Estrogen Plus Progestin Therapy Research Articles

Prediagnostic use of menopausal hormone therapy and long-term survival of localized epithelial ovarian cancer: The Extreme study.

Use of menopausal hormone therapy (MHT) prior to an epithelial ovarian cancer (EOC) diagnosis has been suggested to be associated with improved survival. In a recent nationwide cohort study, we found that prediagnostic long-term MHT use, especially estrogen therapy (ET), was associated with improved long-term survival in women with nonlocalized EOC. Our aim was to investigate the influence of prediagnostic MHT use on long-term survival among women with localized EOC in the same nationwide study. Our study cohort comprised all women aged 50 years or older with an EOC diagnosis in Denmark 2000-2014 (n = 2097) identified from the Extreme study. We collected information on usage of systemic ET and estrogen plus progestin therapy (EPT) from the Danish National Prescription Registry. By using pseudo-values, 5- and 10-year absolute and relative survival probabilities were estimated with 95% confidence intervals (CIs) while adjusting for histology, comorbidity, and income. Relative survival probabilities >1 indicate better survival. The 5-year absolute survival probabilities were 61% and 56%, respectively, among women who were nonusers and users of prediagnostic MHT, whereas these numbers were 46% and 41%, respectively, regarding 10-year survival. Use of MHT was not significantly associated with an improved 5- or 10-year survival in women with localized EOC (5-year relative survival probability = 0.95, 95% CI: 0.89-1.02; 10-year relative survival probability = 0.92, 95% CI: 0.84-1.02). Similar findings were seen for systemic ET or EPT use. Our findings do not suggest a positive benefit from prediagnostic MHT use on long-term survival of localized EOC.

Long‐term survival of nonlocalized epithelial ovarian cancer among women using menopausal hormone therapy prior to diagnosis: The extreme study

Prediagnostic use of menopausal hormone therapy (MHT) has been suggested to be associated with improved survival of epithelial ovarian cancer (EOC). We investigated the potential long‐term survival benefit of prediagnostic MHT use in women ≥50 years with nonlocalized EOC using the Extreme study including all women in Denmark registered with nonlocalized EOC during 2000 to 2014 (N = 3776). We obtained individual‐level information on prediagnostic use of systemic estrogen therapy (ET) and estrogen plus progestin therapy (EPT) from the National Prescription Registry and estimated absolute and relative 5‐ and 10‐year survival probabilities with 95% confidence intervals (CIs) using pseudo‐values, taking into account histology, comorbidity, income and residual disease. Among women not having used prediagnostic MHT, 5‐ and 10‐year absolute survival probabilities were 19% and 11%, respectively. Compared to MHT nonusers, prediagnostic systemic ET use for 3 to 4 years and ≥ 5 years was associated with 1.43 (95% CI: 1.01‐2.02) and 1.22 (95% CI: 0.96‐1.55) times higher 5‐year survival probabilities, respectively. Ten‐year survival probabilities were also increased but not statistically significantly. Among prediagnostic EPT users, increased 5‐year (1.14, 95% CI: 0.85‐1.53) and 10‐year (1.38, 95% CI: 0.91‐2.08) survival probabilities were observed after use for 3 to 4 years compared to MHT nonuse, whereas EPT use for ≥5 years was not associated with long‐term survival of nonlocalized EOC. Our findings may suggest a better long‐term survival of nonlocalized EOC in women having used long‐term prediagnostic ET. However, the statistical precision of our results did not allow firm conclusions and more studies are needed.

Menopausal hormone therapy and women's health: An umbrella review.

