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1.  Long-term postmenopausal hormone therapy and endometrial cancer 
Estrogen alone therapy (ET) or estrogen and progestin (EPT) as menopausal hormone therapy (HT) has been commonly used to alleviate menopausal symptoms. Treatments containing ≥10 days/month (d/m) of progestin are considered relatively safe with respect to endometrial cancer risk. However, the endometrial safety of long-term EPT regimens is uncertain.
We conducted a case-control study of 311 invasive endometrial cancer cases and 570 controls nested within the California Teachers Study cohort. We used unconditional logistic regression to obtain odds ratios (ORs) and 95% confidence intervals (95%CIs) for the association between long term HT use and endometrial cancer risk and to assess the modifying effect of body mass index (BMI).
Long-term (≥ 10 years) use of ET, sequential EPT with < 10 d/m progestin, and continuous-combined EPT (≥ 25 d/m progestin) were all associated with an elevated risk of endometrial cancer (OR: 4.5; 95%CI: 2.5–8.1, OR: 4.4, 95%CI: 1.7–11.2, and OR: 2.1; 95%CI: 1.3–3.3, respectively; all P for trend < .0001). Risk associated with short-term use was elevated only for ET preparations. The association for continuous-combined EPT was confined to thinner women (BMI < 25 kg/m2) (P for interaction: 0.03). Among heavier women (BMI ≥ 25 kg/m2), use of continuous-combined EPT was associated with a statistically nonsignificant reduction in risk.
These findings confirm that long-term use of ET, sequential EPT, or, among normal weight women, continuous-combined EPT is associated with increased risk of endometrial cancer.
PMCID: PMC2821215  PMID: 20086105
2.  Menopausal hormone therapy and subsequent risk of specific invasive breast cancer subtypes in the California Teachers Study 
Although it is well established that combined estrogen-progestin therapy (EPT) increases breast cancer risk, questions remain regarding the impact of different formulations of hormones, whether certain women are at particularly high risk, and whether risk varies by tumor subtype.
We investigated hormone therapy (HT) use in relation to breast cancer risk in the California Teachers Study cohort; after a mean follow-up of 9.8 years 2,857 invasive breast cancers were diagnosed.
Compared to women who had never used HT, women who reported 15 or more years of estrogen therapy (ET) use had 19% greater risk of breast cancer (95% Confidence Interval (CI), 1.03-1.37), while women using EPT for 15 or more years had 83% greater risk (95% CI, 1.48-2.26). Breast cancer risk was highest among women using continuous combined EPT regimens. Risks associated with EPT and ET use were increased with duration of HT use for women with body mass index (BMI)<29.9 kg/m2 but not for women with BMI≥30 kg/m2. Elevated risks associated with EPT and ET use were confined to tumors that were positive for both estrogen and progesterone receptors and those that were HER2+ but were slightly diminished for HER2- tumors.
Breast cancer risks increased with longer duration of ET and EPT use, and risks were highest for continuous-combined EPT use. Further, risks varied by BMI and tumor subtype.
These findings underscore the need for personalized risk-benefit discussions with women contemplating HT use.
PMCID: PMC2936672  PMID: 20699377
3.  Long-term Use of Continuous-Combined Estrogen-Progestin Hormone Therapy and Risk of Endometrial Cancer 
Cancer causes & control : CCC  2011;22(12):1639-1646.
The daily administered dose of progestin in continuous-combined estrogen-progestin therapy is provided to counteract the proliferative effect of estrogen on the postmenopausal endometrium. However, there remains some uncertainty as to whether use of such a combined regimen, over the long-term, is associated with an altered risk of endometrial cancer. We pooled data from four population-based case-control studies of endometrial cancer in western Washington State. Cases, ages 45–74, were diagnosed between 1985 and 2005. Using logistic regression with adjustment for confounding factors, women who had exclusively used continuous-combined estrogen-progestin therapy (90 endometrial cancer cases, 227 controls) were compared to women who had never used any type of hormone therapy (774 cases, 1116 controls). Associations with duration and recency of use were evaluated overall and within strata defined by body mass index. Long-term use of continuous-combined estrogen-progestin therapy (≥10 years) was associated with a reduced risk of endometrial cancer (OR=0.37, 95% CI: 0.21–0.66). This association was most pronounced in women with a body mass index ≥30 kg/m2 (OR=0.19, 95% CI: 0.05–0.68). Associations did not differ according to recency of use. These results suggest that long duration of use of continuous-combined estrogen-progestin therapy is associated with a reduced risk of endometrial cancer risk.
PMCID: PMC3206981  PMID: 21909949
endometrial cancer; hormone therapy; estrogen; progestin; body mass index
4.  Does Hormone Therapy Counter the Beneficial Effects of Physical Activity on Breast Cancer Risk in Postmenopausal Women? 
Cancer causes & control : CCC  2011;22(3):515-522.
Studies consistently demonstrate that physical activity is inversely associated with postmenopausal breast cancer. Whether this association is stronger among non-hormone users or former users of menopausal hormone therapy (HT) is of interest given the marked decline in HT use since 2002.
