Urology/Infertility Update

Educational Objectives

The goal of this program is to improve the management of lower urinary tract symptoms (LUTS) in men, and the evaluation and treatment of prostate cancer and infertility. After hearing and assimilating this program, the clinician will be better able to:

1.   Discuss safety and efficacy data about medical treatment of LUTS in men.

2.   Explain pharmacokinetic differences between tolterodine and fesoterodine.

3.   Recognize men who may benefit from prostate-specific antigen screening.

4.   Identify specific causes of infertility in men and women by performing a thorough work-up.

5.   Counsel and treat women with infertility who may benefit from clomiphene therapy.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the plan­ning committe to disclose relevant financial relationships within the past 12 months that might create any personal conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the following has been disclosed: Dr. Hatchett is a con­sultant for Astellas, Pfizer, and sanofi-aventis. Dr. Christman and the planning committee reported nothing to disclose. In his lecture, Dr. Christman presents information that is related to the off-label or investigational use of a therapy, product, or device.

Acknowledgements

Dr. Hatchett spoke in Staffordshire, UK, on November 10, 2009, at Medical Masterclass, sponsored by Schering-Plough. Dr. Christman was recorded in Ann Arbor, MI, at Update in Family Medicine, presented October 15-19, 2009, by the Uni­versity of Michigan Medical School. The Audio-Digest Foundation thanks the speakers and the sponsors for their coopera­tion in the production of this program.

The Overactive Bladder in Men

R. Lawrence Hatchett, MD, Clinical Professor of Urology, Southern Illinois University School of Medicine, and Director, Southern Illinois Urology, Marion, IL

Lower urinary tract symptoms (LUTS): obstructive  —weak urinary stream; straining; stopping and starting; sensa­tion of incomplete emptying; irritative  —  frequency; urgency; nocturia; prevalence of overactive bladder (OAB) and LUTS equal between men and women (»16%), but more women (6:1) treated for OAB

Causes of LUTS in men: obstructive prostate; irritative symptoms due to loss of bladder elasticity; most patients present with complaints of irritative symptoms

Safety of tolterodine in men: concerns about bladder outlet obstruction (BOO); study  —  BOO confirmed by urody­namic studies (normal maximum flow rate, ³15 mL/sec; normal maximum detrusor pressure, <60 cm H₂O); after 12 wk of tolterodine (2 mg bid), maximum flow rate remained at 8.5 mL/sec, maximum detrusor pressure de­creased from 68 cm H₂O to 60 cm H₂O (not clinically significant) and  no change in urinary retention in placebo or treatment groups; a-blocker and tolterodine  —  study found monotherapy with a-blocker did not change quality of life scores, but combination therapy did; no change in urodynamic parameters; no urinary retention; doxazosin and tolterodine  —  study saw 35% improvement in International Prostate Symptom Score (IPSS) with doxazosin alone (75% improvement with combination therapy); no urinary retention; a-blocker failure  —  a-blocker may improve obstructive symptoms, but not irritative symptoms; consider adding antimuscarinic agent; study found patients with a-blocker failure had 7-point drop in IPSS

Prolonged bladder contraction: leads to straining and ischemia; bladder appears scarred, pale, and thickened; uri­nary retention resulting from use of antimuscarinic agent indicative of bladder weakening and decompensation (re­fer to urologist)

Dietary causes of OAB: soda; coffee; tea; juice; acidic foods (eg, tomatoes); calcium glycerophosphate (eg, Prelief), calcium carbonate (eg, Tums), or baking soda and water can help neutralize acid; consider interstitial cystitis

Reduction of symptoms: best outcomes with combination of behavioral and medical interventions; nighttime  —  reduce drinking at night; adjust timing of diuretic;  use of compressive stockings may contribute to nocturia; inves­tigate desmopressin levels; continuous positive airway pressure (CPAP) helpful for patients with sleep apnea; anti­muscarinic agents and a-blockers safe and effective for LUTS in men; a-blockers used in women (off-label)

