CRYPTORCHIDISM

Board Questions:

1. A 2 month old boy presents for a health supervision visit. Physical examination reveals a normally growing and thriving infant whose left testis is easily palpable but whose right testis cannot be palpated. The remainder of his physical examination results are normal. Of the following, the MOST appropriate approach is to: a. Order chromosomal studies to confirm genetic sex b. Order pelvic ultrasonography c. Plan for surgical exploration at 6 months of age d. Plan for surgical exploration at 2 years of age e. Refer the child immediately for urgent surgical consultation

2. As you are examining a newborn boy in the nursery, you notice that his testicles are not in the scrotum, and you are unable to palpate them in the inguinal canal. You tell his parents that you will be following this closely because of the risk of infertility and malignancy at that surgical correction may necessary if the testicles do not descend into the scrotum. Of the following, the MOST appropriate age at which surgical correction should take place if the testicles do no descend is: a. 1 month b. 2 months c. 1 year d. 2 years e. 5 years

3. You are called to see a newborn who appears to be a male and has a well developed rugated scrotum without palpable testes. The phallus is 3.5cm in length, but there is hypospadias extending to the base of the phallus and what seems to be an open urogenital sinus. It is hard to determine whether there is a separate urethral opening. On reviewing the maternal records, you discover that prenatal amniocentesis obtained because of advanced maternal age showed an XX chromosomal pattern. You arrange a complete initial evaluation for a potential disorder of sexual differentiation. Of the following, the MOST important initial test to obtain on this child is: a. Fluorescence in situ hybridization for sex determining region of Y chromosome b. Measurement of serum 17-hydroxyprogesterone c. Measurement of serum testosterone d. Pelvic ultrasound e. Repeat confirmatory chromosome study

American Board of Pediatric Content Specifications: 1. Distinguish between undescended testes & retractile testes 2. Plan the appropriate management of a patient with undescended testes 3. Know the pathophysiology and natural history of cryptorchidism

1 4. Know the complications of undescended testes: infertility and increased incidence of testicular tumors 5. Know that hypospadias with bilateral cryptorchidism is an indication to evaluate for intersex disorders

Definition: absent or undescended testicles. An absent testicle may be due to agenesis or to intrauterine torsion.  Anorchia: bilaterally absent testicles  Ectopic (<1%): testes descend normally through the external ring but then are diverted to an aberrant position.

 Retractile: testes are suprascrotal testes that can be brought into a dependent scrotal position and will remain there if the cremasteric reflex is overcome. In longitudinal studies over 3 years showed: o 32% become undescended (ascending or acquired undescended) o 30% descended spontaneously o 38% remained retractile

Pathophysiology: Not well understood. Alterations in normal testicular descent thought to result from interaction of mechanical & hormonal effects. Changes in abdominal pressure, androgens, gonadotropins, and MIS are thought to play a role.

Natural History: Testicular descent occurs in 2 phases. During the 1st phase (8-15 wks gestation), testis remains anchored to the inguinal area by insulin-like-hormone-3 driven development of the gubernaculum. The 2nd phase (28 wks-birth) is dependent on testicular androgens to bring testis into the scrotum. Congenital cryptorchidism is often followed by spontaneous testicular descent due to brief increase in endogenous testosterone secretion. Spontaneous descent rarely occurs after 6 month of age.  Changes related to fertility occur in the undescended teste by one year of age therefore to try to preserve this function it is best to perform orchiopexy as soon after 6 months as possible.  32% of retractile testes become undescended (ascending). This is more common in school age boys therefore any retractile testicle needs to be followed yearly.

2 Epidemiology:  Prevalence: o 2-5% of term males are born with undescended testicles o 30% of preterm males are born with undescended testicles o The prevalence increases again to 7% for school age boys due to acquired cryptorchidism (ascending testis). o Congenital undescended testicle present beyond 1 year is 0.8-1.1%.  Location: o 10% are bilateral; when unilateral –left side more common o The most common location is outside the external ring > inguinal canal >abdomen; 20% of cases have at least one nonpalpable testis

Risk Factors: Preterm Birth, low birth weight, small for gestational age, twin gestation  Occurs more commonly among patients with: o Congenital disorders of testosterone: Kallman syndrome o Abdominal wall defects o Neural tube defects o CP o Genetic syndromes: Trisomy 13 & 18, Noonan, Prader-Willi

DDX: A phenotypically male newborn with bilaterally nonpalpable testes  Genetic female with CAH; disorder of the androgen receptor; a true hermaphrodite; hypothalamic-pituitary insufficiency; anorchia.  Work up includes chromosome analysis, electrolytes, and full endocrine work up.