The Women’s Contraceptive and Reproductive Experiences Study, a population-based case-control study of invasive breast cancer, recruited white women and black women ages 35–64 years, and collected histories of lifetime recreational physical activity and HT use including estrogen-alone therapy (ET) and estrogen plus progestin therapy (EPT).
Among postmenopausal women (1908 cases, 2013 control participants), breast cancer risk declined with increasing levels of lifetime physical activity among never HT users; among short-term HT users (fewer than 5 years); and current ET users; Ptrend values ranged from 0.004 to 0.016. In contrast, physical activity had no significant association with risk among long-term and past HT users and among current EPT users. No statistical evidence of heterogeneity was demonstrated for duration or currency of HT use.
Breast cancer risk decreases with increasing lifetime physical activity levels among postmenopausal women who have not used HT, have used HT for less than 5 years, or are current ET users yet this study was unable to demonstrate statistically that HT use modifies the relationship between physical activity and breast cancer. With profound changes in HT use occurring since 2002, it will be important in future studies to learn whether or not any association between physical activity and breast cancer among former HT users is a function of time since last HT use.
PMCID: PMC3229264  PMID: 21213036
Hormone therapy; physical activity; breast cancer
5.  Postmenopausal endometrial cancer risk and body size in early life and middle age: prospective cohort study 
British Journal of Cancer  2012;107(1):169-175.
Greater adiposity in early life has been linked to increased endometrial cancer risk in later life, but the extent to which this association is mediated through adiposity in later life is unclear.
Among postmenopausal women who had never used menopausal hormone therapies and reported not having had a hysterectomy, adjusted relative risks (RRs) of endometrial cancer were estimated using Cox regression.
Among 249 791 postmenopausal women with 7.3 years of follow-up on average (1.8 million person-years), endometrial cancer risk (n=1410 cases) was strongly associated with current body mass index (BMI) at baseline (RR=1.87 per 5 kg m−2 increase in BMI, 95% confidence interval (CI): 1.77–1.96). Compared with women thinner than average at age 10, the increased risk among women plumper at age 10 (RR=1.27, 95% CI: 1.09–1.49) disappeared after adjustment for current BMI (RR=0.90, 95% CI: 0.77–1.06). Similarly, compared with women with clothes size 12 or less at age 20, the increased risk among women with clothes size 16 or larger (RR=1.87, 95% CI: 1.61–2.18) was not significant after adjustment for current BMI (RR=1.03, 95% CI: 0.88–1.22).
Among women who have never used hormone therapy for menopause, the association between body size in early life and endometrial cancer risk in postmenopausal women can be largely explained by women's current BMI.
PMCID: PMC3389421  PMID: 22644298
endometrial cancer; body mass index; obesity; childhood obesity
Results from studies examining the association between hormone therapy (HT) and lung cancer risk disagree.
We examined the associations between HT use and lung cancer risk among 60,592 postmenopausal women enrolled in the prospective California Teachers Study cohort. Between 1995 and 2007, 727 women were diagnosed with lung cancer. Multivariable Cox proportional hazards regression models were fit using age as the time metric.
No measure of HT use was associated with lung cancer risk (all p-values for trend≥0.4). In addition, no variations in risk by smoking status (never, ever, former, current), type of HT (E-alone, E+P use), type of menopause, or lung cancer histology were observed.
Our findings do not support an association between HT and lung cancer.
This large-scale, prospective study, which capitalizes on the detailed hormone use, smoking history, and type of menopause information available within this unique cohort, was unable to find any association between intake of HT and lung cancer risk.
PMCID: PMC3065239  PMID: 21266521
7.  Body size and the risk of ovarian cancer by hormone therapy use in the California Teachers Study cohort 
Cancer causes & control : CCC  2010;21(12):2241-2248.
To investigate whether obesity and hormone therapy (HT) are associated with ovarian cancer risk among women in the California Teachers Study cohort.
Of 56,091 women age ≥45 years, 277 developed epithelial ovarian cancer between 1995 and 2007. Multivariate Cox regression was performed.
Among women who never used HT, greater adult weight gain, waist circumference and waist-to-height ratio, but not adult BMI, increased risk of ovarian cancer. Compared to women who never used HT and had a stable adult weight, risk of ovarian cancer was increased in women who gained ≥40 lb (relative risk (RR) 1.8, 95% confidence interval (CI): 1.0–3.0) or used HT for >5 years (RR 2.3 95% CI: 1.3–4.1). Having both exposures (RR 1.9, 95% CI: 0.99–3.5), however, did not increase risk more than having either alone. Results were similar for waist circumference and weight-to-height ratio; however, differences across HT groups were not statistically significant.
This study suggests that abdominal adiposity and weight gain, but not overall obesity, increase ovarian cancer risk and that there may be a threshold level beyond which additional hormones, whether exogenous or endogenous, do not result in additional elevation in risk. However, large pooled analyses are needed to confirm these findings.
