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The effects of Hodgkin's disease and quadruple chemotherapy on gonadal function have been investigated in 92 male patients with Hodgkin's 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 of 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 quadruple chemotherapy (mustine, vincristine, procarbazine, and prednisolone) on gonadal function was investigated in 15 males and 2 females treated for Hodgkin's 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.

Ovarian function has been studied in 44 adult females who previously received quadruple chemotherapy (MVPP) for Hodgkin's 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.

Growth and growth hormone (GH) secretion were studied in 14 children with brain tumours before radiation and chemotherapy and at various time intervals afterwards. The peak GH response to hypoglycaemia was normal in all patients before radiation. In 6 patients the peak GH response was impaired 1 year after radiation, and in a seventh it was normal at 1 year but impaired 2 years after radiation. In 12 of 13 patients the growth velocity during the first year of chemotherapy was below the 3rd centile, although none of these had an initial standing height below the 3rd centile. Thus it appears that poor growth in such children occurs irrespective of whether radiation-induced GH deficiency develops. The cause of this impaired growth is unknown.

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.

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 16.18 female patients who had received treatment for abdominal lesions in childhood were studied for ovarian function. All had had abdominal surgery and irradiation and 7 had chemotherapy. The dose of irradiation ranged from 2000 to 3000 rad over 25-44 days. Serum follicle stimulating hormone (FSH) and luteinizing hormone (LH) levels were measured by double antibody radioimmunoassay using Medical Research Council standard 69/104, and serum estradiol was measured by radioimmunoassay. 12 of the patients were 13-years-old or over and none was menstruating. The basal serum FSH and LH levels were elevated in all 12. In the 6 patients below age 13, the serum FSH concentration was raised, but the serum LH was elevated in only 3 of the above. The serum LH levels were significantly higher (p less than .02) in the patients aged over 11 years or less. The probable cause of ovarian failure in these patients is abdominal irradiation. A similar hormonal pattern to the other 16 cases was seen in the 2 patients who had received abdominal irradiation with a field extending only as far as the sacral promontory.

We have assessed testicular function with luteinising hormone-releasing hormone (LH-RH) and human chorionic gonadotrophin stimulation tests in 44 boys previously treated with, or currently receiving, chemotherapy for acute lymphoblastic leukaemia (ALL). At the same time a testicular biopsy was performed in each boy and the morphology was studied. Histologically the chemotherapy appeared to damage the tubular system in particular, and the degree of damage was assessed by estimating the tubular fertility (TF) index which is defined as the percentage of seminiferous tubules containing identifiable spermatogonia. The mean TF index in all 44 biopsies was 51%. Only 2 of the 44 boys showed an absent or blunted testosterone response to human chorionic gonadotrophin. This suggests that Leydig cell function is rarely impaired by such chemotherapy and that most of the boys, similarly treat for ALL, will undergo normal pubertal maturation. Apart from the basal luteinising hormone (LH) levels in the prepubertal group which could not be compared, the median basal serum follicle-stimulating hormone (FSH), LH, and testosterone concentrations, the median peak FSH and LH responses to LH-RH, and the mean plasma testosterone responses to human chorionic gonadotrophin stimulation did not differ between the prepubertal, early pubertal, and late pubertal groups compared with normal boys of similar pubertal maturation. Three of 32 prepubertal ALL boys, and 5 of 12 pubertal ALL boys showed abnormalities of gonadotrophin secretion. The increased frequency of abnormalities of FSH secretion in the pubertal ALL boys compared with the prepubertal ALL boys could not be explained by more severe tubular damage in the former group. We conclude that moderately severe damage to the tubular system of the testis unassociated with Leydig cell impairment may not be detected in the prepubertal boy with current tests of testicular function.

