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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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Testicular Function after Cytotoxic TherapyInternational Symposium on Reproductive MedicineIstanbulJune 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 • effects on the exocrine function • take-home messages
www.inquisitr.com/wp-content/conflict.jpg The speaker declares no conflict of interest with the topic presented in this lecture
outline of the lecture • the testis: a brief introduction • effects on the endocrine function • effects on the exocrine function • take-home messages
Ad/Ap-model of stem cell renewal differentiation Clermont 1976 Ehmcke et al. 2005
outline of the lecture • the testis: a brief introduction • effects on the endocrine function • effects on the exocrine function • take-home messages
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
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)
outline of the lecture • the testis: a brief introduction • effects on the endocrine function • effects on the exocrine function • take-home messages
Sertoli cell function after CT / RT Sharpe et al. 2003
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)
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 ?
Effect of single dose RT Rowley et al. 1974, Howell & Shalet 2005
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.)
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)
“Fertility-friendly chemotherapy” • no chemotherapy guarantees 100% fertility • oligozoospermia ≠ fertility • risk aneuploidy and mutagenesis • you never know the final treatment course
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
Testis is ‘quietly active’ rather than ‘truly quiescent’ Kelnar et al. Hum. Reprod. 2002 Control marmoset GnRHa-treated marmoset
>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
Distribution Children’s Cancer Research Group UK Anderson et al. Hum. Reprod. 2008
risk for sterility after cytostatic treatment Anderson et al. Hum. Reprod. 2008
outline of the lecture • the testis: a brief introduction • effects on the endocrine function • effects on the exocrine function • take-home messages
Take-home messages Leydig cell deficiency • clinically not important for most men • no indication for routine substitution • 'vigilant' management
Take-home messages Spermatogenesis • non-proliferative Sertoli cells are resistant • no quiescent prepubertal stage • all patients need proper counseling • cryobanking in adults and children