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Male survivors were about half as likely as their brothers to father a child, and the causes are specific: testicular radiotherapy above 7.5 gray, and high cumulative cyclophosphamide, ifosfamide, procarbazine or cisplatin. A young man with none of those was no less likely than his brother. Sperm banking works; tissue banking before puberty has produced no births.
The numbers that matter, from 6,224 male survivors aged 15 to 44 who were not surgically sterile, compared with siblings in the Childhood Cancer Survivor Study: the hazard ratio for ever siring a pregnancy was 0.56. Risk was concentrated by exposure. Radiotherapy of more than 7.5 gray to the testes carried a hazard ratio of 0.12; the highest tertile of cumulative alkylating agent dose or of cyclophosphamide, 0.42; procarbazine, 0.48 in the second tertile and 0.17 in the third. The result that should be told to every family is the control comparison: for survivors with an alkylating agent dose score of zero, no hypothalamic or pituitary radiation and no testicular radiation, the hazard ratio against siblings was 0.91 (95 per cent confidence interval 0.73 to 1.14, P = .41). No detectable reduction at all.
The later analysis of 10,938 survivors confirmed and extended this: male survivors had a hazard ratio of 0.63 (0.58 to 0.68) for pregnancy and 0.63 (0.58 to 0.69) for a livebirth, with reduced likelihood associated with upper-tertile cyclophosphamide (0.60), ifosfamide (0.42), procarbazine (0.30) and cisplatin (0.56), and a cyclophosphamide equivalent dose relationship of 0.82 (0.79 to 0.86) per 5,000 mg/m2.
Testosterone is a separate question from sperm. Leydig cells are more radioresistant than germ cells, so a young man can be infertile with normal testosterone, or, after higher doses, need testosterone replacement as well. In the St Jude Lifetime Cohort the estimated cumulative prevalence of Leydig cell failure at age 50 among men at risk was 31.1 per cent (27.3 to 34.9). The International Guideline Harmonization Group's 2017 male gonadotoxicity recommendations, developed with PanCareSurFup by a panel of 25 experts, cover both, and state that they "reveal the paucity of high-quality evidence, highlighting the need for further targeted research".
What can be done before treatment. Sperm banking is cheap, quick, effective and under-offered; it is the standard for any post-pubertal boy or young man, and the only real obstacles are that nobody raised it and that the appointment was not made in time. For a boy who cannot yet produce sperm, the only option is testicular tissue cryopreservation, and it remains experimental. The largest coordinated experience banked tissue from 189 patients between January 2011 and November 2018 across a network of academic centres, average age 7.9 years (standard deviation 5), range 5 months to 34 years. The indication was a malignancy in 118, a blood disorder in 45 and another condition in 26. Thirty-nine per cent (74 patients) had already started chemotherapy before the biopsy. Of 189 patients, 137 were analysed for the presence of germ cells and germ cells were confirmed in 132. The authors state the limit plainly: "The function of those spermatogonia was not tested." No child has yet been born from human testicular tissue frozen before puberty. Families should be offered it on that basis and not another.
What comes back, and when: spermatogenesis often recovers, over one to five years and sometimes longer, because spermatogonial stem cells can repopulate the tubules if enough survive. That is why a semen analysis at one year is not the final answer and why contraception still matters. Recovery is unlikely after testicular irradiation above about the threshold above or after transplant conditioning. Leydig cell function that has failed does not return, and testosterone replacement is the treatment.
Spermatogonial stem cells divide continuously and are therefore highly sensitive to alkylating agents and radiation, but a surviving population can repopulate the seminiferous tubules, which is why fertility often returns after moderate exposure and never after an ablative one. Leydig cells divide rarely and tolerate more, so testosterone production usually outlasts sperm production. Tissue banking before puberty aims to preserve spermatogonial stem cells for a future technique, which is why it is offered as research rather than as treatment.
Query for this technology: (TITLE:"Fertility in boys and young men treated for cancer, including testicular tissue banking" OR ABSTRACT:"Fertility in boys and young men treated for cancer, including testicular tissue banking") AND (cancer OR tumor OR tumour OR oncology OR carcinoma OR lymphoma OR leukemia OR leukaemia OR myeloma OR sarcoma OR melanoma OR glioma). Results are unfiltered search hits about Fertility in boys and young men treated for cancer, including testicular tissue banking, not a curated reading list.
Shares Default fertility preservation referral for every patient under 40 before treatment, PanCareSurFup and the European survivor cohorts, Total body and total marrow irradiation, Fertility preservation before lymphoma treatment: a decision with a deadline in days and the tags rejuvenation, survivorship, paediatric, late-effects.
Shares Total body and total marrow irradiation, International Guideline Harmonization Group for late effects of childhood cancer, The pituitary, puberty and the hypothalamic axis after cranial radiotherapy in childhood, The Children's Oncology Group Long-Term Follow-Up Guidelines and the tags rejuvenation, survivorship, paediatric, late-effects.
Shares International Guideline Harmonization Group for late effects of childhood cancer, The Children's Oncology Group Long-Term Follow-Up Guidelines, How much illness childhood cancer survivors carry, and at what age, Germ cell tumours of childhood and adolescence (extracranial and CNS) and the tags rejuvenation, survivorship, paediatric, late-effects.
Shares PanCareSurFup and the European survivor cohorts, International Guideline Harmonization Group for late effects of childhood cancer, The Children's Oncology Group Long-Term Follow-Up Guidelines, How much illness childhood cancer survivors carry, and at what age and the tags rejuvenation, survivorship, paediatric, late-effects.
Shares The Children's Oncology Group Long-Term Follow-Up Guidelines, How much illness childhood cancer survivors carry, and at what age, Childhood Cancer Survivor Study (CCSS), Ifosfamide and the tags rejuvenation, survivorship, paediatric, late-effects.
Shares International Guideline Harmonization Group for late effects of childhood cancer, The Children's Oncology Group Long-Term Follow-Up Guidelines, How much illness childhood cancer survivors carry, and at what age, Childhood Cancer Survivor Study (CCSS) and the tags rejuvenation, survivorship, paediatric, late-effects.
Shares PanCareSurFup and the European survivor cohorts, The Children's Oncology Group Long-Term Follow-Up Guidelines, How much illness childhood cancer survivors carry, and at what age, Childhood Cancer Survivor Study (CCSS) and the tags rejuvenation, survivorship, paediatric, late-effects.
Shares International Guideline Harmonization Group for late effects of childhood cancer, The pituitary, puberty and the hypothalamic axis after cranial radiotherapy in childhood, The Children's Oncology Group Long-Term Follow-Up Guidelines, How much illness childhood cancer survivors carry, and at what age and the tags rejuvenation, survivorship, paediatric, late-effects.