Vaginal Estrogen for Urinary Tract Infection

Overseen By CHARLOTTE TER HAAR, MD

Age: 18+

Sex: Female

Trial Phase: Phase 4

Sponsor: University of California, Irvine

Must not be taking: Vaginal estrogen

Disqualifiers: Diabetes, Fecal incontinence, Catheterization, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 4

Duration: 6 months

111 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to explore how well women adhere to prescribed vaginal estrogen treatments for managing low estrogen levels, focusing on post-menopausal women with frequent urinary tract infections (UTIs). The study will also examine how these treatments affect vaginal tissue and the bacterial composition in the vagina and urine. Participants will randomly receive one of three types of estrogen treatments: a cream (Estrace 0.01% Vaginal Cream), tablets (Vagifem), or a ring (Estring Vaginal Product). Women who have had low estrogen for at least a year and experience recurrent UTIs might be suitable candidates for this trial. As a Phase 4 trial, this research involves FDA-approved treatments and aims to understand how they benefit more patients.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It might be best to discuss this with the trial coordinators or your doctor.

What is the safety track record for these treatments?

Research has shown that vaginal estrogen treatments, like those tested in this trial, are generally well-tolerated. For instance, a study on Vagifem, a vaginal estrogen tablet, found that common side effects include mild issues such as back pain and diarrhea, affecting less than 10% of users.

Estrace cream, another type of vaginal estrogen, may cause headaches and breast pain, though these effects were not severe. Estring, a vaginal ring, releases a low dose of estrogen over time to alleviate menopausal symptoms like vaginal dryness and irritation. Some users might experience unusual vaginal bleeding, which should be reported to a doctor.

These treatments have been used for other conditions and have received FDA approval, indicating general safety. However, discussing potential risks with a healthcare provider before starting any new treatment is always important. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Researchers are excited about these treatments for urinary tract infections (UTIs) because they use localized estrogen delivery methods, which are distinct from the usual antibiotics typically prescribed for UTIs. The treatments being examined include an estrogen drug-eluting ring (Estring), estrogen tablets (Vagifem), and estrogen cream (Estrace 0.01%). Unlike antibiotics that target bacteria, these treatments aim to strengthen the vaginal and urinary lining by delivering estrogen directly to the area, potentially reducing infection risk over time. This approach not only offers a new mechanism by targeting tissue health but also minimizes systemic side effects associated with oral medications.

What evidence suggests that this trial's treatments could be effective for recurrent urinary tract infections?

Research shows that vaginal estrogen can help reduce the frequency of urinary tract infections (UTIs) in post-menopausal women. In this trial, participants will receive one of the following treatments: Estrace cream, Estring ring, or Vagifem tablets. Studies have found that over 55% of women using these treatments experience one or no UTIs in a year, and about 31% have no UTIs at all. These estrogen treatments make the vaginal environment less acidic and improve the health of vaginal tissues, which helps prevent infections. They also increase the number of beneficial bacteria, like lactobacillus, in the vagina, further reducing UTIs. Overall, vaginal estrogen therapy is considered a safe and effective way to reduce recurring UTIs. ^{6 7 8 9 10}

Who Is on the Research Team?

CHARLOTTE TER HAAR, MD

Principal Investigator

University of California, Irvine

Olivia Chang, MD

Principal Investigator

University of California, Irvine

Are You a Good Fit for This Trial?

This trial is for hypoestrogenic women, typically post-menopausal, who frequently suffer from urinary tract infections. Participants should be willing to use one of three vaginal estrogen treatments and attend follow-up visits. Details about their health will be collected via questionnaires and medical tests.

Inclusion Criteria

I am a woman over 18 with low estrogen and frequent UTIs.

Exclusion Criteria

I have a short vaginal length or difficulty moving that may stop me from using an estrogen ring.

I use vaginal estrogen more than twice a month.

I cannot use vaginal estrogen due to an allergy, a hormone-sensitive tumor, or application issues.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Baseline Assessment

Initial visit to collect baseline information, complete questionnaires, and collect specimens for microbiome assessment

1 day

1 visit (in-person)

Treatment

Participants receive one of three vaginal estrogen treatments: cream, tablets, or drug-eluting ring

6 months

Ongoing treatment with periodic assessments

Follow-up

3 and 6 month follow-ups to assess adherence, complete questionnaires, and repeat imaging and microbiome assessments

6 months

2 visits (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Estrace 0.01% Vaginal Cream
• Estring Vaginal Product
• Vagifem

Trial Overview The study compares adherence to different forms of vaginal estrogen therapy: a cream (Estrace), tablets (Vagifem), or a drug-eluting ring (Estring). It also examines changes in the vagina's skin and microbiome using optical coherence tomography imaging and specimen collection.

How Is the Trial Designed?

