Progestin Hormone Replacement Therapy Research Articles

Breast Cancer Incidence and Hormone Replacement Therapy in Canada

In 2002, results of the Women's Health Initiative clinical trial indicated that the long-term risks of combined estrogen and progestin hormone replacement therapy outweighed the health benefits for postmenopausal women. The resulting decline in use of hormone replacement therapy was followed by concurrent decreases in breast cancer incidence in several countries. The aim of the current study was to determine whether similar declines occurred in Canada. Data on prescriptions for hormone therapy were obtained from a national registry of pharmacy-filled prescriptions to confirm the reported trend in use of hormone replacement therapy among approximately 1200 women aged 50-69 years who participated in the National Population Health Survey between 1996 and 2006 and whose data were extrapolated to the Canadian female population. Age-standardized incidence rates for breast cancer were obtained from the population-based Canadian Cancer Registry for the same period, and mammography rates were obtained from the Canadian Community Health Survey. Joinpoint regression was used to examine changes in trends in the use of hormone replacement therapy and breast cancer incidence. A reduced frequency of use of hormone replacement therapy was reflected in the decrease in dispensed hormone therapy prescriptions after 2002. The largest drop in use of combined hormone replacement therapy (from 12.7%, 95% confidence interval [CI] = 10.1% to 14.2%, to 4.9%, 95% CI = 3.4% to 6.8%, of all women) occurred between January 1, 2002, and December 31, 2004, among women aged 50-69 years. This drop occurred concurrently with a 9.6% decline in the incidence rate of breast cancer (from 296.3 per 100,000 women, 95% CI = 290.8 to 300.5 per 100,000 women, in 2002 to 268.0 per 100,000 women, 95% CI = 263.3 to 273.5 per 100,000 women, in 2004). Mammography rates were stable at 72% over the same period. During the period 2002-2004, there was a link between the declines in the use of hormone replacement therapy and breast cancer incidence among Canadian women aged 50-69 years, in the absence of any change in mammography rates.

2-Methoxyestradiol inhibits progesterone-dependent tissue factor expression and activity in breast cancer cells.

2-Methoxyestradiol (2ME) is an endogenous metabolite of 17β-estradiol with antiangiogenic and antitumor properties, although its mechanisms of action remain unclear. Progestins in hormone replacement therapy increase the risk of breast cancer. Progesterone also enhances the procoagulant activity and invasive potential of progesterone receptor (PR)-positive breast cancer cell lines, an effect largely mediated by induction of tissue factor (TF), the cellular activator of the coagulation cascade. Here we show that 2ME abrogates the induction TF expression in progesterone-treated breast cancer cells via a mechanism that does not involve the estrogen receptor. Instead, we demonstrate that by selectively antagonizing ERK1/2 signaling in breast cancer cells, 2ME limits the transactivation potential of ligand-bound PR and inhibits the expression of endogenous progesterone targets, such as TF and signal transducer and activator of transcription 5. We further demonstrate that 2ME can alter the phosphorylation status of PR. Thus, 2ME prevents progesterone-dependent increase in breast cancer cell invasiveness and procoagulant activity by uncoupling PR from the ERK1/2 signal transduction pathway.

