Abstract
The female pelvic floor undergoes a large numbers of adaptive changes, related to life and endocrine events. The injuries and functional modifications of female pelvic floor due to pregnancy, life events and aging are associated to several changes that may predispose to pelvic floor dysfunctions (PFD). PFD globally affects micturition, defecation and sexual activity and their incidence increases dramatically with age and menopause.
The female pelvic floor undergoes a large number of adaptive changes, related to life and endocrine events. The injuries and functional modifications of female pelvic floor due to pregnancy, life events and aging are associated to several changes that may predispose to pelvic floor dysfunctions (PFD). PFD globally affects micturition, defecation and sexual activity and its incidence increases dramatically with age and menopause.
Pelvic organ prolapse (POP), female lower urinary tract symptoms (FLUTS), chronic obstructive defecation syndrome (OFD), constipation and sexual dysfunction are just a few of the many aspects of PFD. POP and FLUTS are the most common pelvic floor dysfunctions in postmenopausal women [1].
Pathophysiology
Menopause, Ageing and PFD
Symptoms and severity of PFD increase after the menopausal transition and worsen with time. The effect of ageing and menopause cannot be clearly separated in midlife women. On the other hand, the sharp decline of estrogen levels cannot be neutral in the pelvic muscular and connective tissues that are estrogen sensitive and responsive. The female genital and lower urinary tracts share a common embryological origin, arising from the urogenital sinus, and both are sensitive to the effects of the female sex steroid hormones. Estrogen receptors (ER) are present in the epithelial tissues of the bladder, trigone, urethra, vaginal mucosa and in the support structures of the utero-sacral ligaments, as well as in levator ani muscles and pubo-cervical fascia [2]. Estrogen is involved in the increase of cell maturation index of these epithelial structures. It has been shown that alterations in the ratio of estrogen to ER may be involved in the development of stress urinary incontinence [3]. Estrogens control the synthesis and metabolism of collagen in the lower genital tract and increase the amount of muscle fibres in the detrusor muscle and in the urethral muscle layer [4, 5]. Estrogens may also influence the neurologic control of micturition in the central nervous system, altering the density of sympathetic nerve fibres in the pelvis and the central and peripheral synthesis of neurotrophins, even if this set of actions is not fully understood [6]. Progesterone receptors (PR) are also expressed in the lower urinary tract, even if with less density than ER. There is evidence that progesterone has adverse effects on female urinary tract function since it is linked to an increase in the adrenergic tone, provoking a decreased tone in the ureters, bladder and urethra.
The sensitivity to sex steroid hormones of the urogenital tissues has been advocated as an explanation for the common appearance of FLUTS at menopause. Most of the urogenital dysfunctions such as urinary incontinence (UI), voiding dysfunction, recurrent urinary tract infection (UTI), dyspareunia and POP are increased by declining levels of estrogen. This observation has been recently elaborated by a panel of experts into a unifying concept called the genitourinary syndrome of menopause (GSM) [7]. GSM is defined as a collection of symptoms and signs associated with a decrease in estrogen and other sex steroids involving changes in the labia majora/minora, clitoris, vestibule/introitus, vagina, urethra and bladder. The syndrome may include but is not limited to genital symptoms of dryness, burning and irritation; sexual symptoms of lack of lubrication, discomfort or pain, and impaired function; and urinary symptoms of urgency, dysuria and recurrent urinary tract infections. Women may present with some or all of the signs and symptoms, which must be bothersome and should not be better accounted for by another diagnosis [7].
Moreover, the ageing process can induce per se several changes in the structure and function of the lower urinary and genital tract. Several physiological and pathological bladder changes that frequently occur with aging are closely related to FLUTS. With aging, the adaptive mechanisms that are able to adjust the functional bladder capacity to urine production become less evident. The bladder sensation and ability to empty the bladder seem to decrease with advancing age as a possible consequence of neuronal loss and remodelling of the bladder and urethra [8]. In women suffering from FLUTS, there is a persistent correlation between age and terminal detrusor overactivity and a reduction of the functional bladder capacity. These age-related changes have also been detected at urodynamic testing [9]. From bladder structure point of view it seems that aging is associated with several changes in bladder properties. Some studies have showed a relationship between aging, oxidative stress, inflammation and bladder dysfunctions [10, 11].
