Vaginal Estrogen for the Prevention of Recurrent Urinary Tract Infection in Postmenopausal Women
Vaginal Estrogen for the Prevention of Recurrent Urinary Tract Infection in Postmenopausal Women
The investigators would like to know if the use of vaginally applied estrogen can prevent the
 problem of repeated urinary tract infections (UTI) in women who have gone through menopause.
 The investigators will use two forms of vaginal estrogen that are available by prescription
 (a ring and a cream) and compare their efficacy to that of a placebo (without any active
 ingredient). The investigators are going to look at if the vaginal estrogen can prevent UTIs
 altogether and also the number of UTIs each group experiences over a 6 month period. After 6
 months, all subjects will receive vaginal estrogen and the women on the non-active treatment
 will be able to choose whether they would like to use either the estrogen ring or cream. The
 investigators will then be able to compare the number of UTIs on and off active vaginal
 estrogen treatment within those subjects who started on the placebo. The investigators are
 also going to look at quality of life before and during treatment using questionnaires and
 whether subjects stop using the treatments or do not use them as directed (compliance).
This was an investigator-initiated, multicenter, single-blind, randomized placebo-controlled
 trial of vaginal estrogen (delivered by estradiol ring or conjugated estrogen cream) compared
 to placebo cream. This study was conducted by the Divisions of Female Pelvic Medicine and
 Reconstructive Surgery at three academic institutions.

 Potential participants were recruited from women receiving care for rUTIs in the clinics of
 each institution. Women were postmenopausal as defined by amenorrhea for >12 months, history
 of bilateral salpingoophrectomy, or in patients with prior hysterectomy defined as menopausal
 symptoms for >1 year or age >55. Participants had documented rUTI (three or more in one year
 or two in six months) by positive urine culture. Participants were excluded if they had
 undergone urologic surgery within three months of screening or planned surgery within one
 year of screening, had the diagnosis of painful bladder syndrome, history of UTI requiring
 the use of intravenous antibiotics or one oral antibiotic available for treatment based on
 allergies and resistance profiles, known etiology of infections (e.g. urologic stones,
 fistulas, fecal incontinence, catheterization or poorly controlled diabetes), urothelial
 cancer, or actively treated estrogen sensitive tumor. Participant enrollment was deferred in
 the setting of undiagnosed hematuria or vaginal bleeding, but enrollment could occur after
 negative workup for malignancy. Participants deferred enrollment if they used vaginal
 androgens, estrogens or progestins within six months or if they used medications or
 supplements known to prevent UTI (e.g. cranberry products, D mannose, prophylactic
 antibiotics, methenamine hippurate) within three months of enrollment, but could enroll after
 washout. Those with a remote history of estrogen-sensitive tumor required approval by her
 oncologist or primary care physician.

 Participants were initially randomized to receive either vaginal estrogen (via estradiol ring
 or conjugated estrogen cream) or placebo cream in a 1:1:1 fashion and were told that there
 were placebo and vaginal estrogen arms, but were unaware that there was not a placebo ring.
 Participants were randomized to either conjugated estrogen cream at a strength of 0.625 mg/g
 dosed at 0.5g (0.312 mg) twice a week, estradiol ring containing 2mg of estradiol placed
 vaginally every three months by study personnel, or placebo cream which was an
 over-the-counter lubricant containing mineral oil, petrolatum, ceresin and paraffin dosed at
 0.5g twice a week. If participants in any arm developed three UTI in the six-month treatment
 period, they were unblinded. If on placebo, they were provided active study drug or if they
 were in the vaginal estrogen arm, they were treated according to the provider's clinical
 practice and their outcomes recorded for the remainder of the study. The primary outcome of
 occurrence of UTI was assessed at six months or the end of study blinding, whichever occurred
 first. In order to improve recruitment and assess long-term compliance, satisfaction and
 efficacy, we offered open label use of estradiol ring or conjugated estrogen cream after
 unblinding until month 12 of the study.

 Clean-catch urine cultures were collected when participants were symptomatic: fever (>38
 degrees C), urgency, frequency, dysuria or suprapubic tenderness. Women were asked to have
 all urine labs done at the parent site as per standard clinical practice. The primary outcome
 of the study was the presence of a UTI in the randomized six months. We also assessed rates
 of UTI over the course of the 12-month study in all participants as-treated. Quality of life
 (QOL) questionnaires were administered at baseline, six months or unblinding, and 12 months.
 Questionnaires included the Pelvic Floor Distress Inventory (PFDI-20), Pelvic Floor Impact
 Questionnaire (PFIQ-7), Medical, Epidemiologic, and Social Aspects of Aging Questionnaire
 (MESA), Female Sexual Function Index (FSFI) and Patient Satisfaction Questionnaire (PSQ),
 Global Perception of Improvement (GPI) and Estimated Percent Improvement (EPI) rating scales.
 Baseline medical history and concomitant pelvic medicine diagnoses were also collected.
 Participants using a cream treatment were asked to keep medication diaries and return tubes
 for weighing at months three, six, nine and 12. Adherence was defined as presence of the
 estrogen ring or tube weights within 20% of expected at follow up visits. In addition, before
 unblinding, the participants were asked whether they believed they were on active treatment,
 placebo, or were unsure.
Inclusion Criteria:

 1. Postmenopausal status as defined by amenorrhea for >12 months, OR history of bilateral
 salpingoophrectomy, OR if the patient has had a hysterectomy defined by menopausal
 symptoms for >1 year OR age >55

 2. Documented recurrent UTIs (3 or more in the last year or 2 or more in the last 6
 months)- one UTI must be documented by culture, others may be documented by urinalysis

 3. Ability to provide informed consent

 Exclusion Criteria:

 1. Use of any investigational drug or device within thirty days of screening

 2. Urologic surgery within the past 3 months of screening or plan for surgery within one
 year of screening

 3. Diagnosis of Interstitial Cystitis/painful bladder syndrome

 4. History of urinary tract infections which require the use of IV antibiotics or where
 only one oral antibiotic is available for treatment, or where the risk of treatment
 with vaginal estrogen only is deemed unacceptable by the principle investigator
 secondary to the severity of prior urinary tract infections

 5. Known etiology of infection such as, but not limited to: kidney or bladder stones,
 enterovaginal/vesical fistula, fecal incontinence, intermittent catheterization,
 indwelling catheter, poorly controlled diabetes

 6. Urothelial cancer

 7. Actively treated estrogen sensitive tumor (breast or endometrial cancer)

 8. Undiagnosed vaginal bleeding

 9. Inability to use a vaginal ring (secondary to advanced prolapse or shortened vaginal
 length)

 10. Any medical reason the investigator deems incompatible with treatment with vaginal
 estrogen

 11. Prolapse requiring pessary use

 Deferral Criteria

 1. Undiagnosed hematuria - may enroll after malignancy is ruled out

 2. Use of a progestin containing intrauterine device or use of any vaginal androgens,
 estrogens or progestins within 3 months of enrollment - may enroll after wash out

 3. Use of drugs/supplements known to prevent UTIs (ie cranberry products, prophylactic
 antibiotics, methenamine hippurate) 1 month prior to enrollment - may enroll after
 wash out if still meets inclusion criteria.

 4. History of estrogen sensitive tumor (breast or endometrial cancer) - requires approval
 by the subject's primary oncologist or primary care physician