Colin G Beardwell

Radiation-induced hypopituitarism is dose-dependent

Radiation‐induced hypopituitarism has been studied prospectively for up to 12 years in 251 adult patients treated for pituitary disease with external radiotherapy, ranging in dose from 20 Gy in eight fractions over 11 days to 45 Gy in 15 fractions over 21 days. Ten further patients were studied 2–4 years after whole‐body irradiation for haematological malignancies using 12 Gy in six fractions over 3 days and seven patients were studied 3–11 years after whole‐brain radiotherapy for a primary brain tumour (30 Gy, eight fractions, 11 days). Five years after treatment, patients who received 20 Gy had an incidence of TSH deficiency of 9|X% and in patients treated with 35–37 Gy, 40 Gy and 42–45 Gy, the incidence of TSH deficiency (22, 35 and 52% respectively) increased significantly (P < 0.001) with increasing dose. A similar relationship was observed for both ACTH and gonadotrophin deficiencies when the 20 Gy group was compared to patients treated with 35–45 Gy (P < 0.01 and P < 0.05 respectively). Growth hormone deficiency was universal by 5 years over the dose range 35–45 Gy. In seven patients who were treated with 30 Gy in eight fractions over 11 days, deficiencies were observed at a similar frequency to the 40 Gy group (15 fractions, 21 days). No evidence of pituitary dysfunction was detected in the ten patients who received 12 Gy (six fractions, 3 days). Both total radiation dose and fractionation schedule may determine the incidence of pituitary hormone deficiencies. The dose below which deficiencies do not occur is probably irrelevant to therapeutic irradiation of pituitary and other intracranial neoplasms.

The severity of growth hormone deficiency in adults with pituitary disease is related to the degree of hypopituitarism

OBJECTIVE A number of studies of the effect of GH replacement therapy in adult patients with GH deficlency have been published, but the definition of GH deficiency has varied considerably. In order to define severe GH deficiency more critically we have determined GH status in the context of gonadotrophin, ACTH and TSH secretion in adult patients with pituitary disease.

The effect of combination chemotherapy on ovarian function in women treated for hodgkin's disease

Ovarian function has been studied in 44 adult females who previously received quadruple chemotherapy (MVPP) for Hodgkins disease. The median age at treatment was 23 years, and the length of time between completion of treatment and study ranged from 6 months to 10 years (median, 30 months). Seventeen women maintained regular menses, 10 developed oligomenorrhea, and 17 developed amenorrhea. At treatment, the 17 women who subsequently developed amenorrhea were significantly older (median, 30 years) than those who maintained regular menses (median, 22 years) or developed oligomenorrhea (median, 23 years). All patients older than 36 years at the start of treatment stopped menstruating during chemotherapy. The cause of the menstrual disturbance in these patients was chemotherapy‐induced ovarian damage characterized by high serum gonadotrophin and low serum estradiol concentrations. After completion of treatment there were 17 pregnancies, which resulted in 9 normal infants, 3 terminations, and 4 spontaneous abortions. Nine patients took the combination oral contraceptive pill throughout chemotherapy; however, subsequently 4 developed amenorrhea and 3 oligomenorrhea, suggesting that these patients had not been protected from chemotherapy‐induced ovarian damage. Estrogen replacement therapy was of definite benefit in the symptomatic patients with premature ovarian failure.

The effects of Hodgkin's disease and combination chemotherapy on gonadal function in the adult male

The effects of Hodgkins disease and quadruple chemotherapy on gonadal function have been investigated in 93 male patients with Hodgkins disease. Nineteen men were studied before they received chemotherapy. Fifteen of the 19 had a sperm count of 20 million/ml or greater and motility was at least 40% in all 15. In the remaining 74 men, gonadal function was studied after completion of chemotherapy (6 months‐8 years). Semen was obtained from 49 men who had received six or more courses of MVPP. Forty‐two were azoospermic and five of the remaining seven had a sperm count below 1 million/ml. Decreased libido and sexual activity was common during treatment but in the majority of men these returned to normal after completion of chemotherapy. The median FSH and LH levels and the median increments in serum FSH and LH levels after LHRH administration were significantly elevated compared with an age‐matched control group. The mean testosterone level of the patients was significantly lower than in controls suggesting Leydig cell damage but androgen replacement therapy was not indicated in any individual patient. No evidence of hyperprolactinaemia as a result of MVPP therapy was found. These results suggest that sperm storage before chemotherapy represents the main possibility for these patients to have children after completing chemotherapy. Before starting chemotherapy, advice should be given to these patients concerning possible changes in sexual behavior during treatment and the very high incidence of permanent infertility following treatment.

