Cryptorchidism

Undescended testicleor CryptorchidismB Zelhof, V TangBased on previous talk by A Parnham, S SrirangamCryptorchidism means hidden testicle. But not all testes hidden therefore correct term should be UDT1TopicsEmbryologyEpidemiologyRetractile/ ectopic/ absent/ undescendedAssociationsProblems (Fertility, Cancer etc)Treatment options at differing agesEmbryology7th weekSRY= sex determining region on short arm of Y chromosome3Phases of testicular descentIntra-abdominalInguino-scrotal

EmbryologyIntra-abdominal phase10-23 weeksEnlargement of distal gubernaculumCSL= cranial suspensory ligament5EmbryologyInguinoscrotal26-28weeks/birthMediated by testosterone and Genitofemoral nerve

HormonesINSL-3 Insulin like growth hormone and RLF relaxin-like factor

Effects differentiation of gubernaculum in transabdominal phaseUse 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).

7AndrogensTestosterone and dihydrotestosteroneInguinoscrotal > 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).8Anti mullerian hormone or Mullerian inhibiting substance? Responsible for transabdominal descentHowever evidence suggests otherwiseTesticular 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). 9Calcitonin gene-related peptide (CGRP) and genitofemoral nerveRole in the inguinoscrotal phaseCauses rhythmic contractions of gubernaculumEffects 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). 10Intra-abdominal pressureUndescended 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 phaseCase studyCalled by paediatric FY2 to see a newborn baby.FY2: I cant feel the babys left testicleUrology ST3: I will be on my way to see him10 minutes later, fast bleep call neonatal ward urgentlyFY2: now i cant feel the RIGHT testicle, which i could feel earlier, can you come immediatelyUrology ST3: ...............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?Incidence2.2 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)

Risk FactorsRisk factorNotesLow Birth weight7.7% 2.5kg at 3 monthsGestational age30.3% of premature infants (Farrington 1970)Family History6.2% 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)GeneticTesticular Dysgenesis Syndrome (cryptorchidism, testicular cancer, hypospadias and spermatogenic impairment )KlinefeltersFG syndromeNoonan syndromeDown syndrome47XXY syndromeMaternal factors maternal age, obesity, pre-eclampsia, breech presentationOthersEnvironmental, Twinsbirth weight alone is the principal determinant of cryptorchidism at birth and at 1 year of life, independent of the length of gestation 15ClassificationClinicalPalpable80%Non-palpable20%SurgicalIntra-abdominalIntracanalicularExtracanalicular (Suprapubic or infrapubic)Ectopic

Different positions of undescended testis

Back to the case..

What are the risks if left untreated?Consequences of undescended testicle/sInfertilityNeoplasiaTorsionHerniaCosmetic/psychologicalInfertilityHistological changes occur between 1-2 years of age numbers of Leydig cells degeneration of Sertoli cellsdelayed disappearance of gonocytesdelayed appearance of spermatogoniafailure of primary spermatocyte developmenttotal germ cell count (but spermatogonia) testis volumeHigher the testis greater the dysfunctionInfertilityPaternity rates in treated bilateral UDT 63.5%Paternity rates in treated unilateral UDT 89.7%Paternity rates in Unaffected men93.2%Lee PA 2001,1997

Untreated bilateral UDT azoospermia in 89%Untreated unilateral UDT azoospermia in 13%Normal population azoospermia 0.4-0.5%Hadziselimovic 2001InfertilityIs early orchidopexy enough?For unilateral probably yesFor bilateral probably no

NeoplasiaTheory? Intrinsic pathological processincreased risk for tumour formation in normally descended contralateral testesRR 3.6

Prener et al, 1996 NeoplasiaLifetime risk 2-3% in cryptorchidismGeneral 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 riskAbdo 6X risk than inguinalIn bilateral cases if ca on one side 15% in contralateralMainly seminomaCIS in 1.7% UDTNot worth routine testicular biospy in orchidopexy for predictive valueNeoplasiaThe United Kingdom Testicular Cancer Study Group 1994Association of testicular ca with UDT and herniaRisk eliminated in those undergoing orchidopexy