Biomedical subjects
Publications and source records attributed to B G Wren.
Sequential transdermal progesterone administered with continuous transdermal oestrogen was insufficient to increase circulating blood progesterone concentrations or induce a secretory response in proliferating endometrium.
OBJECTIVE: To establish the optimum oral daily dose of medroxyprogesterone acetate with estrone sulfate for 2 years to maintain bone density. METHODS: A multicenter, double-blind study involved 568 postmenopausal women given estrone sulfate, 1.25 mg, and randomized to receive 2.5, 5, or 10 mg of medroxyprogesterone acetate. Bone density analyses of the lumbar spine and femoral neck were done at baseline and 12 and 24 months. RESULTS: There was a significant increase from baseline to 24 months in mean lumbar spine (4.0% +/- 0.27%) and femoral neck (3.2% +/- 0.28%) bone density, with no significant differences between the treatment groups. Factors most influencing bone density changes were baseline bone density and treatment duration. Significant increases were seen in the spine over 2 years; in the hip, those occurred in the first 12 months only. In both sites, lower baseline bone density resulted in greater increases. In the spine only, no previous hormone replacement therapy, higher body mass index, more than 2 years postmenopause, and nonsmoking resulted in greater gains. Once those covariates and center-to-center variations were corrected for, in the spine, the 10-mg group had smaller increases than the other groups. Changes were unrelated to age, parity, calcium, and alcohol intakes in either site. CONCLUSION: Daily estrone sulfate, 1.25 mg, with 2.5, 5, or 10 mg medroxyprogesterone acetate was effective for preventing bone loss in postmenopausal women.
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Despite the fact that estrogen replacement therapy has been demonstrated to be of great value to postmenopausal women, many patients are still reluctant to use it. This is primarily because of fears that sex hormone therapy increases the risk of developing uterine and breast cancer. Because retrospective epidemiological studies have failed to clarify the issue for breast cancer, ambitious prospective trials have been initiated to determine the role of hormones in the development of breast cancer and cardiovascular disease. The main studies have been the Women's Health Initiative, the Postmenopausal Estrogen/Progestin Intervention (PEPI) Trial, the Heart and Estrogen-Progestin Replacement Study (HERS), the Women's International Study of long Duration Oestrogen after Menopause (WISDOM) and the Million Women Study. Only the PEPI Trial has been completed. It showed a substantial benefit for women using hormone replacement therapy, but was insufficiently powerful to determine whether such therapy affected the incidence of breast cancer. Despite the immense costs involved and the considerable time that must elapse before results are published, it is imperative that these major prospective studies are completed, analysed and published. Only then can physicians advise their patients in an appropriate manner.
BACKGROUND: Dysfunctional uterine bleeding (DUB) affects about 5% of menstruating women. yet the majority of medical practitioners who manage the problem do not adequately understand the underlying pathophysiology nor the principles involved in appropriate management. OBJECTIVE: This article is an attempt to provide a brief overview of the problem and to review the current information regarding the diagnosis, incidence, cause and management of DUB. DISCUSSION: The majority of cases of DUB occur in the 5-10 years before the menopause or after the menarche, when the ovaries are in an unstable responsive state. Hormonal dysfunction is responsible for most cases of DUB and the condition will usually respond to appropriate hormonal therapy. In those instances where hormones are not a viable option or have not controlled the problem, then prostaglandin inhibitors or the use of tranexamic acid may allow short term relief from excessive bleeding. Surgery by endometrial ablation of hysterectomy should only be considered when all other options have failed.
OBJECTIVE: To determine the detailed effects of hormone replacement therapy (HRT) on non-invasive haemodynamics, including an assessment of the effect on the pulsatile afterload assessed in terms of the augmentation index and pulse-wave velocity. DESIGN: A cross-sectional study of healthy postmenopausal women using carotid and radial tonometry and pulse-wave velocity measurements. SETTING: Community-based ambulatory women attending the menopause centre at a tertiary hospital. PATIENTS: Seventy postmenopausal women divided into those not currently being administered HRT (n = 38, aged 46-72 years) and those who were being administered a variety of HRT (n = 32, aged 49-67 years). METHODS: Central arterial pressure waveforms were measured using carotid applanation tonometry to derive the augmentation index and ejection duration. The arterial pulse-wave velocity was assessed using paired carotid, radial and dorsalis tonometry waveforms. RESULTS: Women being administered HRT had a significantly lower augmentation index (20.4 +/- 8.6 versus 27.0 +/- 10.2%, P = 0.005) and shorter ejection times (320 +/- 17 versus 329 +/- 18 ms, P = 0.037). There was no significant difference in brachial blood pressure (131/76 versus 129/77 mmHg). Women being administered HRT exhibited a greater reversal in the age-related loss of amplification which occurs owing to arterial stiffening. This amplification between central and peripheral systolic blood pressures was greater among women being administered HRT (5.3 +/- 6.2 versus 2.2 +/- 4.0 mmHg, P = 0.014). There was no difference in pulse-wave velocity between the two groups. CONCLUSIONS: HRT appears to improve the pulsatile vascular afterload by decreasing the augmentation of the late systolic blood pressure. This effect is not apparent from routine brachial cuff measurements, which, as a result, may underestimate haemodynamic benefits. Such effects may help to explain a portion of the improvement in cardiovascular morbidity found in other trials.
