Abstract
The female genital and lower urinary tracts share a common embryological origin, arising from the urogenital sinus and both are sensitive to the effects of the female sex steroid hormones throughout life. Estrogen is known to have an important role in the function of the lower urinary tract and estrogen and progesterone receptors have been demonstrated in the vagina, urethra, bladder and pelvic floor musculature. In addition estrogen deficiency occurring following the menopause is known to cause atrophic change and may be associated with lower urinary tract symptoms such as frequency, urgency, nocturia, urgency incontinence and recurrent infection. These may also co-exist with symptoms of urogenital atrophy such as dyspareunia, itching, vaginal burning and dryness. Epidemiological studies have implicated estrogen deficiency in the aetiology of lower urinary tract symptoms with 70% of women relating the onset of urinary incontinence to their final menstrual period.
Whilst for many years systemic and vaginal estrogen therapy was felt to be beneficial in the treatment of lower urinary and genital tract symptoms this evidence has recently been challenged by large epidemiological studies investigating the use of systemic hormone replacement therapy as primary and secondary prevention of cardiovascular disease and osteoporosis.
The aim of this paper is to examine the effect of the sex hormones, estrogen and progesterone, on the lower urinary tract and to review the current evidence regarding the role of systemic and vaginal estrogens in the management of lower urinary tract symptoms and urogenital atrophy.
I ntroduction
The female genital and lower urinary tracts share a common embryological origin, arising from the urogenital sinus and both are sensitive to the effects of the female sex steroid hormones throughout life. Estrogen is known to have an important role in the function of the lower urinary tract, and estrogen and progesterone receptors have been demonstrated in the vagina, urethra, bladder and pelvic floor musculature.1,2 In addition, estrogen deficiency occurring postmenopause is known to cause atrophic change and may be associated with lower urinary tract symptoms such as frequency, urgency, nocturia, urgency incontinence and recurrent infection. These may also co-exist with symptoms of urogenital atrophy such as dyspareunia, itching, vaginal burning and dryness. Epidemiological studies have implicated estrogen 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
Whilst for many years systemic and vaginal estrogen therapy was felt to be beneficial in the treatment of lower urinary and genital tract symptoms, this evidence has recently been challenged by large epidemiological studies investigating the use of systemic hormone replacement therapy (HRT) as primary and secondary prevention of cardiovascular disease and osteoporosis.
Consequently, the aim of this article is to review the current evidence regarding the role of hormones and the lower urinary tract.
Estrogen receptors
The classic estrogen receptor (ER α) was first discovered in 1958 although was not cloned from uterine tissue until 1986 4 whilst the second estrogen receptor (ER β) was identified in 1996. 5 The precise role of the two different receptors remains to be elucidated although ER α appears to play a major role in the regulation of reproduction whilst ER β has a more minor role. 6
Estrogen receptors have been demonstrated throughout the lower urinary tract and are expressed in the squamous epithelium of the proximal and distal urethra, vagina and trigone of the bladder3,7 although not in the dome of the bladder, reflecting its different embryological origin. Pubococcygeus and the musculature of the pelvic floor have also been shown to be estrogen sensitive 8 although estrogen receptors have not yet been identified in the levator ani muscles. 9
The distribution of estrogen receptors throughout the urogenital tract has also been studied with both α and β receptors being found in the vaginal walls and uterosacral ligaments of premenopausal women although the latter were absent in the vaginal walls of postmenopausal women. 10 In addition, α receptors are localised in the urethral sphincter and when sensitised by estrogens are thought to help maintain muscular tone. 11
In addition to estrogen receptors, both androgen and progesterone receptors are expressed in the lower urinary tract although their role is less clear. 2 Progesterone receptors are expressed inconsistently, having been reported in the bladder, trigone and vagina. Whilst androgen receptors are present in both the bladder and urethra, their role has not yet been defined. 12
Further work has investigated the prevalence of receptors throughout the genital and lower urinary tract. Estrogen receptors have been found to be consistently expressed in squamous epithelium within the genital tract although are absent in the urothelial tissues of the lower urinary tract irrespective of estrogen status. Progesterone receptor expression, however, showed more variability being mostly subepithelial and was significantly lower in postmenopausal women not taking estrogen replacement therapy. 13
Hormonal influences on lower urinary tract symptoms
