# Mechanisms of Successful Vaginal Estrogen Prophylaxis for Postmenopausal Women with Recurrent Urinary Tract Infections: Urogenital Microbiota and Host Immune Responses

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2022 · $338,722

## Abstract

Summary/ Abstract
Recurrent urinary tract infections (rUTI) are a significant problem among older women: 13% of female
Medicare beneficiaries experience at least one UTI annually and >40% of these develop chronic recurrent UTI.
Although UTIs are significantly reduced by vaginal estrogen therapy (VET), 50% of those using VET continue
to experience UTI recurrences. It is unknown why some women benefit from VET while others do not. This
application focuses on interrogating two mechanisms likely to be central to the effectiveness of VET. The first
is the urogenital microbiota: an increase in vaginal lactobacilli is the purported mechanism by which VET
reduces rUTI. However, recent studies suggest that not all lactobacilli are equally beneficial: vaginal microbiota
dominated by L. crispatus may be more protective (possibly via the production of D-lactic acid, which inhibits E.
coli growth). Important and unanswered questions include how VET influences specific Lactobacillus spp.,
whether changes to specific Lactobacillus spp are the key to successful prophylaxis, and how VET affects the
urinary microbiota, which may play a critical role in UTI susceptibility. A second mechanism addressed by this
application is the host vaginal and urinary immune response. Estrogen appears to influence localized
urogenital immune responses, including Th17 and Th1 versus Th2 pathway signaling. Animal studies suggest
that these compartmentalized immune responses play a critical role in UTI susceptibility, but human data are
lacking. This application will address these unanswered questions. Postmenopausal women with rUTI will be
treated with VET. Samples collected before and after VET will characterize vaginal and urinary microbiota (16S
rRNA gene sequencing), soluble mediators of inflammation in both compartments, and vaginal D-lactic acid.
Aims 1 and 2 of this proposal will investigate the impact of VET on the urogenital microbiota and urogenital
immune responses, respectively. Aim 3 will characterize the urogenital environments of participants who
continue to experience rUTI during VET versus those who remain UTI-free. The accomplishment of these aims
will provide pilot data for a larger and more definitive clinical trial. Thus, this application is responsive to
program announcement PAS-20-160, which supports small clinical trials to provide critical preliminary data.
This proposed research will provide data needed to plan a rigorous, adequately powered trial to identify the
characteristics associated with successful rUTI prevention. These proposed studies are a key step toward our
goals of identifying biomarkers that reliably predict a successful response to rUTI prophylaxis and ascertaining
the biological conditions required for successful UTI prevention. Ultimately, an understanding of the
mechanisms of rUTI prevention will allow the development of novel and effective prevention strategies for
postmenopausal women suffering from rUTI.

## Key facts

- **NIH application ID:** 10516250
- **Project number:** 1R01DK130856-01A1
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** VICTORIA Lynn HANDA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $338,722
- **Award type:** 1
- **Project period:** 2022-09-05 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10516250

## Citation

> US National Institutes of Health, RePORTER application 10516250, Mechanisms of Successful Vaginal Estrogen Prophylaxis for Postmenopausal Women with Recurrent Urinary Tract Infections: Urogenital Microbiota and Host Immune Responses (1R01DK130856-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10516250. Licensed CC0.

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