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OBJECTIVE Mutations of the DAX1 gene (Dosage-sensitive sex reversal-Adrenal hypoplasia congenita critical region on the X chromosome gene 1), which encodes a novel orphan nuclear receptor, have been identified in patients with X-linked adrenal hypoplasia congenita (AHC) and hypogonadotrophic hypogonadism (HHG). We have investigated two kindreds with AHC and HHG for DAX1 mutations. METHODS Two kindreds with five affected males, four carrier females and four unaffected males were investigated. The gonadotrophin deficiency in three of the boys was observed to be partial until mid-puberty. DAX1 mutations in the entire 1413 bp coding region were sought by DNA sequence analysis. RESULTS Two DAX1 mutations, situated within exon 1, were detected. These consisted of an insertional mutation at codon 183 that led to a frameshift and a premature Stop at codon 184, and a missense mutation Leu278Pro that involved a highly conserved leucine residue within the proposed ligand binding domain. Co-segregation of these mutations with the disease in each family, and their absence from 107 alleles in 73 (39 males and 34 females) unrelated control individuals, was demonstrated by allele specific oligonucleotide hybridization (ASO) analysis for the insertional mutation, and by Ban I restriction endonuclease analysis for the missense mutation. CONCLUSIONS Two novel DAX1 mutations have been detected in two families with adrenal hypoplasia and hypogonadotrophic hypogonadism. The finding of partial gonadotrophin deficiency in the affected males from these families is notable and an early recognition of such a possibility in a patient, which may be facilitated by DAX1 mutational analysis, may help to prevent the sequelae of delayed androgen replacement therapy.

Summary 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. DESIGN Analysis of peak GH response to an insulin tolerance test performed during comprehensive assessment of pituitary function. PATIENTS One hundred and ninety non-acromegalic patients (96 male) with pituitary disease whose ages ranged from 16 to 72 (mean 39·4) years. MEASUREMENTS The patients were divided into four groups according to the number of anterior pituitary hormone deficiencies demonstrated; isolated GH deficiency (GHD0), or GH deficiency plus an additional one, two or three pituitary hormone deficits (GHD1, GHD2, GHD3). RESULTS The four groups were matched for age and blood glucose nadir during the ITT. The median (interquartile range) GH peaks were GHD0, 10·0 (5·4–16); GHD1, 4·0 (2·7–7·7); GHD2, 2·0 (1–2·9); GHDB, 1·8 (1–3·2) mU/l. There was a Significant downward trend in the medians (P < 0·0001). The differences between GHD0 and GHD1, and GHD1 and GHD2, were highly significant (P < 0·0001); however, there was no difference between GHD2 and GHD3. Ninety-one per cent of patients in combined groups GHD2 and GHD3, 55% in GHD1 and 24% in GHD0 had a peak GH < 5 mU/l. CONCLUSIONS Our study has shown that GH deficiency is variable according to the degree of hypopltuitarism present and that the greater the number of pituituary hormone deficits the more severe the GH deficiency. These observations will help to clarify the diagnosis of GH deficiency In adult life.

The aim of this study was to refine the biochemical definition of disease activity in acromegaly by comparing serum growth hormone (GH) measurements during a 10-hour day profile with serum GH values during an oral glucose tolerance test.Using plasma insulin-like growth factor-1 (IGF-1) levels as a measure of disease activity, serum GH data from a day profile and from an oral glucose tolerance test were compared.Thirty-five acromegalic patients were studied, 13 of whom had serum GH measured during a day profile and 22 during an oral glucose tolerance test. In addition, basal plasma IGF-1 levels were estimated in all acromegalic patients, and in 24 normal subjects.Following acid-ethanol extraction of the plasma samples, IGF-1 levels were measured by radioimmunoassay using a polyclonal antibody. In a day profile, six to eight blood samples for serum GH estimation were taken at hourly intervals during the day; during an oral glucose tolerance test samples for serum GH estimation were taken in the fasting state and every 30 minutes for 2 hours and measured by a two-site IRMA for GH.Ninety-four per cent of acromegalic patients with raised plasma IGF-1 levels had serum GH concentrations10 mU/l whilst 98% of acromegalic patients with plasma IGF-1 levels in the normal range had serum GH concentrations6 mU/l. A highly significant positive correlation was found between the mean serum GH concentrations (r = 0.67), the minimum serum GH concentration (r = 0.65) and the area under the GH curve (r = 0.66) estimated during an oral glucose tolerance test and plasma IGF-1 concentrations. The relations between identical indices of serum GH concentration measured during a day profile and plasma IGF-1 levels, although significant, show a less powerful correlation. The relation between serum GH and plasma IGF-1 levels describes a curvilinear model, plasma IGF-1 levels exhibiting a plateau at serum GH concentrations40 mU/l but maintaining a linear relationship with serum GH levels20 mU/l.A highly significant correlation exists between plasma IGF-1 levels and various parameters of serum GH levels in acromegalic patients. Hormonal assessment of disease activity in acromegaly is more accurately reflected by the serum GH concentration during an oral glucose tolerance test rather than by the serum GH level during a day profile. Normalization of plasma IGF-1 levels is rarely achieved unless the mean serum GH level is reduced to6 mU/l.

