Cranial irradiation does not result in pituitary|[ndash]|gonadal axis dysfunction in very long-term male survivors of childhood acute lymphoblastic leukemia

Currently, >75% of all pediatric acute lymphoblastic leukemia (ALL) patients survive and reach adulthood.1 Successful treatment of children with ALL involves administration of multi-agent chemotherapy and includes central nervous system prophylaxis. In the past, central nervous system prophylaxis consisted of cranial irradiation, which has been replaced by intrathecal chemotherapy in most current treatment protocols. An increasing cohort of childhood ALL survivors who have been treated with cranial radiotherapy in the past has now reached reproductive age. It has been reported that cranial irradiation can influence the hypothalamic–pituitary–gonadal axis and potentially lead to impaired endocrine function resulting in growth disturbances and impaired fertility.2, 3 Earlier fertility studies in pediatric ALL survivors were mainly based on pituitary hormone level measurement or on registration of life birth rates and did not include novel markers like Inhibin B.4 Inhibin B is produced by the Sertoli cells and is strongly correlated with sperm characteristics and fertility capacity in men and also correlates with spermatogenic status in testicular biopsies.5, 6 Inhibin B has a negative feedback mechanism with follicle-stimulating hormone (FSH), and it has been shown to be a good marker for testicular damage after chemotherapy.7, 8, 9 We evaluated the impact of childhood cranial radiotherapy on pituitary regulated gonadal function in a large single center cohort of male long-term survivors of childhood ALL including novel markers like Inhibin B. Out of a total cohort of 500 long-term survivors of childhood cancer, 99 registered adult male ALL survivors, diagnosed and treated in our hospital between 1973 and 1998, were identified. Seven survivors refused participation and three were lost to follow-up. All 89 survivors who participated in this cross-sectional study were in continuous complete remission and at least 5 years after completion of therapy. Median age at time of diagnosis was 5 years (range, 0–15 years) and median age at follow-up was 25 years (range, 18–40 years), with a median follow-up time of 19 years (range, 7–34 years). Data concerning treatment protocols, disease and patient characteristics were retrieved from the medical records. Twenty-five male survivors (28%) received cranial irradiation with a median cranial irradiation dosage of 25 Gy (range, 15–30 Gy) (Figure 1). None of the survivors had been treated with craniospinal irradiation. The survivors who received total body irradiation (TBI), testicular irradiation, mediastinal irradiation or orbital irradiation with or without cranial radiotherapy were evaluated separately (n=9). The patient with orbital irradiation and the patient with mediastinal irradiation were excluded from the main analysis of endocrine side-effects. A complete physical examination and serum hormone analysis from peripheral blood samples were taken at time of the visit at our outpatient clinic for childhood cancer survivors. Gonadal function was evaluated by Inhibin B, luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone and sex hormone binding globulin. In addition, thyroid-stimulating hormone (TSH), free T4 (FT4) and insulin-like growth factor (IGF-I) were also measured to determine the more extensive effect of cranial irradiation on the pituitary axis. Levels of IGF-I between the subgroups were compared with reference values by using SDS-scores (Z-scores), which express the difference between the measurement of an individual and the median value of the reference population.10 The thresholds for normal values of hormone levels are indicated in Table 1. All patients (n=7) treated with total body or testicular irradiation showed signs of testicular damage illustrated by high levels of LH, FSH and low levels of Inhibin B (Figure 2). Age at time of treatment did not correlate with levels of Inhibin B, FSH, LH or testosterone in the long-term survivors. No differences in Inhibin B, FSH, LH and testosterone levels were found between survivors treated with chemotherapy in combination with cranial irradiation (n=25) and survivors treated with chemotherapy alone (n=55) (Table 1). Median testicular volumes in both groups were not different (median, 20 ml; range, 10–25; P=0.54). In addition, no difference in pituitary or testicular hormone levels were found between patients treated with 25 Gy (n=21) and those treated with <25 Gy (n=4). TSH and FT4 levels were available in 38 survivors, 37 had FT4 levels within the normal range. TSH levels were normal in all except two survivors (one after chemotherapy only and one after chemotherapy combined with TBI) who had TSH levels of 0.36 and 0.37 mU/l, but normal FT4 levels. No difference in TSH and FT4 levels were found between the patients treated with or without cranial irradiation. The patient treated with orbital, mediastinal or testicular irradiation were excluded from this analysis. IGF-I was measured in 59 survivors of which 38 had received cranial irradiation. After cranial irradiation, men had significantly lower IGF-I levels (P=0.003), lower Z-scores (P=0.02), shorter stature (P=0.006) and a higher body mass index (P=0.04) than those treated with chemotherapy alone (Table 1). Height was significantly lower in the cranial irradiated and TBI group compared with the non-irradiated group. The survivors who had been treated with TBI had a significant higher BMI compared with the non-irradiated group (Table 1). This is the first study that evaluated the long-term effect of cranial irradiation in very long-term male survivors of childhood ALL on fertility, using novel gonadal markers. In contrast to studies performed by Siimes et al. and Quigley et al.,2, 11 in this single center cohort in which all survivors were examined by one and the same physician, we found no deleterious effect of cranial irradiation on gonadal function nor testicular volume thereby providing important information for adult survivors of childhood ALL treated in the past, as well for the small subgroup of ALL patients that still benefits from cranial irradiation in current treatment protocols. In addition, we studied the differential influence of cranial irradiation on the gonadal, the thyroid and growth hormone axes, which confirmed the earlier reported negative effect of cranial irradiation on growth hormone production, and underscores the fact that this damage appears to be selective.12 In addition, our data suggest that impairment of height in the cranial-irradiated group is mainly due to growth hormone deficiency, as illustrated by low IGF1 levels, and not by thyroid hormone depletion, although we realize that growth hormone function tests would be required to confirm these results in these individual survivors. These data show that, in contrast to the negative influence on the growth hormone axis, cranial radiotherapy as part of ALL treatment does not have a deleterious long-term effect on the hypothalamic–pituitary–gonadal axis or pituitary–thyroid axis. However, although currently, cranial irradiation is only administered in a small subset of ALL patients, it remains important to refer all teenage boys for semen preservation before they start gonadotoxic treatment as the course of the disease and the need for eventual stem cell transplantation cannot be predicted in an individual ALL patient at diagnosis. The authors declare no conflict of interest.