Hormone replacement therapy diminishes hearing in peri-menopausal mice

We recently discovered that progestin in hormone replacement therapy (HRT) for post-menopausal women has detrimental effects on the ear and central auditory system [Guimaraes, P., Frisina, S.T., Mapes, F., Tadros, S.F., Frisina, D.R., Frisina, R.D., 2006. Progestin negatively affects hearing in aged women. Proc. Natl. Acad. Sci. – PNAS 103, 14246–14249]. To start determining the generality and neural bases of these human findings, the present study examined the effects of combination HRT (estrogen + progestin) and estrogen alone on hearing in peri-menopausal mice. Specifically, auditory brainstem responses (ABRs-sensitivity of the auditory system) and distortion-product otoacoustic emissions (DPOAEs-cochlear outer hair cell system) were employed. Middle age female CBA mice received either a time-release, subcutaneous implanted pellet of estrogen + progestin, estrogen alone, or placebo. Longitudinal comparisons of ABR threshold data obtained at 4 months of treatment revealed statistically significant declines in auditory sensitivity over time for the combined estrogen + progestin treatment group, with the estrogen only group revealing milder changes at 3, 6 and 32 kHz. DPOAE testing revealed statistically significant differences for the estrogen + progestin treatment group in the high and middle frequency ranges (15–29 and 30–45 kHz) after as early as 2 months of treatment ( p < 0.01 and p < 0.001, respectively). Statistically significant changes were also seen at 4 months of treatment across all frequencies for the combined HRT group. These data suggest that estrogen + progestin HRT therapy of 4 months duration impairs outer hair cell functioning and overall auditory sensitivity. These findings indicate that estrogen + progestin HRT may actually accelerate age-related hearing loss, relative to estrogen monotherapy; findings that are consistent with the clinical hearing loss observed in aging women that have taken combination HRT.

The D&amp;T Report

The D&amp;T Report

Long-term use of progestogens – getting the balance right: Molecular biology and the endometrium

The role of progestins in long-term treatment has recently been under scrutiny, in particular as their effects on organs other than the endometrium, such as the breast or the cardiovascular system, could give rise to undesirable reactions. The use of progestins in hormone replacement therapy has highlighted the importance of choice of progestin. Insights into the molecular biology of normal processes in the endometrium can help to find accurate markers for progestin effects and help select progestins with a better benefit–risk profile. Such insight can also lead to a better understanding of the etiology of menstrual and fertility disorders and ultimately to new therapeutic approaches.

Postmenopausal Hormone Replacement Therapy: Endometrial and Breast Effects

The history of hormone replacement therapy (HRT) dates back to the late 1800s, when animal extracts of ovaries were first used. With the development of synthetic hormones, widespread use in postmenopausal women extended throughout the industrialized world, so that by the late 1900s roughly one-third to one-half of all postmenopausal women in the United States and Europe were taking HRT. Two events changed the course of use of HRT: the association of an increased rate of endometrial carcinoma with estrogen-only HRT and the association of an increased breast cancer rate with combined estrogen and progestin HRT. This review explores the evidence of the effects of HRT on the endometrium and the breast, with emphasis on the pathologic changes.

Oestrogen plus progestin hormone replacement therapy increases venous thrombosis in postmenopausal women

QuestionDoes oestrogen plus progestin hormone replacement therapy increase the risk of venous thrombosis in postmenopausal women?Study designDouble-blind, randomised controlled trial.Main resultsIn postmenopausal women, oestrogen plus progestin hormone replacement therapy increased the risk of venous thrombosis, deep vein thrombosis and pulmonary embolism compared with placebo (see results table). Older, obese or overweight women taking hormone replacement therapy had an increased risk of venous thrombosis (see results table). The homozygous variant of Factor V Leiden was associated with an increased risk of venous thrombosis (OR 7.5, 95% CI 0.6 to 87.8).Authors’ conclusionsOestrogen plus progestin hormone replacement therapy significantly increased the risk of venous thrombosis in postmenopausal women. Increasing age, excess weight and obesity, and the Factor V Leiden genetic variant significantly increased the risk of venous thrombosis associated with this hormone replacement therapy.

