7. Influences and Complications
Mixed urinary incontinence (MUI) refers to the combination of symptoms of both stress and urgency incontinence. According to the International Continence Society (ICS), MUI is defined as the involuntary loss of urine associated with the sensation of urgency and also with exertion, effort, sneezing, or coughing. Although MUI may affect both female and male patients of all ages, it is more common in women. Multiple studies comparing health-related quality of life have found that patients with MUI have a greater negative impact on quality of life than either stress urinary incontinence (SUI) or urgency urinary incontinence (UUI). MUI needs proper assessment, and treatment is challenging, often requiring multiple treatment modalities.
The commonest symptom of pelvic organ prolapse (POP) is the feeling of a bulge through the vagina which causes discomfort. However, POP is commonly associated with bladder, bowel, and sexual dysfunction symptoms.
With obesity rates on the rise, the metabolic syndrome (MetS) is an increasingly common problem. MetS refers to a clustering of interrelated risk factors for cardiovascular disease (CVD) and type 2 diabetes (T2DM). Patients with MetS are at increased risk of a number of other conditions, including LUTS. The presence of MetS identifies a subgroup of the overweight and obese population, that is at increased risk of CVD, T2DM, and LUTS. Physicians should be alert to the presence of MetS and aware of the associated risks in men with LUTS. As all the components of MetS are reversible, a timely diagnosis is important, for the early initiation of effective lifestyle and risk factor modification, to reduce cardiovascular and metabolic risks, and slow the progression of BPH/LUTS.
Recurrent urinary tract infections (rUTIs) are epis odes of UTIs with a frequency of at least three per year. Each rUTI episode should be confirmed by urine culture. They may be caused either by bacterial persistence or by reinfection. In bacterial persistence, recurrent infections are caused by the same organism and the time interval between each infection is short. The bacteria originate from a site within the urinary tract, thus identification and surgical removal or correction of the focus are crucial for successful treatment. Reinfection is often caused by different species and the interval between infection episodes varies and can be rather long. It is uncommon in men and might be associated with an underlying urological condition. In women, on the other hand, reinfection is common and is usually associated with ascending colonization from the bowel flora. Inflammation of the prostate (prostatitis) and infection of the gland are common clinical problems, and around 10% of adult men may have symptoms of prostatitis at any given time.
While a number of risk factors exist for the development of LUTS, sexually transmitted infections (STIs) hav e been suggested to play a pathogenic role. Sexually acquired pathogens, typically during young adulthood, produce genital tract inflammation that may play a role in the development of LUTS at the time and later in life. STIs are prevalent, with millions of cases reported annually. There is much focus on the economic burden of these diseases, given the extraordinary amount of healthcare costs and resources spent on screening and treatment. However, the long-term cost to the patient is less recognized. Through a variety of mechanisms, STI-mediated inflammation appears to play an important role in the development of significant urinary tract morbidity. Though conflicting evidence exists, several clinical studies have found positive associations between moderate or severe LUTS, and history of gonorrhea, syphilis, HIV, and other sexually acquired viruses in high-risk patient populations. Some evidence supports that treatment of the causative pathogen may help to mitigate symptoms, but the effect of urinary symptom-directed treatments in patients with history of STI is unknown. While limitations to the available data must be considered, providers should discuss the risk of LUTS when counseling patients about STI treatment and prevention.
An increased understanding of the contribution of psychiatric and psychological problems to the onset, maintenance, and severity of LUTS is needed in clinical practice. Patients seeking help for LUTS should be screened for affective disorders because this will help to identify those at risk of treatment non-adherence. It is also important to consider the underlying causes of psychological distress. For instance, there is strong evidence for an association between life stressors, abuse (sexual, physical, and emotional), and urinary symptoms [1–3], highlighting the need for clinicians to consider these as possible contributing factors. If causal effects exist between affective symptoms and LUTS, interventions aimed at reducing affective symptoms and/or addressing the causes of psychological distress could lead to an improvement in LUTS. Although further research is needed to determine the exact mechanisms underlying the link between LUTS and affective disorders, treating depression and anxiety in these patients will lead to improvements in their quality of life.
The elderly population frequently manifests lower urinary tract symptoms (LUTS), either transiently or permanently. The susceptibility to LUTS is related to aging, urologic diseases, dementia, and other neurological conditions and polypharmacy. In the elderly population, a thorough medical history, physical exam, urinalysis, and post-void residual are crucial. Physician awareness is of utmost importance. At the other end of the adult age spectrum, adolescents transitioning to the adult urology services need to be cared for with consideration of their specific mechanisms of LUTS, and their personal situation.
7.2 Mixed Urinary Incontinence
Different theories have been de scribed to explain MUI. The first theory suggests that separate disease processes (SUI and UUI) co-exist, cumulatively contributing to more bothersome symptoms . Another theory describes behavioral changes in voiding habits in women with SUI. These women retrain the bladder by voiding more frequently to avoid leakage associated with SUI. This pattern behavior to avoid stress-induced leakage may lead to a “pseudo-urgency syndrome” . So me authors have suggested that urethral dysfunction has a central role in MUI. The third theory on the pathogenesis of MUI hypothesizes that, during intra-abdominal pressure in the presence of bladder neck incompetence, urine enters the proximal urethra leading to a reflex detrusor contraction . Stress-induced detrusor overactivity may thus lead to incorrect classification of symptoms as MUI when, in fact, SUI is the true cause of the complaints .
Assessment of patients with MUI begins with a thorough history of the patient’s urinary symptoms. These include onset and timing of stress and urgency urinary incontinence, history of any urinary tract infection or sexually transmitted diseases, an obstetric history, bowel function, neurological symptoms, validated symptom, and quality of life questionnaires, and history of previous pelvic or vaginal surgery. Urinary symptoms must be assessed in terms of duration, frequency, and impact on quality of life. It is essential to determine whether the patient has stress predominant or urgency predominant urinary incontinence.
Physical examination is the next step in a patient’s evaluation. It includes a general, neurological, abdominal, and pelvic examination. Calculating body mass index (BMI) of the patient is important, since overweight and obesity are important modifiable risk factors for the development of incontinence. The abdominal examination focuses on checking for masses that may be present. Pelvic examination should include evaluation of urethral mobility, pelvic organ prolapse, urogenital atrophy, and objective stress incontinence during stress test. In addition, assessment of the pelvic muscle floor and rectal tone is important. Anatomical changes leading to a lax pelvic floor have been found to contribute to MUI symptoms.
Investigations include a urine dipstick, post-void residual, voiding diary, and pad test. Secondary testing including cystourethroscopy and urine cytology to rule out pathologic conditions of the bladder may be recommende d only in specific cases, acco rding to the results of initial workup . Urodynamic study (UDS) is an important tool in determining the underlying etiology of patient’s MUI especially when symptoms are unclear. The American Urologic Association (AUA) and Society of Urodynamics, Female Pelvic Medicine & Urogenital Reconstruction (SUFU) guideline on Urodynamics state that “in the setting of mixed urinary incontinence, UDS may c ontribute by aiding in symptom correlation. However, these tests may not precisely predict outcomes of treatment” . The utility of UDS in this context is influenced by a poor sensitivity for detection of detrusor overactivity (DO). Physicians may counsel patients that the absence of DO in the UDS does not exclude MUI as the cause of their symptoms. Conversely, guidelines in urinary incontinence proposed by the European Association Urology (EAU) suggest that findings consistent with DO can greatly influence treatment options and the persistence of urgency in patients submitted to surgical treatment to SUI component . The challenge in using UDS is that, in many cases, the test does not show findings that match the patient’s symptoms and is, therefore, inconclusive [10, 11]. Th e UDS is especially important in patients in whom invasive, potentially morbid, or irreversible treatments are considered. Videourodynamics allows simultaneous assessment of structure and function and can be used in cases that conventional UDS was inconclusive .
