Estrogen-only Therapy Research Articles

Does Estrogen-Only Postmenopausal Therapy Increase Breast Cancer Risk?

No evidence of increased risk for breast cancer was found in the estrogen-only arm of the Women’s Health Initiative, yet some uncertainty remains because several retrospective studies had positive findings (Journal Watch Apr 25 2006). In this study, investigators examined national registry data from all …

International Study Supports Conventional WISDOM About Hormone Therapy

Investigators for the Women’s International Study of long Duration Oestrogen after Menopause (WISDOM) have now reported results. Participants were postmenopausal women (median age, 62.8 years) from general practices in the U.K., Australia, and New Zealand. The study goal was to assess the long-term risks and benefits of combined hormone therapy (HT, estrogen plus progestogen) versus placebo, and of estrogen-only therapy …

Hormone therapy and breast cancer risk

Hormone therapy (HT) is the most efficacious intervention for the relief of climacteric symptoms. Controversies surrounding HT have left many women puzzled and afraid. Gynecologists are faced with long-standing beneficial assumptions challenged by an abundance of robust detrimental new data, with little guidance on how to interpret these findings. Prescriptions for HT (and incidence of breast cancers in some areas) have fallen over the last 3 years due to anxiety provoked about breast cancer risk and recurrence. The current ‘clinical climate’ is against HT. Due to a lack of effective alternatives, women suffering from estrogen-deficiency symptoms are still requesting objective information about HT, particularly those at higher risk of breast cancer or those with a past history of breast cancer. In this situation, discussion of the current clinical uncertainty surrounding the use of HT must be undertaken to ensure that women are adequately informed. The objective of this presentation is to provide a framework for understanding breast cancer risk associated with HT. What are the precise molecular mechanisms of estrogen and progestin in the initiation of breast cancer? Does the risk of estrogen-only therapy on breast cancer vary by dose, constituent, route and duration of administration and cessation of use? Does HT, in addition to increasing risk for breast cancer, affect the type of breast cancer (lobular and ductal) diagnosed? Is HT associated with breast cancers that have better prognostic factors? How relevant are the changes in mammographic breast density associated with HT for the evaluation of breast cancer risk? What is the additional global health risk/benefit ratio associated with the selective use of progesterone or progestin that may confer a significant cardiovascular benefit, such as drospirenone? It is currently assumed and tested that new hormones with particular pharmacological profiles may ultimately achieve their therapeutic goal of relieving climacteric symptoms without an associated moderate increased risk of breast cancer.

Do breast cancer risk factors modify the association between hormone therapy and mammographic breast density? (United States)

To evaluate whether the association between hormone therapy (HT) and breast density differs by levels of breast cancer risk factors. We evaluated 80,867 screening mammograms from 39,296 postmenopausal women from Washington State. We estimated odds ratios and 95% confidence intervals for dense breasts (Breast Imaging Reporting and Data System categories 3 "heterogeneously dense" and 4 "extremely dense") compared to fatty breasts (categories 1 "almost entirely fat" and 2 "scattered fibroglandular") among HT users compared to never users. We separately examined former HT use and current HT use by type (estrogen plus progestin therapy (EPT) and estrogen-only therapy (ET)). We stratified the associations by age, BMI, race, family history, and reproductive and menopausal factors. Current EPT users had a 98% (1.87-2.09) greater odds of having dense breasts and current ET users had a 71% (1.56-1.87) greater odds compared to never users. Current HT users were more likely to have dense breasts if they were older, had more children, or younger at first birth compared to never users; these associations were stronger among EPT users than ET users. HT, particularly EPT, may reduce protective effects of older age, parity, and younger age at first birth on mammographic density.