PMCID: PMC3120052  PMID: 20924664
Ovarian cancer; Obesity; Abdominal adiposity; Hormone therapy
8.  Oral contraceptives, menopausal hormone therapy use and risk of B-cell non-Hodgkin lymphoma in the California Teachers Study 
We examined oral contraceptive (OC) and menopausal hormonal therapy (MHT) use in relation to risk of B-cell non-Hodgkin lymphoma (NHL). Women under age 85 years participating in the California Teachers Study with no history of hematopoietic cancer were followed from 1995 through 2007. 516 of 114,131 women eligible for OC use analysis and 402 of 54,758 postmenopausal women eligible for MHT use analysis developed B-cell NHL. Multivariable adjusted and stratified Cox proportional hazards models were fit to estimate relative risks (RR) and 95% confidence intervals (95% CI). Ever versus never OC use was marginally associated with lower B-cell NHL risk, particularly among women first using OCs before age 25 years (RR=0.72, 95%CI=0.51-0.99); yet, no duration-response effect was observed. No association was observed for ever versus never MHT use among postmenopausal women (RR=1.05, 95%CI=0.83-1.33) overall, or by formulation (estrogen alone, ET, or estrogen plus progestin, EPT). Among women with no MHT use, having bilateral oophorectomy plus hysterectomy was associated with greater B-cell NHL risk than having natural menopause (RR=3.15, 95%CI=1.62-6.13). Bilateral oophorectomy plus hysterectomy was not associated with risk among women who used ET or EPT. These results indicate that exogenous hormone use does not strongly influence B-cell NHL risk.
PMCID: PMC3258672  PMID: 20957632
non-Hodgkin lymphoma; oral contraceptives; menopausal hormonal therapy; hysterectomy; bilateral oophorectomy
9.  Selected Polymorphisms in Sex Hormone-Related Genes, Circulating Sex Hormones and Risk of Endometrial Cancer 
Cancer epidemiology  2012;36(5):445-452.
The role of estrogen and progesterone in the development of endometrial cancer is well documented. Few studies have examined the association of genetic variants in sex hormone-related genes with endometrial cancer risk.
We conducted a case-control study nested within three cohorts to examine the association of endometrial cancer risk with polymorphisms in hormone-related genes among 391 cases (92% postmenopausal at diagnosis) and 712 individually-matched controls. We also examined the association of these polymorphisms with circulating levels of sex hormones and SHBG in a cross-sectional analysis including 596 healthy postmenopausal women at blood donation (controls from this nested case-control study and from a nested case-control study of breast cancer in one of the three cohorts).
Adjusting for endometrial cancer risk factors, the A allele of rs4775936 in CYP19 was significantly associated (ORper allele = 1.22, 95% CI = 1.01–1.47, ptrend = 0.04), while the T allele of rs10046 was marginally associated with increased risk of endometrial cancer (ORper allele = 1.20, 95% CI = 0.99 – 1.45, ptrend = 0.06). PGR rs1042838 was also marginally associated with risk (ORper allele = 1.25, 95% CI = 0.96–1.61, ptrend = 0.09). No significant association was found for the other polymorphisms, i.e. CYP1B1 rs1800440 and rs1056836, UGT1A1 rs8175347, SHBG rs6259 and ESR1 rs2234693. Rs8175347 was significantly associated with postmenopausal levels of estradiol, free estradiol and estrone and rs6259 with SHBG and estradiol.
Our findings support an association between genetic variants in CYP19, and possibly PGR, and risk of endometrial cancer.
PMCID: PMC3663487  PMID: 22633539
endometrial cancer; estrogen; sex hormone-binding globulin; progesterone receptor; single nucleotide polymorphism
10.  Variations in Sex Hormone Metabolism Genes, Postmenopausal Hormone Therapy, and Risk of Endometrial Cancer 
We investigated whether variants in sex steroid hormone metabolism genes modify the effect of hormone therapy (HT) on endometrial cancer risk in postmenopausal non-Hispanic white women. A nested-case control study was conducted within the California Teachers Study (CTS). We genotyped htSNPs in six genes involved in the hormone metabolism in 286 endometrial cancer cases and 488 controls. Odds ratio (OR) and 95% confidence interval (CI) were estimated for each haplotype using unconditional logistic regression, adjusting for age. The strongest interaction was observed between duration of estrogen therapy (ET) use and haplotype 1A in CYP11A1 (Pinteraction=0.0027; Pinteraction=0.027 after correcting for multiple testing within each gene). The OR for endometrial cancer per copy of haplotype 1A was 2.00 (95%CI: 1.05-3.96) for long-term ET users and 0.90 (95% CI: 0.69-1.18) for never users. The most significant interaction with estrogen-progestin therapy (EPT) was found for two haplotypes on CYP19A1 and EPT use (haplotype 4A, Pinteraction=0.024 and haplotype 3B, Pinteraction=0.043. However, neither this interaction, nor the ET or EPT interactions for any other genes, was statistically significant after correction for multiple testing. Variations in CYP11A1 may modify the effect of ET use on risk of postmenopausal endometrial cancer; however, larger studies are needed to explore these findings further.
PMCID: PMC3267886  PMID: 21544810
menopausal hormone therapy; genetic polymorphism; hormone metabolism gene; endometrial cancer
11.  Previous oral contraceptive use and breast cancer risk according to hormone replacement therapy use among postmenopausal women 
Cancer Causes & Control   2005;16(5):537-544.
To assess postmenopausal breast cancer risk in relation to particular patterns of oral contraceptive (OC) use according to hormone replacement therapy (HRT) exposure.
