A 53-year-old postmenopausal woman presents to the outpatient clinic with a chief complaint of urinary incontinence. She experiences episodes of loss of small amounts of urine with coughing, laughing, or sneezing multiple times a day. She denies larger volume loss and urgency. Since the start of menopause, she has also noted mild symptoms of hot flashes, occasional dyspareunia relieved by lubrication, and difficulty achieving orgasm. She denies sleep and mood disturbances. She is married, monogamous, and has had normal health maintenance screenings with a history of normal Pap smear results. Her last menses was at the age of 52 years. She denies any history of premenopausal dyspareunia, recurrent bladder infections, interstitial cystitis, or sexually transmitted infections. She has had recurrent vaginal candidiasis, with her last episode occurring at age 50 years. Her medications include daily calcium supplementation with vitamin D and lisinopril 10 mg daily for controlled hypertension. She has no known allergies. She denies vaginal discharge or hematuria, and her husband lacks significant genitourinary symptoms. The physical examination findings are unremarkable except for the presence of thin, dry vulvar skin without erosions or Wickham's striae and the leakage of small amounts of urine with Valsalva maneuver. The results of a dipstick urinalysis obtained in the office are normal.


CLINICAL QUESTION


In postmenopausal women with stress urinary incontinence (SUI), is estrogen therapy effective at improving urinary symptoms?


SEARCH CRITERIA AND 
RESULTS


A MEDLINE search was performed using the search terms stress urinary incontinence AND estrogen. Limiters used included humans AND female AND English AND clinical trial OR meta-analysis OR randomized controlled trial OR research support, US government. Studies were considered for inclusion if they directly evaluated the effect of estrogen therapy (or estrogen and progesterone therapy for women with an intact uterus) on stress urinary incontinence symptomatology. Studies were excluded if they reported primary results based solely on the use of outcomes that were surrogate end points for disease symptomatology.


A total of 51 article citations were retrieved. Articles were assessed for potential level of evidence based on the hierarchy of study methodology,1 yielding two meta-analyses for initial review:


1. Cody JD, Richardson K, Moehrer B, et al. Oestrogen therapy for urinary incontinence in post-menopausal women. Cochrane Database Syst Rev. 2009(4):CD001405. Review. PubMed PMID: 19821277.2


2. Fantl JA, Cardozo L, McClish DK. Estrogen therapy in the management of urinary incontinence in postmenopausal women: a meta-analysis. First report of the Hormones and Urogenital Therapy Committee. Obstet Gynecol. 1994;83(1):12-18. PubMed PMID: 8272292.3


Both meta-analyses met the stated inclusion criteria, but an initial validity assessment of Fantl, Cardozo, and McClish revealed the meta-analysis had significant limitations including a high likelihood of publication bias, a small sample size, and lack of the most recent 15 years of data on the topic. The Fantl and colleagues meta-analysis was excluded.


EVALUATING THE EVIDENCE


Cody and colleagues performed a meta-analysis with the stated objective to "assess the effects of local and systemic estrogens used for the treatment of urinary incontinence." They included controlled trials that used estrogen treatment for a broad range of diagnoses, including various forms of urinary incontinence or postmenopausal urinary symptoms. Three major outcomes were reported: 


  1. Oral estrogen therapy led to worsening of incontinence in comparison to placebo with a relative risk (RR) of 1.32 and a 95% confidence interval (CI) of 1.17 to 1.48;

  2. Oral administration of estrogen and progesterone led to worsening of incontinence (RR, 1.11; 95% CI, 1.04-1.18); and 

  3. Local estrogen therapy improved incontinence (RR, 0.74; 95% CI, 0.64-0.86). 


The authors conclude that during active treatment, local estrogen therapy improves urinary incontinence, but systemic estrogen may make incontinence worse. 


The meta-analysis performed by Cody and colleagues adequately addressed potential causes of bias. The 
databases used to locate studies included medline, CINAHL (the Cumulative Index to Nursing and Allied Health Literature) and the Cochrane Central Register of Controlled Trials (CENTRAL). Although the authors did not contact authors or experts in the field seeking unpublished studies, the reporting of statistically significant negative results (for example, treatment worsens incontinence) makes publication bias less likely for the main results 1 and 2 above. The authors performed a reproducible validity assessment on each article included in the meta-analysis that assessed the quality of the study concealment, blinding, tracking of all subjects, and use of an intention-to-treat model. Validity assessments were clearly presented in table format in the section entitled "Characteristics of Studies." 


Concerns that arise from combining data from heterogeneic studies were addressed by assessing for heterogeneity of forest plots visually and the use of the statistic, 12. In cases where heterogeneity existed among studies (for example, 12 > 0.85 for data included in main result of systemic estrogen worsening incontinence), the use of a random effects model in addition to the original fixed effects model was considered. The use of a subsequent random effects model on the oral estrogen ther­apy worsening incontinence results (RR, 1.32: 95% CI, 1.17-1.48) yields this finding to be no longer statistically significant( RR, 0.82; 95% CI, 0.52-1.28). The study authors noted the loss of this harmful treatment effect was attributable to the random effects model placing the least weight on the largest study (n = 9,000) with the longest follow-up (1 year). The authors reported their primary results of the fixed effects model (that is, they refuted their random effect model results) based on validity assessments of the included studies and the judgment that the large study should be heavily weighted as occurred in the original fixed effects model. The statistical significance of the other primary outcomes was consistent when both a fixed effects model and random effects model were used.


The meta-analysis results for systemic estrogen or estrogen/progesterone therapy are generalizable to the patient described in the case presentation. The participants included in the combined data were postmenopausal women with or without a uterus who had urinary incontinence (not subclassified by type). The results can be further generalized to other types of urinary incontinence in postmenopausal women who lack contraindications to hormone replacement therapy. 


CLINICAL BOTTOM LINE


If the patient described in the case presentation desires treatment for the symptoms of her coexisting atrophic vaginitis, then local estrogen therapy is an appropriate option that may also improve her stress urinary incontinence symptoms. If her atrophic vaginitis symptoms are not viewed as severe enough to warrant the use of local estrogen, then the use of topical estrogen therapy needs to be weighed against alternative treatment modalities for stress urinary incontinence. 


When estrogen therapy is considered for treating urinary incontinence, the most appropriate route of administration is local. Women who are taking systemic estrogen or progesterone for menopausal symptoms may experience new or worsening urinary incontinence. JAAPA


Mark Archambault is an assistant professor in the PA program at Wake Forest University School of Medicine, Winston-Salem, North Carolina, and the department editor for Critically Appraised Topic. He has indicated no relationships to disclose relating to the content of this article.

REFERENCES


1. Oxford Centre for Evidence Based Medicine. Levels of evidence. http://www.cebm. net/index.aspx?o=1025. Accessed November 9, 2010.


2. Cody JD, Richardson K, Moehrer B, et al. Oestrogen therapy for urinary incontinence in postmenopausal women. Cochrane Database Syst Rev. 2009(4):CD001405. 


3. Fantl JA, Cardozo L, McClish DK. Estrogen therapy in the management of urinary incontinence in postmenopausal women: a meta-analysis. First report of the Hormones and Urogenital Therapy Committee. Obstet Gynecol. 1994;83(1):
12-18.