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Testiculos habet, et bene pendentes

Testiculos habet, et bene pendentes. Cryptorchidism - Facts. The most frequent congenital defect of the urogenital tract Orchidopexy is the most common operation on all males Higher risk of infertility and testicular cancer in adulthood Aetiology is for the most part unknown.

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Testiculos habet, et bene pendentes

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  1. Testiculos habet, et bene pendentes

  2. Cryptorchidism - Facts • The most frequent congenital defect of the urogenital tract • Orchidopexy is the most common operation on all males • Higher risk of infertility and testicular cancer in adulthood • Aetiology is for the most part unknown

  3. CRYPTORCHIDISMAetiopathogenesis Embryonic defect in the physiological descent of the testis into the scrotum ? Aetiology is for the most part unknown

  4. Cryptorchidism does not present with a unified symptomatic • Location: abdominal / inguinal • Laterality: bilateral / unilateral • Spontaneous descent • Isolated (unique symptom) / associated with other developmental defects of the male reproductive organs (TDS) / associated with other symptoms of complex diseases • Spermatogenic consequences: from azoospermia to normozoospermia (age at orchidopexy?) • Normally descended testis in cases of unilateral cryptorchidism: completely normal / SCO / cancer

  5. CRYPTORCHIDISM MIGHT BE CONSIDERED A DISEASE WITH MULTIFACTORIAL AETIOPATHOGENESIS HAVING AS PREDISPOSING CAUSES HORMONAL FACTORS, MECHANICAL FACTORS, GENETIC FACTORS

  6. DESCENT AND DEVELOPMENT OF THE TESTIS INTERACTIONS OF FACTORS HORMONAL GnRH - LH - (FSH) AMH, INSL3 TESTOSTERONE MECHANICAL GUBERNACULUM INGUINAL CANAL ABDOMINAL PRESSURE GENETIC D E S C E N T

  7. Bipotential gonad Supporting cell precursors Primordial germ cells Steroidogenic precursors Testis Ovary Sertoli cells Pro- sperma togonia Leydig cells Internal theca cells Oocytes Follicular cells Androgens AMH INSL3 Testosterone Aromatase Estrogens

  8. Posterior abdominal wall A B CSL regression CSL AMH Epidydimis and ductus deferens T S Testis Testis L INSL3 Inguinal canal Gubernaculum Growing gubernaculum Abdominal wall (inguinal ring) C D Inguinal ring GFN T Testis Testis Scrotum Fully regressed gubernaculum Regressing gubernaculum INSL3-dependent transabdominal phase Androgen-dependent inguinoscrotal phase

  9. INSL3-RXFP2 Testiculardescent • INSL3:Insulin-like3 peptide (19p13.2-p12) • RXFP2:Relaxin Family Peptide 2receptor (13q13.1) • G-proteincoupledreceptor • INSL3 is produced by Leydig cells • RXFP2 is expressed in gubernaculum

  10. INSL3-RXFP2 Testicular descent • INSL3:Insulin-like3 peptide (19p13.2-p12) • RXFP2:Relaxin Family Peptide 2receptor (13q13.1) • G-proteincoupledreceptor • INSL3 is produced by Leydig cells • RXFP2 is expressed in gubernaculum • Insl3 KO mice: cryptorchidism • Rxfp2 KO mice: cryptorchidism • INSL3/RXFP2 mutations are associated with human cryptorchidism

  11. Cryptorchidism

  12. Epidemiologia • 3-5% dei bambini nati a termine • Fattori di rischio: • nascita pretermine (9-30%) • basso peso alla nascita (20-25% dei nati con peso <2.5 kg) • In Italia si possono quindi ipotizzare dai 25.000 ai 75.000 casi all’anno • Poiché circa la metà dei testicoli criptorchidi alla nascita discende spontaneamente nei primi mesi di vita (entro i 4-6 mesi), soprattutto nei nati pretermine, la prevalenza del criptorchidismo ad un anno di vita è circa 1-2%

  13. Risk Factors • IUGR, prematurity (“paraphysiological”) • Environmental factors (estrogens, ED) • Familial cases • Smoking, diabetes (mother) • Seasonal (especially winter) • ... ...

