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Nocturia in women
AJOG REVIEWS
Nocturia in women Gunnar Lose MD, DMSc,a Lars Alling-Møller MD, PhD,a and Poul Jennum MD, DMScb Glostrup, Denmark Frequent episodes of nocturnal voiding disturb the sleep and well-being of women. The prevalence of nocturia is more common in parous women and shows a linear increase with age, occurring in more than 50% of women ≥80 years old. Nocturia has a multifactorial origin that develops through a pathophysiologic mechanism of nocturnal polyuria or low functional bladder capacity or through a combination of both. Nocturia is also one of the most bothersome lower urinary tract symptoms and has a significant impact on quality of life. However, most women accept symptoms of nocturia as part of the aging process and few seek medical help. Treatments for nocturia (behavior modification and pharmacologic treatment) are effective in many cases, although it is important to tailor treatment to the underlying pathophysiology. This review discusses the impact of nocturia on women and reviews the current situation regarding the definition, prevalence, diagnosis, and treatment of this condition in this patient population. (Am J Obstet Gynecol 2001;185:514-21.)
Key words: Female, nocturia, prevalence, quality-of-life, therapy
Women of all ages have lower urinary tract symptoms, the most common of which is leakage and frequent nighttime voiding (nocturia),1 yet most accept their symptoms as part of the aging process. Nocturia itself has now been recognized as a symptomatic urinary disorder of multifactorial origin that affects women to the same extent as men.1-3 This review discusses the impact of nocturia on women and reviews the current situation regarding the definition, prevalence, diagnosis, and treatment of this condition in this patient group. Nocturia refers to waking at night to void. Currently, however, there is no standard definition for nocturia. Until general consensus is achieved there will be wide variation in the prevalence rates reported, and the condition will remain underdiagnosed but undoubtedly common. Several definitions have been proposed for nocturia, some involve measuring urine output during a fixed nighttime period (eg, nocturnal urine volume ≥6.4 mL/kg4 or nocturnal urine volume exceeding one third
From the Department of Obstetrics and Gynecologya and the Department of Clinical Neurophysiology, Sleep Laboratory,b Glostrup County Hospital, University of Copenhagen. Reprint requests: Gunnar Lose, Department of Obstetrics and Gynecology, Glostrup County Hospital, University of Copenhagen, Nordre Ringvej, DK-2600 Glostrup, Denmark. Copyright © 2001 by Mosby, Inc. 0002-9378/2001 $35.00 + 0 6/1/116091 doi:10.1067/mob.2001.116091
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of total daily urine output).5 Nocturnal diuresis >0.9 mL/min has also been proposed.6 An updated definition describes a nocturnal overproduction of urine as a function of bladder capacity.7 The World Health Organization classification of ≥2 voids per night has been scrutinized for not accounting for bothersomeness8: for some individuals, it is bothersome and inconvenient to void even once per night. The International Continence Society is scheduled to discuss the development of a standardized definition for nocturia in the near future. There are 3 main pathophysiologic categories for nocturia: nocturnal polyuria (in which a relatively higher proportion of urine is produced and voided during nighttime compared with daytime), low nocturnal bladder capacity (possibly caused by obstruction, detrusor instability, or cystitis), and mixed nocturia (a combination of nocturnal polyuria and low functional bladder capacity). The majority of patients with nocturia have a combination of nocturnal polyuria and low bladder capacity.7 Sleep disturbance is also worth considering as another primary cause of nocturia; some people may wake up because of noise, apnea, pain, or other disturbances and subsequently feel compelled to urinate. Nocturia appears to be as common in women as it is in men.9 The prevalence of nocturia (assuming it represents ≥2 micturitions per night) shows a linear increase with successive decades of age.2 It occurs in 9% of women
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from 19 to 39 years old and 51% of women ≥80 years old.9 Nocturia was reported by 166 of 819 women (20%) in a survey of urinary dysfunction in a Chinese population in Hong Kong,10 whereas the prevalence of lower urinary tract symptoms (including nocturia) occurring more than once a week was 27% (95% confidence interval [CI], 26.2% to 29.4%) in a Danish group of 4000 women who were 40 to 60 years old.11 Nocturia was the most common symptom reported in a study that compared the prevalence of many symptoms of acute and chronic illness3: regardless of their overall state of health, 80.4% of 1927 female subjects >65 years old complained of nocturia.3 A recent study investigated the incidence of lower urinary tract symptoms during 1 year and the remission rates in women who were 40 to 60 years old. Various lifestyle factors are believed to help precipitate lower urinary tract symptoms, and within a year approximately one third of all the women reported either fewer symptoms or a cessation of symptoms. This was not thought to be related to the reproducibility of the questionnaire but appears to show the dynamic changes that occur in the reporting of lower urinary tract symptoms in women.12 This observation provides an indication of the transitional nature of lower urinary tract symptoms. The impact of these symptoms on an individual is subject to change over time and may be influenced by many other coexisting factors. Methods We used PubMed to perform a review of all of the published medical literature on the subject of nocturia in women. Search terms included nocturia, lower urinary tract symptoms (particularly those specific to women), prevalence, age-associated changes in urologic function, diagnosis, quality-of-life assessment, and treatment. We used the following inclusion criteria for an article: (1) studies published in the last 2 decades that investigated nocturia, (2) studies that incorporated robust protocols, that is, randomized controlled trials that used established urologic investigative techniques, and (3) studies published in established and distinguished journals specific to urology and leading publications that cover general medicine. Exclusion criteria included (1) pre-1980 publications and (2) journals not published in English. Results The impact of nocturia. Epidemiologic studies of lower urinary tract symptoms often look at incontinence from a broad perspective,11, 13, 14 and published research about women focuses more on the impact that incontinence has on daily living rather than on addressing the prevalence of specific symptoms.15 Nocturia has been included in some questionnaire-based surveys of lower urinary tract symptoms.11, 13, 14, 16, 17 Studies that include an assessment of nocturia find that it is a com-
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mon and bothersome complaint,11 often regarded as the most troublesome of all urinary symptoms.18 The perception of how bothersome nocturia is may differ, depending on the cultural, sexual, or regional background of the person being questioned. For example, studies have shown incontinence to be more prevalent in white American women than in black American women,19 but whether white women have more episodes of incontinence or are just more bothered by symptoms is not clear. Bothersomeness is therefore a subjective quantification that is open to typical human variation. For example, nocturia was found to be bothersome in 28.4% of women compared with 35.7% of men in a survey of 4873 Danish men and 477 women >50 years old (significant difference P < .001).20 Another study made a similar observation, although in that case women were more bothered by nocturia than men.21 Although patients may exaggerate urinary symptoms22, self-reporting of nocturia appears to be fairly reliable,23 it is important to consider the impact that nocturia has on the individual person. Nocturia was the most frequently reported cause of sleep disturbance in a subjective evaluation of the effects of sex, age, and factors related to self-evaluated quality of sleep in 1485 men and women from 50 to 93 years old, affecting 63.5% of women who were from 50 to 89 years old.2 Some questionnaires have been designed specifically to measure quality of life in women with lower urinary tract symptoms. Although these questionnaires concentrate on the effect of incontinence, some allow for the assessment of nocturia collectively with other lower urinary tract symptoms. Examples include the Bristol Female Lower Urinary Tract Symptoms questionnaire,23 King’s Health Questionnaire,24 and the Urge-Incontinence Impact Questionnaire.25 These questionnaires are still limited, however, in that they are unable to specifically assess the impact of nocturia on quality of life,26 which is probably the main reason for a patient to consult a physician. Few people with lower urinary tract symptoms, including nocturia, ever seek medical help.27 Although the prevalence of lower urinary tract symptoms was high among participants in a study of 2890 Australian adults, and nocturia was the second most common symptom, only 27% of women (179 of 662) with “troublesome” lower urinary tract symptoms consulted a doctor; 63% of men(65 of 104) and 59% of women (162 of 274) with lower urinary tract symptoms did not seek medical advice.28 There were similar findings in a study that assessed the prevalence of urinary incontinence and its influence on quality of life for 2911 urban Swedish women ≥20 years old. Urinary incontinence was prevalent in 3% of women aged 20 to 29 years, increasing in a linear fashion to 32% in women >80 years old. Although women with urinary incontinence reported a significantly poorer quality of life than women with no lower urinary tract symptoms (P < .01), only