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This pilot study was conducted to establish the optimum oral dosage of medroxyprogesterone acetate (Provera) given daily in combination with a fixed dose of piperazine oestrone sulphate (Ogen), as hormone replacement therapy. A group of 32 nonhysterectomized, symptomatic menopausal women were randomly allocated to receive piperazine oestrone sulphate 1.25 mg daily and medroxyprogesterone acetate 2.5 mg, 5 mg or 10 mg daily for a 2-year period. This was an open study and the patients were reviewed at 3-monthly intervals for 2 years. Vaginal bleeding was reported by 58% of patients after the first 3 months of treatment. There was a gradual decline in the reported incidence of bleeding over the following 6 months particularly by women in the 5 mg and 10 mg Provera group. Only 10% of patients were still recording slight bleeding in the 10 mg group at 12 months. By 24 months all the women in the 5 mg and 10 mg Provera groups had ceased bleeding. There were 2 patients in the 2.5 mg Provera group with persistent proliferative endometrium at 24 months. All the remaining patients had atrophic endometrium. There was no significant difference in serum lipid changes between the 3 groups, but there was an overall reduction in total cholesterol, triglycerides and low density lipoprotein cholesterol in all women. There was no significant difference in bone mineral density changes between the groups over the 2-year period. Endometrial protection with increased incidence of amenorrhoea, without significant adverse effects, was seen with the use of 5 mg and 10 mg of provera.
Cancers of the breast and endometrium, although hormonally-dependent, are not complete contraindications to hormonal replacement therapy. About 70% of women with endometrial cancer will be completely cured of their disease using appropriate surgical techniques and therefore can be given oestrogen without in any way compromising their long-term survival. In fact oestrogen will probably allow such women to survive longer with a higher quality of life. Most postmenopausal women with cancer of the breast should be offered an impeded oestrogen such as tamoxifen as their first line of hormonal treatment. There may be improvement in the vagina and bone calcium content following the use of this 'anti-oestrogen' but some women will continue to suffer from vasovagal symptoms. Women with breast cancer which is small, node-free and relatively non-aggressive may also do well on HRT. Because of the influence of progestogens in reducing oestrogen receptor production, in reducing the expression of various growth factors and in inducing apoptosis, it is wise to administer high-dose progestogens to these women as well as oestrogen. There is no clinical evidence that HRT administered to such women will induce any increase in tumour growth or recurrence. Women with a disease-free survival of 10 or more years can also be regarded as 'cured' and can also be offered oestrogen in conjunction with high-dose progestogens. Finally, those women with known secondary spread but who are severely disadvantaged by their oestrogen deficiency symptoms should be offered high-dose progestogens first and if their symptoms persist, then have oestrogen added to the regimen till the symptoms subside.
OBJECTIVE: To review the present state of knowledge regarding the effect of oestrogen on the female cardiovascular system (e.g. atherosclerosis, myocardial infarction, hypertension and thrombosis). DATA SOURCES: Over 100 articles (most published over the last 10 years) were reviewed. They included epidemiological, biochemical, physiological, animal and clinical studies which related to the effect oestrogens have on the cardiovascular system of postmenopausal women. These data contained a wide cross-section of results and outcomes and each study was summarised to provide the most relevant information. Where a particular study provided an opinion or result at variance with the majority opinion, that study has been discussed in greater detail. STUDY SELECTION: All published papers which appeared to be relevant to an understanding of the clinical implications of oestrogen replacement therapy and its impact on the female cardiovascular system were included in this analysis. Some papers which appeared to repeat data and results previously published were not included. DATA SYNTHESIS: The overwhelming eight of evidence from this literature review supports the concept that oestrogen reduces the risk of atherosclerosis and myocardial infarction. It also confirms that postmenopausal "natural" oestrogen is a vasodilating agent which will lead to a fall in blood pressure and an improvement in blood flow and the pulsatility index. Although oral oestrogen did appear to increase thrombogenic activity, there was no clinical evidence that "natural" oestrogen taken after the menopause increased the risk of venous thrombosis. CONCLUSIONS: The consensus of the published data is that oestrogen conveys a highly protective effect on the cardiovascular system of postmenopausal women. There will be a reduction of up to 50% in myocardial infarction and stroke, a reduction in the incidence of hypertension and an improvement in blood flow. Some of the data suggest that even for women who have suffered from an infarct, their long-term survival is enhanced by oestrogen therapy. The medical myth that oestrogen has a deleterious effect on the cardiovascular system of women is finally laid to rest.
