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Cancer and Male Factor Infertility

Cancer and Male Factor Infertility

ABSTRACT: With the increasing success of multimodality anticancer therapy, most men of reproductive age will survive their malignancy. Reproductive function is a principal concern of these men. Health-care providers are shifting the focus of oncologic care toward improving the quality of life in cancer patients, particularly with regard to fertility. For unknown reasons, fertility and sexual function are adversely affected in men with germ cell tumors and Hodgkin’s disease prior to the initiation of therapy. Despite these pretreatment abnormalities, fertility potential remains good. Cancer therapy utilizing physical and chemical treatment methods can temporarily or permanently damage spermatogonia, resulting in azoospermia and infertility. Recovery of spermatogenesis can take up to 10 years after therapy. Alternative treatment regimens can preserve reproductive function while maintaining high therapeutic efficacy. Surgical treatment should be directed toward maintaining the neurovascular mechanisms responsible for seminal emission and ejaculation. With new developments in assisted reproductive techniques, even cancer patients with severe oligoasthenospermia can father children. These techniques have not been found to increase the incidence of major or minor birth defects.[ONCOLOGY 12(4): 557-568, 1998]

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.

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