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6% (174) of the women surveyed would consult a doctor because of lower urinary tract symptoms.29 Even the negative effect of nocturia on well-being, health, and sleep patterns does not prompt individuals to seek treatment. In one study, nocturia occurred in 32 of 491 women questioned (age range, 20 to 59 years; 6.5% of total sample) and had a negative effect on well-being. The prevalence of urinary incontinence in this population was 27.7%, and 3.5% of the women experienced daily leakage, yet fewer than 10 of the women with incontinence sought treatment for the condition.1 Nocturia can lead to reduced productivity in affected individuals. Women from 40 to 60 years old with regular nocturia reported deterioration in their sleep and general state of health.30 The women in this study also took more time off work and received more medication than women who did not have nocturia. The elderly represent the fastest growing population group in many countries, and there are significantly more elderly women than elderly men. Urinary disorders that affect a greater proportion of elderly women are therefore also likely to have a significant impact on the health services of each country. Getting up to urinate in the middle of the night leads to a rise in the number of hospitalizations caused by falls and fractures in the ambulatory elderly.31 Of 988 women and 520 men who reported bone fractures during a 5year period, those who reported ≥2 episodes of nocturia per night were at significantly greater risk of falling (odds ratio [OR], 1.84; 95% CI, 1.05 to 3.22), and the risk increased in subjects who reported more than 3 episodes of nocturia (OR, 2.15; 95% CI, 1.04 to 4.44).31 A greater mortality rate independent of age, general health, and changes in health has been established for elderly persons who void 3 or more times per night compared with those who urinate less often during the night.32 Pathophysiology of nocturia. Factors associated with nocturia are listed in the Table. Nocturia may be the symptom of an underlying condition rather than the primary disorder.33 For example, when an ambulatory person with daytime edema (perhaps caused by venous insufficiency) lies down at night, resorption of excess fluids may increase nocturnal urine output. Nocturnal diuresis can also be affected by caffeine and alcohol consumption, fluid intake during the evening, or timing of diuretic therapy.7 The most common causes of nocturia and the age groups that are affected are discussed below. Aging. People of all ages have lower urinary tract symptoms, but the prevalence of nocturia and related lower urinary tract symptoms increase with advancing age.2, 29 Age-associated urodynamic changes in both men and women are comparable for a number of parameters and suggest that there is a gradual deterioration in bladder function and capacity over time.34, 35
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Fluid excretion is influenced by a number of hormones, including angiotensin II, catecholamines, atrial natriuretic peptide, renin, and the antidiuretic hormone (ADH) arginine vasopressin, and urine output is also controlled by thirst mechanism and responsiveness. Such factors may be affected in elderly people; for example, producing less arginine vasopressin at night may cause an older person to produce more urine nocturnally.36 Age-dependent changes in voiding patterns have also been reported, with a higher prevalence of voiding symptoms, including nocturia, in 583 women assessed by questionnaire with use of the International Prostate Symptom Score.27 Women may be up to twice as likely as men to have incontinence, and they are affected at an earlier age.28 The variations between the sexes may be a result of improved awareness and reporting of the condition in women or there may be physiologic causes. In women, the increase in the prevalence of nocturia and lower urinary tract symptoms does not appear to be as age-dependent as it is in men, yet there is still an obvious age-related trend. Childbirth and endocrinologic changes. Stress incontinence37 and nocturia38 have both been shown to increase in prevalence in women who have had more than 1 child compared with nulliparous or primiparous women. Physical damage to the urinary tract, surrounding structures, and the nervous system during childbirth may be responsible for lower urinary tract symptoms.37, 38 Nocturia is more likely to be caused by endocrinologic changes or changes in the nervous system associated with pregnancy. The duration of menopause has been shown to be related to changes in bladder weight, which may have an important bearing on lower urinary tract symptoms, including nocturia.39 Results of a questionnaire survey found a significant association between estrogen replacement and an improvement in incontinence (OR, 1.9; 95% CI, 1.3 to 2.8),39 but one of the most revealing studies has shown vast improvements in symptoms of nocturia when postmenopausal women received hormone replacement therapy with estrogen.40 This was supported by a recent study that investigated the efficacy of 2 estrogen-releasing formulations. Both treatments relieved nocturia in more than 50% of postmenopausal women,41 showing that a deficiency in estrogen can contribute to lower urinary tract symptoms, including nocturia. One interesting observation from Thom et al38 was that exposure to oxytocin in labor was related to a higher incidence of incontinence in later life (OR, 1.9; 95% CI, 1.0 to 3.6). The risk was increased further for women who received oxytocin on more than 1 occasion.38 Because oxytocin is closely related to vasopressin, it is possible that it mimics vasopressin-like effects on the renal system. However, this is unlikely to be a long-term effect and may need further investigation. Anorexia nervosa can cause bothersome urinary symptoms, including nocturia.42 The lower urinary tract is es-
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Table. Major factors associated with nocturia Aging Psychogenic Behavioral Pathologic causes or underlying diseases Hormonal Sleep changes Polyuria Bladder problems Neurologic disease Combinations of all of the above
Increased fluid intake, depression, anxiety Caffeine and alcohol consumption Diabetes mellitus, diabetes insipidus, urinary tract infections, cancer, venous insufficiency, congestive cardiac failure, hypertension, chronic renal failure Estrogen deficiency, reduced antidiuretic hormone production Disturbance, amount of time spent in bed Nocturnal fluid reabsorption, excessive thirst, reduced arginine vasopressin production Decline in bladder function and capacity Parkinson’s disease, multiple sclerosis, Alzheimer’s disease
trogen-sensitive and anorexia nervosa is associated with endocrine changes such as low estrogen levels and anovulation. Nocturnal enuresis. There may also be a link between nocturnal enuresis in childhood and incontinence and nocturia in adulthood.43 The transition from enuresis to nocturia is developmental: enuresis can be provoked in dry children from 7 to 12 years old by giving excessive fluids at bedtime,44 but the same fluid loading will lead to nocturia in adolescents.45 A prospective study supports the postulated link between childhood enuresis and adult incontinence,46 but further research of the links between nocturnal enuresis in children and adult nocturia is needed. Nocturnal polyuria. Production of >33% of the 24-hour urine volume overnight is an indicator of nocturnal polyuria syndrome,47 although this does not take variations in sleep duration or bladder capacity into account. No consensus exists on a universal definition of “normal” or “abnormal” nocturnal urine output. Simple causes include excessive intake of fluid, particularly diuretics, in the evenings. More complicated causes include a disturbance in the level of hormones responsible for regulation of urine production48 and, more specifically, a change in the circadian pattern of arginine vasopressin secretion that has been noted in the elderly.4 In men without nocturnal polyuria syndrome, ADH levels generally increase at night,49 which reduces nocturnal diuresis. Most women, however, have lower daytime ADH levels that do not rise nocturnally.48 People with enuresis have lower nocturnal ADH levels than unaffected control subjects,50 Asplund and Aberg51 found undetectable levels of ADH (<0.4 pmol · L–1) in 137 of 189 tests (72%) undertaken in 27 subjects with increased nocturnal diuresis aged 74 ± 5 years (men, n = 7) and 71 ± 6 years (women, n = 20; Fig 1). Nocturnal polyuria syndrome is important in the pathogenesis of nocturnal enuresis and nocturia,43, 44 and nocturnal polyuria syndrome creates a vicious cycle whereby voiding frequency and enuresis increase, leading to thirst and sleep disturbance.52 Sleep is one of the most important physiologic mechanisms that influences