There remains uncertainty about the impact of menopausal hormone therapy (MHT) on women's health. A systematic, comprehensive assessment of the effects on multiple outcomes is lacking. We conducted an umbrella review to comprehensively summarize evidence on the benefits and harms of MHT across diverse health outcomes. We searched MEDLINE, EMBASE, and 10 other databases from inception to November 26, 2017, updated on December 17, 2020, to identify systematic reviews or meta-analyses of randomized controlled trials (RCTs) and observational studies investigating effects of MHT, including estrogen-alone therapy (ET) and estrogen plus progestin therapy (EPT), in perimenopausal or postmenopausal women in all countries and settings. All health outcomes in previous systematic reviews were included, including menopausal symptoms, surrogate endpoints, biomarkers, various morbidity outcomes, and mortality. Two investigators independently extracted data and assessed methodological quality of systematic reviews using the updated 16-item AMSTAR 2 instrument. Random-effects robust variance estimation was used to combine effect estimates, and 95% prediction intervals (PIs) were calculated whenever possible. We used the term MHT to encompass ET and EPT, and results are presented for MHT for each outcome, unless otherwise indicated. Sixty systematic reviews were included, involving 102 meta-analyses of RCTs and 38 of observational studies, with 102 unique outcomes. The overall quality of included systematic reviews was moderate to poor. In meta-analyses of RCTs, MHT was beneficial for vasomotor symptoms (frequency: 9 trials, 1,104 women, risk ratio [RR] 0.43, 95% CI 0.33 to 0.57, p < 0.001; severity: 7 trials, 503 women, RR 0.29, 95% CI 0.17 to 0.50, p = 0.002) and all fracture (30 trials, 43,188 women, RR 0.72, 95% CI 0.62 to 0.84, p = 0.002, 95% PI 0.58 to 0.87), as well as vaginal atrophy (intravaginal ET), sexual function, vertebral and nonvertebral fracture, diabetes mellitus, cardiovascular mortality (ET), and colorectal cancer (EPT), but harmful for stroke (17 trials, 37,272 women, RR 1.17, 95% CI 1.05 to 1.29, p = 0.027) and venous thromboembolism (23 trials, 42,292 women, RR 1.60, 95% CI 0.99 to 2.58, p = 0.052, 95% PI 1.03 to 2.99), as well as cardiovascular disease incidence and recurrence, cerebrovascular disease, nonfatal stroke, deep vein thrombosis, gallbladder disease requiring surgery, and lung cancer mortality (EPT). In meta-analyses of observational studies, MHT was associated with decreased risks of cataract, glioma, and esophageal, gastric, and colorectal cancer, but increased risks of pulmonary embolism, cholelithiasis, asthma, meningioma, and thyroid, breast, and ovarian cancer. ET and EPT had opposite effects for endometrial cancer, endometrial hyperplasia, and Alzheimer disease. The major limitations include the inability to address the varying effects of MHT by type, dose, formulation, duration of use, route of administration, and age of initiation and to take into account the quality of individual studies included in the systematic reviews. The study protocol is publicly available on PROSPERO (CRD42017083412). MHT has a complex balance of benefits and harms on multiple health outcomes. Some effects differ qualitatively between ET and EPT. The quality of available evidence is only moderate to poor.

Use of postmenopausal hormone therapies and risk of histology- and hormone receptor-defined breast cancer: results from a 15-year prospective analysis of NIH-AARP cohort

BackgroundMenopausal hormone therapy (MHT) increases breast cancer (BC) risk, but cohort studies largely consider use only at enrollment. Evidence is limited on how changes in MHT use alter the magnitude of risk, and whether risk varies between invasive and in situ cancer, by histology or by hormone receptor status.MethodsWe investigated the roles of estrogen-alone therapy (ET) and estrogen plus progestin therapy (EPT) on BC risk overall, by histology and estrogen receptor (ER) and progesterone receptor (PR) status, and on incidence of in situ disease, in the NIH-AARP cohort. Participants included 118,760 postmenopausal women (50–71 years), of whom 63.5% (n = 75,398) provided MHT use information at baseline in 1996 and in a follow-up survey in 2004, subsequent to the dissemination in 2002 of the Women’s Health Initiative trial safety concerns regarding EPT. ET analyses included 50,476 women with hysterectomy (31,439 with follow-up data); EPT analyses included 68,284 women with intact uteri (43,959 with follow-up data). Adjusted hazard ratios (HRs) were estimated using Cox proportional hazards models using age as the time metric with follow-up through 2011.ResultsEight thousand three hundred thirty-three incident BC cases were accrued, 2479 in women with follow-up data. BC risk was not elevated in current ET users at baseline (HR = 1.05, 95% confidence interval [CI] CI = 0.95–1.16) but was higher in women continuing use through 2004 (HR = 1.35, 95% CI = 1.04–1.75). Ever EPT use at baseline was associated with elevated BC risk overall (HR = 1.54 (1.44–1.64), with a doubling in risk for women with 10 or more years of use, for in situ disease, and across subtypes defined by histology and ER/PR status (all p < 0.004). Risk persisted in women who continued EPT through 2004 (HR = 1.80, 95% CI = 1.39–2.32). In contrast, no association was seen in women who discontinued EPT before 2004 (HR = 1.14, 95% CI = 0.99–1.30).ConclusionsET use was not associated with BC risk in this cohort, although excess risk was suggested in women who continued use through 2004. EPT use was linked to elevated in situ and invasive BC risk, and elevated risk across invasive BC histologic and hormone receptor-defined subtypes, with the highest risk for women who continued use through the 2004 follow-up survey.

