ESTROGEN RECEPTORS AND HORMONAL FACTORS

The effects of the steroid hormone 17β-estradiol are mediated by ligand-activated transcription factors known as estrogen receptors. They are glycoproteins that share common features with androgen and progesterone receptors, and they can be divided into several functional domains.⁶ The classic estrogen receptor (ERα) was first discovered by Elwood Jensen in 1958 and cloned from uterine tissue in 1986,⁷ although it was not until 1996 that the second estrogen receptor (ERβ) was identified.⁸ The precise role of the two different receptors remains to be elucidated, although estrogen receptor-α appears to play a major role in the regulation of reproduction, whereas estrogen receptor-β has a more minor role.⁹

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 bladder ^3,¹⁰ although not in the dome of the bladder, reflecting its different embryologic origin. The pubococcygeus and the musculature of the pelvic floor also are estrogen sensitive,¹¹ although estrogen receptors have not yet been identified in the levator ani muscles.¹²

The distribution of estrogen receptors throughout the urogenital tract has been studied, and ERα and ERβ receptors have been found in the vaginal walls and uterosacral ligaments of premenopausal women, although the latter were absent in the vaginal walls of postmenopausal women.¹³ The ERα receptors are localized in the urethral sphincter, and when sensitized by estrogens, they are thought to help maintain muscular tone.¹⁴

In addition to estrogen receptors, androgen and progesterone receptors are expressed in the lower urinary tract, although their role is less clear. Progesterone receptors are expressed inconsistently, and they have been reported in the bladder, trigone, and vagina. Their presence may depend on estrogen status.⁵ Androgen receptors are present in the bladder and urethra, although their role has not yet been defined.¹⁵ Estrogen receptors have also been identified in mast cells in women with interstitial cystitis^16,¹⁷ and in the male lower urinary tract.¹⁸

The incidence of both estrogen and progesterone expression has been examined throughout the lower urinary tract in 90 women undergoing gynecologic surgery; 33 were premenopausal, 26 were postmenopausal without hormone replacement therapy (HRT), and 31 were postmenopausal and taking HRT.¹⁹ Biopsies were taken from the bladder dome, trigone, proximal urethra, distal urethra, vagina, and vesicovaginal fascia adjacent to the bladder neck. Estrogen receptors were consistently expressed in the squamous epithelia, but they were absent in the urothelial tissues of the lower urinary tract of all women, irrespective of estrogen status. Progesterone receptor expression, however, showed more variability because it was mostly subepithelial and was significantly lower in postmenopausal women not taking estrogen replacement therapy.

HORMONAL INFLUENCES ON LOWER URINARY TRACT SYMPTOMS

To maintain continence, the urethral pressure must remain higher than the intravesical pressure at all times, except during micturition.²⁰ Estrogens play an important role in the continence mechanism, with bladder and urethral function becoming less efficient with age.²¹ 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.²² Estrogens may affect continence by increasing urethral resistance, raising the sensory threshold of the bladder or by increasing α-adrenoreceptor sensitivity in the urethral smooth muscle.^23,²⁴ Exogenous estrogens have been shown to increase the number of intermediate and superficial cells in the vagina of postmenopausal women.²⁵ These changes have also been demonstrated in the bladder and urethra.²⁶

A prospective, observational study was performed to assess cell proliferation rates throughout the tissues of the lower urinary tract.²⁷ Fifty-nine women were studied; 23 were premenopausal, 20 were postmenopausal and not taking HRT and 20 were postmenopausal and taking HRT. Biopsies were taken from the bladder dome, trigone, proximal urethra, distal urethra, vagina, and vesicovaginal fascia adjacent to the bladder neck. The squamous epithelium of estrogen-replete women was shown to exhibit greater levels of cellular proliferation than in those women who were estrogen deficient.

Cyclic variations in the levels of estrogen and progesterone during the menstrual cycle lead to changes in urodynamic variables and lower urinary tract symptoms, with 37% of women noticing a deterioration in symptoms before menstruation.²⁸ Measurement of the urethral pressure profile in nulliparous premenopausal women shows there is an increase in functional urethral length midcycle and early in the luteal phase, corresponding to an increase in plasma estradiol.²⁹ Progestogens have been associated with an increase in irritating bladder symptoms^30,³¹ and urinary incontinence in women taking combined HRT.³² The incidence of detrusor overactivity in the luteal phase of the menstrual cycle may be associated with raised plasma progesterone levels after ovulation, and progesterone has been shown to antagonize the inhibitory effect of estradiol on rat detrusor contractions.³³ This may help to explain the increased prevalence of detrusor overactivity found in pregnancy.³⁴

The role of estrogen therapy in the management of women with fecal incontinence has been investigated in a prospective, observational study using symptom questionnaires and anorectal physiologic testing before and after 6 months of estrogen replacement therapy. At follow-up, 25% of women were asymptomatic, and another 65% were improved in terms of flatus control, urgency, and fecal staining. Anal resting pressures and voluntary squeeze increments were significantly increased after estrogen therapy, although there were no changes in pudendal nerve terminal latency. The investigators concluded that estrogen replacement therapy may have a beneficial effect, although larger studies are needed to confirm these findings.³⁵