CV205-502 is a new non-ergot dopamine agonist currently being studied for the treatment of hyperprolactinaemia. We have assessed the effects of CV205-502 on prolactin secretion and the clinical consequences of hyperprolactinaemia in 16 patients with hyperprolactinaemia who had previously been unsuccessfully treated with bromocriptine. These patients had been either intolerant of and/or resistant to the effects of bromocriptine. Sixteen patients, all women in an age range between 20 and 49 years (mean 31.5 years), were treated for periods of between 8 and 52 weeks with doses of CV205-502 ranging from 0.075 to 0.3 mg taken once daily at night. Seven out of 10 of the patients, who were intolerant of bromocriptine, tolerated CV205-502 better with fewer side effects although the nature of the side effects was similar to that associated with bromocriptine. Only 1 patient from this group stopped taking CV205-502 due to side effects. Six of 11 patients exhibiting bromocriptine resistance showed a significant reduction in the degree of hyperprolactinaemia but normoprolactinaemia was achieved in only 1. Galactorrhoea ceased in 2 of 6 patients, menstruation resumed in 6 of 11 patients presenting with amenorrhoea, and 2 patients conceived. In patients with bromocriptine intolerance and/or resistance, CV205-502 is useful as a second line treatment.

In adults, hypopituitarism is a common consequence of external radiotherapy. The clinical manifestations may be subtle and develop insidiously many years after radiotherapy. Anterior pituitary deficiencies can therefore only be detected by regular testing, including dynamic tests of GH and ACTH reserve. Although the deficiencies most commonly develop in the order GH, gonadotrophins, ACTH then TSH, this sequence may not be predictable in an individual patient and comprehensive testing is therefore required. The tests should ideally be performed annually for at least 10 years after treatment or until deficiency has been detected and treated. It is not only the patients with pituitary disease who are at risk of developing hypopituitarism after radiotherapy. Any patient who receives a total dose of irradiation of 20 Gy or more to the hypothalamic-pituitary axis is at risk of hypopituitarism, although the threshold dose may be lower than this. This is particularly important in the long-term survivors of malignant disease in whom endocrine morbidity may be relatively common and in whom this can be easily treated, with consequent improvement in quality of life. Whilst patients who receive a high total dose of irradiation are at increased risk of developing multiple deficiencies, a higher fraction size also increases the risk of anterior pituitary failure. There is good evidence that the earliest damage to the hypothalamic-pituitary axis after external radiotherapy is at the level of the hypothalamus. However, patients who undergo pituitary ablation with interstitial radiotherapy or heavy particle beams are likely to sustain direct damage to the pituitary. In these patients, the sequence in which individual pituitary hormone deficiencies develop is generally the same as that observed with the hypothalamic damage after conventional external radiotherapy. The increasing use of radiotherapy as a means of treatment for malignant disease means that new groups of patients with potential for endocrine dysfunction are emerging. Whole body irradiation in the preparation for bone marrow transplant is one such treatment and although hypothalamic-pituitary damage appears to be confined to GH deficiency in children, longitudinal experience is limited to date, particularly in adults. The treatment of malignant disease in childhood is of particular importance in terms of the delayed endocrine sequelae. The hypothalamic-pituitary axis may not be the only endocrine tissue damaged by treatment in these patients and management is therefore more complicated. In the growing child, the potential association of growth hormone deficiency, gonadal failure or premature puberty and thyroid dysfunction mean that expert endocrine supervision is essential for optimum long-term outcome.