Estrogens play an important role in the continence mechanism with bladder and urethral function becoming less efficient with age. 14 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. 15 Estrogens may affect continence by increasing urethral resistance, raising the sensory threshold of the bladder or increasing α adrenoreceptor sensitivity in the urethral smooth muscle.16,17 In addition, exogenous estrogens have been shown to increase the number of intermediate and superficial cells in the vagina of postmenopausal women. 18 These changes have also been demonstrated in the bladder and urethra. 19
Cyclical variations in the levels of both estrogen 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. 20 Measurement of the urethral pressure profile in nulliparous premenopausal women shows that there is an increase in functional urethral length midcycle and early in the luteal phase corresponding to an increase in plasma oestradiol. 21 Furthermore, progestogens have been associated with an increase in overactive bladder (OAB) symptoms22,23 and urinary incontinence in those women taking combined HRT. 24 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 antagonise the inhibitory effect of oestradiol on rat detrusor contractions. 25 This may help to explain the increased prevalence of detrusor overactivity found in pregnancy. 26
Hormonal influences on urinary tract infection
Urinary tract infection is also a common cause of urinary symptoms in women of all ages. This is a particular problem in the elderly with a reported incidence of 20% in the community and over 50% in institutionalised patients.27,28 Pathophysiological changes such as impairment of bladder emptying, poor perineal hygiene and both faecal and urinary incontinence may partly account for the high prevalence observed. In addition, changes in the vaginal flora due to estrogen depletion lead to colonisation with Gram-negative bacilli which in addition to causing local irritative symptoms also act as uropathogens. These microbiological changes may be reversed with estrogen replacement following the menopause, offering a rationale for treatment and prophylaxis.
Urogenital atrophy
Urogenital atrophy is a manifestation of estrogen withdrawal following the menopause and symptoms may appear for the first time more than 10 years after the last menstrual period. 29 In addition, an increase in life expectancy has led to an increasingly elderly population and it is now common for women to spend a third of their lives in the estrogen-deficient postmenopausal state, 30 with the average age of the menopause being 50 years. 31
It has been estimated that 10–40% of all postmenopausal women are symptomatic 33 although only 25% are thought to seek medical help. In addition, two out of three women report vaginal symptoms associated with urogenital atrophy by the age of 75 years. 21 However, the prevalence of symptomatic urogenital atrophy is difficult to estimate since many women accept the changes as being an inevitable consequence of the ageing process and thus do not seek help leading to considerable under reporting.
In a study assessing the prevalence of urogenital symptoms in 2157 Dutch women, 34 27% of women complained of vaginal dryness, soreness and dyspareunia whilst the prevalence of urinary symptoms such as incontinence and recurrent infections was 36%. When considering severity, almost 50% reported moderate to severe discomfort although only a third had received medical treatment. Interestingly, women who had previously had a hysterectomy reported moderate to severe complaints more often than those who had not.
The prevalence of urogenital atrophy and urogenital prolapse has also been examined in a population of 285 women attending a menopause, clinic. 35 Overall 51% of women were found to have anterior vaginal wall prolapse, 27% posterior vaginal prolapse and 20% apical prolapse. In addition, 34% of women were noted to have urogenital atrophy, 40% complaining of dyspareunia. Whilst urogenital atrophy and symptoms of dyspareunia were related to menopausal age, the prevalence of prolapse showed no association.
However, whilst urogenital atrophy is an inevitable consequence of the menopause, women may not always be symptomatic. 36 Urogenital symptoms were found to be relatively low and were poorly correlated with age and physical examination findings although not with vaginal cytological maturation index. Women who were taking estrogen replacement therapy had higher symptom scores and physical examination scores.
From this evidence, it would appear that urogenital atrophy is a universal consequence of the menopause although often elderly women may be minimally symptomatic. Hence, treatment should not be the only indication for replacement therapy.
Management of lower urinary tract symptoms
Systemic estrogen therapy
The role of estrogens in the management of postmenopausal women with lower urinary tract symptoms has been investigated in three large epidemiological studies examining the use of combined estrogen/progestogen and estrogen only systemic HRT.37–40 In all of these trials, systemic estrogen replacement therapy was found to increase the risk of developing both stress and urgency urinary incontinence, and in those women who complained of urinary incontinence at baseline, the symptoms were found to deteriorate. This was also reflected in deterioration in quality of life (QoL).
