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Estrogen therapy increased the incidence and severity of urinary incontinence symptoms in postmenopausal women
ARTICLE IN PRESS UROGYNECOLOGY
Estrogen therapy increased the incidence and severity of urinary incontinence symptoms in postmenopausal women Hendrix SL,Cochrane BB, Nygaard IE, HandaVL, Barnabei VM, Iglesia C, Aragaki A, Naughton MJ,Wallace RB, McNeeley SG. Effects of estrogen with and without progestin on urinary incontinence. JAMA 2005; 293:935^ 48.
OBJECTIVE To evaluate the e¡ects of estrogen alone and estrogen plus progestin on the incidence and severity of symptoms of urinary incontinence (UI) in postmenopausal women. DESIGN Two multicentre, randomized, doubleblind, placebo-controlled trials. Allocation was blocked and strati¢ed by age group and centre, using coded medications. SETTING Forty centres in the USA (the Women’s Health Initiative (WHI) trials). SUBJECTS A total of 23,296 healthy postmenopausal women, aged 50^79 years, who were participants in the WHI estrogen alone (8993 women with prior hysterectomy) or estrogen/progestin (14303 women with an intact uterus) trials, and had data recorded on urinary incontinence at baseline and 1 year (85% of the original study population). INTERVENTION Randomization allocated, in the estrogen alone trial, 4476 women to receive oral conjugated equine estrogen (CEE) 0.625 mg daily and 4517 to receive placebo and, in the estrogen plus progestin trial, 7247 women to receive CEE 0.625 mg plus medroxyprogesterone acetate (MPA) 2.5 mg daily and 7056 to receive placebo. The women completed questionnaires about UI symptoms and treatment at baseline and at 1 year after randomization. MAIN OUTCOME MEASURES Incidence (in women asymptomatic at baseline) or worsening (in
0021-9290/$ - see front matter r 2005 Published by Elsevier Ltd. doi:10.1016/j.ebobgyn.2005.06.005
women symptomatic at baseline) of symptoms of stress, urge, or mixed UI at one year.
MAIN RESULTS At baseline, UI symptoms were reported by 64% of women; of these women, 40% reported stress UI, 35% urge UI, and 25% mixed UI. Compliance with treatment at the end of the ¢rst year was about 75% in the estrogen groups and 81% in the placebo groups. The results of the study, subgrouped by trial, are shown in Table 1. The risks of developing any of the three types of UI were signi¢cantly higher in the estrogen groups than in the corresponding placebo group. The deleterious e¡ect of estrogen treatment on the development of stress incontinence was stronger in older women in both trials. A signi¢cant worsening of UI symptoms with estrogen treatment was observed for all three types of UI, again with a stronger e¡ect in older women.
CONCLUSION In postmenopausal women, estrogen treatment, with or without progestins, increased the risk of new onset urinary incontinence and was associated with worsened symptoms in women already experiencing urinary incontinence.
Overall study quality (out of 10) Topic importance Methodological quality Practical relevance
8 9 10
Evidence-based Obstetrics and Gynecology (2005) 7,149^150
149
Table 1
Relative risk of the incidence (in asymptomatic women) or worsening severity (in symptomatic women) of urinary incontinence symptoms at one year, in women in the estrogen (7progestin) group, compared to those in the placebo group. Outcome
Estrogen alone trial relative risk (95% CI)
Estrogen+progestin trial relative risk (95% CI)
2.2 (1.8 2.6) 1.3 (1.1 1.6) 1.8 (1.3 2.5)
1.9 (1.6 2.2) 1.2 (1.0 1.3) 1.5 (1.1 2.0)
1.6 (1.4 1.5 (1.4 1.3 (1.2 1.5 (1.4
1.2 (1.1 1.4 (1.3 1.2 (1.1 1.2 (1.1
Incidence (%)
Stress UI Urge UI Mixed UI
Worsening severity (%)
Worse amount Worse frequency Worse limitations Worse bother
1.8) 1.6) 1.5) 1.7)
1.4) 1.5) 1.3) 1.3)
