Lower urinary tract symptoms in women - aspects on epidemiology and treatment 2009
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Lower urinary tract symptoms in women –
aspects on epidemiology and treatment
Anna Lena Wennberg
2009
Department of Urology
Institute of Clinical Sciences
The Sahlgrenska Academy, University of Gothenburg
Göteborg, SwedenISBN: 978-91-628-7727-9
CONTENTS Abstract ..................................................................................................................................... 4 List of publications.................................................................................................................... 5 Abbreviations ............................................................................................................................ 6 Introduction .......................................................................................................... 7 Aims of the study ............................................................................................... 25 Methods .............................................................................................................. 27 Methodological considerations .......................................................................... 29 Results ................................................................................................................ 37 General discussion.............................................................................................. 51 Conclusions ........................................................................................................ 59 General outlook and future perspectives............................................................ 61 Swedish summary............................................................................................... 63 Acknowledgements ............................................................................................ 67 References .......................................................................................................... 69 Paper I-V Appendix
ABSTRACT Lower urinary tract symptoms in women – aspects on epidemiology and treatment Lower urinary tract symptoms (LUTS) are common conditions that compromise a person’s quality of life and result in increased health care costs for society. The aims of this thesis were to describe the prevalence and natural course of different LUTS in women (Paper I), to assess prevalence changes over time (Paper II), and to evaluate the importance of genetic factors on LUTS (Paper III). The long-term results of the Stamey needle colposuspension for female stress urinary incontinence were also assessed (Paper IV). Paper I: In this population-based, longitudinal study the very same women (n=1081) were assessed regarding the prevalence, progression and remission of various LUTS in 1991 and 2007, using a postal questionnaire. The proportion of women reporting urinary incontinence (UI), overactive bladder (OAB), nocturia and daytime voiding frequency of ≥8 times/day increased markedly over time. Both incidence and remission for most symptoms were considerable. Paper II: The prevalence of LUTS, help-seeking behaviour, treatment and quality of life were compared in two population-based surveys of women performed in 1991 (n=2911) and 2007 (n=3158) using a similar questionnaire. The reported prevalence of UI and OAB was unchanged over time as was help-seeking due to UI. In 2007, more women stated that the presence of UI limited their daily life. Paper III: Questionnaire-based national cohort survey evaluating the prevalence of LUTS in Swedish twins born 1959-1985 (n=25 364). Heritability was assessed in female twins. LUTS were more common in women than in men. The strongest genetic effects were observed for UI and nocturia and the lowest for OAB without incontinence where environmental effects dominated. Shared environment accounted for nearly one third of the total variation for OAB without incontinence and for one fifth of the variation for stress UI. Non-shared environmental effects were in the range of 45-65% for the various LUTS. Paper IV: Twenty-four women, treated by the Stamey method for stress UI, were followed up by means of a questionnaire, urodynamic assessment and a standardised quantification test. Time to follow-up was 63 months. Approximately half of the women considered themselves continent at follow-up. The mean postoperative leakage was significantly reduced as compared to preoperatively. Most women were satisfied with the result of the operation. Conclusions: These studies showed that the prevalence of UI and OAB in women has been largely unchanged in the last 16 years. UI, OAB and other LUTS constitute dynamic conditions. The prevalence of symptoms increases with increasing age, but both progression and remission over time are common. The strongest genetic effects were observed for conditions involving UI and for nocturia while the lowest genetic effects were observed for OAB, where environmental factors were more important. The Stamey procedure may be used in a selected group of women with genuine stress UI and stable detrusor with acceptable long-term results and patient satisfaction. Keywords: Urinary incontinence; Overactive bladder; Lower urinary tract symptoms; Epidemiology; Prevalence; Incidence; Progression; Remission; Twins; Genetic; Heritability; Stress urinary incontinence; Stamey ISBN: 978-91-628-7727-9
LIST OF PUBLICATIONS
I. Longitudinal population-based survey of urinary incontinence, overactive
bladder and other lower urinary tract symptoms in women.
Anna Lena Wennberg, Ulla Molander, Magnus Fall, Christer Edlund, Ralph
Peeker and Ian Milsom.
Eur Urol 2009;55(4):783-791.
II. Lower urinary tract symptoms: Lack of change in prevalence and help-seeking
behaviour in two population-based surveys of women in 1991 and 2007.
Anna Lena Wennberg, Ulla Molander, Magnus Fall, Christer Edlund, Ralph Peeker
and Ian Milsom.
Accepted for publication, BJUI, 15 January 2009.
III. The heritability of lower urinary tract symptoms (LUTS).
A population-based survey in a cohort of adult Swedish twins.
Anna Lena Wennberg, Daniel Altman, Cecilia Lundholm, Åsa Klint, Anastasia
Iliadou, Ralph Peeker, Magnus Fall, Nancy L Pedersen and Ian Milsom.
Manuscript.
IV. Stamey’s abdominovaginal needle colposuspension for the correction of female
genuine stress urinary incontinence.
Long-term results.
Anna Lena Wennberg, Christer Edlund, Magnus Fall and Ralph Peeker.