urine output at night, and older people who wake frequently have a higher urine output than those with fewer sleep interruptions.48, 53 Nocturnal urine excretion decreased in a group of elderly persons given sleeping pills compared with those who received no treatment.54 Symptoms of nocturnal polyuria syndrome may be mistaken for diabetes insipidus. In the person with nocturnal polyuria syndrome, however, daytime urine production is normal and only nocturnal production is excessive—if there are any increases in volume during a 24-hour period, they are moderate; it is the rhythm of the urine secretion that is changed.4 Elderly people with nocturnal polyuria syndrome are also more likely to have other symptoms such as pain, muscle spasms, and night sweats (the latter is particularly more common in women with nocturia).49 Nocturnal polyuria may also result from bladder dysfunction and disturbances in the thirst mechanism.55 There appears to be a greater interindividual difference in the pattern of urine output and voiding frequency in older women than in older men.52 If an elderly person urinates more often between 8 PM and 8 AM than during the day, it is more likely that the nocturnal urinary output is higher than normal rather than that bladder capacity is decreased.54 Obstructive sleep apnea. Primary sleep disturbances are also considered to be an important factor associated with nocturia. Obstructive sleep apnea can cause nocturnal diuresis through hypoxemia-induced atrial natriuretic peptide production.56 Its prevalence is believed to be 2% in women and 4% in men.57 Nocturia may be associated with obstructive sleep apnea. A recent study investigated the relationship between nocturia and sleep-disordered breathing. A random sample of older adults (>55 years old) received a questionnaire that included questions about the characterization of poor sleep quality, nocturia, lower urinary tract symptoms, and obstructive sleep apnea symptoms. The data showed that black American women had significant associations between episodes of nocturia and symptoms of obstructive sleep apnea, which supports the notion that nocturia and sleep-disordered breathing are not related to prostate or sex.58 Another
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Fig 1. Circadian changes in plasma antidiuretic hormone (ADH) levels in men (left panel) and women (right panel).51 (Figure reproduced with permission of Science & Technology Letters).
study used clinical interviews to investigate nocturia in elderly subjects. Significant associations were again found between nocturia and apnea symptoms in the subjects, all of whom had poor sleep quality. Nocturia may act as a useful marker in the identification of sleep apnea because it is such an identifiable symptom.59 Comment Diagnosis and evaluation. There are 2 specific approaches to the diagnosis of nocturia7, 60: (1) Subjective assessment (questionnaires and interviews) and (2) voiding diaries. An algorithm that outlines stages in the diagnosis of nocturia is given in Fig 2. Symptoms such as disturbed sleep, edema, or thirst disturbance may prompt the person with nocturia to seek treatment—nocturnal polyuria alone is often not the main complaint of the patient—therefore it is important to ask about lower urinary tract symptoms when the clinical history is obtained. If the patient describes lower urinary tract symptoms, the clinician should inquire whether the quality of life of the patient has been affected by the symptoms. If the patient (or their caregiver) describes lower urinary tract symptoms as “bothersome,” they should be asked to keep a voiding diary to provide information on the pattern of micturition, continence and leakage, functional bladder capacity, diurnal distribution of voids, and volume of urine. This diary is usually kept for a 3- to 7-day period. Full compliance to a diary can falter over time; therefore keeping a voiding diary for a single 24-hour period, which
is then analyzed to provide a broader picture, has recently been proposed.7 Nocturia can be diagnosed simply by analyzing the events in a voiding diary. However, although the self-reporting of nocturia appears to be reliable,24 subjective accounts of lower urinary tract symptoms are not always supported by objective evidence,23, 61, 62 particularly because there are no standard definitions for normal, abnormal, or bothersome nocturnal urine production and micturition. In one study, objective evidence of voiding difficulty was found by use of urodynamic assessment in just 27 of 127 women who reported lower urinary tract symptoms and an additional 13 of 79 women who did not report symptoms.61 Urodynamic studies may show abnormalities in the storage and voiding phases of micturition,60 but their role in the specific diagnosis of nocturia is confined to the confirmation of suspected detrusor instability or underactivity.63 An investigative technique that is more tailored to nocturia would involve cystometric measurements, which provide an estimate of bladder capacity. Another approach is the Bristol Female Lower Urinary Tract Symptoms questionnaire,23 which is a comprehensive and validated questionnaire that may also be used to assess women with lower urinary tract symptoms, including nocturia, in an objective manner.60 Treatment of nocturia. Therapeutic strategies often treat the symptoms of nocturia, not the causes. Treatment approaches for women can be divided into 2 areas: behavioral and pharmacologic.
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Fig 2. Schematic representation of the diagnosis for nocturia.
Behavior modification. Initial therapeutic steps include behavioral modification, such as reducing caffeine or alcohol consumption or, more commonly, limiting evening fluid intake.7 Fluid restriction is rarely effective in elderly patients with congestive cardiac failure or venous insufficiency, in whom nocturia is caused by the redistribution of interstitial fluid in the lower limbs. Compression therapy, leg elevation, and afternoon naps may reduce or prevent edema.7 Urodynamic parameters may also be improved in women with lower urinary tract symptoms by pelvic floor rehabilitation and bladder training, and behavioral modification therapies such as these are successful in improving the quality of life in a number of women with incontinence.64, 65 Whether such interventions can have the same impact on women with specific symptoms of nocturia, rather than the broadly defined incontinence, remains to be seen. Pharmacologic intervention. Pharmacologic treatments are available. In the patient with edema, diuretics such as furosemide66 and bumetanide67 may reduce the number of voids and nocturnal volume of urine if taken before
early evening. Imipramine has also been used to treat nocturnal polyuria effectively.68 Symptoms of nocturia may also improve after a 6month continuous regimen of combined hormone replacement therapy; in a study involving 95 postmenopausal women who received 2 mg 17β-estradiol in combination with 2.5 to 15 mg oral dydrogesterone once a day, the number of nocturnal voids decreased significantly (from 2-5 to 0-3 episodes per night in women with nocturia before study; P = .0002); nocturia disappeared in 65.4% of the women after treatment.40 Desmopressin, an analog of arginine vasopressin, has been shown to be effective in the alleviation of nocturia in elderly subjects.47 A significant reduction in nocturnal urine volume, frequency, and percentage of urine passed during the night was observed in patients with nocturia given 40 µg desmopressin.47 Desmopressin is an effective and well-tolerated therapy for adult enuresis,69 and this therapy has decreased or eliminated nocturia in patients with multiple sclerosis70 and Parkinson’s disease.71 An early placebo-controlled study investigated the effect of desmopressin in women with nocturia as a symptom of
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multiple sclerosis. Desmopressin significantly reduced nocturia compared with the placebo and had a safety profile similar to the placebo.69 ln women with nocturia in whom antispasmodic medication had been unsuccessful, desmopressin was also shown to be effective.71 Several studies have reported a decrease in nocturnal urine volume in adults who received desmopressin, with the greatest reduction in those in whom nocturia was most severe before therapy.6, 72, 73 One of these studies investigated the efficacy of oral desmopressin in a placebo-controlled trial of elderly men and women. The treatment was well tolerated, with no serious side effects reported. Furthermore, nocturnal voiding was reduced in association with an improvement in the length of uninterrupted sleep.72 The likelihood of fluid retention can be reduced, however, if elderly patients receiving desmopressin are advised to curtail evening fluid intake.48 A recent study indicated that a 2-month course of 40 µg desmopressin therapy has very few side effects in a group of elderly women (mean age, 73 years) with nocturnal polyuria syndrome.73, 74 During treatment with desmopressin it is important to monitor the patient, particularly during the earlier stages of treatment. Regular checks for symptoms associated with water retention should be made, including weighing the patient daily, checking for edema (especially in the lower extremities), and measuring serum electrolytes. Desmopressin treatment should be avoided in patients with polyuria whose daily urine output exceeds 2.5 L. Particular attention should be given to elderly patients who are more susceptible to the effects of water retention. In addition, patients with heart failure should not receive the drug.
