Urinary incontinence occurs in 15–50% of community-dwelling postmenopausal women1–3 and is twice as common in women as in men. Estrogen affects the urethral mucosa, smooth muscle, and α-adrenergic tone,4,5 which suggests that estrogen might improve urinary incontinence in estrogen-deficient postmenopausal women. Medical management of urinary incontinence in postmenopausal women often includes both oral and vaginal estrogen therapy, but the effectiveness of either form of estrogen treatment is not clear.6,7
The Heart and Estrogen/Progestin Replacement Study was a 4-year randomized controlled trial to evaluate daily oral conjugated estrogen plus medroxyprogesterone acetate therapy for the prevention of coronary heart disease events among postmenopausal women with established coronary disease. We measured the effect of this hormone regimen on the severity of urinary incontinence among 1525 participants with at least weekly urinary incontinence at the start of the trial. We hypothesized that hormone therapy would improve the severity of urinary incontinence in postmenopausal women and planned to test this hypothesis among women with both urge and stress incontinence.
Materials and Methods
The design, methods, baseline patient characteristics,8 and main findings9 of the trial have been published. Briefly, participants were postmenopausal women less than 80 years old with established coronary heart disease who had not had a hysterectomy. Participants were randomly assigned to treatment with daily oral conjugated estrogen (0.625 mg) and medroxyprogesterone acetate (2.5 mg) in one tablet (Prempro; Wyeth-Ayerst Research, Radnor, PA) or identical placebo. The randomization codes were prepared with computer generated random numbers. Randomization was stratified by site and performed using randomly permuted blocks of size 4. Eligible participants were assigned with equal probability to the two treatment groups by tamper-proof randomization. Both participants and investigators were blinded to treatment status.
At baseline, participants provided information on age, race, education, age at menopause, parity, cigarette smoking, alcohol consumption, overall health status (excellent, good, fair, poor, or very poor), and chronic medical illnesses (diabetes and hypertension). Height, weight, and waist and hip circumferences were measured, and body mass index (BMI) and waist-to-hip ratio were calculated. Participants were asked to bring all prescription and over-the-counter medications to the clinic to be recorded by research staff.
Participants completed a questionnaire concerning voiding habits and incontinence. All questions began with “During the prior week, how many times, on average….” Voiding questions included, “…have you had to go to the bathroom to urinate during the day?” and “…have you had to get up at night to go to the bathroom to urinate?” Responses were recorded as times per day or per night. Incontinence questions included, “…have you unintentionally leaked some urine with coughing, sneezing, straining, laughing, or lifting?” (stress incontinent episodes) and “…have you unintentionally leaked some urine before you could get to the bathroom?” (urge incontinence episodes). Responses were recorded as times per week. Only women who reported at least one episode of incontinence per week at baseline were included in these analyses.
At follow-up visits at 4 months, and then annually, participants were again questioned about voiding habits and frequency of urinary incontinence with the same questions described above. We also recorded all medications and inquired about hospitalizations and surgeries. We calculated the mean change in the number of urinary incontinent episodes per week from baseline to follow-up by subtracting the reported number of urinary incontinent episodes per week at baseline from the average reported number of incontinent episodes per week over all five follow-up visits (4 months, 1 year, 2 years, 3 years, and end of trial). We also calculated the change from baseline to each follow-up visit.
Because the changes in frequencies of incontinent episodes per week were not normally distributed, we classified the change in the frequency of incontinent episodes per week as markedly improved (decrease of at least five episodes per week), improved (decrease of two to four episodes per week), unchanged (change of at most one episode per week), worsened (increase of two to four episodes per week), and markedly worsened (increase of at least five episodes per week). Between-group differences were assessed with the χ2 test for trend.10 We also estimated a summary odds ratio (OR) and 95% confidence interval (CI) for the effect of treatment on the categoric outcome with a proportional odds model.11 This model estimates the relative odds among women assigned to hormone therapy compared with those assigned to placebo of worsening by one or more category of incontinence severity. We repeated these analyses restricted to changes in the severity of stress incontinence among women who reported at least one episode of stress urine loss per week at baseline and to changes in the severity of urge incontinence among those who reported at least one episode of urge urine loss per week at baseline.
In confirmatory analyses, we compared the change in the number of incontinent episodes (mean follow-up frequency per week minus baseline frequency per week) between women assigned to hormone therapy and those assigned to placebo. Between-group differences were assessed using the nonparametric Wilcoxon rank-sum test. This procedure was repeated for changes in the frequency of stress incontinence episodes and for changes in urge incontinence episodes per week.
The primary and confirmatory analyses were repeated using only data from women whose average compliance with treatment by pill count was at least 80%. Because these “as-treated” analyses compare changes in the severity of urinary incontinence episodes in nonrandomized groups that may not be comparable, the results of these supplementary analyses should be interpreted cautiously.
Between January 1993 and September 1994, the 20 centers enrolled 2763 women. At the beginning of the trial, 1525 participants reported urinary incontinence at least once per week. Of these 1525 participants, 768 were randomly assigned to receive hormone therapy and 757 were assigned to placebo.
There were no significant differences between the treatment groups at baseline in demographic or reproductive characteristics, reported medical conditions, or use of incontinence medications. At baseline, urge incontinence was reported by 26% of the women, stress incontinence by 23%, and mixed incontinence by 51% (Table 1). Two or more episodes of incontinence per week were reported by 78% of the women, and 23% reported seven or more episodes per week. The mean (± standard deviation) number of incontinent episodes per week in the cohort was 5.6 ± 9.1, with 2.6 ± 5.1 episodes of urge incontinence and 3.0 ± 5.5 episodes of stress incontinence. On average, participants reported 6.2 ± 2.9 diurnal voids and 1.8 ± 1.3 nocturnal voids per day. There were no significant differences between the treatment groups in the type or frequency of incontinent episodes, the number of diurnal or nocturnal voids per day, or the number of urinary tract infections in the previous year (Table 1).
