1. Evaluation and Treatment of Cryptorchidism Prepared for: Agency for Healthcare Research and Quality www.ahrq.gov

2.  Introduction to cryptorchidism and the available strategies for evaluating and treating this condition  Systematic review methods  Clinical questions addressed by the comparative effectiveness review  Results of studies and evidence-based conclusions about the effectiveness and safety of various modalities for evaluating and treating cryptorchidism  Gaps in knowledge and future research needs  What to discuss with patients and their caregivers Outline of Material Penson DF, Krishnaswami S, Jules A, et al. AHRQ Comparative Effectiveness Review No. 88. Available at www.effectivehealthcare.ahrq.gov/undescended-testicle.cfm.

3.  Cryptorchidism is a congenital condition in which one or both testicles are not appropriately positioned in the scrotum at birth.  Cryptorchidism may be unilateral or bilateral, and the undescended testicles may be palpable or nonpalpable.  The undescended testicles may be present in the abdomen or the groin area or misplaced in the scrotum.  The undescended testicles may be functional or atrophied.  Some individuals have no testicles at all (anorchia). Background: Definition and Clinical Presentation of Cryptorchidism Penson DF, Krishnaswami S, Jules A, et al. AHRQ Comparative Effectiveness Review No. 88. Available at www.effectivehealthcare.ahrq.gov/undescended-testicle.cfm.

4.  The etiology of cryptorchidism is not well understood.  Cryptorchidism affects an estimated 3 percent of full-term male neonates and up to 30 percent of premature infants.  About 70 percent of cryptorchid testicles spontaneously descend within the first year of life.  However, the number of boys whose condition persists after this period remains constant at approximately 1 percent.  Long-term consequences of cryptorchidism may include testicular malignancy and infertility/subfertility. Background: Etiology, Prevalence, and Consequences of Cryptorchidism Penson DF, Krishnaswami S, Jules A, et al. AHRQ Comparative Effectiveness Review No. 88. Available at www.effectivehealthcare.ahrq.gov/undescended-testicle.cfm.

5.  The appropriate evaluation and treatment strategy for cryptorchidism may be influenced by many factors including:  Whether or not the testicle is palpable  Whether the condition is present unilaterally or bilaterally  The age at presentation  Comorbid conditions  The majority of undescended testicles (UDTs) can be located on physical examination.  For locating nonpalpable UDTs, exploratory laparoscopic surgery is routinely used in clinical practice. Background: Treatment Planning for Cryptorchidism Penson DF, Krishnaswami S, Jules A, et al. AHRQ Comparative Effectiveness Review No. 88. Available at www.effectivehealthcare.ahrq.gov/undescended-testicle.cfm.

6.  Treatment for cryptorchidism is usually initiated between the ages of 6 months and 1 year.  There are three key surgical options commonly used to treat cryptorchidism.  Surgical options depend on the location and appearance of the undescended testicle and include:  Primary orchiopexy  Single-stage Fowler-Stephens orchiopexy  Two-stage Fowler-Stephens orchiopexy Background: Treatment Strategies for Cryptorchidism Penson DF, Krishnaswami S, Jules A, et al. AHRQ Comparative Effectiveness Review No. 88. Available at www.effectivehealthcare.ahrq.gov/undescended-testicle.cfm.

7.  In addition to surgery, clinical treatment planning (imaging versus no imaging; hormonal stimulation testing or none) and intervention approaches including hormonal therapy have been investigated in the literature.  The authors of this systematic review examined the available evidence on the use of imaging and hormonal testing for evaluation and the on use of various treatment options for managing cryptorchidism. Objectives of This Comparative Effectiveness Review Penson DF, Krishnaswami S, Jules A, et al. AHRQ Comparative Effectiveness Review No. 88. Available at www.effectivehealthcare.ahrq.gov/undescended-testicle.cfm.

8.  Topics are nominated through a public process, which includes submissions from health care professionals, professional organizations, the private sector, policymakers, members of the public, and others.  A systematic review of all relevant clinical studies is conducted by independent researchers, funded by AHRQ, to synthesize the evidence in a report summarizing what is known and not known about the select clinical issue. The research questions and the results of the report are subject to expert input, peer review, and public comment.  The results of these reviews are summarized into Clinician Research Summaries and Consumer Research Summaries for use in decisionmaking and in discussions with patients. The Research Summaries and the full report, with references for included and excluded studies, are available at www.effectivehealthcare.ahrq.gov/undescended-testicle.cfm. Agency for Healthcare Research and Quality (AHRQ) Comparative Effectiveness Review (CER) Development Penson DF, Krishnaswami S, Jules A, et al. AHRQ Comparative Effectiveness Review No. 88. Available at www.effectivehealthcare.ahrq.gov/undescended-testicle.cfm.