Scand J Urol Nephrol 2003;37(5):419-423.ABBREVIATIONS BTX-A Botulinum Toxin A DiHA Dextranomers in Hyaluronan DO Detrusor Overactivity DZ Dizygotic EMG Electromyography GSI Genuine Stress Incontinence ICI International Consultation on Incontinence ICS International Continence Society ISD Intrinsic Sphincter Dysfunction LUTS Lower Urinary Tract Symptoms MUI Mixed Urinary Incontinence MZ Monozygotic OAB Overactive Bladder OAB dry Overactive Bladder without Urinary incontinence OAB wet Overactive Bladder with Urinary incontinence PFMT Pelvic Floor Muscle Training QoL Quality of Life RCT Randomised Controlled Trial RTX Resinferatoxin STR Swedish Twin Registry SUI Stress Urinary Incontinence TOT Trans Obturator Tape TVT Tensionfree Vaginal Tape UI Urinary Incontinence UUI Urge Urinary Incontinence VAS Visual Analogue Scale
INTRODUCTION
Historical background prolapse, such as the procedure described
by Kelly 1914 [7, 8], and the main
Lower Urinary Tract Symptoms (LUTS) objective was to restore visible anatomical
s
are common conditions that may be defects. In the 1940 sling-operations were
s
encountered in men and women of all ages routine and in the -50 abdominal vesico-
and by clinicians from many different urethral suspensions were brought forward
disciplines. These symptoms have (Marschall-Marchetti-Krantz, Lapides). In
widespread human and social 1961 Burch published his work on the
implications, causing discomfort, shame open colposuspension technique [9] which
and loss of self-confidence [1-4]. There is by many still considered as “the golden
has been a growing interest in various standard” for the correction of female
LUTS in recent years as a consequence of genuine stress incontinence. In order to
better diagnostic and treatment options, as minimise the surgical trauma inflicted,
well as an increased awareness of the abdominovaginal needle suspensions of
negative impact for the individual sufferer. the bladder neck, such as the Stamey
s
method, were introduced in the 1960 and
s
However, the issue is not new. -70 [10]. Concurrently, urodynamic
Annotations regarding incontinence have investigational methods developed and
been found on Egyptian papyrus rolls from new theories about the pathophysiological
2000 BC and directions for treatment of background to the symptoms were
enuresis have been found from 1550 BC presented. In the early years of 1990
(Kahun gynaecological papyrus approx. Ulmsten and Papa Petros revolutionised
1825 BC, Ebers papyrus approx. 1550 the field with their “integral theory” [11]
BC). Pelvic floor exercises as a means of and the subsequent introduction of the
treating urinary incontinence were tension-free vaginal tape (TVT) procedure
popularised by Kegel in 1948 [5], but have [12]. This minimal-invasive technique
actually been an important part of exercise rapidly gained popularity and is alongside
programmes in Chinese Taoism for more with the Burch procedure one of the
than 6000 years. The first classification of dominating surgical methods used for the
urinary incontinence (UI) is said to have treatment of female stress urinary
been drawn up by Goldberg already in incontinence at present. In the last
1616 [6]. Surgical treatment of UI, mainly decades, we have also gained important
female stress urinary incontinence, has new knowledge regarding the overactive
been performed since the later part of the bladder symptom complex and there has
th
19 century. Over the years more than a been an increased focus on research
hundred different surgical methods have aiming to improve overactive bladder
been tried, developed or rejected. The first treatment.
techniques were vaginal operations often
combined with the correction of a vaginal
7INTRODUCTION
Epidemiology prevalence can be explained by various
reasons such as the use of different
The term LUTS was introduced in 1994 in definitions, the heterogeneity of different
order to describe the patients’ complaints study populations and also population
without implying their cause [13]. sampling procedures. Large cross-
Traditionally, focus has been on UI in sectional population-based samples have
women and on other LUTS, known as however concluded that the prevalence of
“prostatism”, in men. The new term any female urinary incontinence ranges
subsequently proved to be relevant since from 20% to 40% in young and middle-
large population-based surveys in recent aged women, and then steadily increases
years have shown that bladder control with age (Figure 1) [16]. Approximately
symptoms are neither sex-, nor age- or half of the incontinence is stress type
disease-specific. (SUI), about 10% urge urinary incont-
inence (UUI) and one third mixed
Urinary incontinence is, nevertheless, still incontinence (MUI). Stress leakage occurs
the most familiar LUTS in women. more frequently in younger women
Estimates of prevalence range from a few whereas urge and mixed urinary
percent to around 50% in different studies incontinence are more prevalent in the
[14]. The wide variation in the reported older ages [14-17].
Prevalence UI
40
35
30
25 unknow n
UI percent
slight
20
moderate
15
severe
10
5
0
20- 25- 30- 35- 40- 45- 50- 55- 60- 65- 70- 75- 80- 85+
25 29 34 39 44 49 54 59 64 69 74 79 84
Age groups
(Reprinted by permission from J Clin Epid [16])
Figure 1. Prevalence of UI by age and severity.
8INTRODUCTION
Similarly to UI, the estimated prevalence of life and lower work productivity in
of other LUTS varies considerably individuals with OAB symptoms as
between different surveys. In the EPIC compared to controls [23]. Nevertheless,
study [18], which was a large European several investigations have shown that
population-based survey of UI, Overactive only a small number of women actually
bladder (OAB) and other LUTS, 66% of seek help from the medical health care
the participating women reported at least system [24-26].
one LUTS. The most common LUTS, in
both men and women, was nocturia Longitudinal studies on LUTS in women
(48.6% men, 54.5% women), which, in are scarce and only few epidemiological
women, was followed by UI and urgency data are available on the development or
(13.1% and 12.8% respectively). The the natural history of urinary incontinence
overall prevalence of OAB, in the EPIC or other LUTS (Table 1) [15, 27-37]. The
study, was 11.8%. Other large surveys annual overall incidence of UI seems to
from Europe and the United States have gather between 1-9% while estimates of
estimated the prevalence of OAB to remission vary from 4-30%. At present
approximately 17% [19, 20] in both men there are only very few population-based
and women. studies describing the natural course of
other LUTS in the same women. Møller et
Møller et al. described “bothersome al. followed a random sample of 2284
LUTS” as LUTS occurring more often middle-aged Danish women for 1 year and
than weekly, and found a prevalence of reported 10% incidence and 28%
almost 28% in 40-60-year-old Danish remission of LUTS [33]. McGrother et al.
women [21]. Several other authors have presented rather similar figures (15% and
described the bother of various LUTS and 23% respectively) during one year in a
their negative impact on quality of life. large population-based survey [32], while
Nested case-control data from the EPIC Heidler et al. in a selected population of
study showed that more than half of the women without urinary incontinence
individuals reporting OAB were bothered found annual incidence and remission
by their symptoms and that the use of proportions of 5.3% and 4.6% [29]. As for
“coping strategies” was common [22]. UI long-term longitudinal studies on LUTS in
has been shown to have a negative effect women, there are no such studies
on physical activities, confidence, self- published hitherto.
perception and social activities, UUI and
MUI being more detrimental than SUI in A detailed knowledge of the natural
this respect [2, 4, 17]. In a recent study, history of LUTS in women may help to
Coyne et al. also reported greater rates of target treatment resources, to provide ideas
co-morbidities and depression as well as for preventive steps in the future and to
significantly worse health-related quality interpret long-term medical trials.
