Oestrogens and the lower urinary tract
Dr D. Robinson, Department of Urogynaecology, 3rd Floor Golden Jubilee Wing, Kings College Hospital, London SE5 9RS, UK.
The female genital and lower urinary tracts share a common embryological origin, arising from the urogenital sinus. Both are sensitive to the effects of female sex steroid hormones. Oestrogen is known to have an important role in the function of the lower urinary tract throughout adult life with oestrogen and progesterone receptors demonstrated in the vagina, urethra, bladder and pelvic floor musculature.1,2 This is supported by the fact that oestrogen deficiency occurring following the menopause is known to cause atrophic changes within the urogenital tract,3 and is associated with urinary symptoms such as frequency, urgency, nocturia, incontinence, recurrent infection. These may also coexist with symptoms of vaginal atrophy such as dyspareunia, itching, burning and dryness. Epidemiological studies have implicated oestrogen deficiency in the aetiology of lower urinary tract symptoms with 70% of women relating the onset of urinary incontinence to their final menstrual period.3 Lower urinary tract symptoms have been shown to be common in postmenopausal women attending a menopause clinic with 20% complaining of severe urgency, and almost 50% complaining of stress incontinence.4 Urge incontinence in particular is more prevalent following the menopause, the prevalence would appear to rise with increasing years of oestrogen deficiency.
The effects of the steroid hormone 17β-oestradiol are mediated by ligand activated transcription factors known as oestrogen receptors. These are glycoproteins and share common features with both androgen and progesterone receptors and can be divided into several functional domains. The classic oestrogen receptor (ERα) was first discovered by Jensen in 1958 and cloned from uterine tissue in 1986,5 although it was not until 1996 that the second oestrogen receptor (ERβ) was identified.6 The precise role of the two different receptors remains to be elucidated although ERα appears to play a major role in the regulation of reproduction whilst ERβ has a more minor role.7
Oestrogens and lower urinary tract symptoms
Oestrogens play an important role in the continence mechanism with bladder and urethral function becoming less efficient with age.8 Elderly women have been found to have a reduced flow rate, increased urinary residuals, higher filling pressures, reduced bladder capacity and lower maximum voiding pressures. Oestrogens may affect continence by increasing urethral resistance, raising the sensory threshold of the bladder, by increasing α adrenoreceptor sensitivity in the urethral smooth muscle9 or by promoting β-3-adrenoceptor-mediated relaxation of the detrusor muscle.10 In addition exogenous oestrogens have been shown to increase the number of intermediate and superficial cells in the vagina of postmenopausal women.11 These changes have also been demonstrated in the bladder and urethra.12
Cyclical variations in the levels of both oestrogen and progesterone during the menstrual cycle have been shown to lead to changes in urodynamic variables and lower urinary tract symptoms, with 37% of women noticing a deterioration in symptoms prior to menstruation.13 Measurement of the urethral pressure profile in nulliparous premenopausal women shows there is an increase in functional urethral length mid-cycle and early in the luteal phase corresponding to an increase in plasma oestradiol.14 Furthermore, progestogens have been associated with an increase in irritative bladder symptoms and urinary incontinence in those women taking combined hormone replacement therapy.15 The incidence of detrusor overactivity in the luteal phase of the menstrual cycle may be associated with raised plasma progesterone following ovulation and progesterone has been shown to antagonize the inhibitory effect of oestradiol on rat detrusor contractions.16 This may help to explain the increased prevalence of detrusor overactivity found in pregnancy.
Oestrogens in the management of urinary incontinence
Oestrogen preparations have been used for many years in the treatment of urinary incontinence although their precise role remains controversial. Many of the studies performed have been uncontrolled observational series examining the use of a wide range of different preparations, doses and routes of administration. The inconsistent use of progestogens to provide endometrial protection is a further confounding factor making interpretation of the results difficult.
In order to clarify the situation a meta-analysis from the Hormones and Urogenital Therapy (HUT) Committee has been completed.17 Of 166 articles identified that were published in English between 1969 and 1992, only six were controlled trials and 17 were uncontrolled series. Meta-analysis found an overall significant effect of oestrogen therapy on subjective improvement in all subjects and for subjects with urodynamic stress incontinence alone. Subjective improvement rates with oestrogen therapy in randomised controlled trials ranged from 64% to 75%, although placebo groups also reported an improvement of 10% to 56%. In uncontrolled series subjective improvement rates were 8% to 89%.
