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Herman Tournaye, M.D. Ph.D. Centre for Reproductive Medicine Brussels

Testicular Function after Cytotoxic Therapy International Symposium on Reproductive Medicine Istanbul June 4-6, 2010. Herman Tournaye, M.D. Ph.D. Centre for Reproductive Medicine Brussels. outline of the lecture. the testis: a brief introduction effects on the endocrine function

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Herman Tournaye, M.D. Ph.D. Centre for Reproductive Medicine Brussels

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  1. Testicular Function after Cytotoxic TherapyInternational Symposium on Reproductive MedicineIstanbulJune 4-6, 2010 Herman Tournaye, M.D. Ph.D. Centre for Reproductive Medicine Brussels

  2. outline of the lecture • the testis: a brief introduction • effects on the endocrine function • effects on the exocrine function • take-home messages

  3. www.inquisitr.com/wp-content/conflict.jpg The speaker declares no conflict of interest with the topic presented in this lecture

  4. outline of the lecture • the testis: a brief introduction • effects on the endocrine function • effects on the exocrine function • take-home messages

  5. Ad/Ap-model of stem cell renewal differentiation Clermont 1976 Ehmcke et al. 2005

  6. http://www.enlarged-prostate-treatment.info

  7. outline of the lecture • the testis: a brief introduction • effects on the endocrine function • effects on the exocrine function • take-home messages

  8. Leydig cell function after CT / RT • less sensitive than germinal epithelium: slighly elevated LH mild testosterone deficiency to normal (Shalet et al. 1999; Chatterjee et al. 1994) • more prone to irradiation damage in pre-pubertal life (Shalet et al. 1989) and if radiation dose >2400 cGy

  9. Leydig cell function after CT / RT • some of these men with subnormal testosterone levels show reduced bone density (Howell et al. 2000) • blinded placebo controlled RCT shows no benefit/ indication for androgens (Howell et al. 2001)

  10. outline of the lecture • the testis: a brief introduction • effects on the endocrine function • effects on the exocrine function • take-home messages

  11. www.uh.edu/~tgill2/image016.jpg

  12. Sertoli cell function after CT / RT Sharpe et al. 2003

  13. Sertoli cell function after CT / RT • controversy on action on Sertoli cells • unaffected when not replicating (Orth et al. 1988; Jégou et al. 1993) • indirect effect on FSH through loss of germ cells (Jégou et al. 1993)

  14. Sertoli cell function after CT / RT • CT @ age 13 • testisbiopsy @ age 31 • unexpected expression of cytokeratin-18 in 13% of tubuli (prepubertal marker) • cytotoxic effect ?

  15. Effect of single dose RT Rowley et al. 1974, Howell & Shalet 2005

  16. Effect of fractionated RT • > because of scattered irradiation • increased gonadotoxicity vs single-dose • 1.2 Gy = treshold for permanent testicular damage without recovery in most patients • TBI (>10 Gy): ≤ 1% fatherhood (Sanders et al.)

  17. Effect of CT • interference with DNA & RNA synthesis (antimetabolites e.g. fluorouracil) • inhibition of protein synthesis (alkylating e.g. cyclophosphamide,busulfan) • interference with microtubule function (plant alkaloids e.g. vincristine, taxanes)

  18. “Fertility-friendly chemotherapy” • no chemotherapy guarantees 100% fertility • oligozoospermia ≠ fertility • risk aneuploidy and mutagenesis • you never know the final treatment course

  19. A survey among patients • 904 male cancer patients 14-40 yrs old • Texas and Ohio • 27% response rate (n=201, 8% refused survey) • want children after cure? 51% overall • 77% of childless • informed about infertility?: only 60% • informed about banking semen?: only 51% • banked semen?: 24% (27% of childless) • Schover et al., J. Clin. Oncol. 2002

  20. The myth of the ‘testicular quiescence’

  21. Induction of ‘testicular quiescence’

  22. Testis is ‘quietly active’ rather than ‘truly quiescent’ Kelnar et al. Hum. Reprod. 2002 Control marmoset GnRHa-treated marmoset

  23. >80% risk for sterility after cytostatic treatment • whole body irradiation • conditioning for bone-marrow transplantation • Hodgkin treated with alkylating agents • metastatic Ewing’s sarcoma • metastatic soft-tissue sarcoma • testicular radiotherapy Wallace et al. Lancet Oncol. 2005

  24. Distribution Children’s Cancer Research Group UK Anderson et al. Hum. Reprod. 2008

  25. risk for sterility after cytostatic treatment Anderson et al. Hum. Reprod. 2008

  26. outline of the lecture • the testis: a brief introduction • effects on the endocrine function • effects on the exocrine function • take-home messages

  27. Take-home messages Leydig cell deficiency • clinically not important for most men • no indication for routine substitution • 'vigilant' management

  28. Take-home messages Spermatogenesis • non-proliferative Sertoli cells are resistant • no quiescent prepubertal stage • all patients need proper counseling • cryobanking in adults and children

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