The effects of irinotecan HCl (CPT-11) combination chemotherapies on the hypothalamus-pituitary-ovary endocrine system were examined clinically. The incidences of typical menopausal malaises and/or endocrinological findings were investigated in 32 gynecological cancer patients treated by CPT-11 combination chemotherapies. Patients who complained of menopausal malaises or had been treated by hormone replacement therapy before chemotherapy were excluded from the study. Menopausal malaise-like symptoms (MMLS) appeared in 6 of 32 patients (18.8%) during CPT-11 combination chemotherapy, and these symptoms were completely cured within a few days by administration of conjugated estrogen tablets (0.625 mg/day). All the MMLS cases were perimenopausal patients (47-57 years of age), and MMLS were not found in any of the postmenopausal patients who had exceeded 3 years since endocrinological menopause or patients who had recurrent cancer after pelvic radiotherapy. After exclusion of these 3-year-postmenopausal patients and postirradiation patients, 6 of 7 patients aged 45-59 years complained of MMLS during CPT-11 combination chemotherapy. The incidence of CPT-11-induced MMLS showed no relationships with the anticancer drugs combined with CPT-11, mean total CPT-11 dose, mean number of CPT-11 injections, mean individual CPT-11 dose, grade of CPT-11 specific diarrhea or anticancer effects of each CPT-11 combination chemotherapy. The perimenopausal cancer patients with CPT-11-induced MMLS showed decreased serum estradiol and increased serum FSH and LH levels accompanying the CPT-11 injections. A young patient with CPT-11-induced secondary amenorrhea showed decreased serum estradiol and increased serum FSH and LH levels accompanying the CPT-11 injections. None of the postmenopausal patients with high FSH and LH levels showed any significant differences in their serum FSH, LH, PRL and TSH levels during CPT-11 combination chemotherapy. No differences in the results of LHRH and TRH tests during chemotherapy were found for postmenopausal patients. Histopathological examinations of normal ovarian tissues surgically removed from 4 young cervical cancer patients treated with preoperative CPT-11 combination chemotherapies revealed no growing ovarian follicles in the ovarian tissues. CPT-11 injections can induce estrogen-rescued MMLS in cancer patients aged similar to 50 years at a very high rate and may induce secondary amenorrhea in young women. The endocrinological and histopathological studies revealed that CPT-11 causes ovarian follicular loss and ovarian failure within a short time without affecting hypothalamic and pituitary hormone secretion. These clinical results indicate that CPT-11 has strong ovarian toxicity and that repeated CPT-11 administrations may frequently induce ovarian follicular loss and premature ovarian failure, even in young women.
