Jacques E Rossouw’s research while affiliated with National Heart Lung and Blood Institute, National Institutes of Health and other places

OBJECTIVE To assess the long-term changes in cardiovascular biomarkers during the WHI (Women's Health Initiative) hormone therapy (HT) clinical trials of conjugated equine estrogens (CEE) alone and CEE plus medroxyprogesterone acetate (MPA). METHODS HT trial participants from the CEE alone (n=1,188, 0.625 mg/d CEE or placebo) and the CEE+MPA (n=1,508, 0.625 mg/d CEE plus continuous 2.5 mg/d MPA or placebo) trials provided blood samples at baseline and after 1, 3, and 6 years. Low-density lipoprotein cholesterol (LDL-C; primary endpoint), high-density lipoprotein cholesterol (HDL-C), triglycerides, total cholesterol, lipoprotein(a), glucose, insulin, and homeostatic model assessment for insulin resistance were measured. Repeated-measures regression models estimated the geometric means of each log-transformed biomarker by restricted maximum likelihood. A constant treatment effect across visits was used to estimate the overall effect, expressed as a ratio of geometric means, and was complemented with geometric means (95% CIs) by randomization group and corresponding ratios of geometric means (95% CI; HT vs placebo) at each visit. RESULTS During the intervention phase of the CEE-alone trial, randomization to CEE reduced LDL-C by 11% over 6 years (ratio of geometric means 0.89, 95% CI, 0.88–0.91, P <.001). The overall reduction in LDL-C was similar for CEE+MPA relative to placebo (ratio of geometric means 0.88, 95% CI, 0.86–0.89, P <.001). Relative to placebo, HDL-C and triglycerides were 13.0% and 7.0% higher with CEE and CEE+MPA, respectively. The homeostatic model assessment for insulin resistance decreased by 14.0% and 8.0% for CEE-alone and CEE+MPA trial participants, respectively. Relative to placebo, lipoprotein(a) decreased by 15.0% and 20.0% for participants randomized to CEE alone and CEE+MPA, respectively. CONCLUSION Lipoprotein(a), LDL-C, and homeostatic model assessment for insulin resistance were lower and HDL-C levels were higher for HT compared with placebo. Triglycerides increased in both the CEE and CEE+MPA trials, however. Future research should assess whether other progestogens attenuate the effect of estrogen on HDL-C. These results may be used to counsel younger menopausal women with bothersome symptoms who are deciding whether to initiate oral HT within the context of published effects of oral HT on rates of cardiovascular events. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov, NCT00000611.

Importance Approximately 55 million people in the US and approximately 1.1 billion people worldwide are postmenopausal women. To inform clinical practice about the health effects of menopausal hormone therapy, calcium plus vitamin D supplementation, and a low-fat dietary pattern, the Women’s Health Initiative (WHI) enrolled 161 808 postmenopausal US women (N = 68 132 in the clinical trials) aged 50 to 79 years at baseline from 1993 to 1998, and followed them up for up to 20 years. Observations The WHI clinical trial results do not support hormone therapy with oral conjugated equine estrogens plus medroxyprogesterone acetate for postmenopausal women or conjugated equine estrogens alone for those with prior hysterectomy to prevent cardiovascular disease, dementia, or other chronic diseases. However, hormone therapy is effective for treating moderate to severe vasomotor and other menopausal symptoms. These benefits of hormone therapy in early menopause, combined with lower rates of adverse effects of hormone therapy in early compared with later menopause, support initiation of hormone therapy before age 60 years for women without contraindications to hormone therapy who have bothersome menopausal symptoms. The WHI results do not support routinely recommending calcium plus vitamin D supplementation for fracture prevention in all postmenopausal women. However, calcium and vitamin D are appropriate for women who do not meet national guidelines for recommended intakes of these nutrients through diet. A low-fat dietary pattern with increased fruit, vegetable, and grain consumption did not prevent the primary outcomes of breast or colorectal cancer but was associated with lower rates of the secondary outcome of breast cancer mortality during long-term follow-up. Conclusions and Relevance For postmenopausal women, the WHI randomized clinical trials do not support menopausal hormone therapy to prevent cardiovascular disease or other chronic diseases. Menopausal hormone therapy is appropriate to treat bothersome vasomotor symptoms among women in early menopause, without contraindications, who are interested in taking hormone therapy. The WHI evidence does not support routine supplementation with calcium plus vitamin D for menopausal women to prevent fractures or a low-fat diet with increased fruits, vegetables, and grains to prevent breast or colorectal cancer. A potential role of a low-fat dietary pattern in reducing breast cancer mortality, a secondary outcome, warrants further study.

