Impaired pubertal growth in acute lymphoblastic leukaemia.

The growth of 182 patients who were long term survivors of childhood acute lymphoblastic leukaemia was retrospectively analysed. All remained in first remission and were treated with either 1800 or 2400 cGy of cranial irradiation. None had been treated with either testicular or spinal irradiation. Ninety three (51 boys, 42 girls) were treated with 2400 cGy and 89 (42 boys, 47 girls) were treated with 1800 cGy cranial irradiation. All patients were treated with standard chemotherapy including intrathecal methotrexate in similar dose regimens in either group. Mean age (SD) at diagnosis in the group treated with 2400 cGy was 4.8 (2.6) years and mean age in the group treated with 1800 cGy was 6.5 (3.3) years. Mean height SD score at diagnosis in the 2400 cGy group was +0.29 and final height achieved was -0.63. Mean height SD score at the start of treatment in the group treated with 1800 cGy was +0.40 and mean final height was -0.53. There was a similar reduction in height SD score in both groups during the pubertal growth spurt. The decrement in height SD score was greater when treatment was administered at less than 7 years of age in either dose regimen, both in prepubertal and pubertal growth. However, the decrease in height SD score was found to be greater in girls than boys. There was a trend in both sexes for the onset of puberty to be at a younger age with a lower treatment dose of radiotherapy. However, in girls treated with the lower dose regimen there was a significant reduction in the mean age of onset of puberty which was 9.9 years. Our data suggest that girls treated at less than 7 years of age have a severe impairment of pubertal growth, which is probably a combination of the dual endocrinopathy of premature puberty and growth hormone insufficiency.     

Male gonadal toxicity

Cancer treatment with chemotherapy or radiotherapy causes gonadal toxicity in male patients. The endpoint of most concern for future reproductive options is the induction of prolonged azoospermia, which may or may not be reversible. The immediate effects of therapy and its reversibility are most readily observed in post‐pubertal patients, but the same antineoplastic regimens given to prepubertal males can induce permanent azoospermia. The probability of permanent azoospermia is related to the specific agents used and their doses. The most damaging are alkylating agents (particularly chlorambucil, procarbazine, cyclophosphamide, melphalan, and busulfan), cisplatin and radiation to the region of the testicles. Pediatr Blood Cancer 2009;53:261–266. © 2009 Wiley‐Liss, Inc.     

Gonadal dysfunction due to cis-platinum

Gonadal function was studied in 15 patients 12 pubertal or postpubertal, and three prepubertal, who had been treated during childhood for nonmetastatic osteosarcoma of the long bones by chemotherapy regimens that included cis-platinum and adriamycin. Of seven postpubertal female patients assessed (mean age at diagnosis 16.5 years), three were amenorrhoeic and showed evidence of ovarian damage with raised gonadotrophin levels and a low serum oestradiol concentration. One patient who had regular periods had a raised luteal-phase follicle-stimulating hormone (FSH) concentration suggestive of gonadal dysfunction. Severe oligospermia or reduced testicular volumes in the presence of raised gonadotrophin levels were observed in three of the five pubertal males (mean age at diagnosis 13.25 years). A reliable assessment of gonadal function was not possible in three male patients who remained prepubertal at the time of study. The median total dose of cis-platinum received by those patients with gonadal damage (median dose, 490 mg) was significantly higher than in those patients with normal gonadal function (median dose, 300 mg) (P = 0.01). In the boys the damage to the testes was primarily directed at the germinal epithelium. Leydig cell function was intact and the males progressed spontaneously through puberty. In the girls, unlike the boys, there was evidence of reversibility of gonadal damage with time. This is the first study to show gonadal dysfunction due to cis-platinum and adriamycin therapy in childhood.     