THE EFFECT OF VARYING DOSES OF CEREBRAL IRRADIATION ON GROWTH HORMONE PRODUCTION IN CHILDHOOD

The radiation dose, delivered to the hypothalamic‐pituitary region, has been calculated in thirty‐nine children irradiated for brain tumours and in seventeen children who had received prophylactic cranial irradiation for acute leukaemia. All subjects had an insulin tolerance test at least 2 years after their radiotherapy. There is a significant inverse correlation between radiation dose and peak GH response. Thirty‐seven of the fifty‐six patients showed an impaired GH response and thirty‐six of these received more than 2900 rads. Only five patients who received such a dose showed normal GH responses and four of these were aged over 13 years when treated.

Normal growth despite abnormalities of growthhormone secretion in children treated for acute leukemia

We have studied the relationship between abnormalities of the growth hormone-somatomedin axis and growth in 26 children previously treated for acute lymphatic leukemia. Each child had previously received cranial irradiation, was in complete clinical and hematologic remission, and off all drugs. The mean standing height SDS of the 26 children was significantly less than normal. There was no significant difference between the mean standing height SDS, height velocity SDS, somatomedin activities, and degree of bone age retardation between the 17 children who received the higher dose of cranial irradiation (Group 1) and the nine who had the lower dose of cranial irradiation (Group II). Furthermore, there was no significant reduction in mean height velocity SDS, somatomedin activity, or bone age in either group when compared to normal age-matched controls. The peak GH responses to both insulin hypoglycemia and an arginine test were significantly lowered in Groups I and II when compared to a control group of children. We conclude that only a minority of children, who previously received cranial irradiation for ALL were clinically GH deficient and, therefore, likely to benefit from GH therapy despite the finding that the majority of these children had reduced GH responses to pharmacologic stimuli.

Residual disabilities in children treated for intracranial space‐occupying lesions

A retrospective study of 30 long‐term survivors of cranial or craniospinal irradiation for intracranial space‐occupying lesions has demonstrated physical and mental handicaps in the majority. This is most severe in those cases treated before the age of 11 years, and is not confined to those children having craniospinal or whole‐brain irradiation. The mental handicap also appears to be progressive, but cannot be easily examined in this retrospective study.

Ovarian failure following abdominal irradiation in childhood.

Ovarian function was studied in 18 female patients treated for abdominal tumours during childhood. All received abdominal radiotherapy as part of their treatment and were studied between 1 and 26 years after irradiation. The serum gonadotrophins and oestradiol levels were consistent with ovarian failure in each case but there was a disproportionate elevation in serum follicle stimulating hormone (FSH) when compared to serum luteinizing hormone (LH) in 16. In 2 patients, the radiotherapeutic field extended downwards only as far as the sacral promontory. However, these 2 girls show similar evidence of ovarian failure to that in the other 16.

Growth hormone deficiency after treatment of acute leukaemia in children.

Growth hormone (GH) secretion was studied in 15 children at various times after treatment for acute lymphatic leukaemia. Impaired GH responses both to hypoglycaemia and to Bovril were found in 4 children. 13 of the children had been given prophylactic cranial irradiation of either 2500 rads in 10 fractions or 2400 rads in 20 fractions. The reduction in GH responses in those given the former dose was highly significant compared with the reduction in those given the latter dose. However, other differences between the two groups included the length of time since cranial irradiation and the chemotherapy used. The main cause of the GH deficiency is not yet clear, but we conclude that it may occur in children treated successfully for acute lymphatic leukaemia.

Gonadal function after combination chemotherapy for Hodgkin's disease in childhood.

The effect of quadruple chemotherapy (mustine, vincristine, procarbazine, and prednisolone) on gonadal function was investigated in 15 males and 2 females treated for Hodgkins disease during childhood. The 2 females have regular menstrual cycles with evidence of ovulation in one. Twelve of the males have shown normal progression of pubertal development since completing their treatment. Nine out of 10 late pubertal or adult subjects had small testes but only one developed gynaecomastia. All 4 prepubertal subjects had normal basal and peak gonadotrophin responses to luteinising hormone-releasing hormone. Nine of the 12 subjects studied during puberty or adulthood had either an increased basal serum follicle-stimulating hormone (FSH) level or an exaggerated FSH response to luteinising hormone-releasing hormone. Each of the 6 males who provided semen for analysis was azoospermic after an interval of between 2.4 and 8 (mean 5.3) years after completion of treatment. We conclude that severe testicular damage is common after treatment with mustine, vincristine, procarbazine, and prednisolone in childhood. The germinal epithelium is particularly vulnerable and the resultant azoospermia is likely to be irreversible. The Leydig cells are less susceptible to cytotoxic-induced damage. Pubertal development is normal and there is no indication for androgen replacement therapy.