  14. Evidence supporting a genetic cause of human cryptorchidism • Unilateral cryptorchidism: spermatogenic impairment and cancer from the normally descended testis • Familial cases • Animal models

  15. Ferlin, A. et al. JAMA 2008;300:2271-2276.

  16. Klinefelter syndrome RXFP2 mutations Ferlin, A. et al. JAMA 2008;300:2271-2276.

  17. Ferlin, A. et al. JAMA 2008;300:2271-2276.

  18. Testicular dysgenesis syndrome Impaired spermatogenesis Undescended testis Hypospadias Impaired spermatogenesis Undescended testis Impaired spermatogenesis Testis cancer From: Skakkebaek NE et al., 2001

  19. Cause di infertilità nel criptorchidismo • Alterazioni istologiche del testicolo omolaterale e del testicolo controlaterale • Anomalie associate apparato riproduttivo (dissociazione didimo-epididimaria)

  20. SVILUPPO MORFO-FUNZIONALE DEL TESTICOLO N 4 a - 9 a 9 a - 12 a 2 - 3 m > 12 a IN UTERO 6 m - 4 a FASE FASE FASE FASE FASE NEONATALE STATICA ACCRESCITIVA MATURATIVA PUBERALE SPERMATOGONI FETALI SPERMATOGONI SPERMATOGONI SPERMATOCITI SPERMATIDI SPERMATOZOI SPERMATOGONI Ad B I - II

  21. EVOLUZIONE LESIONI ISTOLOGICHE PUBERTÀ DISTROFIA TUBULARE E FIBROSI DIFFUSA 6-12 anni IPOPLASIA GERMINALE E TUBULARE GRAVE 2 - 6 anni IPOPLASIA GERMINALE E TUBULARE MARCATA 1 - 2 anni AUMENTO INDICE SERTOLIANO 6 mesi RIDUZIONE INDICE SPERMATOGONIALE

  22. Effect of orchidopexy

  23. FERTILITA’ POST - ORCHIDOPESSI 82 82 30 46 38 30 15 > 12 anni 9 - 12 5 - 8 3 - 4 < 2

  24. Criptorchidismo e tumore testicolare • Il rischio di sviluppare un tumore del testicolo criptorchide è 4.8 volte rispetto alla popolazione generale • Rischio maggiore se cripto bilaterale • L’orchidopessi, anche se effettuata in età precoce, non annulla il rischio di neoplasia testicolare • Il posizionamento del testicolo in sede scrotale permette una migliore osservazione clinica

  25. Testicoli intraddominali hanno un rischio più elevato di sviluppare una neoplasia, 4 volte superiore di quelli ritenuti nel canale inguinale • L’aumento del rischio di tumore non è limitato al testicolo criptorchide, ma anche al controlaterale non criptorchide (15-20% dei casi)

  26. Common cause (hereditary and/or environmental factors) • Early origin (in utero)  TDS • No effect of age at orchidopexy • TC in the contralateral testis • Cause-effect mechanism • Effect of aberrant position (micro- and macro-environment) • Effect of age at orchidopexy

  27. 2 groups of cryptorchidism • Intrinsic causes: • Bilateral cryptorchidism is frequent • Progressive testicular damage also of the normally descended testis in cases of unilateral cryptorchidism • Increased risk of infertility and testicular cancer • Early orchidopexy might reduce the risk of these sequelae, but doesn’t abolish it • Genetic alterations are frequent • Extrinsic causes: • Include for example low birth weight, prematurity, or complications during pregnancy such as maternal diabetes or pre-eclampsia, • Frequent spontaneous descent in the first months of age • Minor risk of testicular degeneration, especially if orchidopexy is performed early • Genetic causes are far less frequent Ferlin, A. et al. JAMA 2008;300:2271-2276.

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