Hot flushes, coronary heart disease, and hormone therapy in postmenopausal women.

The aim of this study was to examine interactions between hot flushes, estrogen plus progestogen therapy (EPT), and coronary heart disease (CHD) events in postmenopausal women with CHD. We analyzed data from the Heart and Estrogen/Progestin Replacement Study, a randomized, placebo-controlled trial of 0.625 mg conjugated equine estrogens plus 2.5 mg medroxyprogesterone acetate in 2,763 postmenopausal women with CHD. Hot flushes were assessed at baseline using self-administered questionnaires; women reporting bothersome hot flushes "some" to "all" of the time were considered to have clinically significant flushing. Cox regression models were used to examine the effect of EPT on risk of CHD events among women with and without significant flushing at baseline. The mean age of participants was 66.7 ± 6.8 years, and 89% (n = 2,448) were white. Sixteen percent (n = 434) of participants reported clinically significant hot flushes at baseline. Among women with baseline flushing, EPT increased risk of CHD events nine-fold in the first year compared with placebo (hazard ratio = 9.01; 95% CI, 1.15-70.35); among women without baseline flushing, treatment did not significantly affect CHD event risk in the first year (hazard ratio = 1.32; 95% CI, 0.86-2.03; P = 0.07 for interaction of hot flushes with treatment). The trend toward differential effects of EPT on risk for CHD among women with and without baseline flushing did not persist after the first year of treatment. Among older postmenopausal women with CHD, EPT may increase risk of CHD events substantially in the first year of treatment among women with clinically significant hot flushes but not among those without hot flushes.

The Role of Menopausal Hormone Therapy in Reducing All-cause Mortality in Postmenopausal Women Younger than 60 Years: An Adaptive Meta-analysis

Menopausal hormone therapy (MHT) is typically initiated to control climacteric symptoms during early postmenopause. MHT improves quality of life and prevents osteoporotic fracture.1 However, concerns about risks, including cancers and cardiovascular disease, are still highly prevalent. All-cause mortality (ACM) would be one definite endpoint to use in assessing a complex balance of benefits and risks with MHT. A Cochrane Database of Systematic Reviews (CDSR) study conducted by Boardman et al.2 in 2015 concluded that administering MHT at an age less than 10 years after menopause onset had a reduction of ACM (hazard ratio [HR], 0.70; 95% confidence interval [CI], 0.52–0.95) through a systematic review of 5 trials: the Danish Osteoporosis Prevention Study (DOPS; 2012),3 Estonian Postmenopausal Hormone Therapy (EPHT; 2006),4 Estrogen Replacement Therapy (ERT) II (1979),5 Women's Health Initiative (WHI) I (2002),6 and WHI II (2004).7 The U.S. Preventive Services Task Force (USPSTF)8 reported in 2017 that the HR of ACM with estrogen therapy (ET) during the intervention phase was 0.70 (95% CI, 0.46–1.09) among women aged 50 to 59 years but cited only 1 article from the WHI trials.9 In addition, ACM with estrogen plus progestogen therapy (EPT) declined similarly without statistical significance (HR, 0.67; 95% CI, 0.43–1.04). However, the USPSTF recommends against MHT in early postmenopausal women.10 The purpose of this study was to propose a scientific and valid position for the conflicting recommendations of the CDSR (2015)2 and the USPSTF (2017),10 to rearrange and update the selected articles to include newer publications, and to conduct subgroup analyses by MHT regimen.

Change in risk of breast cancer after receiving hormone replacement therapy by considering effect-modifiers: a systematic review and dose-response meta-analysis of prospective studies.

We synthesize the current literatures and use the power of meta-analysis to examine trends on association between hormone replacement therapy (HRT) and the risk of breast cancer (BC). We performed a comprehensive literature search using PubMed, EMBASE, and Web of Science from their inception until Jan 2017. Prospective studies that provided adjusted risk estimates of HRT and BC risk were eligible. Categorical and dose-response meta-analyses followed the PRISMA were conducted using random effects model and restricted cubic spline model, respectively. Forty-seven publications from thirty-five unique studies were included, involving 3,898,376 of participants and 87,845 of BC cases. Compared with non-users, RR for current estrogen-only therapy (ET) users was 1.14 (95% confidence interval (CI) = 1.05–1.22), and for per year increases was 1.02 (95% CI = 1.02–1.02). Moreover, RR for current estrogen plus progestin therapy (EPT) users was 1.76, (95% CI = 1.56–1.96), and for per year increases was 1.08 (95% CI = 1.08–1.08). Dose-response analyses revealed 8–10 years’ onset peaks, and indicated residual increased BC risk remained after stopping use of ET regimen rather than for EPT. Effect-modifiers like BMI, duration of use, race/ethnicity, routes of administration were recognized. In Conclusions, current use of EP or EPT and ever use of tibolone are associated with an elevated risk of BC. Compared with slim HRT users and non-users, lower BC risks were found among overweight/obese HRT users and former EPT users, respectively. Both ET and EPT users are associated with higher risk of lobular BC than ductal BC, and more ER-positive than negative BC cases were detected among EPT users.

