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.     

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.     

Anti-cardiolipin antibodies in ischaemic heart disease.

IgG and IgM anti-cardiolipin antibodies (ACA) were assayed by an ELISA technique in 86 patients with ischaemic heart disease (IHD) and compared to 124 healthy controls and to 62 patients with rheumatoid arthritis (RA) and 20 with tuberculosis (TB). IgG ACA levels in IHD, RA and TB were comparable and significantly higher than in controls (P less than 0.0001). IgM ACA was significantly higher in IHD and RA than controls (P less than 0.0001) but not TB (P = 0.045). The number of IHD patients with raised ACA (IgG and/or IgM) was significantly greater than in RA or TB. (chi 2 = 30.77, P less than 0.0001). ACA were raised in 80.2% IHD patients on one or more occasions during a 1-11 day (mean 4.7) hospital admission. There was no difference in either ACA levels or in the frequency of ACA elevation in patients with stable or unstable angina pectoris or myocardial infarction. We conclude that there is a strong association between IHD and ACA with potentially important therapeutic implications.     

A note on platelet adhesiveness in ischaemic heart disease

Platelet adhesiveness was measured in vitro in a group of patients with ischaemic heart disease and in a group of matched healthy subjects using either 1% EDTA or 3.8% sodium citrate as anticoagulant. When sodium citrate was used platelet adhesiveness was significantly greater in the group with ischaemic heart disease. However, no difference was found when EDTA was used.     

Serum amyloid A concentrations during the course of acute ischaemic heart disease.

Serum amyloid A concentrations were determined in serial serum samples of 41 patients with confirmed acute myocardial infarction (10 with acute ischaemia and two with myocarditis). A sharp increase in serum amyloid A concentration was observed early at onset of infarct; it peaked on the third day (up to 2200 fold of normal values) and declined towards normal during the following days, if no complications occurred. Different patterns were observed in patients with acute ischaemia or myocarditis. Although serum amyloid A is not a specific marker, it may, because of its high sensitivity and characteristic patterns of change, represent an additional useful biochemical variable in the diagnosis, follow up, and prognosis of acute ischaemic heart disease.     

A pilot study of hormone replacement therapy with tibolone in women with mastopathic breasts.

OBJECTIVE: Our purpose was to investigate the effect of tibolone in a prospective randomized, double-blind pilot study in postmenopausal women with clinically palpable mastopathic changes. METHODS: Twenty postmenopausal non-users of hormone replacement therapy undergoing mammography were randomly allocated to receive either 2.5 mg tibolone (Livial, Organon) or placebo (2 mg lactose). Mammographic density according to the Wolfe classification, severity of breast discomfort, parity, smoking habits, body weight and follicle-stimulating hormone (FSH) and estradiol (E(2)) levels were documented at baseline and after 6 months of treatment. RESULTS: There were no statistically significant differences between the two treatment groups in terms of parity, smoking, body weight and FSH and E(2) levels. At 6 months, four patients in the tibolone group showed reduced breast density, compared with one patient in the placebo group. Whereas no significant differences were found between the two treatment groups when the categories 'minimal reduction' and 'reduction' in mammographic density were combined, combination of the categories 'no change' and 'minimal reduction' showed a significant difference (P<0.036). Also, women in the tibolone group showed a statistically significant improvement in breast discomfort (P<0.019). CONCLUSION: This pilot study showed decreases in breast density as well as an attendant significant alleviation of breast discomfort in women with baseline mastopathic changes treated with tibolone for 6 months, which may be due to the inhibitory effect of tibolone on the enzymes involved in the biosynthesis of estradiol demonstrated in previous trials and should be further evaluated in long-term studies.     

The influence of hormone replacement therapy on skin ageing: a pilot study.

