1. Undescended testicle or Cryptorchidism
B Zelhof, V Tang
Based on previous talk by A Parnham, S Srirangam
Cryptorchidism means hidden testicle. But not all testes hidden therefore correct term should be UDT

2. Topics Embryology Epidemiology
Retractile/ ectopic/ absent/ undescended
Associations
Problems (Fertility, Cancer etc)
Treatment options at differing ages

3. Embryology 7th week SRY gene Undifferentiated Gonad Testis
Leydig cells
Testosterone
Insl-3
Wolffian/ mesonephric duct differentiation
Sertoli cells
Mullerian duct inhibiting substance and anti mullerian hormone
Mullerian duct regression
7th week
SRY= sex determining region on short arm of Y chromosome

4. Phases of testicular descent
Intra-abdominal
Inguino-scrotal

5. Embryology Intra-abdominal phase 10-23 weeks
Enlargement of distal gubernaculum
CSL= cranial suspensory ligament

6. Embryology Inguinoscrotal 26-28weeks/birth
Mediated by testosterone and Genitofemoral nerve

7. Hormones INSL-3 Insulin like growth hormone and
RLF relaxin-like factor
Effects differentiation of gubernaculum in transabdominal phase
Use of diethylstilbestrol (DES) during pregnancy in the past was observed to result in cryptorchidism
DES suppresses Insl-3 expression
Mice with insl-3 and RLF knocked out had bilateral undescended testes due to underdeveloped gubernaculum (Nef et al, 1999; Zimmermann et al, 1999; Kubota et al, 2001; Gorlov et al, 2002)
Induction of cell proliferation and growth of gubernaculum seen when synthetic or testes derived INSL-3 in culture(Emmen et al, 2000; Kubota et al, 2002)
INSL-3 in high conc in cord blood in those with descended testes whilst those with undescended have low levels (Bay et al, 2007)
The use of diethylstilbestrol (DES) during pregnancy in the past was observed to result in cryptorchidism (Stillman, 1982). Latter on it was demonstrated that DES suppresses Insl3 expression in male mice foetuses and hence results in undescended testes due to failure of gubernaculum development (Emmen et al, 2000; Nef et al, 2000).

8. Androgens Testosterone and dihydrotestosterone
Inguinoscrotal > transabdominal
(gubernaculum grows without androgens)
A normal hypothalamic-pituitary-gonadal axis is usually necessary for testicular descent.
a large percentage of undescended testes resolve spontaneously at age 1-3 months as a result of a postnatal surge of high serum gonadotropin and steroid hormone supports this. Undescended testis is a common finding in hypogonadotropic hypogonadism (Pitteloud et al, 2002; Giannopoulos et al, 2001), and mutations in the androgen receptor gene (ARG), which causes the androgen insensitivity syndrome (AIS), is known to be associated with undescended testis (Brinkmann, 2001; Sultan et al, 2001; Ferlin et al, 2006; Quigley et al, 1995).

9. Anti mullerian hormone or Mullerian inhibiting substance
? Responsible for transabdominal descent
However evidence suggests otherwise
Testicular descent does not effect in MIS-deficient knockout mice (Behringer et al, 1994).
No effect on testicular descent in foetal rabbits immunized against MIS (Tran et al, 1986)
In transgenic female mice overexpressing MIS, ovarian descent is not observed (Behringer et al, 1994)
The majority of patients with intra-abdominal undesended testes do not have retained mullerian derivatives (Wein et al, 2006).
This theory was based on the observations that an undescended testis is a common feature of persistent mullerian duct syndrome (PMDS), which is caused by genetic defects in the MIS gene or its receptor (Hutson et al, 1997; Guerrier et al, 1989).

