Reproductive Endocrine Function Ovarian Dysfunction

Both chemotherapy and radiation therapy can induce ovarian dysfunction, which can be either transient or permanent. In the pre-pubertal state, ovaries are more resistant to chemotherapy-induced damage than in the post-pubertal individual (Rivkees and Crawford 1988; Halperin et al. 1999). Among all the chemotherapeutic agents, alkylating agents, including cyclophosphamide, ifosfamide, busulfan, BCNU, and CCNU, have most consistently caused ovarian damage. High doses of these agents are very toxic even to young ovaries (Thibaud et al. 1998; Sklar 1999). Patients who have undergone allogenic or autologous bone marrow transplant with high-dose alkylator therapy (e.g., busulfan, melphalan, or thiotepa) are at particularly high risk of developing ovarian failure (Thibaud et al. 1998; Sklar 1999). Furthermore, even if female patients recover ovarian function after treatment is completed, a significant proportion of these patients are at risk of experiencing premature menopause in the future (Byrne et al. 1992).

Radiation-induced ovarian failure is also common in female cancer survivors. As with chemotherapy, pre-pubertal ovaries seem to be more resistant to damage from irradiation than post-pubertal ovaries. Radiation doses above 1000-2000 cGy can, however, cause irreversible ovarian damage in young girls (Stillman et al. 1981; Wallace et al. 1989a); therefore, young females who receive abdominal, pelvic, or spinal irradiation for tumors such as neuroblastoma have a high risk of ovarian failure (Shalet et al. 1976; Stillman et al. 1981; Wallace et al. 1989a; Wallace et al. 1989b). Moreover, we can extrapolate that the concomitant use of intensive chemotherapy in neurob-lastoma definitely increases the risk of ovarian failure and premature menopause. Patients who received TBI are also at significant risk of developing irreversible ovarian failure (Sklar 1995a). The use of more conformal radiation techniques, shielding of the ovaries, or oophoropexy are strategies used to lessen the occurrence of this complication (Halperin et al. 1999). Female patients who receive abdominal irradiation are also at increased risk for spontaneous abortion, preterm labor, and the delivery of low-birth-weight infants once they reach childbearing age (Li et al. 1987).

In our cohort, 12 of 32 patients (38%) developed ovarian dysfunction, which was transient in 3 of the patients. All 12 patients had received cyclophosphamide and 75% had also been treated with abdominal irradiation.

Testicular Dysfunction

Male germ cells are very vulnerable to both radiation and chemotherapy (Aubier et al. 1989; Halperin et al. 1999). Alkylating agents (cyclophosphamide, nitrosoureas) are very toxic to the germinal epithelium (the sperm-producing cells). This effect is more frequent and more severe at higher doses (Aubier et al.

1989; Sklar 1999). The prepubertal state is not always protective (Aubier et al. 1989). Recovery of spermato-genesis has been reported, but the toxicity is often permanent (Halperin et al. 1999; Sklar 1999). The clinical hallmarks of germ-cell damage include reduced testicular volume and an elevated plasma FSH level.

Leydig cell failure with androgen insufficiency has also been described but is seen infrequently and only following high-dose irradiation (>2000 cGy) administered directly to the testicles (Sklar 1999). Compensated Leydig cell dysfunction (i.e., normal testosterone combined with elevated LH levels) is common after chemotherapy with alkylating agents and lower-dose radiation therapy. The patients are usually asymptomatic and usually progress normally through puberty (Sklar 1999).



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