Pelvic floor laxity depends on muscle injury and progressive pelvic floor weakening during the aging process. These result from connective tissue degradation, pelvic denervation, devascularization and anatomical modifications, all determining a decline in mechanical strength and dysynergic pelvic floor function, predisposing to POP and bowel dysfunctions.
Aging can induce changes in the structure and function of the gastrointestinal tract, especially in the colon and in the anorectal region. Within the aging process, there could be a reduced rectal sensation and an increased rectal compliance, anatomical anal canal changes and anal sphincter degeneration and atrophy. These changes can impair bowel habits and evacuation mechanisms [12].
Clinical Assessment of Female Pelvic Floor
An overall assessment should include evaluations of general fitness, balance and mobility and cognitive status. If symptoms suggest a neurologic disease, a basic and pelvic neurologic examination should be performed. In midlife women, the first focus on pelvic examination should always be on overall vulvo-vaginal health.
Several signs are discoverable on pelvic examination. First the evaluation of the presence of signs of vulvo-vaginal atrophy (VVA) and of anatomical defects. Pelvic visceral support is assessed by first observing the presence or absence of a bulge at the introitus with Valsalva effort. Speculum examination is required to accurately assess support. Over the last 15 years, measures to evaluate POP were improved. There is now an internationally accepted standard for describing, quantifying and staging female pelvic support, Pelvic Organ Prolapse Quantification (POP-Q), and a number of valid, reliable and responsive symptom questionnaires and condition-specific health-related quality-of-life (HRQOL) instruments [13, 14]. The POP-Q allows a reproducible description of the support of the anterior, posterior and apical vaginal segments using precise measurements to a fixed reference point, the hymen, and established criteria for staging the various levels of pelvic organ support from good support (POP-Q stage 0 or I) to almost complete lack of support (POP-Q stage IV). Other discoverable signs include the presence of vulvar abnormalities, urethral caruncle and urethral diverticulum.
Pelvic floor muscle assessment is generally assessed by palpating levator muscle contraction and then grading it subjectively. In 2005, the Pelvic Floor Clinical Assessment Group of the International Continence Society recommended use of a simpler classification: absent, weak, normal and strong. Normal muscle tone or abnormal muscle tone in terms of hyper- or hypotonicity should be evaluated. Maximal voluntary contraction (MVC), muscle strength, local muscle endurance and muscle coordination are other important parameters. Pelvic floor muscle assessment may help determine whether a patient is a candidate for a trial of pelvic floor physiotherapy or whether she is a candidate for other treatments.
The presence of stress urinary incontinence (SUI) can be objectively documented at this time by asking the woman to cough forcibly (the ‘cough stress test’). If SUI is present, where surgical intervention is being considered, it is important to ascertain the mobility of the bladder neck. Principal methods are the simple visual assessment of bladder neck descent during straining or cough or the bladder neck position evaluation by ultrasound. At the time of initial clinical assessment, it is simple to assess a postvoid residual (PVR) volume. It can be assessed either by in and out catheterization or ultrasound following a spontaneous or demand void. PVR < 100 ml is generally accepted as normal. This is a key instrument in patients with anterior vaginal wall prolapse but also in women without POP complaining of incomplete emptying or recurrent UTI. Uroflowmetry is a useful clinical adjunct to PVR measurement. It involves measurement of the voided volume, flow rate and flow pattern. As a diagnostic tool, uroflowmetry helps define the voiding function in selective patients.
Finally, a screening urinalysis should be performed to rule out infection. Urine cytology and cystoscopy are in general reserved for those patients with irritative symptoms, recurrent infections, or persistent hematuria, in order to rule out malignancy or foreign body presence in the bladder (usually a stone).