However, there are several reasons why these observations may not translate into clinical practice. These studies were designed to assess the role of HRT in the primary prevention of ischaemic heart disease and osteoporosis as well as evaluating the risk of thromboembolism, and the data regarding incontinence only represent a sub-group post hoc analysis. Since two of the studies were performed in North America conjugated equine estrogens were used rather than synthetic oestradiol, which is more commonly used in Europe, meaning that they are less representative of current practice. In addition, many of the patients under investigation were considerably older than women who regularly use HRT clinically and had a number of co-morbidities, meaning that this may not be applicable to current clinical practice.
Consequently, care needs to be taken when interpreting the data although the reported studies would certainly suggest that oral and transdermal estrogen replacement, with or without progestogen replacement, increases the risk of urinary incontinence. However, the risk remains small with an annual incidence of 1.6% per year 5 or in real terms an increase in incontinence episode frequency of one episode per week. 4 Furthermore, the effects would appear to be reversible with the cessation of therapy. Consequently, the risk of adverse effects on lower urinary tract function needs to be carefully balanced against the benefits in terms of symptom relief which are associated with systemic HRT.
D oes estrogen replacement increase the risk of incontinence?
Whilst historically there is considerable evidence to support the use of systemic and local estrogen therapy in the management of lower urinary tract dysfunction, more recently exogenous estrogen therapy has been shown to have an effect on collagen remodelling. It has been shown to lead to a reduction in total collagen concentration, 41 a decrease in collagen cross linking 42 and an increase in the levels of collagen turnover markers. 43 This reduction in both quantity and strength of collagen may weaken bladder neck support and hence increase the risk of developing stress incontinence. In addition, women with stress urinary incontinence have been shown to have a reduction in total collagen and an increase in the level of collagen degradation products after taking oral estrogen therapy for six months. 44 There is also evidence to suggest that exogenous estrogens increase the collagen to smooth muscle ratio which may lead to an increase in overactive bladder symptoms 45 by reducing bladder wall compliance.
Consequently, there is evidence to suggest that exogenous estrogen therapy may alter collagen metabolism and this may have a detrimental effect on lower urinary tract symptoms. Despite this, historically, there is considerable evidence to suggest that estrogen therapy may be beneficial.
Estrogens in the management of stress urinary incontinence
Whilst there is some evidence to suggest that oral estrogens have been reported to increase maximum urethral pressure and lead to symptomatic improvement in 65% to 70% of women,46,47 other work has not confirmed this.48,49 In addition, two placebo-controlled studies examining the use of oral estrogens in the treatment of urodynamic stress incontinence in postmenopausal women have failed to demonstrate an effect in either subjective or objective outcome mesures.50,51 Furthermore, a review of 8 controlled and 14 uncontrolled prospective trials concluded that estrogen therapy was not an efficacious treatment for stress incontinence but may be useful for symptoms of urgency and frequency. 52
Estrogens in the management of overactive bladder
Although the effect of estrogens on lower urinary tract function remains controversial, there is evidence to show that estrogen deficiency may increase the risk of developing OAB following the menopause. Animal data would suggest that estrogen might inhibit the function of Rho-kinase in bladder smooth muscle, and hence effect smooth muscle contraction, whilst having no effect on its expression. Consequently, estrogen deprivation following the menopause may lead to the development of OAB symptoms. 53 In vivo studies have demonstrated that ovariectomised rats showed a significant decrease in voided volume and an increase in 24-h frequency with an increase in basal and stretch induced acetylcholine release. Conversely, there was a reduction in acetylcholine release from nerve fibres. This may explain why there is a decrease in detrusor contractility following the menopause with a corresponding increase in the development of OAB symptoms. Interestingly, estrogen replacement therapy reversed these changes. 54
Based on these findings, estrogen replacement following the menopause may lead to an improvement in physiological voiding function whilst reducing the risk of developing symptoms of overactive bladder. Given the concerns regarding the use of systemic estrogen replacement therapy, the vaginal route of administration may offer a better treatment approach.
