1. Urogenital symptoms in the menopause Göran Samsioe

2. Urinary incontinence Definition: any involuntary leakage of urine Prevalence rate ~ 30% (females, US population) Women are more likely to be incontinent than men –4:1 < 60 years of age –2:1 ≥ 60 years of age Hunskaar S. In Abrams P, et al., eds. Incontinence, 3rd edn. Paris: Health Publication, 2005:255–312

3. Urinary incontinence in relation to other chronic diseases 1 Hampel C, et al. Urology 1997;50(suppl 6A):4–14; 2 American Heart Association. Electronic Citation, 2001; 3 American Family Physician. Electronic Citation, 2001; 4 NIDDK. Electronic Citation, 2001 1 2 3 4

4. Urinary incontinence is an underreported problem for many women Despite high prevalence and negative impact on quality of life, consultation rates remain low: –Only 33–45% of incontinent women consult a doctor –Many women wait for years before seeking treatment –Reasons for lack of treatment seeking: Shame, embarrassment Misconception that incontinence is normal part of aging/delivery Lack of knowledge about treatment options Fear that surgery is only available therapy Hunskaar S, et al. BJU Int 2004;93:324-30; Kinchen KS, et al. J Womens Health 2003;12:687-98; Shaw C, et al. Fam Pract 2001;18:48-52.

5. Women often wait very long before they seek treatment Symptom duration before consulting a physician % of incontinent women There was no major difference in time to first consultation between the different types of urinary incontinence Sykes D, et al. Maturitas 2005;52(Suppl 2):13–23 0–2 years 3–5 years 6–10 years 11 years or more

6. Direct cost of urinary incontinence in the United States 16.3 billion (1995 US Dollars) –76% of direct cost was for women ($12.4 billion) –24% of direct cost was for men ($3.8 billion) –Costs for women over 65 years were twice the costs for those under 65 years –Largest cost category was for routine care (70% of costs for women) –Only 9% of total costs for women were for treatment, and only 1% of total costs for women were for diagnosis and evaluation Wilson L, et al. Obstet Gynecol 2001;98:398–406

7. Urinary incontinence: treatment costs in the USA Wilson L, et al. Obstet Gynecol 2001;98:398–406

8. Type of surgeryCostMean LOS (£)(days) Colposuspension13177.1 Tension-free vaginal tape (TVT)10142.9 Traditional sling procedures13407.2 Injectables13052.0 Cost of stress urinary incontinence in the UK Cost of stress urinary incontinence in the UK Cost for surgical procedures Cody J, et al. Systemic review of the clinical effectiveness and cost-effectiveness of tension-free vaginal tape (TVT) for treatment of urinary stress incontinence. Report commissioned by NHS R&D HTA Programme on behalf of the National Institute for Clinical Excellence, August 2002.

9. Normal micturition cycle Storage phase Emptying phase Bladder pressure Storage phase Detrusor relaxes + Urethra contracts + Pelvic floor contracts Bladder filling First sensation to void Detrusor relaxes + Urethra contraction increases + Pelvic floor contracts Bladder filling Detrusor relaxes + Urethra contracts + Pelvic floor contracts Normal desire to void Detrusor contracts + Urethra relaxes + Pelvic floor relaxes MICTURITION Elbadawi A. Neurourology and Urodynamics: Principles & Practice, 1986

10. …during an activity such as coughing, sneezing, laughing, running, exercising or lifting?” …with such a sudden strong need to pass water that you could not reach the toilet in time?” Identify the predominant symptom: stress/urge incontinence questionnaire (S/UIQ) “How many times in the last seven days have you had an accidental leakage of urine onto your clothing, underwear, or pad…?” Bent AE, et al. Obstet Gynecol 2005;106:767–73 STRESS urinary incontinence URGE urinary incontinence