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dwelling population using a validated questionnaire. Neurourol Urodyn 1997:16:432-4. Brieger GM, Yip SK, Hin LY, Chung TK. The prevalence of urinary dysfunction in Hong Kong Chinese women. Obstet Gynecol 1996;88:1041-4. Møller LA, Lose G, Jørgensen T. The prevalence and bothersomeness of lower urinary tract symptoms in women 40-60 years of age. Acta Obstet Gynecol Scand 2000;79:298-305. Møller LA, Lose G, Jørgensen T. One-year incidence and remission rates of lower urinary tract in women 40–60 years of age: population based study. BMJ 2000;320:1429-32. Elving LB, Foldspang A, Lam GW, Mommsen S. Descriptive epidemiology of urinary incontinence in 3,100 women age 30-59. Scand J Urol Nephrol Suppl 1989;125:37-43. Sommer P, Bauer T, Nielsen KK, Kristensen ES, Hermann GG, Steven K, et al. Voiding patterns and prevalence of incontinence in women: a questionnaire survey. Br J Urol 1990;66:12-5. Donovan J, Naughton M, Gotoh M, Corcos J, Jackson S, Kelleher C, et al. Symptom and quality of life assessment. In: Abrams P, Khoury S, Wien A, editors. Proceedings of the First International Consultation on Incontinence, 1999. Plymouth (UK): Health Publication Ltd. Barry MJ, Fowler FJ Jr, O’Leary MP, Bruskewitz RC, Holtgrewe HL, Mebust WK, et al. The American Urological Association symptom index for benign prostatic hyperplasia. The Measurement Committee of the American Urological Association. J Urol 1992;148:1549-57. Meyhoff HH, Hald T, Nordling J, Andersen JT, Bilde T, Walter S. A new patient weighted symptom score system (DAN-PSS-1): clinical assessment of indications and outcomes of transurethral prostatectomy for uncomplicated benign prostatic hyperplasia. Scand J Urol Nephrol 1993;27:493-9. Swithinbank LV, Donovan JL, Rogers CA, James MC, Yang Q, Abrams P. Urinary symptoms and incontinence in women: relationships between occurrence, age and troublesomeness. Br J Gen Pract 1999;49:897-900. Fultz NH, Herzog AR, Ragunathan TE, Wallace RB, Diokno AC. Prevalence and severity of urinary incontinence in older African American and Caucasian women. J Gerontol A Biol Sci Med Sci 1999;54:M299-303. Mortensen S, Nordling J, Munkgaard S, and the Danish Prostate Council. Elderly males and females do differ in urinary symptoms and bother [abstract]. Br J Urol 1997;80(suppl 2):21. Kay L, Stigsby B, Brasso K, Mortensen SO, Munkgaard S. Lower urinary tract symptoms—a population survey using the Danish Prostatic Symptom Score (DAN-PSS) questionnaire. Scand J Urol Nephrol 1999;33:94-9. Abrams P, Klevmark B. Frequency volume charts: an indispensable part of lower urinary tract assessment. Scand J Urol Nephrol 1996;179:47-53. Jackson S, Donovan J, Brookes S, Eckford S, Swithinbank L, Abrams P. The Bristol Female Lower Urinary Tract Symptoms questionnaire: development and psychometric testing. Br J Urol 1996;77:805-12. Kelleher CJ, Cardozo LD, Khullar V, Salvatore S. A new questionnaire to assess the quality of life of urinary incontinent women. Br J Obstet Gynaecol 1997;104:1374-9. Lubeck DP, Prebil LA, Peeples P, Brown JS. A health related quality of life measure for use in patients with urge urinary incontinence: a validation study. Qual Life Res 1999;8:337-44. Donovan JL. Measuring the impact of nocturia on quality of life. BJU Int 1999;84(suppl 1):21-5. Yu HJ, Chen J, Lai MK, Chan KA, Chie WC. High prevalence of voiding symptoms in Taiwanese women. Br J Urol 1998;82:520-3. Pinnock C, Marshall VR. Troublesome lower urinary tract symptoms in the community: a prevalence study. Med J Aust 1997;167:72-5. Simeonova Z, Milsom I, Kullendorff AM, Molander U, Bengtsson C. Acta Obstet Gynecol Scand 1999;78:546-51. Asplund R, Aberg H. Nocturnal micturition, sleep and wellbeing in women of ages 40-64 years. Maturitas 1996;24:73-81. Stewart RB, Moore MT, May FE, Marks RG, Hale WE. Nocturia: a risk factor for falls in the elderly. J Am Geriatr Soc 1992;40:1217-20.
