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.     

Development of endometrial cancer in women on estrogen and progestin hormone replacement therapy

The presenting symptoms, hormonal regimens, treatment modalities, tumor pathology, and follow-up of 25 women developing endometrial cancer while receiving postmenopausal estrogen and progestin therapy were investigated retrospectively. Patients were interviewed and hormone therapies were confirmed through medical records. Pathology specimens were reviewed. Patients received conjugated estrogens (n = 20) or another estrogen (n = 5). For those on conjugated estrogens, the mean daily dose was 0.68 mg, monthly duration was 24.9 days, and monthly dose was 17.0 mg. Women also received medroxyprogesterone acetate (n = 23) or norethindrone acetate (n = 2). The most common regimen was sequential medroxyprogesterone acetate, at a mean daily dose of 7.5 mg, monthly duration of 9.3 days, and monthly dose of 68 mg (mean duration = 5.7 years). Most tumors were low stage and grade, with few demonstrating grade 3 disease (n = 2) or greater than 50% myometrial invasion (n = 2). Twenty-three (92%) had disease limited to the uterus, while two had stage IIIA disease. All are alive and disease-free after a median follow-up of 26 months. Estrogen and progestin therapy does not prevent endometrial cancer in all patients. Women who developed this tumor on sequential therapy in general received less than the recommended guidelines for daily dosage and monthly duration of progestin. Most patients had early-stage and low-grade disease. Continued vigilance in the care of women on hormone replacement therapy is necessary even when combination therapy is prescribed.     

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.     

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.     

Growth hormone in postmenopausal women after long-term oral estrogen replacement therapy

Studies of estrogen effects on growth hormone (GH) and its pulsatile release in postmenopausal women have typically utilized estrogen replacement therapy (ERT) of relatively short duration (days to weeks). The purpose of this study was to compare GH measures from healthy postmenopausal women who were on oral ERT for 3 years or more (n = 24; mean ERT duration = 16.1 years) with women not on ERT (NERT; n = 40). Blood samples were drawn remotely every 20 min for 24 h and then analyzed for mean 24-h GH, mean GH during sleep, and mean 24-h insulin-like growth factor-I (IGF-I). GH peak analyses were also performed. Mean 24-h GH and GH during sleep were significantly higher and IGF-I was significantly lower in ERT women compared with NERT women. In addition, use of long-term ERT was associated with more GH peaks relative to women not on ERT, but no change in GH peak amplitude or area. GH was not related to age in either group. GH was strongly and negatively correlated with measures of adiposity in NERT women but not in ERT women. In conclusion, long-term oral ERT is associated with increased circulating GH and decreased IGF-I levels, even after many years of treatment.     

A case-control study of menopausal estrogen therapy and breast cancer

The association between estrogen replacement therapy and female breast cancer was studied in two Los Angeles area retirement communities. The 138 study cases of breast cancer occurring in residents younger than 75 years were compared with age- and race-matched community control subjects. The risk ratio for a total cumulative dose in excess of 1,500 mg was estimated to be 2.5 in women with intact ovaries. This increase was present using various independent sources of drug usage information but was inconsistent at low dose and undetectable in oophorectomized women. No important sources of confounding could be identified, and no risk modifiers could be identified except for a history of surgically confirmed benign breast disease. In such women with intact ovaries, the risk ratio for a high cumulative dose rose to 5.7 relative to nonusers with normal breasts.     

Colorectal cancer and hormone replacement therapy: an unexpected finding

Over the last two decades, mortality rates for colorectal cancer in many developed countries have declined in women but not in men. A role of exogenous female hormones (i.e. oral contraceptives and hormone replacement therapy (HRT) in such different trends is possible. Seven cohort studies reported information on HRT use and colorectal cancer risk, for a total of over 2,400 cases. Most studies showed relative risks (RRs) around or below unity. A significant inverse association was found in two cohort investigations, including the largest one dealing with fatal colon cancer. Of 12 case-control studies, for a total of over 5,000 cases, five reported 20-40% significant risk reductions among ever-users of HRT. Two additional investigations showed moderate, non-significant inverse associations. Studies showing an inverse association between HRT use and colorectal cancer were among the largest and best controlled ones. The apparent protection tended to be stronger among recent users. Differences in RRs by duration of HRT use and anatomic subsite were not consistent, but the protective effect seemed stronger in most recent publications. Available studies support the possibility of an inverse association between colorectal cancer and HRT, but prevention and surveillance bias cannot be ruled out.     

Menopause and hormone replacement therapy

Menopause is a normal part of life of most women and can be made easier with appropriate information about the events that occur. For those women who desire help for bothersome menopausal symptoms, effective therapy can be offered. The use of HRT for prevention is more complex. Several large randomized clinical trials, including the Women's Health Initiative (WHI) and the Heart and Estrogen Replacement Therapy Study (HERS) in the United States, are currently underway. These trials, which have as end points clinical events such as myocardial infarction, sudden death, fractures, and cancer, will provide answers to many of the questions raised in this discussion. Until the results of these trials are available, clinicians must be prudent in their recommendations and should keep their patients apprised of the relevant uncertainties of preventive HRT.     

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.     

Patterns and correlates of hormone replacement therapy use among middle-aged Australian women

In this study, we examine the patterns of use of hormone replacement therapy (HRT) among women age 51 to 60 years and describe the characteristics of women who currently use HRT, previously used HRT, and have never used HRT. A brief postal survey of 800 women in this age range was used to determine HRT status. Telephone interviews were then conducted with 258 women (111 currently using HRT, 47 who previously used HRT, and 100 who had never used HRT) to determine characteristics of women who currently or previously used HRT or never used HRT, type of HRT used, duration of use, and reasons for use and nonuse. Nearly 40% of women were currently using HRT, 14% had previously used HRT, and 47% had never used HRT. Women currently using HRT were more likely than those not using HRT to have had a hysterectomy, attribute a greater number of symptoms to the climacteric, be in paid employment, and report a greater number of visits to the doctor over the past 12 months. HRT use among Australian women in their 50s is high and rising. Hysterectomy status, the attribution of symptoms to menopause, paid employment, and health care use were the most important correlates of HRT use. Few women specified long-term prevention of osteoporosis or heart disease as a reason for taking HRT.     

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.