Approach to Frequent Micturition in Female

Bumsoo Park, MD, PhD

Assistant Professor Departments of Family Medicine and Urology University of Michigan Medical School Oct 3, 2019 Female Urinary Issues in Primary Care

Bumsoo Park, MD, PhD

Assistant Professor Departments of Family Medicine and Urology University of Michigan Medical School Oct 3, 2019 Approach to Frequent Micturition in Female

Bumsoo Park, MD, PhD

Assistant Professor Departments of Family Medicine and Urology University of Michigan Medical School Oct 3, 2019 Conflict of Interest No financial disclosures Learning Objectives

• What will be covered today: – General approach to female frequency – Voiding dysfunction/PVR – OAB – IC/BPS – Recurrent UTI • What will not be covered today: – Urinary incontinence – Pelvic organ prolapse – Gynecologic issues About Me

• Graduated from Kyung Hee University Medical School in South Korea in 2003. • Urology residency (2004-2008) • Public health physician (2008-2011) • Urology fellowship in Uro Onc (2011-2012) • Urology physician (2012-2015) • Family Medicine residency at Henry Ford (2015- 2018) • Family Medicine/Urology faculty at UM (2018- )

Case 1

• 64 y/o female • CC: frequency, nocturia 3-4 times/N for 3 months • PMHx: DM(+), HTN(+) • ROS: urgency(+-), UUI(-), weak stream(+), incomplete emptying (-), dysuria(-), gross hematuria(-) • P/Ex: unremarkable • Bloodwork: EGFR 53, otherwise unremarkable • UA: 0-1 RBC/3-4 WBC. Urine culture negative • Failed lifestyle measures. Pharmacotherapy suggested. What will be your prescription? Case 1

• Oxybutynin ER 5 mg once daily. • After 14 days, frequency & nocturia aggravated. • Referred to Urology • UFM/PVR: – Qmax/Qavg: 6.7/3.9 ml/s – Voided/PVR: 100/170 ml • Tamsulosin 0.4 mg once daily for 30 days • Frequency & nocturia improved. Case 2

• 64 y/o female • CC: weak stream, sense of incomplete emptying for 3 months • PMHx: DM(+), HTN(+) • ROS: frequency(+), nocturia(+), urgency(+), UUI(+-), dysuria(-), gross hematuria(-) • P/Ex & blood work: unremarkable • UA: 0-1 RBC/0-1 WBC. Urine culture negative • Failed lifestyle measures. Pharmacotherapy suggested. What will be your prescription? Case 2

• Tamsulosin 0.4 mg once daily. • After 14 days, frequency, nocturia & urgency aggravated. Even UUI became more significant. • Referred to Urology • UFM/RU: – Qmax/Qavg: 16.7/7.9 ml/s – Voided/PVR: 290/8 ml • Oxybutynin ER 5 mg once daily for 30 days • Symptoms alleviated.

Lower urinary tract physiology

• Storage phase – Bladder function: normal vs. overactive – Urethral function: normal vs. incompetent • Voiding phase – Bladder function: normal vs. underactive vs. acontractile – Urethral function: normal vs. interrupted

Therefore, the following diagnosis is possible and not uncommon:

DHIC (Detrusor hyperactivity with impaired contractility) Distribution of cholinergic and adrenergic receptors in lower urinary tract Lower urinary tract symptoms (LUTS)

• Storage symptoms – Frequency – Urgency, urgency urinary incontinence – Nocturia • Voiding symptoms – Hesitancy – Weak stream – Sense of incomplete emptying – Intermittency – Postvoid dribbling – Splitting – Urinary retention

Frequent Micturition Definition/Terminology

• Normal micturition (Campbell-Walsh Urology) – The normal adult voids five or six times per day, with a volume of approximately 300 ml with each void. • Urinary frequency (2018 ICS definition) – Complaint that voiding occurs more frequently than deemed normal by the individual (or caregivers). Time of day and number of voids are not specified. • NocturiaNocturia (2018 (2002 ICSICS definition)definition) –- The Waking complaint to pass urine that during the individual the main sleep has period.to wake The at first night onenocturiaor more episode times must to void.be preceded by sleep. Subsequent nocturia episodes must be followed by the intention of getting back to sleep.

