scholarly journals Metabolomic Effects of Hormone Therapy and Associations With Coronary Heart Disease Among Postmenopausal Women

2020 ◽  
Vol 13 (6) ◽  
Author(s):  
Raji Balasubramanian ◽  
Olga Demler ◽  
Marta Guasch-Ferré ◽  
Nina P. Paynter ◽  
Ryan Sheehan ◽  
...  
Keyword(s):  
Coronary Heart Disease ◽  
Heart Disease ◽  
Hormone Therapy ◽  
Women's Health ◽  
Women's Health Initiative ◽  
Women’S Health Initiative ◽  
Health Initiative ◽  
Chd Risk ◽  
Conjugated Equine Estrogens ◽  
Equine Estrogens

Background: In the WHI-HT trials (Women’s Health Initiative Hormone Therapy), treatment with oral conjugated equine estrogens and medroxyprogesterone acetate (CEE+MPA) resulted in increased risk of coronary heart disease (CHD), whereas oral conjugated equine estrogens (CEE) did not. Methods: Four hundred eighty-one metabolites were measured at baseline and at 1-year in 503 and 431 participants in the WHI CEE and CEE+MPA trials, respectively. The effects of randomized HT on the metabolite profiles at 1-year was evaluated in linear models adjusting for baseline metabolite levels, age, body mass index, race, incident CHD, prevalent hypertension, and diabetes. Metabolites with discordant effects by HT type were evaluated for association with incident CHD in 944 participants (472 CHD cases) in the WHI-OS (Women’s Health Initiative Observational Study), with replication in an independent cohort of 980 men and women at high risk for cardiovascular disease. Results: HT effects on the metabolome were profound; 62% of metabolites significantly changed with randomized CEE and 52% with CEE+MPA (false discovery rate–adjusted P value<0.05) in multivariable models. Concerted increases in abundance were seen within various metabolite classes including triacylglycerols, phosphatidylethanolamines, and phosphatidylcholines; decreases in abundance was observed for acylcarnitines, lysophosphatidylcholines, quaternary amines, and cholesteryl/cholesteryl esters. Twelve metabolites had discordant effects by HT type and were associated with incident CHD in the WHI-OS; a metabolite score estimated in a Least Absolute Shrinkage and Selection Operator regression was associated with CHD risk with an odds ratio of 1.47 per SD increase (95% CI, 1.27–1.70, P <10 -6 ). All twelve metabolites were altered in the CHD protective direction by CEE treatment. One metabolite (lysine) was significantly altered in the direction of increased CHD risk by CEE+MPA; the remaining 11 metabolites were not significantly changed by CEE+MPA. The CHD associations of a subset of 4 metabolites including C58:11 triacylglycerol, C54:9 triacylglycerol, C36:1 phosphatidylcholine and sucrose replicated in an independent dataset of 980 participants in the PREDIMED trial (Prevención con Dieta Mediterránea). Conclusions: Randomized treatment with oral HT resulted in large metabolome shifts that generally favored CEE alone over CEE+MPA in term of CHD risk. Discordant metabolite effects between HT regimens may partially mediate the differences in CHD risk between the 2 WHI-HT trials.

scholarly journals Comparative Analysis of the Uterine and Mammary Gland Effects of Drospirenone and Medroxyprogesterone Acetate

Endocrinology ◽  
2008 ◽  
Vol 149 (8) ◽  
pp. 3952-3959 ◽  
Author(s):  
Christiane Otto ◽  
Iris Fuchs ◽  
Helga Altmann ◽  
Mario Klewer ◽  
Alexander Walter ◽  
...  
Keyword(s):  
Mammary Gland ◽  
Hormone Therapy ◽  
Women's Health ◽  
Medroxyprogesterone Acetate ◽  
Uterine Activity ◽  
Women's Health Initiative ◽  
Health Initiative ◽  
Conjugated Equine Estrogens ◽  
Equine Estrogens ◽  
The Women’S Health Initiative

The role of progestins in combined hormone therapy is the inhibition of uterine epithelial cell proliferation. The Women’s Health Initiative study provided evidence for an increased risk of breast cancer in women treated with conjugated equine estrogens plus the synthetic progestin medroxyprogesterone acetate (MPA), compared with conjugated equine estrogens-only treatment. These findings continue to be discussed, and it remains to be clarified whether the results obtained for MPA in the Women’s Health Initiative study are directly applicable to other progestins used in hormone therapy. In this study we compared in a mouse model the effects of the synthetic progestins, MPA, and drospirenone in two major target organs: the uterus and mammary gland. As quantitative measures of progestin activity, we analyzed maintenance of pregnancy, ductal side branching in the mammary gland, and proliferation of mammary and uterine epithelial cells as well as target gene induction in both organs. The outcome of this study is that not all synthetic progestins exhibit the same effects. MPA demonstrated uterine activity and mitogenic activity in the mammary gland at the same doses. In contrast, drospirenone behaved similarly to the natural hormone, progesterone, and exhibited uterine activity at doses lower than those leading to considerable proliferative effects in the mammary gland. We hypothesize that the safety of combined hormone therapy in postmenopausal women may be associated with a dissociation between the uterine and mammary gland activities of the progestin component.

