Effects of Local EstrogenTherapy on Recurrent UrinaryTract Infections inyoung Females under Oral Contraceptives

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1 European Urology European Urology 47 (2005) Effects of Local EstrogenTherapy on Recurrent UrinaryTract Infections inyoung Females under Oral Contraceptives Germar-M. Pinggera a, *, Gudrun Feuchtner b, Ferdinand Frauscher b, Peter Rehder a, Hannes Strasser a, Georg Bartsch a, Ralf Herwig a a Department of Urology, University of Innsbruck, 6020 Innsbruck, Austria b Department of Radiology, Innsbruck Medical University, Austria Accepted 21 September 2004 Available online 12 October 2004 Abstract Background: Previous studies have demonstrated the efficacy of local application of estrogen in treating postmenopausal women with recurrent urinary tract infections (RUTI) and urinary incontinence. Younger women under oral contraceptives (OC) can suffer from similar symptoms. The aim of this pilot study was to evaluate the effectiveness of local estrogens on RUTI and the impact of local hormonal supplementation on bladder neck vascularization. Methods: 30 women (mean age 22.7 years) with a longstanding history of RUTI were included. Pre-treatment investigation included complete clinical history, urinalysis, urine culture and cystoscopy. All subjects completed a questionnaire about onset and duration of disease and quality of life before and after treatment. Local (vaginal) estrogen therapy consisted of 1 mg estriol (E3) 7 times a week for two weeks and twice a week for two additional weeks. Sonographic examination of bladder vascularization was performed before and after treatment using transperineal color Doppler ultrasound (6 MHz, Acuson Sequoia 512, Mountain View, CA, USA) with a filled bladder. After angle correction, peak systolic blood flow velocity (PSBFV) and end diastolic blood flow velocity (EDBFV) were measured in 2 bladder arteries; and the Resistive Index (RI) was calculated. Flow velocity in each vessel was measured at least four times and the mean value determined. Results: All patients completed the therapy course without severe side effects. Patients had a mean history of RUTI over 2.3 years; the mean period under OC was 3.2 years. In the follow-up period of 11 months after treatment, 24/30 patients reported no symptoms of cystitis and used no additional medication. Normal bladder epithelium in control cystoscopy after E 3 therapy was seen in all patients with trigonal metaplasia and vulnerable, highly vascularized urothelium at the initial investigation. RI decreased from to after treatment (p < 0.001), concomitantly the mean EDBFV increased highly significantly from 0.82 cm/sec to 4.45 cm/sec after estrogen treatment (p < 0.001). Interpretation: In a majority of young patients under OC and a longstanding history of RUTI, a considerable infection-free period was achieved after local application of estrogen. Decreased RI and increased EDBFV indicate vasodilatation and less peripheral vascular resistance. Responsiveness to local E 3 may correspond to improved cystoscopic findings as a consequence of increased bladder perfusion. # 2004 Elsevier B.V. All rights reserved. Keywords: Female; Recurrent urinary tract infection; Estrogen; Oral contraceptives; Blood perfusion; Sonography * Corresponding author. Tel ; Fax: address: germar-michael.pinggera@uibk.ac.at (G. Pinggera) /$ see front matter # 2004 Elsevier B.V. All rights reserved. doi: /j.eururo

2 244 G.-M. Pinggera et al. / European Urology 47 (2005) Introduction Recurrent urinary tract infections (UTI) are common among young healthy women even though in general they have anatomically and physiologically normal urinary tracts [1]. The management of recurrent UTI is the same as that of sporadic UTI except that the likelihood of infection with an antibiotic-resistant uropathogen is higher in women treated with antimicrobials [1]. Continuous or post-coital prophylaxis with low-dose antimicrobials and intermittent self-treatment with antimicrobials have all been demonstrated to be effective in managing recurrent uncomplicated UTIs in women [1]. In contrast to the predominantly behavioral risk factors for young women, mechanical and/or physiological factors that affect bladder emptying are most strongly associated with recurrent UTI in healthy postmenopausal women [1]. Lack of estrogen, which characterizes