Barry G. Wren

A Case-control Study of Combined Continuous Estrogen—progestin Replacement Therapy among Women with a Personal History of Breast Cancer

Our objective was to examine the effect on all-cause mortality and tumor recurrence rate of combined continuous estrogen-progestin therapy given to symptomatic menopausal women with a personal history of breast cancer. We performed a nested case-control study in a cohort of women with a personal history of breast cancer. The entire database comprised 901 women with surgically confirmed breast cancer attending one of three teaching hospitals in south-eastern Sydney, Australia. Ninety had taken estrogen for relief of severe menopausal symptoms after their diagnosis and treatment of breast cancer. Most were using combined continuous estrogen-progestin therapy, usually an oral estrogen with a moderate dosage progestin. Controls were matched subjects from the same database who had not taken sex steroids after their diagnosis of cancer. The main outcome measures were all-cause mortality and recurrence of breast cancer (or new contralateral breast cancer). Relative risks (RR) were then calculated comparing sex-hormone users with matched controls. Among the 90 estrogen users, there were no deaths and only 7% developed a recurrence, compared to 17% of the nonusers (using two matched controls); RR = 0.40 (95% CI 0.17–0.93). These results suggest that short-term usage of combined continuous hormone replacement therapy (HRT) by women with a personal history of breast cancer may be safe and might even reduce the risk of recurrence. A formal prospective double-blind controlled study is needed to confirm these results.

Transdermal progesterone and its effect on vasomotor symptoms, blood lipid levels, bone metabolic markers, moods, and quality of life for postmenopausal women

Objective To determine whether transdermal progesterone cream has any effect on vasomotor symptoms, mood, sexual response, cardiovascular lipid levels, or bone mineral metabolic markers. Design A parallel, double-blind, randomized, placebo-controlled trial comparing the effect of a transdermal cream containing a progesterone (32 mg daily) with a placebo cream. Eighty postmenopausal women in the Menopause Centre at the Royal Hospital for Women, Sydney, were randomly allocated to receive either the progesterone cream or the placebo. They were evaluated using the Greene Climacteric Scale and the Menopause Quality of Life Questionnaire, as well as blood analysis for lipids and bone markers over a period of 12 weeks. Women were prescribed a cream containing either progesterone at 32 mg daily or a placebo cream for a period of 12 weeks. Results There was no detectable change in vasomotor symptoms, mood characteristics, or sexual feelings, nor was there any change in blood lipid levels or in bone metabolic markers, despite a slight elevation of blood progesterone levels. Conclusion The use of the transdermal route to administer progesterone at 32 mg daily does not seem to allow sufficient hormone to enter the body to achieve a biological effect on lipid levels, bone mineral metabolic markers, vasomotor symptoms, or moods.

A cohort study of hormone replacement therapy given to women previously treated for breast cancer

UNLABELLED Women who have been previously treated for breast cancer are usually advised to avoid hormone therapy for fear of increasing their risk of tumor recurrence. However, for some women, menopausal symptoms are so severe that their quality of life is poor. Because ethic committees are reticent to permit a double-blind randomized trial, we performed a cohort study of hormone therapy after breast cancer. METHODS The study group comprised 1472 women with breast cancer. A total of 167 subjects had used an oral or transdermal estrogen after their treatment for breast cancer. Amongst these estrogen users, 152 (91%) had also used a progestin. In total, 106 other women had used a progestin alone as a treatment for menopausal flushes and not as a treatment for breast cancer. Cox regression analysis was performed using estrogen as a time-dependent covariate with disease-free interval as the outcome. RESULTS The uncorrected hazard ratio for the estrogen-progestin users was 0.67 (95% confidence interval (CI) 0.38-1.16) and for the progestin alone users was 0.85 (95% CI 0.44-1.65). CONCLUSIONS This study was unable to demonstrate a significant increase in risk of breast cancer recurrence for women who used HRT and suggests that the time is now appropriate for a randomized prospective trial of hormone therapy after breast cancer.

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.

Megatrials of hormonal replacement therapy.

SummaryDespite 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.

Do Progestogens Reduce The Risk of Breast Cancer? A Review of the Evidence

&NA; Biological, epidemiologic, and clinical evidence for an inhibitory effect of progestogens on breast cancer cell mitosis was reviewed. There appeared to be substantial documentation that progestogens administered in a continuous regimen not only reduced the rate of spread of breast cancer but may even be responsible for reducing the incidence of new cases. Articles that suggested an association between progestogens and breast cell activity were reviewed after a literature search. Progestogens clearly influence those enzymes and signaling systems within breast cells that control the rate of mitosis. The implications for these effects of progestogens are already well known. High doses of progestogens have been used for many years to reduce the rate of secondary spread of breast cancer. Now evidence is available that mediumdose progestogens relieve some menopausal symptoms and may even reduce the risk of developing breast cancer. Even when estrogens need to be used to relieve menopausal symptoms, the concurrent use with continuous progestogen appears to protect against an adverse influence on the breast cancer.

Hormone replacement therapy after breast cancer: a review

A previous history of breast cancer has long been considered a contra-indication for hormone replacement therapy (HRT), mainly because it has been feared that HRT may promote a tumour recurrence or cause metastases. However, for a small group of such women, menopausal symptoms such as hot flushes may be so severe as to compromise quality of life. Moreover, women with earlystage breast cancer, particularly mammogram-detected disease, are at relatively low risk of death from breast cancer and thus more likely to be affected by problems such as heart disease and osteoporotic fractures which may be prevented by HRT.

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.

The origin of breast cancer.

Biological studies confirm that breast cancer is the result of an accumulation of a large number of individual genetic mutations that collectively alter elements of the complex internal signaling system of a cell. These aberrant genetic alterations, when assembled in a single breast cell, disrupt the control system to the extent that the cell functions autonomously in an erratic and irregular manner. Continual replication of a corrupted cell results in the formation of a colony of abnormal cells that may accumulate other aberrant mutations to eventually initiate cancer. What causes these mutations has been the topic of debate over a number of years, but because so many genetic alterations are involved, it is now conceded that one single factor could not possibly initiate all the changes. One plausible explanation involves a sequence of random, accidental, spontaneous mutations during normal stem cell replication. Some of these mutations may be an advantage to the host and their creation advances the functional ability of the breast, whereas abnormal mutations are usually deleted after activation of the complex apoptotic and inhibitory signaling system. When the defense system is corrupted, cells carrying the abnormal genes are able to avoid elimination, eventually passing abnormal mutations from one cell generation to the next. Accumulation of genetic abnormalities, over time, leads to development of a colony of cells that are pathologically abnormal. Biological studies confirm that cultured stem cells are capable of undergoing spontaneous mutations during mitosis, that sex hormones control the rate of mitosis, and that estrogen and progesterone therefore influence the rate that mutations occur. Accumulating the large number of mutations that eventually cause breast cancer can be achieved only if chromosomal abnormalities are carried from one generation of cells to the next to combine with genetic alterations generated spontaneously during stem cell mitosis.