10. Calcitonin gene-related peptide (CGRP) and genitofemoral nerve
Role in the inguinoscrotal phase
Causes rhythmic contractions of gubernaculum
Effects of androgens on gubernaculum during the inguinoscrotal phase may be due to CGRP (Hutson and Hasthorpe, 2005).
Studies in rodent show sex dependent masculinization of genitofemoral nerve and release of CGRP into the gubernaculum, causing rhythmic contractions (Terada et al, 1994).
Transaction of the GFN prevents gubernacular migration and testicular descent (84 foresta).

11. Intra-abdominal pressure
Undescended testes in prune-belly syndrome, omphalocele, cloacal exstrophy, gastrochisis and a number of syndromes characterized by both undescended testis and congenital abdominal wall muscular defects or agenesis
Important in inguinoscrotal phase

12. Case study Called by paediatric FY2 to see a newborn baby.
FY2: “I can’t feel the baby’s left testicle”
Urology ST3: “I will be on my way to see him”
10 minutes later, fast bleep “call neonatal ward urgently”
FY2: “now i can’t feel the RIGHT testicle, which i could feel earlier, can you come immediately”
Urology ST3: “ ”

13. While you were walking towards the children hospital, you were thinking:
How unlucky is this? (what is the incidence of undescended testes)
What are the risk factors that i need to think about?

14. Incidence 2.2 – 3.8% at birth Bilateral 1.6%
Approximately 70-77% of UDT testes will spontaneously descend by 3 months old (Wein 2006)
1-2% will remain undescended at 1 year (Foresta et al, 2008)

15. Risk Factors Risk factor Notes Low Birth weight
7.7% <2kg, 2.5% 2-2.5kg, 1.4% >2.5kg at 3 months
Gestational age
30.3% of premature infants (Farrington 1970)
Family History
6.2% of the brothers and 1.5-4% of the fathers of cryptorchid subjects have undescended testes (Czeizel et al, 1981)
family history of undescended testes is present in 22.7% of patients with cryptorchidism as compared to 7.5% in controls (Elert et al, 2003).
6.9 for cryptorchidism in newborn males if a brother is affected and 4.6 if the father is affected (Foresta et al, 2008)
Genetic
Testicular Dysgenesis Syndrome (cryptorchidism, testicular cancer, hypospadias and spermatogenic impairment )
Klinefelters
FG syndrome
Noonan syndrome
Down syndrome
47XXY syndrome
Maternal factors
 maternal age, obesity, pre-eclampsia, breech presentation
Others
Environmental, Twins
birth weight alone is the principal determinant of cryptorchidism at birth and at 1 year of life, independent of the length of gestation

16. Classification Clinical Palpable 80% Non-palpable 20% Surgical
Intra-abdominal
Intracanalicular
Extracanalicular (Suprapubic or infrapubic)
Ectopic

17. Different positions of undescended testis

19. Back to the case..
What are the risks if left untreated?

20. Consequences of undescended testicle/s
Infertility
Neoplasia
Torsion
Hernia
Cosmetic/psychological

21. Infertility Histological changes occur between 1-2 years of age
 numbers of Leydig cells
 degeneration of Sertoli cells
delayed disappearance of gonocytes
delayed appearance of spermatogonia
failure of primary spermatocyte development
total germ cell count (but  spermatogonia)
 testis volume
Higher the testis – greater the dysfunction

22. Infertility
Paternity rates in treated bilateral UDT 63.5% Paternity rates in treated unilateral UDT 89.7% Paternity rates in Unaffected men 93.2% Lee PA 2001,1997 Untreated bilateral UDT azoospermia in 89% Untreated unilateral UDT azoospermia in 13% Normal population azoospermia % Hadziselimovic 2001

23. Infertility Is early orchidopexy enough? For unilateral probably yes
For bilateral probably no

24. Neoplasia Theory Prener et al, 1996 ? Intrinsic pathological process
increased risk for tumour formation in normally descended contralateral testes
RR 3.6
Prener et al, 1996

