Cancer and male reproductive function- the effect on sperm DNA integrity and on birth outcomes in the offspring

Sammanfattning: Male cancer survivors (MCS) are at risk of suffering from impaired fertility. Male fertility is dependant on sperm DNA quality. The Sperm Chromatin Structure Assay (SCSA) reflects the proportion of sperm with poor DNA, the DNA fragmentation index, DFI. A high DFI indicates reduced in vivo fertility and the need of ICSI (Intracytoplasmic sperm injection) to achieve pregnancy. A concern with ICSI, in which a single spermatozoon is injected into the oocyte, is the risk of transmitting defect DNA to the offspring. For MCS, due to the potential mutagenicity of radiotherapy (RT) and chemotherapy (CT), demonstrated in animal studies, this concern is even more pronounced. The aims of my thesis were to investigate the impact of cancer disease and its treatment on sperm DNA integrity and to study birth outcomes in the offspring of MCS. In papers 1 and II DFI was investigated in 96 testicular cancer patients (TC) and related to treatment and follow-up time. In paper III sperm DFI was investigated in pretreatment semen from 121 cancer patients in which 58 were analyzed also posttreatment. Cancer disease per se was associated with a moderate increase in DFI, especially TC and Hodgkin’s lymphoma (mean DFI 17.5 and 16.5% respectively) compared to controls (mean DFI 11.5%), but for the majority of patients DFI was not at levels associated with reduced fertility. In TC patients adjuvant RT induced a transient increase in DFI, normalizing within 3-5 years, whereas intense CT induced a persisting decrease in DFI, DFIpost 9.1 vs. DFIpre 12% (median values, p = 0.02). In paper III, in a group with varying diagnoses, the analysis of cryopreserved pre- vs. posttreatment semen demonstrated no change in DFI, regardless of therapy (median follow-up 3 years). Study IV was a Danish-Swedish register study investigating the impact of paternal cancer and mode of conception on birth outcomes, including 1.8 million singleton children, born 1994-2005. A moderate increase in malformation rate, 3.7 %, was seen in the 8879 children fathered by MCS, with a RR of 1.17 (95% CI 1.05, 1.31) compared to non-MCS, of having an infant with a malformation. IVF/ICSI was associated with an equivalent increased malformation rate, but did not constitute an additional risk for MCS. Treatment data was not available, but analyses of specific diagnoses, in which treatment can be anticipated, did not indicate that the increased malformation rate was treatment-induced.