www.ics.org Causes of Frequent Micturition

• Pregnancy • Bladder calculus • Large fluid intake • Bladder cancer • Diabetes mellitus • Pelvic mass • Diabetes insipidus • Bacterial urethritis • Renal impairment • Urethral caruncle • Large PVR • Urethral diverticulum • OAB • Atrophic urethral changes • Upper motor neuron lesion • Periurethral gland infection • IC/BPS • Vulvar carcinoma • Radiation cystitis • Genital condylomata • Chemical irritants (contraceptive • Cervicitis foams, douches, diaphragm, • Diuretic therapy obsessive washing) • Chemotherapy • UTI • Habit Campbell-Walsh Urology, 9th Ed. Causes of Frequent Micturition

• Poorly understood. • Symptoms do not correlate well with objective finding (PVR).

• Sensitivity (8.8-56.1%) and PPV (11.6-22.7%) of voiding dysfunction symptoms to predict UR were low.

Adelowo et al. Female Pelvic Med Reconstr Surg 2012;18:344-7. Prevalence of Female UR

• Prevalence of female UR: 1,532 per 100,000 US female Medicare beneficiaries in 2012. • Independent factors for UR: – Neurologic condition – UTI – POP Cohn et al. Neurourol Urodyn 2017;36:2101-8. Causes of PVR in Women

• Neurogenic bladder – Obvious neuromuscular diseases (spinal cord pathology, ALS, etc) – Diabetes – Radical pelvic surgery (such as APR, hysterectomy, colectomy) • Anti-incontinence surgery (mid-urethral sling) • Postpartum and postoperative • External compression (fibroids, POP, constipation) • Functional female BOO • Fowler’s syndrome Causes of PVR in Women

• Well-known condition • A broad spectrum of LUTS including OAB, voiding dysfunction, and UR. • A manifestation of diabetic neuropathy resulting in decreased bladder sensation, increased bladder capacity, and impaired detrusor contractility.

Yuan et al. J Diabetes 2015;7:442-7. Role of Glycemic Control in DBD Management

• No current evidence that better glycemic control improves DBD. • There is evidence suggesting progression of DBD is related to both the duration of hyperglycemia and to blood sugar levels.

Wittig et al. Urology 2019;123:1-6.

• Worse glycemic control could predict DBD. Kebapci et al. Neurourol Urodyn 2007;26:814-9. Constipation and PVR

• Case control study. 161 constipated women vs 162 healthy female volunteers. • LUTS more common in constipated group. • Frequency 34% vs 14% (p <0.001). • Incomplete emptying 24% vs 9% (p=0.003).

Carter et al. Int Urogynecol J 2012;23:;1785-9. Constipation and PVR

• Prospective study. 52 patients (aged 65-89) enrolled. • Treatment of constipation: – Less frequency (25 vs 47; p<0.001) – PVR decreased from 85 (±39.5) ml to 30 (±22.6) ml.

Charach et al. Gerontology 2001;47:;72-76. Kameda et al. Intern Med 2016;55:2519. Averbeck et al. Int Braz J Urol 2011;37:16-28. Averbeck et al. Int Braz J Urol 2011;37:16-28. Female BOO: Definition

www.ics.org Female BOO

• Incidence: 2.7-23% (lack of consensus in diagnostic cutoff) • Anatomical BOO: – POP, malignancy, structure, iatrogenic (sling) • Functional BOO: – Non-anatomic, non-neurogenic – Dysfunctional voiding, Fowler’s syndrome, primary bladder neck obstruction (PBNO)

Meier et al. Curr Opin Urol 2016;26:334-41. Meier et al. Curr Opin Urol 2016;26:334-41. Fowler’s Syndrome

• First described in 1985. • Definition: urinary retention in young women in the absence of overt neurologic disease. • Typical history: a woman younger than 30 years who has found herself unable to void for a day or more with no urinary urgency but increasing lower abdominal discomfort. Campbell-Walsh Urology, 11th Ed. Fowler’s Syndrome

• Diagnosis: – No clear criteria – A bladder capacity of over 1 L with no sensation of urgency is necessary. – No neurological or laboratory features

Campbell-Walsh Urology, 11th Ed. Fowler’s Syndrome

• Urodynamic findings: – Increased urethral sphincter activity – Detrusor acontractility • Frequent association: PCOS (possible hormonal-based effect on channel receptors?) • Treatment: – Neuromodulation (up to 70% success rate)

Campbell-Walsh Urology, 11th Ed. Diagnosis of PVR

• What is PVR cut-off?

www.ics.org Treatment of Large PVR

Campbell-Walsh Urology, 11th Ed. Alpha-blocker Use for Women

• 14 studies were included.