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32. Asplund R. Mortality in the elderly in relation to nocturnal micturition. BJU Int 1999;84:297-301. 33. Fonda D. Nocturia: a disease or normal ageing? BJU Int 1999;84(suppl 1):13-5. 34. Diokno AC, Brown MB, Brock BM, Herzog AR, Normolle DP. Clinical and cystometric characteristics of continent and incontinent noninstitutionalized elderly. J Urol 1988;140:56771. 35. Maderbascher S, Pycha A, Schatzl, Mian C, Klingler CH, Marberger M. The aging lower urinary tract: a comparative urodynamic study of men and women. Urology 51;1998:206-12. 36. Asplund R, Aberg H. Diurnal variation in the levels of antidiuretic hormone in the elderly. J Intern Med 1991;229:131-4. 37. Groutz A, Gordon D, Keidar R, Lessing JB, Wolman I, David MP, et al. Stress urinary incontinence: prevalence among nulliparous compared with primiparous and grand multiparous premenopausal women. Neurourol Urodyn 1999;18:419-25. 38. Thom DH, van den Eeden SK, Brown JS. Evaluation of parturition and other reproductive variables as risk factors for urinary incontinence in later life. Obstet Gynecol 1997;90:983-9. 39. Aygen EM, Ekmekçioglu O, Basbug M. The menopause and bladder weight. Int Urogynecol J Pelvic Floor Dysfunct 1999;10:316-20. 40. Kok AL, Burger CW, van de Weijer PH, Voetberg GA, PatersMuller ER, Kenemans P. Micturition complaints in postmenopausal women treated with continuously combined hormone replacement therapy: a prospective study. Maturitas 1999;31:143-9. 41. Lose G, Englev E. Oestradiol-releasing vaginal ring versus oestriol vaginal pessaries in the treatment of bothersome lower urinary tract symptoms of postmenopausal onset. Br J Obstet Gynaecol 2000;107:1029–34. 42. Boos K, Hextall A, Cardozo L, Toozs-Hobson P, Anders K, Treasure J. Lower urinary tract symptoms and their impact on women with anorexia nervosa. Br J Obstet Gynaecol 1999;106:501-4. 43. Djurhuus JC, Matthiesen TB, Rittig S. Similarities and dissimilarities between nocturnal enuresis in childhood and nocturia in adults. BJU Int 1999;(suppl 1):9-12. 44. Bonde HV, Andersen JP, Rosenkilde P. Nocturnal enuresis: change of nocturnal voiding patterns during alarm treatment. Scand J Urol Nephrol 1994;28:349-52. 45. Kirk J, Rasmussen PV, Rittig S, Djurhuus JC. Micturition habits and bladder capacity in normal children and in patients with desmopressin-resistant enuresis. Scand J Urol Nephrol 1995;173:49-50. 46. Kuh D, Cardozo L, Hardy R. Urinary incontinence in middle aged women: childhood enuresis and other lifetime risk factors in a British prospective cohort. J Epidemiol Community Health 1999;53:453-8. 47. Cannon A, Carter PG, McConnell AA, Abrams P. Desmopressin in the treatment of nocturnal polyuria in the male. BJU Int 1999;84:20-4. 48. Asplund R. The nocturnal polyuria syndrome (NPS). Gen Pharmacol 1995;26:1203-9. 49. George CP, Messerli FH, Genest J, Nowaczynski W, Boucher R, Kuchel Orofo-Oftega M. Diurnal variation of plasma vasopressin in man. J Clin Endocrinol Metabol 1975;41:332-8. 50. Wille S, Ailli M, Harris A, Aronsson S. Plasma and urinary levels of vasopressin in enuretic and non-enuretic children. Scand J Urol Nephrol 1994;28:119-22. 51. Asplund R, Aberg H. Diurnal rhythm of antidiuretic hormone in elderly subjects with nocturia. Med Sci Res 1991;19:765-6. 52. Asplund R, Aberg H. Health of the elderly with regard to sleep and nocturnal micturition. Scand J Prim Health Care 1992;10:98-104.
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53. Asplund R. Micturition habits and diuresis in relation to sleep and well-being in elderly subjects with emphasis on antidiuretic hormone [thesis]. Stockholm: Strömsund County Hospital and Health Center and the Department of Family Medicine, Karolinska Institute, 1992. 54. Asplund R, Aberg H. Micturition habits of older people: voiding frequency and urine volumes. Scand J Urol Nephrol 1992;26:345-9. 55. Phillips PA, Bretherton M, Johnston CI, Gray L. Reduced osmotic thirst in healthy elderly men. Am J Physiol 1991;261(1 pt 2):R166-71. 56. Yalkut D, Lee LY, Grider J, Jorgensen M, Jackson B, Ott C. Mechanism of atrial natriuretic peptide release with increased inspiratory resistance. J Lab Clin Med 1996;128:322-8. 57. Partinen M. Epidemiology of obstructive sleep apnea syndrome. Curr Opin Pulm Med 1995;1:482-7. 58. Umlauf M, Kurtzer E, Valappil T, Burgio K, Pillion D, Goode P. Sleep-disordered breathing as a mechanism for nocturia: preliminary findings. Ostomy Wound Manage 1999;45:52-60. 59. Umlauf M, Burgio K, Bliwise D, Pillion D, Goode P, Kurtzer E. Mechanisms of nocturia in older adults: preliminary results of clinical interviews. Proceedings of the 29th Annual Meeting of the International Continence Society, 23-26 August, Denver, Colo. Neurourol Urodyn 1999;18:116B. 60. Abrams P. Lower urinary tract symptoms in women: who to investigate and how. Br J Urol 1997;80(suppl 1):43-8. 61. Groutz A, Gordon D, Lessing JB. Prevalence and characteristics of voiding difficulties in women: are subjective symptoms substantiated by objective urodynamic data? Urology 1999;54:269-72. 62. Amundsen C, Lau M, English SF, McGuire EJ. Do urinary symptoms correlate with urodynamic findings? J Urol 1999;161:1871-4. 63. Jackson S. Lower urinary tract symptoms and nocturia in men and women: prevalence, aetiology and diagnosis. BJU Int 1999;84(suppl 1):5-8. 64. Fantl JA. Behavioral intervention for community-dwelling individuals with urinary incontinence Urology 1998;51(suppl 2A):30-4. 65. Seim A, Hermstad R, Hunskaar S. Female urinary incontinence: long term follow-up after treatment in general practice. Br J Gen Pract 1998;48:1731-4. 66. Reynard JM, Cannon A, Yang Q, Abrams P. A novel therapy for nocturnal polyuria: a double-blind randomized trial of frusemide against placebo. Br J Urol 1998;81:215-8. 67. Adam P. Evaluation and management of diabetes insipidus. Am Fam Physician 1997;55:2146-53. 68. Hunsballe JM, Rittig S, Pedersen EB, Olesen OV, Djurhuus JC. Single dose imipramine reduces nocturnal urine output in patients with nocturnal enuresis and nocturnal polyuria. J Urol 1997;158(3 pt 1):830-6. 69. Belmaker RH, Bleich A. The use of desmopressin in adult enuresis. Mil Med 1986;151:660-2. 70. Hilton P, Hertogs K, Stanton SL. The use of desmopressin (DDAVP) for nocturia in women with multiple sclerosis. J Neurol Neurosurg Psychiatry 1983;46:854-5. 71. Suchowersky O, Furtado S, Rohs G. Beneficial effect of desmopressin for nocturnal polyuria in Parkinson’s disease. Mov Disord 1995;10:337-40. 72. Hilton P, Stanton SL. The use of desmopressin (DDAVP) in nocturnal frequency in the female. Br J Urol 1982;54:252-5. 73. Asplund R, Sundberg B, Bengtsson P. Oral desmopressin for nocturnal polyuria in elderly subjects: a double-blind, placebocontrolled, randomized, exploratory study. Br J Urol 1999;83:591-5. 74. Asplund R, Aberg H. Desmopressin in elderly subjects with increased nocturnal diuresis: a two-month treatment study. Scand J Urol Nephrol 1993;27:77-82.
Nocturia in women Gunnar Lose MD, DMSc,a Lars Alling-Møller MD, PhD,a and Poul Jennum MD, DMScb Glostrup, Denmark Frequent episodes of nocturnal voiding disturb the sleep and well-being of women. The prevalence of nocturia is more common in parous women and shows a linear increase with age, occurring in more than 50% of women ≥80 years old. Nocturia has a multifactorial origin that develops through a pathophysiologic mechanism of nocturnal polyuria or low functional bladder capacity or through a combination of both. Nocturia is also one of the most bothersome lower urinary tract symptoms and has a significant impact on quality of life. However, most women accept symptoms of nocturia as part of the aging process and few seek medical help. Treatments for nocturia (behavior modification and pharmacologic treatment) are effective in many cases, although it is important to tailor treatment to the underlying pathophysiology. This review discusses the impact of nocturia on women and reviews the current situation regarding the definition, prevalence, diagnosis, and treatment of this condition in this patient population. (Am J Obstet Gynecol 2001;185:514-21.)