Evaluation of testicular function following long-term treatment for acute lymphoblastic leukemia

A study of reproductive function was carried out in 31 patients following long-term treatment of acute lymphoblastic leukemia (mean: 4 1/12 years); 17 prepubertal; nine pubertal, and five adults. Spontaneous clinical pubertal development was observed in 4 of 17 prepubertal patients. Serum testosterone response to hCG was normal or increased in the nine prepubertal patients studied. Intratesticular testosterone concentration was normal in 11 out of 12 patients. Only two of 14 prepubertal patients had a reduced number of germ cells. Normal progress of spermatogenesis was seen in six out of seven pubertal patients and only moderate hypospermatogenesis with focal hyalinosis was found in the five adults. Two of them had normal sperm count and one fathered two children. In six out of 14 prepubertal patients unexpected early signs of pubertal stimulation were found. Serum gonadotrophins response to LH-RH was normal in most patients. Testicular infiltration of blastic cells was found in four of 26 biopsies, but only one of 23 patients was without clinical signs of testicular relapse. Computerized axial tomography was normal in 10 out of 13 patients. Bone age was significantly below chronological age in four out of 15 patients. This study suggests that the gonad is moderately injured by long-term antileukemic therapy. In addition, microscopic testicular infiltration is not frequent in subjects without testicular enlargement.     

Neuroendocrine function in survivors of childhood acute lymphocytic leukemia and non-Hodgkins lymphoma: a study of pulsatile growth hormone and gonadotropin secretions

To assess the neuroendocrine function of long-term survivors of childhood hematologic malignancies, 10 patients who had acute lymphocytic leukemia and two who had non-Hodgkins lymphoma (NHL) (mean age 13.5 +/- 1 year) were studied, who were treated with similar chemotherapeutic regimens with or without 2,400 rads of prophylactic cranial irradiation. Pharmacologic growth hormone (GH) stimulation tests and three graded doses of the GH-releasing hormone (1-40-OH-GRH, 0.1, 0.3, and 1 microgram/kg) were administered. Venous sampling for GH and gonadotropin determinations was done at 20-min intervals for 24 h, and a new computerized pulse detection algorithm was used to analyze pulses. All the patients who had neuroendocrine abnormalities were in the cranially irradiated group. Two of the 12 patients were GH deficient, and had abnormal 24-h secretory profiles, blunted GH responses to pharmacologic stimuli, and minimal responses to the three doses of GRH. The pulsatile properties of luteinizing hormone (LH) were normal in 10 of the 12 nongonadally irradiated patients, irrespective of previous cranial irradiation and pubertal stage, when compared with available normative data.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hypothalamo-hypophyseal-testicular function in prepubertal boys with acute lymphoblastic leukemia following chemotherapy and testicular radiotherapy

Hypothalamo-hypophyseal-testicular function was studied in twenty-eight prepubertal boys with ALL in clinical and haematological remission. Eighteen were treated with combined systemic chemotherapy (24-36 months) and the other ten, who had testicular leukemic infiltrates, received chemotherapy (38-60 months) and testicular radiotherapy (2 000 rad). Plasma levels of LH and FSH were measured before and after stimulation with LHRH (100 micrograms i.v.) and plasma levels of testosterone before and after stimulation with hCG (1 500 IU/48 h/7 doses). In patients treated with chemotherapy alone, mean basal LH and FSH, mean responses to LHRH stimulation and mean testosterone levels after stimulation with hCG did not significantly differ from those of the controls. Five of these patients who had normal testosterone values after three doses of hCG had testosterone values below the normal range after seven doses. In patients treated with chemotherapy and testicular radiotherapy, mean basal FSH and mean responses to LHRH stimulation were significantly higher than those of the controls. Testosterone values after stimulation with hCG were low in three and very low in the other seven. In both groups of patients data from testicular biopsies were consistent with functional results. We conclude that chemotherapy causes slight testicular damage, but chemotherapy and testicular radiotherapy produce severe testicular damage in patients with testicular leukemic infiltrates.     

The endocrinological aspects of the therapy of testicular involvement in children with acute leukemias

Orchidectomy or testicular irradiation with 24 to 30 Gy are recommended for testicular involvement in boys with acute lymphoblastic leukemia. But, recommended radiation doses for the only occultly involved other testis differ, i.e. they range from 12 to 24 Gy. Low dose (12 or 15 Gy) "preventive" testicular irradiation was delivered to 5 of 14 patients; only one of these 5 experienced a further testicular relapse. According to our observation, in contrast to higher doses, the dose limitation allows spontaneous pubertal development including normal testosterone production and normal development of the masculine stature.     

