5 January, 2022

The number of men surviving cancer at a young age has increased dramatically in the past 20 years as a result of early detection and improved cancer treatment. Quality of life has become an important issue in childhood and adult cancer patients. Fertility is often impaired after chemotherapy and radiation therapy.

Malignant diseases might influence gonadal function through hormonal alterations and metabolic conditions. Reproductive hormones might be low in cancer patients as a result of stress, downregulation by endocrine substances produced by some tumors, such as β-human chorionic gonadotrophins by some TGCT, and as a consequence of a metabolic condition. In leukemia, lymphoma and in central nervous system tumors, the hypothalamus and the pituitary gland function might be directly impaired by tumor cell invasion or damaged by radiation therapy. Malignancy might also result in malnutrition, with deficiencies in the vitamins, minerals and trace elements needed for optimal gonadal function. Some malignancies are accompanied by periods of fever that negatively influence spermatogenesis. Finally, tumor released cytokines might affect spermatozoa function, resulting in low sperm motility.

Surgery might be needed for a tumor that’s in or near an organ, such as a testicle, or the penis, bladder, or rectum. It might also be needed for a tumor that’s in or near nervous system, such as the brain or spinal cord. These surgeries may affect a man’s fertility. A few types of cancer surgeries can damage nerves that are needed to ejaculate semen. They include removing lymph nodes in the abdomen which may be part of the surgery for testicular cancer and some colorectal cancers. Nerves can be damaged when lymph nodes are being removed, and this can cause problems with ejaculation. Sometimes surgery can permanently damage the nerves to the prostate and seminal vesicles causing retrograde ejaculation.

The negative effect of cytotoxic drugs on spermatogenesis has been extensively investigated. Most harmful drugs are nitrogen mustard derivates, such as busulphan and melphalan, and alkylating drugs, such as cyclophospfamide and procarbazine. Combination chemotherapy, such as (MOPP)-regimen given for Hodgkin’s disease, has a high chance of sterilizing the patient. Other multi-drug regimens applied (ABVD) for Hodgkin’s disease and BEP regime for TGCT, have a lower risk of permanent infertility. Recovery of spermatogenesis depends on the drugs used and on the cumulative dose given. Cyclophosphamide is one of the most commonly used alkylating agents in paediatric cancer treatment. Patients receiving a total cumulative dose of more than 10 grams/m2 are at a high risk of developing permanent gonadal damage. The testes are very sensitive to irradiation, especially the germ cells. A dose of more than 4 Gys can cause permanent damage to the germ cells. The Leydig cells are more resistant to irradiation and a dose of more than 20 Gy is needed to produce hypogonadism.

Patients pre-treatment fertility appears to be of prognostic value for future sperm recovery. In men with Hodgkin’s disease receiving >3 courses of MOPP, azoospermia is found in 85–90% of patients after a follow-up of >1 year. The only established method to secure fertility in male cancer patients before gonadotoxic therapy is semen cryopreservation, which in time can be used for assisted reproduction techniques (ART). The patients who are unsuccessful in sperm banking are of younger age, and show higher levels of anxiety and more reluctance to talk about future fertility. Cryopreservation induces the deterioration of semen quality. On an average, sperm freezing decreases motility by 31%, morphology by 37% and mitochondrial activity by 36%.The utilization rate of cryopreserved semen is often less than 10–15%.

Difficult psychosocial and ethical decisions should sometimes be made regarding the possibilities of future parenthood in case of limited life expectancy. The issue of post-mortem use should be discussed if semen is cryopreserved. Informed consent of the patient is usually required for the post-mortem use of banked sperm. So far, the reproductive outcome of children born from fathers that had previous cancer treatment has shown no differences to the outcome of newborn children of a non-cancer population. Importantly, no reported increased risk for congenital malformations is found. In contrast to the situation in children from female cancer survivors, the offspring of male cancer survivors showed no increased risk for obstetric and perinatal problems or decreased birth weight. In boys in whom spermarche has not yet started, no good options for securing their future fertility are available yet. Potential new fertility preservation techniques might use spermatogonial stem cells, which can be harvested from testicular tissue before cancer treatment. Other options, such as in vitro maturation of stem cells into spermatogonia and subsequent xenografting, need further investigation. Harvested germinal cells could be matured in vitro and cryopreserved to be used for future ICSI. Harvesting testicular tissue from prepubertal boys should, therefore, be considered experimental.

Associations between male infertility and cancer are gaining clinical attention. Infertile men are at an elevated risk to develop various malignancies later in life, primarily genitourinary malignancies such as testicular and prostate cancer. Rates of testicular and high-grade prostate cancer in infertile men appear to be at least double the risk than in the general population. The link between infertility and malignancy highlights the importance of thorough evaluation and long-term follow up—beyond a simple semen analysis. A detailed urologic evaluation, possibly including scrotal ultrasound, may be beneficial to screen infertile men for testicular cancer. Publications have also demonstrated that male infertility can be a biomarker for cancer risk in first- and second-degree relatives. Testicular cancer risk in first-degree relatives of infertile men is 52% higher than the risk in relatives of fertile control men. Male infertility has been associated with a two- to threefold elevation in risk of childhood cancer in the siblings of infertile men. Links between infertility and malignancy are multifactorial, and exact mechanistic explanations are still not fully understood.

An infertility diagnosis in a man appears to carry health consequences for that individual, but data increasingly demonstrates that infertility may also be a biomarker of health for the infertile man’s family members. Shared genetics or environmental exposures provide plausible mechanisms.

Dr. A.K. Dewan
Director – Surgical Oncology

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