Time-dependent Cox regression models were used to analyse information on postmenopausal women from a large-scale French cohort. Among a total of 68,670 women born between 1925 and 1950, 1405 primary invasive postmenopausal breast cancer cases were identified from 1992 to 2000.
A non-significant decrease in risk of around 10% was associated with ever OC use as compared to never OC use in postmenopausal women. No significant interaction was found between OC and HRT use on postmenopausal breast cancer risk. Breast cancer risk decreased significantly with increasing time since first OC use (test for trend: p = 0.01); this was consistent after adjustment for duration of use or for time since last use.
No increase in breast cancer risk was associated with previous OC exposure among postmenopausal women, probably because the induction window had closed. Some women may develop breast cancer soon after exposure to OCs, leading to a deficit of cases of older women. Further investigation is therefore required to identify young women at high risk.
PMCID: PMC1976329  PMID: 15986108
Adult; Breast Neoplasms; epidemiology; Cohort Studies; Contraceptives, Oral, Hormonal; therapeutic use; Female; Follow-Up Studies; France; epidemiology; Hormone Replacement Therapy; Humans; Middle Aged; Postmenopause; Proportional Hazards Models; Questionnaires; Risk Assessment; Time Factors; breast cancer; postmenopausal women; oral contraceptives; patterns of use; hormone replacement therapy
12.  Alcohol consumption and breast cancer risk among postmenopausal women following the cessation of hormone therapy use: the California Teachers Study 
Alcohol consumption increases breast cancer risk, but its effect may be modified by hormone therapy (HT) use, such that exposure to both may be synergistic. Because many women stopped taking HT after mid-2002, it is important to quantify risks associated with alcohol consumption in the context of HT cessation, as these risks may be more relevant to cancer prevention efforts today.
Among 40,680 eligible postmenopausal California Teachers Study cohort participants, 660 were diagnosed with invasive breast cancer before 2010. Multivariate Cox proportional hazards regression models were used to estimate relative risks (RR) and 95% confidence intervals (CI).
Increased breast cancer risk associated with alcohol consumption was observed among postmenopausal women who were current HT users (RR=1.60, 95% CI: 1.13–2.26 and RR=2.11, 95% CI: 1.41–3.15 for <20 and ≥20 g/d of alcohol), with risks being similar by HT preparation. Alcohol did not increase risk among women who had stopped using HT within 3 years or 3–4 years before completing the follow-up questionnaire or in the more distant past. Results were similar for ER+ and ER+PR+ tumors; while power was limited, no increase in risk was observed for ER- tumors.
Following the cessation of HT use, alcohol consumption is not significantly associated with breast cancer risk, although a non-significant increased risk was observed among women who never used HT.
Our findings confirm that concurrent exposure to HT and alcohol has a substantial adverse impact on breast cancer risk. However, after HT cessation, this risk is reduced.
PMCID: PMC3721729  PMID: 22832206
breast cancer; alcohol; hormone therapy; cessation; epidemiology
13.  In vivo and in vitro estrogenic and progestagenic actions of Tibolone. 
Biological research  2005;38(2-3):245-258.
Estrogen and progestin combination in hormone replacement therapy (HRT) increases the incidence of breast cancer, but decreases the endometrial cancer risk of unopposed estrogen. Therefore, a SERM such as Tibolone, that delivers the beneficial, but not the adverse side effects, of steroid hormones would be clinically advantageous. However, data from the Million Women Study suggests that Tibolone increases the risk of both breast and endometrial cancer. Herein, we assessed the estrogenic and progestagenic actions of Tibolone using transvaginal sonography studies and an in vitro model of breast (ZR-75, MCF7) and endometrial cancer (Ishikawa). The known cancer associated proteins (ER, EGFR, STAT5, tissue factor and Bcl-xL) were selected for study. Transvaginal sonography demonstrated that postmenopausal women treated with Tibolone displayed a thinner endometrium than in the late proliferative phase, but had a phenotype characteristic of the secretory phase, thus demonstrating the estrogenic and progestagenic actions of this SERM. In vitro, Tibolone acted as an estrogen in downregulating ER and upregulating Bcl-xL, yet as progesterone, increasing STAT5 and tissue factor in breast cancer cells. The increase in tissue factor by Tibolone correlated with its coagulative potential. Interestingly, EGFR was up-regulated by progesterone in the breast and by estrogen in endometrial cells, while Tibolone increased protein levels in both cell types. In conclusion, this study further demonstrates the estrogenic and progestagenic nature of Tibolone. The pattern of regulation of known oncogenes in cells of breast and endometrial origin dictates caution and vigilance in the prescription of Tibolone and subsequent patient monitoring.
PMCID: PMC1343467  PMID: 16238103
breast/endometrium cancer; estrogenic; HRT; progestagenic & tibolone
14.  Lasofoxifene: Evidence of its therapeutic value in osteoporosis 
Core evidence  2010;4:113-129.
