1. Dr. Suad Abul MB,BCh, FRCSC Pediatric surgery Ibn Sina Hospital, Kuwait February 6 th, 2015

2. Outline Introduction Embryology of testicular development and descent When to refer a patient with UDT? Hormonal treatment, does it help? Risk of malignancy and infertility in UDT Surgical approach and outcomes

3. Introduction Cryptorchidism is a common congenital anomaly of the urogenital system One or both testicles are not appropriately positioned in the scrotum at birth (unilateral or bilateral) Palpable or non-palpable.

4. Definitions Cryptorchidism : incomplete descent, testis neither resides nor can be manipulated into the scrotum Ectopic: aberrant course Retractile : normal testicular descent with periodic translocation up due to hyperactive cremasteric reflex can be manipulated into scrotum where it remains without tension Ascended : previously descended, then “ascends” spontaneously

6. Prevalence Cryptorchidism affects 3% of full-term male neonates and up to 30% of premature infants. About 70% of cryptorchid testicles spontaneously descend within the first year of life.

7. Risk Factors IUGR, prematurity First-or second-born Perinatal asphyxia Toxemia of pregnancy Congenital subluxation of hip Seasonal (especially winter)

8. Maternal smoking during pregnancy Androgen deficiency in utero related to placental or pituitary function Prune belly syndrome Gastroschisis Cloacal extrophy

9. Outline Introduction Embryology of testicular development and descent When to refer a patient with UDT? Hormonal treatment, does it help? Risk of malignancy and infertility in UDT Surgical approach and outcomes

10. Testicular development 6 wk: primordial germ cells migrate to urogenital ridge (which contains mesonephros, wolfian duct, and mullerian duct) 7 wk: testicular differentiation 8 wk: testis hormonally active Sertolis secrete MIF 10-11 wk: Leydig cells secrete T 10-15 wk: external genital differentiation

11. 5-8 wk: processus vaginalis Gubernaculum attaches to lower epididymis 12 wk: trans-abdominal descent to internal inguinal ring 26-28 wk: gubernaculum swells to form inguinal canal, testis descends into scrotum Insulin-3 (INSL3) effects gubernacular growth

12. Testicular descent Occur in 2 steps: 1. Transabdominal stage: Controlled by insulin-like-hormone 3 2. Inguinoscrotal stage: Controlled by androgen indirectly by genitofemoral nerve directing the migration of gubernaculum to the scrotum

14. Outline Introduction Embryology of testicular development and descent Risk of malignancy and infertility in UDT When to refer a patient with UDT? Hormonal treatment, does it help? Surgical approach and outcomes

15. Consequences of Cryptorchidism Long-term consequences of cryptorchidism: Testicular malignancy Infertility/subfertility

16. Risk of malignancy The‭ ‬exact‭ ‬mechanism‭ to ‬testicular‭ ‬malignancy‭ ‬is‭ ‬unknown Several‭ ‬risk factors have been proposed, including Testicular‭ ‬atrophy‭ ‬and‭ ‬the‭ ‬increased‭ ‬temperat ure‭ ‬of‭ ‬the inguinal or abdominal region where‭ ‬the cryptorchid testis is located Pettersson‭ ‬A,‭ ‬Richiardi‭ ‬L,‭ ‬Nordenskjold‭ ‬A‭ ‬et‭ ‬al‭ ‬(2007)‭ ‬Age‭ ‬at surgery‭ ‬for‭ ‬undescended‭ ‬testis‭ ‬and‭ ‬risk‭ ‬of‭ ‬testicular‭ ‬cancer. N‭ ‬Engl‭ ‬J‭ ‬Med‭ ‬356:1835–1841

17. Lifetime risk of neoplasia 2-3% 4 fold higher than average risk

18. UnilateralBilateral Untreated13.6% (10/73) 88.6% (31/35) Medically treated 13.3% (28/210) 32.0% (46/142) Surgically treated 13.3% (126/942) 46.4% (224/484) Incidence of Azospermia Azospermia in normal population 0.4-0.5% Hadziselimovic 2001

19. Fertility‭ ‬may‭ ‬be‭ ‬impaired‭ ‬as‭ ‬earl y‭ ‬as‭ ‬1–2‭ ‬years‭ ‬of‭ ‬age‭ ‬in cryptorchid‭ ‬boys‭ ‬ Comploj‭ ‬E,‭ ‬Pycha‭ ‬A‭ ‬(2012)‭ ‬Diagnosis‭ ‬and‭ ‬management‭ ‬of cryptorchidism.‭ ‬Eur‭ ‬Urol‭ ‬Suppl‭ ‬11:2–9

20. Outline Introduction Embryology of testicular development and descent Risk of malignancy and infertility in UDT When to refer a patient with UDT? Hormonal treatment, does it help? Surgical approach and outcomes

21. When to operate? A consensus now to perform orchidopexy before age 1 Yr (6-12 mth) to‭ ‬optimize‭ ‬fertility‭ ‬outcomes.‭ ‬ This‭ ‬conclusion‭ ‬is‭ ‬consistent‭ ‬with‭ ‬the‭ ‬recommendation‭ ‬by‭ a‭ ‬group‭ ‬of‭ ‬experts‭ ‬from‭ ‬five‭ ‬Nordic‭ ‬countries, who‭ ‬suggested‭ ‬that‭ ‬orchiopexy‭ ‬be‭ ‬performed‭ ‬between‭ ‬6 and‭ ‬12‭ ‬months‭ ‬of‭ ‬age Ahmed Nasr et al, ideal timing for orchidopext: systemic review.Pediatr surg int. Nov 2013 John Hustson et al,evaluation and management of infant with cryptorchidism. Current openio. Review.august 2015

22. When to operate? Its been shown that 77% of the retractile testis achieve normal descent without surgical intervention but still no enough data about the testicular size and fertility Sigmund Ein et al.retractile testes:an outsome analysis of 150 patients.‭Journal‭ ‬of‭ ‬Pediatric‭ ‬Surgery,‭ ‬‬Vol‭ ‬39,‭ ‬No‭ ‬7‭ ‬(July),‭ ‬2004:‭

23. Outline Introduction Embryology of testicular development and descent Risk of malignancy and infertility in UDT When to refer a patient with UDT? Surgical approach and outcomes Hormonal treatment, does it help?

