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

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

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

Phases of testicular descent Intra-abdominal Inguino-scrotal

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

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

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).

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).

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).

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).

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

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: “...............”

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?

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)

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

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

Different positions of undescended testis

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

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

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

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 0.4-0.5% Hadziselimovic 2001

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

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

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

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

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

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.

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

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%)

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,

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

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

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

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

Medical HCG GnRH Delivery im injection nasal spray Dosage 250-1500 IU twice weekly 200-400 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

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

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.

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

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

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

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%

Surgery for palpable testes EAU/ESPU No benefit in waiting for spontaneous descent after 1 year Treatment should be finished between 12-18 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

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

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

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.