Menopausal hormone therapy and mortality among endometrial cancer patients in the NIH-AARP Diet and Health Study.

While menopausal hormone therapy (MHT) is an established endometrial cancer risk factor, its relationship with mortality among endometrial cancer patients is understudied. Within the NIH-AARP Diet and Health Study, we examined the associations of pre-diagnosis MHT use with 10-year all-cause and endometrial cancer-specific mortality among 890 endometrial cancer patients. We used Cox proportional hazards regression models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) adjusted for tumor characteristics, treatment, and other risk factors. Endometrial cancer cases were diagnosed a median of 4.6years (range 0.0-10.1years) after the second risk factor questionnaire was completed. We identified a total of 241 deaths, of which 104 were due to endometrial cancer. Compared with non-MHT use, pre-diagnosis use of estrogen plus progestin therapy (EPT)-only was associated with lower 10-year all-cause (HR 0.65, 95% CI 0.43-0.99, based on 29 deaths) and endometrial cancer-specific mortality (HR 0.51, 95% CI 0.26-0.98, based on 11 deaths). Recency of MHT use, assessed approximately 5years prior to the endometrial cancer diagnosis, was associated with mortality. Compared with non-MHT users, former ET users had higher all-cause (HR 1.71, 95% CI 1.02-2.88, based on 18 deaths) and endometrial cancer-specific mortality (HR 2.17, 95% CI 0.96-4.90, based on 8 deaths), whereas current EPT users had nonsignificant lower risks of death. Based on small numbers, we observed that pre-diagnosis use of EPT was related to lower mortality among endometrial cancer patients. Future studies examining the biological mechanisms underlying this association are warranted.

Hormone metabolism pathway genes and mammographic density change after quitting estrogen and progestin combined hormone therapy in the California Teachers Study.

IntroductionMammographic density (MD) is a strong biomarker of breast cancer risk. MD increases after women start estrogen plus progestin therapy (EPT) and decreases after women quit EPT. A large interindividual variation in EPT-associated MD change has been observed, but few studies have investigated genetic predictors of the EPT-associated MD change. Here, we evaluate the association between polymorphisms in hormone metabolism pathway genes and MD changes when women quit EPT.MethodsWe collected mammograms before and after women quit EPT and genotyped 405 tagging single nucleotide polymorphisms (SNPs) in 30 hormone metabolism pathway genes in 284 non-Hispanic white participants of the California Teachers Study (CTS). Participants were ages 49 to 71 years at time of mammography taken after quitting EPT. We assessed percent MD using a computer-assisted method. MD change was calculated by subtracting MD of an ‘off-EPT’ mammogram from MD of an ‘on-EPT’ (that is baseline) mammogram. Linear regression analysis was used to investigate the SNP-MD change association, adjusting for the baseline ‘on-EPT’ MD, age and BMI at time of baseline mammogram, and time interval and BMI change between the two mammograms. An overall pathway and gene-level summary was obtained using the adaptive rank truncated product (ARTP) test. We calculated ‘P values adjusted for correlated tests (PACT)’ to account for multiple testing within a gene.ResultsThe strongest associations were observed for rs7489119 in SLCO1B1, and rs5933863 in ARSC. SLCO1B1 and ARSC are involved in excretion and activation of estrogen metabolites of EPT, respectively. MD change after quitting was 4.2% smaller per minor allele of rs7489119 (P = 0.0008; PACT = 0.018) and 1.9% larger per minor allele of rs5933863 (P = 0.013; PACT = 0.025). These individual SNP associations did not reach statistical significance when we further used Bonferroni correction to consider the number of tested genes. The pathway level summary ARTP P value was not statistically significant.ConclusionsData from this longitudinal study of EPT quitters suggest that genetic variation in two hormone metabolism pathway genes, SLCO1B1 and ARSC, may be associated with change in MD after women stop using EPT. Larger longitudinal studies are needed to confirm our findings.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-014-0477-8) contains supplementary material, which is available to authorized users.