Osteoporosis is a skeletal disorder characterized by compromised bone strength and increased risk of fracture. It is a common disorder in elderly subjects and represents a major public health problem, affecting up to 40% postmenopausal women and 15% of men. Among the several therapeutical interventions, hormone replacement therapy (HRT) was traditionally seen as the gold standard for preventing osteoporotic fractures in postmenopausal women, as well as for the management of menopausal symptoms. However HRT, especially if administered long-term, may lead to an increased risk of breast and, when unopposed by progestins, endometrial cancers. Alternative therapies include bisphosphonates and raloxifene, a selective estrogen receptor modulator (SERM). While the former have been associated with suboptimal adherence, the latter was considerably less potent than estrogen and its effect in the prevention of nonvertebral fractures remain uncertain.
The purpose of this article is to review the clinical trials of lasofoxifene, a new SERM for the treatment of postmenopausal osteoporosis. The medical literature was reviewed for appropriate articles containing the terms “lasofoxifene” and SERMs”.
Evidence review:
There are three (phase II or phase III) clinical trials that clearly demonstrate efficacy and safety of this new SERM in the suppression of bone loss and the prevention of vertebral and nonvertebral fractures. Moreover, lasofoxifene treatment also reduced breast cancer risk and the occurrence of vaginal atrophy.
Place in therapy:
With its increased potency and efficacy on the prevention of nonvertebral fractures lasofoxifene may be an alternative and cost-effective therapy for osteoporosis in postmenopausal women.
PMCID: PMC2899785  PMID: 20694069
osteoporosis; lasofoxifene; SERM; fracture; treatment
15.  Estrogenic Plant Extracts Reverse Weight Gain and Fat Accumulation without Causing Mammary Gland or Uterine Proliferation 
PLoS ONE  2011;6(12):e28333.
Long-term estrogen deficiency increases the risk of obesity, diabetes and metabolic syndrome in postmenopausal women. Menopausal hormone therapy containing estrogens might prevent these conditions, but its prolonged use increases the risk of breast cancer, as wells as endometrial cancer if used without progestins. Animal studies indicate that beneficial effects of estrogens in adipose tissue and adverse effects on mammary gland and uterus are mediated by estrogen receptor alpha (ERα). One strategy to improve the safety of estrogens to prevent/treat obesity, diabetes and metabolic syndrome is to develop estrogens that act as agonists in adipose tissue, but not in mammary gland and uterus. We considered plant extracts, which have been the source of many pharmaceuticals, as a source of tissue selective estrogens. Extracts from two plants, Glycyrrhiza uralensis (RG) and Pueraria montana var. lobata (RP) bound to ERα, activated ERα responsive reporters, and reversed weight gain and fat accumulation comparable to estradiol in ovariectomized obese mice maintained on a high fat diet. Unlike estradiol, RG and RP did not induce proliferative effects on mammary gland and uterus. Gene expression profiling demonstrated that RG and RP induced estradiol-like regulation of genes in abdominal fat, but not in mammary gland and uterus. The compounds in extracts from RG and RP might constitute a new class of tissue selective estrogens to reverse weight gain, fat accumulation and metabolic syndrome in postmenopausal women.
PMCID: PMC3233562  PMID: 22163294
16.  Migraine History, Nonsteroidal Anti-Inflammatory Drug Use, and Risk of Postmenopausal Endometrial Cancer 
Hormones & cancer  2012;3(0):240-248.
Endometrial cancer is primarily a hormonally-mediated disease. As such, factors that mediate or reflect exposure to estrogens, or that mediate response to such exposure, may plausibly be associated with endometrial cancer risk. History of migraines, another hormonally-mediated condition, has recently been associated with a reduced risk of hormone receptor-positive breast cancer; however, the relationship between migraines and endometrial cancer has not previously been explored. We evaluated the relationship between migraine history and endometrial cancer risk in postmenopausal women, considering also the potential impact of nonsteroidal anti-inflammatory drug (NSAID) use, given the relationship of NSAIDs to hormones and to migraine history. We identified 93,384 women participating in the Women's Health Initiative prospective cohort who had an intact uterus at the time of study entry. Using Cox proportional hazards regression, we assessed risk of endometrial cancer during study follow-up according to history of migraines and according to current NSAID use at the time of study entry, adjusting for age, study arm, race, and hormone therapy use. We also evaluated interaction in these associations by body mass index. Having a history of migraines was not associated with endometrial cancer risk [hazard ratio (HR)=0.91, 95% confidence interval (CI): 0.75–1.11], regardless of body mass index (BMI) or NSAID use status. Similarly, current NSAID use was not associated with endometrial cancer risk (HR=1.03, 95% CI: 0.89–1.18), regardless of BMI. Migraine history and NSAID use do not appear to be associated with risk of endometrial cancer.
PMCID: PMC3493676  PMID: 22826191
endometrial cancer; migraine; nonsteroidal anti-inflammatory drugs
17.  Differences in estrogen and progesterone receptor expression in endometrial polyps and atrophic endometrium of postmenopausal women with and without exposure to tamoxifen 
Molecular and Clinical Oncology  2013;1(6):1055-1060.