Breast Cancer Risk in Postmenopausal Women Using Estrogen-Only Therapy

To evaluate whether the risk of estrogen-only therapy on breast cancer varies by dose, constituent, and route of administration. All Finnish women older than age 50 years using oral or transdermal estradiol (n=84,729), oral estriol (n=7,941), or vaginal estrogens (n=18,314) for at least 6 months during 1994-2001 were identified from the national medical reimbursement register. They were followed for breast cancer with the aid of the Finnish Cancer Registry to the end of 2002. Altogether, 2,171 women with breast cancer were identified. The standardized incidence ratio of breast cancer with systemic estradiol for less than 5 years was 0.93 (95% confidence interval 0.80-1.04), and for estradiol use for 5 years or more, 1.44 (1.29-1.59). Oral and transdermal estradiol was accompanied by a similar risk of breast cancer. The risk was most prominent with the dose greater than 1.9 mg/d orally; whereas the risk associated with transdermal route was not dose-dependent. The standardized incidence ratio for the lobular type of breast cancer (1.58) was slightly higher than that for the ductal type (1.36). The use of estradiol was associated with both localized breast cancer (1.45; 1.26-1.66) and cancer spread to regional nodes (1.35; 1.09-1.65). The incidence of carcinoma in situ (n=32) was increased (2.43; 1.66-3.42) among estradiol users. Estradiol for 5 years or more, either orally or transdermally, means 2-3 extra cases of breast cancer per 1,000 women who are followed for 10 years. Oral estradiol use for less than 5 years, oral estriol, or vaginal estrogens were not associated with a risk of breast cancer. II-2.

Combined Estrogen and Testosterone Use and Risk of Breast Cancer in Postmenopausal Women

The role of androgens in breast cancer etiology has been unclear. Epidemiologic studies suggest that endogenous testosterone levels are positively associated with breast cancer risk in postmenopausal women. Given the increasing trend in the use of hormone therapies containing androgens, we evaluated the relation between the use of estrogen and testosterone therapies and breast cancer. We conducted a prospective cohort study in the Nurses' Health Study from 1978 to 2002 to assess the risk of breast cancer associated with different types of postmenopausal hormone (PMH) formulations containing testosterone. During 24 years of follow-up (1 359 323 person-years), 4610 incident cases of invasive breast cancer were identified among postmenopausal women. Information on menopausal status, PMH use, and breast cancer diagnosis was updated every 2 years through questionnaires. Among women with a natural menopause, the risk of breast cancer was nearly 2.5-fold greater among current users of estrogen plus testosterone therapies (multivariate relative risk, 2.48; 95% confidence interval, 1.53-4.04) than among never users of PMHs. This analysis showed that risk of breast cancer associated with current use of estrogen and testosterone therapy was significantly greater compared with estrogen-only therapy (P for heterogeneity, .007) and marginally greater than estrogen and progesterone therapy (P for heterogeneity, .11). Women receiving PMHs with testosterone had a 17.2% (95% confidence interval, 6.7%-28.7%) increased risk of breast cancer per year of use. Consistent with the elevation in risk for endogenous testosterone levels, women using estrogen and testosterone therapies have a significantly increased risk of invasive breast cancer.

Changes in U.S. Prescribing Patterns of Menopausal Hormone Therapy, 2001–2003

In 2002, the combination estrogen-progestin hormone therapy (HT) treatment arm of the Women's Health Initiative was terminated early because cardiovascular and cancer risks were identified, while the estrogen-only therapy (ET) arm of this trial continued. We investigated hormone therapy prescription practice changes between 2001 and 2003 to explore the effects of the clinical trial results. Data were obtained from the National Ambulatory Medical Care Survey and the National Hospital Ambulatory Medical Care Survey for the years 2001 through 2003. These nationally representative surveys sample medical encounters in nonfederally employed physician's offices and outpatient departments of nonfederal short-stay and general hospitals. The proportion and rate of visits with ET and HT prescriptions were calculated. Logistic regression was used to estimate change over time accounting for patient and provider characteristics. Between 2001 and 2003, the number of visits with menopausal hormone prescriptions fell from 26.5 million to 16.9 million. Almost three-quarters of hormone visits were for ET prescriptions. The decrease in the rate of visits was slightly larger for HT prescription visits (44%) than ET prescription visits (35%). The rate of decline was highest among women 50 years of age and over. After controlling for covariates, there was no significant difference in the decline by hormone type. These nationally representative data indicate substantial declines in menopausal hormone prescriptions coinciding with clinical trial results on HT. These declines occurred among all types of therapy and patient characteristics. II-3.