Gonadal development and function after immature testicular tissue banking as part of high-risk gonadotoxic treatment

Background

Experimental fertility preservation programs have been started to safeguard the future fertility of prepubertal and pubertal males requiring high-risk gonadotoxic treatment protocols. However, long-term follow-up studies evaluating the effects on their gonadal development and function related to the testicular biopsy procedure are rather limited.

Design

This two-center follow-up study (between 2002 and 2020) evaluated the gonadal development and function of a cohort of 59 prepubertal and pubertal males who have been offered immature testicular tissue banking (TTB) prior to conventional high-risk chemo- and/or radiotherapy (HR-C/R) or conditioning therapy before hematopoietic stem cell transplantation (CT-HSCT). The aim is to investigate the long-term impact of the testicular biopsy procedure and the high-risk gonadotoxic treatment. Testicular growth and the reproductive hormones luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone (T), and inhibin B (INHB) were analyzed after treatment completion, and compared between males accepting TTB and those refusing TTB (control) as well as between HR-C/R and CT-HSCT treatment protocols.

Results

Of the 59 prepubertal and pubertal males included, 25 were treated by HR-C/R and 34 required CT-HSCT. TTB was accepted for 39 males and refused for 20 males. Most patients were prepubertal at diagnosis (85%), at TTB (79%), and at treatment completion (76%), and pubertal or postpubertal at their last follow-up visit (66%). After 5.0 (1.0–13.0) years post treatment, most patients show normal testicular volumes (83%) and normal LH (89%), FSH (87%), T (87%), and INHB (79%) serum levels. The testicular biopsy procedure did not have an effect on testicular growth, LH, FSH, T, and INHB. Significantly more small postpubertal testicular volumes (p = .0278) and low INHB serum levels (p = .0130) were recorded after CT-HSCT, especially after myeloablative conditioning.

Conclusion

The clinical follow-up data demonstrate no effect related to the biopsy procedure, but a substantial risk for impaired gonadal development after high-risk gonadotoxic treatment, in particular myeloablative CT-HSCT. Longer follow-up studies with a larger study population are needed to confirm these preliminary findings.     

Management of Growth Hormone Deficiency Through Puberty

ABSTRACT. As a model of the growth hormone (GH) dependence of growth in prepuberty and puberty, the growth of 182 children (93 boys, 89 girls) who survived in first remission for treatment of acute lymphoblastic leukaemia was examined. Chemotherapy regimens, including intrathecal methotrexate, were similar in all patients, but CNS treatment differed, in that one group received 2400 cGy cranial irradiation, while the other received 1800 cGy. There was a significant decrease in height SDS during prepuberty, which was equivalent in both sexes, whereas there was a much greater decrease in pubertal growth in girls than in boys. Girls treated with the lower dose regimen of cranial irradiation had their onset of pubertal maturation significantly advanced, to a mean of 9.9 years ( p < 0.001). Previous studies have indicated that the duration of puberty is shortened by GH treatment in patients with idiopathic multiple pituitary hormone deficiency or isolated GH deficiency (GHD). To determine whether an increase in the dose of GH administered during the adolescent growth spurt would improve final height, a prospective randomized trial was performed in 32 children (25 boys, 7 girls) with isolated GHD treated with a GH dose regimen of 15 IU/m²/week as daily s.c. injections. At the onset of the pubertal growth spurt, the patients were randomized either to an unchanged dose or to 30 IU/m²/week. There was no significant change in height velocity with the doubled dose of GH, but there was a trend in the advancement of pubertal maturation which was considered to be dose related. It is suggested that these findings are of relevance to the treatment of GHD in puberty, especially in girls with early or precocious puberty occurring as a consequence of low-dose cranial irradiation. It is concluded that optimum final heights may not be achieved in these patients without the therapeutic manipulation of the onset and/or duration of puberty.     