the postmenopause, plays an important role in the pathogenesis of this infective disease. Exogenous estrogen replacement, however, is very effective in the prevention of bacteriuria in these women [2,3]. Sex hormones have a major influence on the female lower urinary tract throughout adult life, with fluctuations in their levels leading to macroscopic, histological and functional changes. Urinary symptoms may therefore develop during the menstrual cycle, in pregnancy and following the menopause. Estrogen deficiency, particularly when prolonged, is associated with a wide range of urogenital complaints, including frequency, nocturia, incontinence, urinary tract infections and the urge syndrome [4]. Furthermore, estrogen reduction brings about several changes in genitourinary tract such as structural atrophy and depletion of vaginal colonization of lactobacilli, all of which increase the risk of developing UTI [5]. This might explain the presence of similar symptoms in woman taking pills with relative progesterone excess. In our clinic we frequently see young women with recurrent UTI and normal urinary tract, except for mild atrophy of the urethral mucosa and more or less extensive trigonal metaplasia, signs that are often found in postmenopausal women. It was noteworthy that most of these young women were under combined oral contraceptives (COCs). The low-dose combined oral contraceptive pill contains less than 50 micrograms estrogen per pill in combination with different classes of progesterone. We hypothesized that contraception of this kind may cause similar symptoms as in postmenopausal women. It was the aim of this pilot study to evaluate the feasibility and effectiveness of local application of estrogen E3 in the treatment of UTI in such patients. For this purpose, in 30 consecutive patients under lowdose combined oral contraceptive pill, urinalysis, urine culture, cystoscopy as well as a color Doppler ultrasound examination of the bladder neck before and after treatment were carried out. Quality of life was assessed with a questionnaire before and after estrogen therapy. 2.Materialandmethods We investigated 30 consecutive young female patients on COC presenting with recurrent UTI in the outpatient department of our clinic. The mean age of patients was (range 18 37) years, the mean history of recurrent UTI over 2.27 years with a frequency of about 8 episodes of infection (range 2 20) per year, and the mean time of COC use was 3.2 years (range 2 6 years). The mean estradiol level (E2) was pmol/ml, whereas in healthy fertile females, values between 416 and 1399 pmol/ml have been observed. All patients had previously undergone repeated or long-term therapies with various antibiotics for treatment of UTI. Four patients had previously undergone intravesical heparin instillation therapy. Absence of bacteriological infection signs, proofed by standard urinalysis and sterile uriculture was mandatory for treatment onset, otherwise standard antibiotic therapy was accomplished before. After exclusion of vesicorenal reflux or voiding abnormalities with RCG/MCG, ultrasound and additional urodynamics where indicated we measured bladder vascularization and performed cystoscopy. Vascularization was determined with power Doppler (CDE) Ultrasound examination of bladder neck preand post-estrogen therapy (sagittal plane; perineal approach). Standardized settings were established (6C2 MHz transducer, transmitting 5 MHz, harmonic imaging, color Doppler energy (CDE) = 15 db). Power Doppler signal intensity was evaluated visually pre- and post-estrogen therapy (1 = low intensity; 2 = moderate intensity; 3 = high intensity) and quantified by measurement of Mean Pixel Density (MPD) (Scion Image Software Maryland, USA) in a standardized Region of Interest (ROI). After angle correction, peak systolic blood flow velocity (PSBFV) and end-diastolic blood flow velocity (EDBFV) were measured in 2 arterial bladder vessels at maximum cystometric capacity (C max ), the Resistive Index (RI) was calculated according to the formula (PSBFV EDBFV)/PSBFV. Flow velocity measurement in each vessel was repeated at least four times and the mean value determined. Cystoscopy was performed by one and the same investigator who looked for signs of hormonal deficiency such as trigonal metaplasia and abnormal mucosa of the urethra; the endoscopic findings were documented