Presented at the NIH State-of-the-Science Conference: Prevention of Fecal and Urinary Incontinence in Adults - Bethesda, MD - December 10-12, 2007

Hormones mediate numerous effects in women. Because many women first notice urinary incontinence (UI) in their late 40s and early 50s, the same time period in which major hormonal changes occur, estrogens were proposed as a logical treatment for UI. Indeed, there is ample biologic plausibility for a link between estrogen depletion and UI.¹ The urethra, bladder, and pelvic connective tissue and muscles have a rich supply of estrogen receptors. Estrogen increases vaginal maturation, periurethral blood supply, alpha-adrenergic receptor sensitivity, and sympathetic nerve density in the pelvis and inhibits bladder contractions in animals.

Clinical findings also suggested that hormones play a role in pelvic floor function. One-third of women in one study reported worsening bladder symptoms before menstruation. In a large population-based study, self-reported UI was increased in women who had midcycle bleeding or who recently noted decreased bleeding duration.²

In concordance with this basic science evidence and with clinical anecdotes, several uncontrolled studies with subjective outcomes showed that estrogen therapy of various types decreased UI, urgency, and frequency.

However, the early promise of estrogen’s role as a therapeutic agent was not borne out by subsequent studies. Larger cohort studies found that women on estrogen had more UI than those who did not take this hormone.³ In the 1980s and 1990s, many physicians prescribed estrogens to treat incontinence, however, such evidence cannot be used to conclude that estrogens caused the incontinence.

The most recent Cochrane review on this topic, last amended in 2003, concluded, based on 28 trials, with 2,926 women, available at the time, that about 50% of women treated with estrogen were cured or improved compared with about 25% of those on placebo.⁴ Given the timing of this review, it necessarily did not include five large, randomized trials that collectively enrolled 30,914 women.^5–9 These carefully done randomized trials, that compared estrogen to placebo in a masked fashion, were strikingly consistent in their conclusions: at usual doses, estrogens, with or without progestins, increase UI severity and incidence, whereas low-dose transdermal estrogen has no effect.

Why might estrogen actually cause worsening of UI? Although estrogens are poorly studied to date, they appear to reduce collagen in the urethra and pelvic floor and increase collagen turnover.^10,11 In addition, women with stress urinary incontinence (SUI) may differ in important ways from continent women. For example, extracellular matrix protein expressions have been shown to be hormonally regulated in vaginal wall fibroblasts and also to differ between women with and without SUI.¹² In a study that found lower rates of estrogen-receptor staining in connective tissue, smooth muscle, and nerve fibers in women with SUI than in controls, the authors suggested that having fewer estrogen receptors in pelvic floor tissues might be related to SUI and also might explain why estrogen therapy is not effective in treating this condition.¹³

Selective Estrogen-Receptor Modulators (SERMs) impact pelvic floor function in different ways. Randomized trials comparing raloxifene to estrogen or placebo to date have shown no effect on either UI or pelvic organ prolapse.¹⁴ In contrast, an investigational study of levormeloxifene was halted after 10 months because of a marked increase in both UI and uterovaginal prolapse in women receiving this SERM compared to placebo.¹⁵

Androgens have anabolic effects on skeletal muscle and theoretically might improve pelvic floor muscles.¹⁶ Castrating rats and thus removing their androgen source produced the same degree of myofiber atrophy in levator ani muscles as denervation alone.¹⁷ Women also have androgen receptors in the levator ani muscles and cardinal ligaments. Whether androgens are useful for treating pelvic floor disorders has not been studied.

Other hormones, such as relaxin, may also play a role in maintaining continence, particularly during pregnancy.¹⁸

Very few studies have assessed the impact of hormones on either pelvic organ prolapse or fecal incontinence (FI). In an ancillary study of the Women’s Health Initiative, women randomly assigned to estrogen plus progestin had similar prevalence and incidence rates of pelvic organ prolapse as those assigned to placebo.¹⁹ In a small cohort study, after 6 months of estrogen therapy, anal resting and squeeze pressures improved in women with FI, but only one-fourth became asymptomatic.²⁰

Future studies are needed to answer the following questions:

• Is the effect of hormones on UI mediated through the lower urinary tract or another route?
• What is the role of topical estrogens and androgens?
• Can SERMs or Selective Androgen-Receptor Modulators (SARMs) be developed to treat pelvic floor disorders?
• From an ultrastructural point of view, how do different hormones affect bladder, bowel, and pelvic function?
• Is there a critical window at which hormone therapy might have positive versus negative effects?
• Do xenoestrogens, present in many household and industrial products, affect bladder or bowel function?
• What role do other hormones, such as relaxin, play on pelvic floor function?
• Can we identify a subgroup of women who have UI who will respond to targeted hormonal therapy?