Postmenopausal women who use tamoxifen present with an increased incidence of endometrial alterations, such as polyps and hyperplasia, in addition to a higher risk of malignant endometrial neoplasms. Among these endometrial changes, polyps are the most common, with a pathogenesis associated with hormonal influence. The objective of this study was to compare the expression of estrogen receptors (ERs) and progesterone receptors (PRs) in endometrial polyps from tamoxifen users with that in endometrial polyps and the atrophic endometrium of postmenopausal tamoxifen non-users. Among women undergoing surgical hysteroscopy, 84 tamoxifen users with benign endometrial polyps were selected. This group was compared to 84 samples of atrophic endometrium and to 252 benign polyps from postmenopausal women who were not treated with tamoxifen. The expression of ER/PR was assessed by immunohistochemical analysis, according to the percentage of stained cells, intensity of nuclear staining and final score. The polyps from tamoxifen users exhibited a higher expression of ER and PR in the glandular epithelium and stroma compared to the atrophic endometrium (P<0.0001). Compared to the polyps from women not treated with tamoxifen, tamoxifen users exhibited a higher PR expression in the epithelium (P=0.0014) and stroma (P=0.0056), with no difference in the expression of ER. In conclusion, endometrial polyps frequently exhibit an increase in ER expression, regardless of tamoxifen use. High levels of PR expression appear to be consistent with the estrogen agonist effects of tamoxifen.
PMCID: PMC3915668  PMID: 24649292
endometrial polyp; tamoxifen; estrogen receptor; progesterone receptor
18.  Polymorphisms in genes involved in sex hormone metabolism, estrogen plus progestin hormone therapy use, and risk of postmenopausal breast cancer 
Hormone therapy, estrogen plus progestin (E+P) particularly, is associated with increased risk of breast cancer. Functionally relevant polymorphisms in genes involved in sex hormone metabolism may alter exposure to exogenous sex hormones and affect risk of postmenopausal breast cancer. We evaluated associations of common polymorphisms in genes involved in estrogen and/or progesterone metabolism, E+P use, and their interactions with breast cancer risk in a case-control study of postmenopausal women (324 cases; 651 controls) nested within the VITAL cohort. None of the polymorphisms studied was, by itself, statistically significantly associated with breast cancer risk. E+P use was significantly associated with increased breast cancer risk (≥10 years versus never, odds ratio: 1.9; 95% confidence interval: 1.3–2.8; Ptrend: 0.0002). Statistically significant interactions between CYP1A1 Ile462Val (Pinteraction: 0.04), CYP1A1 MspI (Pinteraction: 0.003), CYP1B1 Val432Leu (Pinteraction: 0.007), CYP1B1 Asn453Ser (Pinteraction: 0.04) and PGR Val660Leu (Pinteraction: 0.01), and E+P use were observed. The increased risk of breast cancer associated with E+P use was greater among women with at least one rare allele of the CYP1A1 Ile462Val, CYP1A1 MspI, CYP1B1 Asn453Ser and PGR Val660Leu polymorphisms than among women homozygous for the common allele of these polymorphisms. Risk of breast cancer increased little with increasing years of E+P use among women with at least one CYP1B1 Val432 allele; a large increase in risk was seen among women homozygous for CYP1B1 Leu432. Our results support the hypothesis that specific polymorphisms in genes involved in sex hormone metabolism may modify the effect of E+P use on breast cancer risk.
PMCID: PMC2732341  PMID: 18628428
breast cancer; hormone therapy; polymorphism; gene-environment interaction; postmenopausal
19.  Is estrogen plus progestin menopausal hormone therapy safe with respect to endometrial cancer risk? 
Given the strong link between use of unopposed estrogens and development of endometrial cancers, estrogens are usually prescribed with a progestin, particularly for women with intact uteri. Some studies suggest that sequential use of progestins may increase risk, but the moderating effects of usage patterns or patient characteristics, including body mass index (BMI) are unknown. We evaluated menopausal hormone use and incident endometrial cancer (n=885) in 68,419 postmenopausal women with intact uteri enrolled in the NIH-AARP Diet and Health study. Participants completed a risk factor questionnaire in 1996–1997 and were followed through 2006. Hazard rate ratios (RR) and 95% confidence intervals (CI) were estimated using Cox regression. Among 19,131 women reporting exclusive estrogen plus progestin use, 176 developed endometrial cancer [RR 0.88; 95% CI: 0.74, 1.06]. Long duration (≥10 years) sequential (<15 days progestin/month) estrogen plus progestin use was positively associated with risk [RR 1.88; 95% CI: 1.36–2.60], whereas continuous (>25 days progestin/month) estrogen plus progestin use was associated with a decreased risk [RR 0.64; 95% CI: 0.49–0.83)]. Increased risk for sequential estrogen plus progestin was seen only among thin-to-normal weight women (BMI <25 kg/m2) [RR 2.53]. Our findings support that specific categories of estrogen plus progestin use increases endometrial cancer risk, specifically long durations of sequential progestins; while decreased endometrial cancer risk was observed for users of short duration continuous progestins. Risks were highest among thin-to-normal weight women, presumably reflecting their lower endogenous estrogen levels, suggesting that menopausal hormones and obesity increase endometrial cancer through common etiologic pathways.
PMCID: PMC3427719  PMID: 22553145
cohort; endometrial cancer; estrogen plus progestin; body mass index; menopausal hormone therapy
20.  The influence of menopausal hormone therapy on tumour characteristics and survival in endometrial cancer patients 
Menopausal hormone therapy (MHT) is a well established factor in endometrial carcinogenesis, and therefore, could have prognostic implications. We investigated the effects of ever use of MHT on tumour grade and depth of myometrial invasion, and 5-year relative survival in postmenopausal endometrial cancer patients.