Estrogens have been used in the treatment of urinary urgency and urgency 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 symptoms, 55 although a double-blind multicentre study of the use of oestriol in postmenopausal women complaining of urgency has failed to confirm these findings. 56
In addition, vaginal 17β-oestradiol tablets (Vagifem) therapy may also be useful in managing the symptoms of OAB and in particular improving the symptom of urgency. 57 A further double-blind, randomised, placebo-controlled trial has shown lower urinary tract symptoms of frequency, urgency, urgency and stress incontinence to be significantly improved although there was no objective urodynamic assessment performed. 58 However, some of the subjective improvement in these symptoms may simply represent local estrogenic effects reversing urogenital atrophy rather than a direct effect on lower urinary tract function.
In a review of 10 randomised placebo-controlled trials, estrogen was found to be superior to placebo when considering symptoms of urgency incontinence, frequency and nocturia although vaginal estrogen administration was found to be superior to placebo for the symptom of urgency. 59 Consequently, the implications of these findings are that exogenous estrogen therapy, particularly using the vaginal route of administration may be useful in the management of OAB.
Combination therapy in OAB
Currently, there is an increasing amount of evidence regarding the synergistic use of vaginal estrogen therapy with antimuscarinic therapy in the management of postmenopausal women with OAB although the results are contradictory.
A 12-week prospective randomised trial comparing tolterodine 2 mg bd and vaginal conjugated estrogen cream versus tolterodine 2 mg bd alone has been reported in 80 postmenopausal women complaining of OAB. 60 Overall those women receiving combination therapy had a significantly greater improvement in mean daytime frequency and voided volume as compared to the tolterodine arm. These objective observations were also supported by a significantly greater improvement in QoL in the combination therapy group. Whilst there was a trend to improvement in symptoms of nocturia, urgency and urgency incontinence, these findings were not significantly different between the groups.
However, these finding have not been replicated in a 12-week prospective study of 229 postmenopausal women treated with either tolterodine extended release 4 mg od or tolterodine extended release 4 mg and vaginal oestriol. 61 Overall there were no significant differences between the two treatment groups in terms of efficacy which was assessed subjectively using a three-point scale. Interestingly, however, those women who were subsequently found to have a urodynamic diagnosis of detrusor overactivity were found to have an overall poorer outcome in terms of efficacy. These findings would imply that perhaps the additional efficacy offered by vaginal estrogen therapy is due to reversal of urogenital atrophy rather than a direct effect on the bladder.
A 12-week prospective randomised trial comparing the oestradiol releasing vaginal ring and oral oxybutynin 5 mg bd has also been reported in 59 postmenopausal women with OAB. 62 Overall there was a greater reduction in daytime frequency with the oestradiol ring as compared to oxybutynin although the difference between the groups was not significant. In addition, there was a significant improvement in QoL in both groups although again no difference between groups. The authors concluded that low-dose topical vaginal estrogens were as effective as oxybutynin in reducing micturition frequency in postmenopausal women with OAB.
It remains unclear why the results of these three studies are contradictory. This may be due to the difference in the patient populations; one study included women with detrusor overactivity whilst the other two simply recruited OAB patients. In addition, the different estrogen preparations investigated may also have a significant effect on efficacy as conjugated estrogens are absorbed systemically and therefore may have a greater effect on the lower urinary tract.
Estrogens in the management of recurrent urinary tract infection
Estrogen therapy has been shown to decrease vaginal pH and reverse the microbiological changes that occur in the vagina following the menopause. 63 Initial small uncontrolled studies using oral or vaginal estrogens in the treatment of recurrent urinary tract infection appeared to give promising results64,65 and this has been supported by a larger, randomised, double-blind placebo-controlled trial of 93 women investigating intravaginal oestriol. The incidence of urinary tract infection was significantly lower in the oestriol group when compared to placebo and more women remained infection free. In addition, there was a significant decrease in vaginal pH and colonisation with Enterobactericeae in the treatment arm. 66
Whilst there is good evidence supporting the use of vaginal estrogens, the data concerning oral preparations are less robust. A randomised study of 40 postmenopausal women comparing oral oestriol to placebo found oestriol to be significantly more effective 67 although these findings were not confirmed subsequently in a trial of 72 women, when, following a six-month treatment period with an additional six-month follow-up oestriol was found to be no more effective than placebo. 68
Overall the evidence from a systematic review and meta-analysis would suggest a benefit from estrogen over placebo in the management of recurrent lower urinary tract infection in postmenopausal women, and particularly with the use of vaginal preparations. 69
Estrogens in the management of urogenital atrophy
Whilst the data supporting the use of estrogens in lower urinary tract dysfunction remain controversial, there are considerable data to support their use in urogenital atrophy and the vaginal route of administration correlates with better symptom relief by improving vaginal dryness, pruritis and dyspareunia, greater improvement in cytological findings, and higher serum oestradiol levels. 70 Overall vaginal oestradiol has been found to be most effective in reducing patient symptoms although conjugated estrogens produced the most cytological change and the greatest increase in serum levels of oestradiol and oestrone.