Conservative therapy should be con sidered as first line. Goals include correction of voiding patterns, improvement in the ability to suppress urgency, and increase in bladder capacity and continence. Conservative therapy includes lifestyle interventions such as weight loss, decreased fluid intake and caffeine moderation, bladder training, anti-incontinence devices, electrical stimulation, and pelvic floor muscle training (PFMT). It is important to note that PFMT should be used as first-line therapy in women with urgency predominant incontinence, although it is more likely to show some benefit on the stress incontinence component. There are some studies that show lower effect of PFMT in MUI patients than in women with pure SUI .
Pharmacological t herapy consists of topical hormone replacement, antimuscarinic, beta-3 agonists, or Duloxetine. Topical vaginal estrogen has been generally shown to improve continence in postmenopausal women. Given the potential harm of surgical therapy, it makes sense to first consider a trial of medical therapy (antimuscarinic or beta-3 agonist) for women with urgency predominant MIU or for women who are unable to identify a predominant type of incontinence. A typical clinical scenario in MUI patients on medical therapy with antimuscarinic or beta-3 agonists is resolution of the urgency component in 50–60% of patients, but little to no improvement in the stress incontinence component . If a patient with urgency predominant component has complete resolution of their incontinence, this may suggest that an incorrect classification as MIU probably occurred (for example, the case of stress-induced DO). Duloxetine may be an option for pharmacological treatment of patients with stress predominant incontinence only when surgery is not indicated since a high risk of treatment-related adverse events has been described [8, 13].
Surgical treatment o f MUI is planned according to the dominant component of urinary incontinence. If SUI is the dominant symptom, one might offer mid-urethral slings, bladder neck slings, periurethral bulking agents, or retropubic colposuspension (Burch procedure) in refractory cases. Conversely, in cases of urgency predominant MUI, the patient may be offered intravesical botulinum toxin A injection, sacral neuromodulation, or percutaneous posterior tibial nerve stimulation if the conservative and pharmacological treatments fail.
If the above fails, re-evaluate the patient and re-enter the algorithm at the appropriate stage. It is important to inform the patients with MUI that one single treatment may not cure, and it may be necessary to treat other components of the incontinence problem .
Defining which patients have true MUI can be challenging. It is important to have a good clinical history and physical exam.
It is extremely important to define the predominant symptoms (urgency incontinence symptoms or stress incontinence symptoms).
Urodynamic study (UDS) is an important tool in determining the underlying etiology of a patient’s incontinence especially when symptoms are unclear.
Treatment of MUI is based on the predominant symptom that the patient reports as the most bothersome.
Conservative therapy should be considered as first line for all MUI patients.
One single treatment may not cure, and it may be necessary to treat other components of the incontinence problem.
7.3 Pelvic Organ Prolapse
Pelvic organ prolapse (POP) is d efined as the desce nt into or outside the vagina of pelvic organs, which include the uterus, the vaginal vault post-hysterectomy, the bladder, the rectum, or the small bowel. They are commonly referred to as uterine or vault prolapse (for the upper compartment); cystocele (for bladder or anterior compartment prolapse); rectocele and enterocele (for the rectum or small bowel, respectively, or posterior compartment prolapse).
The joint International Urogynaecological Association (IUGA)/International Continence Society (ICS) terminology report  on pelvic organ prolapse recommends the use of the terms anterior vaginal prolapse, posterior vaginal prolapse, or uterine/vault prolapse, rather than those implying a specific organ prolapsing through a particular vaginal compartment, since it may not always be the case. The commonest sympto m of vaginal prolapse is the feeling of a bulge through the vagina which causes discomfort. However vaginal prolapse is commonly associated with bladder, bowel and sexual dysfunction symptoms.
LUTS are common in women affected by POP. The association includes symptoms of both bladder filling and storage as well as voiding. A causal relationship is likely between POP and voiding dysfunction. Urethral compression or kinking is believed to be the mechanism by which vaginal prolapse can lead to bladder outlet obstruction (BOO), voiding dysfunction, and even to complete urinary retention in rare cases. The downwards movement of the bladder or direct pressure on the urethra or bladder neck by the uterus/vault or posterior wall prolapsing into the vagina can cause urethral obstruction leading to voiding difficulties. POP and storage LUTS s eem to share some etiological factors, rather than necessarily having a cause-and-effect relationship. The pathophysiological basis for the association with bladder storage symptoms such as increased urinary frequency, urgency, urgency incontinence, and stress urinary incontinence is less clear. Nonetheless, a common etiological mechanism of pelvic floor trauma, most commonly from vaginal delivery, for stress urinary incontinence and vaginal prolapse is well known. Urodynamic investigation with dual-channel filling and voiding cystometry with vaginal prolapse reduction (most commonly with a vaginal pessary) is recommended in all women with LUTS and POP prior to consideration for surgical correction of prolapse so as to identify mechanisms and help plan the intervention to ensure that treatment addresses the symptoms and avoids predictable complications [17–19].
7.3.1 OAB in POP
Epidemiological studies have shown that the prevalence of idiopathic overactive bladder syndrome (OAB) symptoms, including urinary urgency, urgency incontinence, frequency, and nocturia, is greater in patients with POP than those without prolapse . However, a cause and effect relationship has not been esta blished. T here is no correlation between the vaginal compartment prolapsing or the anatomical severity of the vaginal prolapse and the presence of OAB. Separate studies have found common risk factors for OAB and vaginal prolapse, including age, menopause, body mass index (BMI), and smoking. They are all well recognized risk factors for pelvic floor dysfunction, which supports the notion of a common etiology for these conditions. The effect of treatment for vaginal prolapse on overactive bladder symptoms is unpredictable. Pre-existing overactive bladder symptoms can persist, get worse, or improve after surgical correction of prolapse. Often, there is a short-term improvement in OAB symptoms, but they commonly recur in the long term. De novo overactive bladder can develop following treatment for prolapse. Post-operative persistence of OAB symptoms after POP repair has not been found to correlate with the severity of the prolapse, age, parity, BMI, or specific urodynamic parameters.
In women considering surgical treatment for prolapse, a trial of a vaginal pessary could be recommended to assess the potential effect of prolapse reduction on their OAB symptoms, with a reversible form of treatment. This could give an indication of the potential effect of prolapse surgery. However, this does not bring certainty since the long-term effect of surgery may well be different to that of a vaginal pessary. More commonly, women should be advised that their OAB symptoms can persist following surgical correction of the prolapse and that they are likely to require additional long-term treatment for it.
Prolapse-induced bladder outlet obstruct ion (BOO) could trigger or worsen OAB symptoms. However, although the reduction of vaginal prolapse with either pessaries or surgery can relieve the obstruction and improve voiding, this often fails to lead to improvement in overactive bladder. In this situation, a trial of pessary could also be useful prior to consideration of surgery, in order to counsel women on the likely outco me.
7.3.2 Stress Urinary Incontinence and POP
SUI is the involuntary leakage of urine on actions or activities that increase the abdominal pressure (coughing, laughing, exercising, lifting, etc.). SUI can co-exist with vaginal prolapse. However, vaginal prolapse can also mask SUI (by urethral kinking or compression), which only becomes apparent on reducing the prolapse—a situation known as “occult stress urinary incontinence.” Urodynamics with v aginal prolapse reduction helps to diagnose occult SUI in women who were previously asymptomat ic of SUI.
