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Cryptorchidism. One of the most common male developmental abnormalities 27,000 orchidopexies annually in USA 89% of untreated males with bilateral cryptorchidism develop azospermia Lifetime risk of neoplasia 2-3% 4 fold higher than average risk. Issues. Definitions & epidemiology

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cryptorchidism
Cryptorchidism
  • One of the most common male developmental abnormalities
  • 27,000 orchidopexies annually in USA
  • 89% of untreated males with bilateral cryptorchidism develop azospermia
  • Lifetime risk of neoplasia 2-3%
    • 4 fold higher than average risk
issues
Issues
  • Definitions & epidemiology
  • Normal testicular development and descent
  • Causes of cryptorchidism
  • Consequences
    • Azospermia
    • Increased risk for neoplasia
  • Treatment
    • Medical/hormonal
    • Surgical
definitions
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
epidemiology
Epidemiology
  • Frequency 3.4 % in term boys
  • By 1 yo, incidence 0.8%
is the incidence of cryptorchidism increasing
Is the incidence of cryptorchidism increasing?
  • Literature controversial
    • Cryptorchidism, hypospadias, micropenis
    • Decreasing semen quality
    • Increasing testicular cancer
    • Increasing demand for assisted reproduction
  • Impact of environmental xenoestrogens
    • Herbicides, pesticides, PCBs, polystyrenes
  • Environmental antiandrogens
    • Linuron, vinclozolin, pp’DDE, polyaromatic hydrocarbons
risk factors hjerkvist 1989
Risk FactorsHjerkvist 1989
  • IUGR, prematurity
    • Incidence in premies 30%
  • First-or second-born
  • Perinatal asphyxia
  • C-section
  • Toxemia of pregnancy
  • Congenital subluxation of hip
  • Seasonal (especially winter)
issues1
Issues
  • Definitions & epidemiology
  • Normal testicular development and descent
  • Causes of cryptorchidism
  • Consequences
    • Azospermia
    • Increased risk for neoplasia
  • Treatment
    • Medical/hormonal
    • Surgical
testicular development
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
testicular descent
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
insl3
INSL3
  • Member of the insulin/relaxin superfamily
  • Highly expressed in Leydig cells
  • In mice, targeted INSL3 deletion associated with bilateral cryptorchidism, abnl gubernaculum development
insl31
INSL3
  • Tomboc 2001
    • DNA analysis of 145 cryptorchid males, 36 controls
    • Found 2 mutations (2/145, 1.4%), several polymorphisms
  • Baker 2002
    • DNA from 118 cryptorchid boys, 48 controls
    • Several polymorphisms
    • No specific mutations
  • Important in descent but mutations an uncommon cause of cryptorchidism
germ cell maturation
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
    • Neonatal surge in LH, FSH, T
  • 4 yo: primary spermatocytes
  • Puberty: spermatogenesis
issues2
Issues
  • Definitions & epidemiology
  • Normal testicular development and descent
  • Causes of cryptorchidism
  • Consequences
    • Azospermia
    • Increased risk for neoplasia
  • Treatment
    • Medical/hormonal
    • Surgical
slide14