External radiotherapy has been used as primary treatment for acromegaly in 29 patients and in combination with surgery in 41 patients in whom growth hormone levels remained elevated postoperatively. Fourteen further patients who did not receive radiotherapy have also been studied, four of whom had undergone surgical treatment. Radiotherapy schedules consisted of 20 Gy in eight fractions over 11 days (n = 23) or 35-40 Gy in 15 fractions over 21 days (n = 47). Growth hormone hypersecretion was either unchanged or increased with time in non-irradiated patients. In those patients who underwent radiotherapy, the likelihood of the mean GH level during GTT falling to less than 5 mU/l was unaffected by the total dose of radiation administered. However, patients with a pre-radiotherapy GH level of less than 30 mU/l showed a significantly increased probability of achieving a post- radiotherapy GH level less than 5 mU/l (P = 0.002). Previous surgery, initial serum prolactin and the age or sex of the patient did not predict the successful outcome of radiotherapy. In view of the known dose dependency of radiation-induced hypopituitarism, lower radiation dose schedules (20 Gy; eight fractions in 11 days) can be used in acromegaly with some benefit, especially in younger patients. However, all patients should undergo operative removal of as much GH-secreting tissue as possible, in order to lower GH levels and increase the probability of achieving a cure following radiotherapy.

Purpose: This study was undertaken to show whether the rate of expression of radiation injury in the rat pituitary gland could be accelerated by the use of growth stimulants. Methods and Materials: Rat pituitary glands were irradiated in situ with a range of single doses up to 20 Gy. The rats were then given subcutaneous slow-release implants containing 17β-estradiol (E 2 ) and sulpiride (S) to stimulate lactotroph proliferation. Two sequential cycles were used, each consisting of stimulation (3 weeks) and withdrawal (2 weeks). Measurements were made of gland weight; BrdU-labeled, giant, and apoptotic cells; lactotrophs; as well as pituitary prolactin content, in response to exogenous thyroid-releasing hormone (TRH). Results: The two cycles of stimulation/withdrawal resulted in marked changes in gland weight, BrdU-labeling index, and serum prolactin (PRL) levels in unirradiated rats. The proportion of immunopositive growth-hormone-producing (GH) cells increased after irradiation. Radiation inhibited the hypertrophic response to E 2 + S and also inhibited increases in BrdU-labeling index and serum PRL levels. Also, giant lactotrophs were observed in the irradiated pituitaries. However, they were not seen in the unirradiated rats or in the irradiated rats treated with E 2 + S. TRH promoted PRL secretion in the unirradiated rat. In contrast, TRH inhibited PRL secretion in the irradiated rat and in all treatment groups receiving E 2 + S. Apoptosis was induced by irradiation and was substantially increased in lactotrophs and in other cell types by withdrawal of the E 2 and S stimulus, although the highest observed incidence was only 7 per 10,000 cells. Conclusion: Both irradiation and E 2 + S treatment removed the hypothalamic control of PRL secretion, which reveals this important inhibitory action of TRH upon PRL secretion. This suggests that it is not suitable as a dynamic test of pituitary PRL reserves in such abnormal situations, where there may also be damage to the hypothalamic-pituitary vasculature. The increasing proportion of GH cells after irradiation indicates that lactotrophs respond more rapidly to irradiation. The stimulation by E 2 + S somehow prevented the radiation-damaged lactotrophs from becoming giant cells. Also, the ratio of apoptotic cells to BrdU-labeled cells was increased by the E 2 + S treatment, indicating that the E 2 + S did enhance radiation-induced cell death relative to cell renewal. However, overall, the E 2 + S stimulus protocol did not promote a dramatic increase in cell death (apoptosis) nor a marked decrease in residual gland weight after irradiation. Hence, its use would probably not be beneficial in the treatment of slow-responding prolactinomas, if malignant lactotrophs respond similarly to the normal pituitary lactotrophs. However, the observation of induced apoptosis after hormone and drug withdrawal suggests that agents which promote tumor shrinkage may be effective by causing rapid apoptosis of tumor cells in vivo.