The mean duration of study treatment was 4.1 years. At the end of the first year of treatment, 82% of the women assigned to hormone therapy and 88% of those assigned to placebo reported taking at least 80% of the study medication; by the end of the fourth year, these percentages had fallen to 69% and 74%, respectively.
During the treatment period, 26.0% of the placebo group improved or markedly improved, compared with 20.9% of the hormone group, while 27.0% of the placebo group worsened or markedly worsened, compared with 38.8% of the hormone group (P = .001 for the overall between-group comparison by χ2 for trend) (Figure 1). The difference between the treatment groups was evident by the 4-month visit and persisted throughout the treatment period (Table 2). The summary OR for worsening by one or more category of incontinence severity among the hormone-treated group compared with the placebo group was 1.51 (95% CI 1.26, 1.82). The number of incontinent episodes per week increased an average of 0.7 per week in the hormone group (5.5 at baseline to 6.2 as the average number of episodes reported during follow-up) and decreased an average of 0.1 per week in the placebo group (5.7 at baseline to 5.6 during follow-up) (P < .001 for the between-group comparison by Wilcoxon test).
At the last study visit, 134 women assigned to placebo (17.9%) and 109 of those assigned to hormone therapy (14.4%) reported no incontinent episodes in the previous week (P = .06). During follow-up, 31 women in the placebo group and 49 in the hormone group began to take medications for urinary incontinence (P = .04), and seven women in the placebo group compared with ten in the hormone group underwent incontinence surgery (P = .4).
An increase in the severity of incontinence was also seen in the hormone group compared with the placebo group when the analysis was limited to the change in the severity of stress incontinence episodes or urge incontinence episodes. The results were also similar in analyses restricted to subgroups of women classified by the number of incontinent episodes per week at baseline (one, two to six, seven or more), BMI (less than 27 or 27 or more kg/m2), and treatment adherence (less than 80%, 80% or more by pill count).
During the mean of 4.1 years of observation, the average number of diurnal and nocturnal voids per day was essentially unchanged in both treatment groups.
Among women assigned to treatment with hormone therapy, incontinence was more likely to worsen and less likely to improve than among women assigned to placebo. There was no improvement among hormone-treated women in the frequency of either stress or urge incontinence and no reduction in either diurnal or nocturnal urinary frequency.
The urethra and trigone of the bladder are covered by nonkeratinized squamous epithelium of similar origin to the vagina.12 These tissues contain estrogen receptors4,13 and respond to estrogens.14–17 Estrogen therapy has been shown to increase urethral closure pressure in baboons,18 which suggests that hormone therapy might be effective treatment for urinary incontinence. There have been at least seven previous randomized trials of the effect of oral estrogen therapy on urinary incontinence.14,15,19–23 These trials were small (total of 267 participants) and of short duration (1–6 months). Four of the trials reported no improvement in the number of incontinent episodes per week.14,20,22,23 One trial reported subjective improvement in women with urge incontinence but not stress incontinence,19 and two other trials reported a higher “cure” rate in women with urge incontinence treated with hormones as compared with placebo.15,21 In the largest and most methodologically sound randomized trial previously published, 83 postmenopausal women with weekly incontinence were randomized to receive either oral cyclic conjugated estrogen plus medroxyprogesterone acetate or placebo.22 After 3 months of therapy, the change in the number of incontinent episodes per week was similar in the hormone-treated and placebo-treated groups. There was also no improvement in urinary frequency or quality-of-life measures.22 In contrast, several large observational studies have shown an increased risk of urinary incontinence among older women taking estrogen.2,3,24
We studied only one specific hormone regimen (conjugated estrogen 0.625 mg and medroxyprogesterone acetate 2.5 mg daily). Thus, it is possible that a beneficial effect of unopposed estrogen is negated by the addition of a progestin to the regimen. Both estrogen alone and estrogen with added progestins relieve vaginal dryness and atrophy, but evidence regarding the effect of progestins on urinary incontinence is limited. In female dogs, systemic progesterone has been reported to increase β-adrenergic response, leading to decreased intraurethral closure pressure,25 an effect that might worsen incontinence. In a study of cynomolgus monkeys randomly assigned to no treatment, oral conjugated estrogen, or conjugated estrogen plus medroxyprogesterone acetate, both hormone regimens increased the surface area of vaginal epithelium, but did not affect urethral epithelium or the thickness of the muscular layer of the urethra. However, the thickness of the loose, vascular connective tissue layer of the urethra was significantly greater in estrogen-treated monkeys and greatest in the animals treated with both estrogen and medroxyprogesterone acetate.26
It is possible that estrogen given transvaginally might be more effective than oral estrogen for the treatment of urinary incontinence. Several small, uncontrolled trials suggested that the use of transvaginal estrogen preparations improves incontinence,16,27–29 but the evidence is weak. In the only small placebo-controlled trial that has been completed, there was no improvement in symptoms of urinary incontinence or amount of urine lost among women with stress incontinence who were treated with vaginal estrogen cream as compared with controls.30
In conclusion, daily oral estrogen plus progestin therapy for 4 years was associated with a statistically significant worsening in the severity of urinary incontinence in older postmenopausal women with weekly incontinence. On the basis of these findings, we do not recommend this therapy for the treatment of urinary incontinence. Although the difference between the treatment groups was statistically significant, it is unlikely to be clinically important, and we do not believe that this effect should influence the decision to take postmenopausal hormone therapy for the treatment of menopausal symptoms or prevention of osteoporotic fractures.
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