HORMONAL INFLUENCES ON URINARY TRACT INFECTION

Urinary tract infection is 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 more than 50% among institutionalized patients.^36,³⁷ Pathophysiologic changes such as impairment of bladder emptying, poor perineal hygiene, and fecal and urinary incontinence may partly account for the high prevalence observed. Changes in the vaginal flora due to estrogen depletion lead to colonization with gramnegative bacilli, which cause locally irritating symptoms and act as uropathogens. These microbiologic changes may be reversed with estrogen replacement after menopause, offering a rationale for treatment and prophylaxis.

HORMONAL INFLUENCES ON LOWER URINARY TRACT FUNCTION

Neurologic Control

Sex hormones are known to influence the central neurologic control of micturition, although their exact role in the micturition pathway has yet to be elucidated. Estrogen receptors have been demonstrated in the cerebral cortex, limbic system, hippocampus, and cerebellum,^38,³⁹ and androgen receptors have been demonstrated in the pontine micturition center and the preoptic area of the hypothalamus.⁴⁰

Bladder Function

Estrogen receptors, although absent in the transitional epithelium at the dome of the bladder, are present in the areas of the trigone that have undergone squamous metaplasia.¹⁰ Estrogen is known to have a direct effect on detrusor function through modifications in muscarinic receptors^41,⁴² and by inhibition of movement of extracellular calcium ions into muscle cells.⁴³ Consequently, estradiol has been shown to reduce the amplitude and frequency of spontaneous rhythmic detrusor contractions,⁴⁴ and there is evidence that it may increase the sensory threshold of the bladder in some women.⁴⁵

Urethral Function

Estrogen receptors have been demonstrated in the squamous epithelium of the proximal and distal urethra,¹⁰ and estrogen has been shown to improve the maturation index of urethral squamous epithelium.⁴⁶ It has been suggested that estrogen increases urethral closure pressure and improves pressure transmission to the proximal urethra, both promoting continence.⁴⁷^–⁵⁰ Estrogens have been shown to cause vasodilatation in the systemic and cerebral circulation, and these changes are also seen in the urethra.⁵¹^–⁵³

The vascular pulsations seen on urethral pressure profilometry resulting from blood flow in the urethral submucosa and urethral sphincter have been shown to increase in size after estrogen administration,⁵⁴ and the effect is lost after estrogen withdrawal at menopause. The urethral vascular bed is thought to account for about one third of the urethral closure pressure, and estrogen replacement therapy in postmenopausal women with stress incontinence has been shown to increase the number of periurethral vessels.⁵⁵

Collagen Metabolism

Estrogens affect collagen synthesis, and they have a direct effect on collagen metabolism in the lower genital tract.⁵⁶ Changes found in women with urogenital atrophy may represent an alteration in systemic collagenase activity,⁵⁷ and urodynamic stress incontinence and urogenital prolapse have been associated with a reduction in vaginal and periurethral collagen levels.⁵⁸^–⁶⁰ There is a reduction in skin collagen content after menopause,⁶¹ and the rectus muscle fascia becomes less elastic with increasing age, resulting in a lower energy requirement to cause irreversible damage.⁶² Changes in collagen content have also been identified, the hydroxyproline content in connective tissue from women with stress incontinence being 40% lower than in continent controls.⁶³

LOWER URINARY TRACT SYMPTOMS

Urinary Incontinence

The prevalence of urinary incontinence increases with age, affecting 15% to 35% of community-dwelling women older than 60 years,⁶⁴ and other studies have reported a prevalence of 49% among women older than 65 years.⁶⁵ Rates of 50% have been reported in elderly nursing home residents.⁶⁶ A cross-sectional population prevalence survey of 146 women between the ages of 15 and 97 years found that 46% experienced symptoms of pelvic floor dysfunction, defined as stress or urge incontinence, flatus or fecal incontinence, symptomatic prolapse, or previous pelvic floor surgery.⁶⁷

Little work has been done to examine the incidence of urinary incontinence. However, a study in New Zealand of women older than 65 years found 10% of the originally continent developed urinary incontinence in the 3-year study period.⁶⁸

Epidemiologic studies have implicated estrogen deficiency in the cause of lower urinary tract symptoms, with 70% of women relating the onset of urinary incontinence to their final menstrual period.⁵ Lower urinary tract symptoms are common in postmenopausal women attending a menopause clinic, with 20% complaining of severe urgency and almost 50% complaining of stress incontinence.⁶⁹ Urge incontinence in particular is more prevalent after menopause, and the prevalence appears to rise with increasing years of estrogen deficiency.⁷⁰ There is, however, conflicting evidence regarding the role of estrogen withdrawal at the time of menopause. Some studies have shown a peak incidence in perimenopausal women,^71,⁷² and other evidence suggests that many women develop incontinence at least 10 years before the cessation of menstruation, with significantly more premenopausal women than postmenopausal women being affected.⁷³