9INTRODUCTION
Table 1. Longitudinal studies of UI, OAB and other LUTS.
First author, Country Study design Evaluated Progression Regression Duration
publication symptoms of
year follow-up
Herzog 1990 USA Prospective Ul Women: 1-yr Women: 1-yr 1+2 yrs
[30] population based incidence = 20% remission = 12%
study, men and Men: 1-yr Men: 1-yr remission
women ≥60 yrs incidence = 10% = 30%
Burgio 1991 USA Prospective Ul Cummulative Not reported 3 yrs
[15] population based incidence (at
study, women least monthly UI)
42-50 yrs = 8%
Nygaard 1996 USA Prospective Ul Baseline to 3 yrs: Baseline to 3 yrs: 3+6 yrs
[34] population based SUI = 24% SUI = 29%
study, women UUI = 20% UUI = 32%
≥60 yrs 3 to 6 yrs: 3 to 6 yrs:
SUI = 21% SUI = 25%
UUI = 28% UUI = 22%
Holtedahl Norway Prospective UI 1-yr incidence No cases of 1 yrs
1998 population based 1% remisssion
[31] study, women
50-74 yrs
Samuelsson Sweden Prospective UI Cummulative 5-yrs remission = 5 yrs
2000 population based incidence = 14% 28%
[35] study, women Mean annual Mean annual
20-59 yrs incidence = 3% remission = 6%
Møller 2000 Denmark Prospective LUTS 1-yr incidence = 1-yr remission = 1 yrs
[33] population based 10% 28%
study, women
40-60 yrs
McGrother UK Population-based LUTS Women: 1-yr Women: 1-yr 1 yrs
2004 study, men and (storage incidence = 15% remission = 23%
[32] women ≥40 yrs symptoms) Men: 1-yr Men: 1-yr remission
incidence = 14% = 26%
Hägglund Sweden Prospective UI Cummulative 4-yrs remission = 4 yrs
2004 population based incidence = 17% 16% Mean annual
[28] study, women Mean annual remission = 4%
22-50 yrs incidence = 4%
Heidler 2007 Austria Prospective LUTS other Mean annual Mean annual 6.5 yrs
[29] cohort study, than UI incidence = 5% remission = 5%
continent
women ≥20 yrs
Wehrberger Austria Prospective UI Cummulative 6.5-yrs remission = 6.5 yrs
2006 cohort study, incidence = 26% 19% Mean annual
[37] women ≥20 yrs Mean annual remission = 3%
incidence = 4%
Donaldson UK Prospective, OAB, SUI OAB: OAB: 3 yrs
2006 population based 1-yr incidence = 1-yr remission =
[27] study, women 7% 35%
≥40 yrs 2-yrs incidence = 2-yrs remission =
6% 34%
3-yrs incidence = 3-yrs remission =
7% 34%
SUI: SUI:
1-yr incidence = 1-yr remission =
7% 39%
2-yrs incidence = 2-yrs remission =
6% 39%
3-yrs incidence = 3-yrs remission =
6% 34%
Townsend USA Prospective UI Cummulative 2-yrs remission = 2 yrs
2007 cohort study, incidence = 14% 14%
[36] women 36-55 yrs Mean annual
incidence = 7%
10INTRODUCTION
Classifications Mixed incontinence (MUI) is the
complaint of involuntary leakage
The International Continence Society associated with urgency and also with
(ICS) is a worldwide organisation working exertion, effort, sneezing or coughing.
to increase the knowledge and awareness
of various problems associated with Increased daytime frequency is the
bladder control. The standardisation Sub- complaint by the patient who considers
committee of the International Continence that he/she voids too often by day.
Society is continuously working to
standardise the terminology of Lower Nocturia is the complaint that the
Urinary Tract Dysfunction. individual has to wake at night one or
more times to void.
Lower urinary tract symptoms (LUTS) are
defined from the individuals’ perspective Urgency is the complaint of a sudden
and are divided in three groups according compelling desire to pass urine, which is
to the current standards recommended by difficult to defer.
the ICS; storage, voiding and post
micturition symptoms. Most women with Urgency, with or without urge
LUTS belong to the first group - storage incontinence, usually with frequency and
symptoms. These include, among others, nocturia can be described as the
increased daytime frequency, nocturia, Overactive bladder syndrome (OAB).
urgency, OAB and urinary incontinence.
The ICS definitions of these symptoms are
as follows [38]: Etiology and pathogenesis
Urinary incontinence (UI) is the Stress urinary incontinence
complaint of any involuntary leakage of A prerequisite for urinary continence is
urine. that the urethral closure pressure exceeds
the intravesical pressure. When the
Stress urinary incontinence (SUI) is the relation is the opposite, the bladder will
complaint of involuntary leakage on effort empty, voluntarily or involuntarily.
or exertion, or on sneezing or coughing. Urethral closure pressure depends on
many factors; an adequate neuromuscular
Urge urinary incontinence (UUI) is the control, adequate pelvic floor muscle
complaint of involuntary leakage function, urethral support by the pelvic
accompanied or immediately preceded by floor, the vaginal and fascial components
urgency. together with different components of the
11INTRODUCTION
urethra itself such as the epithelium, the bladder neck or the proximal urethra to
connective tissue, vascular plexa and secure a better transmission of intra-
smooth as well as striated musculature. All abdominal pressure. Later studies have
these factors are closely linked to each however shown that there is an active
other via a complex arrangement of component to the increase in urethral
ligaments. Urinary leakage will occur if pressure rather than just a passive pressure
either the supportive tissues in the region transmission and the relationship between
of the urethra and the bladder neck are the actual position of the urethra and SUI
denervated or otherwise damaged, or if has been questioned [40].
there is a dysfunction in the urethra itself.
