The management of lower urogenital changes in the menopause

Abstract

Currently, 25% of women seek the advice of a medical professional for symptoms related to the menopause. However, with an increasingly ageing and medically aware population, it is likely this proportion will grow. The main symptoms related to the menopause are systemic vasomotor and localized urogenital symptoms. Numerous forms of estrogen have been used to alleviate these symptoms. Further problems that increase during the menopause include incontinence, pelvic organ prolapse and recurrent urinary tract infections. This article reviews the process by which estrogen affects the tissues of the urogenital tract, what symptoms occur during this period and what modalities of treatments are available.

Keywords

Urogenital atrophy incontinence estrogen prolapse menopause hormone therapy

Introduction

The female genital and lower urinary tract have the same embryological origin; both arising from the urogenital sinus and consequently are both sensitive to the effects of female sex steroid hormones.¹ Estrogen and progesterone receptors have been isolated in the urogenital tract, which encompasses the vagina, bladder, urethra and pelvic floor musculature.² The menopause is defined as the permanent cessation of menses resulting from the loss of ovarian follicular activity.³ The characteristic features of reduced estrogen are systemic including vasomotor symptoms and localized atrophy of the urogenital tract³ The use of systemic hormone therapy in optimizing changes associated with the menopause was once accepted as the ideal approach; however, some studies have challenged this view which has led to the decrease in the use of high-dose systemic treatment and has increased the search for low-dose topical therapies.⁴

Estrogen receptors in the lower urogenital system

The effects of the steroid hormones 17β-estradiol (E2) are mediated by ligand-activated transcription factors known as estrogen receptors⁵ located in the nucleus of the cell. Two estrogen receptors have been identified; α discovered in 1986⁶ and β discovered in 1997.^7,8 The estrogen receptor is found in the trigone, of the bladder, the proximal and distal urethra but not in the dome of the bladder. It is also found in vaginal squamous epithelium.⁹ Chen et al.⁸ found that estrogen receptors were also present in the pubococcygeus muscle and the urethral sphincter. Press et al.¹⁰ showed that in premenopausal women, the expression of estrogen receptors in genital tract changed over the course of the menstrual cycle. Two out of three women report vaginal symptoms associated with urogenital atrophy by the age of 70, but only 20% seek medical help.¹¹ The delay in symptom development for more than 10 years after their last menstrual period¹² may be due to a change in expression of estrogen receptors.¹⁰

The maturation of vaginal tissue can be measured by vaginal cytology and is scored using the vaginal maturation index.¹³ This assesses the percentage of parabasal/intermediate/superficial cells that are shed. A ‘shift to the left’ with more parabasal cells indicates vaginal atrophy as there are more immature cells. A ‘shift to the right’ indicates more mature epithelium and consequently less atrophy. Estrogen deficiency causes a decrease in superficial cells and a relative increase in the proportion of intermediate and parabasal cells. A reduction in superficial cells results in a decrease in glycogen levels within the tissue, which inhibits lactic acid production by the vaginal flora. These changes increase the vaginal pH and consequently cause a change in the microflora and may render the vagina more susceptible to the cultivation of fungal and bacterial infections.¹⁴

Management of urogenital atrophy

Vaginal estrogens are the preferred therapy for isolated lower urogenital symptoms.¹⁵ In a meta-analysis of 10 trials, local estrogen therapy was as effective as systemic therapy when assessing symptomatic improvement in vulvo-vaginal atrophy.¹⁶ Non-hormonal management of urogenital atrophy is also suitable for those who do not want to consider hormonal intervention. These include lifestyle management, vaginal moisturizer and lubricants.¹⁷ Symptoms of urogenital atrophy do not occur until the level of endogenous estrogen is much lower than that required to cause endometrial proliferation.¹⁸ Consequently, it is possible to use low-dose estrogen replacement therapy in order to reduce urogenital atrophy symptoms whilst avoiding the risk of endometrial proliferation, thus negating the need to protect the endometrium with progesterone.¹⁹

A Cochrane meta-analysis (16 trials: 2129 women in total) showed that topical estrogens were better than both placebo and non-hormonal gel in the management of urogenital atrophy.²⁰ There are a variety of different vectors by which estrogen can be applied locally. These include creams, rings and vaginal tablets. The review concluded the efficacy for all local estrogen therapies were found to be the same; however, some estrogen creams were associated with an increased risk of systemic absorption.²⁰ Consequently, conjugated equine estrogen cream has been withdrawn.