A further meta-analysis performed in Italy has analysed the results of randomised controlled clinical trials on the efficacy of oestrogen treatment in postmenopausal women with urinary incontinence.18 A search of the literature (1965–96) revealed 72 articles of which only four were considered to meet the meta-analysis criteria. There was a statistically significant difference in subjective outcome between oestrogen and placebo although there was no such difference in objective or urodynamic outcome. The authors conclude that this difference could be relevant although the studies may have lacked objective sensitivity to detect this.
The role of oestrogen replacement therapy in the prevention of ischaemic heart disease has recently been assessed in a 4-year randomised trial, the Heart and Estrogen/progestin Replacement Study (HERS),19 involving 2763 postmenopausal women younger than 80 years with intact uteri and ischaemic heart disease. In the study 55% of women reported at least one episode of urinary incontinence each week, and were randomly assigned to oral conjugated oestrogen plus medroxyprogesterone acetate or placebo daily. Incontinence improved in 26% of women assigned to placebo as compared with 21% receiving HRT, while 27% of the placebo group complained of worsening symptoms compared with 39% in the HRT group (P= 0.001). The incidence of incontinent episodes per week increased an average of 0.7 in the HRT group and decreased by 0.1 in the placebo group (P < 0.001). Overall combined hormone replacement therapy was associated with worsening stress and urge urinary incontinence, although there was no significant difference in daytime frequency, nocturia or number of urinary tract infections.
The role of oestrogens for urinary incontinence has recently been subjected to Cochrane review.20 Overall 28 trials, including 2926 women, were identified. The trials reported used varying combinations of type of oestrogen, dose, route of administration and duration of therapy. Subjective impression of cure was higher amongst those treated with oestrogen for all types of incontinence and when considered jointly with improvement there was a statistically higher rate in both urge and stress incontinence when compared with placebo; 57%vs 28% and 43%vs 27%, respectively. In women with urge incontinence the chance of cure or improvement was 25% higher than in those with stress incontinence. Overall the data would suggest that 50% of women taking oestrogen were subjectively cured or improved compared with 25% who were taking placebo. Whilst the effect tended to be more marked in those women complaining of urge incontinence there was no statistically significant effect on frequency, nocturia or urgency.
Oestrogens in the management of stress incontinence
In addition to the studies included in the HUT meta-analysis several authors have also investigated the role of oestrogen therapy in the management of urodynamic stress incontinence only. Oral oestrogens have been reported to increase the maximum urethral pressures and lead to symptomatic improvement in 65%–70% of women,21,22 although other work has not confirmed this.23,24 More recently two placebo-controlled studies have been performed examining the use of oral oestrogens in the treatment of urodynamic stress incontinence in postmenopausal women. Neither conjugated equine oestrogens and medroxyprogesterone25 or unopposed oestradiol valerate26 showed a significant difference in either subjective or objective outcomes. Furthermore, a review of eight controlled and 14 uncontrolled prospective trials concluded that oestrogen therapy was not an efficacious treatment for stress incontinence but may be useful for symptoms of urgency and frequency.27
A recently reported meta-analysis has helped determine the role of oestrogen replacement in women with stress incontinence.28 Of the papers reviewed 14 were nonrandomised studies, six randomised trials (of which four were placebo controlled) and two meta-analyses. Interestingly there was only a symptomatic or clinical improvement noted in the nonrandomised studies whilst there was no such effect noted in the randomised trials. The authors conclude that currently the evidence would not support the use of oestrogen replacement alone in the management of stress incontinence.
Oestrogens in the management of urge incontinence
Oestrogens have been used in the treatment of urinary urgency and urge incontinence for many years although there have been few controlled trials to confirm their efficacy. A double-blind placebo-controlled crossover study using oral oestriol in 34 postmenopausal women produced subjective improvement in eight women with mixed incontinence and 12 with urge incontinence.29 However, a double-blind multicentre study of the use of oestriol (3 mg per day) in postmenopausal women complaining of urgency has failed to confirm these findings,30 showing both subjective and objective improvement but not significantly better than placebo.