Commentary Oral estrogen has been used to treat both stress and urge urinary incontinence in postmenopausal women. Alpha and beta estrogen receptors have been identif|ed in the bladder mucosa, trigone, urethra, levator ani muscles, and pubo-cervical fascia, suggesting a role for estrogen in the continence mechanism.1 In 2003, a Cochrane Review of both randomized and non-randomized controlled clinical trials assessing the effect of estrogen on incontinence concluded that estrogen, by any route of administration, was an effective treatment for incontinence.2 Yet the highest level of evidence-from randomized controlled trials-shows that treatment with oral estrogen3,4 or oral estrogen plus progestin5,6 has a negative or neutral effect on incontinence in postmenopausal women.Most of the trials that found no signif|cant effect of estrogen on incontinence were small and may not have observed an effect of estrogen due to limited statistical power. In the Heart and Estrogen/progestin Replacement Study (HERS), conjugated oral estrogens with medroxyprogesterone acetate worsened both stress and urge incontinence symptoms.5 This secondary analysis of the randomized, double-blinded, placebo-controlled trials of the Women’s Health Initiative is the largest study to examine the effects of oral estrogen on incontinence symptoms in postmenopausal women. The study conf|rmed the f|ndings from the HERS incontinence analysis of a worsening of stress and urge incontinence symptoms with the use of estrogen plus progestin. It also provided important novel information.First, estrogen alone worsened all types of incontinence. Second, estrogen alone increased the risk of developing all types of incontinence and estrogen plus progestin increased the risk of new onset stress or mixed incontinence. Additionally, analysis of the secondary outcomes, showing that leakage amount, incontinence bothersomeness, and life impact all increased with estrogen use, emphasizes the clinical importance of the study’s conclusions. The major strengths of this community-based study of postmenopausal women are the rigorous design, very large sample size, and excellent rate of follow-up. The questions assessing incontinence frequency and type were similar to those used in many epidemiological studies. To test the robustness of and provide greater insight into their f|ndings, the authors performed subgroup and sensitivity analyses, including multivariate analysis when appropriate. This study has important limitations, which were acknowledged by the authors. Because this was a secondary analysis, as-
150
Evidence-based Obstetrics and Gynecology (2005) 7,149^150
sessment of the outcomes was limited to simple, non-invasive measures based on questionnaire responses. Conf|rmation of incontinence frequency and type by more objective methods was not feasible in this large sample. However, self-reporting reflects the symptoms rather than the diagnosis of stress and urge incontinence, and the experience of incontinence can be of more direct clinical and public health importance than the presence or absence of urodynamic abnormalities. Whether the results of this randomized, controlled trial, which assessed conjugated equine estrogen alone and with medroxyprogesterone acetate at a standard oral dose, can be generalized to all types, routes, and doses of estrogens is not clear. However, the size and quality of this study provides a high level of evidence to recommend against using estrogen to prevent and treat incontinence in postmenopausal women, at least until treatment with different types, routes, and doses of estrogen can be as rigorously investigated. L. Elaine Waetjen, MD University of California, Davis, Sacramento CA, USA
Literature cited 1. Blakeman PJ, Hilton P, Bulmer JN. Oestrogen and progesterone receptor expression in the female lower urinary tract, with reference to oestrogen status. BJU Int 2000; 86:32^ 8. 2. Moehrer B, Hextall A, Jackson S.Oestrogens for urinary incontinence in women. Cochrane Database Syst Rev 2003(2):CD001405. 3. Jackson S, Shepherd A, Brookes S, Abrams P. The effect of oestrogen supplementation on post-menopausal urinary stress incontinence: a double-blind placebo-controlled trial. Br J Obstet Gynaecol 1999; 106:711^ 8. 4. Goldstein SR, Johnson S, Watts NB, et al. Incidence of urinary incontinence in postmenopausal women treated with raloxifene or estrogen. Menopause 2005; 12:160 ^ 4. 5. Grady D, Brown JS,Vittinghoff E, et al. Postmenopausal hormones and incontinence: the Heart and Estrogen/Progestin Replacement Study. Obstet Gynecol 2001; 97:116^20. 6. Fantl JA, Bump RC, Robinson D, et al. Eff|cacy of estrogen supplementation in the treatment of urinary incontinence. The Continence Program for Women Research Group. Obstet Gynecol 1996; 88:745^9.