Comparison of a transdermal continuous combined and an interrupted progestogen HRT

Objectives Pilot study to compare the effects of a continuous combined hormone replacement therapy (HRT) regimen with an interrupted progestogen regimen administered transdermally, upon the endometrium of postmenopausal women, the incidence of amenorrhoea and relief of menopausal symptoms. Methods Fifty-nine postmenopausal women aged 50–63 years were randomised to either (i) continuous combined regimen: combined oestrogen/progestogen skin patches (releasing continuous 50 μg estradiol and 20 μg levonorgestrel/day) or (ii) interrupted regimen: oestrogen-only patches (releasing 80 μg estradiol/day) for 4 days followed by combined oestrogen/progestogen patches (releasing continuous 50 μg estradiol and 20 μg levonorgestrel/day) for 3 days, for 6 months. An endometrial biopsy was performed at end of treatment for histological analysis. Results Thirty-three women (56%) completed the study. Significantly higher rates of amenorrhoea were observed with the interrupted than continuous combined regimen ( P < 0.0001; 25% versus 7% at 6 months). The interrupted regimen was also associated with fewer days of bleeding overall (total 20 versus 44 days during months 4–6; P = 0.001). Both regimens improved vasomotor symptoms. No endometrial hyperplasia or atypical changes were observed in endometrial biopsies. Conclusions Although significantly less bleeding was observed with the interrupted regimen, it did not have a sufficiently high incidence of amenorrhoea to render it clinically useful.

Sequentially combined estradiol valerate plus levonorgestrel therapy decreases 18:1 trans-fatty acid content of plasma lipids in healthy postmenopausal women

Trans-fatty acids (TFA) have been classified as atherogenic dietary constituents but the effect of hormone replacement therapy (HRT) on their concentrations is not known. We used a washout protocol to study the effect of long-term estrogen and combined estrogen–progestin HRT on plasma elaidate (18:1t), which is the trans isomer of oleate and the major TFA in the diet. The study group comprised 15 women receiving estradiol valerate HRT and 15 women receiving combined HRT with estradiol valerate and levonorgestrel. The concentrations of elaidate in plasma phospholipids, cholesteryl esters and triglycerides were determined by gas chromatography. At baseline, the total plasma elaidate concentration was lower in the combined HRT group than in the estradiol valerate HRT group (p < 0.01). In the combined HRT group, the concentration of elaidate increased significantly after withdrawal of HRT (p < 0.001) and decreased again to the baseline level after restart of therapy (p < 0.001). These changes were due to decreases in the concentrations of phospholipids and triglycerides; in phospholipids there was also a proportional decrease of elaidate. There were no changes in elaidate in women receiving estradiol valerate alone. Our results suggest that long-term combined HRT treatment decreases plasma TFA, which is not achieved by estrogen alone.

The influence of postmenopausal hormone replacement therapy on cognitive functioning: results from an observational study

The aim of this study was to evaluate the impact of hormone replacement therapy (HRT) upon memory deficit in a group of urban Australian women. A cohort of 493 women aged 40-80 years was tested as part of the Longitudinal Study of Ageing in Women (LAW study) at the Royal Brisbane and Women's Hospital, Brisbane, Australia. The current memory functioning of participants was evaluated using the Wechsler Memory Scale - version three (WMS-III) while pre-morbid cognitive functioning was estimated from scores on the National Adult Reading Test (NART). Memory deficit was estimated by comparing NART scores with the age-corrected scale scores of the WMS-III. Overall, NART scores correlated with WMS-III scores, consistent with the expected relationship between pre-morbid functioning and current functioning. For the sample as a whole, memory deficit was evident but mostly, age appropriate. There was considerable variation as to the extent of memory deficit within the sample. When memory functioning for women with a history of five or more years of combined oestrogen plus progestogen HRT or oestrogen replacement therapy (ERT) was compared with that of women who had never used HRT or ERT there was no evidence of any effect for either HRT or ERT on memory deficit. The use of HRT or ERT had neither a protective nor an adverse effect on memory deficit.