Summary OBJECTIVE Recent studies of GH replacement have suggested several beneficial effects for GH deficient adults. It would therefore be helpful to predict the time of onset of GH deficiency after external pituitary irradiation. We have studied the evolution of GH deficiency with time In patients irradiated for pituitary adenomas and other hypothalamic pituitary tumours. DESIGN Analysis of serial peak GH responses to Insulin hypoglycemia following external irradiation to the hypothalamlc-pitultary axis using statistical models which allowed for age, sex, previous surgery and the pre-radiotherapy GH peak response. PATIENTS Eighty-five non-acromegalic adults (48 male), 75 of whom had either a pituitary adenoma or a craniopharyngioma and 10 who had other tumours in the hypothalamic-pituitary region. All the patients had received a radiation dose between 37.5 and 45 Gy divided into 15 fractions given over 21 days. MEASUREMENTS The GH responses to an insulin tolerance test (ITT) performed as part of the regular endocrine follow-up In patients who received Irradiation to the hypothalamic-pituitary region. RESULTS Three hundred and forty-five ITTs were performed over a period of 10 years following radiotherapy. There was a decline In the modelled mean peak GH response to an ITT over the first 5 years which then appeared to plateau. Using an extended model, women had higher GH peak responses than men and this difference was maintained throughout the ten-year period. The magnitude of the post-radiotherapy peak GH response at any given time was dependent on the baseline peak GH response, but the rate of the decrease was not affected (P= 0.66). To develop severe GH deficiency (peak GH response less than 5mU/l) after radiotherapy it took patients with baseline GH peaks of 30, 20 and 10mU/l approximately 4 years, 3 years and 1 year respectively. Those patients with a baseline GH peak of greater than 50mU/l are unlikely to develop severe GH deficiency within the first 5 years following radiotherapy. CONCLUSION These results provide an insight into the pattern of the decline In GH secretion following radiotherapy in patients with pituitary disease and the factors affecting It. This Information will help the clinician predict the frequency and timing of GH deficiency in patients irradiated for pituitary disease and the potential need for GH replacement therapy.

Pituitary-function tests have been done in twenty-seven patients at various times after treatment in childhood for intracranial tumours not directly involving the hypothalamic-pituitary region. Impaired growth hormone (G.H.) responses to hypoglycaemia and 'Bovril' were found in ten children. There seeems to be progressive impairment in G.H. production with time after treatment. During the first 3 months after neurosurgery no child was found to be G.H. deficient, but the peak G.H. response of this group seemed to be blunted when compared with a control group of children who had been treated for abdominal tumours. The rest of anterior-pituitary function in G.H.-deficient children seems quite normal except for a significantly greater basal thyroid-stimulating hormone (T.S.H.) level and T;S.H. response after thyrotrophin-releasing hormone. Two girls have developed secondary amenorrhoea, and one is G.H. deficient.

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.