on standardized bladder data sheet. Additionally, all subjects completed a questionnaire on demographic data, duration and frequency of UTI, complaints during or after sexual intercourse, incontinence in UTI-free intervals and quality of life (QOL). Patients were asked to assess their complaints and QOL in a visual analogue scale (VAS) from 0 (very poor) to 7 (very good). (Table 1). Patients underwent local (vaginal) therapy with Estriol 1 mg (E3) once a day in the evening for 14 days and twice a week for a further period of 14 days. After completion of the 4-week therapy, urinalysis, urine culture and bladder vascularization measurements were carried out once again and questionnaires completed posttherapy were evaluated. Recurrence of UTI and effectiveness of

3 G.-M. Pinggera et al. / European Urology 47 (2005) Table 1 Evaluation of questionnaire data after E3 therapy (n = 30) and patients complaints prior to E3 therapy (n = 30) Mean S.D. Nuisance through UTI Problems during sexual intercourse = severe complaints, 7 = no complaints. Tolerance of medication Handling = very well, 7 = very poor. Mean S.D. p Improvement of complaints during urination Improvement of complaints during sexual intercourse 1 = very much improved, 7 = no improvement. Fig. 1. Recurrence rate of infections after one year of observation in patients with RUTI after E3 therapy. therapy were assessed at a follow-up visit 11 months after treatment. 3. Results All of the 30 enrolled patients completed the suppository therapy without major side effects except for occasional mild vaginal burning under therapy and were seen 11 months after treatment completion in the outpatient department. Before the start of therapy, patients complained of subjectively very severe symptoms. They were asked to categorize the complaints on an analog scale from 1 (very severe complaints) to 7 (no complaints). The mean value reached 2.18 for recurrent infections and 4.23 for complaints during sexual intercourse (Table 1). Most complaints during sexual intercourse were dyspareunia due to lubrication problems. In the 11 months after treatment completion, 24 of the 30 patients reported having had no symptoms of cystitis and no need for additional medication. Five patients reported having had one episode of UTI with positive urine culture and one patient had two such episodes (Fig. 1); both patients were effectively treated with antibiotics. Whereas trigonal metaplasia and vulnerable, highly vascularized urothelium of the urethra were seen at the initial cystoscopic examination, normal epithelium was found in control cystoscopy after E 3 therapy. Power Doppler Ultrasound examination revealed a statistically significant increase (p < 0.001; Wilcoxon) of power Doppler signal intensity after estrogen therapy (Figs. 2 and 3) in all patients (100%). Quantification of power Doppler signal also demonstrated an increase of MPD from to (p = 0.02, t-test), respectively. The RI decreased from to after treatment (p < 0.001), concomitantly, the mean EDBFV increased highly significantly from 0.82 cm/s to 4.45 cm/s after estrogen therapy (p < 0.001). Examples of regularly observed color Doppler ultrasound findings before and after treatment are shown in Figs. 2 and 3. Patients reported good tolerance to E3 and ease in handling of the medication. On an analog scale from 1 (very well) to 7 (very poor), mean value for tolerance reached 1.13 and that for handling 1.23 (Table 1). On an analog scale from 1 (very much improved) to 7 (no improvement), the mean value for improvement of UTI complaints after therapy reached 1.50; the mean value for improvement of complaints during sexual intercourse reached 4.80 (Table 1). Post-therapy, 80% of the patients continued with oral contraception, with some of them switching over to a more estrogen-dominant pill. About 20% made a switch from oral to other forms of contraception (Fig. 4). 4. Discussion UTI is a notable cause of morbidity worldwide and it is estimated that in the United States it is responsible for over 6 million medical consultations per year. This disease shows a certain gender preference, more females being affected than men. With an estimated prevalence of 5% per year, UTI remains one of the most common bacterial infections seen in women and up to 50% [6] all women are likely to experience an episode of UTI at some point during their lifetime.