11. Types of urinary incontinence Complaint of involuntary leakage on effort or exertion, or on sneezing or coughing Stress urinary incontinence (SUI) Complaint of involuntary leakage accompanied by or immediately preceded by urgency Urge urinary incontinence (UUI) Mixed urinary incontinence (MUI) Complaint of involuntary leakage associated with urgency and also with exertion, effort, sneezing and coughing Abrams P. In Abrams P, et al., eds. Incontinence, 3rd edn. Paris: Health Publication, 2005:1589–630

12. Stress incontinence, urge incontinence and overactive bladder are different Complaint of involuntary leakage on sneezing, coughing, laughing, lifting, or exercising Stress urinary incontinence (SUI) Complaint of involuntary leakage preceded by a strong desire to void (urgency) Urge urinary incontinence (UUI) Overactive bladder (OAB) Urgency, with or without UUI, usually with frequency and nocturia Abrams P, et al. Neurourol Urodyn 2002;21:167–78

13. Abrams P, et al. Neurourol Urodyn 2002;21:167–78; Hampel C, et al. Urology 1997;50(suppl 6A):4 – 14; DeMarco EF, Treatment of the Postmenopausal Woman: Basic and Clinical Aspects. 1999:213–27; Thor KB, et al. J Pharmacol Exp Ther 1995;274(2):1014–24; Morrison J, et al. Incontinence 2005:363–422 Stress and urge urinary incontinence differences Stress and urge urinary incontinence differences SUIUUI SymptomsComplaint of involuntaryComplaint of involuntary leakage on sneezing,leakage coughing, laughing, liftingpreceded by a strong or exercisingdesire to void CausesInsufficient urethral Uncontrolled bladder closure contractions ReceptorsSerotonin andCholinergic noradrenalinemuscarinic

14. Difference between stress and urge urinary incontinence URGE urinary incontinence result of involuntary BLADDER contractions STRESS urinary incontinence result of insufficient URETHRAL closure Abrams P, et al. Urology 2003;61:37–49

15. Other conditions causing urinary incontinence Detrusor overactivity Overflow Ectopic ureter* Urethral diverticulum* Fistula* *Very rare

16. Urinary incontinence in women increases with age n = 27,936 Hannestad YS, et al. J Clin Epidemiol 2000;53:1150–7 Total25–2935–3945–4955–5965–6975–7985–89

17. Overall prevalence of urinary incontinence in women * Fukui, 1986; ** Hampel, et al. 1997 Asia (APCAB)JapanUnited StatesEurope * **

18. Prevalence of urinary incontinence in women in Asian countries Apcab Study; Lapitan MC. IJUG 2001;12:226

19. Stress incontinence and HRT Randomized controlled trials show no improvement or even worsening of stress incontinence with use of HRT Some trials show improvement, often in combination with other regimens Several studies show HRT as a risk factor for urinary incontinence Role of progestogens?

20. Urinary incontinence and HRT – what do we know? Estrogen receptors in vagina, urethra, bladder, pelvic floor muscles and ligaments Prevalence of urge incontinence increases linearly with age Prevalence of stress incontinence increases up to perimenopause and then remains unchanged Estrogen seems to reduce urinary tract infections, urgency, urge incontinence, nocturia and frequency Samsioe G. In Lobo R, ed. Treatment of the Postmenopausal Woman, 3rd edn. Academic Press, 2008:251–61

21. Why might HRT use be associated with an increase in stress incontinence? Possible explanations: Incontinent women (mostly stress-) are prescribed HRT by a physician who believes that estrogens are effective in all forms of incontinence HRT actually increases the risk for stress incontinence by collagen synthesis Incontinent women suffer more from other climacteric symptoms than continent

22. Collagen hypothesis Estrogen deprivation decreases collagen synthesis and turnover Newly formed collagen molecules have few secondary bridges between protein chains such as disulfuric and other secondary bridges ’Old’ collagen has a huge numberof secondary bridges and is therefore more rigid Stress incontinence decreases with estrogen loss and HT will enhance it Urge incontinence increases with estrogen decline due mainly to atrophy which leads to increased susceptibility of nerve endings