Hypothalamo-Hypophyseal-Testicular Function in Prepubertal Boys with Acute Lymphoblastic Leukemia following Chemotherapy and Testicular Radiotherapy

ABSTRACT. Hypothalamo-hypophyseal-testicular function was studied in twenty-eight prepubertal boys with ALL in clinical and haematological remission. Eighteen were treated with combined systemic chemotherapy (24–36 months) and the other ten, who had testicular leukemic infiltrates, received chemotherapy (38–60 months) and testicular radiotherapy (2000 rad). Plasma levels of LH and FSH were measured before and after stimulation with LHRH (100 μg i.v.) and plasma levels of testosterone before and after stimulation with hCG (1500 IU/48 h/7 doses). In patients treated with chemotherapy alone, mean basal LH and FSH, mean responses to LHRH stimulation and mean testosterone levels after stimulation with hCG did not significantly differ from those of the controls. Five of these patients who had normal testosterone values after three doses of hCG had testosterone values below the normal range after seven doses. In patients treated with chemotherapy and testicular radiotherapy, mean basal FSH and mean responses to LHRH stimulation were significantly higher than those of the controls. Testosterone values after stimulation with hCG were low in three and very low in the other seven. In both groups of patients data from testicular biopsies were consistent with functional results. We conclude that chemotherapy causes slight testicular damage, but chemotherapy and testicular radiotherapy produce severe testicular damage in patients with testicular leukemic infiltrates.     

Initiation of spermatogenesis during chemotherapy for leukemia

Although the information is sparse, cytotoxic drugs have been suspected to cause serious damage to the immature testis, especially when the treatment is given during puberty. In a prospective, longitudinal study, we have investigated the effect of combination chemotherapy on the maturation of the germinative epithelium in 22 testicular biopsy specimens from 10 pubertal boys with acute lymphoblastic leukemia. Five of the boys developed complete spermatogenesis including spermatozoa during the treatment, the biopsy specimens of two patients showed partial maturation of the seminiferous epithelium, while the germ cells of two boys remained immature. In one patient, who received large doses of cyclophosphamide and cytosine arabinoside, all germ cells disappeared during the therapy. We conclude that a significant proportion of boys with acute lymphoblastic leukemia may develop potential fertility even while on treatment with cytotoxic drugs during puberty.     

Pubertal growth in chronic renal failure

We evaluated the growth records of 15 boys and 14 girls who developed end-stage renal failure before or during puberty and who were regularly followed from the onset to the end of their pubertal growth spurt. Height data were smoothed by using the kernel estimation method. Mean values for age, height, and height velocity at defined points of the pubertal growth period were compared with those of normal children entering puberty both at an average and late age. The start of the pubertal growth spurt was delayed by 2.5 y in both sexes. Its duration and intensity were significantly reduced. Mean pubertal height gain was 17.3 cm in boys and 13.9 cm in girls, i.e. 58 and 48% of that observed in the late maturing control group. Mean height at the onset of the pubertal spurt in the patients was the same as that in the late maturing healthy girls and 1.0 SD below that of corresponding boys. During the pubertal growth spurt, mean height declined to -2.9 SD in boys and -2.3 SD in girls. Although skeletal maturation was increasingly retarded, we did not observe accelerated growth velocity during late puberty. Our data indicate that most patients reaching end-stage renal failure before or during puberty irreversibly lose growth potential during this period. Renal transplantation did not consistently improve pubertal growth.     

Initiation of Spermatogenesis during Chemotherapy for Leukemia

ABSTRACT. Although the information is sparse, cytotoxic drugs have been suspected to cause serious damage to the immature testis, especially when the treatment is given during puberty. In a prospective, longitudinal study, we have investigated the effect of combination chemotherapy on the maturation of the germinative epithelium in 22 testicular biopsy specimens from 10 pubertal boys with acute lymphoblastic leukemia. Five of the boys developed complete spermatogenesis including spermatozoa during the treatment, the biopsy specimens of two patients showed partial maturation of the seminiferous epithelium, while the germ cells of two boys remained immature. In one patient, who received large doses of cyclophosphamide and cytosine arabinoside, all germ cells disappeared during the therapy. We conclude that a significant proportion of boys with acute lymphoblastic leukemia may develop potential fertility even while on treatment with cytotoxic drugs during puberty.     

Pubertal development in girls with sexual precocity after discontinuation of treatment with cyproterone acetate

Twenty-four girls with sexual precocity who had been treated with cyproterone acetate were followed for periods from 1 to 8 1/2 years after the discontinuation of therapy. It was found that their further pubertal development and the resumption or appearance of menstruation followed a natural course within the wide limits of physiological variability. It is concluded that puberty resumes its natural course following cessation of treatment with cyproterone acetate, and it is assumed that the reproductive ability of these patients will not be affected.     