OBJECTIVES: We studied the effect of hormonal treatment on skin ageing in menopausal women. METHODS: Twenty-four patients (45-68 years; mean age, 54.9 years) without hormone treatment for at least 6 months were included. Patients were assigned to three therapy groups: 1, oestrogen only (Estraderm TTS 50) (n=6); 2, transdermal oestrogen and progesterone (Estraderm TTS 50 and 0.4 mg progesterone vaginal suppository) (n=7); and 3, oral oestrogen and progesterone (2 mg Progynova and 0.4 mg progesterone vaginal suppository) (n=8). One group without therapy was included as a control group (n=3). Treatment was continued for 6 months. Three patients, one from group 2 and two from group 3, discontinued therapy before the study endpoint. The following skin parameters were measured at monthly intervals during treatment: skin surface lipids, epidermal skin hydration, skin elasticity and skin thickness. Concomitant clinical evaluation included a subjective clinical evaluation form, a patient questionnaire and laboratory tests for oestradiol, progesterone and follicle stimulating hormone. RESULTS: Mean levels of epidermal skin moisture, elasticity and skin thickness were improved at the end of treatment based on both subjective and objective evaluation in patients with hormone replacement therapy (HRT). Skin surface lipids were increased during combined HRT, which may reflect stimulatory effects of the progestagen component on sebaceous gland activity, while oestrogen alone has a sebum-suppressive action. In the HRT groups, the questionnaire for climacteric complaints demonstrated significant improvements, while laboratory tests showed increases in oestradiol and progesterone and decreases in FSH. CONCLUSIONS: HRT with the mentioned regimes significantly improved parameters of skin ageing.     

A comparative study of two hormone replacement therapy regimens on safety and efficacy variables

Objective: To assess the effect of tibolone on endometrial safety, plasma estradiol concentrations, lipid metabolism and climacteric symptoms in comparison to sequential conjugated equine estrogens and medroxyprogesterone acetate in postmenopausal women. Methods: In a randomised, open-label, 6-cycle, group-comparative study, the effects on the aforementioned parameters were studied with tibolone 2.5 mg/day (N = 13) continuously, and with conjugated equine estrogens 0.625 mg/day continuously, combined with medroxyprogesterone acetate 5 mg/day (N = 11) (CEE/MPA) sequentially, during 12 days of each 28-day cycle. Within-group statistical analysis was performed with Student's t-test for paired samples, whereas between-group statistics were performed using the Student's t-test for independent groups. Results: Cytological evaluation revealed no endometrial stimulation in either group. In the tibolone group, there were no effects on estradiol levels, whereas in the CEE/MPA group, an increase in total and non-SHBG-bound estradiol plasma levels was reported. In the tibolone group, there were significant decreases in plasma total cholesterol, triglycerides, HDL-cholesterol and VLDL-cholesterol, whereas no significant changes in LDL-cholesterol and IDL-cholesterol were reported. In the CEE/MPA group there were significant decreases in plasma total cholesterol, HDL-cholesterol and LDL-cholesterol, whereas there were no significant changes in triglycerides, IDL-cholesterol and VLDL-cholesterol. Climacteric symptoms, particularly vasomotor episodes, decreased similarly in both groups. Conclusions: Both tibolone and CEE/MPA were safe with respect to effects on the endometrium and both treatments induced changes in the plasma profiles of certain lipid and lipoprotein parameters. However, the overall clinical implications of these changes are unknown. Finally, both regimens were equally effective in the treatment of climacteric symptoms     

Anti-heart autoantibodies in ischaemic heart disease patients.

One hundred and ninety-nine ischaemic heart disease (IHD) patients were studied with regard to the prevalence of anti-heart autoantibodies (AHA). The incidence of AHA in IHD patients was 1%: one out of 102 patients who suffered acute myocardial infarction (AMI), one out of seventy-two patients who suffered from acute coronary insufficiency (ACI), and none out of twenty-five patients with other signs and symptoms of IHD, had AHA in their sera. An additional 2% of patients who suffered from AMI developed detectable antibody levels during a follow-up period of 15 days. In comparison,, 53% of patients (eight out of fifteen) who underwent heart surgery and who had no AHA prior to operation, developed these antibodies in their sera during 1-2 weeks following operation.     

AgNORs in the myocardium in ischaemic heart disease complicated by heart failure: a postmortem study.

AIM: To evaluate the interphase ribosomal RNA cistron activity of cardiomyocytes in case with ischaemic heart disease complicated by heart failure. METHODS: Nucleoli were investigated in postmortem myocardium samples from 31 cases with ischaemic heart disease (mean (SEM), 57.4 (6.5) years) with or without severe heart failure (18 and 13, respectively) and from eight healthy people who died in accidents (mean (SEM) 25.3 (4.0) years). Myocardium obtained within one hour after death was frozen in liquid nitrogen. Silver staining for nucleolar organiser regions (AgNOR) was performed with a standard procedure and the mean score obtained. On the basis of these data, the average number of AgNORs per nucleus was determined. The Student's t test was used to compare groups. RESULTS: Compared with controls, the mean numbers of AgNORs per nucleus in cardiomyocytes from ischaemic heart disease patients not complicated with severe heart failure were higher (8.0 v 9.9; p < 0.05), but cases with severe heart failure had a progressive decrease in cardiomyocyte AgNORs. A difference in AgNOR numbers between cases with different ischaemic heart disease courses was found when cases with the same New York Heart Association (NYHA) functional stage III of heart failure were studied. CONCLUSIONS: The significant decrease of AgNORs in cardiomyocytes from cases with severe ischaemic heart disease complicated by heart failure seems to be connected with cardiomyocyte adaptation (a variant of hibernation) to a diminished circulation that, hypothetically, may affect the level of ribosomal RNA synthesis.     

