Testicular Function after Cytotoxic Therapy

International 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

ww

w.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

differentiation Clermont 1976Ehmcke et al. 2005

Ad/Ap-model of stem cell renewal

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

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 LHmild 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

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

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

Sertoli cell function after CT / RT

• CT @ age 13• testisbiopsy @ age 31

• unexpected expression ofcytokeratin-18 in 13% oftubuli (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 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

The myth of the ‘testicular quiescence’

Induction of ‘testicular quiescence’

Testis is ‘quietly active’ rather than ‘truly quiescent’

Kelnar et al. H

um. R

eprod. 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

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