Correlation of gonadal function with histology of testicular biopsies at treatment discontinuation in childhood acute leukemia

Testicular open-wedge biopsy was performed in 35 children in complete remission from acute lymphoblastic leukemia without clinical signs of leukemic testicular infiltration at the time of treatment discontinuation. Histological investigation showed thickening of the tunica propria of the seminiferous tubules in 13 of 35 patients. In 5 of 35 patients, the tubular fertility index was markedly reduced; in 5 of 6 pubertal patients, decreased spermatogenesis or aplasia of germinal epithelium was observed. Histologic damage was found mainly in the germinal cells both in patients treated with cytosine arabinoside and cyclophosphamide and in those treated with antiblastic drugs not considered damaging to the gonads. The extent of impairment was independent of age at start of treatment. On the other hand, endocrinological investigation carried out at the crucial moment of treatment suspension showed normal hypothalamic-hypophyseal-gonadal function as well as normal anthropometric data, bone age, and pubertal stage in the majority of patients. Testicular leukemia was found in only one patient (2.8%) whereas three children with negative testicular biopsies had testicular relapses within 7 months. Therefore, in view of the limits of light microscopy in diagnosing leukemic infiltration at treatment discontinuation, we propose the use of more sophisticated techniques, possibly within 6 months of suspension of therapy.     

Fertility in male patients treated with neoadjuvant chemotherapy for osteosarcoma

PURPOSE: To evaluate fertility in male patients with osteosarcoma after chemotherapy including high doses of alkylating agents. PATIENTS AND METHODS: Postchemotherapy fertility was evaluated in 96 male patients who received chemotherapy at the authors' institution from 1976 to 1996 for localized bone osteosarcoma of the extremities. Four drugs were administrated (doxorubicin, cisplatin, methotrexate, ifosfamide) at different doses according to six different protocols. Eleven patients were prepubertal and 85 were postpubertal at the time of chemotherapy. The median age of these patients at the time of chemotherapy was 17 years (range 10-42), the median age at the time of the interview was 27 years (range 19-53), and the median follow-up from the end of chemotherapy was 9 years (range 4-17). RESULTS: Of the 96 patients, 26 underwent sperm analysis and 20 showed oligo- or azoospermia. Patients who received high-dose ifosfamide showed a higher incidence of azoospermia. Six patients were normospermic and received no ifosfamide or lower doses of ifosfamide. Eight patients fathered a total of 12 children. No birth defects or congenital anomalies were observed in their offspring. CONCLUSIONS: The rate of sterility was related to ifosfamide dosage. It appears that pubertal maturation is not affected by chemotherapy. No congenital malformations were seen in the children of the few patients who fathered children.     

Survival and endocrine outcome after testicular relapse in acute lymphoblastic leukaemia

Survival and endocrine status in a cohort of boys with acute lymphoblastic leukaemia (ALL) who started treatment between 1972 and 1987 and subsequently developed a testicular relapse were analysed. During this period there was a significant improvement in the overall event free survival for boys, but no significant decrease in the testicular relapse rate. Thirty three boys had an apparently isolated testicular relapse, whereas 21 boys had a combined relapse. The event free survival for boys with an isolated testicular relapse was 59% at six years (95% confidence interval (CI) 42 to 74%). The event free survival for the 16 patients with a combined relapse who received a second course of treatment was 32% (95% CI 17 to 60%). Those patients receiving adequate second line treatment for an isolated testicular relapse whose first remission was longer than or equal to two years had an event free survival of 82% (95% CI 63 to 93%) at six years. No boy relapsing within two years from diagnosis has survived. Endocrine late effects are significant, with 82% of the boys requiring hormonal treatment at some stage for induction of puberty or continuing pubertal maturation, or both. It is concluded that, despite the increasing intensity of initial treatment for ALL, isolated testicular relapse is treatable by conventional means in most patients. Careful endocrine follow up of these patients is essential as most will require hormone replacement treatment.     