4 246 G.-M. Pinggera et al. / European Urology 47 (2005) Fig. 2. Power Doppler ultrasound image and RI measurement before E3 therapy. Recurrent infections occur in 12% to 27% of women after their first attack of UTI and in 48% of women who had previously experienced a recurrence [7]. Recurrence may be attributed to a relapse of the original bacterial infection or to re-infection with the same or a different organism. It was shown that approximately over 80% of recurrent UTIs are a consequence of reinfection, with more than one third caused by the same bacterial strain. A recurrent UTI is a symptomatic UTI that follows clinical resolution of an earlier UTI generally, but not necessarily, after treatment [1]. Ikaheimo found that 36% of young women with Escherichia coli cystitis experience recurrence within 1 year [8], although in general, they have anatomically and physiologically normal lower urinary tracts [1]. Occasionally, recurrences are due to a persistent focus of infections (relapse), but the vast majority is thought to represent re-infections [9]. Recurrent UTIs (RUTI) in young women are generally distinguished from RUTIs in postmenopausal women. Postmenopause is characterized by a signifi-

5 G.-M. Pinggera et al. / European Urology 47 (2005) Fig. 3. Power Doppler ultrasound image and RI measurement after E3 therapy. cant reduction of ovarian estrogen secretion, which is often associated with urogenital atrophy. Clinically it is manifested as a syndrome consisting of vaginal dryness, itching, irritation and dyspareunia, which may appear for the first time >10 years after the last menstrual period [10]. A higher incidence UTI and urinary incontinence are also frequently associated with the postmenopausal condition [11,12]. Several studies have demonstrated the effectiveness of oral or vaginal E3 application in the treatment of RUTIassociated urinary incontinence in postmenopausal women [13 16]. Batra demonstrated the existence of high-affinity estradiol binding sites in the female urethra and urinary bladder similar to those found in the uterus or vagina of virgin albino rabbits [17]. According to Blakeman and co-workers the estrogen receptors are not found in the transitional epithelium of the bladder, but in areas in the trigone which have undergone squamous metaplasia [18]. Recent experiments on human tissues also indicated the existence of estradiol receptors in the female urethra and trigonum [19]. Such receptors may be involved in the regulation of blood flow in the urethra following topical application of low-dose estrogen, which was shown in rabbits [20]. This study showed that the female urethra, like the vagina and the uterus, is highly sensitive to low doses of estrogen even in the manifestation of early responses. On the other hand, the existence of high-affinity low capacity progester-

6 248 G.-M. Pinggera et al. / European Urology 47 (2005) Fig. 4. Type of contraception used one year after E3 therapy for RUTI. one binding in the female urethra and urinary bladder was also shown [21]. This suggests a possible link between estrogen- progesterone interaction and the appearance of urinary symptoms during pregnancy in women. In recent years, low-dose combined oral contraceptive pill has gained popularity among young women as a birth control method. It contains less than 50 micrograms gestodene and about 35 mg or less (20 to 15 mg) ethinyl estradiol. The ratio of estrogen and progesterone is another variable of great importance in the development of unwanted side effects such as vaginal dryness. Cystoscopy, performed during investigation of the cause of RUTI in young women, showed morphological features and urinary symptoms similar to those in postmenopausal women. It was interesting to note that all of these patients were taking low-dose combined oral contraceptive pill (COC). Till now, no relationship between this kind of contraception and RUTI has been reported. For this reason, 30 consecutive young women with RUTI, who were taking the COC were investigated with cystoscopy and color Doppler ultrasound of the bladder neck before treatment with E3. In all patients cystoscopy showed a vulnerable urethra with reduction of the urethral mucosa and trigonal metaplasia. Additionally, the patients showed high RI with low blood flow (EDBFV) in the color Doppler ultrasound. Although the major complaints of these women were about RUTI, some patients also complained of vaginal dryness and dyspareunia, symptoms typical in the postmenopausal woman. In view of the clinical, cystosopic and color Doppler ultrasonography findings, we treated these women with vaginal E3 suppositories, found to have been effective in the treatment of RUTI in postmenopausal women. The treatment was mostly described as suitable, well tolerated, except for occasional mild vaginal burning, and uncomplicated in handling. After therapy the mean RI decreased from to (p < 0.001) and the EDBFV increased from 0.82 cm/s to 4.45 cm/s (p < 0.001). The increase of power Doppler signal intensity suggests improved perfusion of bladder neck due to E3-mediated vasodilatation. Patients experienced significant improvement of RUTI and vaginal symptoms. In 80% (24/30) of the patients, there were no episodes of UTI in the 11 months of