Kim et al. Int Neurourol J 2019;23:56-68. Kim et al. Int Neurourol J 2019;23:56-68. Kim et al. Int Neurourol J 2019;23:56-68. Kim et al. Int Neurourol J 2019;23:56-68. Kim et al. Int Neurourol J 2019;23:56-68. Alpha-blocker Use for Women

• 15 studies were reviewed. • Many studies showed LUTS improvement. • Most studies also reported adverse events such as dizziness and hypotension. • Limitations include small sample sizes, inconsistent study designs, and short duration of therapy.

Boyd et al. Ann Pharmacother 2014;48:711-22.

Alpha-blocker Use for Women

• Feasible and effective. • Safety and adverse effects still need to be considered, and further studied. Causes of Frequent Micturition

• OAB is a symptom-based diagnosis.

www.ics.org Definition of OAB

• OAB is not a disease. • It is a symptom complex that generally is not a life- threatening condition.

2019 AUA/SUFU Guideline on OAB Pathophysiology Epidemiology

• Overall prevalence in US1: 23.2% • The incidence increases with age.

1. Coyne et al. Neurourol Urodyn 2013;32:230-7. Diagnosis of OAB Diagnosis of OAB

• Document symptoms and signs that characterize OAB. • Exclude other disorders. – Careful history – Physical exam – Urinalysis

2019 AUA/SUFU Guideline on OAB Diagnosis of OAB

• At the clinician’s discretion, – Urine culture – PVR – Bladder diaries – Symptom questionnaires

2019 AUA/SUFU Guideline on OAB

Symptom questionnaires

• Validated symptom questionnaires1 – Urogenital Distress Inventory (UDI) – UDI-6 Short Form – Incontinence Impact Questionnaire (II-Q) – Overactive Bladder Questionnaire (OAB-q) • Overactive bladder symptom scores (OABSS)2 – Developed in Japan by Y. Homma, 2006 – 4 items

1. 2019 AUA/SUFU Guideline on OAB 2. Lin et al. Incont Pelvic Floor Dysfunct 2009; 3(Suppl 1): 9-14. Diagnosis of OAB = Total score ≥ 3 (with Item 3 at least 2)

Mild: ≤ 5 Moderate: 6-11 Severe: ≥ 12 Homma et al. Urology 2014;84:46-50. Diagnosis of OAB

• Should not be used in the initial work- up of the uncomplicated patient: – Urodynamics – Cystoscopy – Diagnostic renal/bladder US

2019 AUA/SUFU Guideline on OAB Treatment of OAB Issues to consider

• OAB generally does not affect survival. • OAB is a symptom complex that may compromise QoL. • Consider the balance between benefits and risks/burdens. • In patients who cannot perceive symptom improvements, treatment may not be appropriate. First-Line Treatments: Behavioral Therapies Treatment of OAB: 1st Line

• Clinicians should offer behavioral therapies as first line therapy to all patients with OAB (Grade B).

2019 AUA/SUFU Guideline on OAB Treatment of OAB: 1st Line

• Bladder training • Bladder control strategies • Pelvic floor muscle training • Fluid management • Behavioral therapies may be combined with pharmacologic management (Grade C).

2019 AUA/SUFU Guideline on OAB Fluid Management

- Randomized controlled trial - 25% reduction in fluid intake reduced frequency and urgency.

Hashim et al. BJU Int 2008; 102: 62-66. Caffeine and OAB

- Prospective cohort study in 65,176 women

- High but not lower caffeine intake is associated with a modest increase in the incidence of frequent urgency incontinence.

- But not on the stress and mixed incontinence

Jura et al. J Urol 2011; 185: 1775-1780. Caffeine and OAB

- Oral caffeine administration results in detrusor overactivity and increased bladder sensory signaling in the mouse.

Kershen et al. J Urol 2012; 188: 1986-1992. Second-Line Treatments: Pharmacologic Management Treatment of OAB: 2nd Line

• Clinicians should offer oral antimuscarinics or beta3-adrenoceptor agonists as second-line therapy (Grade B): • ER formulations should preferably be prescribed over IR because of lower rates of dry mouth (Grade B).

