Vaginal Testosterone for Recurrent Urinary Tract Infections

(PIVoT Trial)

Overseen By Alison Polland, MD

Age: 18+

Sex: Female

Trial Phase: Phase 4

Sponsor: Maimonides Medical Center

Must not be taking: Antibiotics, Vaginal estrogen

Disqualifiers: Current UTI, STI, Urinary retention, others

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 4

Duration: 9 months

100 Participants Needed

Trial Summary

What is the purpose of this trial?

Women over the age of 60 years have an estimated 10 to 15 % risk of recurrent urinary tract infections (UTI). This is believed to be due to hormonally induced changes in the vaginal flora associated with menopause. After menopause, there is a chemical changes in the vagina that may predispose to bacterial infections. The role of vaginal estrogen creams to restore vaginal atrophy and prevent urinary tract infections has been well characterized. Vaginal testosterone (VT) application use in postmenopausal breast cancer patients on aromatase inhibitors have been shown to improve vaginal pH, vaginal atrophy symptom scores, dyspareunia, and vaginal dryness. Although testosterone has been used to improve sexual function in postmenopausal women, the effects of VT on vaginal flora and recurrent UTIs are unknown. The purpose of this study is to determine whether topically applied vaginal testosterone cream is more effective than placebo in reducing the incidence of urinary tract infections in postmenopausal women with recurrent urinary tract infections and to ascertain the effects of topical estrogen on the vaginal pH and flora.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you've used antibiotics or vaginal probiotics in the last 4 weeks. If you're on oral estrogen therapy, you can still join the study.

What data supports the effectiveness of the drug Vaginal Testosterone Cream for treating recurrent urinary tract infections?

There is no direct evidence provided for the effectiveness of Vaginal Testosterone Cream for recurrent urinary tract infections, but similar treatments like vaginal estrogen have been used to help prevent these infections in postmenopausal women by addressing hormone deficiencies. ^{1 2 3 4 5}

Is vaginal testosterone safe for humans?

There is limited safety data specifically on vaginal testosterone, but general testosterone treatments have been associated with some risks like skin irritation and potential blood clot issues. However, these findings are mostly from studies on men and other forms of testosterone therapy. ^{6 7 8 9 10}

How is vaginal testosterone cream different from other treatments for recurrent urinary tract infections?

Vaginal testosterone cream is unique because it uses testosterone, a hormone not typically used for urinary tract infections, and is applied directly to the vaginal area, unlike the more common estrogen creams. This approach may offer a novel way to address hormone-related changes in the urinary tract that contribute to infections. ^{1 2 4 5 11}

Eligibility Criteria

This trial is for postmenopausal women aged 60-90 with recurrent UTIs, who are not using vaginal estrogen but may be on oral estrogen or have a history of breast/endometrial cancer and taking aromatase inhibitors. Women with prior vaginal surgeries can join, but those with current UTI, recent antibiotic/probiotic use, large post-void residual volume, untreated hematuria or chronic catheter/stent use cannot participate.

Inclusion Criteria

I am currently taking oral estrogen therapy.

I cannot or do not want to use topical estrogen.

I have had 3 or more UTIs in the last year.

Exclusion Criteria

You have unexplained blood in your urine.

I am able to follow the study's requirements and attend all follow-ups.

You currently have a sexually transmitted infection.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either vaginal testosterone cream or placebo cream, applied once each night for two weeks followed by twice-weekly applications for a total duration of nine months

9 months

Initial visit, 4.5 months visit, 9 months visit

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment of vaginal flora, pH, and UTI symptoms

4 weeks

Treatment Details

Interventions

• Vaginal Testosterone Cream

Trial Overview The study tests if applying vaginal testosterone cream reduces urinary tract infections in postmenopausal women more effectively than a placebo. It also examines the impact on vaginal pH and flora. Participants will receive either the testosterone cream or placebo through an applicator to apply themselves.

Participant Groups

Group I: Vaginal Testosterone Cream Arm Experimental Treatment 1 Intervention

Women enrolled in this arm will receive vaginal testosterone cream to be applied once each night for two weeks followed by twice-weekly applications for a total duration of nine months.

Group II: Vaginal Placebo Cream Arm Placebo Group 1 Intervention

Women enrolled in this arm will receive vaginal placebo cream to be applied once each night for two weeks followed by twice-weekly applications for a total duration of nine months.

Vaginal Testosterone Cream is already approved in United States, European Union for the following indications:

Approved in United States as Vaginal Testosterone Cream for:

• Hypoactive Sexual Desire Disorder (HSDD) in premenopausal women
• Not specifically approved for UTI prevention

Approved in European Union as Vaginal Testosterone Cream for:

• Not specifically approved for UTI prevention

Who Is Running the Clinical Trial?

Maimonides Medical Center

Lead Sponsor

Trials

72

Recruited

15,400+

American Urological Association

Collaborator

Trials

5

Recruited

640+

Findings from Research

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 systematic review of seven studies, including four randomized trials, found insufficient evidence to determine if vaginal estrogens effectively reduce the risk of urinary tract infections in postmenopausal women.

The overall certainty of the evidence regarding the effectiveness of vaginal estrogens for preventing urinary infections was rated as very low, indicating that more research is needed to draw definitive conclusions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Are vaginal estrogens effective for preventing urinary tract infection in postmenopausal women? Canales, JP., Castro, V., Rada, G.[2018]

Vaginal estrogen therapy has been shown to improve symptoms of overactive bladder (OAB) in postmenopausal women, although its effectiveness may vary when combined with other treatments.