Clinical Conditions and Management
Female Lower Urinary Tract Symptoms (FLUTS)
FLUTS, such as UI, overactive bladder syndrome (OAB) and voiding dysfunctions (incomplete bladder emptying, urinary retention), are prevalent in postmenopausal and elderly women. These conditions can interfere with daily life and can lead to negative effects on HRQOL.
According to the definition of the International Continence Society (ICS), UI is the complaint of any involuntary leakage of urine. Urgency urinary incontinence (UUI) is defined as involuntary leakage of urine, accompanied or immediately preceded by urgency. SUI is the complaint of involuntary leakage on effort or exertion or sneezing or coughing. Mixed urinary incontinence (MUI) encompasses urge UI and SUI. The complaint is of involuntary leakage associated with urgency and with exertion, effort, sneezing, or coughing [15].
Prevalence and severity of UI increases with age. Current data provide very disparate prevalence estimates for UI in women. Isolated SUI accounts for approximately half of all incontinence, with most studies reporting 10–39 per cent prevalence. With few exceptions, MUI is found to be next most common, with most studies reporting 7.5–25 per cent prevalence. Isolated UUI is uncommon, with 1–7 per cent prevalence, and where recorded at all, other causes of incontinence occur with approximately 0.5–1 per cent prevalence. Prevalence rates from cross-sectional studies uniformly demonstrate an association with age [16, 17]. Annual incidence rates for broad definitions of UI (‘monthly’ or ‘any’) range from 0.9 to 18.8 per cent, while rates for weekly UI show less variation at 1.2–4.0 per cent [17]. The age distribution for incontinence of all causes reported in the EPINCONT study shows a distinct peak in slight incontinence around the time of the menopause.
Despite a number of high-quality longitudinal studies, the literature on risk factors for incontinence is very heterogeneous. Among women, age, BMI, parity and mode of delivery are associated with incontinence.
OAB is urinary urgency, with or without urgency incontinence, usually with increased daytime frequency and nocturia, if there is no proven infection or obvious pathology [15]. There is evidence that estrogen deficiency may increase the risk of developing OAB after menopause [5]. The prevalence of OAB increases with age (19.1 per cent in women between 65 and 74 years of age) [18]. OAB incidence varies between 3.7 and 8.8 per cent [19]. While age is a clear risk factor for urinary urgency and/or OAB, other risk factors have not been that well studied.
OAB and UI are terms to describe the clinical problem of urgency and incontinence from a symptomatic rather than from a urodynamic perspective [20]. Symptoms alone can help determine treatment paths and define the impact on quality of life. Urodynamic testing is performed for objective diagnosis and is often used prior to surgery. Such testing defines urodynamic stress incontinence as objective urine loss with increased intra-abdominal pressure in the absence of a detrusor contraction. This objective finding would be expected in most women complaining of SUI. Additionally, urodynamics objectively define the condition of detrusor overactivity, a bladder dysfunction with uninhibited detrusor muscle contractions (with or without urine loss) on bladder filling in the absence of infection or the obvious bladder pathology. Detrusor overactivity is most often associated with UUI and/or OAB symptoms.
Management and Treatment of Urinary Incontinence (UI)
In the management and treatment of UI different options are available, including pelvic floor muscle training (PFMT) and physical therapies, drugs, surgery and neuro-modulation strategies.
Conservative Management: Behavioural Modification, Physical Therapy and PFMT
UI can successfully be managed initially at the primary care level in most patients. Referral to a specialist is usually indicated when conservative measures fail to improve symptoms. Women with all types of UI can be advised to decrease their intake of fluids, caffeine and carbonated drinks. Further behavioural modification includes timed voiding, with a goal of reducing voiding frequency to every two to three hours. Bladder training (BT) should be recommended as first-line conservative therapy for UI in women. Constipation should be managed and avoided because this contributes to UI and voiding dysfunction [21].