Estradiol ring

The estradiol ring continually releases approximately 7.5 µg of estradiol over a period of 24 h for up to 90 days. The ring has proven superior to both placebo or no treatment and to be just as effective as vaginal tablets and creams in the relief of symptoms as well as reducing vaginal pH levels and maturing the vaginal mucosa.²¹ The vaginal ring is self-inserted and can be changed every three months. In patients with limited manual dexterity or vaginal capacity, the ring can be inserted by a doctor. An open-label trial of 129 women demonstrated that treatment with the ring was related to a rise in bone density suggesting a degree of systemic absorbtion.²²

Vaginal tablets (17 β-estradiol)

Estradiol hemihydrate 25 µg (Vagifem 25 µg®) was discontinued as of December 2012 responding to recent recommendations from the International Menopause society that state best practice is to use the lowest effective dose of HRT where possible.²³ Ultra-low-dose vaginal estradiol (Estradiol hemihydrate 10 µg) allows similar symptomatic improvement with similar improvements in vaginal cytology, urethral cytology and vaginal pH when compared with the 25 µg preparation, with no effect on endometrial proliferation and serum estrogen levels remaining in the normal postmenopausal range.²⁴ Another randomized controlled trial studying the effects of estradiol hemihydrate 25 µg and estradiol hemihydrate 10 µg in 58 women showed that only 74% of women on estradiol hemihydrate 25 µg had estradiol in the normal range for a postmenopausal woman, comparing with 96% in the estradiol hemihydrate 10 µg group.²⁵ Endometrial safety associated with estradiol hemihydrate 10 µg was evaluated by endometrial biopsy over two 52-week clinical trials; these showed that there was no significant increase in the development of endometrial hyperplasia or cancer above the background rate of 0–1%.²⁶ Further studies have found that there was no evidence of endometrial thickening on ultrasound after 12 months usage of estradiol hemihydrate 10 µg.²⁶ A multicenter randomized double-blind parallel group study involving 230 women had treatment of estradiol hemihydrate 25 µg, estradiol hemihydrate 10 µg or placebo for 12 weeks. Results showed that estradiol hemihydrate 10 µg was as effective in treating symptoms as the estradiol hemihydrate 25 µg dose.²⁷

Stress incontinence

The prevalence of both stress urinary incontinence (UI) and urge incontinence increases steadily after the menopause, although the prevalence of stress incontinence reduces after the age of 65 but still remains far higher than premenopausal values.²⁸ Stress incontinence is defined by NICE as the involuntary urine leakage on effort or exertion or on sneezing or coughing.²⁹ It is believed that stress incontinence is due to poor urethral support. The supporting structures to the urethra and bladder neck comprised the muscles of the pelvic floor along with their intact nerve supply and the sub-urethral endopelvic fascia, which is mainly composed of collagen. Studies looking at collagen turnover have demonstrated a difference in collagen remodeling in premenopausal women with stress incontinence compared with continent controls. Stress incontinence is associated with a change in collagen content including a reduction in total collagen concentration,³⁰ a decrease in collagen cross linking³¹ and an increase in the level of collagen turnover markers.³² One hypothesis to support the use of systemic or local estrogen therapy in the management of lower urinary tract dysfunction in the postmenopausal population suggests that estrogens stimulate a strengthening in connective tissues. Six-month estrogen therapy does stimulate greater collagen degradation and the laying down of new collagen (which may be stronger) compared with placebo in postmenopausal women with stress incontinence.³³ Urodynamic evaluation has also shown that oral estrogen increases maximum urethral pressure and leads to symptomatic improvement in 65–70% of women.³⁴ However, there is no evidence to suggest whether this is attributed to changes in the muscle, connective tissue or properties in the urothelium. Unfortunately, in clinical practice, a placebo controlled study failed to show any difference in either subjective or objective symptoms of stress incontinence in postmenopausal women after six months estrogen therapy compared with controls.³⁵

Detrusor overactivity

Overactive bladder syndrome (OAB) is defined as urgency that occurs with or without urge UI and usually with frequency and nocturia.²⁹ On urodynamics, it can be identified by a rise in detrusor pressure during the filling phase. Although estrogen receptors are absent in the transitional epithelium of the dome of the bladder, they are present in the trigone.⁹ Estrogen is known to have an effect on detrusor function by modifying the muscarinic receptors³⁶ and inhibiting the movement of Ca²⁺ into muscle cells.³⁷ By this mechanism, estrogen may reduce the amplitude and frequency of spontaneous detrusor contractions and can improve the sensory threshold in some women.

