GONADAL DAMAGE FROM CHEMOTHERAPY AND RADIOTHERAPY

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Cytotoxic chemotherapy and radiotherapy have improved the survival rates in many conditions, particularly in patients with hematologic, breast, and testicular malignancies. Treatment is associated with significant morbidity in many patients, and alterations in gonadal function are among the most common long-term side effects of therapy. Gonadal dysfunction following treatment may be temporary, but recovery is often unpredictable, and damage is permanent in a proportion of patients.

Germinal epithelial damage resulting in oligospermia or azoospermia has long been a recognized consequence of certain chemotherapeutic agents and radiotherapy, and some evidence suggests Leydig cell dysfunction following treatment. Testicular damage is drug-specific and dose-related.24, 51, 63, 91 The chance of recovery of spermatogenesis following cytotoxic insult and the extent and speed of recovery are related to the agent used and the dose received. The germinal epithelium of the adult testis is more susceptible to damage than that of the prepubertal testis,68 implying that patient age or maturation of the testis at the time of cytotoxic insult may influence the degree of damage. Radiotherapy-induced testicular damage is similarly dose-dependent, with the speed of onset, chance of reversal, and time to recovery of spermatogenesis all related to the testicular dose of irradiation.71 The limited data available regarding the influence of pubertal status suggest that, unlike the germinal epithelium, Leydig cell function may be more prone to damage from irradiation in prepubertal life compared with adulthood.77

Although the ovary is less vulnerable to the effects of cytotoxic chemotherapy or radiotherapy than is the testis, ovarian failure is not uncommon following cytotoxic treatments. As is true in the testis, ovarian dysfunction is agent- and dose-dependent.7, 43, 87 In addition, clear evidence in women suggests that age at the time of cytotoxic or radiation insult is important in determining the speed of onset and the duration of amenorrhea and the chance of retaining normal ovarian function.5, 15, 74 The course of ovarian function following chemotherapy is variable, and predicting the likely outcome in any individual patient is often difficult. This may create problems regarding the need for contraception or hormone replacement therapy. Because of the significant morbidity associated with chemotherapy and radiotherapy, much attention is now being directed toward the appropriate management of gonadal dysfunction. At the same time, research efforts are continuing to seek ways to prevent damage to, or enhance the recovery of, gonadal function.

Section snippets

Chemotherapy

Spitz and co-workers83 first described testicular damage from cytotoxic drugs in humans in 1948 when they found azoospermia in 27 of 30 men at autopsy following treatment with nitrogen mustard. Many other drugs, particularly alkylating agents, have subsequently been shown to be gonadotoxic. The agents most commonly implicated are listed in Table 1. The germinal epithelium is far more sensitive to the effects of cytotoxic drugs than are the Leydig cells. Although complete azoospermia is not

PREVENTION OF TESTICULAR DAMAGE

The deleterious effects of chemotherapy and radiotherapy on germinal epithelial function have initiated a search for possible strategies to preserve fertility in men undergoing therapy. Cryostorage of semen has become standard practice and should be offered to all men before they undergo potentially sterilizing therapy. Although improvements in the techniques used to store semen72 and advances in the field of assisted reproduction such as intracytoplasmic sperm injection (ICSI) have increased

Chemotherapy

The gonadotoxic effects of chemotherapy in women were first reported by Louis and co-workers48 in patients treated with busulfan for chronic myeloid leukemia. Subsequently, several drugs have been implicated in the development of ovarian dysfunction.

The effects of cyclophosphamide used in the treatment of breast cancer, renal disorders, and rheumatologic conditions have been widely studied. Ovarian damage has been shown to be dose-dependent and age-dependent,5, 43 with progressively smaller

PREVENTION OF OVARIAN FAILURE

Because of the consequences of ovarian failure in young women, several strategies have been tried in an attempt to reduce the gonadotoxic effect of cancer treatment. Transposition of the ovaries before radiotherapy can reduce the dose of irradiation to the ovaries to approximately 10% of the given dose during pelvic radiotherapy.33, 59, 66 Although this has been shown to reduce the incidence of ovarian dysfunction,66 the routine use of ovarian transposition in patients with Hodgkin's disease

SUMMARY

Treatment with cytotoxic chemotherapy and radiotherapy is associated with significant gonadal damage in men and women. Alkylating agents such as cyclophosphamide and procarbazine are the most common agents implicated. The vast majority of men receiving procarbazine-containing regimens for the treatment of lymphomas become permanently infertile. Cisplatin-based chemotherapy for testicular cancer results in temporary azoospermia in most men, with a recovery of spermatogenesis in about 50% after 2

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    Address reprint requests to Stephen Shalet, MD, Department of Endocrinology, Christie Hospital NHS Trust, Wilmslow Road, Manchester, M20 4BX, United Kingdom

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    Department of Endocrinology, Christie Hospital NHS Trust, Manchester, United Kingdom

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