Hormonal replacement therapy and breast cancer]

Hormonal replacement therapy is prescribed more and more frequently to increase quality of life and decrease the symptomatic and organic consequences of the menopausal status. The different studies which analyzed the risk of breast cancer for women under hormonal replacement therapy show opposed conclusion. We reviewed articles published between 1980 and 1997 to try to conclude about the consequences of the action of this treatment in the risk of breast cancer from the characteristic of the hormonal replacement therapy and from known risk of breast cancer. Hormonal replacement therapy increases the incidence of breast cancer. Risk increase with the treatment duration and a low estrogen dose would be sufficient to palliate to the hormonal lack (< 0.625 mg/j). The risk of breast cancer becomes the same that this of women without hormonal replacement treatment when treatment interrupted. The association of estrogen and progestin should not be protective of breast cancer. But the hormonal treatment seems to be synergistic for the risk of breast cancer with late menopause, late age at the birth of first child. Hormonal treatment could increase the estrogenic period and should increased the risk of breast cancer in women with late age at menarche, late age at menopause and late age at first child. It should not increase the risk of breast cancer in women with benign breast disease, with family history of breast cancer and in nulliparous women. For women who undergone a bilateral oophorectomy before hormonal replacement treatment the risk would be the same than for women with natural menopause and without hormonal replacement treatment. However breast cancer should be diagnosed earlier in women with hormonal treatment because mammographies were made more frequently. Overall survival should not different between the women who were under hormonal therapy and theses were not.     

The role of hormone replacement therapy in the risk for breast cancer and total mortality in women with a family history of breast cancer

BACKGROUND: The risks and benefits of hormone replacement therapy (HRT) are of considerable interest and importance, especially in terms of whether they differ among subsets of women. OBJECTIVE: To determine whether HRT is associated with increased risks for breast cancer and total mortality in women with a family history of breast cancer. DESIGN: Prospective cohort study. SETTING: Population-based sample of midwestern post-menopausal women enrolled in an observational study of risk factors for cancer. PARTICIPANTS: Random sample of 41,837 female Iowa residents 55 to 69 years of age. MEASUREMENTS: Incidence rates of and relative risks for breast cancer (n = 1085) and total mortality (n = 2035) through 8 years of follow-up were calculated by using data from the State Health Registry of Iowa and the National Death Index. RESULTS: A family history of breast cancer was reported by 12.2% of the cohort at risk. Among women with a family history of breast cancer, those who currently used HRT and had done so for at least 5 years developed breast cancer at an age-adjusted annual rate of 61 cases per 10,000 person-years (95% CI, 28 to 94 cases); this rate was not statistically significantly higher than the rate in women who had never used HRT (46 cases per 10,000 person-years [CI, 36 to 55 cases]). Among women with a family history, those who used HRT had a significantly lower risk for total mortality than did women who had never used HRT (relative risk, 0.67 [CI, 0.51 to 0.89]), including total cancer-related mortality (relative risk, 0.75 [CI, 0.50 to 1.12]). The age-adjusted annual mortality rate for women using HRT for at least 5 years was 46 deaths per 10,000 person-years (CI, 19 to 74 deaths); this is roughly half the rate seen in women who had never used HRT (80 deaths per 10,000 person-years [CI, 69 to 92 deaths]). CONCLUSIONS: These data suggest that HRT use in women with a family history of breast cancer is not associated with a significantly increased incidence of breast cancer but is associated with a significantly reduced total mortality rate.     

Hormonal events during female puberty in relation to breast cancer risk

Cigarette smoking among adolescents continues to be a major public health problem in the United States. Smoking trends from 1976-1977 to 1992-1994 were examined in the Bogalusa Heart Study, an investigation of cardiovascular disease risk factors among black and white, male and female adolescents in a semirural town in the southern United States. Age-race-sex specific chi 2 tests for trends over five survey periods were conducted. In almost every age group, black boys and girls were less likely to be current smokers or to have ever smoked or tried cigarettes, as compared with white boys and girls, respectively (P < 0.01). Within age groups, few significant trends in smoking status from 1976-1977 through 1992-1994 were observed among white boys and girls. Among black males and females, however, sharp decreases were observed among all age groups in the prevalence of having ever smoked or tried cigarettes (P = 0.0001) and among the older age groups in the prevalence of being a current smoker (P = 0.0001). Thus, substantial declines in the prevalence of smoking were observed among black children but not among white children. Further research is required to understand why these ethnic differences in smoking occurred so that public health programs may target further the smoking behaviors in children.     