Prenatal developmental toxicity studies of 1,1,1-trichloro-2,2-bis(4-methoxyphenyl)ethane (methoxychlor) in rats and rabbits

ABSTRACT  The studies were conducted in rats and rabbits to elucidate the potential developmental toxicity of methoxychlor in general accordance with the improved Japanese MAFF guidelines (12-Nousan-No. 8147, 2–1–18, 2000). Methoxychlor dissolved in corn oil was administered orally to pregnant Jcl:SD rats on gestational days (GD) 6–19 at a dose of 0,1,50, or 150 mg/kg/day and to pregnant Kbl:JW rabbits on GD 6–27 at a dose of 0,1, 15, or 45 mg/kg/day. Maternal animals were killed on the day after the last day of administration for morphological examination of their fetuses with special attention to the reproductive organs.
Adverse effects on maternal animals were found at 2 higher doses in both species; i.e. vaginal red discharge (rat only), abortion or premature delivery (rabbit only), and significantly decreased body weight gains and food consumption. While the numbers of corpora lutea and implants were comparable between the control and treated groups in both species, slight increase in the percent resorptions and fetal deaths in rats and a reduction of fetal weights in both species were observed at the highest dose. Anogenital distance and testicular histology were not affected in rats. Although fetal examination revealed significant increase in the incidences of 27 presacral vertebrae at 2 higher doses in rabbits, there was no treatment-related increase in the incidence of malformations in rats and rabbits.
Based on these results, it is concluded that methoxychlor causes no malformations, including male reproductive organ abnormalities, in either rats or rabbits, although it results in decreased fetal weights and an increased incidence of fetal resorptions or skeletal variations at maternally toxic doses.     

Survival and endocrine outome after testicular relapse in acute lymphoblastic leukaemia

Accepted 4 November 1996
Survival and endocrine status in a cohort of boys with acute lymphoblastic leukaemia (ALL) who started treatment between 1972and 1987 and subsequently developed a testicular relapse were analysed. During this period there was a significant improvement in the overall event free survival for boys, but no significant decrease in the testicular relapse rate. Thirty three boys had an apparently isolated testicular relapse, whereas 21 boys had a combined relapse. The event free survival for boys with an isolated testicular relapse was 59% at six years (95% confidence interval (CI) 42 to 74%). The event free survival for the 16 patients with a combined relapse who received a second course of treatment was 32% (95% CI 17 to 60%). Those patients receiving adequate second line treatment for an isolated testicular relapse whose first remission was longer than or equal to two years had an event free survival of 82% (95% CI 63 to 93%) at six years. No boy relapsing within two years from diagnosis has survived. Endocrine late effects are significant, with 82% of the boys requiring hormonal treatment at some stage for induction of puberty or continuing pubertal maturation, or both. It is concluded that, despite the increasing intensity of initial treatment for ALL, isolated testicular relapse is treatable by conventional means in most patients. Careful endocrine follow up of these patients is essential as most will require hormone replacement treatment.

     

Testicular function after OPA/COMP chemotherapy without procarbazine in boys with Hodgkin's disease. Results in 25 patients of the DAL-HD-85 study

Gonadal function was evaluated in 25 boys treated for Hodgkin's disease according to the DAL-HD-85 protocol with OPA- or OPA/COMP-chemotherapy (vincristine-prednisone-adriamycine/cyclophosphamide-vincristine-m ethotrexate- prednisone). All boys were in first continuous complete remission for 6 to 45 months at chronological ages varying from 14.0 to 18.9 years. Testosterone, basal and GnRH-stimulated LH- and FSH-levels were measured. Gonadal function was normal in 16 patients treated with 2 cycles of OPA-chemotherapy in Hodgkin stages I-IIA. 9 patients were treated with 2 OPA- and 2 or 4 COMP-cycles of chemotherapy and had received mean cyclophosphamide doses ranging from 2004 to 3722 mg/m2. Again, no major testicular damage was noted, though some patients had increased stimulated LH-levels possibly indicating compensated Leydig cell-insufficiency. Our results demonstrate, that testicular function is not severely affected when patients are treated for Hodgkin's disease without procarbazine even if cyclophosphamide is given in cumulative doses below 3800 mg/m2. The previously documented severe testicular damage in boys treated according to the DAL-studies HD-78 and HD-82 is thus a result of the gonadotoxic action of procarbazine.