Protein-A purified human thyroid stimulating immunoglobulins (TSIg) and thyrotrophin binding inhibiting immunoglobulins (TBIIg) were measured in euthyroid subjects and thyrotoxic patients by bioassay and TSH radioligand receptor assay respectively. Unextracted sera from euthyroid and thyrotoxic subjects inhibited both basal and TSH stimulated iodide uptake in the bioassay, which was based on iodide uptake in porcine thyrocytes. Similar effects were seen with Ig and TSIg extracted from sera using either polyethylene glycol or ammonium sulphate. However IgG and TSIg prepared using Protein-A Sepharose CL-4B from sera of euthyroid subjects had little effect in this system. The majority of Protein-A purified TSIg preparations from sera of thyrotoxic patients stimulated iodide uptake in procine thyrocytes in a dose-dependent manner and most (85%) diluted parallel to both bovine and human TSH. TSIg and TBIIg from 73 patients with thyrotoxicosis were assessed using the bioassay and receptor assay and compared to a control group of 35 euthyroid subjects. The median (and range) values for TSIg and TBIIg in the euthyroid group were 4.35 (0.8 to 7.5, % stimulation over control) and 2.7 (-9.3 to 8.6, TBII index) for the bioassay and radioreceptor assay respectively. A value of greater than 10.0 in both assays was taken as a positive result. Of the thyrotoxic patients 61 out of 73 were positive in the bioassay (83.6%) compared to 60 in the radioreceptor assay (82.2%). There was a positive correlation between the two assays (r = 0.821, P less than 0.001). Of the 73 thyrotoxic patients 40 were untreated, 18 had received carbimazole and 15 had been previously treated with iodine-131. TSIg levels in the untreated thyrotoxics were similar to those in either group of treated patients. However they were higher (P less than 0.05) in the iodine-131 group than in the patients treated with carbimazole. Similar results were obtained for TBIIg. The coupling of a specific extraction method for human serum IgG with a bioassay for TSIg has demonstrated a high prevalence of these immunoglobulins in patients with thyrotoxicosis. The agreement between this assay and a radioreceptor assay was good, indicating that TSH displacing and thyroid stimulating activities of these immunoglobulins are closely related.

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.

In ninety-nine patients with pituitary adenomas, forty-six with acromegaly, the serum level of the glycoprotein hormone alpha subunit was elevated in eighteen cases. Thirteen of these were acromegalic and one had an FSH-producing tumour. Alpha levels varied little during the day, from one day to the next and over a 6 month period. In twenty-five patients with a variety of other hypothalamic-pituitary disorders examined, one patient with a craniopharyngioma had a mildly elevated alpha level. External pituitary irradiation was followed by an acute and often transient fall in alpha level in several of these patients. Of the fifty-four patients with pituitary adenomas who had received external irradiation before testing, only five had elevated alpha subunit levels compared with thirteen patients of the forty-five who had not been irradiated. This difference in incidence of elevated alpha level was statistically significant (P less than 0.025). We conclude that external irradiation may reduce alpha subunit level chronically in many patients with pituitary adenoma.

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.

Summary. Fifty pregnancies occurred in 37 women with hyperprolactinaemia. Thirty women (81%) initially attended with infertility and 24 (65%) had secondary amenorrhoea. Twelve women (31%) had pituitary macroadenomas, of whom seven (19%) were treated with neurosurgery and/or external radiotherapy before conception. Fortyone conceptions (82%) followed treatment with bromocriptine. There were no unusual obstetric or endocrinological complications. Scrum prolactin measured at least 6 months post partum when under basal conditions, without bromocriptine and not breast feeding, showed no significant trends compared with initial values. Tumour growth was not stimulated by the high oestrogen levels of pregnancy.

Serum α subunit of the glycoprotein hormones was measured in 370 samples from 55 patients with metastatic malignant melanoma before, during and after chemo-immunotherapy. Ten of 20 premenopausal, one of 11 postmenopausal and one of 24 male patients had levels above the upper limit of normal before treatment. There was a statistically significant reduction in survival for the 10 premenopausal patients with elevated pretreatment α-levels (median 19 weeks ) compared to the 10 premenopausal patients with normal pretreatment α levels (median 83 weeks ). Also pretreatment α-levels were significantly lower in the premenopausal patients who responded to chemo-immunotherapy (median 0.5 ng/ml ) than those who failed to respond (median 4.9 ng/ml ). Maximum α-levels during clinical course, α-levels at regression or progression of disease and α-levels at the end of therapy did not influence patient survival. The presence of pretreatment elevated α-subunit levels could be taken as indirect evidence of a more malignant, unresponsive type of melanoma in a proportion of premenopausal patients.

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.

Pituitary function has been studied in 25 children after treatment of acute leukemia. Impaired growth hormone responses both to hypoglycemia and to Bovril were found in 11 subjects. Elevated basal thyroid-stimulating hormone levels were seen in five children, three of whom had an augmented TSH response to thyrotrophin-releasing hormone. Radiation-induced damage to the hypothalamic-pituitary region is thought to be the cause of these abnormalities in growth hormone and in secretion of TSH. The peak cortisol response to hypoglycaemia is significantly decreased in the group of subjects who received the higher dose of cranial radiation therapy, but no individual child is hypothyroid or shows impaired adrenal function, clinically or biochemically. Three prepubertal girls studied have biochemical evidence of ovarian failure following the use of combination chemotherapy.

