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Discussion: The effect of estrogens
DISCUSSION:
THE EFFECT OF ESTROGENS LINDA
the genital and urinary tracts derive from a comIbothnmonwomen, embryologic origin, the primitive urogenital sinus, and are sensitive to the effects of female sex steroids. Estrogen and progesterone receptors are present in the vagina, urethra, bladder, and pelvic floor and symptomatic, cytologic, and urodynamic changes in the lower urinary tract (LUT) have been demonstrated during the menstrual cycle, in pregnancy, and following the menopause. Deteriorating ovarian function at the time of the menopause results in an increased incidence of urinary symptoms, including frequency, nocturia, urgency, incontinence, and dysuria, as well as the development of recurrent urinary tract infections. These symptoms may present as “the urge syndrome” and estrogens have been prescribed, usually empirically, in an attempt to improve this distressing symptom complex. Unfortunately, there have been few controlled studies of estrogen therapy reported in the literature, despite the known large placebo response in the treatment of urge incontinence. Samsioe et al.1 entered 34 women 75 years of age into a double-blind, placebo-controlled, cross-over study of oral estriol (3 mg/day) for 3 months. Despite the lack of objective assessment, they found that urge incontinence and mixed incontinence were improved by estriol, although in women with stress incontinence there was no difference between estriol and placebo. Unfortunately, we have not been able to replicate these results. In a double-blind, randomized, placebo-controlled, multicenter study involving 64 postmenopausal women with “the urge syndrome,” 3 mg/day oral estriol produced both subjective and objective improvement in urinary symptoms, particularly urgency and nocturia, but was not significantly better than placebo.2 IosiP has shown that urogenital atrophy, a late manifestation of estrogen deficiency, is completely relieved only after 1 year of treatment with 0.5 mg estriol suppositories and that symptoms recur with discontinuation of treatment. It is quite possible that 3 mg/day oral estriol is an inappropriate estrogen, given by the wrong route of administration, or given at too low a dose. It is unclear whether low-dose topical therapy, which improves genital atrophy without significant endometrial stimulation, is sufficient to treat urinary symptoms. Indeed, it is possible that estrogen is actually no better than placebo for the management of postmenopausal women with the urge syndrome, although Fantl et a1.4 have suggested that estrogen supplementation raises the sensory threshold of the bladder. We have subsequently assessed the efficacy of sustainedrelease 17P-estradiol vaginal tablets in the management of postmenopausal urinary urgency (Benness CJ, Wise BG, and Cardozo LD: unpublished data). These tablets are well absorbed from the vagina and have been shown to induce matFrom the King’s College Hospital, London, United Kingdom Reprint requests: Prof. Linda Cardozo, Professor of LJrogynecolony, King’s College Hospital, 8 Devonshire Place, London WIN 1RR, United Kingdom
0
1997, ELSEVIER SCIENCE INC.
ALL RIGHTS RESERVED
CARDOZO
uration of the vaginal epithelium within 14 days.5 In a randomized study, 110 postmenopausal women suffering from urgency received either 25 /@day 17/3-estradiol or a matching placebo for 6 months. The women were divided into 3 groups according to their urodynamic diagnosis: detrusor instability, sensory urgency, or normal urodynamics. At the end of the treatment period, the only significant difference between active and placebo therapy was the improvement in the symptom of urgency in those women with a diagnosis of sensory urgency, which responded better to estradiol than to placebo. It is possible that localized atrophy causes or aggravates sensory urgency and therefore topical estrogen therapy is useful for its management. In a 12-week double-blind, randomized, placebo-controlled trial that also used 25 pg/day 17P-estradiol, Eriksen and Rasmussen showed a significant improvement in the LUT symptoms of frequency, urgency, urge incontinence, and stress incontinence with active treatment as compared to placebo. Unfortunately, they did not select women on the basis of their urinary symptoms, and the study lacked the benefit of objective urodynamic assessment. At present, our knowledge regarding the effect of estrogens on the “overactive bladder” is incomplete. It would appear that urogenital atrophy responds to long-term, low-dose local therapy, which ameliorates some of the irritative LUT symptoms. However, it is unlikely that the urge syndrome in postmenopausal women can be treated by low-dose therapy, and it remains to be seen whether the efficacy of systemic estrogen therapy can be proven. We currently have a double-blind, randomized, placebo-controlled trial of 25 mg estradiol pellets in progress to try to answer this question. REFERENCES 1. Samsioe G, Jansson I, Mellstrom D, and Svandborg A: Occurrence, nature and treatment of urinary incontinence in a 70 year old female population. Maturitas 7: 335-342, 1985. 2. Cardozo LD, Reekers H, Tapp A, et al: Estriol in the treatment of postmenopausal urgency-a multicentre study. Maturitas 18: 47-53, 1993. 3. Iosif CS: Effects of protracted administration of estriol on the lower genitourinary tract in postmenopausal women. Arch Gynaecol Obstet 251: 115-120, 1992. 4. Fantl JA, Wyman JF, Anderson RL, Matt DW, and Bump RC: Postmenopausal urinary incontinence: comparison between non-estrogen supplement and estrogen-supplemented women. Obstet Gynecol71: 823-826,1988. 5. Nilsson K, and Heimer G: Low dose estradiol in the treatment of urogenital estrogen deficiency-a pharmacokinetic and pharmacodynamic study. Maturitas 15: 121-127, 1992. 6. Eriksen PS, and Rasmussen H: Low-dose 17 beta estradiol vaginal tablets in the treatment of atrophic vaginitis: a double-blind placebo controlled study. Eur J Obstet Gynaecol Reprod Bio144: 137-144, 1992.