Effect of estradiol valerate and levonorgestrel on vaginal health

Objectives: To evaluate the effect of the combined hormone replacement therapy (HRT) estradiol valerate/levonorgestrel on vaginal symptoms, vaginal health index, vaginal pH, and vaginal cytology. Study design: A prospective, open-label study involving 32 postmenopausal women was performed in Ramathibodi Hospital, Mahidol University, Bangkok, Thailand. All the subjects received sequential oral estrogen–progestogen hormone replacement therapy, which contains 2 mg estradiol valerate and 0.15 mg levonorgestrel, for 6 months. The results in terms of vaginal health index, vaginal pH, and vaginal cytology before and after treatment were analyzed. Results: The mean age of these postmenopausal women was 52.56±3.33 years (range: 46–60 years). The mean time since the last menstrual period was 3.41±2.95 years (range: 1–15 years). The vaginal health index, which indicates vaginal health by means of scores for vaginal moistness, vaginal fluid volume, vaginal elasticity, vaginal mucosa, and vaginal pH rose significantly in all the women. The mean vaginal pH became significantly lower. The vaginal cytology showed an estrogenic effect on the karyopyknotic index (KPI) and the maturation value (MV) after 3 and 6 months of treatment. Conclusion: During estradiol valerate and levonorgestrel treatment, there were demonstrable improvements in the objective signs of vaginal atrophy: atrophic vaginal epithelium became thicker and vaginal pH lower, and the morphology of the vaginal cells was better.

New Progestogens

The progestins have different pharmacological properties depending upon the parent molecule, usually testosterone or progesterone, from which they are derived. Very small structural changes in the parent molecule may induce considerable differences in the activity of the derivative. In postmenopausal women with an intact uterus, progestins are used in combination with estrogen as hormone-replacement therapy (HRT). The development of new generations of progestins with improved selectivity profiles has been a great challenge. Steroidal and nonsteroidal progesterone-receptor (PR) agonists have been synthesised as well, although the latter are still in a very early stage of development. Several new progestins, which have been synthesised in the last 2 decades, may be considered fourth-generation progestins. These include dienogest, drospirenone, Nestorone (Population Council, New York, NY, USA), nomegestrol acetate and trimegestone. The fourth-generation progestins have been designed to have no androgenic or estrogenic actions and to be closer in activity to the physiological hormone progesterone. Drospirenone differs from the classic progestins as it is derived from spirolactone. It is essentially an antimineralocorticoid steroid with no androgenic effect but a partial antiandrogenic effect. The antiovulatory potency of the different progestins varies. Trimegestone and Nestorone are the most potent progestins synthesised to date, followed by two of the older progestins, 3-keto-desogestrel and levonorgestrel. The new molecules trimegestone, drospirenone and dienogest also have antiandrogenic activity. Following the publication of the results of the Women's Health Initiative study, the role of progestins in HRT became controversial. Unfortunately, this concern has been directed towards progestins as a class, although striking differences exist among the progestins. Natural progesterone and some of its derivatives, such as the 19-norprogesterone molecules, and the new molecules drospirenone and dienogest are not androgenic and, therefore, have no negative effect on the lipid profile. The effects of progestins on breast tissue remain controversial as well. However, depending on the progestin and the duration of application, breast cell differentiation and apoptosis may predominate over proliferation. It is still unclear if the currently available progestins are able to bind specifically to the PR isoforms PR-A or PR-B and whether this is of clinical relevance to breast cell proliferation is also unclear. Although it is likely that the new progestins may have neutral effects on the risk of coronary heart disease or breast cancer in younger postmenopausal women, this hypothesis must be confirmed in large randomised, well controlled clinical trials.

The combination of a novel selective estrogen receptor modulator with an estrogen protects the mammary gland and uterus in a rodent model: the future of postmenopausal women's health?