Estrogen plus progestin increase superoxide dismutase and total antioxidant capacity in postmenopausal women

Objective This cross-sectional study aimed to evaluate the behavior of blood antioxidant enzymes (superoxide dismutase (SOD), catalase and glutathione peroxidase), plasma total antioxidant capacity and oxidative damage (lipid oxidation and protein carbonyl levels) and their relationship with the serum levels of steroid hormones in premenopausal and postmenopausal women without and with estrogen alone (ET) or estrogen plus progestin therapy (EPT).Methods Blood was collected from four groups of subjects: premenopausal women (n = 24), postmenopausal women without hormone therapy (n = 31), postmenopausal women with ET (n = 12) and postmenopausal women with EPT (n = 16).Results The activities of the different SOD isoforms (CuZnSOD and MnSOD) and the plasma total antioxidant power were significantly higher in the postmenopausal women under EPT than in the postmenopausal women without hormone replacement therapy (HRT). Only CuZnSOD activity was increased in women receiving ET compared to the postmenopausal women without HRT. However, no differences were observed in the levels of lipid or protein oxidation or in the non-enzymatic plasma antioxidants (uric acid and albumin) among the groups. The duration of HRT and serum estrogen levels were positively correlated to the blood CuZnSOD activity and to plasma total antioxidant power, whereas the serum progesterone levels were positively correlated to CuZnSOD activity and negatively correlated to protein carbonyl groups. Interestingly, the total antioxidant power of plasma was positively correlated to CuZnSOD and glutathione peroxidase activities.Conclusion We conclude that EPT increases blood MnSOD and CuZnSOD activity in postmenopausal women, leading to an increased plasma total antioxidant capacity. This finding may be relevant to the prevention of oxidative stress-related disorders in postmenopausal women.

Abstract LB-294: Growth factor genes, interaction with hormone therapy use and breast cancer risk in the California Teachers Study

Abstract Background: Growth factor and angiogenesis pathway genes are important candidate genes in breast carcinogenesis. Breast cell proliferation is modified by exogenous hormone therapy (HT) use, particularly estrogen plus progestin therapy (EPT). Estrogen-dependent cell proliferation requires activation of growth factor pathways, such as IGF-1, and potential interactions between a few FGFR2 single nucleotide polymorphisms (SNPs) and EPT have been reported. Further, angiogenesis genes such as VEGF and EGR3 were shown to be induced by steroid hormones. Therefore, we investigated SNPs in growth factor and angiogenesis genes and their interaction with HT in relation to breast cancer risk. Methods: We analyzed data from a breast cancer case-control study nested within the California Teachers Study. We genotyped 202 tagging SNPs in 12 growth factor and angiogenesis genes in 2746 non-Hispanic white women: 1351 cases and 1395 controls. We used conditional logistic regression models to estimate odds ratios (ORs) per minor allele and 95% confidence intervals (CI), and we repeated the analyses separately by HT use at cohort enrollment. P values were corrected for multiple testing using the Bonferroni method (Padj). Results: The most significant associations were observed for rs6899540 in VEGFA and 3 other VEGFA SNPs that are not in linkage disequilibrium with rs6899540. After Bonferroni correction within this gene, only rs6899540, located 4kb distal of the 3’end of the gene, remained statistically significant: OR per C allele=1.27 (95% CI=1.10-1.47), P=0.001, Padj=0.020. Additional SNPs nominally associated with breast cancer risk included rs2072454 in EGFR, rs4970503 in RPS6KA1, and rs9580185 in FGF9. Analyses among postmenopausal EPT users identified nominal associations with 5 VEGFR3 SNPs including rs6889643 and rs2290983 (ORs per risk allele ranging from 1.28 to 1.46; P-values range 0.008-0.015). Although none of these associations were statistically significant after Bonferroni correction, P values for interaction with EPT use (vs. never-HT use) were 0.03 for both rs6889643 and rs2290983. Among ET users, rs308441 in FGF2 was significantly associated with breast cancer risk (OR=1.69, Padj=0.019). Conclusions: Our results suggest that SNPs in growth factor and VEGF pathways may be associated with breast cancer risk, and these associations may be modified by ET or EPT use. Of particular interest are potential gene-HT interactions for SNPs in VEGFA, a key player in angiogenesis, and FGF2, a gene involved in VEGF signaling. Our results provide a strong rationale for further exploring these pathways and potential gene-environment interactions in pooled analyses. Citation Format: Eunjung Lee, Fredrick Schumacher, Susan L. Neuhausen, Hoda Anton Culver, Argyrios Ziogas, David Van Den Berg, Leslie Bernstein, Giske Ursin. Growth factor genes, interaction with hormone therapy use and breast cancer risk in the California Teachers Study. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-294. doi:10.1158/1538-7445.AM2014-LB-294

Hemodynamic and metabolic effects of estrogen plus progestin therapy in hypertensive postmenopausal women treated with an ACE-inhibitor or a diuretic.