Estrogen-Only Therapy After Hysterectomy and Breast Cancer Risk

Earlier findings from the Women’s Health Initiative indicated that, in contrast to combined estrogen-progestin therapy, 7 years of estrogen therapy

A Longitudinal Investigation of Mammographic Density: The Multiethnic Cohort

Mammographic densities are hypothesized to reflect the cumulative exposure to risk factors that influence breast cancer incidence. This report analyzed percent densities over time and explored predictors of density change in relation to age. The study population consisted of 607 breast cancer cases and 667 frequency matched controls with 1,956 and 1,619 mammographic readings, respectively. Mammograms done over >20 years and before a diagnosis of breast cancer were assessed for densities using a computer-assisted method. Using multilevel modeling to allow for repeated measurements, we estimated the effect of ethnicity, case status, reproductive characteristics, hormonal therapy, body mass index, and soy intake on initial status and longitudinal change. After integrating the area under the percent density curve, cumulative percent density was compared with age-specific breast cancer rates in Hawaii. Percent densities decreased approximately 5.6% per 10 years but a nonlinear effect indicated a faster decline earlier in life. Cumulative percent densities and age-specific breast cancer rates increased at very similar rates; both standardized regression coefficients were >0.9. Japanese ancestry, overweight, estrogen/progestin treatment, and, to a lesser degree, estrogen-only therapy predicted a slower decline in densities with age. Case status and adult soy intake were related to higher densities whereas overweight and having any child were associated with lower densities at initial status. Risk factors that influence the decline in mammographic densities over time may be important for breast cancer prevention because cumulative percent densities may reflect the age-related increase in breast cancer risk.

Alcohol consumption and mammographic density in a multiethnic population

This report examined the association between alcohol intake and breast cancer risk as assessed by mammographic densities in a multiethnic population. Information for this analysis was available from 2 previous investigations: a nutritional intervention study (The Breast, Estrogens, and Nutrition Study; BEAN) with 217 premenopausal women and a nested case-control study within The Multiethnic Cohort (MEC) with 1,250 primarily postmenopausal women. On the basis of self-reported alcohol intake from a validated food frequency questionnaire, women were categorized into abstainers (<1 drink/month), low (<1 drink/day) and high (>or=1 drink/day) alcohol consumers. On average, 3 mammograms were available per woman. Using mixed models, we calculated mean percent densities for each alcohol consumption category while adjusting for covariates. Mean alcohol intakes for women in the BEAN study and for cases and controls in the MEC study were 2.0, 2.7 and 1.8 drinks/week, respectively. Overall, the difference in densities between abstainers and the highest alcohol intake category was only 1-2% and the differences were not statistically significant. However, the difference was 3-5% for women aged 55-65 years and for breast cancer cases. In postmenopausal women without hormone replacement therapy (HRT), breast density increased by 2% for each higher alcohol intake category. Breast densities were also elevated for high alcohol consumers on estrogen-only therapy as compared to abstainers and low consumers, whereas combined HRT use was associated with higher mammographic densities independent of alcohol use. In conclusion, despite the low alcohol intake in our population, alcohol consumers had higher percent breast densities than did abstainers. The larger difference in some subgroups suggests that women with certain characteristics may be more susceptible to the influence of alcohol on breast density than others.

Effects of estrogen-only therapy on LDL oxidation in women with hysterectomy: Does paraoxonase genotype play a role?