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OBJECTIVE: To evaluate the cost-effectiveness of hormone replacement therapy in the menopause with particular reference to osteoporotic fracture and myocardial infarction. DESIGN: The multiple-decrement form of the life table was the mathematical model used to follow women of age 50 through their lifetime under the "no hormone replacement" and "hormone replacement" assumptions. Standard demographic and health economic techniques were used to calculate the corresponding lifetime differences in direct health care costs (net costs in dollars) and health effects ("net effectiveness" in terms of life expectancy and quality, in "quality-adjusted life-years"). This was then expressed as a cost-effectiveness ratio or the cost ($) per quality-adjusted life-year (QALY) for each of the chosen hormone replacement regimens. SETTING AND PATIENTS: All women of age 50 in New South Wales, Australia (n = 27,021). RESULTS: The analysis showed that the lifetime net increments in direct medical care costs were largely contributed by hormone drug and consultation costs. Hormone replacement was associated with increased quality-adjusted life expectancy, a large percentage of which was attributed to a relief of menopausal symptoms. Cost-effectiveness ratios ranged from under 10,000 to over a million dollars per QALY. Factors associated with improved cost-effectiveness were prolonged treatment duration, the presence of menopausal symptoms, minimum progestogen side effects (in the case of oestrogen with progestogen regimens), oestrogen use after hysterectomy and the inclusion of cardiac benefits in addition to fracture prevention. CONCLUSIONS: Hormone replacement therapy for symptomatic women is cost-effective when factors that enhance its efficiency are considered. Short-term treatment of asymptomatic women for prevention of osteoporotic fractures and myocardial infarction is an inefficient use of health resources. Cost-effectiveness of hormone replacement in asymptomatic women is dependent on the magnitude of cardiac benefits associated with hormone use and the treatment duration.
Oestrogen is cardioprotective for women. Not only does it have a beneficial effect on the circulating blood lipid fractions, but it is now established that oestrogen has a positive influence in preventing the deposit of cholesterol in the arterial endothelium. It also induces vasodilation, increases peripheral blood flow and leads to a fall in blood pressure. The use of oestrogen to reduce cardiovascular disease far outweighs any potential adverse changes.
One hundred post-menopausal women given HRT were reviewed 12 months after their first visit to determine their compliance with treatment. Sixty-one percent continued to take the therapy while 27% ceased. Most often the reason for ceasing HRT was return of bleeding but a number of women expressed fear of developing cancer or other long term complications.
A double-blind crossover study that compared clonidine and a placebo, which were administered to 19 postmenopausal women who were suffering from hot flushes, failed to demonstrate any statistical reduction in the number of hot flushes. Therefore, clonidine is not recommended as a treatment drug for this symptom.
Osteoporosis of the spine and femoral neck is a major problem in aging populations, but detection prior to a fracture remains a challenge. Forearm bone mineral content has been advocated as a useful screening test in this situation. We have examined the correlation between distal forearm bone mineral content, by single photon absorptiometry, and lumbar vertebral and femoral neck bone mineral density, by dual photon absorptiometry. Eighty women aged 20 to 76 years were studied and significant correlations (p less than .001) were found between the measurements on the forearm and at the two axial sites (r = 0.66 and 0.69, respectively). However, forearm bone mineral content was an unreliable predictor of axial bone mineral density. For prediction of lumbar spine osteopenia with a sensitivity of 88%, the false positive rate was 91%. Conversely, to achieve a specificity of 82%, the false negative rate was 65%. Similarly, for prediction of femoral neck osteopenia at a sensitivity of 92%, the false positive rate was 87%, and at a specificity of 90%, the false negative rate was 33%. These data demonstrate that forearm bone densitometry cannot be used as a screening procedure for osteopenia of the lumbar spine or femoral neck.
Evidence from two groups of post-menopausal women who were randomly allocated to be treated with either conjugated equine oestrogens or piperazine oestrone sulphate demonstrates that the two oestrogens produce markedly different effects on blood pressure. The conjugated equine oestrogens appear to produce no significant change in either systolic or diastolic blood pressure whereas piperazine oestrone sulphate produced a significant fall in both systolic and diastolic blood pressure. This finding is discussed in relationship to the known causes for a change in cardiovascular response to oestrogen and several hypotheses are put forward.