PFMT has a crucial role in the treatment of UI. Because PFM integrity appears to be a key factor in the continence mechanism, there is a biological rationale to support the use of PFMT in preventing and treating both SUI and UUI in women. The role of PFMT in the treatment of UUI is related to the capacity of PFM contraction to prevent the leakage during detrusor contraction as well as inhibit and suppress detrusor contraction [21].
Laser therapy has gained attention as an effective treatment for VVA and an increasing body of evidence suggests its potential in improving urinary continence and possibly pelvic support. The concept behind laser procedures to treat vulvo-vaginal conditions is to use a wavelength having high water absorption, such as the carbon dioxide (CO2) laser and the Erbium (Er:YAG) [22, 23]. Laser treatment induces tissue remodelling, with histological evidence of the restoration of vaginal mucosa, a thickening of the epithelium, with the maturation of epithelial cells, a new formation of papillae indenting the epithelium with newly formed and extended small vessels [22, 23]. In addition, in the connective tissue underlying the epithelium, the formation of new thin fibrils and morphological features of fibroblasts supporting a renewal of the extracellular matrix with functional restoration are generated. Fractional CO2 laser was the first used to treat vaginal atrophy. According to the concept of fractional photothermolysis, CO2 lasers ablate a fraction of the vaginal mucosa in the treatment area. At variance, the second-generation non-ablative vaginal Er:YAG laser (VEL) induces morphological changes via a non-ablative thermal diffusion to the vaginal walls. Besides the effects of VEL on the treatment of VVA, the efficacy of VEL in SUI has been reported in observational studies, in long-term cohort studies, and confirmed in a RCT study [22–31]. VEL may provide a safe and effective alternative in women suffering from PFD, being less invasive than the current surgical gold standard for SUI, offering a possible solution for women suffering from mild-moderate SUI that are not candidates for surgery. The possible synergistic effect of VEL and PFMT is currently under investigation.
Drug Treatments and Surgical Options
Medical therapy is a usually a valid option for women with UUI and MUI. Estrogen has been used to treat incontinence over a number of years, either alone or in combination with some of these other options, and there is evidence that UI may improve with local estrogen treatment [10]. In contrast, systemic hormone replacement therapy seems to worsen UI [11]. The possible worsening of UI with systemic estrogen therapy as well as the concerns about adverse effects of systemic treatment (for example regarding breast cancer, effects on endometrium or thromboembolic diseases) makes further evaluation of local estrogen therapy in the treatment of UI of great value. The currently available evidence has to be interpreted with caution because the treatment effects are based on a relatively low number of patients and a wide range of types, dosages and durations of estrogen treatment [32]. Moreover, also in the studies regarding local estrogen treatment for urinary tract symptoms, there is a diversity in the outcomes measured (urodynamic or clinical) and populations studied. The available evidence regarding vaginal estrogen therapy in postmenopausal women with OAB symptoms (urinary urgency, frequency, nocturia, with or without UUI) is encouraging [33]. However, it is not clear if subjective improvement in OAB symptoms reflects a direct effect on lower urinary tract function or an indirect effect via reversing vaginal atrophy [34].
A positive effect of the new SERM Ospemifene administration has been reported in women suffering from mixed urinary incontinence and OAB [35]. The possible role of Ospemifene in women suffering from PFD warrants further, properly sized studies.