The Women's Health Initiative Study and other reports have created major uncertainty among postmenopausal women and physicians concerning hormone replacement therapy. We have thus investigated the possibility of replacing the progestin in hormone replacement therapy by a novel selective estrogen receptor (ER) modulator having potent and pure antiestrogenic activity in the mammary gland and uterus. As measured by changes in histology and Cdc47 labeling in the rat model, the present study shows that the stimulatory effect of estradiol in the mammary gland and uterus is efficiently blocked by simultaneous administration of the novel selective ER modulator EM-652, but bone mineral density is preserved and serum cholesterol is decreased. After the administration of 14C-labeled EM-652, we observed that there is no detectable radioactivity in the brain. Moreover, ER alpha immunoreactivity remained constant in the hypothalamus after EM-652 treatment, whereas ER alpha became almost undetectable in the mammary gland and uterus. The present data show the poor or absent access of EM-652 to the brain, whereas the effects of estrogens are efficiently neutralized in the mammary gland and uterus. Such data support the exciting possibility of a novel approach that could meet most of the needs of women's health at menopause, namely control of hot flushes and prevention of breast, uterine, and ovarian cancer as well as osteoporosis and potentially helping brain function and preventing Alzheimer's disease with no identifiable risk or negative effect.

Effects of trimonthly progestin administration on the endometrium in elderly postmenopausal women who receive hormone replacement therapy: A pilot study

Objective: The purpose of this study was to determine the effect of trimonthly progestin administration on the endometrium in elderly postmenopausal women who receive hormone replacement therapy. Study Design: This was a prospective, randomized, double-blind, placebo-controlled study at a university teaching program. Twenty-five postmenopausal women who were ≥75 years old with an intact uterus were assigned randomly to receive conjugated equine estrogens (0.625 mg/d plus medroxyprogesterone acetate 5 mg/d for 13 days every 3 months (n = 13) or placebo (n = 12) for 9 months). At the end of the 9 months, patients in the hormone replacement therapy arm continued therapy for an additional 9 months. Statistical analysis was performed with the Student t test, the χ2 test, and the Fisher exact test. Results: Transvaginal sonography was performed at baseline and at 9 and 18 months. Endometrial biopsy was performed if the endometrial thickness was >4 mm or as clinically indicated at 18 months. Patients in the hormone replacement therapy group demonstrated a significant increase in endometrial thickness between baseline (3.9 + 0.8 mm) and 9 months (8.0 + 4.8 mm). There were no cases of endometrial hyperplasia at the 18-month endometrial biopsy. Conclusion: Trimonthly progestin administration in elderly postmenopausal women who receive hormone replacement therapy may be a reasonable alternative to the monthly administration of progestin in hormone replacement therapy. (Am J Obstet Gynecol 2003;189:11-5.)

Trends in Incidence Rates of Invasive Lobular and Ductal Breast Carcinoma

Research has suggested that use of combined estrogen and progestin hormone replacement therapy (CHRT) increases breast cancer risk and that CHRT use is more strongly associated with the risk of invasive lobular breast carcinoma than that of invasive ductal carcinoma. Lobular carcinoma is less common than ductal carcinoma but can be more difficult to diagnose because of its subtle elusive infiltrative pattern. To evaluate trends in invasive lobular and ductal carcinoma incidence rates from 1987 through 1999, during which time use of CHRT increased in the United States. Descriptive epidemiologic study. Nine cancer registries that participate in the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute and that cover Atlanta, Ga; Detroit, Mich; San Francisco-Oakland, Calif; Seattle, Wash; and Connecticut, Hawaii, Iowa, New Mexico, and Utah. Women 30 years of age and older residing in the areas covered by the 9 SEER registries. Proportional changes in incidence rates of invasive lobular and ductal carcinoma among women with no prior history of breast cancer. A total of 190 458 women were included in this analysis who were identified through the registries as having invasive breast cancer; 7682 of the 198 140 potentially eligible women (ie, those identified as not having in situ breast cancer) were excluded from this analysis because stage of cancer was unknown. Invasive breast cancer incidence rates adjusted for age and for SEER historic stage increased 1.04-fold (95% confidence interval [CI], 1.004-1.07) from 1987-1999 (206.7/100 000 to 214.1/100 000, age-adjusted). However, incidence rates of tumors classified as lobular increased 1.52-fold (95% CI, 1.42-1.63), and those classified as mixed ductal-lobular increased 1.96-fold (95% CI, 1.80-2.14); rates of these types combined increased 1.65-fold (95% CI, 1.55-1.78) (19.8/100 000 to 33.4/100 000, age-adjusted). In contrast, ductal carcinoma rates remained largely constant (153.8/100 000 to 155.3/100 000, age-adjusted; proportional change, 1.03 [95% CI, 0.99-1.06]). The proportion of breast cancers with a lobular component increased from 9.5% in 1987 to 15.6% in 1999. Ductal carcinoma incidence rates remained essentially constant from 1987-1999 while lobular carcinoma rates increased steadily. This increase presents a clinical challenge given that lobular carcinoma is more difficult to detect than ductal carcinoma by both physical examination and mammography.