There has been conflicting evidence for the use of oral estrogen therapy to improve symptoms of OAB, as much of the data comes from observational studies.³⁸ Cardozo et al.³⁹ found both subjective and urodynamic improvement in OAB symptoms in women taking estrogen compared with placebo; however, this was not statistically significant. Benness et al.⁴⁰ found a statistically significant improvement in urgency in women taking vaginal estrogen compared with placebo. More recently, a review of 10 RCTs showed that estrogen was superior to placebo when considering symptoms of urge incontinence, frequency and nocturia, although vaginal estrogen administration was found to be superior for symptoms of urgency. In those patients taking estrogens, there also was a significant increase in first sensation and bladder capacity compared with a placebo.⁴¹

Recurrent urinary tract infection

The NICE definition of recurrent urinary tract infections (RUTIs) is as follows:

Two or more episodes of UTI with acute pyelonephritis/upper urinary tract infection,

One episode of UTI with acute pyelonephritis/upper urinary tract infection plus one or more episode of UTI with cystitis/lower urinary tract infection or

Three or more episodes of UTI with cystitis/lower urinary tract infection.

The main factors associated with RUTI in postmenopausal women are UI, prolapse including cystocoele and a large post-void residual, all of which have been associated with estrogen deficiency.⁴² It is thought that estrogen therapy can reduce RUTI by improving the maturation of the vaginal and urethral epithelium⁴⁰ and reducing the vaginal pH to reverse the microbiological overgrowth that can occur during the menopause.⁴³ A review of the role of estrogens in the prevention of RUTI found that oral estrogen was as effective as oral antibiotic prophylaxis but had systemic side effects that were troublesome to the patient and so concluded that local estrogen may play a role in RUTI where antibiotic therapy cannot be tolerated by the patient.⁴⁴

Prolapse

The International Continence Society defines pelvic organ prolapse (POP) as the downward descent of pelvic organs, which results in a protrusion of the vagina and/or cervix.⁴⁵ The pelvic organs are supported by levator ani (pubococcygeus, iliococcygeus and ischiococcygeus) and suspensory (uterosacral and cardinal) ligaments, which are condensations of the endopelvic fascia. Both estrogen receptors (α and β) have been identified in the pubococcygeous muscle as well as vaginal walls and uterosacral ligaments of premenouasal women.⁴⁶ Limited evidence has shown a reduction in the number of estrogen receptors in the pelvic organs after the menopause.⁴⁷ On the strength of this, it has been suggested that an estrogen-deficient state may weaken the supporting ligaments of the pelvic floor, leading to prolapse.⁴⁷

Selective estrogen receptor modulators (SERMs) mediate their effect through the estrogen receptor. Both raloxifene and tamoxifen have been shown to be associated with a trend toward increased POP (demonstrated by the POP-Q scale).⁴⁸ Currently, there is no evidence to prove that the administration of systemic or topical estrogen therapy improves POP unless symptoms are due to atrophy rather than prolapse.¹³ However, topical estrogen cream can be of benefit in patients with ulceration secondary to procidentia or pessaries, and as a pre-treatment prior to prolapse surgery to improve vaginal tissues.

Conclusion

In conclusion, urogenital symptoms associated with estrogen deficiency remain a troubling aspect of the menopause. Topical estrogens have been shown to be effective in managing symptoms of urogenital atrophy. There are a variety of different vectors used to administer estrogen. The International Menopause Society recommends using the lowest dose wherever possible. There is no evidence to suggest estrogens are useful in the treatment of stress incontinence. However, topical estrogens do improve symptoms of urgency in women with detrusor overactivity. Topical estrogen therapy is as efficacious as prophylactic low-dose antibiotics in preventing recurrent urinary tract infections but has greater systemic side effects. For those patients who find oral antibiotics intolerable, it remains a good alternative. Estrogens are not useful in treating POP. Anecdotal evidence suggests topical therapy is useful as an adjunct to pessary usage or prior to surgery.