The main consideration in women affected by both SUI (either overt or occult) and vaginal prolapse, who are considering surgical treatment, is whether to perform concomitant surgery for prolapse and incontinence or to do a two-stage procedure, i.e., correct the prolapse first and then consider treating the SUI. The evidence in the literature is conflicting, with some studies suggesting performing concomitant surgery and others recommending a two-stage procedure. Overall, combination surgery for POP and SUI reduces the risk of post-operative SUI but increases the risk of adverse events . Since there are several different operations for both prolapse and SUI, with many different possible combinations, the results of individual studies cannot be extrapolated to patients having a different combination of surgical procedures. The treatment for these women must be individualized, and consideration should be given to the woman’s expectations, any comorbidities, and the treatment modalities for both the prolapse and the incontinence.
Stress incontinence can also be a de novo occurrence after prolapse surgery; it is therefore essential to counsel continent women undergoing surgery for POP about the potential risk of developing de novo post-operative S UI.
7.3.3 Voiding Dysfunction and POP
Voiding dysfunction re fers to an abnormally slow and/or incomplete bladder emptying. There is no agreement in the literature regarding the exact diagn ostic criteria of voiding dysfunction in women, i.e., the normal limits of the average and maximum urinary flow rates on uroflowmetry, or the thresholds for significant post-void residual. The prevalence of voiding dysfunction in women with vaginal prolapse can be as high as 40%. The severity of POP correlates positively with obstruction and voiding dysfunction symptoms but not with other LUTS. Anterior vaginal wall prolapse can lead to voiding dysfunction and urinary retention by kinking of the urethra or bladder neck. In very severe untreated cases (a complete vaginal eversion, or procidentia), there can also be pulling down and kinking of the ureters by the prolapse, leading to upper tract obstruction and hydronephrosis. Prolapse of the posterior vaginal wall and the upper compartment (uterus or vaginal vault) can cause voiding dysfunction by compression of the urethra.
In clinical practice, a combination of symptoms including hesitancy, poor flow, straining to void, incomplete bladder emptying, position-dependent voiding, and post-void dribble may be described. Often, women affected describe having to push up (reduce) the prolapse to improve or facilitate voiding, or having to change position, i.e., leaning backwards or forwards, to empty their bladder. They can present with a history of recurrent urinary tract infections. There is generally a gradual decrease in the maximum and average urinary flow rates with increased severity of pelvic organ prolapse. Hence, uroflowmetry and post-void residual measurement are used in assessment.
It is generally accepted that in most cases, prolapse leads to voiding difficulties and treatment of prolapse with either vaginal pessaries or surgery would improve voiding. However, in a proportion of women voiding will not improve after reduction of the prolapse and some can also develop de novo voiding dysfunction after prolapse treatment. Although there are no entirely reliable urodynamic or clinical features to predict this, it is recommended that women affected by prolapse and voiding dysfunction should generally undergo urodynamic investigation with prolapse reduction in order to advise them on the likely outcome of surgery with regard to voidin g.
7.4 Erectile Dysfunction
Penile erection is a multifactorial phenomenon which requires co-ordinated neurological, vascular and smooth muscle function in the penile corpora cavernosa. It comprises arterial dilation, trabecular smooth muscle relaxation, and activation of the corporeal veno-occlusive mechanism . In the state of flaccidity, sympathetic innervation produces a tonic contraction of the smooth muscles of the arteries and the corpus, reducing the blood flow through the cavernous artery in the cavernous spaces. Central psychogenic stimuli and/or sensory stimuli from the penis increase parasympathetic activity and reduce sympathetic activity. The result is a smooth muscle relaxation of the penis and an increase in blood flow through the cavernous and helicine arteries, leading to congestion and erection. The increase in blood volume and the compression of the trabecular smooth muscle released against the relatively rigid tunica albuginea reduces the venous flow at the output (veno-occlusive mechanism). Sympathetic activity reverses the process, leading to detumescence. Thus, an adequate blood flow to the penis is vital in this process. Erectile dysfunction (ED) is def ined as the persistent inability to attain and maintain an erection sufficient to permit satisfactory sexual performance .
ED Cla ssification
Recreational habits (e.g., cigarette smoking); lack of regular physical exercise; obesity
Cardiovascular diseases (e.g., hypertension and peripheral vascular disease); diabetes mellitus; hyperlipidemia; metabolic syndrome
Major pelvic surgery (e.g., radical prostatectomy) or radiotherapy (pelvis or retroperitoneum)
Central causes brain or spinal cord disease
Peripheral causes chronic renal failure; chronic liver failure; polyneuropathy; surgery; or radiotherapy
Anatomical or structural
Phimosis; Peyronie’s disease; penile cancer; hypospadias; epispadias; micropenis
Diabetes mellitus; metabolic syndrome; hypogonadism; hyperprolactinemia; hyper- and hypothyroidism; hyper- and hypocortisolism; panhypopituitarism, and multiple endocrine disorders
Mixed pathophysiology pathways
Chronic systemic diseases (e.g., diabetes mellitus, hypertension, metabolic syndrome, chronic renal failure, chronic liver disorders, hyperhomocysteinemia); obstructive sleep apnea; psoriasis; gouty arthritis; ankylosing spondylitis; non-alcoholic fatty liver; chronic periodontitis; inflammatory bowel disease; iatrogenic causes (e.g., TRUS-guided prostate biopsy)
Antihypertensives; antidepressants; antipsychotics; antiandrogens (GnRH analogs and antagonists; 5-ARIs); recreational drugs (e.g., alcohol, heroin, cocaine, marijuana, methadone, synthetic drugs, and anabolic steroids)
Generalized type (e.g., lack of arousability and disorders of sexual intimacy)
Situational type (e.g., partner-related, performance-related issues, or due to distress)
Penile or pelvic fracture
Epidemiological data have shown a high prevalence and inc idence of ED worldwide. Among others, the Massachusetts Male Aging Study (MMAS)  reported an overall prevalence of 52% ED in non-institutionalized men aged 40–70 years in the Boston area; specific prevalence for minimal, moderate, and complete ED was 17.2%, 25.2%, and 9.6%, respectively. The incidence rate of ED (new cases per 1000 men annually) was 26 in the long-term data from the MMAS study  and 19.2 (mean follow-up of 4.2 years) in a Dutch study . In a cross-sectional real-life study among men seeking first medical help for new-onset ED, one in four patients was younger than 40 years, with almost 50% of the young men complaining of severe ED .
ED shares both unmodifiable and modifiable commo n risk factors with CVD (e.g., obesity, diabetes mellitus, dyslipidemia, metabolic syndrome, lack of exercise, and smoking) . The association between ED status and age, diabetes mellitus duration, poor glycemic control, body mass index (BMI) , obstructive sleep apnea, hyperhomocysteinemia, and chronic liver failure associated with hepatitis B is described . An association between ED status and vitamin D deficiency has also been reported .
Epidemiological studies have also demonstrated consistent evidence for an association between LUTS/benign prostatic hyperplasia (BPH) and sexual dysfunction, regardless of age, other comorbidities, and various lifestyle factors . From the 83% of men who self-reported to be sexually active, the overall prevalence of LUTS was 90%, with the overall prevalence of ED being 49%, and a reported complete absence of erection in 10% of patients. Moreover, an association between chronic prostatitis/chronic pelvic pain syndrome and ED has also been confirmed . Effects on erectile function vary according to the type of surgery performed in men with LUTS/BPH .
7.4.1 Clinical Assessment
The first step in evaluating ED is always a detailed medical and sexual history of patient, and partner if possible. This will make it easier to ask questions about erectile function and other aspects of the patient’s sexual history, and to explain the diagnosis and therapeutic approach to the patient and his partner.