ObjectivesThe aim of the study was to assess the hemodynamic and metabolic actions of estrogen plus progestin therapy (EPT) in hypertensive, postmenopausal women treated with perindopril (ACEI) or hydrochlorothiazide (HCTZ). A group of normotensive postmenopausal women was also studied.Methods100 hypertensive and 40 normotensive postmenopausal women were recruited for the study. The hypertensive females were randomly assigned to receive ACEI or HCTZ for 12 months. The patients of the ACEI group and the patients of the HCTZ group, as well as normotensives, were further subdivided into two subgroups each. One subgroup received estrogen plus progestin therapy (EPT+), the other subgroup received no hormone replacement (EPT−). Combined hormone replacement with transdermal patches releasing 17β-estradiol and norethisterone was used. Office and 24-hour ambulatory blood pressure was measured at baseline and during follow-up. Renal plasma flow (RPF) was measured using the clearance of [125I]-iodohippuran. Pulse wave velocity (PWV) was determined with an automatic device.ResultsIn normotensive postmenopausal women, transdermal estrogen plus progestin therapy increases RPF and insulin sensitivity, decreases PWV, decreases total and LDL cholesterol, and decreases uric acid serum levels. Perindopril (4 mg/day) and hydrochlorothiazide (25 mg/day) were equally effective in reducing blood pressure in postmenopausal, hypertensive subjects. In these females, perindopril increased RPF and decreased PWV and plasma insulin levels. These effects of the ACEI were not altered by estrogen plus progestin therapy. Hydrochlorothiazide decreased RPF and increased plasma insulin and uric acid concentrations in hypertensive subjects whom were not receiving estrogen plus progestin therapy.ConclusionsThe unfavorable metabolic and hemodynamic actions of the diuretic were counteracted by estrogen plus progestin therapy. Concomitant estrogen plus progestin therapy may be a method to avoid unfavorable hemodynamic and metabolic effects of thiazide diuretics in hypertensive, postmenopausal women.

Oral low-dose estradiol plus norethisterone acetate with or without simvastatin in dyslipidemic and symptomatic menopausal women: A randomized clinical trial

Context and Objective: Cardiovascular diseases are the leading causes of death in postmenopausal women and dyslipidemia has important contributing factor. The objective of the study was to evaluate low-dose estrogen plus progestogen therapy (EPT) + simvastatin for vasomotor symptoms and lipid and lipoprotein profiles. Design and Setting: Clinical trial was conducted in a private clinical research center. Methods: Two hundred forty symptommatic postmenopausal women with dyslipidemia were randomized to one of three treatment groups: A) 1 mg estradiol/ 0.5 mg norethisterone acetate (E2/NETA) + 20 mg simvastatin; B) E2/NETA + placebo; or C) 20 mg simvastatin + placebo. Lipid and lipoprotein profiles and menopausal symptoms were evaluated after 16 weeks. Results: Total cholesterol, LDL cholesterol, non-HDL cholesterol decreased (P cholesterol, non-HDL cholesterol, LDL cholesterol, Apo B and ApoB/Apoa1 (P Conclusions: Thus in postmenopausal women with dyslipidemia, the association of E2/ NETA low-dose with simvastatin relieved climacteric symptoms similar to that observed with isolated E2/NETA and improved lipid and lipoprotein profile similar to the isolated use of simvastatin. The use of E2/NETA alone decreased menopausal symptoms, but did not improve dyslipidemia.

Progestogen levels, progesterone receptor gene polymorphisms, and mammographic density changes

Estrogen plus progestin therapy (EPT) in postmenopausal women increases breast cancer risk and mammographic density to a higher extent than does estrogen therapy alone. Data from the randomized placebo-controlled Postmenopausal Estrogen/Progestinv Interventions trial showed that EPT-induced increases in serum estrone and estrone sulfate levels were positively correlated with increases in mammographic density. Here, after adjusting for serum estrone and estrone sulfate levels, we investigated the roles of posttreatment serum progestogen increase and of progesterone receptor gene (PGR) genetic variations on changes in mammographic density. We measured the percent mammographic density and serum progestogen levels in 280 Postmenopausal Estrogen/Progestin Interventions trial participants randomized to EPT treatment. Analyses of genetic variations in PGR were limited to 260 white women for whom we successfully obtained PGR genotypes. We used linear regression analyses to determine how an increase in progestogen levels and PGR genetic variation influenced mammographic density change after EPT. The increase in posttreatment serum progestogen level was positively associated with greater increases in mammographic density after adjustment for covariates (P trend = 0.044). Compared with women in the lowest quartile of serum progestogen level, women in the highest quartile experienced a 3.5% greater increase in mammographic density (P = 0.046). We did not find a strong indication that genetic variation in PGR was associated with mammographic density increase or modified the association with serum progestogen; however, confidence in these null findings is constrained by our small sample size. Our results suggest that higher serum progestogen levels resulting from EPT treatment lead to greater increases in mammographic density.

