Descent of scrotal testes and temperature regulation

1. Descent of scrotal testes and temperature regulation Rebecca C. Bott, MS Erica K. Gee, BVSc, PhD BS 640 Fall 2006

2. Importance of scrotal descent • Failure of testis descent into the scrotum is one of the two most frequent male reproductive pediatric complications. • 3% mature male newborns (up to 4-5%) • 1% in 1 year old boys • 30% prevalence in premature boys

3. Importance of scrotal descent • Undescended testes leads to an increased incidence in testicular cancer. • 15-fold increase in unilateral crytporchidism • 30-fold increase in bilateral cryptorchidism • Descent is essential for normal fertility as spermatogenesis can be greatly affected.

4. Scrotal Animals Scrotal: Swine, Cattle, Goats, Sheep, Felids, Canines, Primates, Rodents… Non-scrotal: Birds, Reptiles, Elephants, Dolphins, Fish…

5. Comparative view of testes

6. Testis development & migration • Intra-abdominal • Inguino-scrotal

7. Testis development & migration

8. Gubernacular development • Thick ligamentous structure comprised of condensed mesenchymal cells. • Peritoneal cells infiltrate the gubernaculum at the levels of the inguinal cannal.

9. Role of gubernaculum in descent • Gubernaculum penetrates the inguinal ring and grows rapidly from the distal end.

10. Role of gubernaculum in descent • Once the testes are in the inguinal region the first phase of testicular descent in complete.

11. Role of gubernaculum in descent • The gubernaculum begins to regress. This regression is the driving force pulling testes into the scrotum.

12. Orchestrators of testis descent • In 1973 scientists removed one or both testes from dogs and found abnormal gubernacular growth. • Testes or testis extract must be present to stimulate gubernacular growth in vivo and in vitro. • “descendin”

13. Role of INSL3 • Produced and secreted by Leydig cells prior to mesenchymal proliferation and gubernacular growth. • Transgenic INSL3 -/- mice are cryptorchid with undeveloped gubernaculum.

14. Role of INSL3

15. Role of INSL3 • Many labs have found implications for INSL3 in cryptorchidism… • Very few clinical cases of cryptorchidism have been linked to mutations in INSL3 or its receptor.

16. Role of Androgens • Androgens have been implicated as the primary factors involved in the second phase of testis descent. • Androgens are important for gubernacular bulb development. • When given anti-androgens, gubernaculum growth and testis descent is inhibited. This is easily reversed by addition of androgens. • Timing of the actions of androgens is critical!!!

17. Additional Factors “We know more about what we don’t know, than what we do know.”

18. Problems with testicular descent • Cryptorchidism • Aetiology is multifactorial • Risk factors include low birth weight when adjusted for gestational age, twinning, maternal exposure to estrogen in 1st trimester • May be heritable, some breeds appear more at risk • Surgical correction, prevent loss of germ cells in humans • Induced: promotion of rapid, lean muscle growth; investigated as a form of contraception in humans…

19. Problems with testicular descent • Ectopic testes • Inguinal hernia • Rabbits and rats have a patent inguinal canal throughout life

21. Thermoregulation • Maintenance of testicular temperature of 2-7°C below body temperature is essential for spermatogenesis • Five main anatomical features for thermoregulation • Thin scrotal skin, often hairless, lots of sweat glands • Tunica dartos • Pampiniform plexus • Cremaster muscle • Absence of fat

22. Thermoregulation • Scrotum: thermosensor, cooler and protector • Supports testes • Bilobed sac, 4 major layers • Skin: sweat glands and thermosensitive nerves

23. Thermoregulation

24. Scrotum as a ‘swamp cooler’ • Scrotum has many sweat glands • Innervated by sympathetic nerves • Hypothalamus is sensitive to increases in testis or core body temperature • Stimulates sweat glands to provide evaporative cooling. • Respiration

25. Scrotum as a ‘swamp cooler’

26. Importance of thermoregulation • Waites (1961 and 1962) • Heating device for scrotum of ram • Scrotal exposure to 40°C for 30 minutes resulted in the ram panting (up to 200 bpm), and lowering core body temperature by 1 degree • Heating other areas of the body had little influence on respiratory rate

27. Importance of thermoregulation

28. Countercurrent exchange • Testicular artery is highly convoluted and passed through the spermatic cord and surrounds the testes (ventromedial) • Testicular veins are in close proximity to the tortuous testicular artery in spermatic cord • Pampiniform plexus is the spermatic venous network which has lots of finger-like wrappings surrounding the spermatic artery. This allows for countercurrent heat exchange of veins with the testicular artery

29. Countercurrent exchange

30. Thermoregulation • Tunica dartos: smooth muscle in the scrotum • Capable of sustained contraction, elevating testes in cold environmental temperatures • Cremaster muscle is continuous with internal abdominal oblique muscle • Capable of short-term contraction • Short term elevation of testicles during fear or excitement • Contraction and relaxation acts as a pump on the pampiniform plexus

31. Thermoregulation • Men and underwear…. • Varicoeles • Inguinal ‘lipomas’

32. Thermoregulation and testicular descent • Testicular descent allow testicles to be kept at lower than core body temperature, essential for normal spermatogenesis • Core body temperature is lethal for germ cells • But there are always exceptions…

33. Exceptions…. • Approximately 1500 species of mammals are ‘non-scrotal’ • Most of these still have a trans-abdominal migration phase • Why is spermatogenesis still successful? • Some have testicles in a ‘cooler’ position • Eg tapir has subcutaneous testicles • Some have specialized cooling systems • E.g dolphin and vascular counter-current heat exchanger (dorsal fin and tail flukes) • Some have a low core body temperature • Eg hedgehog • Some we just don’t know

34. Questions! If you would like copies of our slides, or a list of our references we would be happy to share! Please email rebecca.bott@colostate.edu.

35. Role of Androgens • Androgens may act by regulating calcitonin gene related peptide (CGRP). • CGPR localized in the genitofemoral nerve. • Potential neurotransmitter dictating growth of the tip of the gubernaculum and directed migration of the gubernaculum into the scrotum… • Role of key factors is still debatable!