The sexual history must include information about sexual orientation, previous and current sexual relationships, current emotional status, onset and duration of the erectile problem, and previous consultations and treatments. A detailed description should be made of the rigidity and duration of both sexually stimulated and morning erections and of problems with sexual desire, arousal, ejaculation, and orgasm. Validated psychometric questionnaires such as the International Index for Erectile Function (IIEF) he lp to assess the different sexual function domains (i.e., sexual desire, erectile function, orgasmic function, intercourse, and overall satisfaction), as well as the potential impact of a specific treatment modality. Patients should be screened for symptoms of possible hypogonadism (testosterone deficiency), including decreased energy, libido, fatigue and cognitive impairment, as well as for LUTS.
Physical examination i s focused on the genitourinary, endocrine, vascular, and neurological systems. A physical examination may reveal unsuspected diagnoses, such as Peyronie’s disease, pre-malignant or malignant genital lesions, prostatic enlargement or irregularity/nodularity, or signs and symptoms suggesting hypogonadism (small testes, alterations in secondary sexual characteristics, etc.).
Laboratory testing must be tailor ed to the patient’s complaints and risk factors. Patients may need a fasting blood glucose or HbA1c and lipid profile if they have not recently been assessed for diabetes mellitus. Hormonal tests include an early morning total testosterone. If indicated, the bio-available or calculated free testosterone may be needed to corroborate total testosterone measurements. Additional laboratory tests may be considered in selected patients (e.g., prostate-specific antigen, prolactin, and luteinizing hormone). Specialized diagnostic tests may include nocturnal penile tu mescence and rigidity assessment done on at least two separate nights. A functional erectile mechanism is indicated by an erectile event of at least 60% rigidity recorded on the tip of the penis that lasts for ten or more minutes. The intracavernous injection test gives limited information about the vascular status. A positive test is a rigid erectile response (unable to bend the penis) that appears within 10 min after the intracavernous injection and lasts for 30 minutes. A Duplex ultrasound of the penis should be performed in the assessment of the vascular integrity of the penis. A peak systolic blood flow >30 cm/s, an end-diastolic velocity of <3 cm/s, and a resistance index >0.8 are generally considered normal. Arteriography and dynamic infusion cavernosometry or cavernosography should be performed only in patients who are being considered for vascular reconstructive surgery.
7.4.2 ED Treatment in LUTS
Lifestyle changes and risk factor modification must precede or accompany any physical or/and pharmacological treatment. Likewise, ED may be associated with concomitant and underlying pathologies (such as endocrine disorders and metabolic disorders, e.g., diabetes, and some cardiovascular problems, e.g., hypertension) which should always be well-controlled as the first step of any ED treatment. The assessment of treatment options must be tailored according to patient and partner satisfaction, QoL factors as well as treatment-related invasiveness safety and efficacy.
PDE5 inhibitors are first-line medications for ED, and tadalafil 5 mg once daily is indicated for voiding LUTS, so this is a first-line consideration. Where LUTS and ED are both symptomatic and bothersome, combination medical therapy may be considered. Treatment with combination therapy using PDE5 inhibitor and an alpha blocker is more effective for the improvement symptoms than flow rate, with equivocal advantage for ED response . Potentially medications used to treat LUTS, notably 5-alpha reductase inhibitors, could risk worsening of ED, and this needs to be considered when selecting therapy.
7.5 Metabolic Syndrome
IDF/NHLBI/AHA/WHF/IAS criteri a for the clinical diagnosis of the metabolic syndrome 
Patients need to have at least three of the following:
• High triglyceride levels (≥1.7 mmol/L/150 mg/dL), or drug treatment for this
• Low high-density lipoprotein (HDL) cholesterol levels <1.0 mmol/L/40 mg/dL in men, <1.3 mmol/L/50 mg/dL in women, or drug treatment for this
• Raised blood pressure (systolic ≥130 and/or diastolic ≥85 mmHg), or drug treatment for this
• Elevated fasting glucose (5.6 mmol/L/≥100 mg/dL), or drug treatment for this
The different cut-off points for WC reflect the fact that the risk associated with a specified waist measurement varies in different populations. However, many people in the world are of mixed-ethnicity, and in such cases, pragmatic decisions will be required . While the IDF/NHLBI/AHA/WHF/IAS recommends the measurement of glucose, in practice, many clinicians now favor HbA1c for diagnostic investigations. Evidence supports using an HbA1c of ≥39 mmol/mol (≥5.7%) (“pre-diabetes”) as an appropriate hyperglycemic criterion to define MetS, and this may increase its detection rate [45, 46].
MetS has a rising prevalence worldwide, mainly due to increasing obesity rates and sedentary lifestyles . The estimated prevalence of MetS in different populations will be affected by the diagnostic criteria used, as well as by a variety of modifiable and non-modifiable factors, which are often interlinked. These include age, sex, ethnicity, obesity and fat distribution, diet and physical activity, birth weight, genetic factors, endocrine factors, inflammation, alcohol, and comorbidity . In Europe, Mets prevalence has been estimated as 41% in men and 38% in women, using 2005 International Diabetes Federation diagnostic criteria, which had abdominal obesity as a mandatory component (WC ≥94 cm in men or ≥80 cm in women for Europids). These figures are based on nine European population-based studies, where the baseline examinations were carried out sometime between 1986 and 2002 and the participants were followed up for between 3.9 and 20.6 years .
More recently, a collaborative analysis of ten large cohort studies from seven European countries found the percentage of obese subjects with MetS ranged from 24% to 64% in women and from 43% to 78% in men, according to 2001 National Cholesterol Education Program Expert Panel on detection, evaluation, and treatment of high cholesterol in Adults (NCEP ATP III) criteria and an adapted set of less strict criteria . Another study, published the same year, also investigated the prevalence of MetS using NCEP ATP III criteria, in subjects from 12 cohorts from 10 European countries and 1 cohort from the USA. MetS prevalence was 24.3% (23.9% in men and 24.6% in women) and rates increased with age . The lower prevalence rates found in these studies were probably due to the higher WC cut-off points used in NCEP ATP III (>102 cm for men and >88 cm for women ).
MetS is provoked by weight gain and a predisposition to deposit fat intra-abdominally . It is strongly linked to a lifestyle characterized by over consumption of high calorie, low nutrient-dense, foods, and a lack of physical activity [51, 52]. An individual’s propensity to deposit fat intra-abdominally may be determined very early in life , and evidence suggests that both high and low birth weight children are at increased risk of MetS in adulthood . Most patients with T2DM will have MetS, based on the IDF/NHLBI/AHA/WHF/IAS criteria for diagnosis . While the links between some of the components of MetS relate to insulin resistance, this is by no means universal, and it is thought that around one in three patients with MetS have normal insulin sensitivity .
In brief, insulin resistance cau ses a rise in circulating free fatty acids (FFAs), w hich further inhibits its antilipolytic effect [55, 56]. FFAs also have adverse effects on the muscles, leading to reduced glucose uptake, the liver, increasing the production of glucose and atherogenic lipoproteins, and the pancreas, resulting in decreased insulin secretion [55, 57]. Insulin resistance also plays an important role in the development of hypertension, via the loss of vasodilation attributable to insulin, and vasoconstriction related to FFAs [55, 58]. Insulin resistance further increases the risk of CVD by increasing serum viscosity, inducing a prothrombotic state and stimulating the release of pro-inflammatory cytokines from adipose tissue [55, 59].