Vaginal hormone therapy, including estrogen and prasterone (DHEA), is effective for treating recurrent urinary tract infections (UTIs) but has inconclusive results for stress urinary incontinence (SUI) and interstitial cystitis/bladder pain syndrome (ICS/BPS).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vaginal Hormone Therapy for Conditions of the Lower Urinary Tract. Nemirovsky, A., Villela, NA., Yuan, JC., et al.[2023]

In a double-blind, randomized trial involving 72 postmenopausal women over 60 years old, oral oestriol (3 mg per day) did not show a significant advantage over placebo in preventing recurrent urinary tract infections.

Both oestriol and placebo improved urinary symptoms, suggesting that while oestriol may not be effective for this specific purpose, it could still provide some symptomatic relief.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low dose oestrogen prophylaxis for recurrent urinary tract infections in elderly women. Cardozo, L., Benness, C., Abbott, D.[2022]

A systematic review of 11 studies, including 6 randomized control trials with 2,236 participants and 5 observational studies with over 1.2 million participants, found no significant association between testosterone therapy and the risk of venous thromboembolism (VTE).

Despite concerns about the safety of testosterone therapy, the evidence currently available does not support an increased risk of VTE, although the overall certainty of the evidence is low.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Testosterone therapy and venous thromboembolism: A systematic review and meta-analysis. Houghton, DE., Alsawas, M., Barrioneuvo, P., et al.[2023]

In a systematic review of 13 randomized controlled trials involving 5050 men, testosterone replacement therapy (TRT) did not show an increased risk of venous thromboembolism (VTE) compared to placebo, with a relative risk of 1.03 (95% CI: 0.49-2.14).

Despite the findings suggesting no significant association between TRT and VTE, the wide confidence intervals indicate that a clinically important increased risk cannot be completely ruled out, highlighting the need for further research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Testosterone replacement therapy and the risk of venous thromboembolism: A systematic review and meta-analysis of randomized controlled trials. Ayele, HT., Brunetti, VC., Renoux, C., et al.[2021]

In a study of 60 healthy adult males, scrotal testosterone transdermal systems caused significantly less topical irritation compared to nonscrotal systems, with only 5% of scrotal users reporting moderate irritation versus 32% for nonscrotal users.

No confirmed cases of allergic contact dermatitis were observed with the scrotal system, while 12% of subjects using nonscrotal systems experienced allergic reactions, indicating that the scrotal system may be a safer option for testosterone delivery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Allergy and topical irritation associated with transdermal testosterone administration: a comparison of scrotal and nonscrotal transdermal systems. Jordan, WP.[2013]

Testosterone replacement therapy (TRT) does not appear to significantly increase the risk of disease progression in men with prostate cancer compared to those not receiving TRT, based on a systematic review of 36 studies involving 2,459 patients.

However, TRT may be harmful for men with advanced prostate cancer, those undergoing active surveillance, and those with high-risk disease after treatment, indicating that caution is needed in these populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Testosterone Replacement Therapy in Men with Untreated or Treated Prostate Cancer: Do We Have Enough Evidences? Kim, M., Byun, SS., Hong, SK.[2021]

Testosterone replacement therapy (TRT) shows promise for treating hypogonadism in older men, but significant safety concerns remain unresolved due to a lack of large-scale randomized trials comparing untreated hypogonadism with long-term TRT use.

Meta-analyses have identified key adverse events associated with TRT, including polycythemia, increased prostate-related events, and a slight reduction in HDL cholesterol, but the overall safety and utility of TRT continue to be debated in the medical community.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Review of health risks of low testosterone and testosterone administration. Jia, H., Sullivan, CT., McCoy, SC., et al.[2022]

In a study of 45 postmenopausal women, the use of intravaginal estrogen cream significantly reduced the incidence of recurrent urinary tract infections (UTIs) compared to an oral antibiotic treatment, with only 2 out of 27 women in the estrogen group experiencing UTIs versus 12 out of 15 in the antibiotic group.

The estrogen cream not only decreased UTI occurrences but also improved vaginal health indicators, such as the presence of Lactobacilli and vaginal cell maturation, suggesting a beneficial effect on vaginal flora and overall health in postmenopausal women.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Prevention and treatment of recurrent urinary system infection with estrogen cream in postmenopausal women]. Xu, R., Wu, Y., Hu, Y.[2014]

References

1. United States 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. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

Efficacy of vaginal estrogen for recurrent urinary tract infection prevention in hypoestrogenic women. [2023]

3. Chile pubmed.ncbi.nlm.nih.gov

Are vaginal estrogens effective for preventing urinary tract infection in postmenopausal women? [2018]

4. United States pubmed.ncbi.nlm.nih.gov

Vaginal Hormone Therapy for Conditions of the Lower Urinary Tract. [2023]

5. England pubmed.ncbi.nlm.nih.gov

Low dose oestrogen prophylaxis for recurrent urinary tract infections in elderly women. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

Testosterone therapy and venous thromboembolism: A systematic review and meta-analysis. [2023]

7. United States pubmed.ncbi.nlm.nih.gov

Testosterone replacement therapy and the risk of venous thromboembolism: A systematic review and meta-analysis of randomized controlled trials. [2021]

8. Canada pubmed.ncbi.nlm.nih.gov

Allergy and topical irritation associated with transdermal testosterone administration: a comparison of scrotal and nonscrotal transdermal systems. [2013]

9. Korea (South) pubmed.ncbi.nlm.nih.gov

Testosterone Replacement Therapy in Men with Untreated or Treated Prostate Cancer: Do We Have Enough Evidences? [2021]

10. United States pubmed.ncbi.nlm.nih.gov

Review of health risks of low testosterone and testosterone administration. [2022]

11. China pubmed.ncbi.nlm.nih.gov

[Prevention and treatment of recurrent urinary system infection with estrogen cream in postmenopausal women]. [2014]