Objectives This study investigated the effects of estrogen-only therapy on lipid profile (through susceptibility of low density lipoproteins to oxidation) and on oxidant-antioxidant parameters in surgical menopausal women. PON genotypes are also evaluated considering that they may be associated with the personal differences observed in antioxidant effects induced by estrogen. Methods Thirty women who had undergone hysterectomy + bilateral ovariectomy in the last 3 years, with causes other than malignancy were included and given estrogen-only (Premarin-Wyeth Inc. 0.625 mg/day/6 months, equine conjugated estrogen). Blood samples were collected at baseline, first and sixth month of treatment. Serum (total antioxidant activity-TAO and PON activity), erythrocyte (TBARS and catalase activity), LDL and Cu 2+ induced ox-LDL (TBARS and diene levels) samples were evaluated and PON1 192 polymorphisms were determined by PCR amplification & restriction enzyme digestion. Results At the sixth month, a higher TAO activity ( p = 0.016) and a lower eTBARS ( p = 0.028) were detected compared to the basal values. LDL and Cu induced ox-LDL TBARS levels at the sixth month of treatment were significantly ( p = 0.012 and 0.026, respectively) lower compared to the pretreatment values. Baseline eTBARS ( p = 0.007), LDL TBARS ( p = 0.044) and eCAT ( p = 0.033) activities were significantly higher in homozygote Q allele carriers compared to subjects with R allele. LDL TBARS and Cu 2+ induced ox-LDLTBARS of QQ subjects ( p = 0.018 and 0.050) as well as LDL TBARS of QR subjects ( p = 0.044) showed a significant decrease with estrogen-only treatment. Conclusions Our study drives the attention to PON polymorphism in postmenopausal women who have risk for atherosclerosis. Although our data is limited, this study is the first that focuses on the role of PON genotypes in antiatherosclerotic effects of estrogen-only and provides important points for further studies.

Breast cancer risk in the WHI study: The problem of obesity

In the climacteric, about 40% of the women have occult breast tumors the growth of which may be stimulated by hormones. Many genetic, reproductive and lifestyle factors may influence the incidence of breast cancer. Epidemiological data suggest that the increase in the relative risk (RR) of breast cancer induced by hormone replacement therapy (HRT) is comparable with that associated with early menarche, late menopause, late first birth, alcohol consumption, etc. One of the most important risk factors is obesity which exceeds the effect of HRT by far, and in overweight postmenopausal women the elevated risk of breast cancer is not further increased by HRT. As in the WHI study the majority of women was overweight or obese, this trial was unsuitable for the investigation of breast cancer risk. In the women treated with an estrogen/progestin combination, the RR of breast cancer rose only in those women who have been treated with hormones prior to the study, suggesting a selection bias. In the women not pretreated with hormones, it was not elevated. In the estrogen-only arm of the WHI study, there was no increase but a steady decrease in the RR of breast cancer during 6.8 years of estrogen therapy. This result was unexpected, as estrogens are known to facilitate the development and growth of breast tumors, and the effect is enhanced by the addition of progestins. Obese women are at high risk to develop a metabolic syndrome including insulin resistance and hyperinsulinemia. In postmenopausal women, elevated insulin levels are not only associated with an increased risk for cardiovascular disease, but also for breast cancer. This might explain the effects observed in both arms of the WHI study: HRT with relative low doses of estrogens may improve insulin resistance and, hence, reduce the elevated breast cancer risk in obese patients, whereas this beneficial estrogen effect may be antagonized by progestins. The principal options for the reduction of breast cancer risk in postmenopausal women are the prevention of overweight and obesity to avoid the development of hyperinsulinemia, the medical treatment of insulin resistance, the use of low doses of estrogens and the reduction of exposure to progestins. The latter might include long-cycles with the sequential use of appropriate progestins every 3 months for 14 days. There are large inter-individual variations in the proliferative response to estrogens of the endometrium. Control by vaginalsonography and progestin challenge tests may help to identify those women who may be candidates for low-dose estrogen-only therapy.