Hormone replacement therapy and breast cancer: revisiting the issues

OBJECTIVE: To assess current ideas about the benefits and risks of estrogen and hormone replacement therapy (ERT/HRT) in postmenopausal women. DATA SOURCES: MEDLINE searches, supplemented by various texts, of the literature on HRT, ERT, and selective estrogen receptor modulators (SERMs): tamoxifen, toremifene, and raloxifene. DATA SYNTHESIS: HRT is primarily used for improving quality of life in women suffering from vasomotor symptoms associated with menopause. HRT is beneficial in postmenopausal women for preventing cardiovascular disease, osteoporosis, and Alzheimer's disease. Review of meta-analyses of clinical trials showed that ERT/HRT ever-users (patients who have ever used ERT/HRT) did not have an increased risk of breast cancer, but current users did have an increased risk, with some studies reporting increasing risk with duration of ERT. No relationship was found between dose or the addition of progestin to ERT and increased breast cancer risk. Overall breast cancer mortality rates associated with HRT were decreased in current users. In general, HRT does not increase the risk of breast cancer in women with a family history of the disease, compared with those without a family history. New HRT strategies that could potentially prevent breast cancer are now being developed. The SERMs tamoxifen and toremifene appear to have positive clinical effects on bone and serum lipids; they are currently being investigated for use as breast cancer chemopreventive agents. Raloxifene, a new SERM used for the prevention of osteoporosis, is an alternative for women who cannot tolerate HRT. Unfortunately, these SERMS have anti-estrogenic effects and thus cause vasomotor adverse effects such as hot flashes and vaginal dryness. In addition, SERMs do not protect against heart disease or prevent osteoporosis as well as does HRT. CONCLUSION: Presently, SERMs will not become first-line HRT, as the positive effects of ERT/HRT may outweigh any potentially increased risk of breast cancer. The development of new agents with pharmacodynamic profiles similar to that of ERT/HRT but lacking its adverse effects would be greatly beneficial for postmenopausal women.     

DHEA as physiological replacement therapy at menopause

BACKGROUND: We report on a case of combined sciatic nerve block and 3-in-1 block for amputation of lower limb in an ASA IV-V patient 6 days after intraoperative cardiopulmonary resuscitation following induction of general anaesthesia. CASE REPORT: A 54-year old male patient was admitted for necrosectomy of a crural ulcer due to end-stage peripheral vascular disease and non-insulin dependent diabetes mellitus. The patient also suffered from toxic cardiomyopathy. After induction for general anaesthesia the haemodynamic situation deteriorated progressively and ended up in cardiac arrest with consequent successful cardiopulmonary resuscitation. The operation was cancelled and the patient was admitted to the intensive-care unit, where he was extubated after 2 days of further haemodynamic stabilisation. Following development of a septic situation of the lower limb the patient was again admitted for amputation six days after the cardiopulmonary resuscitation. Regional anaesthesia was conducted with a combination of a sciatic nerve block via the posterior approach and a 3-in-1 block facilitated by ultrasonographic guidance. For each of the blocks we used 20 mL mepivacaine 1%. Sensory blockade was sufficient and the patient remained haemodynamic and respiratorily stable. DISCUSSION AND CONCLUSIONS: The combined sciatic and 3-in-1 block is a rarely used technique, but for haemodynamically unstable patients it is a safe method for surgery of the lower limb.     

Age differences in attitudes toward menopause and estrogen replacement therapy

The purpose of the present study was to develop and test attitude scales for menopause and estrogen replacement therapy (ERT) using 116 college-aged and 136 mid-aged women. Factor scores indicate that mid-aged women view menopause in a more benign fashion than college-aged women and are more likely to view ERT as positive while recognizing side effects. Restricted variability on ERT attitude items suggests limited knowledge or opinions and a need for education across ages. Women's perceptions of ERT are in terms of a solution for immediate relief of symptoms in contrast to current medical recommendations that emphasize ERT as long-term disease prevention therapy.     

