Do female sex hormones initiate breast cancer? A review of the evidence.

Over the past 2 years, the media have highlighted a number of epidemiological articles which suggest that estrogen therapy, with or without progestogens, is responsible for initiating breast cancer in postmenopausal women. However, the essential biological mutations necessary to induce a new breast cancer suggest that the increase in diagnosis is due to promotion of an already existing, but undiagnosed, oncogenic change, rather than to sex hormones initiating malignant mutations. In this review, anomalies in the hypothesis that hormonal therapy causes breast cancer are identified, the sequence of mutations which must occur prior to development of an invasive breast cancer are defined and the influence of the sex hormones on these changes is briefly reviewed. The conclusion is that sex hormones are mitogenic but not oncogenic.

Breast cancer in premenopausal women: recurrence and survival rates and relationship to hormone replacement therapy.

OBJECTIVES: To determine any association between hormonal replacement therapy (HRT) usage and breast cancer recurrence and survival rates in women who were premenopausal at the time of diagnosis of breast cancer. METHODS: The study group comprised 524 women who were diagnosed with breast cancer when they were premenopausal. Of these, 277 women reached menopause before recurrence of the disease, being lost to follow-up, or reaching the end of the study. In this group, 119 women took HRT to control menopausal symptoms. The majority took combined continuous estrogen-progestin treatment. Times from diagnosis to cancer recurrence or new breast cancer, to death from all causes, and to death from primary tumor were compared between HRT users and non-users. RESULTS: Women who used HRT after their menopause had an adjusted relative risk of recurrence or new breast cancer of 0.75 (95% confidence interval (CI), 0.29-1.95) compared to that of non-users. The relative risk of death from all causes was 0.36 (95% CI, 0.11-1.16) and that of death from primary tumor was 0.24 (95% CI, 0.05-1.14). CONCLUSION: HRT use in women who were premenopausal at the diagnosis of primary invasive breast cancer is not associated with worse outcomes in terms of breast cancer recurrence or mortality.

Pharmacokinetics of estradiol, progesterone, testosterone and dehydroepiandrosterone after transbuccal administration to postmenopausal women.

OBJECTIVE: To evaluate the pharmacokinetic profiles of estradiol, progesterone, testosterone and dehydroepiandrosterone in postmenopausal women following single and multiple dosing using a troche and the transbuccal route of administration. METHODS: Each troche contained estradiol (0.5 mg), progesterone (200 mg), testosterone (2.0 mg) and dehydroepiandrosterone (10 mg). A half troche was administered to each of six women and the plasma concentration-time profiles determined over 24 h. Thereafter, a one-half troche was taken twice daily for 2 weeks and concentrations determined over a dosage interval (12 h). Blood and saliva samples were collected at specified time intervals on the first day and again after 2 weeks. RESULTS: Each of the hormones was readily absorbed via the buccal mucous membrane. Peak plasma concentrations of estradiol and progesterone were comparable to those found normally in young menstruating women. CONCLUSION: The transbuccal route is a novel approach to provide therapy for the management of menopause-related symptoms of postmenopausal women without the need to resort to conjugated or synthesized hormones, and may overcome the poor or erratic systemic availability associated with other routes of administration.

A cohort study of topical vaginal estrogen therapy in women previously treated for breast cancer.

OBJECTIVE: To estimate the risk of recurrence of breast cancer associated with the use of topical vaginal estrogen therapy in the management of vaginal atrophy in women previously treated for breast cancer. METHODS: The study group comprised 1472 women with histologically confirmed breast cancer. In 69 of these subjects (4.7%) their only bothersome menopausal problems were vaginal symptoms. In these women, poorly absorbed topical vaginal estrogen cream or tablets were used. The response of these patients was compared with that of the rest of the database. A Cox regression analysis was performed using sex hormone usage after diagnosis as a time-dependent covariate. Disease-free interval was the outcome measured. Results are expressed as a hazard ratio with 95% confidence intervals. The hazard rate is defined as the probability of disease recurrence or of a subject dying from breast cancer over the study period. A second analysis was performed adjusting for factors known to affect breast cancer prognosis. RESULTS: Hormone usage was entered as a time-dependent covariate with disease-free interval as the outcome. Subjects who used a topical estrogen alone for menopausal symptoms had an uncorrected hazard ratio of 0.30 (95% confidence interval (CI) 0.11-0.80, p = 0.02). The corrected hazard ratio was 0.57 (95% CI 0.20-1.58, p = 0.28). The hazard rate for a subject dying was not analyzed, as there were too few numbers. CONCLUSIONS: Although the small numbers of this study preclude a definitive result, topical estrogen usage does not appear to be associated with an increased risk of recurrence of breast cancer.