Key words: Female, nocturia, prevalence, quality-of-life, therapy
Women of all ages have lower urinary tract symptoms, the most common of which is leakage and frequent nighttime voiding (nocturia),1 yet most accept their symptoms as part of the aging process. Nocturia itself has now been recognized as a symptomatic urinary disorder of multifactorial origin that affects women to the same extent as men.1-3 This review discusses the impact of nocturia on women and reviews the current situation regarding the definition, prevalence, diagnosis, and treatment of this condition in this patient group. Nocturia refers to waking at night to void. Currently, however, there is no standard definition for nocturia. Until general consensus is achieved there will be wide variation in the prevalence rates reported, and the condition will remain underdiagnosed but undoubtedly common. Several definitions have been proposed for nocturia, some involve measuring urine output during a fixed nighttime period (eg, nocturnal urine volume ≥6.4 mL/kg4 or nocturnal urine volume exceeding one third
From the Department of Obstetrics and Gynecologya and the Department of Clinical Neurophysiology, Sleep Laboratory,b Glostrup County Hospital, University of Copenhagen. Reprint requests: Gunnar Lose, Department of Obstetrics and Gynecology, Glostrup County Hospital, University of Copenhagen, Nordre Ringvej, DK-2600 Glostrup, Denmark. Copyright © 2001 by Mosby, Inc. 0002-9378/2001 $35.00 + 0 6/1/116091 doi:10.1067/mob.2001.116091
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of total daily urine output).5 Nocturnal diuresis >0.9 mL/min has also been proposed.6 An updated definition describes a nocturnal overproduction of urine as a function of bladder capacity.7 The World Health Organization classification of ≥2 voids per night has been scrutinized for not accounting for bothersomeness8: for some individuals, it is bothersome and inconvenient to void even once per night. The International Continence Society is scheduled to discuss the development of a standardized definition for nocturia in the near future. There are 3 main pathophysiologic categories for nocturia: nocturnal polyuria (in which a relatively higher proportion of urine is produced and voided during nighttime compared with daytime), low nocturnal bladder capacity (possibly caused by obstruction, detrusor instability, or cystitis), and mixed nocturia (a combination of nocturnal polyuria and low functional bladder capacity). The majority of patients with nocturia have a combination of nocturnal polyuria and low bladder capacity.7 Sleep disturbance is also worth considering as another primary cause of nocturia; some people may wake up because of noise, apnea, pain, or other disturbances and subsequently feel compelled to urinate. Nocturia appears to be as common in women as it is in men.9 The prevalence of nocturia (assuming it represents ≥2 micturitions per night) shows a linear increase with successive decades of age.2 It occurs in 9% of women
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from 19 to 39 years old and 51% of women ≥80 years old.9 Nocturia was reported by 166 of 819 women (20%) in a survey of urinary dysfunction in a Chinese population in Hong Kong,10 whereas the prevalence of lower urinary tract symptoms (including nocturia) occurring more than once a week was 27% (95% confidence interval [CI], 26.2% to 29.4%) in a Danish group of 4000 women who were 40 to 60 years old.11 Nocturia was the most common symptom reported in a study that compared the prevalence of many symptoms of acute and chronic illness3: regardless of their overall state of health, 80.4% of 1927 female subjects >65 years old complained of nocturia.3 A recent study investigated the incidence of lower urinary tract symptoms during 1 year and the remission rates in women who were 40 to 60 years old. Various lifestyle factors are believed to help precipitate lower urinary tract symptoms, and within a year approximately one third of all the women reported either fewer symptoms or a cessation of symptoms. This was not thought to be related to the reproducibility of the questionnaire but appears to show the dynamic changes that occur in the reporting of lower urinary tract symptoms in women.12 This observation provides an indication of the transitional nature of lower urinary tract symptoms. The impact of these symptoms on an individual is subject to change over time and may be influenced by many other coexisting factors. Methods We used PubMed to perform a review of all of the published medical literature on the subject of nocturia in women. Search terms included nocturia, lower urinary tract symptoms (particularly those specific to women), prevalence, age-associated changes in urologic function, diagnosis, quality-of-life assessment, and treatment. We used the following inclusion criteria for an article: (1) studies published in the last 2 decades that investigated nocturia, (2) studies that incorporated robust protocols, that is, randomized controlled trials that used established urologic investigative techniques, and (3) studies published in established and distinguished journals specific to urology and leading publications that cover general medicine. Exclusion criteria included (1) pre-1980 publications and (2) journals not published in English. Results The impact of nocturia. Epidemiologic studies of lower urinary tract symptoms often look at incontinence from a broad perspective,11, 13, 14 and published research about women focuses more on the impact that incontinence has on daily living rather than on addressing the prevalence of specific symptoms.15 Nocturia has been included in some questionnaire-based surveys of lower urinary tract symptoms.11, 13, 14, 16, 17 Studies that include an assessment of nocturia find that it is a com-
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mon and bothersome complaint,11 often regarded as the most troublesome of all urinary symptoms.18 The perception of how bothersome nocturia is may differ, depending on the cultural, sexual, or regional background of the person being questioned. For example, studies have shown incontinence to be more prevalent in white American women than in black American women,19 but whether white women have more episodes of incontinence or are just more bothered by symptoms is not clear. Bothersomeness is therefore a subjective quantification that is open to typical human variation. For example, nocturia was found to be bothersome in 28.4% of women compared with 35.7% of men in a survey of 4873 Danish men and 477 women >50 years old (significant difference P < .001).20 Another study made a similar observation, although in that case women were more bothered by nocturia than men.21 Although patients may exaggerate urinary symptoms22, self-reporting of nocturia appears to be fairly reliable,23 it is important to consider the impact that nocturia has on the individual person. Nocturia was the most frequently reported cause of sleep disturbance in a subjective evaluation of the effects of sex, age, and factors related to self-evaluated quality of sleep in 1485 men and women from 50 to 93 years old, affecting 63.5% of women who were from 50 to 89 years old.2 Some questionnaires have been designed specifically to measure quality of life in women with lower urinary tract symptoms. Although these questionnaires concentrate on the effect of incontinence, some allow for the assessment of nocturia collectively with other lower urinary tract symptoms. Examples include the Bristol Female Lower Urinary Tract Symptoms questionnaire,23 King’s Health Questionnaire,24 and the Urge-Incontinence Impact Questionnaire.25 These questionnaires are still limited, however, in that they are unable to specifically assess the impact of nocturia on quality of life,26 which is probably the main reason for a patient to consult a physician. Few people with lower urinary tract symptoms, including nocturia, ever seek medical help.27 Although the prevalence of lower urinary tract symptoms was high among participants in a study of 2890 Australian adults, and nocturia was the second most common symptom, only 27% of women (179 of 662) with “troublesome” lower urinary tract symptoms consulted a doctor; 63% of men(65 of 104) and 59% of women (162 of 274) with lower urinary tract symptoms did not seek medical advice.28 There were similar findings in a study that assessed the prevalence of urinary incontinence and its influence on quality of life for 2911 urban Swedish women ≥20 years old. Urinary incontinence was prevalent in 3% of women aged 20 to 29 years, increasing in a linear fashion to 32% in women >80 years old. Although women with urinary incontinence reported a significantly poorer quality of life than women with no lower urinary tract symptoms (P < .01), only
