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 effects on the exocrine function take-home messages

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

differentiation Clermont 1976 Ehmcke et al A d /A p -model of stem cell renewal

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

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) Leydig cell function after CT / RT

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

Sharpe et al 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

age 13 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

> 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 fractionated RT

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) Effect of CT

“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 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

The myth of the ‘testicular quiescence’

Induction of ‘testicular quiescence’

Testis is ‘quietly active’ rather than ‘truly quiescent’ Kelnar et al. Hum. Reprod Control marmosetGnRHa-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

outline of the lecture the testis: a brief introduction effects on the endocrine function effects on the exocrine function 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 Take-home messages