Group I: Estrogen tablet Experimental Treatment 1 Intervention

Participants in this arm will receive the vaginal estrogen tablets (Vagifem) for treatment. Participants will place one tablet (10 mcg) into the vagina twice per week for the duration of the study.

Group II: Estrogen drug-eluting ring Experimental Treatment 1 Intervention

Participants in this arm will receive the vaginal estrogen drug-eluting ring (Estring) for treatment. Participants will have the ring placed by a provider at their clinical visit. The ring will be exchanged every 12 weeks.

Group III: Estrogen cream Experimental Treatment 1 Intervention

Participants in this arm will receive the vaginal estrogen cream (Estrace 0.01%) for treatment. Participants will apply 0.5gm twice per week for the duration of the study.

Estrace 0.01% Vaginal Cream is already approved in United States, Canada, European Union for the following indications:

Approved in United States as Estrace 0.01% Vaginal Cream for:

• Moderate to severe dyspareunia, a symptom of vulvar and vaginal atrophy due to menopause

Approved in Canada as Estradiol 0.01% Vaginal Cream for:

• Atrophic vaginitis, kraurosis vulvae, and moderate to severe dyspareunia

Approved in European Union as Estradiol 0.01% Vaginal Cream for:

• Vulvar and vaginal atrophy due to estrogen deficiency

Who Is Running the Clinical Trial?

University of California, Irvine

Lead Sponsor

Trials

580

Recruited

4,943,000+

Published Research Related to This Trial

Menopausal women experience significant urogenital changes due to reduced ovarian steroids, with estrogen therapy effectively alleviating symptoms like atrophic vaginitis and dryness, and reducing urinary tract infections.

Low-dose estrogen therapies, even in minimal amounts, can be absorbed systemically and help preserve bone density and improve lipid profiles, but should be combined with progestogen to mitigate the risk of endometrial cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vaginal hormone therapy for urogenital and menopausal symptoms. Ballagh, SA.[2005]

The estradiol vaginal ring provides controlled local delivery of low doses of estradiol, resulting in minimal changes to plasma estradiol levels and a high margin of safety for postmenopausal women.

Clinical studies indicate that this method has very low systemic exposure to estradiol, which reduces the risk of estrogen-related side effects and drug interactions compared to other therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetic data on estradiol in light of the estring concept. Estradiol and estring pharmacokinetics. Gabrielsson, J., Wallenbeck, I., Birgerson, L.[2013]

In a study of 167 postmenopausal women with recurrent urinary tract infections (rUTIs), 67.7% experienced improvement or resolution of symptoms with vaginal estrogen cream alone, indicating its efficacy as a first-line treatment.

Women with urinary incontinence were found to be 2.3 times more likely to require additional therapies for rUTIs, highlighting the importance of this condition as a risk factor in treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vaginal Estrogen as First-Line Therapy for Recurrent Urinary Tract Infections in Postmenopausal Women and Risk Factors for Needing Additional Therapy. Chang, E., Kent, L., Prieto, I., et al.[2022]

In a study of 5,638 women with hypoestrogenism, prescribing vaginal estrogen led to a significant reduction in urinary tract infections (UTIs), with the frequency dropping from an average of 3.9 to 1.8 infections per year, representing a 51.9% decrease.

Factors such as older age, higher baseline UTI frequency, urinary incontinence, urinary retention, and diabetes were linked to an increased risk of UTIs after starting vaginal estrogen, while surprisingly, women with higher medication adherence had a smaller reduction in UTI frequency, suggesting potential confounding factors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of vaginal estrogen for recurrent urinary tract infection prevention in hypoestrogenic women. Tan-Kim, J., Shah, NM., Do, D., et al.[2023]

A review of 8 studies on systemic estrogen therapy for preventing recurrent urinary tract infections (rUTI) in postmenopausal women found that none met all criteria for ideal research, indicating a lack of strong evidence for its efficacy.

Current guidelines recommend vaginal estrogen for rUTI prevention, but the evidence for systemic estrogen is inconclusive and based on studies with significant methodological limitations, highlighting the need for further research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of systemic estrogen for preventing urinary tract infections in postmenopausal women. Fox, KA., Lokken, EM., Reed, SD., et al.[2023]

A study involving 185 women found that both the continuous low-dose estradiol-releasing vaginal ring (ESTring) and the vaginal estradiol tablet (Vagifem) were equally effective in relieving symptoms of urogenital estrogen deficiency over 12 months.

The ESTring showed a significant safety advantage with no reported bleeding or spotting, while Vagifem users experienced some bleeding, indicating that the vaginal ring may be a preferable option for long-term treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Endometrial and vaginal effects of low-dose estradiol delivered by vaginal ring or vaginal tablet. Weisberg, E., Ayton, R., Darling, G., et al.[2013]

Both 25-microg 17beta-estradiol vaginal tablets and 1.25-mg conjugated equine estrogen vaginal cream effectively relieve symptoms of atrophic vaginitis in menopausal women, as shown in a study with 159 participants over 24 weeks.