The lectin-binding properties of serum α subunit were studied by lectin affinity chromatography. Normal individuals and most patients with pituitary tumours produced α subunit which bound specifically to Concanavalin A–Sepharose (Con A). Some patients with pituitary tumours produced both Con A-reactive α subunit and α subunit which did not bind to Con A. Concanavalin A–Sepharose-binding α subunit from all sources bound strongly to Ricinus communis agglutinin–Sepharose after treatment with neuraminidase. Serum α subunit from those patients with pituitary tumours, which did not bind to Con A, bound to wheat germ agglutinin–Sepharose, exhibiting both weakly binding and strongly binding forms. Serum α subunit from both patients and controls, which did bind to Con A, showed only weak affinity for wheat germ agglutinin–Sepharose. Neither the low affinity nor the high affinity of serum α subunit from any source for wheat germ agglutinin–Sepharose was affected by neuraminidase. These findings show that (a) the predominant pattern of glycosylation of serum α subunit from normal controls is a Con A-reactive, biantennate complex oligosaccharide and (b) that the structural alteration which results in serum α subunit which does not bind to Con A in some patients with pituitary tumours is not an absence of carbohydrate, rather the α subunit contains highly branched, either complex or hybrid oligosaccharides. J. Endocr. (1984) 103, 111–116

Nine children with brain tumors are described who have received various combinations of treatment, including surgery, radiotherapy, and chemotherapy. Many of the children were noted to be of short stature. Endocrine assessment was carried out from 2 to 10 years after treatment. The combined results of insulin tolerance and Bovril stimulation tests show an impaired growth hormone response in six of the nine children. Bone age is retarded in all cases, and the present height is below the 10th percentile in five of the six. The cause of this growth hormone deficiency is obscure, but further studies are in progress.

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.

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% 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 less than 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 less than 0.01 and P less than 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.

Two patients presenting with diabetes mellitus and hypokalaemia resulting from markedly increased ACTH and cortisol secretion are described. Neither patient showed any evidence of a tumour and both responded dramatically to treatment with metyrapone in that all abnormal clinical features disappeared, ACTH concentrations returned to normal and both patients showed prolonged remission after metyrapone treatment was stopped. One patient relapsed after a severe viral illness and the administration of dexamethasone and cortisone. It is suggested that these cases may represent an unusual form of Cushing's syndrome in which ACTH secretion is stimulated by increasing concentrations of cortisol. When these are reduced by metyrapone administration ACTH secretion falls in parallel and prolonged remission of disease may result.

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. In conclusion, cerebral irradiation is a potent cause of GH deficiency in children.

Thyroid-stimulating hormone (T.S.H.), triiodothyronine (T3), and thyroxine (T4) concentrations were estimated on 432 blood specimens from patients with a provisional diagnosis of thyrotoxicosis. 59 patients had a raised serum T3 concentration with T.S.H. and T4 levels in the normal range. Further information was obtained in 41 of these patients, and T3 toxicosis was diagnosed in 17 cases, thus providing a projected total of 24 patients with T3 toxicosis. In addition, there were 56 patients, with more common biochemical features of thyrotoxicosis, having both a raised serum T3 and T4 concentration. Therefore 30% of the patients considered thyrotoxic in this retrospective survey were only diagnosed with the aid of a serum-T3 estimation.

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. (auth)

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.

Serum α subunits from patients with pituitary tumours and from normal controls were studied for their ability to bind to Lens culinaris agglutinin–Sepharose (LCA), l-phytohaemagglutinin–agarose (l-PHA) and soybean agglutinin–Sepharose (SBA). Serum α subunits from normal controls which had previously been shown to bind to Concanavalin A–Sepharose (Con A) were not retained by LCA. In contrast, Con A-reactive α subunits from patients with pituitary tumours bound specifically to LCA. Non-Con A-reactive α subunits from patients with pituitary tumours were also largely not bound to LCA, but were retained by l-PHA. No α subunits from any source bound to SBA. These results indicate that the structural alterations resulting in non-Con A-reactive serum α subunits include highly branched complex oligosaccharides in addition to the hybrid-type glycans previously described. The increased branching appears to be associated with fucosylation in the core region of the oligosaccharides. Serum α subunit from any source appears to be devoid of terminal N-acetylgalactosamine residues. These structural modifications may be related to the variable biological activity of α subunit which has been reported. J. Endocr. (1984) 103, 117–122