Unopposed estrogen and estrogen plus progestin menopausal hormone therapy and lung cancer risk in the NIH–AARP Diet and Health Study Cohort

Previous studies have reported that lung cancer risk may be decreased, increased, or unaffected by prior use of menopausal hormone therapy (MHT). To assess this issue further, we examined relationships among 118,008 women, ages 50-71years who were recruited during 1995-1996 for the NIH-AARP Diet and Health Study and in whom 2,097 incident lung carcinomas were identified during follow-up through 2006. Multivariable Cox proportional hazards models estimated relative risks (RR) and 95% confidence intervals (CIs) associated with various measures of self-reported MHT use. We found no evidence that either estrogen therapy (ET)-only or estrogen plus progestin therapy (EPT) use was substantially related to subsequent lung cancer risk (respective RRs and 95% CIs for ever use=0.97, 0.86-1.09 and 1.03, 0.90-1.17). There were no significant variations according to currency or duration of use of either formulation, nor was there evidence that risks varied within subgroups defined by cigarette smoking or body size. The absence of effect was seen for nearly all lung cancer subtypes, with the exception of an increased risk of undifferentiated/large cell cancers associated with long-term ET-only use (p (trend)=0.02), a relationship not observed among EPT users. Our results failed to support any substantial alterations in lung cancer risk associated with use of either unopposed estrogen or estrogen plus progestin MHT, even when detailed exposure measures and other risk predictors were considered.

Stopping menopausal hormone therapy: If breast cancer really decreased, why did colorectal cancer not increase?

ObjectiveThe Women's Health Initiative (WHI) study of postmenopausal hormone therapy (HT) found that estrogen plus progestogen therapy (EPT) decreased colorectal cancer risk. Thus, the decline in EPT use from 2002 to 2003 should have precipitated an increase in the incidence of colorectal cancer. We tested this prediction using the SEER 9 epidemiologic database. MethodsWe analyzed WHI data concerning the effects of EPT and estrogen therapy (ET) on colorectal cancer risks. We also examined HT prescription sales data, as well as SEER 9 colorectal cancer incidences from 2001 to 2004. ResultsIn the WHI study, the incidence of colorectal cancer was comparable in EPT placebo-users, ET users, and ET placebo-users, but significantly lower in EPT users. Assuming that 30% of eligible women used HT in 2001, the decline in EPT sales from 2002 to 2003 of 63% should have increased the incidence of colorectal cancer by 2.8% in the overall population at risk. However, the SEER 9 colorectal cancer incidence fell by 5.9% in this population, which is comparable to the 6.7% decrease observed for invasive breast cancer from 2002 to 2003. ConclusionsDeclining EPT use from 2002 to 2003 should have precipitated an increase in the incidence of colorectal cancer, but the opposite trend was seen in the SEER 9 database during this time. The incidences of invasive breast cancer and colorectal cancer both declined by a similar amount from 2002 to 2003, despite the results of the WHI study predicting opposing trends for the two different types of cancer. Thus, the SEER 9 findings are fundamentally incompatible with expectations from the WHI findings. This implies that reductions in HT use from 2002 to 2003 cannot account for the contemporaneous changes in invasive breast cancer and colorectal cancer incidences. Alternative explanations must be found.