0090-4295/97/$17.00 PII SOO90-4295(97)00569-7
85
THE EFFECT OF ESTROGENS LINDA
the genital and urinary tracts derive from a comIbothnmonwomen, embryologic origin, the primitive urogenital sinus, and are sensitive to the effects of female sex steroids. Estrogen and progesterone receptors are present in the vagina, urethra, bladder, and pelvic floor and symptomatic, cytologic, and urodynamic changes in the lower urinary tract (LUT) have been demonstrated during the menstrual cycle, in pregnancy, and following the menopause. Deteriorating ovarian function at the time of the menopause results in an increased incidence of urinary symptoms, including frequency, nocturia, urgency, incontinence, and dysuria, as well as the development of recurrent urinary tract infections. These symptoms may present as “the urge syndrome” and estrogens have been prescribed, usually empirically, in an attempt to improve this distressing symptom complex. Unfortunately, there have been few controlled studies of estrogen therapy reported in the literature, despite the known large placebo response in the treatment of urge incontinence. Samsioe et al.1 entered 34 women 75 years of age into a double-blind, placebo-controlled, cross-over study of oral estriol (3 mg/day) for 3 months. Despite the lack of objective assessment, they found that urge incontinence and mixed incontinence were improved by estriol, although in women with stress incontinence there was no difference between estriol and placebo. Unfortunately, we have not been able to replicate these results. In a double-blind, randomized, placebo-controlled, multicenter study involving 64 postmenopausal women with “the urge syndrome,” 3 mg/day oral estriol produced both subjective and objective improvement in urinary symptoms, particularly urgency and nocturia, but was not significantly better than placebo.2 IosiP has shown that urogenital atrophy, a late manifestation of estrogen deficiency, is completely relieved only after 1 year of treatment with 0.5 mg estriol suppositories and that symptoms recur with discontinuation of treatment. It is quite possible that 3 mg/day oral estriol is an inappropriate estrogen, given by the wrong route of administration, or given at too low a dose. It is unclear whether low-dose topical therapy, which improves genital atrophy without significant endometrial stimulation, is sufficient to treat urinary symptoms. Indeed, it is possible that estrogen is actually no better than placebo for the management of postmenopausal women with the urge syndrome, although Fantl et a1.4 have suggested that estrogen supplementation raises the sensory threshold of the bladder. We have subsequently assessed the efficacy of sustainedrelease 17P-estradiol vaginal tablets in the management of postmenopausal urinary urgency (Benness CJ, Wise BG, and Cardozo LD: unpublished data). These tablets are well absorbed from the vagina and have been shown to induce matFrom the King’s College Hospital, London, United Kingdom Reprint requests: Prof. Linda Cardozo, Professor of LJrogynecolony, King’s College Hospital, 8 Devonshire Place, London WIN 1RR, United Kingdom
0
1997, ELSEVIER SCIENCE INC.
ALL RIGHTS RESERVED
CARDOZO
uration of the vaginal epithelium within 14 days.5 In a randomized study, 110 postmenopausal women suffering from urgency received either 25 /@day 17/3-estradiol or a matching placebo for 6 months. The women were divided into 3 groups according to their urodynamic diagnosis: detrusor instability, sensory urgency, or normal urodynamics. At the end of the treatment period, the only significant difference between active and placebo therapy was the improvement in the symptom of urgency in those women with a diagnosis of sensory urgency, which responded better to estradiol than to placebo. It is possible that localized atrophy causes or aggravates sensory urgency and therefore topical estrogen therapy is useful for its management. In a 12-week double-blind, randomized, placebo-controlled trial that also used 25 pg/day 17P-estradiol, Eriksen and Rasmussen showed a significant improvement in the LUT symptoms of frequency, urgency, urge incontinence, and stress incontinence with active treatment as compared to placebo. Unfortunately, they did not select women on the basis of their urinary symptoms, and the study lacked the benefit of objective urodynamic assessment. At present, our knowledge regarding the effect of estrogens on the “overactive bladder” is incomplete. It would appear that urogenital atrophy responds to long-term, low-dose local therapy, which ameliorates some of the irritative LUT symptoms. However, it is unlikely that the urge syndrome in postmenopausal women can be treated by low-dose therapy, and it remains to be seen whether the efficacy of systemic estrogen therapy can be proven. We currently have a double-blind, randomized, placebo-controlled trial of 25 mg estradiol pellets in progress to try to answer this question. REFERENCES 1. Samsioe G, Jansson I, Mellstrom D, and Svandborg A: Occurrence, nature and treatment of urinary incontinence in a 70 year old female population. Maturitas 7: 335-342, 1985. 2. Cardozo LD, Reekers H, Tapp A, et al: Estriol in the treatment of postmenopausal urgency-a multicentre study. Maturitas 18: 47-53, 1993. 3. Iosif CS: Effects of protracted administration of estriol on the lower genitourinary tract in postmenopausal women. Arch Gynaecol Obstet 251: 115-120, 1992. 4. Fantl JA, Wyman JF, Anderson RL, Matt DW, and Bump RC: Postmenopausal urinary incontinence: comparison between non-estrogen supplement and estrogen-supplemented women. Obstet Gynecol71: 823-826,1988. 5. Nilsson K, and Heimer G: Low dose estradiol in the treatment of urogenital estrogen deficiency-a pharmacokinetic and pharmacodynamic study. Maturitas 15: 121-127, 1992. 6. Eriksen PS, and Rasmussen H: Low-dose 17 beta estradiol vaginal tablets in the treatment of atrophic vaginitis: a double-blind placebo controlled study. Eur J Obstet Gynaecol Reprod Bio144: 137-144, 1992.
0090-4295/97/$17.00 PII SOO90-4295(97)00569-7
85