The renin-angiotensin-aldosterone system (RAAS) is considered an important neurohormonal pathway in the pathogenesis of MetS. While the RAAS is regulated by several causative components of the metabolic syndrome, including obesity, hyperglycemia, and hypercholesterolamia, it also contributes to the disorders of the metabolic syndrome, including insulin resistance, hypertension, elevated fasting glucose, hypertriglyceridema, and an atherogenic cholesterol profile. This suggests that the RAAS may be a common bond linking these disorders .
Chronic low-grade inflammatio n is thought to play a role in the pathogenesis of obesity and the development of MetS . Obesity- and insulin-resistance-induced systemic oxidant stress results in atherogenesis and tissue fibrosis. Inflammation contributes to activation of local RAAS pathways, the development of a prothrombotic state, and the pathogenesis of CVD [55, 62].
Type 2 diabetes
Non-alcoholic fatty liver disease
Polycystic ovary syndrome
Lower urinary tract symptoms (LUTS)
MetS cannot be used to calculate future risk of CVD because it does not include many of the factors that determine absolute risk (e.g., age, sex, smoking, total, and HDL cholesterol). However, patients with this syndrome are twice as likely to develop CVD over the next 5–10 years as those without it and their lifetime risk will be even higher. MetS also confers a fivefold increase in the risk of T2DM .
7.5.2 MetS and LUTS
Mets is significantly associated with predictors for the progression of clinical benign prostatic hyperplasia (BPH), and the frequency and severity of LUTS, particularly the voiding symptoms . Body weight, body mass index (BMI), and WC have all been associated with increased prostate volume in numerous study populations [65–67]. WC is also significantly associated with worsened voiding symptoms . Obesity is significantly associated with the onset of overactive bladder (OAB) , and OAB is significantly more prevalent in patients with MetS than those without . While the exact biological pathways linking MetS and LUTS remain unclear, the numerous interrelated components of MetS are thought to promote endothelial and smooth muscle dysfunction, and MetS-induced inflammation may be an important contributor to BPH/LUTs in men , and OAB, urinary incontinence, and urinary tract infection in women [72, 73].
LUTS can have a significant negative impact on a patient’s quality of life , and the modification of MetS components may prevent LUTS from worsening, or even developing in the first place . Many patients with LUTS will be overweight and found to have features of MetS if the appropriate investigations are initiated. This provides an opportunity to encourage weight loss as an adjunct to medical therapy for LUTS, as well as a window of opportunity to address cardiovascular risk factors and prevent future cardiovascular morbidity and mortality. Weight loss via lifestyle modification or bariatric surgery has been shown to improve stress and urge incontinence, as well as LUTS .
Because the associations between the metabolic disorders seen in MetS and its adverse effects on health are influenced by a portfolio of risk factors, the management of Mets and MetS-associated LUTS should also be multifaceted. Lifestyle changes are important first-line interventions, including weight control, consumption of a healthy, Mediterranean-style diet, and regular exercise. In addition, pharmaceutical therapies to improve glucose metabolism and insulin resistance control blood pressure and modulate dyslipidemia, may help reduce or delay the adverse effects of MetS , and improve LUTS . First-line therapies include statins for dyslipidemia, RAAS inhibitors for hypertension, and metformin for dysglycemia. Additional agents may be appropriate in T2DM patients.
7.6 Recurrent Urinary Tract Infections
Reinfection is often caused by different species, and the interval between infection episodes varies and can be rather long. It is uncommon in men and might be associated with an underlying urological condition. In women, on the other hand, reinfection is common and is usually associated with ascending colonization from the bowel flora .
The diagnosis is based on the history of common lower urinary tract symptoms and is confirmed by a positive urine culture (midstream urine bacterial count of ≥105 CFU/mL). The symptoms include dysuria, frequency, urgency, urgency incontinence, or less commonly hematuria. Patients often report an intermittent, suprapubic discomfort, associated with a full bladder, which can be (at least partly) relieved by voiding. Nevertheless, voiding itself usually causes pain as well (dysuria), that is referred to the distal urethra. At the end of micturition, a sharp, stabbing, suprapubic pain can occur, which is termed strangury. Besides pain, frequent voiding (increased frequency) is a common symptom. During urgency, patients sometimes experience involuntary loss of urine (urgency incontinence). Less often the infection causes hematuria (blood in the urine), in more severe cases even with blood clots. After successful treatment, these symptoms typically resolve completely [76, 78, 79]. The physical examination includes abdominal and pelvic examination, and should aim to exclude any anatomical or functional abnormalities of the upper and lower urinary tract . Post-void residual (PVR) urine should be evaluated, especially in postmenopausal women, as it potentially might contribute to rUTIs .
Other extensive routine diagnostic workup should be omitted as it has been shown that the yield of most diagnostic procedures in this group of patients is low . Under specific circumstances, additional diagnostic workup may be indicated : prior urinary tract surgery or trauma, gross hematuria after resolution of infection, previous bladder or renal calculi, voiding symptoms, urea-splitting bacteria on culture, bacterial persistence after sensitivity-based therapy, prior abdominopelvic malignancy, diabetes or otherwise immunocompromised, pneumaturia, faecaluria, anaerobic bacteria or a history of diverticulitis and repeated pyelonephritis.
In the case of trauma, malignancy, or urinary calculi history (with or without urea-splitting bacteria on culture), urinary tra ct imaging will provide an accurate assessment of the urinary tract, its anatomical characteristics, and some functional status. In the presence of voiding symptoms, hematuria, pneumaturia, or fecaluria, cystoscopy (with or without imaging) should provide some additional information on the possible obstruction, bladder dysfunction, or fistula. In the case of repeated pyelonephritis, a voiding cysto-urethrogram should be performed, to exclude vesico-ureteric reflux [78, 83].
Postmenopausal women frequently suffer from rUTIs, which can be attributable to increased PVR urine (perhaps due to POP), or suffer from atrophic vaginitis, due to estrogen deficiency. On the other hand, in premenopausal women, use of spermicide, sexual intercourse, and a new sexual partner can contribute to rUTIs [76, 78].
In the case of bacterial persistence, several correctable urologic abnormalities have been identified, which require surgical correction in order to remove the cause of rUTIs. These abnormalities may include  infection stones, chronic bacterial prostatitis, unilateral infected atrophic kidneys, ureteral duplication and ectopic ureters, foreign bodies, urethral diverticula and infected periurethral glands, unilateral medullary sponge kidneys, infected ureteral stumps after nephrectomy, infected urachal cysts, infected communicating cysts of the renal calyces, papillary necrosis, perivesical abscess, and fistula to bladder.
7.6.1 Behavioral Modification Treatment
There are several behavioral modifications that have been proposed to reduce the incidence of rUTIs. They include adequate hydration, regular voiding, and proper toilet habits (including early post-coital voiding), vaginal lactobacilli supplementation, avoidance of vaginal douches and scented bubble baths, using pads instead of tampons and avoidance of spermicides or diaphragm as contraceptive methods. Unfortunately, none of these lifestyle changes have been proven successful in medical studies in reducing rUTIs .
7.6.2 Non-Antimicrobial Me asures
Immunoactive prophylaxis. In female patients with rUTIs, but maybe also in other patient groups, immunoprophylaxis with OM-89 (Uro-Vaxom®) has shown to be beneficial. It is an oral preparation, consisting of 18 different serotypes of heat-killed uropathogenic Escherichia coli (E. coli), which stimulate innate immunity. Similar antigens are also found in various other classes of uropathogens. In studies, OM-89 has shown to be more effective than placebo for preventing rUTIs in women, caused by E. coli as well as other common uropathogens [86, 87]. Another form of immunoprophylaxis with vaginal vaccine containing different heat-killed uropathogenic bacteria was thought to reduce the number of rUTI episodes. The role of vaccination remains controversial, since there are conflicting results, with some studies showing to slightly reduce the rUTI rates , while others show no benefit of such treatment .