Understanding the answers to these questions through basic and clinical research has the potential to affect the lives of millions of women worldwide.

Written by: Nygaard I, M.D., M.S.

References

1. Griebling TL, Nygaard IE. The role of estrogen replacement therapy in the management of urinary incontinence and urinary tract infection in postmenopausal women. Endocrinol Metab Clin North Am. 1997;26:347–360.
2. Hvidman L, Foldspang A, Mommsen S, Bugge Nielsen J. Menstural cycle, female hormone use and urinary incontinence in premenopausal women. Int Urogynecol J Pelvic Floor Dysfunct. 2003;14:56–61.
3. Grodstein F, Lifford K, Resnick NM, Curhan GC. Postmenopausal hormone therapy and risk of developing urinary incontinence. Obstet Gynecol. 2004;103:254–260.
4. Moeher B, Hextall A, Jackson S. Oestrogens for urinary incontinence in women. Cochrane Database Syst Rev. 2003;2:CD001405.
5. Hendrix SL, Cochrane BB, Nygaard IE. Effects of estrogen with and without progestin on urinary incontinence. JAMA. 2005;293:935–948.
6. Waetjen LE, Brown JS, Vittinghoff E, et al. The effect of ultralow-dose transdermal estradiol on urinary incontinence in postmenopausal women. Obstet Gynecol. 2005;106:946–952.
7. Steinauer JE, Waetjen LE, Vittinghoff E. Postmenopausal hormone therapy: does it cause incontinence? Obstet Gynecol. 2005;106:940–945.
8. Vestergaard P, Hermann AP, Stilgren L, et al. Effects of 5 years of hormonal replacement therapy on menopausal symptoms and blood pressure—a randomised controlled study. Maturitas. 2003:46;123–132.
9. Goldstein SR, Johnson S, Watts NB, Ciaccia AV, Elmerick D, Murram D. Incidence of urinary incontinence in postmenopausal women treated with raloxifene or estrogen. Menopause. 2005;12:160–164.
10. Edwall L, Carlstrom K, Jonasson AF. 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.
11. Jackson S, James M, Abrams P. The effect of oestradiol on vaginal collagen metabolism in postmenopausal women with genuine stress incontinence. BJOG. 2002;109:339–342.
12. Wen Y, Polan ML, Chen B. Do extracellular matrix protein expressions change with cyclic reproductive hormones in pelvic connective tissue from women with stress urinary incontinence? Hum Reprod. 2006;21:1266–1273.
13. Zhu L, Lang J, Feng R, Chen J, Wong F. Estrogen receptor in pelvic floor tissues in patients with stress urinary incontinence. Int Urogynecol J Pelvic Floor Dysfunct. 2004;15:340–343.
14. Waetjen LE, Brown JS, Modelska K. Effect of raloxifene on urinary incontinence: a randomized controlled trial. Obstet Gynecol. 2004;103:261–266.
15. Goldstein SR, Nanavati N. Adverse events that are associated with the selective estrogen receptor modulator levormeloxifene in an aborted phase III osteoporosis treatment study. Am J Obstet Gynecol. 2002;187:521–527.
16. Ho MH, Bhatia NN, Bhasin S. Anabolic effects of androgens on muscles of female pelvic floor and lower urinary tract. Curr Opin Obstet Gynecol. 2004;16:405–409.
17. Nnodim JO. Quantitative study of the effects of denervation and castration on the levator ani muscle of the rat. Anat Rec. 1999;255:324–333.
18. Kristiansson P, Samuelsson E, von Schoultz B, Svardsudd K. Reproductive hormones and stress urinary incontinence in pregnancy. Acta Obstet Gynecol Scand. 2001;80:1125–1130.
19. Nygaard I, Bradley C, Brandt D; Women’s Health Initiative. Pelvic organ prolapse in older women: prevalence and risk factors. Obstet Gynecol. 2004;104:489–497.
20. Donnelly V, O’Connell PR, O’Herlihy C. The influence of oestrogen replacement on faecal incontinence in postmenopausal women. Br J Obstet Gynaecol. 1997;104:311–314.

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