2019 AUA/SUFU Guideline on OAB Treatment of OAB: 2nd Line

• Transdermal oxybutynin (patch or gel) may be offered (Grade C). • If ineffective or intolerable, – Dose modification – Switch to different antimuscarinics – Switch to beta3-agonists • Combination of antimuscarinic and beta3- agonists in failed monotherapy (Grade B).

2019 AUA/SUFU Guideline on OAB - Systematic literature search. 44 RTCs involving 27,309 patients. - Mirabegron vs darifenacin, tolterodine IR/ER, oxybutynin IR/ER, trospium, solifenacin, and fesoterodine - Mirabegron 50 mg was as effective as antimuscarinics in reducing the frequency of micturition incontinence and UUI episodes. - With the exception of solifenacin 10 mg that was more efficacious than mirabegron 50 mg. - Mirabegron 50 mg had an incidence of dry mouth similar to placebo, and significantly lower than all included antimuscarinics. Maman et al. Eur Urol 2014; 65: 755-65. Treatment of OAB: 2nd Line

• Antimuscarinics should not be used for narrow-angle glaucoma unless approved by the treating ophthalmologist. • Extreme caution with antimuscarinics in impaired gastric emptying or a history of urinary retention.

2019 AUA/SUFU Guideline on OAB Treatment of OAB: 2nd Line

• Manage dry mouth and constipation before abandoning effective antimuscarinic therapy. – Bowel management, fluid management, dose modification, or alternative antimuscarinics • Caution in antimuscarinic use in patients who are already on medications with anticholinergic properties (TCA, anti- Parkinson’s, COPD inhalers).

2019 AUA/SUFU Guideline on OAB Treatment of OAB: 2nd Line

• Caution in prescribing antimuscarinics or beta3-agonists in the frail OAB patient. • Patients who are refractory to behavioral and pharmacologic therapy should be evaluated by an appropriate specialist if they desire additional therapy.

2019 AUA/SUFU Guideline on OAB Third-Line Treatments: PTNS and Neuromodulation Treatment of OAB: 3rd Line

• Intradetrusor onabotulinumtoxinA (100 U) • Peripheral tibial nerve stimulation (PTNS) • Sacral neuromodulation (SNS)

2019 AUA/SUFU Guideline on OAB Treatment of OAB: 4th Line

• Augmentation cystoplasty • Urinary diversion • Indwelling catheters (transurethral or suprapubic) are not recommended for OAB management because of the adverse risk/benefit balance except as a last resort in selected patients.

2019 AUA/SUFU Guideline on OAB Follow-up of OAB

• The clinician should offer follow-up with the patient to assess compliance, efficacy, side effects, and possible alternative treatments.

2019 AUA/SUFU Guideline on OAB

Causes of Frequent Micturition

• IC/BPS is a symptom-based diagnosis.

www.ics.org Pathophysiology

• Poorly understood • Potential genetic susceptibility • Defects in GAG layer • Upregulation of pain sensation in the bladder Epidemiology

• Varying statistics on prevalence given variations in diagnostic criteria • Female to male = 5 : 1 • Overall prevalence: 2.6-4.4%

Davis et al. Transl Androl Urol 2015; 4: 506-11. Diagnosis of IC/BPS Diagnosis of IC/BPS

• No objective marker to establish the presence of IC/BPS • Basic assessment to rule in and out: – Careful history – Physical examination – Laboratory

2014 AUA Guideline on IC/BPS Diagnosis of IC/BPS

• Baseline voiding symptoms and pain levels should be obtain in order to measure subsequent treatment effects. • Cystoscopy and urodynamics – Considered as an aid to diagnosis only for complex presentations. These tests are not necessary for making the diagnosis in uncomplicated presentations.

2014 AUA Guideline on IC/BPS Total score ≥6 - Possible diagnosis

Total score ≥12 - Strong diagnosis 2014 AUA Guideline on IC/BPS Treatment of IC/BPS Treatment Principle

• Initial treatment type and level should depend on symptom severity, clinician judgement, and patient preferences. • Multiple, simultaneous treatments may be considered if it is in the best interests of the patient. • Ineffective treatments should be stopped once a clinically meaningful interval has elapsed.