Fesoterodine vs tolterodine: pharmacokinetics of tolterodine  —tolterodine metabolized to 5-hydroxymethyl toltero­dine (5-HMT; potent antimuscarinic metabolite) by cytochrome P₄₅₀ 2D6 (CYP2D6); drug poorly metabolized (ie, small amount of 5-HMT produced) by 7% of whites and 2% of blacks; pharmacokinetics of fesoterodine  —  rapidly hydrolyzed by esterases; not affected by ethnicity; produces high amount of 5-HMT when activated; 16% excreted in urine (lack of accumulation makes it safe for elderly)

Fesoterodine: dosing  —  recommended starting dose, 4 mg or 8 mg once daily; > 4 mg/day not recommended for pa­tients with severe renal insufficiency or patients taking CYP450 3A4 potent inhibitors (eg, ketoconazole); moderate CYP450 3A4 inhibitors (eg, erythromycin) may be used; not recommended for patients with severe hepatic dis­ease; no dose adjustments required for age, ethnicity, mild or moderate renal or hepatic impairment, or use of oral contraceptives; contraindications  —  urinary retention; gastric retention; uncontrolled narrow-angle glaucoma; sen­sitivity to drug ingredients; use cautiously in patients with BOO, decreased gastric motility, controlled narrow-an­gle glaucoma, or myasthenia gravis; extended-release pill (tablet cannot be broken); half-life, 7 hr; steady state achieved in 35 hr; studies showed no effect on QT interval with up to 3.5 times dose (28 mg); tolterodine compo­nent of drug causes QT effects; United States and international studies  —primary and secondary end points include change in urge incontinence episodes in 24 hr, micturition, voided volume, and safety; exclusion criteria include contraindication, lower urinary tract pathology (eg, urinary tract infection [UTI] or recent bladder surgery), neuro­logic influences (eg, multiple sclerosis), and postvoid residual volume >100 mL; at 2 wk, fesoterodine shown to im­prove urge incontinence (clinically significant); at 12 wk, patients needed to use 0 to 1 absorbent pad; try drug for ³1 mo before changing dose; 16% to 18% reduction in number of daily voids acceptable result; voided volume in­creased £33% with use of 8 mg/day; side effects  —  dry mouth; constipation; central nervous system side effects no different from placebo; 3-yr extended trial  —  after 1 mo, 16% opted to reduce daily dose from 8 mg to 4 mg; study showed 12.5% reduction at 3 yr; stop drug periodically (eg, every 3 mo) to monitor need for therapy

PSA and Prostate Cancer Screening

Dr. Hatchett

Prostate-specific antigen (PSA) testing: controversial; sensitivity high, specificity low; sensitivity of prostate exam­ination low, but specificity high; »17% of men develop prostate cancer; risk factors include black ethnicity and pos­itive family history; recommendations  —  American Urological Association recommends screening men starting at age 40 yr; American Cancer Society (ACS) recommends offering screening starting at age 50 yr, or age 45 yr in men with risk factors; continue screening in men with life expectancy >10 yr; American Academy of Family Physi­cians states that data about screening asymptomatic general population insufficient; United States Preventive Ser­vices Task Force (USPTF) recommends against screening men >75 yr of age; 3% of men die from prostate cancer (benefits of screening questionable); risks of prostate biopsy include infection with resistant Escherichia coli; con­sider starting PSA screening in men with 2 risk factors at age 40 yr; spacing out PSA screening  —  cost-effective; perform first PSA test at age 45 to 50 yr; if PSA <1 ng/mL, repeat testing in 5 yr; if PSA 1 to 2 ng/mL, repeat test­ing in 2 yr; if PSA >2 ng/mL, annual PSA testing recommended

PSA screening and suspected UTI: treat with antibiotic (eg, quinolone) for 3 to 4 wk; significant BOO symptoms can be treated with a-blocker; repeat PSA testing in 3 mo

