Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women

In healthy postmenopausal women with a uterus, the unfavorable risk-benefit profile for combined estrogen plus progestin therapy makes this therapy a nonviable intervention for primary prevention of chronic disease. This study (part of the Women’s Health Initiative) evaluates hormone therapy in postmenopausal women. Patients are randomized to either combination therapy or to a placebo. The study concluded that risks of hormone therapy (including breast cancer and cardiovascular disease) outweighed the benefits of therapy, including a reduction of fractures. It is appropriate to initiate hormone therapy for women with bothersome vasomotor symptoms who are within 10 years of menopause and are healthy.1

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

Background Menopausal 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. Methods We 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. Results Eight 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). Conclusions ET 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.

Abstract MP46: Metabolomic Response to Randomized Treatment With Estrogen and Estrogen Plus Progestin Therapy in Postmenopausal Women

Introduction: Hormone therapy (HT) has been linked to chronic disease risk in postmenopausal women, but the effect of HT on the metabolome is unclear. Hypothesis: Randomized HT is associated with perturbations in the metabolome. Methods: The discovery set, from the Women’s Health Initiative (WHI), included 288 women in the conjugated equine estrogens-alone (CEE) trial (139 active; 149 placebo) and 244 women in the CEE + medroxyprogesterone acetate (CEE+MPA) trial (133 active; 111 placebo). Blood samples were collected 1 year after intervention. The validation set included 494 women from the Nurses’ Health Study (NHS) and NHS2 (264 non-users, 158 estrogen-alone users, and 72 estrogen + progestogen users). Plasma metabolome was profiled by liquid chromatography-tandem mass spectrometry; 478 known metabolites were used in analyses. We used elastic net regressions to develop metabolomic signatures for CEE and CEE+MPA in the WHI, adjusting for age and race. We applied the signature models to NHS/NHS2 and compared the signatures of current HT users to those of non-users. Pathway analysis was done using MetaboAnalyst. Results: In the WHI, we identified a CEE metabolomic signature comprised of 42 metabolites and a CEE+MPA signature comprised of 34 metabolites ( Fig. A ). The two signatures shared 8 metabolites (4 amino acids, 2 glycerophospholipids, and 2 quaternary amines). In NHS/NHS2, CEE and CEE+MPA signatures were highly correlated ( r =0.85) and both significantly higher in current HT users than non-users ( P ≤2.7х10 -15 ) ( Fig. B ). The CEE+MPA signature metabolites were enriched in 3 pathways (glycerophospholipid metabolism; aminoacyl-tRNA biosynthesis; and glycine, serine and threonine metabolism); no pathway enrichment was found for the CEE signature. Conclusions: We identified and validated metabolomic signatures for CEE and CEE+MPA use in postmenopausal women from WHI and NHS/NHS2. Whether alterations in lipid or amino acid metabolism mediate associations of HT use with chronic disease needs future investigation.

Lung cancer in African-Americans and analysis of estrogen plus progestin use.

e18258 Background: The 15-year Women’s Health Initiative (WHI) sponsored by the NIH has provided a robust dataset on health risks for post-menopausal black women (BW), including the impact of hormone therapy (HRT) on cancer risk. Women enrolled in the WHI randomized, placebo-controlled trial and taking HRT demonstrated no increase in lung cancer incidence, but a statistically significant increase in mortality. However, effects of estrogen plus progestin on non-small cell lung cancer (NSCLC) incidence and outcomes has not been extensively examined, especially in African Ancestry (AA) and smoking history. Methods: Study participants were identified who met WHI clinical trial entry criteria. Cox regression models and Kaplan-Meier method plots were utilized. Analyses adjusted for age, BMI, education, smoking status, alcohol use, health status, and physical activity. A secondary analysis was performed on BW based on AA via Affymetrix Human SNP Array. Results: 161, 808 pts were enrolled from October 1993 to December 1998 (after exclusions total analytic cohort = 142,503). 128,682 (90%) were white (WW) and 13,821 (10%) were BW. BW had lower incidence of NSCLC compared to WW (HR 0.68; P < .0001). HRT participants had a 55% increase in incidence of NSCLC (p < .0001). Former alcohol users had highest risk of NSCLC incidence (HR 2.72; p < 0.0001). Age groups (55-59 years; 60-69 years; 70-79 years) were significantly less associated with BW compared to the youngest(50-54 years; P < .0001). HRT participants were more likely BW (OR 1.17; p < .0001). More current smokers were BW compared to WW (OR 1.75; p < .0001). HRT participants had increased risk of death to NSCLC (HR 1.29; p < .001). There was a trend for survival (p = 0.3667) in WW participants compared to BW (32 vs 28.0 months, respectively). BW who had > 80% AA had a decreased incidence NSCLC trend compared to BW with < 80% AA (HR 0.81; p = 0.2806). Conclusions: BW, especially those with high levels of AA had decreased incidence of NSCLC. Those patients who received HRT had higher incidence and death from NSCLC. Further investigations are required to understand the mechanisms that AA and HRT alter risks associated with NSCLC.