in ventricular function in either treatment group. At baseline the serum estradiol levels in the transdermal group were comparable with those in the oral group. CONCLUSIONS: The estradiol levels after HT increased in both groups, but there was no significant difference between the two groups. B-type natriuretic peptide levels increased without cardiac dysfunction, and the chest symptoms were relieved in some participants after HT. Thus, estrogen supplementation augments natriuretic peptide levels without harmful effects on ventricular function.     

HRT and the primary prevention of cardiovascular disease

Observational studies have consistently shown a benefit of hormone replacement therapy (HRT) on coronary heart disease (CHD), but some randomised studies have not shown any significant effect. Thus questions still remains as to whether HRT is beneficial for CHD, and in whom this benefit might be achieved. The biological effects of oestrogen on the cardiovascular system have been extensively studied, and beneficial effects on metabolic CHD risk factors, as well as on arterial function and on surrogate clinical markers of CHD, have been demonstrated. Thus it seems implausible that HRT should not benefit CHD in postmenopausal women. Most randomised trials using clinical outcomes have studied just one dose of one HRT regimen, a dose inappropriately high with the average starting age of the participants being in their mid-60s. The observational population studies largely comprise women starting on HRT at appropriate dose around the age of menopause, i.e. early 50s. In fact, it was the older women in the randomised trials that failed to show benefit, whereas there was a trend to benefit in the younger ones for whom the starting dose of HRT was appropriate. Furthermore, a pilot study of lower dose HRT in older women did not show any cardiovascular harm. Inappropriately high doses of oestrogen could cause cardiovascular harm due to transient disturbances in thrombogenesis and vascular remodelling. Whilst the greatest CHD benefit may be seen by starting HRT in the early postmenopause, this does not exclude benefit in older women given appropriate low dose therapy.     

Cardiovascular risk factors in a cohort of Danish women born in 1936 prior to use of hormone therapy

OBJECTIVE: Many observational studies suggest hormone therapy protects against coronary heart disease in contrast to findings from large randomised clinical trials and an observational Danish study. A potential bias in the observational literature concerning the cardiovascular risk and benefits associated with use of hormone therapy is the so-called 'healthy user' phenomenon, i.e. self-selection to HT use is associated with healthier cardiovascular risk profile. This study investigates whether a random sample of Danish women using HT was characterised by a favourable cardiovascular risk profile prior to menopause. METHODS: A sample of 621 women born in 1936 living in Copenhagen County was included in a prospective population-based study initiated in 1976 with follow-ups in 1981, 1987 and 1996. Investigations comprised questionnaires and physical examinations. RESULTS: At 51 and 60 years, respectively, one-third and one-half had ever used HT. At 40 years women who subsequently use HT had lower body mass index, lower self-rated health and lower fasting glucose, but no differences according to blood pressure, cholesterol, triglyceride, physical activity, smoking habits or alcohol consumption. CONCLUSION: In a cohort of Danish women from the general population ever users of HT could not be characterised as unambiguous 'healthy users'.     

EMAS position statement: Managing menopausal women with a personal or family history of VTE

Introduction

Venous thromboembolism (VTE), including deep venous thrombosis (DVT) and pulmonary embolism (PE), is a serious cardiovascular event whose incidence rises with increasing age.

Aims

To formulate a position statement on the management of the menopause in women with a personal or family history of VTE.

Material and methods

Literature review and consensus of expert opinion.

Results and conclusions

Randomized controlled trials have shown an increased risk of VTE in oral hormone therapy (HT) users. There are no randomized trial data on the effect of transdermal estrogen on VTE. Recent observational studies and meta-analyses suggest that transdermal estrogen does not increase VTE risk. These clinical observations are supported by experimental data showing that transdermal estrogen has a minimal effect on hepatic metabolism of hemostatic proteins as the portal circulation is bypassed. A personal or family history of VTE, especially in individuals with a prothrombotic mutation, is a strong contraindication to oral HT but transdermal estrogen can be considered after careful individual evaluation of the benefits and risks. Transdermal estrogen should be also the first choice in overweight/obese women requiring HT. Observational studies suggest that micronized progesterone and dydrogesterone might have a better risk profile than other progestins with regard to VTE risk. Although these findings should be confirmed by randomized clinical trials, they strongly suggest that both the route of estrogen administration and the type of progestin may be important determinants of the overall benefit-risk profile of HT.     

Health behaviors and other characteristics of women on hormone therapy: results from the Third National Health and Nutrition Examination Survey, 1988-1994

OBJECTIVE: To examine the prevalence of hormone therapy (HT) use and compare demographic characteristics, health behaviors, and health indicators between current HT users and never-users in a nationally representative sample of postmenopausal women. DESIGN: The Third National Health and Nutrition Examination Survey was a cross-sectional survey conducted between 1988 and 1994, including 3,673 postmenopausal women aged 40 years and older. RESULTS: Overall, 419 (11.4%) of the women reported current HT use, 857 (23.3%) reported past use, and 2,397 (65.3%) were never-users. Non-Hispanic black women and women aged 70 years or older were less likely to be current users. Higher socioeconomic status (education and income) and surgical menopause were associated with increased odds of current hormone use. After adjusting for the above variables, women who reported being inactive during leisure time and obese women (body mass index >or= 30) were less likely to be current users. Women who had 5 to 29 alcoholic drinks per month, perceived their health status as "good," took a multiple vitamin, were aware of having high blood cholesterol, and had a clinic for regular medical care were more likely to be current users. Smoking habits were not significantly different between the groups. CONCLUSIONS: Current HT users have different demographic profiles and may lead healthier lives than never-users. This is important to take into account when studying the effects of HT, and it may partly explain differences in findings regarding the health effects of HT use in observational studies compared with randomized clinical trials.     

