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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. Definitions & epidemiology

MikeCarlo
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Cryptorchidism

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  1. 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

  2. Issues • Definitions & epidemiology • Normal testicular development and descent • Causes of cryptorchidism • Consequences • Azospermia • Increased risk for neoplasia • Treatment • Medical/hormonal • Surgical

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

  5. 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

  6. 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)

  7. Issues • Definitions & epidemiology • Normal testicular development and descent • Causes of cryptorchidism • Consequences • Azospermia • Increased risk for neoplasia • Treatment • Medical/hormonal • Surgical

  8. 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

  9. 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

  10. INSL3 • Member of the insulin/relaxin superfamily • Highly expressed in Leydig cells • In mice, targeted INSL3 deletion associated with bilateral cryptorchidism, abnl gubernaculum development

  11. 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

  12. 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

  13. Issues • Definitions & epidemiology • Normal testicular development and descent • Causes of cryptorchidism • Consequences • Azospermia • Increased risk for neoplasia • Treatment • Medical/hormonal • Surgical

  14. 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

  15. 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)

  16. 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

  17. Issues • Definitions & epidemiology • Normal testicular development and descent • Causes of cryptorchidism • Consequences • Azospermia • Increased risk for neoplasia • Treatment • Medical/hormonal • Surgical

  18. 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

  19. Incidence of AzospermiaAzospermia in normal population 0.4-0.5% Hadziselimovic 2001

  20. 3-7 8-12 13-18 19-25 29-60 <120 Hadziselimovic 2001

  21. Number Ad spermatogonia/tubular cross-section from 0-9 yo Hadziselimovic 2001

  22. 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

  23. 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

  24. Total germ cell counts significantly higher in undescended testes, p=0.024 Huff 2001

  25. Total gonocyte counts significantly higher in undescended testes, p<00005 Huff 2001

  26. Adult dark spermatogonia Total adult dark spermatogonia counts significantly lower in undescended testes, p<00005, Huff 2001

  27. 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

  28. 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

  29. 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

  30. 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

  31. 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)

  32. Issues • Definitions & epidemiology • Normal testicular development and descent • Causes of cryptorchidism • Consequences • Azospermia • Increased risk for neoplasia • Treatments • Medical/hormonal • Surgical

  33. Treatments • Hormonal • hCG • GnRH • hMG • Combined (hCG & GnRH) • Surgical

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

  35. 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

  36. 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

  37. Changes in position in boys with bilateral cryptorchidism after treatment. Christiansen 1992

  38. Rates of descent of the undescented testes following treatment. Christiansen 1992. Bilateral: p=0.0016 Unilateral: p=0.013

  39. 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

  40. 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)

  41. Mean success rate (%) for treatment in combined RCTs comparing hGC and GnRH with placebo. Pyorala 1995 # Trials 9 2 11 Testes 472 148 554

  42. 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

  43. 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

  44. 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

  45. 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

  46. 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

  47. 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

  48. 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

  49. 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

  50. 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

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