Background Lower density of carotenoids lutein and zeaxanthin (L/Z) in the macula (i.e., macular pigment) has been linked to greater risk for age-related eye disease. Objectives We evaluated whether macular pigment optical density (MPOD) was associated with manifest primary open-angle glaucoma (POAG) among older women in the Carotenoids in Age-Related Eye Disease Study 2 (CAREDS2). Methods MPOD was measured with customized heterochromatic flicker photometry in women who attended CAREDS2 (2016–2019) and CAREDS1 (2001–2004) study visits. Manifest POAG at CAREDS2 was assessed using visual fields, disc photos, optical coherence tomography, and medical records. Age-adjusted linear and logistic regression models were used to investigate the cross-sectional association between POAG and MPOD at CAREDS2, and MPOD measured 15 years earlier at CAREDS1. Results Among 426 CAREDS2 participants (mean age: 80 y; range: 69–98 y), 26 eyes with manifest POAG from 26 participants were identified. Glaucomatous eyes had 25% lower MPOD compared to nonglaucomatous eyes [mean (SE): 0.40 (0.05) compared with 0.53 (0.01)] optical density units (ODU), respectively (P = 0.01). Compared with MPOD quartile 1, odds for POAG were lower for women in quartiles 2–4 (P-trend = 0.01). After excluding eyes with age-related macular degeneration, associations were similar but not statistically significant (P-trend = 0.16). Results were similar for MPOD measured at CAREDS1. Conclusions Our results add to growing evidence that low MPOD may be a novel glaucoma risk factor and support further studies to assess the utility of dietary interventions for glaucoma prevention.

Background: The United States has high and increasing rates of maternal morbidity and mortality, large proportions of which are related to cardiovascular health (CVH). Methods: We searched for National Institutes of Health (NIH) supported research as well as that of two other Agencies in the U.S. Department of Health and Human Services (DHHS) for fiscal years (FY) 2016-2021. Grants included maternal health conditions or exposures across all pregnancy stages, but excluded grants that focused entirely on birth, neonatal, infant/childhood outcomes. Results were manually curated by reviewing the abstract and specific aims. Grants deemed to be relevant were grouped by category. Results: Between FY 2016-2021, overall Maternal Health grants remained unchanged at an average of 1.4% of total DHHS grant funding. Maternal CVH-specific (MCVH) funding amounted to $278,926,105 for 755 grants,$191,344,649 was for 534 Type-1 grants, representing a twofold increase. Non-NIH DHHS agencies most commonly funded general Maternal Health related to CVH; NIH focused funding classified as hypertensive disorders of pregnancy, maternal morbidity and mortality, obesity, and diabetes. Non-NIH DHSS Agencies most commonly funded clinical applied research. In addition to clinical applied grants, NIH funded substantial proportions of grants classified as basic research, clinical trials, and/or translational. National Heart, Lung, and Blood Institute (NHLBI) MCVH grants studied participants in the pre-partum period (78.5%), followed by the post-partum period (50.5%), with relatively few in pre-pregnancy and peri-partum periods (10.8% and 9.7%, respectively); at the NIH level, the peri-partum period had better representation at 20.3%, whereas the pre-pregnancy period remained low at 9.9%. Conclusions: Federal grant funding for maternal health including MCVH increased at the same rate as its funding for overall research, and represented only 1.4% of overall total funding. The pre-pregnancy period was understudied in overall NIH funding and represents a gap area whereby funding agencies could further foster research advances.