25. Neoplasia Lifetime risk 2-3% in cryptorchidism
General population 1:100,000 vs 1:2550 in UDT (40x higher than general population)
(Cortes et al, 2001)
Approximately 10% of testicular tumours arise from an undescended testis
Higher the UDT the greater the risk
Abdo 6X risk than inguinal
In bilateral cases if ca on one side 15% in contralateral
Mainly seminoma
CIS in 1.7% UDT
Not worth routine testicular biospy in orchidopexy for predictive value

26. Neoplasia The United Kingdom Testicular Cancer Study Group 1994
Association of testicular ca with UDT and hernia
Risk eliminated in those undergoing orchidopexy <10 y/o
Moller et al 1996
RR for ca in men with treated or persistent UDT 3.6 but no increase in spontaneous descent
RR increases with age of treatment
Ca also associated with atrophy but not hernia in absence of UDT/ atrophy
Prener et al 1996
RR 5.2
No observed decrease in RR associated with treatment in early childhood

27. Hernia PPV in 90% of patients with UDT
Normally closes after descent in 1st month from birth
Requires androgenic stimulation for closure
Reduces efficacy of hormone treatment for UDT
49.5% descent in non-patent PPV
0% in patent PPV
Varela Cives et al, 1996
Hernia/ hydrocele at surgery in 77% of cases after failed treatment of cryptorchism
Adamsen and colleagues 1989

28. Testicular torsion
Greater relative broadness of the testicle than its mesentery
64% of adults with torsion in an UDT had an associated germ cell tumor
Although torsion of an UDT is rare, it should be considered in any child with abdominal or groin pain and an empty ipsilateral hemiscrotum.

29. Cosmetic /psychological
Child
Parents
On its own doesn’t cause psychological disorders but in combination with common distinctive family pathology can do
Parents have a worried preoccupation with the genitals—constant poking, checking, and medical exams—conjoined with blatant denial that anything was wrong. The mothers were controlling and discouraged boyish aggression; the fathers were remote and dissatisfied with their son whose physical defect was equated to their own personal failures.
Blos (1960) noted that themes of castration and defective maleness were prominent in his cases. These boys were passive, shrank from boyish competition, and were accident-prone.
In each of Blos’ cases corrective surgery produced a euphoric upsurge of male sexuality followed by major advances in assertiveness, learning, and socializing

30. Investigation Imaging overall accuracy 44%
There is no benefit in performing ultrasound, CT, MRI or angiography (EAU 2013)
Efficacy 0-50%
(Gadolinium enhanced MRI 100%)

31. Investigation
Laboratory testing only in bilateral non-palpable testes or associated features such as hypospadias or ambigous genitalia
hcg stimulation test
5000units hcg in 6 divided doses over six weeks with DHT, FSH and LH checked within 24 hrs of last dose
confirms presence of testicle by detecting response by secretion of testosterone.
All boys with normal gonadotrophin levels must undergo exploration independent of hcg stimulation test
FSH raised in prepubescent boy suggests anorchia
Others include inhibin B and Mullerian inhibiting substance, LH,

32. Tenants of Treatment
Proper identification of the anatomy, position, and viability of the undescended testis   
Identification of any potential coexisting syndromic abnormalities
Placement of the testis within the scrotum in timely fashion to prevent further testicular impairment in either fertility potential or endocrinologic function
Attainment of permanent fixation of the testis with a normal scrotal position that allows for easy palpation   
No further testicular damage resulting from the treatment

33. Impalpable testis 20% UDT impalpable of which:
40% intra-abdominal testis (usually just above inguinal ring)
30% absent intra-abdominal (blind-ending vessels)
20% absent intracananalicular (nubbin)
10% inguinal testis
Thus ~ 50% have salvageable testis

34. Treatment options Medical Surgical Exogenous hcg
Standard abdo/goin orchidopexy
Exogenous GnRH/ LHRH
Fowler-Stephens one stage
Fowler-Stephens two stage
Laparoscopically assisted
Micro-vascular re-anastomosis

