Stephen M Shalet

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.

Abdominal irradiation in childhood; the potential for pregnancy

Objective To investigate the impact of premature ovarian failure due to whole abdominal radiotherapy (DXT) in childhood on uterine physical characteristics and blood flow and measuring the uterine response to exogenous sex steroid replacement

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.

High incidence of obesity in young adults after treatment of acute lymphoblastic leukemia in childhood

To determine whether obesity complicated the treatment of childhood acute lymphoblastic leukemia, we studied the body mass index (BMI) of 63 female when and 51 male patients from the time of diagnosis of acute lymphoblastic leukemia to the time when final height was attained. The BMI z score was calculated for each patient at diagnosis, at end of treatment, and at attainment of final height. Obesity at attainment of final height was defined as a BMI greater than the 85th percentile of the normal reference population. At final height 23 of 51 male (45%) and 30 of 63 female patients (47%) were obese. Girls became obese between diagnosis and the end of chemotherapy (p = 0.02), after which they had no further increase, indicating that chemotherapy may have played a role in their obesity. Boys had a progressive and gradual increase in BMI z score through to attainment of final height. Obesity did not appear to be associated with growth hormone insufficiency, disproportionate growth, or abnormal timing of puberty. We conclude that approximately half the survivors of leukemia in childhood become obese young adults. Many of those treated with the more recent regimens studied are still only in their mid or preteen years and should be advised regarding a more active lifestyle and a healthy diet in an attempt to reduce the incidence of obesity.

Ovarian failure following abdominal irradiation in childhood: Natural history and prognosis

Ovarian function has been reviewed sequentially since 1975 in 53 patients treated in childhood between 1942 and 1985 for an intraabdominal tumour with surgery and external abdominal radiotherapy (XRT). Of 38 patients who received whole abdominal XRT (20-30 Gy), 27 failed to undergo or complete pubertal development (pubertal failure) and a premature menopause (median age 23.5 years) occurred in a further ten. Of 15 patients who received flank XRT (20-30 Gy), ovarian function (median age at last assessment 15.2 years) was normal in all but one in whom pubertal failure occurred. In only one patient, who developed pubertal failure after whole abdominal XRT and required sex steroid replacement therapy (HRT) to achieve normal secondary sexual characteristics, has there been evidence of reversibility of ovarian function with a documented conception at the age of 22.7 years. Five patients who developed pubertal failure required bilateral augmentation mammoplasties despite sex steroid replacement therapy. Four patients have had documented conceptions, all received whole abdominal XRT (20-26.5 Gy) and subsequently developed a premature menopause. There have been no live births, with all miscarriages occurring in the second trimester. The outlook for normal ovarian function following whole abdominal XRT is poor, flank XRT introduced intermittently from 1972, has resulted in less pubertal failure but the possibility of a premature menopause may with time become a reality.

Effect of spinal irradiation on growth.

Standing height, sitting height, and leg length were measured in 79 patients (aged 16-30 years), who had been given craniospinal irradiation (n = 37) or cranial irradiation (n = 42) in childhood for a brain tumour and had completed their growth. Their measurements were compared with established standards for sitting height and leg length in British children (aged 16-18 years). To examine the effects of spinal irradiation on spinal growth independent of growth hormone deficiency we analysed the leg length (LL) minus sitting height (SH) standard deviation score (SDS) and used the cranial group as controls. There was an overall significant difference between the median craniospinal LL-SH SDS (1.98) and the median cranial LL-SH SDS (0.545). Within the craniospinal group there was a significant correlation with age at treatment, but there was no such correlation for the cranial group. After splitting age at treatment into three groups (0 less than 5, 5 less than 10, and 10-15 years) there was a significant difference between the LL-SH SDS of the craniospinal and cranial groups for each of the age ranges. In conclusion, spinal irradiation has a profound effect on spinal growth and the younger the child is when given irradiation the greater the subsequent skeletal disproportion. Our most conservative figures indicate that the eventual loss in height is 9 cm when irradiation is given at 1 year, 7 cm when given at 5 years, and 5.5 cm when given at 10 years.

Endocrine deficit after fractionated total body irradiation.

Endocrine function was assessed in 31 children (17 boys) after fractionated total body irradiation used in the preparative regimen for bone marrow transplantation. Endocrine dysfunction was present in 25 children. Fifteen of 29 had growth hormone insufficiency 0.9-4.9 years after total body irradiation, yet only three of the 15 had received previous cranial irradiation. Five of 30 had thyroid dysfunction: two with a low thyroxine and raised thyroid stimulating hormone (TSH) concentration and three with a raised TSH and normal thyroxine concentration. Thus the incidence of thyroid dysfunction (16%) is much lower than that reported after single fraction total body irradiation (39-59%). In only two children were abnormalities of the hypothalamic-pituitary-adrenal axis demonstrated. The majority of pubertal children assessed (n = 15) showed evidence of gonadal damage. All the pubertal girls (n = 5) had ovarian failure, although there was evidence of recovery of ovarian function in one girl. All seven boys in late puberty showed evidence of damage to the germinal epithelium, and two of three in early puberty had raised follicle stimulating hormone concentrations. Despite the use of a fractionated total body irradiation regimen, endocrine morbidity is substantial and children undergoing such procedures will require long term endocrine review and management.