Estrogen therapy increased the incidence and severity of urinary incontinence symptoms in postmenopausal women Hendrix SL,Cochrane BB, Nygaard IE, HandaVL, Barnabei VM, Iglesia C, Aragaki A, Naughton MJ,Wallace RB, McNeeley SG. Effects of estrogen with and without progestin on urinary incontinence. JAMA 2005; 293:935^ 48.
OBJECTIVE To evaluate the e¡ects of estrogen alone and estrogen plus progestin on the incidence and severity of symptoms of urinary incontinence (UI) in postmenopausal women. DESIGN Two multicentre, randomized, doubleblind, placebo-controlled trials. Allocation was blocked and strati¢ed by age group and centre, using coded medications. SETTING Forty centres in the USA (the Women’s Health Initiative (WHI) trials). SUBJECTS A total of 23,296 healthy postmenopausal women, aged 50^79 years, who were participants in the WHI estrogen alone (8993 women with prior hysterectomy) or estrogen/progestin (14303 women with an intact uterus) trials, and had data recorded on urinary incontinence at baseline and 1 year (85% of the original study population). INTERVENTION Randomization allocated, in the estrogen alone trial, 4476 women to receive oral conjugated equine estrogen (CEE) 0.625 mg daily and 4517 to receive placebo and, in the estrogen plus progestin trial, 7247 women to receive CEE 0.625 mg plus medroxyprogesterone acetate (MPA) 2.5 mg daily and 7056 to receive placebo. The women completed questionnaires about UI symptoms and treatment at baseline and at 1 year after randomization. MAIN OUTCOME MEASURES Incidence (in women asymptomatic at baseline) or worsening (in
0021-9290/$ - see front matter r 2005 Published by Elsevier Ltd. doi:10.1016/j.ebobgyn.2005.06.005
women symptomatic at baseline) of symptoms of stress, urge, or mixed UI at one year.
MAIN RESULTS At baseline, UI symptoms were reported by 64% of women; of these women, 40% reported stress UI, 35% urge UI, and 25% mixed UI. Compliance with treatment at the end of the ¢rst year was about 75% in the estrogen groups and 81% in the placebo groups. The results of the study, subgrouped by trial, are shown in Table 1. The risks of developing any of the three types of UI were signi¢cantly higher in the estrogen groups than in the corresponding placebo group. The deleterious e¡ect of estrogen treatment on the development of stress incontinence was stronger in older women in both trials. A signi¢cant worsening of UI symptoms with estrogen treatment was observed for all three types of UI, again with a stronger e¡ect in older women.
CONCLUSION In postmenopausal women, estrogen treatment, with or without progestins, increased the risk of new onset urinary incontinence and was associated with worsened symptoms in women already experiencing urinary incontinence.
Overall study quality (out of 10) Topic importance Methodological quality Practical relevance
8 9 10
Evidence-based Obstetrics and Gynecology (2005) 7,149^150
149
Table 1
Relative risk of the incidence (in asymptomatic women) or worsening severity (in symptomatic women) of urinary incontinence symptoms at one year, in women in the estrogen (7progestin) group, compared to those in the placebo group. Outcome
Estrogen alone trial relative risk (95% CI)
Estrogen+progestin trial relative risk (95% CI)
2.2 (1.8 2.6) 1.3 (1.1 1.6) 1.8 (1.3 2.5)
1.9 (1.6 2.2) 1.2 (1.0 1.3) 1.5 (1.1 2.0)
1.6 (1.4 1.5 (1.4 1.3 (1.2 1.5 (1.4
1.2 (1.1 1.4 (1.3 1.2 (1.1 1.2 (1.1
Incidence (%)
Stress UI Urge UI Mixed UI
Worsening severity (%)
Worse amount Worse frequency Worse limitations Worse bother
1.8) 1.6) 1.5) 1.7)
1.4) 1.5) 1.3) 1.3)