References

Iosif

Batra

. Estrogen receptors in the human female lower urinary tract. Am J Obstet Gynaecol 1981; 141: 817–820.

Batra

Iosif

. Progesterone receptors in the female lower urinary. J Urol 1987; 138: 1301–1307.

Teede

Vincent

. Hormone therapy – where are we now? Aust Fam Phys 2011; 40: 2011–2011.

Chollet

. Efficacy and safety of ultra-low-dose Vagifem (10 mcg). Patient Prefer Adherence 2011; 5: 571–574.

Warner

Nilsson

Gustafsson

. The oestrogen receptor family. Curr Opin Obstet Gynecol 1999; 11: 249–254.

Green

Walter

Kumar

. Human oestrogen receptor cDNA: sequence, expression and homology to v-erbA. Nature 1986; 320: 134–139.

Kuiper

Enmark

Pelto-Huikko

. Cloning of a novel oestrogen receptor expressed in rat prostrate and ovary. Proc Natl Acad Sci USA 1996; 93: 5925–5930.

Chen

Oliver

Leung

. Oestrogen receptor α and β expression in the vaginal walls and uterosacral ligaments of premenopausal and postmenopausal women. Fertil Steril 1999; 71: 1099–1102.

Blakeman

Hilton

Bulmer

. Oestrogen and progesterone receptor expression in the female lower urinary tract, with reference to oestrogen status. BJU Int 2000; 86: 32–38.

10.

Press

Nousek-Goebl

Bur

. Estrogen receptor localization in the female genital tract. Am J Pathol 1986; 123: 280–292.

11.

Cumming

Herald

Moncur

. Women’s attitudes to hormone replacement therapy, alternative treatments and sexual health. Menopause Int 2007; 13: 79–83.

12.

Iosif

. Effects of protracted administration of oestriol on the lower genitourinary tract in postmenopausal women. Acta Obstet Gynaecol Scand 1992; 251: 115–120.

13.

Nilsson

Risberg

Heimer

. The vaginal epithelium in the postmenopause – cytology, histology and pH as methods of assessment. Maturitas 1995; 21: 51–56.

14.

Bachmann

Nevadunsky

. Diagnosis and treatment of atrophic vaginitis. Am Fam Physician 2000; 61: 3090–3096.

15.

Hickey

Saunders

. Practical clinical guidelines for assessing and managing menopausal symptoms after breast cancer. Ann Oncol 2008; 19: 1669–1680.

16.

Cardozo

Bachmann

McClish

. Meta-analysis of oestrogen therapy in the management of urogenital atrophy in postmenopausal women: second report of the Hormones and Urogenital Therapy Committee. Obstet Gynaecol 1998; 92: 722–727.

17.

Johnston

Farrell

. The detection and management of vaginal atrophy. [SOGC Clinical Practice Guideline No. 145]. J Obstet Gynaecol Can 2004; 26: 503–508.

18.

Samicoe

. Urogenital ageing – a hidden problem. Am J Obstet Gynaecol 1998; 178: S245–S249.

19.

Mettler

Olsen

. Long term treatment of atrophic vaginitis with low dose oestradiol vaginal tablets. Maturitas 1991; 14: 23–31.

20.

Suckling

Lethaby

Kennedy

. Local oestrogen for vaginal atrophy in postmenopausal women. Cochrane Database Syst Rev 2003; 4: CD001500–CD001500.

21.

Crandall

. Vaginal estrogen preparations: a review of safety and efficacy for vaginal atrophy. J Womens Health (Larchmt) 2002; 11: 857–877.

22.

Naessen

Berglund

Ulmsten

. Bone loss in elderly women prevented by ultralow doses of parenteral 17 beta-estradiol. Am J Obstet Gynecol 1997; 177: 115–119.

23.

Sturdee

Panay

. on behalf of the International Menopause Society Writing Group. Recommendations for the management of postmenopausal vaginal atrophy. Climacteric 2010; 13: 509–522.

24.

Santen

Pinkerton

Conaway

. Treatment of urogenital atrophy with low dose oestradiol: preliminary results. Menopause 2002; 9: 179–187.

25.

Notelovitz

Funk

Nanavati

. Oestradiol absorption from vaginal tablets in postmenopausal women. Obstet Gynaecol 2002; 99: 556–562.

26.