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.     

The effects of hormone therapy on pulmonary function tests in postmenopausal women

OBJECTIVE: To investigate the effects of hormone therapy (HT) administered to postmenopausal women on pulmonary function tests (PFT). METHODS: Eighty-two postmenopausal women who were having natural or surgically initiated menopause and had no risk factor that could affect the respiratory system were included into this prospective, randomized study. Twenty-five women who refused to use HT were assessed as the control group (Group I). Nineteen women who accepted using HT and who were having surgically initiated menopause were given continuous estrogen (Group II), 23 were given continuous estrogen and progesterone in combination (Group III) and 15 were given cyclic estrogen and progesterone combination (Group IV). Forced expiratory volume (FEV1), forced vital capacity (FVC), FEV1/FVC, forced expiratory flow rate over 25-75% of the forced vital capacity volume and peak expiratory flow rate were assessed at the beginning of the treatment and in the third month in order to evaluate the effects of HT regimens on the women's PFT. RESULTS: A statistically significant increase was observed only in the FEV1 and FVC parameters of Group III after three months of therapy (P<0.05). The comparison between pre- and posttherapy FEV1 and FVC values showed an increase in the Group IV, but the difference was not statistically significant, while there was no difference between basal and third month FEV1 and FVC values of the group receiving estrogen only. CONCLUSIONS: It was seen that particularly continuous combined HT regimen positively affected the FEV1 and FVC parameters of the postmenopausal women.     

Attitudes towards the menopause and hormone therapy over the turn of the century

Objective

To assess attitudes and beliefs about the menopausal transition in a population of peri- and postmenopausal women, and if these attitudes differed before and after publication of studies on risks and benefits with hormone therapy (HT).

Materials and methods

In 1999 and 2003 all women aged 53 and 54 years in the community of Linköping, Sweden, were sent a questionnaire about use of HT, menopausal status and attitudes regarding menopause and HT.

Results

Most women regarded menopause as a natural process characterized by both hormonal deficiency and aging and these views did not differ between 1999 and 2003. A majority of women thought that significant climacteric symptoms were a good reason to use HT, but not that women without symptoms should use HT. The fraction of women who supported HT use was, however, significantly lower in 2003 than in 1999. Most women agreed that menopause leads to increased freedom and that it is a relief not to have to think about contraception and pregnancies.

Conclusions

Most Swedish women had a mainly biological view on menopause but nevertheless they thought that only women with climacteric symptoms should use HT. Women's attitudes towards HT have changed after recent reports on risks from long-term use of HT whereas the attitudes towards the menopausal transition were stable. Other factors than attitudes towards menopause affect women's actual use of HT. Probably women's and health care provider's apprehension of the risk-benefit balance of HT use is one such factor.     

WHI risks: Any relevance to menopause management?

Two randomised controlled trials of hormone therapy (HT) were conducted within the US Women's Health Initiative. Both were chronic disease prevention trials, undertaken to determine whether HT reduced cardiovascular risk and increased breast cancer risk. Because the majority of subjects in both trials were asymptomatic and many years postmenopausal, and because substantial numbers had received HT prior to recruitment to the trials, care must be taken in drawing conclusions that the observed risks are applicable to women for whom HT is conventionally prescribed. Each of the reported risks must be examined critically to determine its likely applicability to symptomatic women treated for two to three years to relieve symptoms, but sometimes for substantially longer periods. Further, the risks reported in each of the two trials must be considered separately. Concerning cardiovascular disease, many subjects in the trials were at increased baseline risk because of their age, body mass index, smoking status, blood pressure and years since menopause, in contrast to the usual situation for symptomatic perimenopausal women. Therefore the reported overall cardiovascular risks in WHI, in both treatment arms, should be regarded as irrelevant to menopause management. In contrast, breast cancer risk is relevant, providing that proper note is taken of the fact that there was no increased risk after five years of combined hormone therapy in non-prior HT users and there was a tendency to a decreased risk in oestrogen only treated individuals. Other risks are analysed similarly.     

The association between early menopause and risk of ischaemic heart disease: influence of Hormone Therapy

Randomised clinical trials find no protection against development of ischaemic heart disease by use of Hormone Therapy (HT) after the age of 50 years. Observational studies suggest that early menopause is a risk factor for ischaemic heart disease. Yet, a clinical very relevant question is whether HT reduces this risk associated with early menopause. OBJECTIVE: To analyse whether early menopause based on various causes are independent risk factors for ischaemic heart disease, and to investigate whether the risks are modified by use of HT. METHODS: In a prospective cohort study questionnaires were mailed to Danish female nurses above 44 years of age in 1993. Information on menopause, use of HT and lifestyle was obtained. In total 19,898 (86%) nurses fulfilled the questionnaire, among them 10.533 were postmenopausal with definable menopausal age, free of previous ischaemic heart disease, stroke or cancer. Through individual linkage to national register incident cases of ischaemic heart disease were identified until end of 1998. RESULTS: Menopause below both age 40 and 45 was associated with an increased risk of ischaemic heart disease, seeming most pronounced for women who had an early ovariectomy but also among spontaneous menopausal women. Generally HT did not reduce the risk except for the early-ovariectomised women, where no increased risk of ischaemic heart disease for HT users was found. CONCLUSION: We found an increased risk of ischaemic heart disease associated with early removal of the ovaries that might be reduced with HT. The present study need confirmation from other studies but suggests that early ovariectomised women could benefit from HT.     

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).