The menopause and hormone replacement therapy: views of women in general practice receiving hormone replacement therapy.

Women's views on the menopause and hormone replacement therapy were explored using a questionnaire given to women attending one general practice who were having hormone replacement therapy under the supervision of their doctor. Sixty four women (67%) responded. Although only 5% of women had requested hormone replacement therapy from their general practitioner the majority of women indicated that they had been helped by hormone replacement therapy. Eight per cent of women were using hormone replacement therapy primarily to treat menopausal symptoms with only 6% of women using it primarily as prophylaxis against osteoporosis. Many women were correctly informed about the effects of hormone replacement therapy but mistaken beliefs about its side effects may indicate the need for further health education. The desire for further information was striking: 59% of women wanted further information about hormone replacement therapy, and 80% of women would have liked to have had more information about the menopause before its onset. The media appeared to be an important source of information about health matters: 61% of women obtained information about hormone replacement therapy from either the television, magazines or newspapers. The role of the media and health workers in health education is discussed.     

A comparative study of prescribing of hormone replacement therapy in USA and Europe

Objectives: The use of hormone replacement therapy (HRT) has been shown to vary from one country to another through international studies of sample populations and by comparison of data obtained from comparable national studies. Drawing international prescribing comparisons is very difficult as data sources are few, incomplete and of uncertain accuracy and comparability. As an alternative to direct prescribing information, pharmaceutical sales information indicates medication used. This paper sought to demonstrate international differences in the use of HRT using an economic analysis methodology based on national pharmaceutical sales statistics. Methods: A recognised economic analysis methodology was used to translate 1991/1992 pharmaceutical sales data into women treatment years of HRT used in each country. From this was calculated the percentage of the female population in each country, eligible for HRT, who would have been taking HRT. Results: The results show a wide variance in the percentage of the eligible female population in each country calculated to have been taking HRT, from <1%–20%. The results indicated that HRT usage fell into three groupings: USA being the greatest user with UK and Scandinavian countries in the middle group and continental Europe having the lowest usage. Conclusions: National patterns of HRT usage, as calculated by this study, correlate well with those of other studies. Since similar morbidity could be expected as menopause is a naturally occurring event, not a disease, possible reasons for the variance in national prescribing patterns are discussed. The study indicates the need for further research on health beliefs and physicians' and womens' attitudes to HRT in different countries to explain the variance in HRT usage, also considering access to healthcare, in particular women's health services. It confirms the validity of using economic analysis of pharmaceutical sales data as a proxy for prescribing data in the arena of prescribing research.     

A preliminary study of growth hormone therapy for Crohn's disease

BACKGROUND: Crohn's disease is a chronic inflammatory disorder of the bowel. In a preliminary study, we evaluated whether the administration of growth hormone (somatropin) as well as a high-protein diet would ameliorate the symptoms of the disease. METHODS: We randomly assigned 37 adults with moderate-to-severe active Crohn's disease to four months of self-administered injections of growth hormone (loading dose, 5 mg per day subcutaneously for one week, followed by a maintenance dose of 1.5 mg per day) or placebo. We instructed all patients to increase their protein intake to at least 2 g per kilogram of body weight per day. Patients continued to be treated by their usual physicians and to receive other medications for Crohn's disease. The primary end point was the change in scores on the Crohn's Disease Activity Index from base line to month 4. Scores can range from 0 to 600, with higher scores indicating more disease activity. RESULTS: At base line, the mean (+/-SD) score on the Crohn's Disease Activity Index was somewhat higher among the 19 patients in the growth hormone group than among the 18 patients in the placebo group (287+/-134 vs. 213+/-120, P=0.09). Three patients in the placebo group withdrew before their first follow-up visit and were not included in the data analysis. At four months, the Crohn's Disease Activity Index score had decreased by a mean of 143+/-144 points in the growth hormone group, as compared with a decrease of 19+/-63 points in the placebo group (P=0.004). Side effects in the growth hormone group included edema (in 10 patients) and headache (in 5) and usually resolved within the first month of treatment. CONCLUSIONS: Our preliminary study suggests that growth hormone may be a beneficial treatment for patients with Crohn's disease.     

