Normal or Early Development of Puberty despite Gonadal Damage in Children Treated for Acute Lymphoblastic Leukemia

Abstract

To determine the timing of pubertal development and the frequency of gonadal dysfunction in children who survive acute lymphoblastic leukemia, we assessed pubertal status and the plasma levels of sex steroids, gonadotropin, and inhibin in 45 children (20 girls and 25 boys) who had received combination chemotherapy along with 24 Gy of irradiation to the cranium (modified LSA2L2 protocol). We also reexamined testicular biopsy specimens, obtained at the time of the cessation of chemotherapy, for the presence of germ cells. Germ-cell damage, indicated by marked elevations in the plasma level of follicle-stimulating hormone (P less than 0.001 for the comparison with normal children), was evident in both sexes and was confirmed in the boys by the absence of germ cells in the testicular biopsy specimens and by the small size of the testes for pubic-hair stage. Only 44 percent of the pubertal girls had measurable plasma inhibin levels, as compared with more than 93 percent of normal pubertal girls. Although plasma sex-steroid levels were normal, the secretion of luteinizing hormone in response to stimulation with gonadotropin-releasing hormone was elevated in the pubertal children (P less than 0.01 for the comparison with normal controls)--a finding that suggests compensation for decreased gonadal function. Despite clear evidence of gonadal damage, girls had early menarche at a mean age (+/- SD) of 11.95 +/- 0.91 years, as compared with the Australian standard of 12.98 +/- 1.11 years (P less than 0.01). Thus, in girls, puberty was early despite primary gonadal damage. Thirteen of 23 boys reached puberty at a mean age of 12.36 +/- 0.73 years. We conclude that treatment for acute lymphoblastic leukemia may lead to primary gonadal damage in both sexes, regardless of the age at treatment, but that the secondary characteristics of puberty develop at a normal age or, in girls, relatively early.

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

“…The spinal component of craniospinal irradiation seems to be the major risk factor, but cyclophosphamide may also be contributory. [12][13][14][15] Ten percent of girls have sustained asymptomatic ovarian damage after conventional chemotherapy for acute lymphoblastic leukemia (ALL) and are likely to develop premature menopause. 12 In long-term survivors of childhood ALL, irradiation of the ovarian zone was found to be the main gonadotoxic treatment.…”

“…13 However, a high prevalence of primary gonadal damage followed high doses of cyclophosphamide, cytosine-arabinoside and lomustine. 14 A high incidence of ovarian failure with MOPP and MVVP regimens for Hodgkin's disease, [5][6][7] but not with the ABVD regimen has been reported. 16,17 Amenorrhea is often transient in young patients and persistent in older patients after chemotherapy for Hodgkin's disease.…”

Low incidence of second neoplasms among children diagnosed with acute lymphoblastic leukemia after 1983

“…2 With 2500 to 3000 children diagnosed with ALL annually, we expect approximately 2000 long-term survivors of childhood ALL each year. Long-term sequelae of treatment, such as impaired intellectual and psychomotor functioning, 3 neuroendocrine abnormalities, 4 impaired reproductive capacity, [5][6][7][8] cardiotoxicity, 9 and second malignant neoplasms [10][11][12][13][14][15][16][17] are being reported with increased frequency in the growing cohort of survivors.…”

Radiation and Hypothalamic Pituitary Function

“…There is a high incidence of early puberty but predominantly among girls (29,30). The number of boys entering puberty early is no greater than that anticipated in a In cross-sectional endocrine and blood flow studies performed before irradiation, 6 months, one year and more than five years after irradiation regional hypothalamic blood flow was reduced after cranial irradiation but there was no significant difference in the hypothalamic/occipital blood flow ratio between six months and more than five years after irradiation.…”