Postmenopausal estrogen-only therapy increased the risk of stroke but not heart disease or breast cancer

Postmenopausal estrogen-only therapy increased the risk of stroke but not heart disease or breast cancer

Clinical background of women prescribed tibolone or combined estrogen + progestogen therapies: a UK MediPlus® study

Objectives To describe and compare the history and clinical characteristics of women who were prescribed tibolone or one of the following combined estrogen + progestogen therapies (CEPT): sequential conjugated equine estrogens (CEE)/norgestrel, sequential CEE/medroxyprogesterone acetate (MPA), continuous CEE/MPA or continuous estradiol/norethisterone acetate (NETA).Methods This was a descriptive study using MediPlus®, a UK Primary Care database; 3762 women participated who, between July 1st, 1999 and June 30th, 2001, were prescribed either tibolone or one of the CEPT regimens mentioned above. Risk factors associated with endometrial cancer and breast cancer were assessed.Results The results of this study suggest that the clinical background of women who were prescribed tibolone differed from that of the women who were prescribed the combination products. More frequently than expected women who were most recently prescribed tibolone have a history of chronic breast disease, a personal history of breast cancer or a history of being prescribed (long-term) estrogen-only therapy. Furthermore, this group of women more frequently had hypertension and performed uterine procedures recorded in their medical records. This preferential prescribing of tibolone occurs at first-ever prescription of hormone therapy but is, in some instances, the underlying reason for switch behavior.Conclusion In the UK, general practitioners seem to preferentially prescribe tibolone to women with an increased risk for breast and endometrial cancer, as compared to women being prescribed other CEPT products.

Continuation rate of hormone replacement therapy in Hong Kong public health sector

Objectives: To assess the 1-year continuation rate of HRT prescribed in Hong Kong public health sector and to identify factors affecting this continuation rate. Methods: All women who received at least one dispensed prescription of estrogens between January 1998 and December 2000 from 36 specialist outpatient clinics of the Hospital Authority were selected, and observed for at least 2 years and at most 3 years. The duration of use and variables including age, types of hormones, routes of delivery, dose of estrogen, and prescribing specialty were retrieved from the central prescription database of the Hospital Authority. Results: Of 12,711 incident users of HRT, more than half were aged 50–59. Most (78.5%) of the users took conjugated equine estrogens (CEE) 0.625 mg or related products. Only a small proportion (3.0%) of women used CEE 0.3 mg. Initial estrogen prescriptions were written by gynaecologists in 86.7%. The overall 1-year continuation rate was 68.3%. The highest and lowest continuation rates were observed in women aged 40–49 and the two extreme age groups (35–39 and 70–79), respectively. Better continuation rate was observed in women taking estrogen-only therapy such as CEE or estradiol (overall 76.3%) than in women using continuous combined therapy (58.6%), sequential combined therapy (64.8%), or transdermal estrogen (60.6%). In the age group 60–69, the use of CEE 0.3 mg was associated with better continuation rate than CEE 0.625 mg. Conclusions: Better continuation rate at 1 year was associated with age younger than 60, oral route of HRT and hysterectomy.

Continuation rate of hormone replacement therapy in Hong Kong public health sector

Objectives: To assess the 1-year continuation rate of HRT prescribed in Hong Kong public health sector and to identify factors affecting this continuation rate. Methods: All women who received at least one dispensed prescription of estrogens between January 1998 and December 2000 from 36 specialist outpatient clinics of the Hospital Authority were selected, and observed for at least 2 years and at most 3 years. The duration of use and variables including age, types of hormones, routes of delivery, dose of estrogen, and prescribing specialty were retrieved from the central prescription database of the Hospital Authority. Results: Of 12,711 incident users of HRT, more than half were aged 50–59. Most (78.5%) of the users took conjugated equine estrogens (CEE) 0.625 mg or related products. Only a small proportion (3.0%) of women used CEE 0.3 mg. Initial estrogen prescriptions were written by gynaecologists in 86.7%. The overall 1-year continuation rate was 68.3%. The highest and lowest continuation rates were observed in women aged 40–49 and the two extreme age groups (35–39 and 70–79), respectively. Better continuation rate was observed in women taking estrogen-only therapy such as CEE or estradiol (overall 76.3%) than in women using continuous combined therapy (58.6%), sequential combined therapy (64.8%), or transdermal estrogen (60.6%). In the age group 60–69, the use of CEE 0.3 mg was associated with better continuation rate than CEE 0.625 mg. Conclusions: Better continuation rate at 1 year was associated with age younger than 60, oral route of HRT and hysterectomy.