Growth hormone (GH) secretion has been studied under physiological conditions and in response to standard pharmacological stimuli in 14 children, who had previously received cranial irradiation between two and fourteen years earlier. All fourteen showed a blunted GH response to insulin hypoglycaemia and, in twelve, the GH response to arginine stimulation was also subnormal. Physiological GH secretion was studied by measuring integrated GH concentrations in 30 min blood samples collected over a 24 hour period by a continuous withdrawal pump. Compared to normal controls (n=5), the irradiated patients showed a significant reduction in the mean integrated GH concentration (2.2: 8.8 mU/l; p< 0.002), the total 24 hour GH output (mean 105.7 mU vs. 391.7 mU; p< 0.002) and the mean GH output during the first six hours of sleep (mean 48.2 mU vs. 226 mU; p< 0.002). There was no significant correlation between the maximum peak GH response to either pharmacological test and the total 24 hour GH output. Conventionally most short children undergo two provocative tests of GH release and if the GH response to one of the two tests is normal, it is usually assumed that GH production is adequate. Adopting these criteria in this study it would have been assumed incorrectly that GH production was normal in two children. Nonetheless all 14 children showed a blunted GH response to an ITT as well as a reduced total 24 hour GH output. Therefore we would suggest that in children suspected of radiation-induced GH deficiency pharmacological tests of GH secretion remain useful, the ITT being the test of choice because of the marked radiation sensitivity of the GH response to hypoglycaemia.

Testicular function was studied in ten men, aged between 17 and 36 years, who had received irradiation for a nephroblastoma during childhood. The dose of scattered irradiation to the testes ranged from 268 to 983 rad. Eight subjects had either oligo- or azoospermia (0 to 5.6 million/ml), seven of whom had an elevated serum follicle-stimulating hormone (FSH) level. One subject showed evidence of Leydig cell dysfunction with a raised serum luteinizing hormone level (LH) and a low plasma testosterone concentration. A second group of eight prepubertal males, aged between 8 and 14 years, were studied. These had also been irradiated for abdominal malignancies during childhood and received a similar dose of irradiation to the testis as the first group studied. The plasma testosterone levels were within the normal range for prepubertal boys in all eight. The mean gonadotrophin levels were not significantly different from the mean levels of normal prepubertal males. Thus irradiation-induced damage to the germinal epithelium in prepubertal boys produces raised FSH levels after puberty but not before it. We conclude, therefore, that inhibition has a minor role in the control of the prepubertal hypothalamic-pituitary testicular axis and its contribution to gonadal control of gonadotrophin secretion changes with sexual maturation.

Thyroid function was studied in 32 patients who had received neck irradiation during childhood for Hodgkin's disease. All except one patient received a dose of 2500–3000 rad over a period of 19–25 days. In 12 patients lymphangiography was performed. Clinically all patients were considered euthyroid. One had a thyroid swelling which was cystic in nature. Five (16%) patients were biochemically hypothyroid, 17 (53%) were euthyroid with an elevated basal serum TSH concentration and a further seven (22%) were euthyroid with a normal basal serum TSH level but an augmented thyroid-stimulating hormone (TSH) response to thyrotrophin-releasing hormone (TRH). Only three (9%) patients had completely normal thyroid function tests. The basal serum TSH concentration and the peak serum TSH response to TRH were significantly greater in the patients who received neck irradiation and lymphangiography than in those who received neck irradiation alone. In addition the free thyroxine index decreased significantly as the time interval between treatment and study increased in the lymphangiography group. These data demonstrate that the normal thyroid gland is vulnerable to the damaging effects of external irradiation, and that the combination of neck irradiation and lymphangiography is more likely to result in thyroid dysfunction than is neck irradiation alone. Furthermore, in view of the deterioration in thyroid function with time, periodic clinical and biochemical assessment of thyroid function is clearly indicated.