2) The integral theory
Stress urinary incontinence is the most The integral theory states that “stress
prevalent type of involuntary leakage in symptoms, urge symptoms, and symptoms
women and is by far more common in of defective flow may all derive, for
women than in men due to the anatomical different reasons, from laxity in the vagina
differences between men and women. or its supporting ligaments, as a result of
Several different theories behind the altered connective tissue” [11]. The theory
pathogenesis of female SUI have been proposes that the anterior vaginal wall,
published four of which will be presented through its connection to pubourethral
below: ligaments and pelvic musculature,
transmits specific pelvic muscle
1) The intra-abdominal pressure contractions which open or close the
equalization theory bladder neck and the urethra. The two
s
This theory was introduced in the 1960 most important elements are the fixation
and was dominating for a long period of of the urethra to the pubourethral-vaginal
time. It hypothesizes that the increase in ligaments and the fixation of the urethra to
abdominal pressure during straining is the suburethral vaginal wall, the so called
passively transmitted to the proximal anterior forces. The vaginal wall is also
(intra-abdominal) part of the urethra, and linked to the pubococcygeus and levator
thus contributes to the urethral closure ani muscles, constituting forces working in
pressure at physical stress. Urethral the posterior direction. Defects or
hypermobility would, according to this slackness of any of these structures can
theory, position this high pressure zone of cause SUI as a result of an imbalance
the urethra below the pelvic floor during between anterior and posterior forces, but
straining and stress leakage would occur laxity of the pubourethral ligaments and
as a consequence of incomplete suburethral hammock are thought to be
transmission of intraabdominal pressure to especially important in causing SUI. The
the proximal part of the urethra [39]. integral theory is currently the dominating
Several surgical procedures, introduced at pathophysiologal theory behind SUI
this time, consequently aim at elevating together with the “hammock hypothesis”.
12INTRODUCTION
3) The hammock hypothesis and upper urethra closed during the
The “hammock concept” does not storage phase.
contradict the integral theory but gives • The striated muscle sphincter, the so
more emphasis to the supportive layer called rhabdosphincter, is part of the outer
underlying the urethra. This anatomically layer of the female urethra. This sphincter
based theory postulates that the tissues is, together with the smooth muscle
posterior to the proximal urethra, component, responsible for upholding a
composed of the anterior vaginal wall and continuous urethral pressure at rest and
the endopelvic fascia, constitute a during bladder filling, but it is also under
hammock-like supportive layer against voluntary control. It consists of an inner
which the urethra is compressed during portion (the intrinsic striated sphincter)
strain. The stability of the suburethral and an extrinsic portion which is part of
layer depends on an intact connection of the pelvic floor musculature [42].
the vaginal wall and endopelvic fascia to
the arcus tendineus fascia pelvis and the In women who have been subjected to
levator ani muscles. In stress incontinent obstetric trauma, extensive pelvic surgery
women the supportive hammock is or irradiation stress urinary incontinence
thought to be defective and unable to may occur as a consequence of a
provide strong enough support to dysfunction in the urethra itself, so called
compress the urethra when intra- intrinsic sphincter dysfunction (ISD). ISD
abdominal pressure rises [41]. can also result from neurological or
congenital disease [43]. The urethral
4) Intrinsic sphincter dysfunction, ISD pressure in these cases is low and in its
The female urethral wall consists of an most pronounced form the condition is
outer layer of striated muscle fibres, and characterised by a permanent open bladder
an inner layer of smooth muscle fibres, neck and urethra, incapable of resisting
lined by the mucosa, submucosal vessels expulsive forces. The amount leaked is
and connective tissues. The mucosa and usually substantial and often manifests
vessels help to form a watertight seal. Two already at low physical activity. The
urethral sphincteric mechanisms are prevalence of ISD increases with
involved in controlling urine flow in increasing age and studies on apoptosis
women: have revealed an age-correlated increase
in aoptotic activity in the rhabdosphincter
• The smooth muscle sphincter consists musculature [44]. In later years, ISD as a
of the smooth muscle layer of the bladder sole diagnosis has, however, been
neck and the proximal urethra. This questioned. It is probable that
sphincter, which is a physiological and not hypermobility and intrinsic sphincter
an anatomical sphincter, is under dysfunction in many cases are interrelated
involuntary control and keeps the bladder and occur simultaneously [45].
13INTRODUCTION
Overactive bladder (with or women irrespective of UI type [48].
without incontinence) Gunnarsson and Mattiasson showed a
Urgency and OAB are believed to decreased ability to activate vaginal
originate in the bladder or from more or wall/pelvic musculature during short
less prominent neurological disorders. The contraction, measured by surface
neural regulation of bladder filling and electromyography (EMG), in women with
micturition is very complex involving both all kinds of incontinence, in contrast to
voluntary control mechanisms and healthy controls [49]. A common
involuntary reflex loops. The superior pathophysiological pathway is also
control of the micturition cycle is exerted suggested in the integral theory.
by the so-called pontine micturition centre According to this theory the laxity of the
which is under influence of the cerebral suburethral vagina and its supporting
cortex and several other brain areas. The ligaments may not only cause UI but in
cerebral voluntary control is mainly addition urge symptoms and symptoms of
inhibitory and responsible for the defective flow. The proposed mechanism
micturition reflex. An injury to this circuit is that the slackness of the pubourethral
may result in an insufficient cortical ligaments and anterior vaginal wall allows
inhibition and thereby bladder control urine to pass into the proximal urethra and
dysfunction [46]. induces a premature micturition reflex by
stimulating stretch receptors in the bladder
Abnormalities of bladder smooth muscle neck, thus causing urgency [11]. Another
have also been related to the occurrence of interesting observation, which might
bladder overactivity, for instance in cases support the presence of a common
of bladder outlet obstruction. Prolonged pathophysiological mechanism, is that
obstruction could lead to partial nerve several treatment alternatives aiming to
damage as well as metabolic effects on the treat SUI also may have a favourable
muscle cells through the production of free effect on urge or mixed symptoms [50-
radicals and lipid peroxidises [47]. 53].