Prevalence of estrogen or estrogen–progestin hormone therapy use

Objective To use nationally representative data to produce prevalence estimates of combination estrogen–progestin therapy and estrogen-only therapy by covariates, and to evaluate differences between current use of short duration (less than 5 years) and current long-term use. Methods We analyzed data from female respondents 40 years of age and older ( n = 9400) who were interviewed in the 1999 National Health Interview Survey. Hormone therapy use was categorized into four types: current estrogen–progestin therapy use, current estrogen-only therapy use, former hormone therapy use, and never use. We calculated the prevalence of hormone therapy by different levels of previously identified covariates of hormone therapy, as well as overall prevalence of hormone therapy use by length of use. Results Approximately 24% of women aged 40 years or older were current hormone users. Of these, 30% were taking estrogen–progestin therapy, and 70% were taking estrogen-only therapy. The prevalence of hormone use differed dramatically by hysterectomy status and age, and less so by many demographic, health-risk behavior, medical access, and medical history variables. Among women with no hysterectomy, the associations with many of the covariates were stronger for estrogen–progestin therapy use than for estrogen-only therapy use. Only 3% of women were estimated to be current estrogen–progestin therapy users for 5 or more years, whereas 10% were current estrogen-only therapy users for 5 or more years. Conclusion Although many women at midlife and older were current hormone users, very few were long-term users of estrogen–progestin therapy.

Estrogen-Only Therapy after Menopause Is Linked to Ovarian Cancer

Estrogen-Only Therapy after Menopause Is Linked to Ovarian Cancer

Estrogen replacement therapy in patients with endometrial cancer: prescription attitude of Belgian gynecologists

Background: Endometrial cancer is estrogen dependent and has been considered as a contraindication for HRT. Some uncontrolled studies reported no increase in recurrence in women who received ERT after they had suffered early stage endometrium cancer and many opinion leaders have mandated that early uterus cancer should not be considered as an absolute contraindication to HRT. Aim: We conducted a survey evaluating the prescription attitude of Belgian gynecologists ( n=1363) towards a case describing a patient who presents indication for ERT (climacteric symptoms and osteoporosis) and a past history of early stage endometrium cancer. Results: We obtained a 32% response rate. Overall, the physicians prescribed treatment in 67% of the cases. There was no difference in the prescription attitude in relation to gender or age of the physicians. Among the physicians who prescribed HRT, 49% stated that they would prescribe estrogen-only therapy (unopposed estrogens) and 27% would prescribe a combined estrogen-progestin therapy. Conclusion: Two out of three gynecologists, in Belgium, would accept, at least theoretically, to prescribe HRT to a woman with a history of early stage endometrial cancer, no signs of recurrence and recognized indications for HRT.

A COMPUTER MODEL TO ANALYZE THE COST-EFFECTIVENESS OF HORMONE REPLACEMENT THERAPY

This paper gives a detailed presentation of a computer model for evaluating the cost-effectiveness (CE) of hormone replacement therapy (HRT), describing the model's design, structure, and data requirements. The model needs data specified for costs, quality of life, risks, and mortality rates. As an illustration, the CE of HRT in Sweden is calculated. Two treatment strategies are evaluated for asymptomatic women: estrogen-only therapy and estrogen combined with a progestin. The model produces similar results compared with earlier studies. The CE ratios improve with the size of the risk reduction and generally with age. Further, estrogen-only therapy is associated with a lower cost per gained effectiveness unit compared with combined therapy. Uncertainty surrounding the long-term effects of HRT means that the CE estimates should be interpreted carefully. The model permits the inclusion of indirect costs and costs in added life-years, allowing the analysis to be made from a societal perspective, which is an improvement relative to previous studies.