follow-up; 17% (5/30) experienced one and 3% (1/30) two episodes of UTI with positive bacteriological results, which were successfully treated with usual antibiotics. Interestingly, in this failure group the primary complaints remained ameliorated. None of them reported in the control visits symptoms of vaginal dryness or dyparneuria. During the observed period the majority of patients continued with the used oral contraception, whereas only 20% changed to an alternative contraceptive method. We observed no statistically significant difference in the RUTI rate between those continuing with oral contraception and those who switched to an alternative birth control method after completion of therapy. Restoration of altered epithelium and perfusion by local estrogen therapy may lead to prevention of frequent episodes of UTI. One intriguing fact is that relief of symptoms and prevention of recurrence of UTI were achieved after local application of estrogen for a short period. After a four-week treatment course, endoscopic findings of trigonal metaplasia vanished and normal urothelium was restored, which was maintained for nearly a year. This observation is consistent with a recently published randomized, double blind, placebo-controlled study on 71 healthy postmenopausal women treated with lowdose estrogens. Marx and coworkers assessed changes in vaginal cytology, measured by maturation index, vaginal mucosa and ph after a 4-week treatment regimen with estrogens and reported highly significant improvements in all parameters assessed, with the improvements maintained over a period of 16 weeks of follow-up [22]. Thus, we conclude that therapy with locally applied E3 can effectively treat RUTI in young females using low-dose combined oral contraceptive pill. The therapy is well-tolerated, uncomplicated and easy to handle. Increased urethral and bladder perfusion via the previously described estrogens binding sides seems to be the underlying mechanism of action. We suggest that

7 G.-M. Pinggera et al. / European Urology 47 (2005) young females with RUTI should be carefully observed during cystoscopy for signs of estrogen deficiency. If these symptoms are found, therapy with E3 as described before may be considered as an additional effective treatment option. To verify these novel results, a randomized double-blind study in a larger population should be carried out, assessing the interactions between local administration of estrogens, changes in bladder neck perfusion and resolution of RUTI. References [1] Hooton TM. Recurrent urinary tract infection in women. Int J Antimicrob Agents 2001;17: [2] Raz R. Postmenopausal women with recurrent UTI. Int J Antimicrob Agents 2001;17: [3] Raz R. Hormone replacement therapy or prophylaxis in postmenopausal women with recurrent urinary tract infection. J Infect Dis 2001;183:S74 6. [4] Hextall A, Cardozo L. The role of estrogen supplementation in lower urinary tract dysfunction. Int Urogynecol J Pelvic Floor Dysfunct 2001;12: [5] Maloney C. Estrogen & recurrent UTI in postmenopausal women. Am J Nurs 2002;102: [6] Asscher AW. Urinary tract infection. J R Coll Physicians Lond 1981;15: [7] Cardozo L, Robinson D. Special considerations in premenopausal and postmenopausal women with symptoms of overactive bladder. Urology 2002;60:64 71 [Discussion 71]. [8] Ikaheimo R, Siitonen A, Heiskanen T, Karkkainen U, Kuosmanen P, Lipponen P, Makela PH. Recurrence of urinary tract infection in a primary care setting: analysis of a 1-year follow-up of 179 women. Clin Infect Dis 1996;22:91 9. [9] Hooton TM. A simplified approach to urinary tract infection. Hosp Pract 1995;30: [10] Iosif CS. Effects of protracted administration of estriol on the lower genito urinary tract in postmenopausal women. Arch Gynecol Obstet 1992;251: [11] Haspels AA, Luisi M, Kicovic PM. Endocrinological and clinical investigations in post-menopausal women following administration of vaginal cream containing oestriol. Maturitas 1981;3: [12] Thomas TM, Plymat KR, Blannin J, Meade TW. Prevalence of urinary incontinence. Br Med J 1980;281: [13] Iosif CS, Bekassy Z. Prevalence of genito-urinary symptoms in the late menopause. Acta Obstet Gynecol Scand 1984;63: [14] Brocklehurst JC, Dillane JB, Griffiths L, Fry J. A therapeutic trial in urinary infection of old age. Gerontol Clin 1968;10: [15] Raz R, Stamm WE. A controlled trial of intravaginal estriol in postmenopausal women with recurrent urinary tract infections. N Engl J Med 1993;329: [16] Valiquette L. Urinary tract infections in women. Can J Urol 2001;8:6 12. [17] Batra SC, Iosif CS. Female urethra: a target for estrogen action. J Urol 1983;129: [18] 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. [19] Iosif CS, Batra S, Ek A, Astedt B. Estrogen receptors in the human female lower uninary tract. Am J Obstet Gynecol 1981;141: [20] Batra S, Bjellin L, Sjogren C, Iosif S, Widmark E. Increases in blood flow of the female rabbit urethra following low dose estrogens. J Urol 1986;136: [21] Batra SC, Iosif CS. Progesterone receptors in the female lower urinary tract. J Urol 1987;138: [22] Marx P, Schade G, Wilbourn S, Blank S, Moyer DL, Nett R. Low-dose (0.3 mg) synthetic conjugated estrogens A is effective for managing atrophic vaginitis. Maturitas 2004;47:47 54.