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Atypical Male Genital Development: Update of Care of Cryptorchidism and

Hypospadias

Beth Drzewiecki, MD Associate Professor

Division of Pediatric Urology

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Cryptorchidism

• Affects 3% of newborn, full term males.1 – Unilateral vs bilateral – Palpable vs non-palpable

• 70% of testicles descend in the first 6 months of life

• Approximately 0.8-1% of males have persistent

cryptorchidism at one year of life

1. Penson DF, et al. Evaluation and treatment of cryptorchidism. Agency for Health Care and Research Quality; Dec 2012

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Cryptorchidism

• “Ectopic” – Lie outside the natural path

of descent • “True”

– Lie within the natural path of descent

• Absent • Retractile

Skandalakis’ Surgical Anatomy, Chapter 25. Male Genital system

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Causes of cryptorchidism

• Unclear!

• Intra-abdominal phase of descent androgen dependent

• Passage through inguinal canal 28th week combination of mechanical, hormonal, neurotransmitter effects

• Other associated conditions – Prune Belly, DSD, genetic disorders

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Evaluation of cryptorchidism

• History – Descended at birth? – Family history – Prior inguinal surgery/trauma to area

• Physical examination

– Frog leg position – Lubrication

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Evaluation of cryptorchidism

• Need for imaging?

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Overall the recommendation is that radiologic evaluation of the non-palpable testicle is not warranted.1-3

1. Penson DF, et al. Evaluation and treatment of cryptorchidism. Agency for Health Care and Research Quality; Dec 2012 2. Docimo SG et al. The undescended testicle: diagnosis and management. Am Fam Physician 2000 3. Tasian GE and Copp HL. Diagnositc performance of ultrasound in nonpalpable cryptorchidism: a systematic review and meta-

analysis. Pediatr 2011

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Evaluation of cryptorchidism

• Need for imaging?

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Evaluation of cryptorchidism

• Hormonal treatment – Use of hCG to stimulate testosterone production and

produce further descent of the testicle – Can also confirm presence of testicular tissue in bilateral,

non-palpable testes

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Evaluation of cryptorchidism

• Timing of referral – Immediately if associated with a hypospadias or bilateral

non-palpable testes – 6 months of age if unilateral with no other abnormalities of

genitalia – As soon as it is felt that the testicle is not palpable in

scrotum in child older than 6 months

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Do testicles ascend?

• Reascent of testes after the first year of life can occur in up to 40% of boys1

• Most evidenced by higher than expected age at time of orchiopexy

• Ascended testicles – Unilateral – Identified in childhood – Located distal to the inguinal canal

1. Barthold JS and Gonzalez R. The epidemiology of congenital cryptorchidism, testicular ascent and orchiopexy. J Urol 2003.

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Reasons for orchiopexy • Prevention of potential sequelae1

– Parental anxiety – Testicular cancer

• Up to 20 fold increased risk of malignancy – Subfertility

• Histologic changes occur in testicles that reside in warmer temperatures

• Fertility rates with a normal, contralateral testicle are the same as general public (85-90%)

– Testicular torsion/inguinal hernia • Higher torsion rate in undescended testes?

1. Docimo SG et al. The undescended testicle: diagnosis and management. Am Fam Physician 2000

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Surgical considerations

• Timing – 6 months corrected age, or whenever the UDT is identified – Post pubertal

• Approach – Abdominal/laparoscopic – Inguinal – Scrotal

• Recovery – Testicular self examinations

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Hypospadias: Epidemiology • Ranges from 0.26 – 4.1 per 1000 births

• Increase incidence in last 3 decades1,2

• Environmental and genetic factors (20-25% of cases)

• Racial and ethnic discrepancy:

– White >> black, higher in Jewish and Italian

1. Paulozzi et al. Pediatrics. Nov 1997;100(5):831-834

2. Kallen et al. Acta Paediatr Scand Suppl. 1986;324:1-52.

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Hypospadias risk factors • Advanced maternal age • Twin gestation • Low birth weight • Endocrine disruption/smoking • Family history • Associated syndromes • Testicular dysgenesis syndrome

– Hypospadias, cryptorchidism, impaired spermatogenesis and testis cancer

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Pathogenesis • Failure of urethral

folds to close properly secondary to disruption of the androgenic stimulation required – Also leads to

failure of the ventral curvature of the penis to straighten and ventral closure of the foreskin