24. Treatment Planning for UDT Factors influence the treatment strategy for UDT : Is the testicle palpable or not? Unilaterally or bilaterally? The age at presentation Comorbid conditions

25. Surgical treatment Surgical options depend on the location and appearance of the undescended testicle Options: Primary orchidopexy Single-stage Fowler-Stephens orchidopexy Two-stage Fowler-Stephens orchidopexy Penson DF, Krishnaswami S, Jules A, et al. AHRQ Comparative Effectiveness Review

26. For locating non-palpable UDTs, exploratory laparoscopic surgery is routinely used in clinical practice. Vas vessel Gubernaculum T

27. Outcome Of Orchidopexy The overall success rate for achieving testicular descent with: Primary orchiopexy= 96.4 % (89.1–100%). One-stage Fowler-Stephens orchiopexy= 78.7 % (33– 94.3%). Two-stage Fowler-Stephens orchiopexy= 86 % (67– 98%). Andrew Holland et al.surgical approachto the palpable undescended testis. Pediatr Surg Int.2014

28. Fertility post orchidopexy Several ‭ ‬ measures ‭ (surrogates of ‭ ‬ fertility) have ‭ ‬ been ‭ ‬ examined ‬ : ‬ Testicular ‭ ‬ growth/size, ‭ ‬ Testicular ‭ ‬ histology, ‭ ‬ Semen ‭ ‬ analysis, ‭ ‬ and ‭ ‬ Paternity rate. Paternity ‭ ‬ rate ‭ ‬ and ‭ ‬ time ‭ ‬ until ‭ ‬ conception ‭ ‬ are ‭ ‬ the ‭ ‬ only direct ‭ ‬ measures ‭ ‬ of ‭ ‬ male ‭ ‬ fertility.

29. Fertility post orchidopexy Pt operated within 1 st yr: Normal total sperm count= 96.3% Normal sperm motility= 96.3% Pt operated after 1 yr of life: Normal total sperm count= 75% Normal sperm motility= 66.7% 89% of untreated males with bilateral cryptorchidism develop azospermia Andrew Holland et al.surgical approachto the palpable undescended testis. Pediatr Surg Int.2014

30. Outcome post orchidopexy The overall testicular atrophy rate for: primary orchiopexy:1.83% (range 0–4%). one-stage Fowler-Stephens orchiopexy: 28.1% (range 22–67%) two-stage Fowler-Stephens orchiopexy 8.2% (range 0– 12%) Laparoscopy and open surgical repair were associated with similar rates of testicular atrophy.

31. Follow up Treatment should not end with the first postoperative follow-up. The child should be evaluated at 2-3 weeks and again at 6-12 months following surgery to determine testis location, size and viability. When the child reaches puberty, the doctor should advise of potential issues of fertility and testicular cancer, and give information about a monthly testicular self-examination.

32. Outline Introduction Embryology of testicular development and descent When to refer a patient with UDT? Risk of malignancy and infertility in UDT Surgical approach and outcomes Hormonal treatment, does it help?

33. Hormonal Therapies in Treating Cryptorchidism The studies on hormonal therapies had several limitations: The studies were and mainly of poor quality. The studies included patients with retractile testicles. The doses of human chorionic gonadotropin used in the studies were highly variable.. Ercan Malkoc et al.The‭ ‬influence‭ ‬of‭ ‬hormonal‭ ‬treatment with‭ ‬beta- human‭ ‬chorionic‭ ‬gonadotropinfor‭ ‬cryptorchidism‭ ‬on‭ ‬future‭ ‬fertility‭ ‬in rat. Journal of Pediatric urology,2015

34. ‭Mean‭ ‬sperm‭ ‬count‭ ‬in‭ ‬cauda‬ epididymis: Groups‭ ‬Sperm‭ ‬counts‭ ‬(‭x‬10/ml) Group‭ ‬1‭ ‬(Sham)‭ ‬425 Group‭ ‬2‭ ‬(EC)‭ ‬265.89 Group‭ ‬3‭ ‬(EC-HT)‭ ‬168.22 The‭ ‬rats‭ ‬in‭ ‬EC-HT‭ ‬group‭ ‬received‭ SC‭ ‬injection ‬of‭ ‬50‭ ‬IU/kg‭ ‬Beta-HCG‭ ‬daily‭ ‬for‭ ‬7‭ days

35. Recent study suggests that Beta-HCG treatment may decrease sperm counts and decrease the future fertility potential. There is no direct correlation of sperm count with either testicular weight or testicular index.

36. 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% 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). 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

37. 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. The follow up period in all the reported studies was short, so there were insufficient data on long-term fertility and cancer outcomes.

38. Conclusion Boys with UDT should be referred to pediatric surgeon at age of 6 moths Orchidopexy should be done before age 1 yr Long term follow up necessary to assess testicular size and growth Hormonal therapy still debatable and not useful in cryptorchidism but may have some role in retractile testis