Women in midlife face unique health challenges—such as menopause, rising cardiovascular risk, and increased vulnerability to chronic disease—that have been historically under-researched. Supporting targeted studies in this area helps close that gap, ensuring women receive care that is informed by real data and evidence.

ORWH, with support from the Director of the NIH Office of Intramural Research (OIR), is supporting one-year, proof-of-concept pilot awards on women’s midlife health to incentivize interdisciplinary research collaborations across NIH intramural programs. The call for FY25 proposals was circulated to senior investigators, investigators, senior clinicians, senior scientists, assistant clinical investigators, and Independent Research Scholar Program research fellows in December 2024, and applications were due January 31, 2025. Required elements for the project included collaboration across NIH Institutes and Centers (ICs), teams of multiple principal investigators (PIs), and mentorship opportunities. Applications were reviewed in February with awards issued beginning in June. 

Applications were received from PI teams representing 14 IC intramural programs, with initial awards made to four teams at eight ICs: 

• National Human Genome Research Institute (NHGRI)
• National Institute of Mental Health (NIMH)
• National Institute on Aging (NIA)
• National Cancer Institute (NCI)
• National Institute of Environmental Health Sciences (NIEHS)
• National Center for Advancing Translational Sciences (NCATS)
• National Heart, Lung, and Blood Institute (NHLBI)
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Initial Awardees from the ORWH Intramural Innovation Call for Proposals on Women’s Midlife Health

Characterizing the impacts of menopause stage, sex hormones, and sex chromosomes on brain aging and disease

Principal Investigators: Melissa Wilson (NHGRI), Stephano Maraceno (NIMH), Alex R. DeCasien (NIA), Xylena Reed (NIA), Armin Raznahan (NIMH), Mark Cookson (NIA)

Abstract: Biological sex influences risk for neurodegenerative diseases (NDDs), with Alzheimer’s disease occurring more often in females and Parkinson’s disease occurring more often in males. Here, we propose to investigate how hormonal fluctuations (associated with menopause and andropause) and sex chromosome dynamics shape both sex differences and within-sex variability in brain aging and NDD risk. We will generate new blood-based endocrine measures and integrate these data with existing intramural and published single-nucleus RNA sequencing (snRNA-seq) datasets from various brain regions to examine how menopause stage, sex hormone concentrations, and sex chromosome loss contribute to brain aging in specific brain cell types. By sampling males and females across the reproductive aging period—including the menopause transition—this work can illuminate how hormonal fluctuations due to reproductive aging contribute to changes in brain gene expression in ways that may impact susceptibility to NDDs. Our findings will enhance our understanding of how sex-related mechanisms and aging interact to influence brain health, potentially revealing novel therapeutic targets for NDDs.

The impact of menopause and hormone therapy on the fecal microbiome in the Sister Study

Principal Investigators: Emily Vogtmann (NCI) and Dale Sandler (NIEHS)

Abstract: Menopause, which represents the final reproductive stage for women, can lead to a variety of symptoms that may be treated with hormone therapy. After menopause, women have increased risks of some adverse health conditions including cardiovascular disease and cancer. The gut microbiome (i.e., bacteria and other microbes in the digestive tract) has a bidirectional relationship with circulating hormones, but there has been very limited research investigating associations between menopause, use of hormone therapy, and the gut microbiome. Large human studies, with detailed data on cause and timing of menopause and histories of hormone therapy use are needed to fully characterize the relationship between menopause, hormone therapy treatment, and the gut microbiome. The National Institute of Environmental Health Sciences Sister Study has been following about 50,000 women from across the United States since enrollment in 2003−2009. Comprehensive reproductive and health histories along with biological samples were collected at enrollment and throughout follow-up. Therefore, we will conduct a nested, cross-sectional study of the gut microbiome measured using shotgun metagenomic sequencing from 1,200 postmenopausal women in the Sister Study cohort. We plan to (1) compare the gut microbial communities of women who experienced natural menopause to those who experienced earlier menopause due to hysterectomy and/or oophorectomy and to evaluate the association of the gut microbiome with time since menopause and (2) compare the microbial communities of women reporting current use of hormone therapy by type to former users and non-users in addition to differences by administration route (e.g., pill, patch, other) and duration of use. The gut microbiome may reflect a pathway through which menopause impacts women’s health, and the results from this study may provide important data for improved treatment for menopause-related symptoms and prevention of adverse health effects.

Discovery of environmental factors that contribute to menopausal hot flashes via modulation of NK3R receptor activity

Principal Investigators: Natalie Shaw (NIEHS), Menghang Xia (NCATS), Vukasin Jovanovic (NCATS), Carlos Tristan (NCATS)

Abstract: Hot flashes are one of the most common and distressing symptoms associated with menopause. Hot flashes are believed to result from disrupted communication between the reproductive centers and thermoregulatory (heat sensing) centers of the brain. The signaling pathway between these two parts of the brain involves the hormone neurokinin B and its receptor, NK3R. Not every woman, however, experiences the same degree of hot flashes, suggesting a role for genetic background and different environmental exposures in increasing the risk of hot flashes in some midlife women. We propose to identify such environmental factors by conducting a screen of a large chemical library (i.e., Tox 21 10K compound library) for compounds that may activate or inhibit NK3R activity in a human cell line that stably overexpresses NK3R. Results of these studies may inform new treatment strategies for menopausal hot flashes and alter public policy surrounding the safety of certain environmental exposures.

Exploring immune-adipose dysfunction in the menopause transition

Principal Investigators: Michael Sack (NHLBI), Rachel Klein (NHLBI), Aaron Cypess (NIDDK)

Abstract: Many autoimmune diseases exhibit a clear female predominance, with hormones such as estrogens playing a recognized pathogenic role. However, a paradox exists: as humans age, our immunologic responses to infection become impaired, yet menopausal women experience an increase in selective autoimmune diseases and other inflammation-related conditions, notably metabolic disease. This paradox, differential activation of immune populations, remains incompletely understood. Additionally, whole-body metabolic dysfunction is closely associated with menopause, marked by a shift in fat distribution and an increase in insulin resistance and lipid dysfunction. Resident adipose tissue immune cells contribute to local homeostasis and have been linked to systemic metabolic dysfunction. We hypothesize that hormonal shifts of menopause lead to imbalanced inflammatory control, contributing to the disruption of the immune-adipose axis and adipose tissue metabolic dysfunction. We propose the use of high-dimensional single-cell sequencing and cytometric technologies to delineate changes in immune cell function and adipose tissue inflammation and metabolism linked to menopause hormonal shifts. This exploratory and hypothesis-generating study will utilize an existing disease discovery protocol (NCT01143454) to recruit individuals for peripheral blood and adipose tissue sampling. In Aim 1 we will perform deep immunometabolic phenotyping of immune cells in the peripheral blood and adipose tissue. In Aim 2, we will determine the effect of menopause on CD4+ cell immunometabolism. The novelty of this study lies in its multi-omics and integrative approach. Characterizing the effect of menopause on immune cells and adipose tissue individually and via integrative bioinformatics will generate the foundation to further investigate their interactions on the immune-adipose axis.