A prospective study of different types of hormone replacement therapy use and the risk of subsequent breast cancer: the women's health in the Lund area (WHILA) study (Sweden).

Reports suggest that combined estrogen plus progestin hormone replacement therapy (HRT) confers a higher breast cancer risk than estrogen alone. We aimed to establish whether breast cancer risk depends on the type of HRT formula. The cohort consisted of 6586 women, aged 50-64 years, from the Lund area, Sweden, with no reported breast cancer upon inclusion. We obtained information such as HRT use through a questionnaire between December 1995 and February 2000. New breast cancers were identified through the South Swedish tumor registry. Between inclusion and December 2001, 101 women developed breast cancer. Only ever use of the continuous combined estrogen plus progestin (CCEP) formula differed between cases and controls (45.2% versus 23.5%; p = 0.000001). Compared with never users, exclusive CCEP users had the highest age-adjusted hazard ratio HR 3.3 (95% CI: 1.9-5.6; p < 0.001), followed by users of CCEP in addition to other HRT formulas HR 2.8 (95% CI: 1.4-5.5; p = 0.003). No significant increase was seen in women who exclusively used other HRT formulas. Women who used CCEP had over three times the risk of developing breast cancer compared with never users and twice the risk compared with users of other types of HRT.

Hormone Replacement Therapy and the Risk of Invasive Epithelial Ovarian Cancer in Swedish Women

Estrogen replacement therapy (ERT), which is mainly used to relieve climacteric symptoms, increases a woman's risk for uterine endometrial cancer and epithelial ovarian cancer (EOC). Estrogens are often combined with progestins in hormone replacement therapy (HRT) to reduce the risk of uterine endometrial cancer. Data on the association between HRT including progestins and EOC risk are limited. This nationwide case-control study examined EOC risk in relation to HRT regimens with sequentially added progestins (HRTsp) and continuously added progestins (HRTcp). Between 1993 and 1995, we enrolled 655 histologically verified incident case patients with EOC and 3899 randomly selected population controls, all 50-74 years of age. Data on HRT use were collected through mailed questionnaires. Multivariate-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by the use of unconditional logistic regression. Risks of EOC were elevated among ever users as compared with never users of both ERT (OR = 1.43, 95% CI = 1.02 to 2.00) and HRTsp (OR = 1.54, 95% CI = 1.15 to 2.05); risks were elevated for serous, mucinous, and endometrioid subtypes. For all EOC types combined, the greatest risk increases were seen with hormone use exceeding 10 years. Ever use of HRTcp was not associated with increased EOC risk relative to HRTcp never use (OR = 1.02, 95% CI = 0.73 to 1.43). The risk of EOC was elevated among HRTsp ever users as compared with HRTcp ever users (OR = 1.78, 95% CI = 1.05 to 3.01). ORs for EOC after ever use of low-potency estrogens were 1.18 (95% CI = 0.89 to 1.55) for oral and 1.33 (95% CI = 1.03 to 1.72) for vaginal applications, but no relationship was seen between EOC risk and duration of use. Ever users of ERT and HRTsp but not HRTcp may be at increased risk of EOC.