9.  Key Question 1a. For determining a course of treatment, is imaging equivalent to laparoscopy in determining the presence and location of a nonpalpable undescended testicle?  Key Question 1b. In male children with bilateral nonpalpable undescended testicles, does the use of hormonal stimulation testing reduce the need for surgery as part of a treatment plan? Clinical Questions Addressed by This Comparative Effectiveness Review (1 of 4) Penson DF, Krishnaswami S, Jules A, et al. AHRQ Comparative Effectiveness Review No. 88. Available at www.effectivehealthcare.ahrq.gov/undescended-testicle.cfm.

10.  Key Question 2. What is the effectiveness of initial hormonal therapy (human chorionic gonadotropin or luteinizing hormone-releasing hormone) for the treatment of cryptorchidism for outcomes, including but not limited to:  Further surgical intervention?  The effect on infertility/subfertility?  The development of testicular malignancy?  The size, location, and function of the testicles Clinical Questions Addressed by This Comparative Effectiveness Review (2 of 4) Penson DF, Krishnaswami S, Jules A, et al. AHRQ Comparative Effectiveness Review No. 88. Available at www.effectivehealthcare.ahrq.gov/undescended-testicle.cfm.

11.  Key Question 3. What is the effectiveness of surgical therapies (one- stage vs. two-stage Fowler-Stephens orchiopexy; laparoscopic vs. open approach) for the treatment of cryptorchidism for outcomes including but not limited to:  Further surgical intervention?  The effect on infertility/subfertility?  The development of testicular malignancy?  The size, location, and function of the testicles? Clinical Questions Addressed by This Comparative Effectiveness Review (3 of 4) Penson DF, Krishnaswami S, Jules A, et al. AHRQ Comparative Effectiveness Review No. 88. Available at www.effectivehealthcare.ahrq.gov/undescended-testicle.cfm.

12.  Key Question 4. How do the age at presentation, physical presentation of cryptorchidism (unilateral vs. bilateral; palpable vs. nonpalpable; anatomic location), and occurrence of associated abnormalities (e.g., hernia) modify diagnosis, treatment, and outcomes?  Key Question 5. What are the nature and frequency of harms associated with workup or treatment for cryptorchidism? Clinical Questions Addressed by This Comparative Effectiveness Review (4 of 4) Penson DF, Krishnaswami S, Jules A, et al. AHRQ Comparative Effectiveness Review No. 88. Available at www.effectivehealthcare.ahrq.gov/undescended-testicle.cfm.

13.  The strength of evidence was classified into four broad categories: Rating the Strength of Evidence From the Comparative Effectiveness Review Penson DF, Krishnaswami S, Jules A, et al. AHRQ Comparative Effectiveness Review No. 88. Available at www.effectivehealthcare.ahrq.gov/undescended-testicle.cfm.

14.  The overall sensitivity and specificity of the various imaging modalities are reported in Table 1 in the next slide.  The evidence is based on mostly poor-quality studies and only one good-quality study.  The studies were too limited to provide evidence for changing current practice for evaluating nonpalpable testes. Evaluation of Cryptorchidism: Imaging Modalities Used To Identify Nonpalpable Undescended Testicles * Penson DF, Krishnaswami S, Jules A, et al. AHRQ Comparative Effectiveness Review No. 88. Available at www.effectivehealthcare.ahrq.gov/undescended-testicle.cfm. * The strength of evidence was not assessed for these findings.

15. Table 1. Overall Accuracies of Imaging Modalities in Identifying Nonpalpable Undescended Testicles Penson DF, Krishnaswami S, Jules A, et al. AHRQ Comparative Effectiveness Review No. 88. Available at www.effectivehealthcare.ahrq.gov/undescended-testicle.cfm. Imaging Technique Number and Quality of StudiesPerformance Characteristic Measures GoodFairPoorSensitivity*Specificity † Positive Predictive Value** Negative Predictive Value †† Overall Accuracy Rate § US12615 – 8067 – 100 0 – 8021 – 76 MRI03733 – 9156 – 10083 – 1000 – 7542 – 92 CT00157100 1460 MRA ¶ 011100NA – 100100NA – 100100 MRV ¶ 001100 MRI & MRAr/V00157NA100057 CT = computed tomography; MRA = magnetic resonance angiography; MRAr/V = magnetic resonance arteriography/venography; MRI = magnetic resonance imaging; MRV = magnetic resonance venography; NA = not available; US = ultrasonography *Sensitivity: The proportion of testicles correctly identified as present by imaging among those identified as present by surgery. † Specificity: The proportion of testicles correctly identified as absent or vanishing by imaging among those considered absent by surgery. **Positive predictive value: Among those testicles identified as present by imaging, what is the probability that it will be confirmed by surgery? †† Negative predictive value: Among those with a negative imaging result, what is the probability that the surgery also did not find them? § Overall accuracy rate: The proportion of testicles correctly identified by imaging as present or absent among all testicles subjected to both imaging and surgery. ¶ MRA and MRV are invasive techniques that require anesthesia or sedation.