Evaluation:  Visual inspection for hypospadius, abnormalities of the scrotum (hemiscrotum or poorly developed scrotum), look for inguinal fullness.  Perform examinations at all well child examinations (AAP & AUA guideline)  Examination Maneuvers: 70% of undescended testes are palpable by physical exam o have child sit in the cross-legged position (“tailor’s position”) o place a warm compress along the inguinal canal o place the child in the knee-chest or squatting position o have older child stand and perform the valsalva maneuver. o holding the testis that can be manipulated in the dependent portion of the scrotum in position for at least 1 min. fatigues the cremasteric muscle; after this maneuver, a retractile testis remains in the scrotum whereas an ectopic testis immediately springs out of the scrotum

Complications:

3  Testicular neoplasm- Germ Cell (1/1000-1/2500 vs 1/100,000 general population): About 10% of testicular tumors occur in patients with a h/o undescended testicle. There is a 3-8 fold increase in testicular cancer in males with undescended testicle (49/100,000-12/1,075). Bilateral cryptorchidism carries a higher risk than unilateral. In unilateral, the tumor most often occurs in the undescended testis, but the contralateral, normally descended testicle is also at risk. Intra-abdominal testes are at the greatest risk. Surgical correction does not eliminate the risk of having testicular cancer, but the earlier the surgery is performed the more the risk is reduced.  Infertility: Men with bilateral undescended testes have decreased sperm count, low testosterone, inhibin B, and higher FSH, LH levels which put them at risk for infertility. In one study, surgery before 4 years of age led to normal sperm count in 76%. Fertility does not seem to be affected in men with unilateral undescended testicle who had orchiopexy performed before puberty.  Torsion: 10% higher in undescended testicle than normal scrotal testes.  Inguinal Hernia: 90% of undescended testes have an associated patent processus vaginalis. This is usually closed at the time of orchiopexy.  There is an increased risk of breast cancer with undescended testicles.  Patients with cryptorchidism and hypospadias have an increased risk of having an intersex disorder.

Labs: Not warranted except for the situations below, See attached guidelines (American Urological Association 2014)  Assess for the possibility of sex development disorder when there is increasing severity of hypospadias & cryptorchidism (RECOMMENDATION, GRADE C) o Karyotype, electrolytes (looking for female with CAH), 17- hydroxyprogesterone, LH, FSH, testosterone, androstenedione o Consult with pediatric urologist & endocrinologist  In boys who do not have CAH with bilateral non-palpable testes, providers should measure Mullerian Inhibiting Substance (MIS or Anti-Mullerian Hormone -AMH) and consider additional hormone testing to evaluate for anorchia (OPTION, GRADE C)

Imaging: Not warranted in evaluation of boy with non-palpable testis secondary to lack of sensitivity & specificity. However, may be advisable in the following circumstances:  To look for gonads & exclude presence of a uterus in phenotypically male infant with bilateral non-palpable testes  In obese males, in whom intracanalicular testes may be difficult to feel

Referral: See attached guidelines (American Urological Association 2014)  Cryptorchidism: any undescended testis at or after the age of 6 months should be referred for orchiopexy. It is not recommended to perform US for nonpalpable testis prior to referral (STANDARD, GRADE B EVIDENCE)  Retractile testes: should be followed annually until the outcome of descent or non-descent is clear, which in many cases will be until puberty.

4 o When the contralateral testis is descended, the probability of descent of the retractile testis was 69% o When the contralateral testis was undescended, the probability of intervention was 66%  Atrophic testis: referral to urologist as this may represent gubernaculum or dissociated epididymis and vans deferens

Treatment:  Goal: to achieve improved spermatogenesis in the undescended testis; bring testis into scrotum to better monitor for development of cancer.  Hormonal: Human chorionic gonadotropin (HCG) therapy stimulates leydig cells to produce testosterone. Most successful for the most distally undescended testes or for testes that have been previously descended. Side effects include penile enlargement, growth of pubic hair, increased testicular size, aggressive behavior, and premature epiphyseal closure. Not the preferred treatment, not recommended in new AUA guidelines (STANDARD, GRADE B).  Orchiopexy: operation for the palpable undescended testis. The testicle is manipulated into the scrotum and sutured into place. A rare complication is testicular atrophy due to dissection of the testicular vessels, postoperative swelling and inflammation leading to ischemic injury. 1. Surgery should occur within 1 yr after referral (by 18 months) (STANDARD, GRADE B) to preserve fertility 2. Progressive loss of germ & leydig cells over time  Exploration: 2 Managements for nonpalpable testis: either open inguinal approach or laparoscopic approach 1. Surgeons should perform exam under anesthesia prior to proceeding in pre-pubertal boys with undescended testicles (STANDARD, GRADE B)

Board PREP Answers: #1: PREP 2012, #73: C #2: PREP 2010, #51: C #3: PREP 2010, #170: B

References: 2. Callagham P, Cheng T. Undescended Testis. Pediatr. Rev.2000; 21;395 3. Cooper C, Docimo S, Drutz J. Undescended testes (cryptorchidism) in children & adolescents. Uptodate May 2012 4. Elder J. Ultrasonography is unnecessary in evaluating boys with a nonpalpable testis. Pediatrics 2002 110 (4): 748-751 5. Kokorowksi PJ, Routh JC, Graham DA, Nelson CP. Variations in timing of surgery among boys who underwent orchidopexy for cryptorchidism. Pediatrics 2010; 126; e576-582. 6. Ritzen M. Treatment of undescended testicles-how, when and where? Acta Paediatrica 2007 96: 607

5 7. Timing of elective surgery on the genitalia of male children with particular reference to the risks, benefits, and psychological effects of surgery and anesthesia. American Academy of Pediatrics. Pediatrics 1996; 97:590. 8. Virtanen HE, Toppari J. Epidemiology and pathogenesis of cryptorchidism. Human Reproduction Update 2008 14(1): 49-58 9. Virtanen HE, Bjerknes R, et al. Cyrptorchidism: classification, prevalence, and long-term consequences. Acta Paediatrica 2007 96: 611-616.

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