Materials and Methods
We used a nationwide, population-based case-case design, of 683 Swedish women aged 50–74 years diagnosed with endometrial cancer during 1994 to 1995, followed up to 5 years after diagnosis. We applied polytomous multiple logistic regression to investigate the associations between use of MHT and tumour grade, and myometrial invasion and Poisson regression for modelling 5-year excess mortality.
Compared to never use, ever use of any MHT entailed lower risks of having moderately and poorly differentiated tumours. The lowest odds ratios for poorly differentiated tumours were seen for ever users of cyclically combined oestrogen-progestin [OR = 0.23 (95% CI = 0.07–0.73)]. Ever users of any form of MHT; particularly, medium potency MHT users, had significantly lower risks for tumours with deep myometrial invasion. Adjusted estimated relative excess hazard ratios revealed significantly improved survival for ever users of any form of MHT [RER = 0.40 (95% CI = 0.16–0.97)]; in particular ever users of any form of oestrogens [RER = 0.38 (95% CI = 0.15–0.99)].
Endometrial cancer patients who were ever users of MHT had more favourable tumour characteristics and better survival compared to never users of MHT. These findings support the notion that MHT induces endometrial cancer with less aggressive characteristics.
PMCID: PMC2783257  PMID: 19493676
Endometrial cancer; menopause hormone therapy; postmenopausal; tumour grade; myometrial invasion; relative survival; mortality
21.  Age-related variation in the relationship between menopausal hormone therapy and the risk of dying from breast cancer 
Multiple past studies have reported a reduced risk of breast cancer-related mortality (BCM) in relation to pre-diagnostic use of hormone therapy (HT); however, the extent to which this reduction is due to heightened screening or tumor biology is unknown.
Using a population-based cohort of 1,911 post-menopausal women diagnosed with invasive breast cancer at ages 45-79 from 1993-1999, we investigated the extent to which the reduced risk in BCM observed in relation to HRT might be explained by screening patterns or tumor features.
Estrogen-progestin therapy (EPT) use was associated with a decreased risk of BCM (after adjustment for age, study, mammography, stage, and treatment), but only among older women (ever use: ≥65 years: HR = 0.45 [95% CI: 0.26-0.80]; <65 years: HR = 1.03 [95% CI: 0.60-1.79]). Estrogen-alone therapy (ET) use was not associated with risk of BCM (ever use: ≥65 years: HR= 0.76 [95% CI: 0.51-1.12]; <65 years: HR = 1.20 [95% CI: 0.71-2.02]). HT users had a much greater frequency of mammography (p-value < 0.001). EPT use was associated with tumor characteristics related to improved prognosis in older women after adjustment for screening, including an inverse association with poorly differentiated tumors (OR = 0.57 [95% CI: 0.38-0.85]) and an association with lobular tumors (OR = 1.68 [95% CI: 1.07-2.65]).
Beyond the influence of EPT use on screening uptake, these data indicate that the improved survival associated with pre-diagnostic EPT use may be due in part to the development of more favorable tumor characteristics.
PMCID: PMC3059400  PMID: 20878463
breast cancer; mortality; hormone therapy; prognosis
22.  Use of different postmenopausal hormone therapies and risk of histology- and hormone receptor-defined invasive breast cancer 
We previously found that the risk of invasive breast cancer varied according to the progestagen component of combined postmenopausal hormone therapy (CHT): progesterone, dydrogesterone, or other progestagens. We conducted the present study to assess how these CHTs were associated with histology- and hormone receptor-defined breast cancer.
Patients and Methods
We used data from the French E3N cohort study, with 80,391 postmenopausal women followed for a mean duration of 8.1 years; 2,265 histologically confirmed invasive breast cancers were identified through biennial self-administered questionnaires completed from 1990 to 2002. The relative risks (RRs) were estimated using Cox proportional hazards models.
Compared with postmenopausal hormone therapy (HT) never-use, ever-use of estrogen+progesterone was not significantly associated with the risk of any breast cancer subtype, but increasing duration of estrogen+progesterone was associated with increasing risks of lobular (P=.06) and estrogen receptor–positive/progesterone receptor–negative (ER+/PR−; P=.02). Estrogen+dydrogesterone was associated with a significant increase in risk of lobular carcinoma (RR, 1.7; 95% CI, 1.1 to 2.6). Estrogen+other progestagens was associated with significant increases in risk of ductal and lobular carcinomas (RR, 1.6; 95% CI, 1.3 to 1.8; and 2.0; 95% CI, 1.5 to 2.7, respectively), of ER+/PR+ and ER+/PR− carcinomas (RR, 1.8; 95% CI, 1.5 to 2.1; and 2.6; 95% CI, 1.9 to 3.5, respectively), but not of ER−/PR+ or ER−/PR− carcinomas (RR, 1.0; 95% CI, 0.5 to 2.1; and 1.4; 95% CI, 0.9 to 2.0, respectively).
The increase in risk of breast cancer observed with the use of CHTs other than estrogen+progesterone and estrogen+dydrogesterone seems to apply preferentially to ER+ carcinomas, especially those ER+/PR−, and to affect both ductal and lobular carcinomas.