Commentary Oral estrogen has been used to treat both stress and urge urinary incontinence in postmenopausal women. Alpha and beta estrogen receptors have been identif|ed in the bladder mucosa, trigone, urethra, levator ani muscles, and pubo-cervical fascia, suggesting a role for estrogen in the continence mechanism.1 In 2003, a Cochrane Review of both randomized and non-randomized controlled clinical trials assessing the effect of estrogen on incontinence concluded that estrogen, by any route of administration, was an effective treatment for incontinence.2 Yet the highest level of evidence-from randomized controlled trials-shows that treatment with oral estrogen3,4 or oral estrogen plus progestin5,6 has a negative or neutral effect on incontinence in postmenopausal women.Most of the trials that found no signif|cant effect of estrogen on incontinence were small and may not have observed an effect of estrogen due to limited statistical power. In the Heart and Estrogen/progestin Replacement Study (HERS), conjugated oral estrogens with medroxyprogesterone acetate worsened both stress and urge incontinence symptoms.5 This secondary analysis of the randomized, double-blinded, placebo-controlled trials of the Women’s Health Initiative is the largest study to examine the effects of oral estrogen on incontinence symptoms in postmenopausal women. The study conf|rmed the f|ndings from the HERS incontinence analysis of a worsening of stress and urge incontinence symptoms with the use of estrogen plus progestin. It also provided important novel information.First, estrogen alone worsened all types of incontinence. Second, estrogen alone increased the risk of developing all types of incontinence and estrogen plus progestin increased the risk of new onset stress or mixed incontinence. Additionally, analysis of the secondary outcomes, showing that leakage amount, incontinence bothersomeness, and life impact all increased with estrogen use, emphasizes the clinical importance of the study’s conclusions. The major strengths of this community-based study of postmenopausal women are the rigorous design, very large sample size, and excellent rate of follow-up. The questions assessing incontinence frequency and type were similar to those used in many epidemiological studies. To test the robustness of and provide greater insight into their f|ndings, the authors performed subgroup and sensitivity analyses, including multivariate analysis when appropriate. This study has important limitations, which were acknowledged by the authors. Because this was a secondary analysis, as-
150
Evidence-based Obstetrics and Gynecology (2005) 7,149^150
sessment of the outcomes was limited to simple, non-invasive measures based on questionnaire responses. Conf|rmation of incontinence frequency and type by more objective methods was not feasible in this large sample. However, self-reporting reflects the symptoms rather than the diagnosis of stress and urge incontinence, and the experience of incontinence can be of more direct clinical and public health importance than the presence or absence of urodynamic abnormalities. Whether the results of this randomized, controlled trial, which assessed conjugated equine estrogen alone and with medroxyprogesterone acetate at a standard oral dose, can be generalized to all types, routes, and doses of estrogens is not clear. However, the size and quality of this study provides a high level of evidence to recommend against using estrogen to prevent and treat incontinence in postmenopausal women, at least until treatment with different types, routes, and doses of estrogen can be as rigorously investigated. L. Elaine Waetjen, MD University of California, Davis, Sacramento CA, USA
Literature cited 1. Blakeman PJ, Hilton P, Bulmer JN. Oestrogen and progesterone receptor expression in the female lower urinary tract, with reference to oestrogen status. BJU Int 2000; 86:32^ 8. 2. Moehrer B, Hextall A, Jackson S.Oestrogens for urinary incontinence in women. Cochrane Database Syst Rev 2003(2):CD001405. 3. Jackson S, Shepherd A, Brookes S, Abrams P. The effect of oestrogen supplementation on post-menopausal urinary stress incontinence: a double-blind placebo-controlled trial. Br J Obstet Gynaecol 1999; 106:711^ 8. 4. Goldstein SR, Johnson S, Watts NB, et al. Incidence of urinary incontinence in postmenopausal women treated with raloxifene or estrogen. Menopause 2005; 12:160 ^ 4. 5. Grady D, Brown JS,Vittinghoff E, et al. Postmenopausal hormones and incontinence: the Heart and Estrogen/Progestin Replacement Study. Obstet Gynecol 2001; 97:116^20. 6. Fantl JA, Bump RC, Robinson D, et al. Eff|cacy of estrogen supplementation in the treatment of urinary incontinence. The Continence Program for Women Research Group. Obstet Gynecol 1996; 88:745^9.