Tamoxifen, hormone receptors and hormone replacement therapy in women previously treated for breast cancer: a cohort study.

OBJECTIVE: To determine the risk of recurrence of breast cancer associated with the use of hormone replacement therapy (HRT) in the management of menopausal symptoms in women previously treated for breast cancer who were taking concurrent tamoxifen or who were estrogen receptor-positive. METHODS: The study group comprised 1472 women with histologically confirmed breast cancer, of whom 342 subjects (23.2%) elected to use hormonal therapy in the management of their menopausal symptoms. Women were not excluded from treatment with hormonal therapy if they were taking adjuvant tamoxifen or if they had receptor-positive breast cancer. The response of these patients was compared with that of the rest of the database. A Cox regression analysis was performed with sex hormone usage as time-dependent covariate. Disease-free interval was the outcome measured. RESULTS: Subjects who took concurrent tamoxifen with combined continuous estrogen-progestogen therapy had a hazard ratio of 0.67 (95% confidence interval (CI) 0.14-3.24, p = 0.62), while concurrent tamoxifen and topical vaginal estrogen users had a hazard ratio of 0.31 (95% CI 0.10-2.57, p = 0.28). The hazard ratio for the estrogen-progestogen users who were estrogen receptor-positive was 0.24 (95% CI 0.10-1.49, p = 0.14). CONCLUSIONS: The use of HRT was not associated with an increased risk of recurrence of breast cancer in women taking concurrent tamoxifen or who were estrogen receptor-positive.

Effect of sequential transdermal progesterone cream on endometrium, bleeding pattern, and plasma progesterone and salivary progesterone levels in postmenopausal women.

BACKGROUND: Transdermal progesterone is being used in some countries as a purported treatment for menopausal symptoms, either alone or prescribed in conjunction with estrogen, but little information exists regarding the biological activity and effectiveness of this method of delivery of progesterone in protecting the endometrium from excess proliferation. This study was designed to evaluate the use of sequential transdermal progesterone. End-points evaluated included endometrial cellular response and bleeding pattern as well as plasma hormone levels and salivary progesterone estimations. METHOD: Twenty-seven postmenopausal women were treated with continuous transdermal estrogen (28-day cycle) and a cream containing 16, 32 or 64 mg of progesterone in each 4-cm extrusion from a tube of Pro-Feme administered daily in a sequential (days 15-28 of cycle) regimen. Blood and endometrial samples were analyzed for progesterone response prior to therapy, after the first 14 days of unopposed transdermal estrogen and following 14 days of transdermal progesterone. Saliva samples were taken during the last 14 days of the 84-day study, when the final progesterone cream therapy was being applied. RESULTS: Hormone assay indicated that physiological levels of estradiol were achieved, but progesterone levels were insufficient to induce any detectable change in the endometrium. Only one patient experienced bleeding during the study period. Levels of salivary progesterone were so variable as to be considered completely unreliable in determining the potential influence on biological activity. INTERPRETATION: Pro-Feme transdermal progesterone administered in a 16-, 32- or 64-mg daily dose for 14 days in a sequential regimen does not appear to be effective in inducing a secretory change in a proliferative endometrium. Salivary progesterone levels were not of value in managing the therapy of postmenopausal women.

Micronised transdermal progesterone and endometrial response.

Sequential transdermal progesterone administered with continuous transdermal oestrogen was insufficient to increase circulating blood progesterone concentrations or induce a secretory response in proliferating endometrium.

Bone density effects of continuous estrone sulfate and varying doses of medroxyprogesterone acetate. Ogen/Provera Study Group.

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.

Megatrials of hormonal replacement therapy.

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.

Dysfunctional uterine bleeding.

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.

Effect of hormone replacement therapy on non-invasive cardiovascular haemodynamics.

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.

Continuous combined piperazine oestrone sulphate and medroxyprogesterone acetate hormone replacement therapy--a study of bleeding pattern, endometrial response, serum lipid and bone density changes.

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.

Hormonal therapy following female genital tract cancer.

Following treatment of genital tract cancer, women are often left in an estrogen-deficient state suffering both short- and long-term effects which markedly reduce the quality of life. In the belief that sex hormones may induce an adverse effect on all these women, attending physicians often refuse to prescribe hormonal replacement therapy (HRT). In an attempt to introduce a rational approach to this problem the effect of sex hormones on genital tract cancer growth is reviewed and some general guidelines for administering sex hormones to women following treatment for genital tract cancer are developed. A plea is made to improve the well-being of patients following cancer treatment by considering the judicious use of appropriate hormonal therapy, including estrogens.

Hormone therapy following breast and uterine cancer.

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.

The effect of oestrogen on the female cardiovascular system.

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.