2014 AUA Guideline on IC/BPS Treatment Principle

• Pain management should be continually assessed. Multidisciplinary approach and/or specialty referral should be considered. • The IC/BPS diagnosis should be reconsidered if no improvement occurs after multiple treatment approaches.

2014 AUA Guideline on IC/BPS First-Line Treatments: Should be performed on all patients Treatment of IC/BPS: 1st Line

• Patient education – Normal bladder function – What is known and not known about IC/BPS – Benefits vs risks/burdens of treatment options – The fact that no single treatment has been found effective for the majority of patients – The fact that acceptable symptom control may require trials of multiple therapeutic options

2014 AUA Guideline on IC/BPS Treatment of IC/BPS: 1st Line

• Self-care practices and behavioral modifications that can improve symptoms should be discussed and implemented as feasible. • Patient should be encouraged to implement stress management practices to improve coping techniques and manage stress-induced symptom exacerbations.

2014 AUA Guideline on IC/BPS Second-Line Treatments Treatment of IC/BPS: 2nd Line

• Appropriate manual physical therapy techniques (Grade A) – Maneuvers that resolve pelvic, abdominal and/or pelvic hip muscular trigger points, lengthen muscle contractures, and release painful scars and other connective tissue restrictions • Pelvic floor strengthening exercise (e.g., Kegel exercises) should be avoided (Grade A).

2014 AUA Guideline on IC/BPS Treatment of IC/BPS: 2nd Line

• Multimodal pain management approaches (pharmacological, stress management, manual therapy if available) should be initiated. • Pharmacologic intervention (no hierarchy is implied) – Amitriptyline (Grade B) – Cimetidine (Grade B) – Hydroxyzine (Grade C) – Pentosan polysulfate (Grace B) • Intravesical treatments (no hierarchy is implied) – DMSO (Grade C) – Heparin (Grade C) – Lidocaine (Grade B) 2014 AUA Guideline on IC/BPS Other Treatments Treatment of IC/BPS: 3rd Line

• Cystoscopy under anesthesia for short-duration, low-pressure bladder hydrodistension (Grade C) • If Hunner’s lesions are present, then fulguration (with laser or electrocautery) and/or injection of triamcinolone should be performed (Grace C).

2014 AUA Guideline on IC/BPS Hunner’s lesion/ulcer Treatment of IC/BPS

• Fourth line – Intradetrusor botulinum toxin (BTX-A) injection (Grade C) – Neurostimulation (Grade C) • Fifth line – Oral cyclosporine A (Grade C) • Sixth line – Major surgery (substitution cystoplasty, urinary diversion with or without cystectomy)

2014 AUA Guideline on IC/BPS Treatments That Should Not Be Offered

• Long-term oral antibiotic administration • Intravesical BCG instillation • High-pressure, long-duration hydrodistension • Systemic (oral) long-term glucocorticoid administration

2014 AUA Guideline on IC/BPS

Causes of Frequent Micturition

• Clinicians should obtain a complete patient history and perform a pelvic exam. • To make a diagnosis of rUTI, clinicians MUST document positive urine cultures associated with prior symptomatic episodes. • Clinicians should obtain repeat urine studies when an initial urine specimen is suspected for contamination, with consideration for obtaining a catheterized specimen.

2019 AUA/CUA/SUFU Guideline on Recurrent uncomplicated UTI Evaluation of Recurrent UTI

• Cystoscopy and upper tract imaging – Should not be routinely performed • Clinicians may offer patient-initiated treatment (self-start treatment) to select rUTI patients with acute episodes while awaiting urine cultures.

2019 AUA/CUA/SUFU Guideline on Recurrent uncomplicated UTI Antibiotic Treatment

• First-line therapy (dependent on local antibiogram) – Nitrofurantoin – TMP-SMX – Fosfomycin • As short a duration of antibiotics as possible, generally no longer than 7 days. • For resistant organisms, may treat with culture-directed parenteral antibiotics as short a duration of antibiotics as possible, generally no longer than 7 days.