Hormonal replacement. Alt hough oral estrogens did not reduce rUTIs, several studies did confirm that vaginal estrogen replacement has a trend toward preventing rUTIs in postmenopausal women. In a randomized, double-blind, placebo-controlled trail, women who received 0.5 mg of estriol in vaginal cream (once each night for 2 weeks followed by twice-weekly applications for 8 months) showed a significant reduction in the incidence of rUTIs [86, 90].
Cranberries have been used for decades for preventing and treating UTIs, which was also supported by several studies, which showed a beneficial effect of such prophylaxis. Despite that, a Cochrane database meta-analysis, which included a total of 24 studies, with a total of 4473 participants, concluded that cranberry juice is less effective than previously thought, so it cannot be currently recommended for preventing rUTIs .
D-mannose administere d as 2 g of D-mannose powder in 200 mL of water daily for 6 months significantly reduces rUTIs to the same extent as antibiotic prophylaxis with 50 mg of nitrofurantoin, but with significantly less side effects .
Probiotics. It has been s uggested that specific lactobacilli strains can affect adherence, growth, and colonization of uropathogenic bacteria on urogenital epithelial cells. Therefore, several attempts have been made to reduce the frequency of rUTIs using different lactobacilli preparations for prophylaxis. Neither vaginal application nor oral preparations of lactobacilli have shown to be superior to placebo [86, 93].
Endovesical prophylactic therapy. The glycosa minoglycan (GAG) layer of the bladder mucosa is believed to have an important role in the interaction between bacteria and epithelial cells. Supposedly, a damaged GAG layer could lead to enhanced bacterial adherence and consequently rUTIs. In the attempt to repair the GAG layer, several endovesical therapy regimes have been studied, and some studies showed a benefit of intravesical administration of hyaluronic acid and chondroitin sulfate in preventing rUTIs . On the other hand, a review of 27 clinical studies has shown that many studies are poorly designed and therefore their results are questionable. The authors conclude that large-scale, well-designed studies are urgently needed to assess the role of endovesical therapy in rUTIs .
7.6.3 Antimicrobial Prophylaxis
Continuous low-dose antimicrobial p rophylaxis. Based on a Cochrane Database systematic review, continuous antibiotic prophylaxis for 6–12 months reduces the rates of rUTIs, although side effects such as vaginal and oral candidiasis or gastrointestinal symptoms might appear more often than in placebo groups . The suggested dosages of the above-mentioned antibiotics are TMP/SMX 40 mg/200 mg daily, nitrofurantoin 50–100 mg daily, cephalexin 125–250 mg daily, or ciprofloxacin 125 mg daily, although “every-other-day” therapy might be effective as well. Therapy lasts usually for around 6 months; afterwards patients are monitored for relapses [78, 83].
Post-coital prophylaxis. This type of prophylaxis is appropriate for women who are prone to experience rUTIs after sexual intercourse. Studies showed that post-coital treatment in this population is as effective as continuous antibiotic treatment . The therapy is taken as a single dose within 2 h after the intercourse and consists of same therapeutics as for the continuous treatment .
Self-treatment. Patients who are able to recognize symptoms of rUTIs and are compliant with given instructions are eligible for self-treatment. They are given a prescription for a short course (usually 3 days), full dose, broad-spectrum antibiotic, as prescribed for sporadic, acute, uncomplicated UTIs. If symptoms persist for more than 2 days, patients are advised to visit their physician, to perform a urine culture. Such treatment has been proven safe and effective [76, 83, 98].
Recurrent urinary tract infections present a burden for the patient and a challenge for the treating physician. Extensive routine diagnostic workup is usually unnecessary, especially in premenopausal women without risk factors, since it does not reveal any additional information. Treatment options include behavioral modifications, non-antimicrobial measures, and antimicrobial prophylaxis. Despite all efforts, rUTIs present with a high recurrence rate and long-term medical management is often needed. Ongoing research includes a trial of methenamine, another oral non-antibiotic agent which is one arm of a study in women with rUTI scheduled to report s oon .
The prevalence of prostatitis-like symptoms ranges from 2% to 16%, with a median prevalence rate approximating 7% for chronic prostatitis and chronic pelvic pain syndrome . Prostatitis is more likely to affect younger men, typically in the 18 t o 50 years age range . Because the prostate surrounds the urethra, patients who have prostatitis frequently complain of LUTS.
The classification of prostatitis syndrome includes acute bacterial prostatitis (ABP), chronic bacterial prostatitis (CBP), chronic pelvic pain syndrome (CPPS) or, synonymously, chronic nonbacterial prostatitis, and asymptomatic inflammatory prostatitis (AIP) . Chronic nonbacterial pro statitis is divided into two subgroups, inflammatory and noninflammatory. Nonbacterial prostatitis is a condition of unknown origin, and it is the most common cause of prostatitis symptoms. Clinically, nonbacterial prostatitis is similar to CBP, except that both bacteriologic cultures and history of urinary tract infections are negative. Patchy acute and chronic inflammation is present in the prostate of most adult men without symptoms. Histologically, symptomatic CBP cannot be distinguished from chronic inflammation commonly seen in specimens removed from patients with BPH. Granulomatous prostatitis is a distinctive form of prostatitis that can be mistaken for carcinoma. It is subdivided into infectious granulomas, nonspecific granulomatous prostatitis, post-biopsy granulomas, and systemic granulomatous prostatitis (also referred as allergic granulomatous prostatitis). The association of infection or inflammation of the prostate with prostate cancer has been suggested but is not established .
7.7.1 Acute and Chronic Bacterial Prostatitis
Bacterial prostatitis is associated with urinary tract infections, increased number of inflammatory cells in prostatic secretions, and growth of bacterial organisms from prostatic secretions. The organisms causing bacterial prostatitis are similar to those seen in UTIs. Most cases of ABP are caused by gram-negative organisms, including Escherichia coli (80%) and other Enterobacteriaceae, such as Pseudomonas, Serratia, and Klebsiella (10–15%), and Enterococci (5–10%). Although prostatitis due to Neisseria gonorrhoeae was common in the pre-antibiotic era, it is rare today . CBP is characterized by recurrent urinary tract infections caused by the same pathogens. Patients with human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS) have an increased incidence of bacterial prostatitis. Acute bacterial prostatitis may progress to chronic bacterial prostatitis in around 5% of patients . Clinical prostatitis may give rise to elevated serum PSA.
The inflammatory process in the prostate nearly always remains localized to the gland itself, although pyrexia and general malaise are frequently encountered. The most common presentation of ABP i s s udden onset of fever, chills, malaise, nausea, vomiting, and pain in the lower back, rectum, or perineum, combined with storage and obstructive voiding symptoms. The patient typically reports increased urinary frequency, urgency, and dysuria. Voiding complaints including hesitancy, poor interrupted stream, strangury, and even acute urinary retention. The patient can also present with perineal and suprapubic pain, and may have associated pain or discomfort of the external genitalia. Hematuria and hematospermia can also be reported. The combination and severity of symptoms in acute bacterial prostatitis vary from patient to patient. On examination, the prostate is swollen, tender, and warm and may be partially or totally indurated. Diagnosis is based on the finding yielded by the urine culture and expressed prostatic secretions, and biopsy is contra-indicated because of the potential for sepsis. Acute prostatitis may progress to abscess formation, and the lesion may point and eventually drain either per urethra or per rectum. Abscess is a potential but rare complication of ABP .