The use of sustained release 17β-oestradiol vaginal tablets (Vagifem, Novo Nordisk) has also been examined in postmenopausal women with urgency and urge incontinence or a urodynamic diagnosis of sensory urgency or detrusor overactivity. These vaginal tablets have been shown to be well absorbed from the vagina and to induce maturation of the vaginal epithelium within 14 days.31 However, following a 6-month course of treatment the only significant difference between active and placebo groups was an improvement in the symptom of urgency in those women with a urodynamic diagnosis of sensory urgency.32 A further double-blind, randomised, placebo-controlled trial of vaginal 17βα-oestradiol vaginal tablets has shown lower urinary tract symptoms of frequency, urgency, urge and stress incontinence to be significantly improved although there was no objective urodynamic assessment performed.33 In both of these studies the subjective improvement in symptoms may simply represent local oestrogenic effects reversing urogenital atrophy rather than a direct effect on bladder function.
More recently a randomised, parallel group, controlled trial has been reported comparing the oestradiol-releasing vaginal ring (Estring, Pharmacia, Uppsala, Sweden) with oestriol vaginal pessaries in the treatment of postmenopausal women with bothersome lower urinary tract symptoms.34 Low-dose vaginally administered oestradiol and oestriol were found to be equally efficacious in alleviating lower urinary tract symptoms of urge incontinence (58%vs 58%), stress incontinence (53%vs 59%) and nocturia (51%vs 54%) although the vaginal ring was found to have greater patient acceptability.
To try and clarify the role of oestrogen therapy in the management of women with urge incontinence a meta-analysis of the use of oestrogen in women with symptoms of ‘overactive bladder’ has been reported by the HUT Committee.35 In a review of 11 randomised placebo-controlled trials including 430 women oestrogen was found to be superior to placebo when considering symptoms of urge incontinence, frequency and nocturia, although vaginal oestrogen administration was found to be superior for symptoms of urgency. In those taking oestrogens there was also a significant increase in first sensation and bladder capacity as compared with placebo. In conclusion oestrogen therapy was found to improve lower urinary tract symptoms as well as urodynamic variables and local administration was superior to systemic.
RECURRENT URINARY TRACT INFECTIONS
Oestrogens in the management of recurrent urinary tract infection
Oestrogen therapy has been shown to increase vaginal pH and reverse the microbiological changes that occur in the vagina following the menopause.36 Initial small uncontrolled studies using oral or vaginal oestrogens in the treatment of recurrent urinary tract infection appeared to give promising results,37,38 although unfortunately this has not been supported by larger randomised trials. Several studies have been performed examining the use of oral and vaginal oestrogens although these have had mixed results.
Kjaergaard and colleagues39 compared vaginal oestriol tablets with placebo in 21 postmenopausal women over a 5-month period and found no significant difference between the two groups. However, a subsequent randomised, double-blind placebo-controlled study assessing the use of oestriol vaginal cream in 93 postmenopausal women during an 8-month period did reveal a significant effect.40
Kirkengen randomised 40 postmenopausal women to receive either placebo or oral oestriol and found that although initially both groups had a significantly decreased incidence of recurrent infections, after 12 weeks oestriol was shown to be significantly more effective.41 These findings, however, were not confirmed subsequently in a trial of 72 postmenopausal women with recurrent urinary tract infections randomised to oral oestriol or placebo. Following a 6-month treatment period and a further 6-month follow up oestriol was found to be no more effective than placebo.42
More recently a randomised, open, parallel-group study assessing the use of an oestradiol-releasing silicone vaginal ring (Estring; Pharmacia) in postmenopausal women with recurrent infections has been performed which showed the cumulative likelihood of remaining infection free was 45% in the active group and 20% in the placebo group.43 Estring was also shown to decrease the number of recurrences per year and to prolong the interval between infection episodes.
Oestrogens are known to have an important physiological effect on the female lower genital tract throughout adult life leading to symptomatic, histological and functional changes. The use of oestrogen replacement therapy has been examined in the management of lower urinary tract symptoms although only recently has it been subjected to randomised placebo-controlled trials and meta-analysis.
Oestrogen therapy alone has been shown to have little effect in the management of urodynamic stress incontinence, although when used in combination with an α-adrenergic agonist may lead to an improvement in urinary leakage.
When considering the irritative symptoms of urinary urgency, frequency and urge incontinence oestrogen therapy may be of benefit, although this may simply represent reversal of urogenital atrophy rather than a direct effect on the lower urinary tract.
The role of oestrogen replacement therapy in the management of women with recurrent lower urinary tract infection remains to be determined although there is now some evidence that vaginal administration may be efficacious.