Cryptorchidism

1
Cryptorchidism

• Dr Rajesh Kumar
• MD (PGI), DM (Neonatology) PGI, Chandigarh, India
• Rani Children Hospital, Ranchi

2

• Cryptorchidism is the most common genital problem
  encountered in pediatrics
• Untreated cryptorchidism clearly has deleterious
  effects on the testis over time
• 89 of untreated males with bilateral
  cryptorchidism develop azospermia
• Lifetime risk of neoplasia 2-3
• 4 fold higher than average risk
• Despite more than 100 years of research, many
  aspects of cryptorchidism are not well defined
  and remain controversial

3
Definitions

• Cryptorchid testis neither resides nor can be
  manipulated into the scrotum
• Ectopic aberrant course
• Retractile can be manipulated into scrotum where
  it remains without tension
• Gliding can be manipulated into upper scrotum
  but retracts when released
• Ascended previously descended, then ascends
  spontaneously

4

• Nonpalpable testes occur in approximately 20-30
  of those who have cryptorchidism
• Only 20-40 of nonpalpable testes are absent upon
  surgical exploration.

5
Distribution

• Kleintach et al compiled results on 14,548 testes
  from several studies, and the results were
  abdominal, 10 inguinal, 68 prescrotal, 24
  ectopic/SIP, 11.5 bilateral, 30 and
  unilateral right (vs left) testis, 70.

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Epidemiology

• Frequency 3.4 in term boys
• By 1 yo, incidence 0.8

7
Risk Factors

• IUGR, prematurity
• Incidence in premies 30
• First-or second-born
• Perinatal asphyxia
• C-section
• Toxemia of pregnancy
• Congenital subluxation of hip
• Seasonal (especially winter)

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Syndrome associated Cryptorchidism

• Pradder-Willi Syndrome (deletion on chromosome
  15) Hypotonia, Obesity, MR, Short stature,
  Strabismus
• Kallman Syndrome (recessive) anosmia or severe
  hyposmis
• Laurence moom biedl syndrome AR polydactyly,
  retinitis pigmentosa, MR, progressive ataxia,
  Spastic paraplagia

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Testicular development

• 6 wk primordial germ cells migrate to genital
  ridge
• 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

10
Testicular descent

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

11
Germ cell maturation

• 8 wk gonocytes (fetal stem cells)
• 15 wk spermatogonia
• 3 mo of age adult dark spermatogonia (adult stem
  cells) appear and remain
• 4 yr primary spermatocytes
• Puberty spermatogenesis

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Low/absent GnRH Kallmanns Prader Willi
Hypothalamus
GnRH
Pituitary
Hypopituitarism
FSH
LH
Dysgenesis/anorchia Testosterone biosynthetic
problems
Sertoli
Leydig
Germ cells
MIF deficiency/persistent Mullerian ducts
Testosterone
MIF
5 ? reductase
5 ? reductase deficiency
dihydrotestosterone
Androgen resistance
Androgen receptor
Post-receptor effects
13
Abnormal gonadotropins in cryptorchid infants and
boys

• Insufficient T response to hCG in 36.5
• Blunting of LH and FSH surge at 3 mo
• Leydig cell hypoplasia in some undescended testes

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Incidence of AzospermiaAzospermia in normal
population 0.4-0.5
Hadziselimovic 2001
15
3-7
8-12
13-18
19-25
29-60
lt120
Hadziselimovic 2001
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Number Ad spermatogonia/tubular cross-section
from 0-9 yo
Hadziselimovic 2001
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Ad spermatogonia
No Ad spermatogonia
germ cells/tubular cross-section Normal in 1st
6 mo, greatly decreased Between 6-24
mo Hadziselimovic 2001
Sperm/ejaculate (1x106) If Ad spermatogonia
present at orchidopexy, Tended to have normal
sperm count as adults
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Total germ cell counts significantly higher in
undescended testes, p0.024 Huff 2001
19
Total gonocyte counts significantly higher in
undescended testes, plt00005 Huff 2001
20
Adult dark spermatogonia
Total adult dark spermatogonia counts
significantly lower in undescended testes,
plt00005, Huff 2001
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Neoplasia cryptorchidism

• Risk of neoplasia 5 with intraabdominal testes,
  abnormal external genitalia or abnormal karyotype

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Management

• Immediate exclude genital ambiguity, may require
  steroid therapy
• Medium Term Observation( prevalence of
  cryptorchidism 3 at birth, 1 at 1 year),
  orchioperxy, hormonal treatment
• Long Term Infertilty risk (6 times in B/L, twice
  in U/L), Testicular cancer

23
Lab studies

• For unilateral undescended testis without
  hypospadias, no lab studies are needed.
• For unilateral or bilateral undescended testes
  with hypospadias or bilateral nonpalpable testes,
  tests include the following
• Testing to rule out intersex condition
  (mandatory)
• 17-hydroxylase progesterone
• Testosterone
• Luteinizing hormone (LH)
• Follicle-stimulating hormone (FSH)

24
Ab studies

• To determine anorchia in cases of bilateral
  nonpalpable gonads, perform the following
• LH testing
• FSH testing
• Testosterone level testing before and after
  stimulation with human chorionic gonadotropin
  (hCG) If both elevated basal gonadotropin levels
  and a negative testosterone response to hCG
  stimulation are observed, then congenital
  bilateral anorchism is suggested. Numerous
  protocols exist for hCG stimulation tests, but
  the most practical is one injection of hCG (100
  IU/kg or 2940 IU/body surface area) with a
  testosterone level 72-96 hours postinjection.