Chronic prosta titis mainly involves the peripheral zone of the prostate, but the inflammation may spread to involve the transitional zone and central zone as well. Usually, there is a history of documented recurrent UTIs. Patients with chronic bacterial prostatitis may be relatively asymptomatic between acute episodes, or they may present with a long history of a CPPS .
7.7.2 Chronic Nonbacterial Prostatitis/Chronic Pelvic Pain Syndrome
Some researchers have proposed that in some patients diagnosed with prostatitis, a bladder-orientated interstitial cystitis mechanism actually accounts for the symptoms, and the prostate is indirectly involved . The pain and voiding symptoms of interstitial cystitis and chronic prostatitis overlap to some extent, and men with this condition have cystoscopic and urodynamic findings very similar to those of patients with interstitial cystitis.
The predominant symptom is pain, which is most commonly localized to the perineum, suprapubic area, and penis, and can also occur in the testes, groin, or lower back. Pain during or after ejaculation is one of the most important and bothersome features in many patients. LUTS reported include urgency, increased frequency, hesitancy, and poor interrupted flow. Symptoms like bladder spasm, dysuria, and awakening at night with pain are also common. Erectile dysfunction and sexual disturbances also have been reported in patients with CPPS . Thi s syndrome becomes chronic after 3 months duration. Approximately 1/3 of patients (usually those with a shorter duration of illness and fewer symptoms) improve over 1 year. The impact of this condition on quality of life is bad; some investigations suggest that these patients’ QoL is lower than that observed in men with congestive heart failure and diabetes mellitus [108–110].
7.7.3 Asymptomatic Inflammatory Prostatitis
By definition, this conditio n does not cause symptoms; it is an observation when microscopy of semen or histologic examination of prostatic tissue discloses inflammatory cells. Such samples might be obtained during investigation or treatment of prostatic obstruction, elevated PSA, prostate cancer, or infertility.
7.7.4 Symptom Assessment
The National Institutes of Health (NIH) Chronic Prostatitis Collaborative Research Network (CPCRN) developed a reproducible and valid instrument to measure the symptoms and quality of life of patients with CP for use in research protocols as well as clinical practice .The NIH–Chronic Prostatitis Symptom Index (NIH-CPSI) consists of nine questions that address three important domains. Pain was captured in four questions focusing on its location, severity, and frequency. Urinary function was captured in two questions, one concerning storage and the other voiding function. The quality of life was captured in three additional questions related to daily activities.
Although not confirmatory in making a definitive diagnosis, physical examination is very helpful in further classifying the disorder and directing therapy. The main goal is to exclude identifiable causes that may be responsible for the patient’s symptoms, ruling out other perineal, anal, neurologic, pelvic, or prostate abnormalities. In acute bacterial prostatitis the patient may be flushed, febrile, tachycardic, tachypneic, and even hypotensive. The patient usually has suprapubic discomfort and perhaps has acute urinary retention. Perineal pain and anal sphincter spasm may complicate the digital rectal examination. The prostate is usually described as hot, boggy, and exquisitely tender. The expression of prostatic fluid is believed to be totally unnecessary and perhaps even harmful. If a prostatic abscess is present, the gland becomes fluctuant and exquisitely tender. In chronic bacterial prostatitis and chronic nonbacterial prostatitis, the physical examinatio n is usually unremarkable, apart from identifying tenderness. Abdominal examination is usually normal, except for occasional suprapubic tenderness. On pelvic examination, identifiable diseases can be recognized or excluded. A rectal examination should assess for other sources of perineal pain such as anal fissure, and the presence of masses.
The number of daily voidings and average volume can be determined from a bladder diary. Patients with this condition can void an average of 16 times per day. Bladder diaries can also be useful during and after the treatment for comparison and to determine the progress in therapy.
Urinalysis and cultures are required. Urine cytology should also be obtained to rule out the possibility of carcinoma. If hematuria is found, a full urinary tract workup should be performed to exclude malignancy.
Cystoscopy is not indicated in the majority of men with prostatitis. It should be done when the history (hematuria), lower urinary tract evaluation (urinalysis), or other exams (urodynamics) indicate the possibility of a diagnosis other than chronic prostatitis/CPPS, like lower urinary tract malignancy, stones, urethral strictures, bladder neck abnormalities, and other lower urinary tract abnormalities that can be surgically corrected. Cystoscopy is usually normal in appearance in prostatitis patients.
Urodynamic studies are not routinely indicated in evaluation of these patients. Urodynamic investigation can b e performed if the patient’s symptoms include incontinence, severe urgency, or voiding complaints. Cystometry may demonstrate an intense urge to void with as little as 150 mL of water filling and a capacity of up to 350 mL, limited by discomfort. Compliance may be normal or decreased. Detrusor overactivity may co-exist. A study of treatment-refractory chronic prostatitis patients with no infection determined that 60% had bladder neck hypertrophy diagnosed by endoscopic and urodynamic criteria . The high-pressure, dysfunctional voiding may result in intraprostatic ductal reflux in susceptible individuals. Documentation of uroflowmetry and residual urine bladder scan abnormalities may suggest proceeding to more detailed urodynamics .
Transrectal ultrasonograph y has become one of the best radiologic methods to evaluate prostate disease and a helpful tool for the assessment of gland volume and guidance of biopsy needles. The diagnostic value of ultrasonography in differentiating benign from malignant prostate disease is controversial, and the further differentiation of the various benign conditions of the prostate is even more so. It can be valuable in diagnosing prostatic cysts in patients with prostatitis-like symptoms, diagnosing and draining prostatic abscesses, or diagnosing and draining obstructed seminal vesicles. It is not required in all cases of acute bacterial prostatitis but rather only in those patients in whom antimicrobial therapy is failing.
The establishment of new definitions and a classification system, and better understanding that patients with prostatitis have variable clinical phenotypes have radically changed the way this condition is managed. Acute bacterial prostatitis is relatively simple to treat. Bacteria are eradicated with appropriate antibiotic therapy. However, ESBL infection related to prostate biopsy is becoming a critical problem. The objective for chronic bacterial prostatitis is identical, but long-term symptom improvement can sometimes prove elusive. Antimicrobial therapy and α-blocker therapy are effective in the majority of men with ABP or CBP. Surgical or percutaneous drainage is usually required in the presence of prostatic abscess.
In chronic nonbacterial prostatitis/ CPPS, the following medical therapies have been advocated: antibiotics, α-adrenergic blockers, anti-inflammatory agents, hormonal therapy, phytotherapy, and pregabalin. However, medical therapy generally offers disappointing symptom improvement. Minimally invasive therapies have also been evaluated in CPPS, like extracorporeal shockwave therapy, transurethral microwave therapy, neuromodulation, and botulinum toxin; again, these show only modest benefit [114, 115].
7.8 Genital Sexually Transmitted Infections
Despite implementation of widespread screening and improved treatment practices, sexually transmitted infectio ns (STIs) remain a worldwide healthcare concern. In the United States, 20 million new STIs are diagnosed each year, requiring expenditure of over 15 billion healthcare dollars . Chlamydia (Chlamydia trachomatis), gonorrhea (Neisseria gonorrhoeae), and syphilis (Treponema pallidum) are the most frequent STI, with incidences rising every year. Chlamydia is the most common STI w ith 1.6 million cases diagnosed annually and is particularly prevalent in young women. Almost half of reported cases occur in women aged 15–24. Gonorrhea accounts for over 450,000 STI and syphilis for nearly 30,000 incident cases annually . Less common causes of non-gonococcal urethritis include genital mycoplasma (Ureaplasma urealyticum, Mycoplasma genitalium, and Mycoplasma hominis), trichomonas (Trichomonas vaginalis), human immunodeficiency virus (HIV), and herpes simplex virus.