PMCID: PMC2346534  PMID: 18323549
Adult; Aged; Breast Neoplasms; drug therapy; metabolism; pathology; Carcinoma; Ductal; Breast; drug therapy; metabolism; pathology; Carcinoma; Lobular; drug therapy; metabolism; pathology; Cohort Studies; Dydrogesterone; therapeutic use; Estrogens; therapeutic use; Female; Humans; Middle Aged; Postmenopause; Progesterone; therapeutic use; Progestins; therapeutic use; Receptors; Estrogen; metabolism; Receptors; Progesterone; metabolism; Risk Factors; SEER Program
23.  The risks and benefits of long-term estrogen replacement therapy. 
Public Health Reports  1989;104(Suppl):62-65.
Estrogen replacement therapy (ERT) for postmenopausal women greatly reduces the risk of osteoporotic fractures, but carries an increased risk of endometrial cancer. This risk can be reduced by the addition of progestin, which does not interfere with the osteoporotic benefit of estrogen. Although long-term use data are few, there is presently little evidence for an increase or decrease in breast cancer risk associated with estrogen by itself (unopposed estrogen), or estrogen plus progestin. In contrast, a large body of evidence suggests that unopposed estrogen significantly reduces the risk of cardiovascular disease; there is no evidence that this benefit will persist when a progestin is added. The preferred method of estrogen replacement therapy, to prevent osteoporosis in a postmenopausal woman with an intact uterus, should be chosen with these different risks and benefits in mind.
PMCID: PMC1580373  PMID: 2517703
24.  Profile of bazedoxifene/conjugated estrogens for the treatment of estrogen deficiency symptoms and osteoporosis in women at risk of fracture 
Decreasing levels of estrogens during menopause are associated with reduced bone density and an increased risk of osteoporosis. Many women also experience bothersome vasomotor and vaginal symptoms during the menopausal transition. Results of systematic reviews and meta-analyses of randomized controlled trials have shown that both systemic estrogen therapy or hormone therapy (estrogen combined with a progestin) are useful to prevent bone loss, and they are the most effective treatment for such climacteric symptoms as hot flushes, sweating, vaginal dryness, and dyspareunia. Unfortunately, estrogen therapy and hormone therapy increase the risk of endometrial and breast cancer, respectively. The selective estrogen receptor modulators (SERMs) result in positive estrogenic effects on bone, with no negative effects on the endometrium and breast but do not provide relief from postmenopausal symptoms. The combination of a SERM with estrogen as a tissue selective estrogen complex (TSEC) is a new strategy for the prevention of bone loss and the treatment of climacteric symptoms. This combination is particularly interesting from a clinical point of view, taking into account that estrogen alone did not increase breast cancer risk by the Women’s Health Initiative. TSEC is hypothesized to provide the benefits of estrogen-alone therapy, with an improved tolerability profile because the SERM component can make possible the elimination of progestin. The objective of this review was to critically evaluate the evidence from the reports published to date on the use of bazedoxifene (a third-generation SERM) in combination with conjugated estrogens in postmenopausal women. The conclusion is that effectively, the combination of bazedoxifene and conjugated estrogens may be a promising alternative to hormone therapy for the prevention of osteoporosis and the treatment of postmenopausal symptoms in non-hysterectomized postmenopausal women.
PMCID: PMC3724601  PMID: 23901263
tissue selective estrogen complex; menopause; bone mineral density; bone turnover markers; climacteric symptoms
25.  Menopausal Hormone Therapy and Breast Cancer Risk in the NIH-AARP Diet and Health Study Cohort 
Results from the Women’s Health Initiative (WHI) trial raise new questions regarding the effects of estrogen therapy (ET) and estrogen plus progestin therapy (EPT) on breast cancer risk.
We analyzed data from 126,638 females, 50–71 years of age at baseline, who completed two questionnaires (1995–1996, 1996–1997) as part of the NIH-AARP Diet and Health Cohort Study and in whom 3,657 incident breast cancers were identified through June 30, 2002. Hormone-associated relative risks (RR) and 95% confidence intervals (CI) of breast cancer were estimated via multivariable regression models.
Among thin women (body mass index <25 kg/m2), ET use was associated with a significant 60% excess risk after 10 years of use. EPT was associated with a significantly increased risk among women with intact uteri, with the highest risk among current, long-term (≥10 years) users (RR=2.44, 95% CI 2.13–2.79). These risks were slightly higher when progestins were prescribed continuously than sequentially (<15 days/month) (respective RRs of 2.76 vs. 2.01). EPT associations were strongest in thin women, but elevated risks persisted among heavy women. EPT use was strongly related to estrogen receptor positive (ER+) tumors, requiring consideration of this parameter when assessing relationships according to other clinical features. For instance, ER− ductal tumors were unaffected by EPT use, but all histologic subgroups of ER+ tumors were increased, especially low-grade and mixed ductal-lobular tumors.
Both ET and EPT were associated with breast cancer risks with the magnitude of increase varying according to body mass and clinical characteristics of the tumors.
PMCID: PMC2755180  PMID: 18990757
breast cancer; hormones; menopause; risk; tumor characteristics

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