The effect of various regimens of hormone replacement therapy on mammographic breast density

OBJECTIVES: To evaluate the effect of three distinct hormone replacement therapy regimens on mammography. METHODS: 121 postmenopausal women who had never received or were past users of hormone replacement therapy were studied prospectively. Women with an intact uterus were randomly allocated either to conjugated equine estrogens 0.625 mg plus medroxyprogesterone acetate 5 mg (CEE/MPA, n=34) or to 17beta-estradiol 2 mg plus norethisterone acetate 1 mg (E(2)/NETA, n=35). Hysterectomized women received CEE 0.625 mg (CEE, n=25). Women who either declined or did not qualify for treatment served as controls (n=27). Treatment was continuous and the study period lasted 12 months. Main outcome measures were the changes according to Wolfe classification between baseline and 12-month-mammograms. RESULTS: No increase in breast density was identified in any of the women in the control group. Two women (8%) in the CEE group showed an increase in breast density. Four women (11.8%) in the CEE/MPA and 11 women (31.4%) in the E(2)/NETA group revealed an increase in breast density. No woman in the therapy groups showed an involution of fibroglandular tissue while seven women (25.9%) in the control group exhibited involution of breast parenchyma. CONCLUSIONS: Our study suggests that hormone replacement therapy may suspend breast involution but does not increase breast density in the majority of patients. In the minority of patients who show a density increase, the magnitude of this increase varies according to the regimen employed.     

Climacteric skin ageing of the face--a prospective longitudinal comparative trial on the effect of oral hormone replacement therapy.

BACKGROUND: It is still a matter of debate whether HRT improves the physical quality of sun damaged skin. OBJECTIVES: To compare in a prospective longitudinal study the effects of climacteric aging controlled or not by HRT upon the tensile properties of facial skin. METHOD: A total of 140 women aged 40-52 years were enrolled in the study. The HRT group comprised 90 volunteers and a control group encompassed 50 non recipient volunteers. Yearly measurements of tensile functions of facial skin were performed for 5 years. A computerized suction device equipped with a 2-mm diameter hollow probe derived tensile variables quantifying skin distensibility, viscosity and elasticity. RESULTS: Climacteric aging was characterized by increased skin distensibility (1.1% per year) and viscosity (1.3% per year) mirrored by a decrease in elasticity (1.5% per year). HRT helped mitigate such changes. However, the HRT efficacy was not similar in all volunteers. Groups of good and poor responders were clearly identified as far as benefit on skin elasticity was concerned. CONCLUSION: The beneficial effect of HRT upon climacteric skin aging of the face is confirmed, at least in a subgroup of menopausal women.     

Beneficial effect of hormone replacement therapy on weight loss in obese menopausal women

Objective: at the onset of menopause, weight-gain and the aggravation of certain cardiovascular risk factors are frequently observed. The aim of this study was to examine the metabolic effects of combined hormone replacement therapy (17β-oestradiol transdermic 50 μg for 21 days and oral medroxyprogesterone acetate 5 mg from day 10 to 21) using, in particular, indirect calorimetry. Methods: patients (21; 12 substituted and nine controls) were studied twice (3 months apart) during an oral glucose load (75 g). Results: total body weight was unaltered after 3 months in the control group, whereas a fat-loss of 2.1±0.2 kg and a decrease of the waist:hip ratio were observed in the substituted group. In the latter group, a significant increase in lipid oxidation was observed (0.58±0.06 mg/kg/min before and 0.75±0.04 mg/kg/min after substitution P<0.05), whilst total energy expenditure and thermogenesis were also increased. Glucose, lipid and protein oxidation remained stable during three months in the control group. The insulin response to an oral glucose load diminished by 30% with hormone replacemnet therapy (102.3±32.8 mμ/l versus 71.4±20.0 mμ/l). Total and LDL-cholesterol improved after hormone replacement therapy whereas plasma triglycerides were not altered. Conclusions: combined hormone replacement therapy not only prevented weight-gain, but favored weight-loss by significantly increasing lipid oxidation after 3 months of treatment. It also favourably influenced the insulin response, plasma lipids and energy expenditure.