Early Initiation of Hormone Therapy in Menopausal Women Is Associated with Increased Hippocampal and Posterior Cingulate Cholinergic Activity

The role of ovarian hormones in maintaining neuronal integrity and cognitive function is still debated. This study was undertaken to clarify the potential relationship between postmenopausal hormone use and the cholinergic system. We hypothesized that early initiated hormone therapy (HT) preserves the cholinergic system and that estrogen therapy (ET) would be associated with higher levels of acetylcholinesterase activity in the posterior cingulate cortex and hippocampus compared to estrogen plus progestin therapy (EPT) or no HT. We conducted a cross-sectional study at a university teaching hospital. Fifty postmenopausal women (age, 65.2 ± 0.7 yr) with early long-term HT (n = 34; 13 ET and 21 EPT) or no HT (n = 16) participated in the study. There were no interventions. We measured cholinergic activity (acetylcholinesterase) in the hippocampus and posterior cingulate brain regions as measured by N-[(11)C]methylpiperidin-4-yl propionate and positron emission tomography as a marker of cholinergic function. Significant effects of treatment on cholinergic activity measures were obtained in the left hippocampus (F = 3.56; P = 0.04), right hippocampus (F = 3.42; P = 0.04), and posterior cingulate (F = 3.76; P = 0.03). No significant effects were observed in a cortical control region. Post hoc testing identified greater cholinergic activity in the EPT group compared to the no-HT group in the left hippocampus (P = 0.048) and posterior cingulate (P = 0.045), with a nonstatistically significant trend in the right hippocampus (P = 0.073). A differential effect of postmenopausal ET and EPT on cholinergic neuronal integrity was identified in postmenopausal women. The findings are consistent with a preservation of cholinergic neuronal integrity in the EPT group.

Involvement of G-463A MPO gene polymorphism in the response of postmenopausal women to hormone therapy

The aims of this work were to determine (1) the effects of estrogen plus progestogen therapy (EPT) and raloxifene on oxidative stress and cardiovascular risk biomarkers in postmenopausal women and (2) the involvement of the functional G-463A polymorphism of the myeloperoxidase (MPO) gene in the therapy responses. Postmenopausal women (45-55 y old) were assigned to three groups receiving (1) EPT (continuous 50 μg transdermal estradiol daily and 200 mg/d micronized progesterone orally the first 14 d of each month; n = 21), (2) raloxifene (60 mg daily; n = 17), and (3) no treatment (control; n = 21). Blood and urine samples were taken before and after 6 months of therapy. Measurements were serum lipid profile, C-reactive intercellular adhesion molecule 1 (ICAM-1), α-tocopherol, γ-tocopherol, uric acid, total antioxidant activity (TAA), malondialdehyde, and urinary 1,4-dihydroxynonane-mercapturic acid (the major urinary 4-hydroxynonenal metabolite). The G-463A MPO polymorphism was analyzed by polymerase chain reaction and restriction fragment length polymorphism. EPT significantly decreased TAA and the levels of ICAM-1, not modifying other cardiovascular risk or oxidative stress markers. The raloxifene and control groups experienced no modifications in oxidative stress or endothelial dysfunction markers. The MPO genotype specifically influenced the outcomes in the EPT group. Thus, TAA decreased significantly in GG (high-expression genotype) homozygotes, whereas ICAM-1 levels were reduced in A allele carriers. EPT exerted a negative action on the serum oxidant/antioxidant balance in the MPO GG homozygotes and a positive effect on the ICAM-1 endothelial dysfunction marker in carriers of the low-expression A allele. This observation provides evidence of the importance of this polymorphism in the response to EPT.

Does hormone therapy counter the beneficial effects of physical activity on breast cancer risk in postmenopausal women?

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 (1,908 cases, 2,013 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 among current ET users; P (trend) 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.

A randomized controlled study of taper-down or abrupt discontinuation of hormone therapy in women treated for vasomotor symptoms

The aim of this study was to investigate whether tapering down of combined estrogen plus progestogen therapy (EPT) reduced the recurrence of hot flashes and resumption of therapy compared with abrupt discontinuation. A secondary aim was to evaluate whether health-related quality of life (HRQoL) was affected after discontinuation of EPT and to investigate the possible factors predicting resumption of EPT. Eighty-one postmenopausal women undergoing EPT because of hot flashes were randomized to tapering down or abrupt discontinuation of EPT. Vasomotor symptoms were recorded in self-registered diaries, and resumption of hormone therapy (HT) was asked for at every follow-up. The Psychological General Well-being Index was used to assess HRQoL. Neither the number nor the severity of hot flashes or HRQoL or frequency of resumption of HT differed between the two modes of discontinuation of EPT during up to 12 months of follow-up. About every other woman had resumed HT within 1 year. Women who resumed HT after 4 or 12 months reported more deteriorated HRQoL and more severe hot flashes after discontinuation of therapy than did women who did not resume HT. Women who initiate EPT because of hot flashes may experience recurrence of vasomotor symptoms and impaired HRQoL after discontinuation of EPT regardless of the discontinuation method used, abrupt or taper down. Because, in addition to severity of flashes, decreased well-being was the main predictor of the risk to resume HT, it seems important to also discuss quality of life in parallel with efforts to discontinue HT.