Constant estrogen, intermittent progestogen vs. continuous combined hormone replacement therapy: tolerability and effect on vasomotor symptoms

Objective: To compare the efficacy and tolerability of a novel oral constant estrogen plus intermittent progestogen hormone replacement therapy (HRT) regimen to a continuous combined HRT regimen in postmenopausal women. Methods: Subjects were randomly assigned to receive treatment with either constant 17β-estradiol (E 2), 1 mg, plus intermittent norgestimate (NGM) 90 μg (3 days off, 3 days on) ( n=221) or E 2 2 mg/norethisterone acetate (NETA) 1 mg ( n=217) for 1 year. Treatments were evaluated based on the incidence of hot flushes and uterine bleeding. Results: Both regimens had similar bleeding profiles and provided comparable vasomotor symptom relief. However, breast discomfort and edema were experienced by twice as many subjects who received E 2/NETA. Conclusions: The constant E 2/intermittent NGM regimen was well tolerated and possesses similar efficacy compared with a continuous combined E 2/NETA regimen and may be considered whenever HRT without withdrawal bleeding is deemed appropriate.

Clinical evidence supporting the rationale for constant oestrogen, intermittent progestogen hormone replacement therapy

Hormone replacement therapy (HRT) effectively relieves vasomotor and other symptoms associated with menopause, yet is underutilised by the majority of menopausal women. Current HRT regimens combine continuous oestrogen with continuous or sequential progestogen in order to achieve the beneficial effects of oestrogen while avoiding the potential for increased risk of endometrial cancer. Uterine bleeding and other adverse progestogenic effects are major reasons for patient noncompliance and early discontinuation of combination HRT, which can ultimately limit the achievement of long-term oestrogenic benefits. A novel constant 17β-oestradiol, intermittent norgestimate regimen has been developed based on theoretical hormone receptor dynamics in an attempt to minimise the hormonal doses needed, thereby potentially reducing the occurrence of adverse effects associated with higher oestrogen and progestogen doses. Clinical trial data with this novel low-dose HRT regimen demonstrate effective relief of vasomotor symptoms in postmenopausal women, acceptable bleeding rates, no endometrial hyperplasia, beneficial effects on lipids, and excellent tolerability. This regimen has the potential to increase long-term use resulting in important clinical benefits.

Hormone Replacement Therapy in Relation to Risk of Lobular and Ductal Breast Carcinoma in Middle-Aged Women

BACKGROUND In the majority of studies, long term, recent use of hormone replacement therapy has been associated with an increased risk of breast carcinoma. However, little attention has been paid to the possibility that the magnitude of this association may vary according to the histologic type of breast carcinoma. METHODS In this population-based case–control study, interviews were conducted with 537 female residents of King County, Washington who were ages 50–64 years and who had been diagnosed with primary breast carcinoma between January 1, 1988 and June 30, 1990. Interviews with 492 randomly selected King County women without a history of breast carcinoma served as a basis for comparison. Analyses were performed separately for women with lobular and for those with ductal tumors. RESULTS Compared with nonusers of menopausal hormones, those who currently were using combined estrogen and progestin hormone replacement therapy (CHRT) and had done so for at least 6 months had an elevated risk of lobular breast carcinoma (odds ratio [OR] = 2.6; 95% confidence interval [95% CI], 1.1–5.8), but no change in their risk of ductal breast carcinoma was noted (OR = 0.7; 95% CI, 0.5–1.1). The OR associated with current use of unopposed estrogen for at least 6 months was 1.5 (95% CI, 0.5–3.9) for lobular tumors and 0.7 (95% CI, 0.4–1.1) for ductal tumors. Similar results were found when cases of invasive tumor were analyzed separately. CONCLUSIONS The results of this study suggest that CHRT use increases the risk of lobular, but not ductal, breast carcinoma in middle-aged women. Cancer 2000;88:2570–7. © 2000 American Cancer Society.