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6% (174) of the women surveyed would consult a doctor because of lower urinary tract symptoms.29 Even the negative effect of nocturia on well-being, health, and sleep patterns does not prompt individuals to seek treatment. In one study, nocturia occurred in 32 of 491 women questioned (age range, 20 to 59 years; 6.5% of total sample) and had a negative effect on well-being. The prevalence of urinary incontinence in this population was 27.7%, and 3.5% of the women experienced daily leakage, yet fewer than 10 of the women with incontinence sought treatment for the condition.1 Nocturia can lead to reduced productivity in affected individuals. Women from 40 to 60 years old with regular nocturia reported deterioration in their sleep and general state of health.30 The women in this study also took more time off work and received more medication than women who did not have nocturia. The elderly represent the fastest growing population group in many countries, and there are significantly more elderly women than elderly men. Urinary disorders that affect a greater proportion of elderly women are therefore also likely to have a significant impact on the health services of each country. Getting up to urinate in the middle of the night leads to a rise in the number of hospitalizations caused by falls and fractures in the ambulatory elderly.31 Of 988 women and 520 men who reported bone fractures during a 5year period, those who reported ≥2 episodes of nocturia per night were at significantly greater risk of falling (odds ratio [OR], 1.84; 95% CI, 1.05 to 3.22), and the risk increased in subjects who reported more than 3 episodes of nocturia (OR, 2.15; 95% CI, 1.04 to 4.44).31 A greater mortality rate independent of age, general health, and changes in health has been established for elderly persons who void 3 or more times per night compared with those who urinate less often during the night.32 Pathophysiology of nocturia. Factors associated with nocturia are listed in the Table. Nocturia may be the symptom of an underlying condition rather than the primary disorder.33 For example, when an ambulatory person with daytime edema (perhaps caused by venous insufficiency) lies down at night, resorption of excess fluids may increase nocturnal urine output. Nocturnal diuresis can also be affected by caffeine and alcohol consumption, fluid intake during the evening, or timing of diuretic therapy.7 The most common causes of nocturia and the age groups that are affected are discussed below. Aging. People of all ages have lower urinary tract symptoms, but the prevalence of nocturia and related lower urinary tract symptoms increase with advancing age.2, 29 Age-associated urodynamic changes in both men and women are comparable for a number of parameters and suggest that there is a gradual deterioration in bladder function and capacity over time.34, 35
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Fluid excretion is influenced by a number of hormones, including angiotensin II, catecholamines, atrial natriuretic peptide, renin, and the antidiuretic hormone (ADH) arginine vasopressin, and urine output is also controlled by thirst mechanism and responsiveness. Such factors may be affected in elderly people; for example, producing less arginine vasopressin at night may cause an older person to produce more urine nocturnally.36 Age-dependent changes in voiding patterns have also been reported, with a higher prevalence of voiding symptoms, including nocturia, in 583 women assessed by questionnaire with use of the International Prostate Symptom Score.27 Women may be up to twice as likely as men to have incontinence, and they are affected at an earlier age.28 The variations between the sexes may be a result of improved awareness and reporting of the condition in women or there may be physiologic causes. In women, the increase in the prevalence of nocturia and lower urinary tract symptoms does not appear to be as age-dependent as it is in men, yet there is still an obvious age-related trend. Childbirth and endocrinologic changes. Stress incontinence37 and nocturia38 have both been shown to increase in prevalence in women who have had more than 1 child compared with nulliparous or primiparous women. Physical damage to the urinary tract, surrounding structures, and the nervous system during childbirth may be responsible for lower urinary tract symptoms.37, 38 Nocturia is more likely to be caused by endocrinologic changes or changes in the nervous system associated with pregnancy. The duration of menopause has been shown to be related to changes in bladder weight, which may have an important bearing on lower urinary tract symptoms, including nocturia.39 Results of a questionnaire survey found a significant association between estrogen replacement and an improvement in incontinence (OR, 1.9; 95% CI, 1.3 to 2.8),39 but one of the most revealing studies has shown vast improvements in symptoms of nocturia when postmenopausal women received hormone replacement therapy with estrogen.40 This was supported by a recent study that investigated the efficacy of 2 estrogen-releasing formulations. Both treatments relieved nocturia in more than 50% of postmenopausal women,41 showing that a deficiency in estrogen can contribute to lower urinary tract symptoms, including nocturia. One interesting observation from Thom et al38 was that exposure to oxytocin in labor was related to a higher incidence of incontinence in later life (OR, 1.9; 95% CI, 1.0 to 3.6). The risk was increased further for women who received oxytocin on more than 1 occasion.38 Because oxytocin is closely related to vasopressin, it is possible that it mimics vasopressin-like effects on the renal system. However, this is unlikely to be a long-term effect and may need further investigation. Anorexia nervosa can cause bothersome urinary symptoms, including nocturia.42 The lower urinary tract is es-
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Table. Major factors associated with nocturia Aging Psychogenic Behavioral Pathologic causes or underlying diseases Hormonal Sleep changes Polyuria Bladder problems Neurologic disease Combinations of all of the above
Increased fluid intake, depression, anxiety Caffeine and alcohol consumption Diabetes mellitus, diabetes insipidus, urinary tract infections, cancer, venous insufficiency, congestive cardiac failure, hypertension, chronic renal failure Estrogen deficiency, reduced antidiuretic hormone production Disturbance, amount of time spent in bed Nocturnal fluid reabsorption, excessive thirst, reduced arginine vasopressin production Decline in bladder function and capacity Parkinson’s disease, multiple sclerosis, Alzheimer’s disease
trogen-sensitive and anorexia nervosa is associated with endocrine changes such as low estrogen levels and anovulation. Nocturnal enuresis. There may also be a link between nocturnal enuresis in childhood and incontinence and nocturia in adulthood.43 The transition from enuresis to nocturia is developmental: enuresis can be provoked in dry children from 7 to 12 years old by giving excessive fluids at bedtime,44 but the same fluid loading will lead to nocturia in adolescents.45 A prospective study supports the postulated link between childhood enuresis and adult incontinence,46 but further research of the links between nocturnal enuresis in children and adult nocturia is needed. Nocturnal polyuria. Production of >33% of the 24-hour urine volume overnight is an indicator of nocturnal polyuria syndrome,47 although this does not take variations in sleep duration or bladder capacity into account. No consensus exists on a universal definition of “normal” or “abnormal” nocturnal urine output. Simple causes include excessive intake of fluid, particularly diuretics, in the evenings. More complicated causes include a disturbance in the level of hormones responsible for regulation of urine production48 and, more specifically, a change in the circadian pattern of arginine vasopressin secretion that has been noted in the elderly.4 In men without nocturnal polyuria syndrome, ADH levels generally increase at night,49 which reduces nocturnal diuresis. Most women, however, have lower daytime ADH levels that do not rise nocturnally.48 People with enuresis have lower nocturnal ADH levels than unaffected control subjects,50 Asplund and Aberg51 found undetectable levels of ADH (<0.4 pmol · L–1) in 137 of 189 tests (72%) undertaken in 27 subjects with increased nocturnal diuresis aged 74 ± 5 years (men, n = 7) and 71 ± 6 years (women, n = 20; Fig 1). Nocturnal polyuria syndrome is important in the pathogenesis of nocturnal enuresis and nocturia,43, 44 and nocturnal polyuria syndrome creates a vicious cycle whereby voiding frequency and enuresis increase, leading to thirst and sleep disturbance.52 Sleep is one of the most important physiologic mechanisms that influences
urine output at night, and older people who wake frequently have a higher urine output than those with fewer sleep interruptions.48, 53 Nocturnal urine excretion decreased in a group of elderly persons given sleeping pills compared with those who received no treatment.54 Symptoms of nocturnal polyuria syndrome may be mistaken for diabetes insipidus. In the person with nocturnal polyuria syndrome, however, daytime urine production is normal and only nocturnal production is excessive—if there are any increases in volume during a 24-hour period, they are moderate; it is the rhythm of the urine secretion that is changed.4 Elderly people with nocturnal polyuria syndrome are also more likely to have other symptoms such as pain, muscle spasms, and night sweats (the latter is particularly more common in women with nocturia).49 Nocturnal polyuria may also result from bladder dysfunction and disturbances in the thirst mechanism.55 There appears to be a greater interindividual difference in the pattern of urine output and voiding frequency in older women than in older men.52 If an elderly person urinates more often between 8 PM and 8 AM than during the day, it is more likely that the nocturnal urinary output is higher than normal rather than that bladder capacity is decreased.54 Obstructive sleep apnea. Primary sleep disturbances are also considered to be an important factor associated with nocturia. Obstructive sleep apnea can cause nocturnal diuresis through hypoxemia-induced atrial natriuretic peptide production.56 Its prevalence is believed to be 2% in women and 4% in men.57 Nocturia may be associated with obstructive sleep apnea. A recent study investigated the relationship between nocturia and sleep-disordered breathing. A random sample of older adults (>55 years old) received a questionnaire that included questions about the characterization of poor sleep quality, nocturia, lower urinary tract symptoms, and obstructive sleep apnea symptoms. The data showed that black American women had significant associations between episodes of nocturia and symptoms of obstructive sleep apnea, which supports the notion that nocturia and sleep-disordered breathing are not related to prostate or sex.58 Another
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Fig 1. Circadian changes in plasma antidiuretic hormone (ADH) levels in men (left panel) and women (right panel).51 (Figure reproduced with permission of Science & Technology Letters).