35. Medical HCG Stimulates Leydig cells to produce testosterone
Increased serum testosterone
Testicular descent
GnRH/ LHRH
Pituitary stimulation leading to incresased FSH and LH
HCG like LH

36. Medical HCG GnRH Delivery im injection nasal spray Dosage 250-1500 IU
twice weekly
g 3-6 times daily
Duration
6 weeks
4 weeks
Side-effects
scrotal rugae, pigmentation, pubic hair, penile growth, stunted growth
Increased penile/testicular size, scrotal erythema, erections
Success rates
6-21% in RB studies
6-38%
All need to have regular follow up as reascent reported in 25%
Overall efficacy <20% for cryptorchid testes and is significantly dependent on pretreatment testicular location. Therefore, surgery remains the gold standard for the management of undescended testes

37. Medical Predictors of success positive Negative Low initial position
Older children
Retractile testes
Negative
PPV

38. The overall efficacy of hormonal treatment is less than 20% for cryptorchid testes and is significantly dependent on pretreatment testicular location. Therefore, surgery remains the gold standard for the management of undescended testes.

39. Post orchidopexy GnRH 3 studies show benefit
Significant increase in fertility indices on biopsy
Significant increases in sperm count on semen analysis
Hadziselimovic et al 1997 & 2008
Huff et al 2001

40. Pre-orchidopexy GnRH
2 RCTs and 4 other studies show significant increases in fertility indices on testicular biopsy
Hadziselimovic et al 1987
Bica et al 1992
Lala et al 1997
Zivkovic et al 2007
Schwentner et al 2005
Jallouli et al 2009

41. Pre orchidopexy GnRH Jallouli et al 2009 2 RCTs 42 boys; 63 UDT
Overall fertility index significantly higher in GnRH
group Vs Controls; 1.05 Vs 0.52 (P<0.05)
Bilateral UDT all ages (P<0.005)
Schwentner et al 2005
26 boys; 26 UDT
Mean fertility index significantly higher in GnRH
group Vs Controls; 0.88 Vs 0.49 (P<0.02)
Jallouli et al 2009

42. Surgical- Overview Type of orchidopexy
Success (%)- desecended + no atrophy
Standard abdo/groin orchidopexy
92%
Fowler-Stephens one stage
67%
Fowler-Stephens two stage
77%
Laparoscopically assisted
up to 100%
Microvascular re-anastomosis
84%

43. Surgery for palpable testes EAU/ESPU
No benefit in waiting for spontaneous descent after 1 year
Treatment should be finished between months of age
EUA first
Palpable testis orchidopexy inguinal approach and excision of PPV. Sutures not to be used or only between tunica vaginalis and dartos

44. Surgical for non-palpable EAU/ESPU
Non-palpable testisInguinal approach +/- laparoscopy
≥10yrs with normal contralateral testis orchidectomy of affected side
<10yrs Bilateral UDT 1/2 stage Fowler-Stephens or microvascular autotransplantation

46. Laparoscopic orchidopexy
Mean op time
No. pts
No. testes
Success(%)- scrotal testicle without atrophy
Lindgren 1998
135 36 44 93
Poppas 1996
130 11 13 62
Docimo 1995
156 9 12
100

47. UDT in adults Previously <32 yrs old
Unilateral orchidectomy/orchidopexy and close f/u
Bilateral orchidectomy
>32 yrs old or high ASA close observation
Now
<50 as above
>50 or high ASA observation
Wood HM 2009
Oh J 2002
Based on the belief that the risk of death from surgery first exceeds the risk of death from testis cancer at age 32 years
Improvements in therapy for germ cell neoplasia and perioperative care in the last 25 years have dramatically decreased the mortality of each cause. However, the decrease in perioperative mortality has been greater. In contrast to a generation ago, accidental death during routine elective surgery is now extremely rare in healthy patients. Thus, we advocate orchiectomy in all healthy males (ASA I and II) who present with postpubertal cryptorchidism until age 50 years.