Approximately 850,000 men receive a new diagnosis of cancer each year in the United States, and yet, fortunately, overall cancer death rate in males is decreasing by 1.8% per year (1). Many of these male patients will receive gonadotoxic cancer treatments. Accordingly, these patients are concerned with current or future fertility. Many of the therapies used to treat cancer can cause fertility problems in men, including chemotherapy, radiation, and surgery. Importantly, strategies exist to limit the risks to fertility during and following cancer treatment. The information below will highlight the current state of the science and management options to foster fertility preservation in male oncology patients.
Anatomy of the Testis and Physiology of Spermatogenesis
Three types of cells make up the testis: germ cells that develop into sperm, Sertoli cells that support the developing germ cells, and Leydig cells that produce testosterone (2). Spermatogenesis occurs in the seminiferous tubules, and the process of forming spermatozoa from a germ cell occurs over approximately seventy days. Once spermatozoa form, they travel through the seminiferous tubules and are stored in the epididymis.
Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) regulate testicular function. Gonadotropin releasing hormone (GnRH) is released from the hypothalamus and stimulates both LH and FSH to be made and released from the pituitary. LH stimulates the Leydig cells in the testes to make testosterone. The Leydig cells are responsible for about 95% of the circulating testerostone in the male. Testosterone is converted further to the androgen dihydrotestosterone (DHT), but most of this conversion takes place outside of the testes. Testosterone released from the Leydig cells stimulates spermatogenesis in the seminiferous tubules. FSH acts on the Sertoli cells to stimulate spermatogenesis via the production of a wide variety of proteins and enzymes, one of which is inhibin B. Testosterone produced in the Sertoli cells exerts feedback inhibition on LH and FSH. Inhibin B from the Sertoli cells also exerts negative feedback on FSH production.
Leydig cell dysfunction can occur during chemotherapy, but cell failure and low testosterone are relatively uncommon (3). Some men report loss of libido, erectile dysfunction, decreased bone density, and decreased muscle mass (4). Measurements of testosterone and gonadotropin levels should be performed following chemotherapy treatment, and males with a high LH and low testosterone should be considered for androgen replacement therapy (5).
Interestingly, following chemotherapy treatment, while testosterone levels may normalize, sperm production may not recover. Due to their rapid turnover, the germ cells are much more sensitive to damage by chemotherapy than the Leydig cells. Spermatogenesis is very sensitive to damage by alkylating agents such as cyclophosphamide, ifosfamide, cisplatin, chlorambucil, mechlorethamine, procarbazine, and busulfan (6-15). This damage tends to occur in a dose-dependent manner and can be additive when multiple agents are used in a treatment regimen.
Radiation therapy effects
As with chemotherapy, spermatogenesis is more sensitive to radiation injury than hormone production. Patients that receive radiation directly to the testes or near the testes experience impaired spermatogenesis. The Childhood Cancer Survivor Study (CCSS) was a longitudinal cohort study of cancer survivors who were younger than 21 years of age at diagnosis, compared with a sibling control group. In this study, patients exposed to more than 7.5 Gy of radiation to the testes had lower fertility when compared to the healthy sibling control group that did not receive radiation (6). Reversible oligospermia and azoospermia occur at 10 cGy and 35 cGy respectively (16). Exposures higher than 200 cGy result in irreversible azoospermia (16-18).
Cranial radiation therapy can also cause problems with fertility. Specifically, radiation to hypothalamic-pituitary axis causes impaired spermatogenesis and hormone production. Following decreased growth hormone levels, the second most frequent manifestation of radiation-induced hypothalamic-pituitary dysfunction is impaired gonadotropin levels (19). Dual damage to the hypothalamus and pituitary occurs with doses of 40 Gy, and gonadotropin deficiency increases with higher radiation doses (19). The incidence of clinically significant gonadotropin deficiency is 20-50% after long-term follow-up (19). Gonadotropin deficiency can result from either reduced GnRH from the hypothalamus resulting in decreased release of LH and FSH, or from direct damage to the pituitary resulting in decreased production of LH and FSH.
As expected, gonadal surgery can also affect the production of sperm and reproductive hormones, negatively impacting fertility. In a study of 680 patients with testicular cancer, 169 patients treated with unilateral orchiectomy alone without chemotherapy or radiotherapy reported 85% success conceiving without intervention with a median follow up period of 11 years (20). Most patients have no difficulty with fertility following removal of one testicle.
Additionally, surgery on the glands of the hypothalamic-pituitary axis can cause problems with fertility. Surgery on hypothalamus can cause injury of the gonadotropin releasing hormone area. Surgery on the pituitary can cause problems with the gonadotropin producing area. In a study of pituitary function in prolactinoma, 4 of 15 men treated with surgery had deterioration of gonadal function, but recovered function with testosterone stimulation (21).
Men can also suffer from erectile dysfunction and the inability to achieve or maintain an erection following pelvic surgery for colorectal cancer. A review of 677 patients in 19 studies revealed the incidence of complete erectile dysfunction following surgery for rectal cancer is approximately 25%; 34% for patients after low anterior resection and 20% for patients after abdominoperineal resection (22). Loss of ejaculation occurred in 16% of patients after surgery for rectal cancer (22). The mechanisms for this surgical threat to fertility are multifactorial. After retroperitoneal lymph node dissection (RPLND) or prostatectomy, surgery can interfere with the transport of sperm from the testes to the urethral opening through damage to the autonomic nervous system and subsequent loss of control of urethral sphincters and/or vasodilation. Fortunately, the risk of ejaculatory dysfunction from RPLND for lower-stage testicular cancer has been mitigated with the advent of nerve-sparing surgical techniques (23).
With the increasing success of cancer treatments, many more patients are surviving cancers treated during the reproductive years. Many of the therapies used to treat cancer are gonadotoxic, including chemotherapy, radiation therapy, and surgery. It is important to counsel patients regarding fertility preservation prior to initiating any treatment that may have adverse effects on a patient’s future ability to father children.