Case presentations: 1) man 65 yr of age with PSA level 12.5 ng/mL; prostate feels normal and slightly tender; pa­tient has noticed increased urinary frequency and urgency; last year’s PSA level, 2.1 ng/mL; management  —  treat with antibiotics for 1 mo; repeat PSA testing in 3 mo; 2) man 82 yr of age with PSA level 6.0 ng/mL; 1-cm firm nodule found on rectal examination suggests cancer; management  —discuss risks associated with biopsy (eg, uro­sepsis, prostatitis) with patient and family members; if PSA doubles within 1 yr, or PSA reaches >20 ng/mL, refer to urologist to discuss options; 3) man 60 yr of age with PSA level 14 ng/mL; over past 4 yr, patient had 2 negative 12-core biopsies with PSA level 12 ng/mL; management  —  starting 5a-reductase inhibitor (eg, dutasteride; off-la­bel use) should reduce PSA by 50% in 6 mo; if PSA drops <50%, consider repeating biopsy, and consider checking percentage of free PSA

5a-reductase inhibitor for prostate cancer prevention: prostatitic intraepithelial neoplasia (PIN) associated with risk for development of prostate cancer; discuss dutasteride and finasteride data (eg, shown to decrease develop­ment of prostate cancer by 25%, but unknown whether risk of dying from prostate cancer decreases); unlikely to cause higher grade of prostate cancer, but not certain; ACS recommends counseling patients, consider starting 5a-reductase inhibitor, and screening more often (eg, every 6 mo)

Case presentation: man 50 yr of age with PSA level 2.5 ng/mL (high; normal PSA for men 50 yr of age,  £1 ng/mL); treat with antibiotic for 1 mo and repeat PSA testing in 3 mo (perform biopsy if PSA still high)

Infertility: Work-up and Treatment

Gregory M. Christman, MD, Associate Professor of Obstetrics and Gynecology, University of Michigan Medi­cal School, Ann Arbor

Infertility: common; »8% of women of reproductive age infertile; 25% of couples concerned with infertility (only 15% seek medical care due to embarrassment); classically defined as failing to become pregnant after 1 yr of try­ing; treat factors that may be reducing fecundity and normal conception rate for age

Age-related infertility: women  —  growing concern; associated with social demands and changes; factors that de­crease female fertility include fibroids, endometriosis, comorbidities, and lack of partner availability; in women 25 yr of age, likelihood of failing to become pregnant after 1 yr of trying, 10% (90% in women 42 yr of age); men  — fertility decreases with age; may be due to changes in semen parameters, varicoceles, medical illness and condi­tions, and increased rate of nondisjunction in sperm; etiologies  —  endometriosis or tubal disease; consider both fe­male and male factors (perform semen analysis); ovulation defects; unexplained infertility

Evaluation of men: history  —  ask about mumps, urologic factors (eg, infection), industrial exposure, chemotherapy, and marijuana smoking; semen analysis  —  check sperm count (20 million/mL normal); evaluate sperm motility (50% should appear motile); assess sperm morphology based on World Health Organization morphology classifica­tion criteria (50% should appear normal) or strict morphology (ie, examine sperm at 1000-fold magnification; 15% should appear normal); check for liquefaction, white cells (sign of infection), and antisperm antibodies (risk factors include history of trauma, vasectomy reversal, or prostatitis); requires abstinence for 2 to 5 days; if 1 factor on se­men analysis abnormal, repeat in 2 mo; if 3 factors (eg, motility, count, morphology) abnormal, refer to urologist; consider testicular failure, high follicle-stimulating hormone (FSH; >15 mIU/mL), low testosterone (common in obesity), and prolactin level; if semen analysis markedly abnormal, work up or refer to urologist; physical examination  —  measure testicular size to rule out testicular failure; check for varicocele (usually on left side; simple outpatient surgery corrects varicocele and restores normal semen analysis); drug history  —  long-term use of sulfon­amides, sulfonamide-based drugs, and chemotherapy can affect semen analysis and fertility

Evaluation of women: family history  —  endometriosis; recurrent spontaneous abortion; fragile X syndrome; early menopause; medical history  —  pelvic inflammatory disease (PID); abdominal surgery; ectopic pregnancy; ruptured appendix; menstrual history  —  regular menstrual cycles <25 days or >35 days highly associated with infertility (in­dicates low progesterone level); only 2% of women of reproductive age have regular 28-day cycles; evaluate pa­tients with bleeding concerns; severe dysmenorrhea sign of endometriosis; coital function  —  ask about coital frequency, pain during intercourse, use of vaginal lubricants (olive oil, canola oil, and saliva safe); coital and ejacu­latory dysfunction in partner; tests  —  endocrine testing for women with irregular menstrual cycles; timed progester­one test; postcoital test; check for ovulation; luteal phase defect test; imaging  —  transvaginal ultrasonography to determine size of ovaries