Risks, benefits and costs of hormone replacement therapy in menopause

OBJECTIVE: To gain insight into whether ondansetron treatment induces changes in total cholecystokinin (CCKT) plasma levels before and after administration of the cholecystokinin tetrapeptide (CCK-4) panic challenge procedure in healthy men. METHODS: Thirty-eight volunteers received a 50-microgram bolus of CCK-4 60 minutes after a single oral dose (acute treatment) and multiple oral doses (chronic treatment) of ondansetron or placebo. RESULTS: Results showed no difference in CCKT plasma levels of CCKT elimination rate constant between the ondansetron and the placebo groups after either acute or chronic treatment. CONCLUSION: Results from this study suggest that total CCK plasma levels are not influenced by either acute or chronic treatment with ondansetron. However, the effect of ondansetron on the different CCK component fractions still needs exploration.     

Hormone replacement therapy and endometrial cancer risk: a meta-analysis

OBJECTIVE: To assess the association of unopposed estrogen or estrogen plus progestin and the risk of developing endometrial cancer or dying of that disease. DATA SOURCES: A literature search of English-language studies was performed using MEDLINE, a review of bibliographies, and consultations with experts. METHODS OF STUDY SELECTION: We identified 30 studies with adequate controls and risk estimates. DATA EXTRACTION AND SYNTHESIS: Risk estimates were extracted by two authors and summarized using meta-analytic methods. The summary relative risk (RR) was 2.3 for estrogen users compared to nonusers (95% confidence interval [CI] 2.1-2.5), with a much higher RR associated with prolonged duration of use (RR 9.5 for 10 or more years). The summary RR of endometrial cancer remained elevated 5 or more years after discontinuation of unopposed estrogen therapy (RR 2.3). Interrupting estrogen for 5-7 days per month was not associated with lower risk than daily use. Users of unopposed conjugated estrogen had a greater increase in RR of developing endometrial cancer than users of synthetic estrogens. The risk for endometrial cancer death was elevated among unopposed estrogen users (RR 2.7, 95% CI 0.9-8.0). Among estrogen plus progestin users, cohort studies showed a decreased risk of endometrial cancer (RR 0.4), whereas case-control studies showed a small increase (RR 1.8). CONCLUSIONS: Endometrial cancer risk increases substantially with long duration of unopposed estrogen use, and this increased risk persists for several years after discontinuation of estrogen. Although not statistically significant, the risk of death from endometrial cancer among unopposed estrogen users is increased, similar to the increased risk of developing the disease. Data regarding risk for endometrial cancer among estrogen plus progestin users are limited and conflicting.     

Hormonal treatment of advanced breast cancer

Endocrine therapy for breast cancer has been used for almost a century, but because of the enormous success of tamoxifen there has been a resurgence of interest by the pharmaceutical industry to develop new and innovative endocrine therapies. Overall, the strategy is quite simple. Estrogen stimulates growth; therefore, the goal is to deny the breast tumor estrogens. Tamoxifen accomplishes this by blocking the estrogen receptor. The new antiestrogens, toremifene and droloxifene, however, appear to have no greater activity than tamoxifen in the treatment of advanced disease and therefore may ultimately offer no advantages over current therapy. In contrast, the pure antiestrogens hold additional promise as they may produce a more profound inhibitory effect on the tumor, and the response may be maintained longer. An orally active, pure antiestrogen, however, would be an important advance. The strategy of using GnRH agonists for premenopausal patients clearly has merit to produce a chemical oophorectomy. The strategy could be integrated into the general treatment plan for the young premenopausal patient taking tamoxifen who may not have had her menstrual cycles stopped by combination chemotherapy. The GnRH agonists would block the reflex rise in estradiol caused by tamoxifen therapy and ultimately produce a more efficient antihormonal therapy. Indeed, the different specific aromatase inhibitors can also be integrated into the treatment plan to produce a complete estrogen blockade. Whether the use will be found to be superior to pure antiestrogens, however, must await the completion of comparative clinical studies. If all the results of endocrine therapy are therapeutically similar, the final strategy may depend on the acceptability by the patient of an individual delivery method for each pharmaceutical approach.     