Many women present with a mixture of
urinary symptoms related to urinary Risk factors
incontinence and several studies have, in
fact, shown an association between The main risk factors for urinary
different kinds of UI and OAB suggestive incontinence are age, pregnancy/childbirth
of a common pathophysiological pathway. (especially the first delivery) and
Mattiasson and Teleman demonstrated an overweight [16, 54-56].
overactive opening mechanism of the
urethra during the filling phase and a more Although pregnancy itself seems to be a
effective opening of the bladder outlet risk factor, the mode of delivery has been
during micturition in all incontinent shown to influence the risk of UI. In
14INTRODUCTION
women who have had vaginal deliveries, SUI among first-degree relatives of
the risk of UI is about twice the risk for women with SUI compared to first-degree
nulliparous women, while the relative risk relatives of continent women [63-65].
for women who have had caesarean Furthermore, the genetic influence on SUI
sections is approximately 1.5 [55]. The and pelvic organ prolapse has been studied
increased risk of UI due to vaginal in female Swedish twins, showing that
delivery might be explained by stretching genetic factors contributed to approxi-
of the pelvic floor tissues or ischaemic mately 40% of the variation in liability for
trauma to the distal branches of the both disorders [66]. There is, however, a
pudendal nerve causing denervation of the need of further studies to evaluate the
intrinsic urethral sphincter. The effect of importance of genetic factors for UI, OAB
parturition is, however, elicited by age and other LUTS. It is probable that
[55]. When specifically studying the effect different subgroups of UI are differently
of parity or delivery on the different related to genetic and environmental
subtypes of UI the data is divergent. factors [67].
Rortveit et al. found an association with
parity or mode of delivery for SUI as well While a wide variety of risk factors for the
as MUI, but not for UUI [55, 56]. Viktrup occurrence of UI have been identified,
et al., however, showed an increase of more information regarding the risk
both SUI and UUI after vaginal delivery factors for OAB and other LUTS is still
[57], which was sustained by Altman et al. needed. OAB symptoms increase with
who, in addition to increased SUI, found a increasing age and are often accompanied
significant increase in the frequency of by urinary incontinence (OAB wet) [19].
urinary urgency after vaginal delivery Neurological diseases, such as
independent of age [58]. Parkinsonism, multiple sclerosis, adult
normal pressure hydrocephalus as well as
Other suggested risk factors include cerebrovascular disease are markedly
smoking, chronic obstructive pulmonary related to OAB symptoms. However, in
disease, diabetes and neurological disease, many cases, the patient may demonstrate
previous hysterectomy and possibly also bladder overactivity without any overt
hereditary factors [54, 59-62]. neurological disease [68]. It is conceivable
that these individuals still suffer from
There is little evidence as yet available discrete pelvic floor nerve damage or
regarding the relative importance of subtle disorders in the parts of the central
hereditary factors for the development of nervous system responsible for micturition
LUTS. Family history studies have found control [69, 70].
a two- to threefold greater prevalence of
15INTRODUCTION
Diagnostic measures mobility and urinary leakage upon
provocation can be assessed. A negative
When a patient presents with any LUTS, cough provocation test does, however, not
an investigation is initiated to objectify, exclude urinary leakage. In cases of
diagnose and eventually treat her urinary leakage at straining a Bonney’s
symptoms. The basic examination aims at test can be performed. If the leakage
discovering underlying causes, suggesting ceases when the bladder neck is stabilised
a diagnosis and selecting patients for digitally (=positive Bonnney’s test) this is
specialist care. an indication of hypermobility rather than
sphincteric dysfunction. It is, however,
difficult to lift the bladder neck without
History compressing the urethra and thus the value
A careful history at the beginning of the of Bonney’s test is uncertain.
consultation is central and will form the
base for the coming assessment. The
history should include information Neurological examination
concerning previous pregnancy and Bladder dysfunction may be the initial
delivery, pathological conditions, surgical sign of a neurological disease, e.g.
interventions, radiotherapy to the pelvic multiple sclerosis [69, 70]. A brief
region, neurological diseases and previous neurological examination concerning anal
trauma. Current medication is of interest. sphincter tonus, perineal sensitivity as well
Direct questioning concerning the urinary as sensitivity and other neurological
symptoms and leakage is of paramount manifestations in the lower extremities can
importance. When and how often do the give valuable information. Thorough
symptoms appear? When did it all start? neurological testing is, however, difficult
Are there any provoking events or to perform and interpret and, hence,
situations? It is also important to serious or progressive symptoms should
understand the patient’s subjective prompt a consultation by a neurologist.
perception of her symptoms, how they
affect her quality of life and what her Micturition chart
expectations of treatment are. A self-administered micturition chart, or
volume/frequency chart, gives information
concerning the number of micturitions and
Gynaecological examination volume voided at each micturition. It also
A gynaecological examination, including gives information on the number of
cough provocation test, provides leakage episodes, the daily urine volume
information on skin changes, vaginal and the patient’s fluid intake. The
atrophy, concomitant prolapse and other micturition chart is thus a valuable
possible conditions, such as diverticula, instrument that should be included in the
tumours or myomas. Urethral hyper- basic investigation.
16INTRODUCTION
Pad test Post-voiding residual volume
A pad test is generally used in order to Post-voiding residual volume is measured
objectify a leakage and measure its either with a catheter post micturition or
magnitude. This information can also be by a bladder scan. This investigation is
obtained by a standardised quantification important to exclude possible urinary
test (below). retention.
Standardised quantification test [71] Urethrocystoscopy
The bladder is filled with a catheter to a A sudden onset of urgency symptoms and
specified volume (half the cystometric urinary leakage or concomitant bleeding
capacity) and the patient performs the increases the risk of an underlying urinary
following exercises wearing a pre-weighed tract tumour. In such cases, an endoscopic
pad: examination of the urethra and the bladder
1. Coughing strongly 5 times should be undertaken. The examination
2. Running on the spot for one minute also gives an opportunity to reveal
3. Washing hands under running cold inflammatory disorders of the lower
water for one minute urinary tract.