Abstract P301: Menopausal Characteristics and Chronic Kidney Disease in the Women’s Health Initiative

Circulation ◽  
2014 ◽  
Vol 129 (suppl_1) ◽  
Author(s):  
Katharine L Cheung ◽  
Jessica Kubo ◽  
Marcia Stefanick ◽  
Matthew A Allison ◽  
Erin S LeBlanc ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Coronary Heart Disease ◽  
Heart Disease ◽  
Kidney Disease ◽  
Women's Health ◽  
Women's Health Initiative ◽  
Women’S Health Initiative ◽  
Health Initiative ◽  
All Cause Mortality ◽  
The Women’S Health Initiative

Introduction: Vasomotor symptoms (VMS) are common menopausal symptoms and the timing of these symptoms, specifically onset of late VMS, has recently been linked with cardiovascular risk factors. Chronic kidney disease (CKD) affects 13% of all women in the US and carries high risk for cardiovascular disease (CVD). The association between CKD and VMS has not been studied. Hypothesis: We hypothesized that the timing of VMS would differ between women with CKD compared to women without CKD. We also hypothesized that CKD would modify the effect of VMS on all-cause mortality, coronary heart disease and stroke. Methods: We studied the Women’s Health Initiative (WHI) biomarker cohort, which is comprised of all black and Hispanic participants in the WHI observation study and clinical trials plus a subset of white WHI participants such that the biomarker cohort reflects the age distribution of the HT population. CKD was defined as estimated glomerular filtration rate <60 mL/min/1.73m 2 and VMS was defined as self-report of hot flushes and night sweats. We used polytomous logistic regression to determine the cross-sectional associations (unadjusted, demographics-adjusted and multivariable-adjusted between CKD and reported VMS categories (none, early, late, persistent). We used Cox proportional hazards models with an interaction term to determine whether the association between late VMS and all-cause mortality or incident CVD was modified by CKD. Results: Among the 18,024 WHI participants, 1281 women (5.86%) had CKD. VMS were less common in women with CKD versus without CKD (37.6% vs 45.8%, p<0.001). Prevalent CKD was associated with an OR of 0.85 (95% CI: 0.72, 1.00) for early VMS, OR 0.80 (95% CI: 0.66, 0.97) for late VMS, and OR 0.59 (95% CI: 0.50, 0.70) for persistent VMS, as compared to having no VMS. The overall association of CKD was not significant after adjusting for potential confounders (p=0.17). CKD was associated with increased risk for mortality (HR 1.72, 95% CI: 1.52, 1.95), coronary heart disease (HR 1.60, 95% CI: 1.33, 1.92) and stroke (HR 1.49, 95% CI: 1.18, 1.87). Late VMS were associated with increased all-cause mortality (HR 1.16, 95%CI 1.04, 1.30) but not significantly associated with coronary heart disease or stroke. No significant interactions were found between late VMS and CKD on any of the endpoints studied. Conclusions: In this multiethnic cohort, VMS were less common in women with CKD and CKD did not appear to modify the association between VMS and either incident CVD or total mortality.

Understanding the Effects of Menopausal Hormone Therapy: Using the Women’s Health Initiative Randomized Trials and Observational Study to Improve Inference

2011 ◽  
Author(s):  
Garnet L. Anderson ◽  
Ross L. Prentice
Keyword(s):  
Chronic Disease ◽  
Disease Prevention ◽  
Women’S Health ◽  
Women's Health ◽  
Women's Health Initiative ◽  
Women’S Health Initiative ◽  
Health Initiative ◽  
Conjugated Equine Estrogens ◽  
Equine Estrogens ◽  
The Women’S Health Initiative

Over the last decade, several large-scale randomized trials have reported results that disagreed substantially with the motivating observational studies on the value of various chronic disease–prevention strategies. One high-profile example of these discrepancies was related to postmenopausal hormone therapy (HT) use and its effects on cardiovascular disease and cancer. The Women’s Health Initiative (WHI), a National Heart, Lung, and Blood Institute–sponsored program, was designed to test three interventions for the prevention of chronic diseases in postmenopausal women, each of which was motivated by a decade or more of analytic epidemiology. Specifically, the trials were testing the potential for HT to prevent coronary heart disease (CHD), a low-fat eating pattern to reduce breast and colorectal cancer incidence, and calcium and vitamin D supplements to prevent hip fractures. Over 68,000 postmenopausal women were randomized to one, two, or all three randomized clinical trial (CT) components between 1993 and 1998 at 40 U.S. clinical centers (Anderson et al., 2003a). The HT component consisted of two parallel trials testing the effects of conjugated equine estrogens alone (E-alone) among women with prior hysterectomy and the effect of combined estrogen plus progestin therapy (E+P), in this case conjugated equine estrogens plus medroxyprogesterone acetate, among women with an intact uterus, on the incidence of CHD and overall health. In 2002, the randomized trial of E+P was stopped early, based on an assessment of risks exceeding benefits for chronic disease prevention, raising concerns among millions of menopausal women and their care providers about their use of these medicines. The trial confirmed the benefit of HT for fracture-risk reduction but the expected benefit for CHD, the primary study end point, was not observed. Rather, the trial results documented increased risks of CHD, stroke, venous thromboembolism (VTE), and breast cancer with combined hormones (Writing Group for the Women’s Health Initiative Investigators, 2002). Approximately 18 months later, the E-alone trial was also stopped, based on the finding of an adverse effect on stroke rates and the likelihood that the study would not confirm the CHD-prevention hypothesis.

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