Ovarian function after autologous bone marrow transplantation in childhood: high-dose busulfan is a major cause of ovarian failure

Abstract

Summary:We studied pubertal status and ovarian function in 21 girls aged 11-21 years who had earlier received 1.2-13 years (median 7 years) high-dose chemotherapy and autologous BMT without TBI for malignant tumors. Ten of them were given busulfan (600 mg/m 2 ) and melphalan (140 mg/m 2 ) with or without cyclophosphamide (3.6 g/m 2 ). Eleven others did not receive busulfan. Twelve girls (57%) had clinical and hormonal evidence of ovarian failure. Among nine others who had completed normal puberty, six had normal gonadotropin levels, one had elevated gonadotropin levels and two had gonadotropin levels at the upper limit of normal. The 10 girls who received busulfan all developed severe and persistent ovarian failure. High-dose busulfan is therefore a major cause of ovarian failure even when given in the prepubertal period. These findings emphasize the need for long-term endocrine follow-up of these patients in order to initiate estrogen replacement therapy. Keywords: ovarian function; high-dose chemotherapy; bone marrow transplantation; busulfan; childhood Increasing numbers of children who receive hematopoietic stem cell transplants (HSCT) for malignancies now survive. It is therefore important to evaluate ovarian toxicity secondary to the therapeutic regimens. New chemotherapy protocols will have to aim towards effecting long-term survival with minimal late morbidity. Chemotherapy is used alone or in combination with total body irradiation. Total body irradiation, used in the preparative regimens for hematologic malignancies, is deleterious to gonadal function. 1,2 Myeloablative therapy consisting of cyclophosphamide, busulfan or melphalan, has been used as an alternative to avoid the side-effects of irradiation on endocrine functions and growth. 1,3,4 Cytotoxics are known to induce ovarian toxicity in adults, dependent upon type of agent, dosage, administration schedule and patient age. 5-7 Much less is known about the effects of high-dose chemotherapy on ovarian function in children. 2,8,9 We report an analysis of ovarian function in long-term survivors following myeloablative chemotherapy and bone marrow transplantation. Patients and methodsWe screened all long-term female survivors older than 11 years who had received high-dose chemotherapy and autologous bone marrow transplantation without abdominal or pelvic radiation for malignant tumors at Institut Gustave Roussy. Twenty-one girls fulfilled these criteria.At time of transplantation, they were aged 2-17 years (median 9 years). Pubertal development was evaluated clinically according to Tanner. 10 Fourteen girls were prepubertal (stage 1), two were undergoing puberty (stage 3) and five had regular menses (stage 5). No hormonal evaluation was carried out before chemotherapy, but pubertal stages of all the patients were appropriate for their age.The study took place 1.2-13 years (median 7 years) after bone marrow transplantation and discontinuation of chemotherapy. At time of study, girls were aged 11.5-21 years (median 14.5 years).Serum concentrations of 17...

Growth and endocrine function in children with acute myeloid leukaemia after bone marrow transplantation using busulfan/cyclophosphamide

“…In contrast, girls receiving similar intensive therapy followed by a non-BU-containing BMT therapy, are more likely to have normal gonadotrophins. 19,20 This has been seen particularly with single agent melphalan. 20 Although the majority of children undergoing BMT for AML are conditioned with BUCY, good results have been reported with the use of melphalan alone.…”

“…19,20 This has been seen particularly with single agent melphalan. 20 Although the majority of children undergoing BMT for AML are conditioned with BUCY, good results have been reported with the use of melphalan alone. 21 If these results could be duplicated in a larger group of patients, preferably in a randomised study comparing BUCY with melphalan, then it would be reasonable to prefer the less toxic conditioning regimen.…”

Fertility Preservation in Young Women Undergoing Breast Cancer Therapy

“…This stems from the observation that the incidence of immediate amenorrhea is lower in younger women. Because young women have a larger primordial follicle pool, they are less likely to lose all their reserve immediately, but because they have lost a significant proportion of it, they will eventually experience premature ovarian failure [34][35][36][37][38]. On the other hand, permanent gonadal damage can be induced with smaller doses of the implicated chemotherapeutic agents in older women with lower primordial follicle reserve.…”

Endocrine dysfunction and parameters of the metabolic syndrome after bone marrow transplantation during childhood and adolescence

“…35 We found that hypogonadism was significantly associated with conditioning with TBI or TAI, but not with the type of conditioning chemotherapy, perhaps owing to the high percentage of patients who received alkylating agents. Older age and advanced pubertal stage at BMT were both significantly associated with hypogonadism, although Teinturier et al 36 found that high-dose busulfan is a major cause of ovarian failure, even when given in the prepubertal period without TBI or abdominal or pelvic radiotherapy.…”