23. Social embarrassment has the highest negative impact on quality of life Impact for patients with severe UI symptoms Monz B, et al. Maturitas 2005;52(Suppl 2):24–34

24. Restraint on exercise most pronounced in women with MUI and SUI Impact for patients with severe UI symptoms Monz B, et al. Maturitas 2005;52(Suppl 2):24–34

25. Onuf’s nucleus Nerves, neurotransmitters and receptors involved in continence/voiding

26. Urge incontinence Bladder training Pelvic floor exercise Surgery

27. SNRI analogues Theoretically very interesting SSRI + NRI do not work. Must be single molecule Duloxetine is the sole agent currently approved Too narrow therapeutic window Improved efficacy Fewer (milder) side-effects Less central and more peripherel effects More selective for the GU tract

28. Recommendations from International Consultation on Incontinence (ICI) Initial management of urinary incontinence in women HISTORY/SYMPTOM ASSESSMENT Adapted from Abrams P, et al. In Abrams P, et al. Incontinence, 3rd edn. Paris: Health Publication, 2005:1589–630 CLINICAL ASSESSMENT PRESUMED DIAGNOSIS TREATMENT *Subject to local regulatory approval Incontinence on physical activity Incontinence with mixed symptoms Incontinence with urgency/frequency EVALUATION STRESS INCONTINENCE presumed due to sphincteric incompetence MIXED INCONTINENCEURGE INCONTINENCE presumed due to detrusor overactivity Treat predominant problem first Assess estrogen status and treat as appropriate Lifestyle interventions Pelvic floor muscle training, bladder retraining Other physical therapies Devices Dual serotonin and noradrenaline reuptake inhibitors* Failure SPECIALIZED MANAGEMENT Antimuscarinics Failure

29. Lifestyle interventions Pelvic floor muscle training SNRI Surgery Stress urinary incontinence Lifestyle interventions Pelvic floor muscle training Antimuscarinics Urge urinary incontinence Treat predominant symptom first Mixed urinary incontinence Andersson KE, et al. In Abrams P, et al. Incontinence, 3rd edn. Paris: Health Publication, 2005:809–54 Abrams P, et al. In Abrams P, et al. Incontinence, 3rd edn. Paris: Health Publication, 2005:1589–630 Recommendations from ICI: Condition-specific treatment

30. Overactive bladder Germany, Italy, Spain, Sweden and UK (= USA) 20.2 million ≥ 40 years had symptoms in 2000 Expected to rise to 25.5 million by 2020 Total costs in 2000, €4.2 billion Expected to rise by 26% to €5.2 billion in 2020 Major cost: incontinence pads (63%) Reeves P, et al. Eur Urol 2006;50:1050–7

31. Overactive bladder Antimuscarinic drugs (M2) and M3 specific: darifenacin, solifenacin Tolterodin Calcium channel blockers still under debate Oxybutunin transdermal patch may widen its therapeutic window Botulinum toxin type A Surgical procedures Low-dose (topical) estrogen

32. Botulinum toxin type A To be injected at multiple sites into the detrusor 23 men + 77 women, mean age 63; 12 weeks 88% improved bladder function Urgency vanished (82%). Incontinence resolved (86%) Mean frequency decreased from 14 to 7 per day Nocturia decreased from 4 to 1.5 episodes Bladder capacity increased from 246 to 381 ml Schmid DM, et al. J Urol 2006;176:177–85

33. Pelvic floor muscle training (PFMT) PFMT is effective, but not suitable for everyone: –Low long-term compliance 70% of women continue PFMT at least weekly after 5 years, but only 28% do so after 15 years Many are unaware that PFMT should be carried out indefinitely –Not everyone benefits from PFMT Treatment failure more likely in women with: –≥ 2 daily leakages before treatment –Baseline positive stress test result at first cough –Chronic use of psychotropic drugs Many are unsure how to perform PFMT correctly Bø K, Talseth T. Obstet Gynecol 1996;87:261–5; Bø K, et al. Obstet Gynecol 2005;105:999–1005; Cammu H, et al. Am J Obstet Gynecol 2004;191:1152–7; Chiarelli P, et al. Neurourol Urodyn 2003;22:246–9