Hormonal therapy and genital tract cancer

Patient B.G. is a 29-yr-old female with a lifelong bleeding disorder characterized clinically by a highly increased bleeding time, menorrhagias, long-lasting bleeding after cuts and tooth extractions and large post-traumatic haematomas. Her coagulation tests were within normal range, platelet count was 140,000-160,000 per microliters, but platelet function was impaired as demonstrated by the absence of collagen-induced aggregation, although no abnormalities were detected in aggregation response to ADP and ristocetin. Morphologically her platelets were characterized by gigantic size-average profile area was about 2.5 times higher than that of control donors, and severe deficiency of alpha-granules-only 16% of their number in control donors. These features taken together indicated the diagnosis of grey platelet syndrome. As has been shown by quantitative immunoblotting, patient's platelets contained small amounts of alpha-granule membrane protein P-selectin-about 15% of that in control donors. The content of plasma membrane glycoproteins IIb-IIIa and Ib was not reduced, suggesting the specific deficiency of alpha-granule membrane protein. Thus, B.G. is the second patient described in the literature (see also Lages et al, J Clin Invest 1991: 87: 919-929) with combined deficiency of alpha-granules and P-selectin.     

Physiologic effects of steroid hormones and postmenopausal hormone replacement on the female breast and breast cancer risk

Most data demonstrate that breast cancer is hormonally influenced. For the woman with no history of breast cancer, the benefits of HRT may outweigh the risks. Although it remains the standard of care to discourage hormone use in patients who have had breast cancer, future studies may result in a change of this standard. There needs to be more research into these complex hormonal interactions so that we will have a better understanding of the true risks and benefits when we attempt to advise our patients regarding the best treatment regimens for them.     

Low biologic aggressiveness in breast cancer in women using hormone replacement therapy

In a multicenter study the metabolic effects of 5 yr of GH therapy in children with idiopathic short stature were evaluated. Patients received 0.3 mg/kg.week recombinant human GH. Of the 121 patients who entered the study, data for 62 were analyzed at the final 5 yr point. Routine laboratory determinations were available for all 62 subjects at the 5 yr point. Special laboratory determinations, such as postprandial glucose and insulin, were available for only a subset of patients. Mean insulin-like growth factor I levels rose to 283 +/- 101 micrograms/L, within the normal range using age-appropriate reference standards. T4, cholesterol, triglycerides, blood chemistries, and blood pressure showed no significant changes during the 5-yr period. Mean baseline and 2-h postprandial glucose levels remained unchanged. Both fasting and postprandial insulin levels rose substantively from low normal levels to the normal range (median, 4.9-43 mU/L). Mean hemoglobin A1c levels remained within the normal range throughout the study. In summary, careful monitoring has not revealed any currently discernible metabolic side-effects of clinical significance after GH therapy in this 5-yr study of children with idiopathic short stature.     

Is there an association between hormone replacement therapy and breast cancer?

The fear of breast cancer has been suggested as a potential reason why only a relatively small percentage of postmenopausal women who would benefit from hormone replacement therapy (HRT) are current users. The equivocal results from a large number of epidemiologic studies make it difficult to evaluate whether an association does indeed exist between the use of HRT and the incidence of breast cancer. The inability to provide conclusive evidence for or against this relationship may be attributed to methodologic problems in these studies, including small sample sizes, lack of information on specific hormonal preparations (e.g., dose and type), failure to control for the type of menopause, and surveillance bias. In an attempt to generalize results from different studies in a systematic manner, several meta-analyses have been conducted of the effects of estrogen replacement therapy (ERT) or HRT on the risk of breast cancer. This article summarizes the data from these meta-analyses and incorporates data from studies published after these meta-analyses that have addressed this question. Data from ongoing studies that use a randomized, controlled, longitudinal design on large numbers of women are necessary before a possible association between the use of HRT and breast cancer can be ascertained.