Low/absent GnRH

Kallmann’s

Prader Willi

Hypothalamus

GnRH

Pituitary

Hypopituitarism

FSH

LH

Dysgenesis/anorchia

Testosterone biosynthetic problems

Sertoli

Leydig

Germ cells

MIF deficiency/persistent Mullerian ducts

MIF

Testosterone

5  reductase

5  reductase deficiency

dihydrotestosterone

Androgen resistance

Androgen receptor

Post-receptor effects

abnormal gonadotropins in cryptorchid infants and boys
Abnormal gonadotropins in cryptorchid infants and boys
  • Insufficient T response to hCG in 36.5% (Forest 1979)
  • Blunting of LH and FSH surge at 3 mo (Gendrel 1980)
  • Leydig cell hypoplasia in some undescended testes (Hadziselimovic 1986)
defective onset of meiosis at 4 5 yo
Defective onset of meiosis at 4-5 yo?
  • Normally see increase in urinary LH and increased prominence of Leydig cells,
  • Appearance of primary spermatocytes
  • In cryptorchid males,
    • Low urinary LH & FSH
    • Impaired T response to hCG
    • May indicate deficiency of HP-gonadal axis as a cause of defective meiosis
issues3
Issues
  • Definitions & epidemiology
  • Normal testicular development and descent
  • Causes of cryptorchidism
  • Consequences
    • Azospermia
    • Increased risk for neoplasia
  • Treatment
    • Medical/hormonal
    • Surgical
impact on fertility
Impact on Fertility
  • At bx, # spermatogonia/tubule prognostic for subsequent fertility potential
    • Bx without germ cells 33-100% risk of infertility
  • Possible causes of subfertility
    • Reduction in total # germ cells (already present in 1st year of life)
    • Defect in one or more steps in germ cell maturation
      • Defective transformation of gonocytes into Ad spermatogonia (Hadziselimovic 1986)
      • Delayed disappearance of gonocytes
slide20

3-7

8-12

13-18

19-25

29-60

<120

Hadziselimovic 2001

slide22

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

abnormal germ cell deveopment huff 2001
Abnormal germ cell deveopmentHuff 2001
  • 767 boys with unilateral cryptorchidism
  • Bilateral bx and orchidopexy between 0-9 yo
  • 238 < 1 yo at orchidopexy
    • Transformation of gonocytes into Ad spermatogonia
  • 529 2-9 yo at orchidopexy
    • Onset of meiosis
slide26

Adult dark spermatogonia

Total adult dark spermatogonia counts significantly lower in undescended testes,

p<00005, Huff 2001

boys 1 yo
Boys < 1 yo
  • Gonocytes failed to disappear
  • Adult dark spermatogonia failed to appear
  • Indicates defect in germ cell maturation and failure to establish an adequate adult stem cell pool
boys 2 9 yo
Boys 2-9 yo
  • In undescended testes
    • Primary spermatocyte counts lower (p<0.0005) failed to appear in undescended testes

Appeared in only 19% of contralat descended testes

    • Total germ cell counts lower (p<0.0005)
    • Adult dark spermatogonia lower (p<0.0005)
  • Indicates defect in onset of meiosis
    • Which normally occurs at 4-5 yo
  • Similar, less severe changes in contralateral descended testes
abnormal epididymal growth de miguel 2001
Abnormal Epididymal Growthde Miguel 2001
  • Decrease in differentiation of each segment
  • Decreased size of efferent and epididymal ducts
  • Decreased epithelial height, muscular wall height, & lumen of epididymis
  • Cryptorchid epididymis grows more slowly during transition to puberty, smaller in adult males
  • Suggests a primary congenital defect of testis
  • Implies surgical descent would not completely reverse these changes
increased risk of neoplasia
Increased risk of neoplasia
  • Cortes 2001: 1638 testicular samples from 1335 patients (23% bilateral, 77% unilateral)
  • Mean age @ surgery 11.7 yo (0.1-18.9 yr)
  • 1 invasive germ cell tumor
  • 6 carcinoma in situ
  • 1 Sertoli cell tumor
neoplasia cryptorchidism
Neoplasia & cryptorchidism
  • 3 neoplasms in intra-abdominal testes
  • 4 neoplasms in boys with abnormal external genitalia
  • 2 neoplasms in boys with known abnormal karyotype
  • Risk of neoplasia 5% with intraabdominal testes, abnormal external genitalia or abnormal karyotype (Cortes 2001)
issues4
Issues
  • Definitions & epidemiology
  • Normal testicular development and descent
  • Causes of cryptorchidism
  • Consequences
    • Azospermia
    • Increased risk for neoplasia
  • Treatments
    • Medical/hormonal
    • Surgical
treatments
Treatments
  • Hormonal
    • hCG
    • GnRH
    • hMG
    • Combined (hCG & GnRH)
  • Surgical
hormonal therapy
Hormonal Therapy
  • hCG since 1930
  • GnRH since 1974 (IM) and 1975 (intranasal) (Europe)
  • Variable rates of success
    • hCG 0-55%
    • GnRH 9-78%
confounding variables in data
Confounding Variables in Data
  • Inclusion/exclusion of retractile testes
  • Variable ages of treatment
  • Randomized or not
  • Different dose regimens and durations
  • Original testicular position not documented in all studies
  • Small patient numbers
hcg vs gnrh multicenter trial
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
slide38

Rates of descent of the undescented testes following treatment.