2019 AUA/CUA/SUFU Guideline on Recurrent uncomplicated UTI Antibiotic Treatment

2019 AUA/CUA/SUFU Guideline on Recurrent uncomplicated UTI Antibiotic Prophylaxis

• Clinicians may prescribe antibiotic prophylaxis to decrease the risk of future UTIs in women of all ages previously diagnosed with UTIs. • The use of fluoroquinolones (such as ciprofloxacin) for prophylactic antibiotic use is not recommended. • Little evidence on the benefits of rotating antibiotics as a means of controlling resistance rates.

2019 AUA/CUA/SUFU Guideline on Recurrent uncomplicated UTI Antibiotic Prophylaxis

• No difference in risk of any adverse event. • There is sparse reporting of antibiotic resistances, with little data specifically on the impact of long-term antibiotic therapy on antibiotic resistance. Even transient use of antibiotics can affect the carriage of resistant organisms as antibiotic resistance is related to an individual’s bacterial gene pool.

2019 AUA/CUA/SUFU Guideline on Recurrent uncomplicated UTI Antibiotic Prophylaxis: Duration of Therapy

• In clinical practice, the duration can be variable, from 3 to 6 months to one year, with periodic assessment and monitoring. • Continuing prophylaxis for years is not evidence- based.

2019 AUA/CUA/SUFU Guideline on Recurrent uncomplicated UTI Antibiotic Prophylaxis: Regimen, Dosing, and Schedule

• TMP 100 mg once daily • TMP-SMX 40 mg/200 mg once daily • TMP-SMX 40 mg/200 mg three times weekly • Nitrofurantoin monohydrate/macrocrystals 50 or 100 mg daily • Cephalexin 125 or 250 mg once daily • Fosfomycin 3 g every 10 days

2019 AUA/CUA/SUFU Guideline on Recurrent uncomplicated UTI Antibiotic Prophylaxis: Post-Coital

• In women who experience UTIs temporarily related to sexual activity, antibiotic prophylaxis before or after sexual intercourse has been shown to be effective and safe. • Significant reduction in recurrence rates and decreased risk of adverse events

2019 AUA/CUA/SUFU Guideline on Recurrent uncomplicated UTI Antibiotic Prophylaxis: Post-Coital Regimen

• Single dose immediately before or after sexual intercourse – TMP-SMX 40 mg/200 mg – TMP-SMX 80 mg/400 mg – Nitrofurantoin 50-100 mg – Cephalexin 250 mg

2019 AUA/CUA/SUFU Guideline on Recurrent uncomplicated UTI Non-Antibiotic Prophylaxis

• Clinicians may offer cranberry prophylaxis for women with rUTIs.

2019 AUA/CUA/SUFU Guideline on Recurrent uncomplicated UTI Fu et al. J Nutr 2017;147:2282-88. Non-Antibiotic Prophylaxis

• Lack of evidence: – Lactobacillus – Increased water intake – D-mannose – Methenamine – Herbs/supplements – Intravesical hyaluronic acid/chondroitin – Biofeedback – Ummunoactive therapy

2019 AUA/CUA/SUFU Guideline on Recurrent uncomplicated UTI Follow-Up for rUTI

• Clinicians should not perform a post-treatment test of cure UA or UCx in asymptomatic patients. • Clinicians should repeat UCx to guide further management when symptoms persist following antimicrobial therapy.

2019 AUA/CUA/SUFU Guideline on Recurrent uncomplicated UTI Follow-Up for rUTI

• In peri- and post-menopausal women with rUTIs, clinicians should recommend vaginal estrogen therapy to reduce the risk of future UTIs if not contraindicated. • Multiple randomized trials using a variety of formulations of vaginal estrogen therapy demonstrated a decreased incidence and time to recurrence of UTI in hypoestrogenic women.

2019 AUA/CUA/SUFU Guideline on Recurrent uncomplicated UTI Vaginal Estrogen: Regimen

2019 AUA/CUA/SUFU Guideline on Recurrent uncomplicated UTI

Causes of Frequent Micturition

• When a woman comes with frequent urination: – First, always rule out pregnancy if reproductive age. – Then, ask if it is acute or chronic. – If it is acute, more consider possibility of acute cystitis. – If it is chronic, rule out possible medical condition such as diabetes or renal dysfunction and review medications, fluid intake and lifestyle. – Then, assess micturition (would obtain UA & PVR): • Voiding dysfunction vs OAB vs IC/BPS – If persistent or indicated, consider thorough pelvic/GU exam, imaging (US, CT, or MRI), or cystoscopy.