Cancer and Male Factor Infertility

In 1996, over 400,000 males between the ages of 17 and 50 years were diagnosed with cancer in the United States.[1] Over the past 25 years, there have been increases in the diagnosis of malignancy in men of reproductive age, both in the United States and throughout the world; in particular, a significant increase in the incidence of testicular cancer has been noted.[2,3] Fortunately, with the development of aggressive multimodality therapy, a majority of patients will survive their malignancy.

With the increased success of cancer treatment in young men, the emphasis is shifting toward improving the side effects of therapy. One significant side effect of multimodality therapy in males (as well as females) is damage to reproductive function. Surgery, chemotherapy, and radiation therapy are particularly damaging to the testis. Over the past decade, an increasing number of studies in the oncologic literature have focused on the evaluation and maintenance of reproductive function in young men with cancer.[4,5]

Sexual function and fertility are of principal importance to young men of reproductive age faced with the diagnosis of a cancer. Over 80% of male cancer patients between the ages of 17 and 50 years express concern regarding their fertility potential.[6] However, some studies have indicated that patients’ concern about future fertility may be overrated or underrated by physicians treating them.[7] It is important for clinicians to address fertility issues with patients at diagnosis, both to gather information about the patient’s level of concern and to consider the patient’s wishes when developing the treatment regimen.

Health-care providers involved in the treatment of young men with cancer should evaluate patients’ germ cell function prior to initiating therapy. Knowledge of pretreatment abnormalities in gonadal function will direct care so as to help preserve fertility potential.

New assisted reproductive techniques, including in vitro fertilization and intracytoplasmic sperm injection, allow patients with severe defects in sperm production to father children. Familiarity with these techniques also aids the oncologist in counseling and treating young men.

Pretreatment Abnormalities in Gonadal Function

Certain malignancies are associated with pretreatment abnormalities in sperm production and function, as well as abnormalities in testosterone production and feedback to the hypothalamic-pituitary-gonadal axis. Hodgkin’s disease and germ cell tumors produce nonspecific damage to the seminiferous epithelium, leading to poor seminal parameters and decreased fertility. These pretreatment defects do not appear to be widespread in other malignancies. Despite these abnormalities, the fertility potential of these men is only moderately below that of males without cancer.

Hodgkin’s Disease
Hodgkin’s disease is a lymphoproliferative disorder characterized by circulating malignant cells of poorly defined origin associated with a systemic lymphocytic reaction. Male patients with Hodgkin’s disease demonstrate significant damage to the seminiferous epithelium and the Leydig cell endocrine mechanism early in the disease process. These abnormalities do not appear to be related to disease stage or dominant cell type.[8-12]

Up to 80% of men with Hodgkin’s disease have an abnormal semen analysis at diagnosis (see Table 1 for a review of the literature on these abnormalities). Histologic abnormalities are noted in 90% of testicular biopsy specimens; these range from maturation arrest to complete testicular fibrosis.[9,13,14] A decrease in the number of Sertoli cells, Leydig cell hyperplasia, and Leydig cell aplasia are also noted in biopsy specimens.

Endocrine function is abnormal in most male patients with Hodgkin’s disease.[8,15] These endocrinopathies are manifested by decreased serum testosterone, abnormal stimulatory response to human chorionic gonadotropin (HCG), and an elevation or a decrease in gonadotrophs (with accompanying changes in follicle-stimulating hormone [FSH]/ luteinizing hormone [LH] levels).

The mechanism of pretreatment testicular injury in patients with Hodgkin’s disease is not understood. Possible theories include: genetic abnormalities at the germ cell level; germ cell and Leydig cell injury secondary to systemic release of interleukin-6 (IL-6), tumor necrosis factor (TNF), and other cytokines; and negative local effects from resident testicular lymphocytes and macrophages.[16] Additional research is needed to evaluate these pretreatment abnormalities in germ cell function on a genetic and cellular level.

Germ Cell Tumors
Despite the overwhelming success of treatment for patients with germ cell tumors, significant defects in reproductive function are associated with the diagnosis of testicular cancer. An increased worldwide incidence of germ cell tumors also heightens concern over the effects of testicular cancer on reproductive function. Germ cell tumors in males are associated with pretreatment abnormalities in sperm production and function.[17-24] Defects in the hypothalamic- pituitary-gonadal axis also occur.[25]

Table 1 reviews the literature on pretreatment semen analysis in patients with germ cell tumors. Biopsy specimens of the contralateral testis in patients with testicular cancer show defects in the seminiferous epithelium. Significant fibrosis is present in 20% to 60% of patients with germ cell tumors, and “Sertoli cell only” histology is noted in 8%. Intratubular germ cell neoplasia, formerly known as carcinoma in situ, has been noted in up to 10% of patients with contralateral germ cell tumors.[20,26] While the natural history of intratubular germ cell neoplasia is uncertain, it is estimated that as many as 50% of these patients will ultimately develop clinical germ cell tumors.

The mechanism of decreased sperm production and function in patients with germ cell tumors is also poorly understood. Several factors may contribute to abnormal seminal parameters. Unilateral orchiectomy, as well as the stress of diagnosis of a malignancy (see discussion below), may lower sperm numbers and motility by 50%. From 15% to 73% of germ cell neoplasms produce HCG, which may decrease spermatogenesis and Leydig cell function by inhibiting pituitary gonadotrophs.[20] Local tumor effects, including elevation of scrotal temperature and alterations in blood flow, also impair contralateral testicular function. Other theories regarding pretreatment abnormalities in germ cell function include: systemic release of cytokines, alterations in resident leukocyte function, and constitutional effects of malignancy.

Gene deletions in the DNA of primordial germ cells may be responsible for pretreatment abnormalities in patients with germ cell tumors. Subfertile males with idiopathic oligospermia, cryptorchidism, or germ cell tumors have an associated increased incidence of intratubular germ cell neoplasia.[26-29] These three clinical entities may be different manifestations of similar genetic alterations in germ cells.

Other Malignancies
Young men with leukemia, Wilms’ tumor, or sarcoma appear to have normal semen analyses and reproductive function prior to treatment with chemotherapy, surgery, or radiation.[30,31] Ultimate fertility potential seems to be related to testicular injury from the treatment regimen.

There is evidence to suggest that advanced stages of malignancy, with accompanying malnutrition and decreasing physical status, have a deleterious effect on gonadal function in both male and female patients.[19,32] The effects of disseminated malignancy on germ cell function are also poorly understood.

Stress
Recent interest has focused on the effects of stress on sperm production and function.[33] A decrease in seminal parameters occurs in individuals with significant life stressors. It is reasonable to conclude that patients with a diagnosis of malignancy, who are undergoing extensive treatment, may be included in this group. It is important that the oncologic health-care provider assist the patient and his family with the associated stress of a malignancy by offering supportive measures and counseling.