Christiansen 1992.

Bilateral: p=0.0016

Unilateral: p=0.013

a review meta analysis of hormonal treatment of cryptorchidism pyorala 1995
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
review meta analysis
Review & meta-analysis
  • 33 studies including 3282 boys, 4524 undescended testes
  • RCTs (n=11) included 872 boys, 1174 undescended testes
  • Meta-analysis only on RCTs that compared GnRH vs placebo (n=9 trials)
    • Risk ratio for descent after GnRH 3.21 (1.83-5.64) (p<0.001)
    • 4 trials excluded retractile testes, risk ratio 2.57 (1.39-4.74) (p<0.01)
slide41

Mean success rate (%) for treatment in combined RCTs comparing

hGC and GnRH with placebo. Pyorala 1995

# Trials 9 2 11

Testes 472 148 554

slide42

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

slide43

Mean success rates (%) by original location, includes both RCTs and

nonRCTs after GnRH and hCG. Pyorala1995

# trials 17 21 14 4

# testes 907 1430 295 67

slide44

Mean success rates (%) of hormonal treatment (GnRH or hCG) in combined

RCTs in boys under 4 yo vs boys > 4 yo. Pyorala 1995 p=NS

# trials 2 2 3 4

# testes 48 49 167 267

long term outcomes
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
combined gnrh and hcg giannopoulous 2001
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
4 different regimes bertelloni 2001
4 different regimesBertelloni 2001
  • 155 boys 10-48 mo with unilateral inguinal testis
  • 1. hCG 500 IU/wk (<2yo), 1000 IU/wk (>2yo)
  • 2. hCG as in 1 + hMG 75 IU/wk x 6 wk
  • 3. GnRH 1200 ug/d x 28 d
  • 4. GnRH as in 3, + hCG 1500 IU/wk x 3 wk
bertelloni 2001 cont
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
when to treat hamza 2001
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
impact of age on treatment success
Impact of age on treatment success
  • Job 1982: success with hCG twice as high in 3-4 yo than in boys < 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 < 4 yo vs > 4 yo
when to operate
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
slide52
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
is further treatment after surgery indicated
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
hormonal treatment for subfertility of cryptorchidism huff 2001
Hormonal treatment for subfertility of cryptorchidism Huff 2001
  • 12 boys (7 mo – 12 yo) with cryptorchidism & poor prognosis for fertility (<0.21 germ cells/tubule)
  • Treated with Naferelin 200 ug biweekly x 6 mo after orchidopexy
  • Biopsy 5 mo after Naferelin completed (2-14 yo)
  • Improvement if 2nd bx > 1 category
hormonal treatment for subfertility of cryptorchidism huff 20011
Hormonal treatment for subfertility of cryptorchidism Huff 2001
  • 8/12 (67%) showed improvement in total germ cell counts in one or both testes
  • No significant change if patients
    • Had no germ cells initially
    • Were older at treatment
  • 8/18 (44%) undescended testes improved
  • 5/6 (83%) contralateral descended testes improved
  • Naferelin induced improvement in 75% of patients
erythropoietin and germ cells
Erythropoietin and germ cells
  • Cortes 2001
  • 2 boys (6 mo, 21 mo) with renal function impairment
  • Epo 100 IU/kg SQ weekly x 3 mo before orchidopexy for inguinal cryptorchidism
  • # spermatogonia unusually high (& normal) compared to 698 controls
possible mechanisms
Possible mechanisms
  • Stimulation of T production
    • ?direct on Leydig cells
  • Direct effect on germ cell proliferation and antiapoptotic signalling by blocking p53-gene mediated apoptosis (as seen in erythropoiesis)
  • Clinical trial ongoing
issues5
Issues
  • Definitions & epidemiology
  • Normal testicular development and descent
  • Causes of cryptorchidism
  • Consequences
    • Azospermia
    • Increased risk for neoplasia
  • Treatment
    • Medical/hormonal
    • Surgical