Ovarian reserve: number of eggs remaining; check for elevated (>15 mIU/mL) FSH on third day of cycle

Ovulatory dysfunction: caused by hypothyroidism and elevated prolactin; treated with clomiphene (eg, Clomid)

Clomiphene: safe; reliable; use first-line for 2 cycles; maintain lowest dose needed to induce ovulation for 3 cycles; if ineffective after 3 cycles, refer to specialist for midcycle monitoring; study showed midcycle monitoring and checking estradiol levels do not add value to improving conception in first 4 cycles; clomiphene challenge test no longer used; elevated FSH on day 3 indicates low ovarian reserve

Assessment of ovulation: basal body temperature (30% of women with flat basal body temperature for 1 yr ovulate normally); single progesterone level 6 to 8 days after detection of ovulation with luteinizing hormone surge (if >15 ng/mL, no further testing needed; <3 ng/mL, indicates lack of ovulation; if <10 ng/mL, patient may benefit from clomiphene)

Hysterosalpingography: in women with history of ectopic pregnancy, check for open tubes; women with 5 men­strual periods per year and polycystic ovary syndrome, may be treated with clomiphene without undergoing hys­terosalpingography if pelvic examination normal; findings may include hydrosalpinx, salpingitis isthmica nodosum (sign of chlamydial infection), and divot in uterus (may explain infertility or be linked to miscarriage)

Suggested Reading

Abrams P et al: Muscarinic receptor antagonists for overactive bladder. BJU Int 100:987, 2007; Abrams P et al: Safety and tolerability of tolterodine for the treatment of overactive bladder in men with bladder outlet obstruction. J Urol 175:999, 2006; Agalliu I et al: Prostate cancer mortality in relation to screening by prostate-specific antigen testing and digital rectal examina­tion: a population-based study in middle-aged men. Cancer Causes Control 18:931, 2007; Baltaci S et al: Effectiveness of an­tibiotics given to asymptomatic men for an increased prostate specific antigen. J Urol 181:128, 2009; Chapple C et al: Tolterodine treatment improves storage symptoms suggestive of overactive bladder in men treated with alpha-blockers. Eur Urol 56:534, 2009; Dhaliwal LK et al: The need for clinical evaluation and semen analysis of infertile men. Int J Fertil Wom­ens Med 45:232, 2000; Lee JY et al: Comparison of doxazosin with or without tolterodine in men with symptomatic bladder outlet obstruction and an overactive bladder. BJU Int 94:817, 2004; Malhotra B et al: The design and development of fesoter­odine as a prodrug of 5-hydroxymethyl tolterodine (5-HMT), the active metabolite of tolterodine. Curr Med Chem 16:4481, 2009; Malhotra BK et al: Influence of age, gender, and race on pharmacokinetics, pharmacodynamics, and safety of fesotero­dine. Int J Clin Pharmacol Ther 47:570, 2009; Miller DC et al: Processed total motile sperm count correlates with pregnancy outcome after intrauterine insemination. Urology 60:497, 2002; Ross KS et al: Comparative efficiency of prostate-specific an­tigen screening strategies for prostate cancer detection. JAMA 284:1399, 2000; Shavers VL et al: Race/ethnicity, risk percep­tion, and receipt of prostate-specific antigen testing. J Natl Med Assoc 101:698, 2009; Smith YR et al: Comparison of low-technology and high-technology monitoring of clomiphene citrate ovulation induction. Fertil Steril 70:165, 1998; Spitz A et al: Contemporary approach to the male infertility evaluation. Obstet Gynecol Clin North Am 27:487, 2000; Stovall DW et al: Abnormal findings on hysterosalpingography: effects on fecundity in a donor insemination program using frozen semen. Ob­stet Gynecol 80:249, 1992.