Estrogen therapy – Cochrane review
Incontinence
The most recent meta-analysis of the effect of estrogen therapy on the lower urinary tract has been performed by the Cochrane group 71 and is notable as the conclusions are starkly different to those drawn from the previous review.72 Overall 33 trials were identified, including 19,313 incontinent women (1262 involved in trials of local administration) of which 9417 received estrogen therapy.
Systemic administration (of unopposed oral estrogens – synthetic and conjugated equine estrogens) resulted in worse incontinence than placebo (relative risk (RR) 1.32; 95% confidence interval (CI): 1.17–1.48) although this is heavily influenced by the size of the WHI study. 6 When considering combination therapy, there was a similar worsening effect on incontinence when compared to placebo (RR 1.11; 95% CI: 1.04–1.18). There was some evidence suggesting that the use of local estrogen therapy may improve incontinence (RR 0.74; 95% CI: 0.64–0.86) and overall there were 1–2 fewer voids in 24 h and less frequency and urgency.
The authors conclude that local estrogen therapy for incontinence may be beneficial although there was little evidence of long-term effects. The evidence would suggest that systemic hormone replacement using conjugated equine estrogens may make incontinence worse. In addition, they comment that there are too few data to comment reliably on the dose, type of estrogen and route of administration.
Estrogens and urogenital atrophy
The most recent meta-analysis of intravaginal estrogen treatment in the management of urogenital atrophy was reported by the Cochrane group in 2003. 71 Overall 16 trials including 2129 women were included, and intravaginal estrogen was found to be superior to placebo in terms of efficacy although there were no differences between types of formulation. Fourteen trials compared safety between the different vaginal preparations and found a higher risk of endometrial stimulation with conjugated equine estrogens as compared to oestradiol.
Conclusion
The past decade has seen a dramatic shift in our thinking regarding the use of systemic HRT and concerns regarding breast cancer and thrombo-embolic disease have considerably reduced the number of women seeking treatment. There have also been similar concerns regarding the use of systemic estrogen replacement therapy in the management of postmenopausal women with lower urinary tract symptoms although this is largely based on observations from post hoc analyses of large epidemiological studies. Given these findings, there is currently no role for the use of systemic HRT in the management of women with urinary incontinence.
The currently available evidence would appear to suggest that intra-vaginal estrogen therapy should be considered rather than systemic therapy as this avoids systemic adverse effects and also removes the need for endometrial surveillance. In addition, the long-term safety of vaginal estrogens is supported by a recent change in prescribing guidelines allowing long-term therapy.
Vaginal estrogens are integral in the management of women with urogenital atrophy and also are effective in the management and prophylaxis of recurrent lower urinary tract infections in postmenopausal women. More recently, there is some evidence to suggest their use in overactive bladder and particularly in terms of improving the symptom of urgency although this may be related to an effect on urogenital atrophy rather than a direct effect on the lower urinary tract.
The synergistic use of vaginal estrogens with other treatment modalities in the management of lower urinary tract symptoms may also be useful. At present, there are no data to support the use of vaginal estrogen therapy with duloxetine in women with stress urinary incontinence although there is some evidence to support combination therapy in overactive bladder when combined with an antimuscarinic.
HRT remains important in managing those women with troublesome menopausal symptoms and whilst systemic therapy has historically been used in managing lower urinary tract symptoms the recent evidence is contradictory. Consequently, the focus has now shifted towards vaginal estrogen therapy and the evidence would suggest it has proven efficacy and safety in the management of urogenital atrophy, recurrent urinary tract infections and overactive bladder.