16.  The overall success rate* for achieving testicular descent with primary orchiopexy** was 96.4 percent (range 89.1 – 100%). Strength of Evidence: High  The overall success rate for achieving testicular descent with one-stage Fowler-Stephens orchiopexy* was 78.7 percent (range 33 – 94.3%). Strength of Evidence: Moderate  The overall success rate for achieving testicular descent with two-stage Fowler-Stephens orchiopexy* was 86 percent (range 67 – 98%). Strength of Evidence: Moderate  However, each of the three types of surgery is used for a different clinical presentation, so the success rates cannot be compared with one another. Evidence for the Benefits of Surgical Interventions in Treating Cryptorchidism (1 of 2) Penson DF, Krishnaswami S, Jules A, et al. AHRQ Comparative Effectiveness Review No. 88. Available at www.effectivehealthcare.ahrq.gov/undescended-testicle.cfm. * Success rate was defined as the proportion of testicles achieving testicular descent or testicular positioning. ** These findings were based on retrospective studies. Each intervention was compared with an implicit control based on the known natural history of the disease.

17.  Laparoscopy and open repair surgery appeared to be equally effective in achieving testicular descent. Strength of Evidence: Low Evidence for the Benefits of Surgical Interventions in Treating Cryptorchidism (2 of 2) Penson DF, Krishnaswami S, Jules A, et al. AHRQ Comparative Effectiveness Review No. 88. Available at www.effectivehealthcare.ahrq.gov/undescended-testicle.cfm.

18.  The studies on hormonal therapies had several limitations:  The studies were small (the number of patients ranged from 33 to 324) and mainly of poor quality.  The studies included patients with retractile testicles.  The initial location of the testis was lower in most of the patients included in the studies.  The doses of human chorionic gonadotropin used in the studies were highly variable.  Luteinizing hormone-releasing hormone is not available for the treatment of cryptorchidism in the United States and has been discussed here for purposes of comparison.  The followup period in the included studies was short, so there were insufficient data on long-term reascension/treatment failure.  These studies excluded patients with an inguinal hernia, which can accompany an undescended testicle and would require surgical treatment. Evidence for the Benefits of Hormonal Therapies in Treating Cryptorchidism (1 of 2) Penson DF, Krishnaswami S, Jules A, et al. AHRQ Comparative Effectiveness Review No. 88. Available at www.effectivehealthcare.ahrq.gov/undescended-testicle.cfm.

19.  Human chorionic gonadotropin (hCG) achieves slightly higher rates of testicular descent when compared with placebo (successful bilateral and unilateral descent rates* of 23% and 15%, respectively, with hCG vs. 0% with placebo in both cases). Strength of Evidence: Low  Luteinizing hormone-releasing hormone (LHRH)** achieves slightly higher rates of testicular descent when compared with placebo (successful descent rates of 9 – 62% with LHRH vs. 0 – 18% with placebo). Strength of Evidence: Moderate  hCG is as effective as LHRH in achieving testicular descent (successful descent rates of 0 – 18.8% with LHRH vs. 5.9 – 23% with hCG). Strength of Evidence: Low Evidence for the Benefits of Hormonal Therapies in Treating Cryptorchidism (2 of 2) Penson DF, Krishnaswami S, Jules A, et al. AHRQ Comparative Effectiveness Review No. 88. Available at www.effectivehealthcare.ahrq.gov/undescended-testicle.cfm. * The success rate was defined as the proportion of testicles achieving testicular descent or testicular positioning. ** LHRH is not available in the United States for treating cryptorchidism and has been included for comparative data.