4. Jumping on the spot with the feet
together for half a minute
5. Jumping on the spot with the feet apart Urodynamics
and together for half a minute Cystometry is the most important of the
urodynamic procedures. Through fine
The amount of leakage is determined by catheters inserted in the bladder and
weighing the pads, and the voided volume vagina or rectum the intravesical and intra-
is measured. abdominal pressures can be measured
during filling and micturition. The
examination gives a good picture of the
Urine examination integrity of the parts in the neural system
A simple urinary test should be included responsible for micturition control, but
in the basic investigation to exclude also a good impression concerning the
urinary tract infection and detect detrusor function as well as the true
haematuria. compliance of the wall of the urinary
bladder. A “bladder cooling test” can give
The abovementioned diagnostic measures additional information about involuntary
constitute the base for assessing urinary detrusor contractions and help discrimin-
symptoms and leakage. If the symptoms ate between upper and lower motor
are complicated, the diagnosis is difficult neurone lesions [72].
or if complementary information is needed
to plan certain interventions, any of the
following examinations may be indicated:
17INTRODUCTION
Important to note, however, is that, Pelvic floor muscle training
although the diagnosis detrusor over- The aim of pelvic floor muscle training
activity (DO) requires urodynamic (PFMT) is to enable the pelvic floor
measurement, OAB is a clinical and not a muscles to regain as much strength as
urodynamic diagnosis. Patients with OAB possible in order to maintain continence in
may or may not display premature physically provocative situations. It may
detrusor contractions upon filling also improve the actions of neuromuscular
cystometry and, conversely, a connections and reflexes in the region of
dysfunctional detrusor activity may be the bladder and urethra [52]. It is primarily
found in non-symptomatic individuals. a technique to treat stress urinary
incontinence, although in some cases
patients with mixed or urge symptoms
Urography, computer tomography may also benefit from pelvic floor
and/or ultrasound exercises [50, 52]. A training programme
These investigations are indicated when should always be introduced by a
there is a macroscopic bleeding from the physiotherapist or urotherapist and should
urinary tract, when a tumour is suspected include instructions to correctly identify
or to check the upper urinary tract in the the pelvic floor muscles, exercises towards
case of bladder outlet obstruction. strength and endurance as well as training
in provocative situations. In current
practice, PFMT is advocated as first-line
Treatment options treatment for UI in women with an
estimated improvement in 60-70 per cent
Behavioural treatment of the patients [80-82]. The obvious
The simplest behavioural treatment clinical role of PFMT has, however, been
consists of different life-style questioned lately, based on the arguments
modifications such as fluid restriction, that substantial evidence from well-
weight loss and smoke cessation [73-75]. powered randomised controlled trails is
In disabled patients or patients with lacking [83].
cognitive insufficiency, toilet assistance,
routine voiding schemes or awareness
training, so-called prompted voiding, can Biofeedback
be of good help. Bladder training, whereby Biological feed-back is a technique
the individual is provided strategies to whereby the patient, by the help of
improve bladder control and prolong the technical support, is made conscious of
interval between micturitions, has also unaware events in her body. A sound or a
been shown to have good short- and long- light connected to a scale indicates either
term effect on urge/urge incontinence and the strength of the pelvic muscle
mixed urinary incontinence [76-79]. contraction, registered by a vaginal
18INTRODUCTION
squeeze device, or the activity in the detrusor contractions by inhibiting
nerves registered by surface EMG. muscarinic receptors on the surface of
Biofeedback, in combination with PFMT, smooth muscle cells and urothelial cells in
can be useful in women who have the urinary bladder. Many other organs,
difficulties in identifying and contracting besides the bladder, express muscarinic
the pelvic musculature. The effect of this receptor activity, so adverse effects are
technique in addition to PFMT alone has, common (e.g. dry mouth, blurred vision
however, not been shown to be and constipation). Several antimuscarinic
significantly better in patients with SUI drugs are available, each with a different
[84] but may have a better effect when specificity to bladder muscarinic
treating women with OAB [53]. In receptors, thus producing different adverse
patients with urge urinary incontinence effect profiles. To limit undesired side-
urodynamic measures have been tried to effects alternative routes of administration
make patients recognise and respond with (e.g. transdermal or intravesical) and
inhibition to detrusor contractions [76, extended release oral formulations have
85]. Still, the method is time-consuming been developed for certain compounds
and evidence of the effect is scarce. [89, 90].
Duloxetine is a selective serotonin/
norepinephrine reuptake inhibitor which is
Pharmacological treatment thought to increase pudendal nerve
Oestrogen substitution has been signalling to the striated urethral sphincter,
recommended for the treatment of UI in and hence increase its tonus. Although
post-menopausal women. Low-dose, duloxetine in randomised controlled trials
vaginally administered oestrogens may be (RCTs) has been shown to reduce the
of benefit for the irritative symptoms of number of incontinence episodes in
urgency, frequency and UUI. The effect is women with SUI [91, 92], the clinical use
however rather a result of the reversal of has been limited due to side-effects
urogenital atrophy than a direct action on (mainly nausea) and low compliance.
the lower urinary tract. Several Desmopressin (a vasopressin analogue)
randomised controlled studies in can be used to treat nocturia, provided that
postmenopausal women with incontinence other reasons of frequent nocturnal
have, on the contrary, shown that hormone micturitions, such as cardiac failure,
therapy either has no effect or actually diabetes and renal failure, are excluded.
worsens pre-existing incontinence [86-88]. Hyponatremia may occur as a
consequence of fluid retention and patient
Anticholinergic/antimuscarinic medica- surveillance regarding weight gain or
tion constitutes together with behavioural deranged serum natrium levels is
therapy first-line treatment of urgency/ important.
OAB and UUI. Antimuscarinics reduce
19INTRODUCTION
Intravesical treatment regimens Electrical stimulation
The antimuscarinic substance Oxybutynin Functional electrical stimulation with
is available for intravesical administration vaginal, rectal or external transducers has
in patients with detrusor overactivity (DO) been used for many years to treat SUI,
[90]. This route of administration may MUI and OAB symptoms. The basis for
result in symptom amelioration, while side this kind of management is to activate the
effects are reduced. However, the pelvic floor muscle fibres and to reinforce
intravesical route is inconvenient unless existing inhibitory reflexes from the
the patient already performs intermittent vaginal and anal region. It can be used
self-catheterisation. Other substances used either as a single treatment or in
for intravesical regimens in the treatment combination with PFMT. Treatment
of severe DO are Capsaicin, Resinfera- protocols vary in terms of stimulation
toxin (RTX) and Botulimum toxin pulse frequency, intensity and duration
subtype A (BTX-A). RTX is a potent depending on the type of incontinence and
analogue of capsaicin and belongs to a equipment used. When treating urgency
group of substances known as vanilloids. symptoms the aim of the treatment is to
These compounds act by desensitising the activate reflex mechanisms that have an
vanilloid type 1 receptor (TRPV 1) and inhibitory effect on the bladder.