Summary Pituitary function was assessed in 39 patients with previously untreated hyperprolactinaemia. Primary hypothyroidism, drug-induced hyperprolactinaemia and chronic renal failure were excluded in all patients. All of the 22 patients (group 1), who had either a normal pituitary fossa or a minor radiological change on lateral skull X-ray, had completely normal pituitary function with the exception of 2 who were partially growth hormone-deficient. However, 9 of the 17 patients with macroadenomas (group 2) had a deficit of one or more anterior pituitary hormones. After the lateral skull X-ray 13 patients in group 1 had further neuroradiological investigations. In only one was a minor abnormality noted which had not been observed on the plain film and this was not of practical significance. In centres where hyperprolactinaemic patients with a normal pituitary fossa or a minor radiological change on lateral skull X-ray are treated with bromocriptine, further neuroradiological investigations and dynamic tests of pituitary function are not required.

The concentration of the common alpha subunit of the glycoprotein hormones was high in the serum of 21/56 (38%) of premenopausal patients and 22/106 (21%) of postmenopausal patients with primary breast cancer, at the time of presentation. 7/59 (12%) of patients with benign disease also had high alpha subunit levels. Tumour cytosol oestrogen and progesterone receptor status was determined in 80% of the patients with cancer, and there was a trend towards higher alpha levels in patients without receptors, but this was not statistically significant. In the premenopausal patients with cancer there was a significant correlation between alpha subunit level and disease stage, R = 0.47, P = 0.0001, but not in the postmenopausal patients. In view of the correlation with disease stage, high levels of alpha subunit in premenopausal patients with breast cancer at presentation with the primary tumour may indicate poor prognosis.

Summary Hypothalamic-pituitary disease is a well-recognized, although uncommon, occurrence in sarcoidosis. Almost always the endocrine manifestations occur in a patient with widespread disease involving the lungs, skin or liver. A case is reported of central nervous system (CNS) sarcoidosis with no other clinical, biochemical or histological evidence of the disease.

Testicular biopsies were performed in boys, previously treated or currently receiving chemotherapy for ALL, to establish the incidence of occult leukaemic infiltration. The general morphology of the testicular biopsies was also studied and each boy underwent an HCG test and an LHRH test. We studied 44 boys, 32 prepubertal, 8 early pubertal and 4 late pubertal. The mean tubular fertility index (TFI = percentage of tubules containing spermatogonia) was reduced to 51%. The mean basal FSH, LH and testosterone levels, mean peak gonadotrophin responses to LHRH and mean testosterone responses to HCG did not differ between the prepubertal and early pubertal ALL groups compared to groups of normal boys of similar pubertal maturation. The late pubertal ALL group was too small for such comparison. No significant relationship existed between the TFI and any of the hormonal indices studied. Individually 3 prepubertal ALL boys (n=32), 3 early pubertal (n=8) and 2 late pubertal (n=4) showed an abnormality in their gonadotrophin responses to LHRH but only 1 of the 44 ALL boys had no testosterone response to HCG. We conclude that moderately severe tubular damage of the testis unassociated with Leydig cell impairment may not be detected in the prepubertal boy using current tests of testicular function.

Six children who received cranial irradiation for brain tumours which did not directly involve the hypothalamic-pituitary axis, were studied. The radiation dose received by the hypothalamic-pituitary axis ranged from 3000-4750 rads (over 3 weeks).Pituitary function was assessed between 2 and 10 years after DXT and impaired GH responses to insulin hypoglycaemia and Bovril stimulation tests were seen in all subjects. The remainder of pituitary function was essentially normal. The bone age was retarded in 5 of the 6 subjects and the initial standing height SDS varied between -1.7 and -3.3. During the pre-treatment year the children, all of whom were prepubertal, grew between 2.0 and 5.1 cm.Subsequently all received 5 units GH 3 times weekly for 1 year.The growth rate of each child was at least 2 cm. greater during the treatment year (range 6.0 to 10.1cm.) than the pre-treatment year.In 5 of the 6 the improved growth rate could be totally ascribed to GH therapy. In the sixth there was significant pubertal maturation during the treatment year and only in this subject did the bone age advance at a significantly greater rate than the chronological age.We conclude that radiation-induced GH deficiency is one of several important factors in the aetiology of short stature complicating the treatment of brain tumours in childhood. If such a child is clinically well,shows a poor growth rate and biochemical evidence of GH deficiency,then a 1 year trial of GH is justified.