Cancer continues to be a leading cause of morbidity and mortality in our society and does not discriminate based on age. Many patients are of reproductive age or younger. Approximately 9.2% of patients diagnosed with cancer in the United States are less than 45 years old, and 1.1% are under 20 years old [1]. As advancements in medicine lead to improvements in cancer diagnosis and treatment , more of these younger patients survive. The 5-year survival rate is now greater than 80% among all age groups [2]. In this context of increasing survival among oncology patients with reproductive potential, it is becoming increasingly important to consider future fertility in patients undergoing cancer treatment.

Although new modalities are emerging, surgery, chemotherapy, and radiation remain the foundation of cancer treatment. Unfortunately, all of these modalities can negatively affect fertility potential. The American Society of Clinical Oncology released formal recommendations for fertility preservation in 2006 and an updated version in 2013 [3]. The recommendations include discussing fertility preservation with all patients of reproductive age or their guardians if the patients are minors and referring patients who express an interest in fertility preservation to reproductive specialists.

Despite these recommendations, many patients with not only reproductive potential but also interest in future fertility are not referred for fertility preservation . Schover et al. reported that of men and women who were childless before cancer diagnosis, 76% desired children in the future [4]. Additionally, only 57% received information from their physicians about fertility after cancer treatment, and only 24% of childless men banked sperm before cancer treatment. Kohler et al. found that, although 86% of responding pediatric oncologists agreed with the recommendations to refer all pubertal males to a physician who specializes in fertility preservation prior to oncologic treatment, only 46% of respondents reported actually doing so more than half of the time [5]. It is also important not to make assumptions based on age about desired fertility. Salonia et al. found that up to 20% of men preparing to undergo a radical prostatectomy with an average age of 62.2 years reported desire to cryopreserve sperm before the procedure [6]. Therefore, it is imperative that the physician include a discussion of fertility preservation when counseling patients before receiving treatment for cancer.

This chapter reviews the effects of cancer and its treatment on male fertility in regard to natural conception specifically, as the use of assisted reproductive technologies and sperm cryopreservation before cancer therapy will be covered elsewhere. The literature describing the impact of cancer and its treatment on spermatogenesis, likelihood of natural conception, and discussion of potential congenital abnormalities as a result of DNA damage in sperm is discussed.

Spermatogenesis occurs in the seminiferous tubules which account for approximately 70–80% of the testicular volume. There are an estimated 83,000,000 diploid germ cells present in the seminiferous tubules prior to pubertal development [7, 8]. Spermatogonial cells are comprised of three subtypes with specific roles: type A (dark), type A (pale), and type B. Type A (dark) spermatogonia function as quiescent, diploid reserve cells, which are active only during initial pubertal development and following stem cell depletion from exposure to gonadotoxins. Type A (pale) spermatogonia are more mitotically active and serve as permanent progenitor cells, with self-renewal occurring at each mitotic division. Type B spermatogonia also undergo frequent division as the immediate precursors to primary spermatocytes that then undergo two meiotic divisions before ultimately producing spermatids. Type A (dark) spermatogonia are therefore considered the most resistant to injury from chemotherapy or radiation, as opposed to type A (pale) and type B spermatogonia which have higher mitotic activity. These cellular qualities likely explain the transient arrest in spermatogenesis and preservation of sperm production observed following small, finite doses of chemotherapy and radiation [9–19].

It is important to discuss abnormal semen parameters seen in men with cancer prior to receiving treatment. It is not unusual to see abnormal semen parameters in men without cancer; however, men with cancer prior to treatment are more frequently observed to have abnormal semen parameters at baseline as a result of the disease. One study reviewed all patients presenting for sperm cryopreservation in an American sperm bank and found that over 35% of all men having sperm cryopreserved for any reason had low sperm counts, while over 50% of men presenting with testicular cancer had oligospermia [20]. Hendry et al. found that 50–70% of testicular cancer patients were subfertile or had impaired spermatogenesis before the start of chemotherapy [21]. These authors also described that impaired spermatogenesis was neither related to stage of disease nor to the duration or severity of symptoms attributed to testicular cancer. Although impaired semen parameters in pretreatment cancer patients have been most extensively study in the testicular cancer population, a clear association also exists with Hodgkin’s lymphoma. Williams et al. retrospectively evaluated 717 semen samples from 409 men with 8 different types of cancer including testicular cancer and lymphoma. The investigators found that men with most types of cancer had pretreatment semen parameters that were within the fertile range in regard to density and in the intermediate range for motility, but men with testicular cancer had statistically lower semen quality compared to those with other malignancies [20].

The etiology for abnormal semen parameters in cancer patients prior to treatment is likely multifactorial. Several putative mechanisms have been proposed. These include hormones and cytokines secreted by tumors that may disrupt spermatogenesis, disturbances between the balance of subpopulations of T lymphocytes in lymphomas, hyperthermia, and central endocrine disruption—all of which may play a role in this pathologic process [22, 23]. Barr et al. described local effects of the disease on the testis itself that are likely immune mediated, resulting in significant fibrosis in testicular cancer and hyalinization of the seminiferous tubules in lymphoma [24]. Stahl and colleagues conducted a study to evaluate the DNA integrity in cryopreserved sperm from 121 cancer patients before treatment [25]. Testicular cancer and Hodgkin’s lymphoma patients had a higher degree of DNA fragmentation than controls prior to treatment. The same trend was observed for other cancer diagnoses, but this trend did not reach statistical significance.

Abnormal sperm DNA condensation is adversely correlated with fertility potential. Spermon et al. evaluated DNA condensation and DNA breaks using chromomycin A3 (CMA3) and the TdT-mediated dUTP nick-end labelling assay (TUNEL) in patients who received hemi-orchiectomy for testicular cancer, but before receiving chemotherapy [26]. In all patients with testicular cancer after hemi-orchiectomy, 22% were found to have teratospermia before the start of chemotherapy, and 47% had teratospermia after chemotherapy. In contrast, the iatrogenic causes of germ cell loss through chemotherapy and radiation affecting mitosis and meiosis are well understood.

Surgery, chemotherapy, and radiation are the mainstays of cancer treatment, and all affect spermatogenesis leading to abnormal semen parameters after treatment. Typically, the depression of spermatogenesis is transient, but occasionally it can lead to permanent sterility.