Urogenital Atrophy

Urogenital atrophy is a manifestation of estrogen withdrawal after menopause, and symptoms may appear for the first time more than 10 years after the last menstrual period.⁷⁴ Increasing life expectancy has led to an increasingly elderly population, and with the average age of the menopause being 50 years,⁷⁶ it is now common for women to spend one third of their lives in the estrogen-deficient postmenopausal state.⁷⁵

Postmenopausal women comprise 15% of the population in industrialized countries, with a predicted growth rate of 1.5% over the next 20 years. Overall, in the developed world, 8% of the total population is estimated to have urogenital symptoms.⁷⁷ This represents 200 million women in the United States alone.

It has been estimated that 10% to 40% of all postmenopausal women are symptomatic,⁷⁸ although only 25% are thought to seek medical help. Two out of three women report vaginal symptoms associated with urogenital atrophy by the age of 75 years.⁷⁹ However, the prevalence of symptomatic urogenital atrophy is difficult to estimate, because many women accept the changes as being an inevitable consequence of the aging process and do not seek help, leading to considerable underreporting.

In a study assessing the prevalence of urogenital symptoms in 2157 Dutch women,⁸⁰ 27% complained of vaginal dryness, soreness, and dyspareunia, and the prevalence of urinary symptoms such as leakage and recurrent infections was 36%. When considering severity, almost 50% reported moderate to severe discomfort, although only a third had received medical intervention. Women who had had a hysterectomy reported moderate to severe complaints more often than those who had not.

The prevalence of urogenital atrophy and urogenital prolapse was examined in a population of 285 women attending a menopause clinic.⁸¹ Overall, 51% of women had anterior vaginal wall prolapse, 27% had posterior vaginal prolapse, and 20% had apical prolapse. In this same group, 34% of women had urogenital atrophy, and 40% complained of dyspareunia. Although urogenital atrophy and symptoms of dyspareunia were related to menopausal age, the prevalence of prolapse showed no association.

Although urogenital atrophy is an inevitable consequence of menopause, women may not always be symptomatic. In one study, 69 women attending a gynecology clinic were asked to fill out a symptom questionnaire before examination and undergoing vaginal cytology.⁸² Urogenital symptoms were found to be relatively low and were poorly correlated with age and physical examination findings, although not with vaginal cytologic maturation index. Women who were taking estrogen replacement therapy had higher symptom scores and physical examination scores.

From this evidence, it appears that urogenital atrophy is a universal consequence of menopause, although elderly women often may be minimally symptomatic. Treatment therefore should not be the only indication for replacement therapy.

MANAGEMENT OF LOWER URINARY DYSFUNCTION

Estrogens in the Management of Incontinence

Estrogen preparations have been used for many years in the treatment of urinary incontinence,^83,⁸⁴ 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 endo-metrial protection is another confounding factor, making interpretation of the results difficult.

To clarify the situation, a meta-analysis was conducted by the Hormones and Urogenital Therapy (HUT) Committee.⁸⁵ Of 166 articles identified that were published in English between 1969 and 1992, only 6 were controlled trials, and 17 were uncontrolled series. Meta-analysis found an overall significant effect of estrogen therapy on subjective improvement in all patients and for patients with urodynamic stress incontinence alone. Subjective improvement rates with estrogen therapy in randomized, 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%, with patients with urodynamic stress incontinence showing improvement rates of 34% to 73%. However, when assessing objective fluid loss, there was no significant effect. Maximum urethral closure pressure was found to increase significantly with estrogen therapy, although this outcome was influenced by a single study showing a large effect.⁸⁶

Another meta-analysis performed in Italy analyzed the results of randomized, controlled clinical trials on the efficacy of estrogen treatment in postmenopausal women with urinary incontinence.⁸⁷ A search of the literature (1965-1996) 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 estrogen and placebo, although there was no such difference in objective or urodynamic outcome. The investigators concluded that this difference could be relevant, although the studies may have lacked objective sensitivity to detect this effect.

The role of estrogen replacement therapy in the prevention of ischemic heart disease was assessed in a 4-year, randomized trial, the Heart and Estrogen/Progestin Replacement Study (HERS),⁸⁸ involving 2763 postmenopausal women younger than 80 years with intact uteri and ischemic heart disease. In the study, 55% of women reported at least one episode of urinary incontinence each week, and they were randomly assigned to oral conjugated estrogen plus medroxyprogesterone acetate or to placebo daily. Incontinence improved in 26% of women assigned to placebo and in 21% receiving HRT, and 27% of the placebo group complained of worsening symptoms, compared with 39% in the HRT group (P = .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 < .001). Overall, combined HRT 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.

Only gold members can continue reading. Log In or Register to continue