study used clinical interviews to investigate nocturia in elderly subjects. Significant associations were again found between nocturia and apnea symptoms in the subjects, all of whom had poor sleep quality. Nocturia may act as a useful marker in the identification of sleep apnea because it is such an identifiable symptom.59 Comment Diagnosis and evaluation. There are 2 specific approaches to the diagnosis of nocturia7, 60: (1) Subjective assessment (questionnaires and interviews) and (2) voiding diaries. An algorithm that outlines stages in the diagnosis of nocturia is given in Fig 2. Symptoms such as disturbed sleep, edema, or thirst disturbance may prompt the person with nocturia to seek treatment—nocturnal polyuria alone is often not the main complaint of the patient—therefore it is important to ask about lower urinary tract symptoms when the clinical history is obtained. If the patient describes lower urinary tract symptoms, the clinician should inquire whether the quality of life of the patient has been affected by the symptoms. If the patient (or their caregiver) describes lower urinary tract symptoms as “bothersome,” they should be asked to keep a voiding diary to provide information on the pattern of micturition, continence and leakage, functional bladder capacity, diurnal distribution of voids, and volume of urine. This diary is usually kept for a 3- to 7-day period. Full compliance to a diary can falter over time; therefore keeping a voiding diary for a single 24-hour period, which
is then analyzed to provide a broader picture, has recently been proposed.7 Nocturia can be diagnosed simply by analyzing the events in a voiding diary. However, although the self-reporting of nocturia appears to be reliable,24 subjective accounts of lower urinary tract symptoms are not always supported by objective evidence,23, 61, 62 particularly because there are no standard definitions for normal, abnormal, or bothersome nocturnal urine production and micturition. In one study, objective evidence of voiding difficulty was found by use of urodynamic assessment in just 27 of 127 women who reported lower urinary tract symptoms and an additional 13 of 79 women who did not report symptoms.61 Urodynamic studies may show abnormalities in the storage and voiding phases of micturition,60 but their role in the specific diagnosis of nocturia is confined to the confirmation of suspected detrusor instability or underactivity.63 An investigative technique that is more tailored to nocturia would involve cystometric measurements, which provide an estimate of bladder capacity. Another approach is the Bristol Female Lower Urinary Tract Symptoms questionnaire,23 which is a comprehensive and validated questionnaire that may also be used to assess women with lower urinary tract symptoms, including nocturia, in an objective manner.60 Treatment of nocturia. Therapeutic strategies often treat the symptoms of nocturia, not the causes. Treatment approaches for women can be divided into 2 areas: behavioral and pharmacologic.
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Fig 2. Schematic representation of the diagnosis for nocturia.
Behavior modification. Initial therapeutic steps include behavioral modification, such as reducing caffeine or alcohol consumption or, more commonly, limiting evening fluid intake.7 Fluid restriction is rarely effective in elderly patients with congestive cardiac failure or venous insufficiency, in whom nocturia is caused by the redistribution of interstitial fluid in the lower limbs. Compression therapy, leg elevation, and afternoon naps may reduce or prevent edema.7 Urodynamic parameters may also be improved in women with lower urinary tract symptoms by pelvic floor rehabilitation and bladder training, and behavioral modification therapies such as these are successful in improving the quality of life in a number of women with incontinence.64, 65 Whether such interventions can have the same impact on women with specific symptoms of nocturia, rather than the broadly defined incontinence, remains to be seen. Pharmacologic intervention. Pharmacologic treatments are available. In the patient with edema, diuretics such as furosemide66 and bumetanide67 may reduce the number of voids and nocturnal volume of urine if taken before
early evening. Imipramine has also been used to treat nocturnal polyuria effectively.68 Symptoms of nocturia may also improve after a 6month continuous regimen of combined hormone replacement therapy; in a study involving 95 postmenopausal women who received 2 mg 17β-estradiol in combination with 2.5 to 15 mg oral dydrogesterone once a day, the number of nocturnal voids decreased significantly (from 2-5 to 0-3 episodes per night in women with nocturia before study; P = .0002); nocturia disappeared in 65.4% of the women after treatment.40 Desmopressin, an analog of arginine vasopressin, has been shown to be effective in the alleviation of nocturia in elderly subjects.47 A significant reduction in nocturnal urine volume, frequency, and percentage of urine passed during the night was observed in patients with nocturia given 40 µg desmopressin.47 Desmopressin is an effective and well-tolerated therapy for adult enuresis,69 and this therapy has decreased or eliminated nocturia in patients with multiple sclerosis70 and Parkinson’s disease.71 An early placebo-controlled study investigated the effect of desmopressin in women with nocturia as a symptom of
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multiple sclerosis. Desmopressin significantly reduced nocturia compared with the placebo and had a safety profile similar to the placebo.69 ln women with nocturia in whom antispasmodic medication had been unsuccessful, desmopressin was also shown to be effective.71 Several studies have reported a decrease in nocturnal urine volume in adults who received desmopressin, with the greatest reduction in those in whom nocturia was most severe before therapy.6, 72, 73 One of these studies investigated the efficacy of oral desmopressin in a placebo-controlled trial of elderly men and women. The treatment was well tolerated, with no serious side effects reported. Furthermore, nocturnal voiding was reduced in association with an improvement in the length of uninterrupted sleep.72 The likelihood of fluid retention can be reduced, however, if elderly patients receiving desmopressin are advised to curtail evening fluid intake.48 A recent study indicated that a 2-month course of 40 µg desmopressin therapy has very few side effects in a group of elderly women (mean age, 73 years) with nocturnal polyuria syndrome.73, 74 During treatment with desmopressin it is important to monitor the patient, particularly during the earlier stages of treatment. Regular checks for symptoms associated with water retention should be made, including weighing the patient daily, checking for edema (especially in the lower extremities), and measuring serum electrolytes. Desmopressin treatment should be avoided in patients with polyuria whose daily urine output exceeds 2.5 L. Particular attention should be given to elderly patients who are more susceptible to the effects of water retention. In addition, patients with heart failure should not receive the drug.
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