20.  The overall testicular atrophy rate for primary orchiopexy was 1.83 percent (range 0 – 4%). Strength of Evidence: Moderate  The overall testicular atrophy rates for one-stage and two-stage Fowler- Stephens orchiopexy were 28.1 percent (range 22 – 67%) and 8.2 percent (range 0 – 12%), respectively. Strength of Evidence: Low  Laparoscopy and open surgical repair were associated with similar rates of testicular atrophy. Strength of Evidence: Low  Other adverse events associated with surgery were rare and included Veress needle puncture (injury to the sigmoid colon during laparoscopy), laparoscopic port-site hernia, and incarcerated hernia.* Evidence for the Adverse Effects of Surgical and Hormonal Interventions in Treating Cryptorchidism (1 of 2) Penson DF, Krishnaswami S, Jules A, et al. AHRQ Comparative Effectiveness Review No. 88. Available at www.effectivehealthcare.ahrq.gov/undescended-testicle.cfm. *This finding was not rated.

21.  Reported harms of hormonal treatments were mild and included virilizing effects (e.g., pubic hair, increase in penis size and in erections) and behavioral changes (e.g., aggression). All harms were transient. Strength of Evidence: Moderate  The followup period in all the included studies was short, so there were insufficient data on long-term fertility and cancer outcomes. Evidence for the Adverse Effects of Surgical and Hormonal Interventions in Treating Cryptorchidism (2 of 2) Penson DF, Krishnaswami S, Jules A, et al. AHRQ Comparative Effectiveness Review No. 88. Available at www.effectivehealthcare.ahrq.gov/undescended-testicle.cfm.

22.  With regard to treatment planning, current evidence does not suggest that any specific imaging technique is able to evaluate nonpalpable, undescended testicles with sufficient accuracy to eliminate the need for laparoscopic evaluation.  For the treatment of cryptorchidism, surgical options are effective.  Rates of achieving successful testicular positioning are 96.4 percent with primary orchiopexy and 78.7 percent and 86 percent with one-stage and two-stage Fowler- Stephens orchiopexy, respectively.  Rates of testicular atrophy vary with these surgical procedures, and adverse effects are rare.  However, each of the three types of surgery is used for a different clinical presentation, so the success rates cannot be compared with one another.  Low levels of evidence suggest that open and laparoscopic repair appear to be equally effective in achieving testicular positioning. Conclusions (1 of 2) Penson DF, Krishnaswami S, Jules A, et al. AHRQ Comparative Effectiveness Review No. 88. Available at www.effectivehealthcare.ahrq.gov/undescended-testicle.cfm.

23.  With regard to hormonal treatment options for undescended testicles, only human chorionic gonadotropin is available in the United States.  Studies on hormonal treatment are small and mostly of poor quality, with evidence related to benefits and harms too limited to inform changes in practice. Conclusions (2 of 2) Penson DF, Krishnaswami S, Jules A, et al. AHRQ Comparative Effectiveness Review No. 88. Available at www.effectivehealthcare.ahrq.gov/undescended-testicle.cfm.

24.  The studies included in this review are of poor quality and are too limited to determine:  The relative effectiveness of computed tomography, magnetic resonance venography, and magnetic resonance angiography in locating testicles  The comparative effectiveness of single-stage or two-stage Fowler-Stephens orchiopexy for treating cryptorchidism  In the studies that assessed treatment modalities, analyses are not stratified based on the pretreatment location of the testicles, which might affect treatment outcomes. Gaps in Knowledge (1 of 2) Penson DF, Krishnaswami S, Jules A, et al. AHRQ Comparative Effectiveness Review No. 88. Available at www.effectivehealthcare.ahrq.gov/undescended-testicle.cfm.

25.  Data on the long-term effects, including harms, of hormonal therapy for undescended testicles are missing in the literature.  The appropriate age for treatment remains unknown, and data on the effect of age on outcomes are limited.  Studies of important long-term outcomes of treatment, including infertility and testicular cancer, have not been identified in the current literature. Gaps in Knowledge (2 of 2) Penson DF, Krishnaswami S, Jules A, et al. AHRQ Comparative Effectiveness Review No. 88. Available at www.effectivehealthcare.ahrq.gov/undescended-testicle.cfm.

26.  What cryptorchidism is and the consequences of the condition  The clinical characteristics of the patient’s case, including the location and viability of the undescended testicle(s)  How cryptorchidism is evaluated and the options for guiding its treatment, and the associated benefits and/or harms of those options  The limited value of imaging for locating nonpalpable undescended testicles in these patients What To Discuss With the Parents and/or Caregivers of Your Patients Penson DF, Krishnaswami S, Jules A, et al. AHRQ Comparative Effectiveness Review No. 88. Available at www.effectivehealthcare.ahrq.gov/undescended-testicle.cfm.