The vaginal tablets were associated with fewer systemic side effects, lower rates of endometrial proliferation, and higher patient satisfaction, leading to a lower withdrawal rate compared to the vaginal cream.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

17beta-estradiol vaginal tablet versus conjugated equine estrogen vaginal cream to relieve menopausal atrophic vaginitis. Rioux, JE., Devlin, C., Gelfand, MM., et al.[2022]

The estradiol-releasing silicone vaginal ring (Estring) significantly prolongs the time until the first recurrence of urinary tract infections in postmenopausal women, with a cumulative likelihood of remaining free of infection at 45% compared to 20% in the control group after 36 weeks.

Estring not only lowers vaginal pH and improves mucosal health but is also safe and well tolerated, showing no unexpected adverse events during the study involving 108 women.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized, open, parallel-group study on the preventive effect of an estradiol-releasing vaginal ring (Estring) on recurrent urinary tract infections in postmenopausal women. Eriksen, B.[2019]

Both 25-μg 17β-estradiol vaginal tablets and 1.25-mg conjugated equine estrogen vaginal cream effectively relieve symptoms of atrophic vaginitis in menopausal women, as shown in a study of 159 participants over 24 weeks.

The vaginal tablets resulted in fewer systemic side effects and lower rates of endometrial proliferation compared to the cream, along with higher patient satisfaction and lower withdrawal rates, indicating they may be a safer and more acceptable option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

17β-estradiol vaginal tablet versus conjugated equine estrogen vaginal cream to relieve menopausal atrophic vaginitis. Rioux, JE., Devlin, MC., Gelfand, MM., et al.[2022]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8058921/

Update in Female Hormonal Therapy: What the Urologist ... The use of vaginal estrogen therapy is both safe and efficacious in lowering UTI risk. Vaginal estrogen increases the presence of lactobacillus in the vagina in ...

2. contemporaryobgyn.net contemporaryobgyn.net/view/vaginal-estrogen-effective-against-recurrent-utis

Vaginal estrogen effective against recurrent UTIs In a recent study, recurrent urinary tract infection rates decreased by over 50% in women using vaginal estrogen.

3. clinicaltrials.gov clinicaltrials.gov/study/NCT06353269

NCT06353269 | Adherence to Vaginal Estrogen Therapy in ... Participants in this arm will receive the vaginal estrogen cream (Estrace 0.01%) for treatment. ... Efficacy of vaginal estrogen for recurrent urinary tract ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5865261/

A Randomized, Multicenter, Double-Blind, Study to ... Conclusions: Very low-dose estradiol vaginal cream (0.003%) dosed twice weekly is an effective and well-tolerated treatment for VVA symptoms and dryness ...

5. urologytimes.com urologytimes.com/view/dr-winter-highlights-the-benefits-of-vaginal-estrogen

Dr. Winter highlights the benefits of vaginal estrogen So, unlike your anticholinergics for overactive bladder, a low dose vaginal estrogen can address the root cause, can prevent UTIs, can prevent ...

6. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2005/86069s018lbl.pdf

estrace cream - accessdata.fda.gov ESTRACE® (estradiol vaginal cream, USP, 0.01%) should not be used in patients with known hypersensitivity to its ingredients. ESTROGENS INCREASE THE RISK OF ...

7. rxabbvie.com rxabbvie.com/content/dam/rxabbvie/pdf/ESTRACE-(estradiol)-Cream-USPI-Jun2018-Clean.pdf

ESTRACE® Cream (estradiol vaginal cream, USP, 0.01%) ... • Vaginal yeast infection. • Reactions from inserting ESTRACE Vaginal Cream ... General information about safe and effective use of ESTRACE Vaginal Cream.

8. mayoclinic.org mayoclinic.org/drugs-supplements/estradiol-vaginal-route/description/drg-20075648

Estradiol (vaginal route) - Side effects & dosage Estradiol vaginal gel, insert, and ring are used to treat changes in and around the vagina (such as vaginal dryness, itching, and burning) ...

9. webmd.com webmd.com/drugs/2/drug-78021-7027/estradiol-vaginal/details

Estradiol vaginal (Estrace, Estring, Vagifem) - Uses, Side ... It is used after menopause to reduce vaginal dryness and itching. The most common side effects are headache and breast pain and tenderness.

10. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5779318/

A randomized, multicenter, double-blind study to evaluate ... Lower-dose estradiol vaginal cream (0.003%) dosed three applications/week is an effective and well-tolerated treatment for VVA-related dyspareunia.