Ulrich

Naessen

Elia

. Endometrial safety of ultra-low-dose Vagifem 10 microg in postmenopausal women with vaginal atrophy. Climacteric 2010; 13: 228–237.

27.

Bachmann

Lobo

Gut

. Efficacy of low-dose estradiol vaginal tablets in the treatment of atrophic vaginitis: a randomized controlled trial. Obstet Gynecol 2008; 111: 67–76.

28.

Kondo

Kato

Saito

. Prevalence of hand washing urinary incontinence in females in comparison with stress and urge incontinence. Neurourol Urodyn 1990; 9: 330–331.

29.

NICE guideline: CG40 Urinary incontinence, 23 October 2006.

30.

Keane

Sims

Abrams

. Analysis of collagen status in premenopausal nulliparous women with genuine stress incontinence. Br J Obstet Gynaecol 1997; 104: 994–998.

31.

Falconer

Blomgren

Johansson

. Different organization of collagen fibrils in stress-incontinent women of fertile age. Acta Obstet Gynecol Scand 1998; 77: 87–94.

32.

Edwall

Carlström

Jonasson

. Endocrine status and markers of collagen synthesis and degradation in serum and urogenital tissue from women with and without stress urinary incontinence. Neurourol Urodyn 2007; 26: 410–415.

33.

Jackson

James

Abrams

. The effect of oestradiol on vaginal collagen metabolism in postmenopausal women with genuine stress incontinence. Br J Obstet Gynaecol 2002; 109: 339–344.

34.

Caine M and Raz S. The role of female hormones in stress incontinence. In: Proceedings of the 16th Congress of the International Society of Urology, Amsterdam, The Netherlands.

35.

Jackson

Shepherd

Brookes

. The effect of oestrogen supplementation on post-menopausal urinary stress incontinence: a double-blind, placebo controlled trial. Br J Obstet Gynaecol 1999; 106: 711–718.

36.

Shapiro

. Effect of estrogens on the weight and muscarinic cholinergic receptor density of the rabbit bladder and urethra. J Urol 1986; 135: 1084–1087.

37.

Elliott

Castleden

Miodrag

. The direct effects of diethylstilboestrol and nifedipine on the contractile responses of isolated human and rat detrusor muscles. Eur J Clin Pharmacol 1992; 43: 149–155.

38.

Koski

Chermansky

. Does estrogen have any real effect on voiding dysfunction in women? Current Urol Rep 2011; 12: 345–350.

39.

Cardozo

Rekers

Tapp

. Oestriol in the treatment of postmenopausal urgency: a multicentre study. Maturitas 1993; 18: 47–53.

40.

Benness

Wise

Cutner

. Does low dose vaginal oestradiol improve frequency and urgency in postmenopausal women. Int Urogynaecol J 1992; 3: 281–281.

41.

Cardozo

Lose

McClish

. Estrogen treatment for symptoms of an overactive bladder, results of a meta-analysis. Int J Urogynaecol 2001; 12: V–V.

42.

Perrotta

Aznar

Mejia

. Oestrogens for preventing recurrent urinary tract infection in postmenopausal women. Cochrane Database Syst Rev 2008(2): CD005131–CD005131.

43.

Brandberg

Mellstrom

Samsioe

. Low dose oral oestriol treatment in elderly women with urogenital infections. Acta Obstet Gynaecol Scand 1987; 140: 33–38.

44.

Leckie

. What is the evidence for the role of oestrogen in the prevention of recurrent urinary tract infections in postmenopausal women? An evidence-based review. J Clin Gerontol Geriatr 2010; 1: 31–35.

45.

Abrams

Cardozo

Fall

. The standardisation of terminology in lower urinary tract function: report from the standardisation sub-committee of the International Continence Society. Neurourol Urodyn 2002; 21: 167–168.

46.

Ingelman-Sundberg

Rosen

Gustafsson

. Cytosol estrogen receptors in the urogenital tissues in stress-incontinent women. Acta Obstet Gynecol Scand 1981; 60: 585–586.

47.

Lang

Zhu

Sun

. Oestrogen levels and oestrogen receptors in patients with stress urinary incontinence and pelvic organ prolapse. Int J Gynaecol Obstet 2003; 80: 35–39.

48.

Vardy

Scotti

Lindsay

. Short term urogenital effects of raloxifene, tamoxifen and estrogen. Int Urogynecol J 2000; 11(S1): O11–O11.