The WHI (Women’s Health Initiative) enrolled 161,808 racially and ethnically diverse postmenopausal women, ages 50-79 years, from 1993 to 1998 at 40 clinical centers across the United States. In its clinical trial component, WHI evaluated 3 randomized interventions (menopausal hormone therapy; diet modification; and calcium/vitamin D supplementation) for the primary prevention of major chronic diseases, including cardiovascular disease, in older women. In the WHI observational study, numerous clinical, behavioral, and social factors have been evaluated as predictors of incident chronic disease and mortality. Although the original interventions have been completed, the WHI data and biomarker resources continue to be leveraged and expanded through ancillary studies to yield novel insights regarding cardiovascular disease prevention and healthy aging in women.

Background The association of social isolation or lack of social network ties in older adults is unknown. This knowledge gap is important since the risk of heart failure (HF) and social isolation increase with age. The study examines whether social isolation is associated with incident HF in older women, and examines depressive symptoms as a potential mediator and age and race and ethnicity as effect modifiers. Methods and Results This study included 44 174 postmenopausal women of diverse race and ethnicity from the WHI (Women's Health Initiative) study who underwent annual assessment for HF adjudication from baseline enrollment (1993–1998) through 2018. We conducted a mediation analysis to examine depressive symptoms as a potential mediator and further examined effect modification by age and race and ethnicity. Incident HF requiring hospitalization was the main outcome. Social isolation was a composite variable based on marital/partner status, religious ties, and community ties. Depressive symptoms were assessed using CES‐D (Center for Epidemiology Studies‐Depression). Over a median follow‐up of 15.0 years, we analyzed data from 36 457 women, and 2364 (6.5%) incident HF cases occurred; 2510 (6.9%) participants were socially isolated. In multivariable analyses adjusted for sociodemographic, behavioral, clinical, and general health/functioning; socially isolated women had a higher risk of incident HF than nonisolated women (HR, 1.23; 95% CI, 1.08–1.41). Adding depressive symptoms in the model did not change this association (HR, 1.22; 95% CI, 1.07–1.40). Neither race and ethnicity nor age moderated the association between social isolation and incident HF. Conclusions Socially isolated older women are at increased risk for developing HF, independent of traditional HF risk factors. Registration URL: http://www.clinicaltrials.gov ; Unique identifier: NCT00000611.

Reproductive longevity is essential for fertility and influences healthy ageing in women1,2, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations³. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.

Background /Objective: Insomnia is common in older women and is associated with higher cardiovascular disease risk (CVD). Nonbenzodiazepine GABA agonists (Z-drugs) are the most commonly prescribed sleep aids. The study objective was to determine whether the use of Z-drugs is associated with the risk of developing CVD and mortality in older women with sleep disturbances. Patients/Methods The study cohort included post-menopausal women who, at baseline, scored ≥9 with the Women’s Health Initiative Insomnia Rating Scale (N=40,728). Members of the cohort were categorized as users of Z-drugs, users of other prescription hypnotics, or non-users. Outcomes were composite CVD (congestive heart failure, stroke, and fatal/non-fatal myocardial infarction) and mortality. Hazard ratios were estimated from Cox proportional hazards regression models adjusted for demographic, medical history, and sleep measures. To address potential confounding by indication, we also adjusted for propensity to be prescribed hypnotics. Results The mean age of our cohort was 63.57 years (SD = 7.23) and mean follow-up time after the initial follow-up visit was 14.0 years (SD = 6.3). Z-drug use was significantly associated with an increased risk of composite CVD (HR= 1.35, 95%CI: 1.02-1.79) and all-cause mortality (HR= 1.38, 95%CI: 1.13-1.69). When groups were divided by heavy and casual use, only heavy users (≥3 times per week) had an increased risk of mortality. Conclusions Z-drugs use was associated with an increased risk for death and CVD in post-menopausal women being treated for sleep disturbances. Additional research is needed to evaluate both frequency and duration of Z-drug use.

A Correction to this paper has been published: https://doi.org/10.1038/s41588-021-00832-z.