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Lab Radiology

• Radiologic studies to localize the testis are
  currently of very little value.
• CT scan and ultrasonography are associated with
  high false-negative rates in the evaluation of a
  nonpalpable testis and are not recommended.
• Magnetic resonance angiography (MRA) has been
  reported to have a nearly 100 sensitivity but
  requires sedation or anesthesia and is expensive
  and may not be cost-effective.
• To date, examination by a pediatric urologist has
  proven to be more valuable than ultrasound, CT
  scan, or MRA findings.
• Ultrasound of abdomen and pelvis along with
  genitography should be used when the diagnosis of
  intersex is considered.

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Treatments

• Hormonal
• hCG
• GnRH
• Combined (hCG GnRH)
• Surgical

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Hormonal Therapy

• hCG since 1930
• GnRH since 1974 (IM) and 1975 (intranasal)
  (Europe)
• Variable rates of success
• hCG 0-55
• GnRH 9-78

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hCG

• Action is virtually identical to that of
  pituitary LH, also appears to have a small degree
  of FSH activity. stimulates Leydig cells to
  produce androgens.
• Schedules twice a week for 5 weeks
• 250 IU/dose in young infants,
• 500 IU/dose for children 6 years or younger,
• 1000 IU/dose for individuals older than 6 years
  given

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GnRH

• stimulate the release of the pituitary
  gonadotropins, LH and FSH, resulting in a
  temporary increase of gonadal steroidogenesis
• hormone is available as a nasal spray

30
hCG vs GnRH multicenter trial

• 330 boys (?ages)
• Randomized to
• hCG 100 IU/kg IM twice weekly x 3 wk
• GnRH 200 ug intranasal TID x 28 d
• Placebo intranasal TID x 28 d
• Success if both testes located at bottom of
  scrotum after treatment

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Rates of descent of the undescented testes
following treatment. Christiansen 1992.
Bilateral p0.0016 Unilateral p0.013
32
A review meta-analysis of hormonal treatment of
cryptorchidism (Pyorala 1995)

• Reports from 1958-1990, in English
• Primary treatment with GnRH or hCG
• Excluded articles not documenting final
  testicular position
• Durations of treatment
• GnRH 1 day 4 wk
• hCG 1 wk 12 mo

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Review meta-analysis

• 33 studies including 3282 boys, 4524 undescended
  testes
• RCTs (n11) included 872 boys, 1174 undescended
  testes
• Meta-analysis only on RCTs that compared GnRH vs
  placebo (n9 trials)
• Risk ratio for descent after GnRH 3.21
  (1.83-5.64) (plt0.001)
• 4 trials excluded retractile testes, risk ratio
  2.57 (1.39-4.74) (plt0.01)

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Mean success rate () for treatment in combined
RCTs comparing hGC and GnRH with placebo.
Pyorala 1995
Trials 9
2 11 Testes
472 148 554
35
Mean success rate () for treatment in RCTs
exluding retractile testes, comparing hGC and
GnRH with placebo. Pyorala 1995
Trials 4
2 5 Testes
308 148 335
36
Mean success rates () by original location,
includes both RCTs and nonRCTs after GnRH and
hCG. Pyorala 1995
trials 17 21 14
4 testes 907 1430
295 67
37
Mean success rates () of hormonal treatment
(GnRH or hCG) in combined RCTs in boys under 4
yo vs boys gt 4 yo. Pyorala 1995 pNS
trials 2 2
3 4 testes 48
49 167 267
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Long term outcomes

• 5/11 randomized GnRH trials
• 24 (13-35) ascended/relapsed
• Conclusions
• GnRH more effective than placebo
• hCG seems effective, but not as much data

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Combined GnRH and hCG Giannopoulous 2001

• 2467 boys with 2962 cryptorchid or gliding testes
• GnRH nasal spray 1.2 ug QD x 4 wk
• hCG 5 doses (by age) at 2 d intervals
• 59 in scrotum after combined rx

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Bertelloni 2001 cont.

• Overall success rate 19.3 (30/155)
• No significant differences between regimes
• Relapse 23.3 (7/30)
• No significant difference between regimes

41
When to treat?Hamza 2001

• As spontaneous testicular descent closely related
  to postnatal LH and T surges,
• In term boys, 4 mo
• In premies, 6 mo

42
Impact of age on treatment success

• Job 1982 success with hCG twice as high in 3-4
  yo than in boys lt 3 yo
• Hagberg 1982 highest success with GnRH in 2-5
  yo
• De Muinck Keizer-Schrama 1986 most success with
  GnRH in 5-12 yo
• Pyorala 1995 no significant differences lt 4 yo
  vs gt 4 yo

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When to operate?

• Lee 2002
• Inverse correlation between age at surgery and T
• Inverse correlation between body wt and T
• Direct correlation between T and sperm density,
  motility, morphology
• Indicates direct relationship between
  spermiogenesis and T in cryptorchid men

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• No differences in mean free T, T, LH between pts
  and controls
• No differences in time to conception in fertile
  cryptorchid men vs controls
• Suggests that orchidopexy later in childhood
  assoc with subclinically depressed Leydig cell
  function
• May result in subotpimal hormonal milieu for
  adult reproduction

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Is further treatment after surgery indicated?

• Subfertility correlates with reduced total germ
  cell counts
• Defects in germ cell maturation associated with
  blunting of normal surges LH/FSH
• Prepubertal treatment with GnRH could
  theoretically trigger normal germ cell maturation
  proliferation

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Councelling

• Incidence 150-200 male babies
• If the testis has not descended at 6 months, it
  is unlikely to happen
• Treatment is required for
• To maximize the chance of fertility
• Improve physical appearance
• To decrease the chance of injury to testis
• Treatment may decrease the chance of malignancy