inactivating C-fibres responsible for Experimental studies have indicated that
mediation of noxious stimuli and initiating frequencies of 5-10 Hz are optimal while
painful bladder sensations [93, 94]. intensity should be close to the maximum
Capsaicin and RTX have been shown to that the patient can tolerate. The
reduce symptoms in patients with detrusor stimulation is given in 20-minute sessions,
overactivity, but RCT’s are scarce and one to several times a week for five to six
more information is needed on long-term weeks. When SUI is to be treated the aim
efficacy and side-effects [95, 96]. BTX-A is to activate the slow as well as the fast
selectively blocks the release of twitch fibres in the pelvic floor
acetylcholine from nerve-endings and musculature. This requires a higher
intramuscular injections into the detrusor frequency, around 50 Hz, lower intensity
have been used to treat neurogenic and a longer simulation period (8-14 hours
detrusor overactivity. This chemical every night or day for three to four
denervation is not permanent and the months). A similar kind of long-term
injection therapy must be repeated with treatment can sometimes also be offered to
regular intervals (approximately 4-6 treat OAB. The best results of functional
months). The results have been promising, electrical stimulation have been demon-
but little is known about long-term side strated when treating urgency symptoms
effects [97-99]. Patient counselling [53, 100-102] but it has also been
regarding self-catheterisation before the questioned whether the short-term
treatment is necessary since bladder treatment is really cost-effective as a
emptying failure is common. single treatment in routine practice due to
20INTRODUCTION
poor results in the long term [103]. ing their descent during periods of
increased intra-abdominal pressure,
Voiding dysfunctions that are refractory to include pubovaginal sling procedures,
conservative treatment, particularly severe vesico-urethral suspensions (e.g.
UUI, urinary frequency and idiopathic Marschall-Marchetti-Krantz, Lapides) and
non-obstructive retention can also be abdominovaginal colposuspension techni-
treated by sacral neuromodulation, often ques (e.g.Burch). The Burch procedure
referred to as sacral nerve stimulation. [9], in which the anterior vaginal wall is
This implies direct stimulation of sacral sutured to Cooper’s ligament bilaterally, is
nerve roots at the level of S3 or S4 by by many considered as “the golden
permanently implanted electrodes. There standard” for the correction of female SUI.
are arguments that the stimulation operates The procedure can be performed as an
through the afferent nerves all the way up open or laparoscopic operation with
to the level of the cortex cerebri, like in similarly good results [106]. Needle
peripheral electrostimulating methods, but suspensions of the bladder neck, such as
the exact mode of action remains to be the Stamey method, are minimal-invasive,
elucidated [104]. The method is safe, but abdominovaginal techniques in which the
expensive and should be reserved for bladder neck is sutured to the abdominal
selective cases [105]. musculature or rectus fascia by the use of
specially designed long needles [10, 107,
108]. Most needle suspensions are
Surgical treatment performed under endoscopic control. As
First-line treatment for female SUI is for the Stamey suspension, the initial
usually conservative. In cases refractory to results of this procedure were promising,
conservative measures, surgery is but did not always seem to be maintained
generally advocated. Many surgical at long-term follow-up. Reports on long-
procedures have been described over the term results are, however, somewhat
last century. Based on the conflicting [109-112].
pathophysiological theories presented
earlier, the general surgical approaches for 2) Strengthening the urethral support
the correction of female SUI today are: Following the integral theory and the
correction of urethral hypermobility, hammock hypothesis, modern surgical
enhancing or strengthening the urethral therapy of female SUI is focused on
support or strengthening the intrinsic providing additional support at the mid-
sphincter mechanism. urethra to restore continence (e.g. TVT or
TOT). In the TVT-procedure, a poly-
1) Correction of urethral hypermobility propylene sling is placed beneath the mid-
Procedures to suspend and stabilise the urethra in a tension-free manner, through a
bladder neck and proximal urethra in a retropubic route, using specially designed
high retropubic position, thereby prevent- troacars. The method is minimal-invasive
21INTRODUCTION
and several publications have reported on sphincter [127].
its simplicity, safety and efficacy [113-
116]. However, in order to avoid the risk A sling procedure implies the placement
related to the blind passage of troacars of a sling around the urethra through an
through the retropubic space, a incision in the abdominal wall on either
transobturator route to sling placement has side. Biological or artificial sling materials
been developed (TOT) [117]. The TOT- can be used. Pubovaginal slings enhance
sling passes through the obturator the bladder outlet resistance through two
foramina and beneath the mid-urethra, mechanisms. During an increase in the
thus preserving the principle of mid- intrabdominal pressure the sling is drawn
urethral support while avoiding the upwards and thereby increases the
potential risks of TVT-placement. The intraurethral pressure (active mechanism).
TOT method is theoretically safer, with The sling also supports the urethra and the
less risk of serious complications such as bladder neck, thus increasing the passive
bladder perforation and injury to the bowel resistance. Common complications of the
and major blood vessels. At present, the sling procedures are voiding difficulties
published experience from RCT’s shows including urinary retention and, for
no significant differences in cure rate or artificial slings, erosion into the urethra or
complications rate between the two rejection of the graft [128-130].
techniques [118-120].
Periurethral injection of various expansion
Although mid-urethral sling procedures substances is a minimal-invasive option to
are effective and generally associated with treat ISD by creating an artificial
less morbidity than colposuspension and cushioning around the urethra. Several
pubovaginal slings, they have potential compounds have been tried for this
disadvantages. These are mostly related to purpose, e.g. Teflon, silicone, collagen,
the blind passage of needles and troacars autologous fat and dextranomers in
through body tissues, postoperative hyaluronan (DiHA). Teflon and silicone
voiding dysfunction and complications of both have the disadvantage of possible
using a synthetic sling material [116, 121- distant migration, collagen may cause
124]. allergy and is rapidly degraded and
injection of autologous fat may cause fat-
3) Strengthening the intrinsic sphincter embolism. DiHA seems to be a more
mechanism favourable substance, but blind injection
Surgical techniques to support a damaged by the use of an implacer has been
sphincter mechanism comprise pubo- associated to the development of sterile
vaginal sling procedures including TVT abscesses. Cure rates of around 50% using
[125], periurethral injections of a bulking periurethral injections have been reported
agent [126] or implantation of an artificial [126, 131-135]. Considering the difficulty
22INTRODUCTION
in treating sphincter insufficiency, incontinence operation [51] in accordance
especially iatrogenic, an attempt with with the integral theory.
injection therapy may be justified.