Drug should be initiated after conservative methods have been tried and antimuscarinic drugs, combined with local estrogens, constitute first-line medical treatment in postmenopausal women with symptoms suggestive of an OAB [36]. Antimuscarinic agents may be associated with adverse effects. The human bladder tissue, the brain, the salivary glands, the cardiovascular system and the eye contain muscarinic receptors. As a result, antimuscarinic agents are effective in treating OAB symptoms, but they may also be associated with adverse effects such as dry mouth, constipation, cognitive impairment, tachycardia and blurred vision. These side effects are not uncommon and may lead to failure of treatment due to people stopping the use of the drugs. The use of these medications is contraindicated in patients with narrow-angle glaucoma, urinary retention or gastric retention. New-generation drugs such as solifenacin and fesoterodine have been shown to be more efficacious than tolterodine [37]. A beta-3 adrenergic receptor agonist (β3-AR agonist) has been introduced as a means of medical management of OAB. It is a safe, effective and well-tolerated new class of drug. Pharmaceutical companies have developed selective β3-AR agonists targeted at urinary inconsistencies approved such as Mirabegron. Mirabegron has a particular affinity for β3 adrenoceptors and improves the storage capacity of the bladder with little effect on the contractile ability of the bladder [38]. Mirabegron can improve the symptoms of patients who have not had adequate response to antimuscarinics and its tolerability profile offers potential to improve patients’ adherence with treatment for OAB [39].
In case conservative management and medical treatment are not successful after 8–12 weeks, specialized management should be considered [40]. According to the American Urology Association and European Urology Association guidelines recommendations, onabotulinumtoxin-A intravesical injection and neuromodulation are considered the third-line treatments for patients without response to medical treatment [41]. Onabotulinumtoxin-A is a neurotoxin that inhibits acetylcholine release from presynaptic neurons with decrease in acetylcholine availability in the neuromuscular junction and detrusor paralysis. The technique involves injection of onabotulinum-A in multiple sites throughout the bladder wall, whilst avoiding injecting the trigon. This technique is being increasingly used to treat severe OAB refractory to standard management both for neurogenic and idiopathic overactive bladder. The most frequent adverse effects following the administration of the toxin are urinary retention and urinary tract infection. The duration of effect of botulinum toxin type A may range from 3 to 12 months. Intravesical botulinum toxin appears to be an effective therapy for refractory OAB symptoms, but as yet little controlled trial data exist on benefits and safety compared with other interventions, or with placebo [42]. Sacral nerve stimulation can be used as an alternative to botulinum injections in patients who are dissatisfied or in whom such treatment with botulinum toxin-A treatment fails. Sacral nerve stimulation follows a test phase with temporary electrodes placed next to the S3 sacral nerve root. If sufficient symptomatic improvement is given, the definitive electrode can be placed, with a subcutaneous stimulator. Incontinence episodes and voiding frequency are both reduced while receiving sacral nerve stimulation, with a significant improvement of quality of life [43]. Percutaneous tibial nerve stimulation (PTNS) is a form of peripheral neuromodulation. PTNS uses a removable device with a fine needle, penetrating the skin at the level of the posterior tibial nerve two fingers above the malleolus medialis of the ankle. The indication of proximity to the nerve is the observation for intrinsic foot muscle contraction. The stimulus is applied for half an hour. Treatment is repeated at weekly intervals. There is strong evidence for the efficacy of PTNS on frequency and urgency UI and limited evidence for nocturia and urgency [44].
From a surgical perspective injectable bulking agents, laparoscopic suspensions (laparoscopic ‘Burch’ colposuspension), mid-urethral slings, pubovaginal slings and open retropubic suspensions are available strategies in treatment of SUI.
Retro pubic (RP-TVT) and trans obturator mid-urethral (TO-TVT) mid-urethral sling (MUS) are today the most popular surgical treatments for female SUI. The surgical strategy of sling stems from the ‘hammock’ hypothesis. This describes the urethra as being compressed against a hammock-like supportive layer to assist in the urethral closure mechanism during an increase in intra-abdominal pressure, such as during a cough. This theory originated with the work of Petros and Ulmsten, who described how alterations in connective tissue may cause laxity in the vagina and its supporting ligaments and lead to incontinence [45]. Success rates of mid-urethral slings range from 84 to 99 per cent [46]. Risks of surgical correction include bleeding, pain, infection, de novo urgency, urinary retention and failure of treatment. The long-term efficacy and safety of the procedures is still a topic of intense clinical research and several randomized controlled trials (RCTs) have been published in the last years.
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