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Hypospadias and IUGR

• Active Malformations Surveillance Program 1972-2012 – Identified 316/289,365 births

• 52.2% glanular; 11.7% subcoronal, 27.8% penile, 8.2% penoscrotal

• Highest frequency of IUGR (34.6%) in infants with penoscrotal hypospadias

• Possible low testosterone and placental HCG during 10-14 weeks gestation

Toufaily MH, et al. Hypospadias, Intrauterine Growth Restriction, and Abnormalities of the Placenta. Birth Defects Research 2017

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Gene Function Proposed role in hypospadias Reference

HOXA13, HOXD13

Transcription factor Loss of FGF8, BMP7 signaling in developing urothelium

Beleza-Meireles et al (2007), Morgan et al (2003)

FGF8, FGF10

Growth factor Induction of GT outgrowth and development, downstream target of SHH

Beleza-Meireles et al (2007), Haraguchi et al (2001), Yucel et al (2004)

SHH Transcription factor GT outgrowth and differentiation Haraguchi et al(2001), Yucel et al (2004)

DKK2, SFRP1

Cell signalling Wnt inhibitory Miyagawa et al (2009)

ATF3 Transcription factor Cell cycle suppression and cellular stress response, estrogen dependent, upregulated in hypospadias

Beleza-Meireles et al (2008) Liu et al (2005), Wang et al (2007), Willingham et al (2007)

MAMLD1

Transcriptional co-activator

External genitalia development via androgen metabolism

Chen et al (2010), Fukami et al (2006), Kalfa et al (2010)

CTGF Growth factor Estrogen responsive, TGFβ pathway downstream element, upregulated in hypospadias

Kalfa et al (2010), Wang et al (2007)

FKBP52 Co-chaperone of androgen receptor

Knock out causes hypospadia phenotype Beleza-Meireles et al (2007), Chen et al (2010)

CYR61 Extracellular signalling molecule

Cell proliferation, upregulated in hypospadias Wang et al (2007)

GADD45β

Growth arrest Cell cycle, upregulated in hypospadias Wang et al (2007)

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Rule of 10s • 10% of fathers • 10% of siblings • 10x increased incidence in twins • 10% have UDT • 10% have inguinal hernias • 10% incidence of utricle in those

with penoscrotal hypospadias (57% in those with perineal defect)

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Spectrum of Hypospadias

50% of cases

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Presentation • Incomplete foreskin • Chordee • Intersex evaluation: rule of 2/3

– If 2 of the 3 genital structures are abnormal then evaluate for intersex

– ie. Hypospadias + impalpable testis

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Examples

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A

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Chordee (Ventral Curvature without Hypospadias)

Causes • Skin • Atretic urethra • Buck’s or Dartos fascia • Corpora disproportion

• Normal in fetal phallic

development

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Principles of Hypospadias Surgery • Orthoplasty • Glansplasty • Urethroplasty • Scrotoplasty • Skin coverage

penoscrotal angle penopubic angle penoscrotal configuration (i.e. transposition) multi-layer coverage

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To circumcise or not?

• Generally no….

• Megameatus intact prepuce variant – If circumcision is started and concern for hypospadias, can

complete or abort

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Timing of referral

• Surgical repair typically delayed until child is at least 6 months of age

• Parental anxiety

• Immediate referral if concerned for association with other syndromes/DSD

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Post-operative Care

• Dressing (tegaderm, coban) x 24 hours

• Urethral stent x 5-10 days • Antibiotic prophylaxis

until stent removed • Anticholinergic for older

children

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Complications Urethrocutaneous fistula 5-7% incidence More complex repairs: 10-20% Repair 6-8 months following initial surgery Meatal stenosis Dilation Ventral incision

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Complications BXO Usually presents with meatal

stenosis remote from surgery Urethral Diverticulum Usually secondary to meatal

stenosis, large Island flap Stricture Secondary to ischemia of urethral

plate/flap

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Current Controversies in Hypospadias/Chordee Repair

• Concerns over genital reconstruction in children before the age of consent / Loss of autonomy of body

• Legislation in 3 states presented that includes a moratorium on surgery in children less than age of majority

• Data exists that supports early surgery for increased risk of complication in operating on older patients

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Current Controversies in Hypospadias/Chordee Repair

• Distal or balanitic hypospadias do not always need

immediate repair

• Discussion on waiting/observation

• Rates of chordee later in life unknown

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• Thank you!