In severe cases of urge urinary
The artificial urinary sphincter is a incontinence, refractory to conservative
mechanical device applied around the measures, a clam cystoplasty might lead to
urethra, which compensates for urethral symptom resolution [137, 138]. This is a
sphincter insufficiency by compressing the procedure in which the bladder is split
urethra. The equipment consists of a transversally in two halves down to the
silicone inflatable cuff positioned around trigone. Between them, an antimesenteric-
the urethra, a pressure-regulating balloon ally opened section of the small intestine
placed in the abdominal cavity and a pump is interponated. In this way, dysfunctional
placed in the labium majus in women or in detrusor contractions are damped. The
the scrotum in men. The patient regulates procedure increases bladder capacity and
the opening of the sphincter during reduces intravesical pressure upon detrus-
micturition by squeezing the pump, which or contraction by neutralisation of the
in turn decompresses the urethral cuff. The pressure wave. Bladder emptying can,
success rate is high, but the procedure is however, be unsatisfactory and clean
more risky in women and the equipment is intermittent self-catheterisation is necess-
expensive. Malfunction over time is ary in approximately one third of the cases
common [127, 136]. Implantation of an postoperatively. Other common side
artificial sphincter should thus be effects are increased bowel frequency,
considered a last resort procedure. vitamin B12-deficiency and sporadic
urinary tract infections. For very severe
Major reconstructive surgery for cases, in which it is not possible to achieve
refractory OAB an acceptable function via reconstruction
Surgical management is generally not of the lower urinary tract, a urinary
first-line treatment for UUI. Nevertheless, diversion may sometimes be the only
some patients with mixed incontinence remaining option.
may benefit from a conventional
2324
AIMS OF THE STUDY
The overall aims of this thesis were to describe the prevalence and natural course of
different LUTS in women, to assess possible changes in the prevalence of various LUTS
over time, and to evaluate potential genetic influence on the prevalence of LUTS.
SPECIFIC AIMS:
• To describe the natural course • To assess the relative contribution of
(prevalence, progression and genetic and environmental factors for
remission) of UI, OAB and other the occurrence of LUTS in women.
LUTS in women through a population-
based longitudinal study. • To evaluate long-term results of the
Stamey abdominovaginal colposuspen-
• To assess possible time-trends sion for the correction of female stress
regarding the prevalence of various urinary incontinence.
LUTS, health care seeking and
treatment due to UI in women.
• To estimate the prevalence of UI, OAB
and other LUTS in a large population
of Swedish twins.
2526
METHODS
In 1991, a population based survey of UI those who did not answer the first
was conducted in Gothenburg, Sweden invitation.
[17]. Every fourth woman (n=2911) from
the total female population aged ≥20 years, We (re-)assessed the data on UI, OAB and
resident in the Central District of other LUTS from 1991 and the data
Gothenburg, was randomly selected from obtained in 2007 according to the current
the Swedish Population Register and definitions approved by the International
invited by letter to complete a Continence Society (ICS) 2002. In Paper I
questionnaire regarding UI and other longitudinal comparisons of the data from
LUTS, e.g. frequency, urgency and the same women participating in the study
nocturia (Appendix 1). The women’s in 1991 and 2007 was made. In Paper II
quality of life (QoL) was assessed using a comparisons between the two cross-
visual analogue scale. Medication being sectional samples were performed.
taken at the time was recorded, as was
reproductive history and demographic Paper III is a national, population-based,
parameters considered to be relevant. cross-sectional survey of UI, OAB and
Validation of the questionnaire, including other LUTS in a cohort of Swedish twins
a detailed medical history and examina- born in 1959-1985 (n=42 582) identified
tion, was made in 1991 in a sub-sample of through the Swedish Twin Register (STR).
women (n=140) complaining of UI, and The twins were contacted by letter in 2005
UI was confirmed in 98%. and invited to participate in a web-based
survey in order to screen for common
In Paper I, the participants from 1991 who complex diseases and common exposures.
were still alive and available in the Those not responding to the web
Swedish Population Register in 2007 questionnaire were phoned and offered the
(n=1408) were asked by letter to complete possibility of answering the survey
a similar questionnaire as in 1991. If no through a telephone interview. The
reply was received follow-up letters were questionnaire comprised a section of
mailed after approximately one and three questions relating to lower urinary tract
months. function. Prevalence rates of UI, OAB,
nocturia and frequency were determined
In Paper II, a new group of 3158 women according to the ICS definitions. Twin
aged 20 years or above (every fourth), similarity and heritability of these
resident in the same urban district in 2007, symptoms were estimated in female twins.
was randomly selected from the Swedish
Population Register and was invited to Paper IV is a retrospective study in which
complete the same postal questionnaire. 24 out of 37 women consecutively
Follow-up letters were mailed after operated on at the Dept. of Urology,
approximately two and three months to Sahlgrenska University Hospital, with the
27METHODS
Stamey needle colposuspension method on any of these preoperative investigations
for the treatment of SUI, between October was missing. All patients had gone
1992 and March 1999, were followed up. through a standardised surgical procedure
and had been subjectively evaluated after
The inclusion criteria were: 6 months by the surgeon. Long-term
1. Preoperatively stable detrusor follow up was performed at a minimum of
2. Preoperatively normal filling- 24 months postoperatively. The patients
cystometry were requested to complete a question-
3. Preoperatively normal naire with questions about UI, co-
urethrocystoscopy morbidities, complications and satisfaction
4. Preoperatively objectively confirmed of the Stamey operation during a personal
urinary leakage on a standardised (or a telephone) interview (Appendix 4).
quantification test They were also asked to undergo a filling
cystometry and a new standardised
Women were only excluded if the above quantification test.
criteria were not fulfilled or if information
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