Common to these STIs are their ability to progress insidiously. When left untreated, asymptomatic infections predispose men and women to severe morbidities, such as chronic pain and infertility. Those who do not receive care are not only vulnerable to health consequences but also become a reservoir that harbors the pathogen, facilitating transmission to others. As a result, these infections are difficult to eradicate. This is most evident in the case of syphilis. Although nearly eliminated a decade ago, the incidence is accelerating and is especially prominent among men who have sex with men . Compounding to this problem is the concern for antibiotic resistance, particularly in the case of gonorrhea, which has grown highly resilient to most pharmaceuticals used for treatment .
7.8.1 Pathogenesis of LUTS
In men, STI can le ad to long-term development of LUTS by a variety of mechanisms. Initially, STI often present as urethritis (urethral discharge and/or dysuria), epididymitis, genital ulcers, or genital warts. Local inflammation can result in scar tissue deposition and urethral stricture disease, which over time may manifest as LUTS. These sequelae are more commonly seen with gonorrheal infections but are now uncommon with the availability of antibiotic use .
The prostate can harbor urogenital pathogens, and several sexually acquired pathogens have been linked to chronic histological inflammation within the prostate. Ascending infections of gonorrhea, chlamydia, trichomonas, and syphilis have been found to produce persistent inflammatory responses within the gland’s parenchyma, leading to acute prostatitis and potentially chronic infection . Chronic asymptomatic retention of trichomonas in prostatic tissue has been documented to occur in about 20–25% of men with benign prostatic hyperplasia (BPH) . In symptomatic men, studies have revealed positive associations between sexually acquired pathogens and chronic prostatitis (CP) symptoms in the absence of clinically active infection. Serum antibody titers and cultures of prostate tissue specimens expressed prostatic secretions, urethral swabs, and semen have identified pathogens such as chlamydia, Mycoplasma genitalium, Staphylococcus epidermidis, Staphylococcus haemolyticus, and several isolates of coryneform bacteria (most notably Corynebacterium seminale) in men with symptoms of CP or chronic pelvic pain syndrome [121–127]. Other evidence suggests that the prevalence of LUTS, prostatitis, and STIs is linked. In a study of the Health Professionals Follow-up Study (HPFS) cohort, Collins et al. found that men with a reported history of prostatitis were at 1.8-fold increased odds (95% CI 1.5–2.1) of having a prior STI. In addition, a self-reported history of prostatitis was correlated with moderate (OR 1.8, 95% CI 1.7–2.0) and severe (OR 2.8, 95% CI 2.3–3.3) LUTS, as measured by the American Urological Association symptom indices . Likely through chronic inflammation, STI appears to promote the risk of LUTS through long-term symptomatic prostatitis.
Chronic infection has been suggested to potentially play a role in BPH pathogenesis, as chronic inflammation is a common histological finding in tissue specimens of men with BPH . In vitro rat models have demonstrated prostate epithelial cell upregulation of pro-inflammatory cytokines and chemokine genes in response to Chlamydia murinarum exposure . Further studies have demonstrated chlamydia persistence for 3 months after introduction into the prostate gland, which was accompanied by significant histological changes and inflammatory cell infiltration .
As a result, STIs are thought to contribute to chronic inflammation-mediated secretion of growth factors and hyper-proliferation of prostatic epithelial cells, leading to both irritative and obstructive urinary symptoms in men [132–134].
In women, research in female subjects regarding mechanisms of LUTS secondary to STI is limited. Acute STI presentation in women is varied and can include nonspecific storage LUTS, urethritis, cervicitis, or salpingitis. Ascending infection may result in pelvic inflammatory disease (PID), which is estimated to occur in 8% of women of reproductive age . Typically associated with chlamydia or gonorrhea infections, PID can increase risk of recurrent PID, ectopic pregnancy, infertility, and chronic pelvic pain . Most STI in women, particularly chlamydia and gonorrhea, are asymptomatic , allowing for urinary tract sequelae of chronic inflammation. Accordingly, cases of chronic chlamydial infection and urge incontinence have been reported .
For both sexes, processes that result in systemic inflammation are postulated to afflict the urinary tract and contribute to new or worsening LUTS [138, 139]. Late-stage or neuro-syphilis, now uncommon because of widespread treatment efforts, has been associated with incontinence and other lower tract symptoms [140, 141]. Similarly, end-organ damage secondary to HIV and toxicity from HIV treatment has been associated with several urologic morbidities including stone disease, urinary tract infection (UTI), sexual dysfunction, and nephropathy [142–145]. DO and urodynamic abnormalities, thought to result from damage to pelvic nerves that control the bladder, have also been observed in patients with HIV [146, 147].
7.8.2 Clinical Evidence
Recently, a study aimed t o attenuate recall bias by correlating STI serology and/or reported history of STI to BPH/LUTS prevalence and incidence . Breyer et al. used participants of the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO), a large randomized trial initially designed to determine the effects of prostate, lung, colorectal, and ovarian cancer screening on cancer-specific mortality . Generally null results were observed between BPH/LUTS-related outcomes and both STI serology and self-reported STI. The findings suggested that most STI did not contribute to BPH/LUTS development. The most significant associations from this study were seen with serologically detected trichomonas infection. Those with a positive trichomonal serology had a greater prevalence of nocturia (PR 1.36, 95% CI 1.18–1.65) and larger prostate volumes (PR 1.21, 95% CI 1.02–1.43) independently, and with both nocturia and an enlarged prostate combined (PR 1.32, 95% CI 1.09–1.61). On the other hand, associations that did reach significance for self-reported histories of gonorrhea and syphilis were weak and inconsistent across BPH/LUTS outcomes .
Only one other study evaluated the correlation between LUTS symptoms and STI serology. Sutcliffe et al. evaluated the prevalence of viral STI in male participants of the Third National Health and Nutrition Examination Survey. Positive associations were found between serological evidence of several sexually acquired viruses and reporting of two or more LUTS symptoms in men aged 30–59 years, but as in the prior study, not in subjects ≥60 years old .
The PLCO findings contrasted to observational studies of a similar cohort, where Sutcliffe et al. described the impact of STI on LUTS in subjects enrolled in the HPFS. A history of gonorrhea was associated with any (OR 1.76, 95% CI 1.43–2.15), moderate/severe (OR 1.89, 95% CI 1.51–2.37), and severe (OR 2.69, 95% CI 1.97–3.67) LUTS . Importantly, incident LUTS were studied as data was taken from biennial surveys. A history of gonorrhea correlated to any (OR 1.63, 95% CI 1.14–2.33) and severe (OR 2.4, 95% CI 1.32–4.38) new-onset symptoms.
The subject population of the PLCO is predominantly older white men who have a lower prevalence of STI compared with black men or men who have sex with men. Several studies have addressed LUTS and history of STI in at-risk populations, including African American men, men who have sex with men, and women [150–152]. Joseph et al. describes a cohort of African American men where >50% reported a history of any STI (gonorrhea, syphilis, genital herpes, or genital warts). Positive STI history conferred a 1.5-fold increased risk of developing moderate to severe LUTS . Similarly, Ejike et al. investigated the role of STI and CP symptoms by performing a cross-sectional survey of black undergraduate students in Nigeria . Presence and severity of symptoms were assessed by use of the National Institute of Health-Chronic Prostatitis Symptom Index. Of the 2003 men who completed the survey, 73% of those with history of STI had CP symptoms. Presence of CP symptoms correlated positively and significantly with self-reported history of STI.