34. *As measured by the Sexual Activity Questionnaire. This scale has not been validated n = 79 Changes in sexual arousal after menopause* Avis NE, et al. Menopause 2000;7:297–309

35. Effect of menopausal transition on parameters of sexual functioning Effect of menopausal transition on parameters of sexual functioning Cross-sectional data reported from a longitudinal, population-based cohort of Australian women, 45–55 years of age n = 438; SPEQ, Shortened version of the Personal Experiences Questionnaire *p < 0.05 for postmenopausal compared with perimenopausal women * * * * * Dennerstein L, et al. Fertil Steril 2001;76:456–60

36. Physiology of vulvovaginal changes: structure and histology Loss of collagen and adiposity in vulva 1 Clitoral glans loses protective covering 2 Vaginal surface thinner, less elastic; more friable 2 1 Oriba HA, Maibach HI. Acta Derm Venereol 1989;69:461 – 5; 2 Bachmann GA, et al. In Treatment of the Postmenopausal Woman: Basic and Clinical Aspects. 2nd edn. 1999:195–201

37. Effects of loss of estrogen on vagina Premenopause –Well estrogenized, multi-layered squamous epithelium. Good blood supply, moist, superficial cells rich in glycogen. pH 3.5–4.5 Postmenopause –Estrogen deficiency, atrophy, reduced blood supply, dry, loss of glycogen. pH 5.0–5.4

38. Symptoms Presenting genital symptoms and physical signs of vaginal atrophy Signs on physical exam Pale, smooth, or shiny vaginal epithelium Loss of elasticity or turgor of skin Sparsity of pubic hair Dryness of labia Fusion of labia minora Introital stenosis Friable, unrugated epithelium Pelvic organ prolapse Rectocele Vulvar dermatoses Vulvar lesions Vulvar patch erythema Petechiae of epithelium Dryness Itching Burning Dyspareunia Burning leukorrhea Vulvar pruritus Feeling of pressure Yellow malodorous discharge Adapted from Bachmann GA, Nevadunsky NS. Am Fam Physician 2000;61:3090–6

39. Lower estrogen levels are associated with increased prevalence of sexual problems n = 93; significance not reported Sarrel PM. J Womens Health Gend Based Med 2000;9:S25–32; Adapted from Sarrel PM. Obstet Gynecol 1990;75:26S–30S

40. Prevalence of superficial dyspareunia and vulvovaginal atrophy by menopausal age Atrophy increased significantly with increase in menopausal age (p < 0.001) Perimenopause (n = 133) 0–1 year (n = 52) 2–3 years (n = 39)  4 years (n = 67) Adapted from Versi E, et al. Int Urogynecol J 2001;12:107–10

41. Women's HOPE study Women's HOPE study Effect of CEE, CEE/MPA on vaginal maturation* *p < 0.05 vs. baseline and placebo for all active treatment groups; † p < 0.05 vs. CEE 0.625; ‡ p < 0.05 vs. CEE 0.3/MPA 1.5 Superfical cells (median) (%) Treatment groups 0.625 mg0.625 /2.5 mg 0.45 mg0.45 /2.5 mg 0.45 /1.5 mg 0.3 mg0.3 /1.5 mg PlaceboCEECEE/MPA Utian WH, et al. Fertil Steril 2001;75:1065–79 †‡ † ‡ †

42. Vaginal lubricants and moisturizers Multiple vaginal moisturizers and lubricants are available over the counter Selection of product is based on individual preference Examples of over-the-counter lubricants include Astroglide  and Replens ®

43. Treatment options for sexual dysfunction/complaints Sex therapy/couples’ therapy Hormone therapy –Topical estrogen –Systemic estrogen –Estrogen ± progestin –Estrogen/androgen* –Androgens* Lubricants/moisturizers *Not FDA approved for treatment of sexual complaints