Effects of intravaginal estriol and pelvic floor rehabilitation on urogenital aging in postmenopausal women.

Capobianco G, Donolo E, Borghero G, Dessole F, Cherchi PL, Dessole S.
Arch Gynecol Obstet. 2012; 285: 397-403.

MJ Strauhal, PT, BCB-PMD

October 9, 2013

 Primary Aim:  To assess the effects of the combination of pelvic floor rehabilitation (PFR) and intravaginal estriol administration on stress urinary incontinence (SUI), urogenital atrophy (UGA), and recurrent urinary tract infections (UTI’s) in postmenopausal women

 Subjects:  Italian women between the ages of 55-70 years old living in Sassari, Italy were recruited by issuing a leaflet explaining the aim of the study and requesting their participation

• Inclusion criteria- symptoms and signs of SUI (loss of urine on exertion with coughing, sneezing, intercourse, etc.), vaginal atrophy (vaginal dryness and dyspareunia), and history of recurrent UTI’s, no previous estrogen replacement, patients with hysterectomy were eligible
• Exclusion criteria- pathologies or anatomical lesions of the urogenital tract (such as grade II and II pelvic organ prolapse per Baden and Walker classification), the presence of severe systemic disorders, thromboembolic diseases, biliary lithiasis, previous breast or uterine cancer, abnormal uterine bleeding, BMI >25 kg/m2, DO, and abnormal cystometric capacity

Study design:  prospective randomized controlled study

 Methods:

• Sample size/ power analysis was calculated on the basis of prevalence of UI, UGA, and recurrent UTI’s and increased by 10% (to safeguard at an optimal level of precision (5%) against possible effect of disease reduction and non-response numbers)
• Theoretical sample size was 576 minus 110 women who chose not to participate = 466 were evaluated
• Initial assessment (visit 1) included recent history of somatic symptoms, complete medical and surgical history, complete physical exam, complete gynecological exam
• Midstream urine specimens were rated for bacteriuria
• UGA was assessed visually by the authors taking into account pallor, petechiae, friability, and vaginal dryness (yes, no) and rated as none, moderate, or severe
• Also included (?) the Incontinence Impact Questionnaire (IIQ) and UI was assessed as none, mild, moderate, severe (they did not indicate if it was the long or short form IIQ)
• Baseline visit (visit 2) included determination of vaginal pH, colposcopic exam, vaginal and urethral smears, urodynamic study (UDS)
• Schiller’s test was performed- a test for cancer of the cervix, in which the cervix is stained with a solution of iodine and potassium iodide and turns dark-brown in all noncancerous areas
• Vaginal and urethral smears had cytologic fixation and sent to a pathologist
• Papanicolaou stain (also Pap stain) is a multichromatic staining cytological technique developed by George Papanikolaou, the father of cytopathology
• Pap staining is used to differentiate cells in smear preparations of various bodily secretions; the specimens can be gynecological smears, sputum, brushings, washings, urine, cerebrospinal fluid, abdominal fluid, pleural fluid, synovial fluid, seminal fluid, fine needle aspiration material, tumor touch samples, or other materials containing cells
• Pap staining is a very reliable technique. As such, it is used for cervical cancer screening in gynecology; the entire procedure is known as Pap smear
• Vaginal and urethral epithelium was estimated using the karyopyknotic index (KPI) to assess the percentage of superficial cells in the total population of squamous cells examined and is consider a reliable cellular index of estrogen activity
• UDS included the urethral pressure profile and urethrocystometry per the ICS
• Means of 3 profiles for max urethral pressure (MUP), max urethral closure pressure (MUCP) were calculated
• After visits 1 and 2 there were 206 postmenopausal women included in the study and randomly assigned into a treatment or control group (see Figure 1)
• Randomization used sets of sequenced, sealed, opaque envelopes containing the bottle number (of estriol ovules?) to be given to each subject
• Group I- intravaginal estriol ovules (IEO) at 1 mg once daily for 2 weeks and then 2 ovules once weekly for 6 months PLUS pelvic floor muscle training (PFMT) and electrical stimulation (ES)
• Group II- IEO regime as in Group I
• Both groups were asked to keep a diary to record local and systemic side effects (of the IEO?)
• Urogenital symptomology, urine cultures, colposcopic findings, urethral cystologic findings, urethral pressure profile (UPP), urethrocystometry before and at 6 months post treatment

Results:

• Characteristics of the groups were homogenous (see Table 1)
• Dropouts- 9 in Group I and 11 in Group II (of these 20, all experienced side effects of the IEO)
• Statistical analysis included X2 test and one-way anova
• Group I (see Table 2)
• 83/103 had mild to mod SUI à at 6 months 61/83 had subjective improvement (per IIQ?) (43 cured, 18 improved) (see page 399 for description of how the researchers assessed change)
• 103/103 c/o UGA ranging from mod to severe vaginal dryness à at 6 months 71/103 reported improvement
• 75/103 c/o dyspareunia à at 6 months 88/103 reported improvement
• Group II (see Table 2)
• 103/103 has mild to mod SUI à at 6 months 10/103 reported improvement
• 103/103 c/o UGA ranging from mod to severe vaginal dryness à at 6 months 21/103 reported improvement
• 65/103 c/o dyspareunia à at 6 months 46/103 reported improvement
• Both groups improved in bacteriuria, vaginal pH, colposcopic parameters, and KPI index (see Tables 2 and 3)
• Group I demonstrated significant increases in mean MUP, MUCP, and PTR compared to Group II (see Table 4)
• Both groups improved in urethrocystometric findings but did not reach statistical significance (see Table 5)

Discussion:

Results suggest that combined IEO and PFR (PFM training and ES) improved both signs and symptoms of SUI, UGA, and UTI’s more than IEO alone, and is safe and well tolerated by subjects; should be first-line treatment for SUI in postmenopausal women

• Limitations
• Power analysis 576, actual subjects 206
• No placebo group
• No report on IIQ
• No discussion of PFM strength pre and post treatment
• No discussion of study weaknesses
• Strengths
• RCT
• No conflict of interest with pharmaceutical company (Colpogyn)
• Compliance was high; all subjects completed the study
• Included dropouts in statistical analysis (however, there is no indication of dropouts in the groups… both groups look to have analyzed date from 103 subjects)
• No adverse drug systemic effects; local effects were limited to pruritus and burning
• Excluded those with DO and abnormal bladder capacity
• Reproduced the findings of Ishiko (ref #31), a RCT that demonstrated that combined estriol with PFMT was better than PFMT only

 Clinical Application:

• 10-40% of postmenopausal women have been found to have symptoms related to UGA but only 25% seek help.  How does this impact your clinical practice?
• Symptoms relating to urogenital aging are categorized into 2 groups (see below).  Do you frequently see these symptoms in your postmenopausal patients?
• Localized LUT (urethra and bladder) symptoms
• Urgency, frequency, nocturia, dysuria, UTI’s, UI
• Vaginal and vulvar symptoms
• Vaginal dryness, itching, burning, dyspareunia
• Were you aware of the research that demonstrates that urogenital organs are highly sensitive to the influence of estrogen?  That estrogen receptors have been found in the urethra and trigone, the round ligaments, and the LA m muscles?
• Estriol is considered to be free of the potential risks associated with systemic use of estrogen therapy.  How does this information change how you might counsel a postmenopausal patient?
• What is your understanding of the findings from the WHI study on HRT?

Additional Resource:

North American Menopause Society- www.nams.org