The effects of growth hormone (GH) therapy were studied in 6 children, previously treated for brain tumours which did not directly involve the hypothalamic-pituitary axis, and who had received cranial irradiation between 2.1 and 10 years earlier. All 6 were short with a standing height standard deviation score (SDS) from -1.7 to -3.3. Impaired growth hormone responses to an insulin tolerance test (ITT) were observed in all 6 and to a Bovril stimulation test in 5 children. The remainder of pituitary function was essentially normal. All 6 were prepubertal and 5 had a retarded bone age. During the pre-treatment year the 6 children's growth rates varied fom 2.0 to 5.1 cm. Subsequently all received human GH in a dose of 5 units 3 times weekly for 1 year. The growth rate in each was at least 2 cm greater during the treatment year than the pre-treatment year. Growth during the treatment year ranged from 6.0 to 10.1 cm. In 5 of the 6 the improvement in growth rate could be totally ascribed to the 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.

SUMMARY We have studied a women who presented at the age of 51 with a large FSH and a-subunit producing pituitary adenoma. Following insertion of ventriculo-peri-toneal shunts and external pituitary irradiation there was no change in the elevated serum concentrations of FSH, and α-subunit over a four year period although she developed both ACTH and TSH deficiency. Various drugs, however, did alter the FSH and α-subunit concentrations and these changes suggest possible mechanisms controlling FSH secretion. Ethinyloestradiol 0.03 mg daily for three weeks suppressed serum FSH to 77% of the basal level (240 ± 35 i.u./l to 184 ±20 i.u./l) but α-subunit rose to 130% of basal level (281±50 ng/ml to 366±40 ng/ml). On ethinyloestradiol 01 mg daily, FSH suppressed to 17% of basal (40 ±11 i.u./l) with no change in a-subunit concentration, while on 0.2 mg daily suppression of FSH was similar but α-subunit fell to 59% of basal (190 ±28 ng/ml). Dexamethasone, 3 mg daily for one week reduced FSH to 53% of the initial concentration and α-subunit to 74% while bromocriptine 7.5 mg daily for three months, reduced FSH to 39% and α-subunit to 66% of basal. Neither thyroxine, 0-2 mg daily for four weeks, nor an LHRH analogue, (Buserelin, Hoechst) 200 μg, three times daily for three months elicited any effect. Chromatography on Sephadex G100 showed that serum FSH and α-subunit both had Kav values somewhat lower than those of their standard counterparts (FSH, 0-20 vs 0-25; α-subunit 0-35 vs 045). We conclude that the dissociation between changes in FSH and α-subunit after giving oestrogen, bromocriptine and dexamethasone suggests that these drugs inhibit the synthesis of both a and β-subunits of FSH with the latter being more sensitive to their effects. The results seem inconsistent with the alternative possibility of impaired release of both subunits or impaired α-β combination as the mechanism causing the fall in FSH secretion.

Twenty-one patients with hyperthyroid Graves' disease were treated with carbimazole 30 mg daily, given as a single dose. Propranolol was also given for the first 3 weeks. All became clinically euthyroid with normal serum thyroxine (T4) levels, usually within 1-3 months. Patients with large goitres and raised serum alkaline phosphatase concentrations took longer to respond. In 19 patients a positive thyroid stimulating hormone (TSH) response to intravenous thyrotrophin releasing hormone (TRH) developed. Carbimazole was stopped soon after (median time of treatment 18 weeks, range 9-41 weeks) and 18 patients have been followed. Seven of these (39%) have remained in remission from hyperthyroidism for more than one year (median 77 weeks). Carbimazole 30 mg once daily is a convenient and effective treatment for hyperthyroid Graves' disease. Many patients will achieve prolonged remissions if treatment is stopped when serum T3 and T4 levels are in the low-normal range, usually 2-4 months after clinical euthyroidism has been reached.

SUMMARY Ten pituitary giants have been seen in hospitals in the Manchester region between 1938 and 1980, nine of whom are still alive. We report the clinical and hormonal features in eight of these cases. Marked skeletal deformity and psychological problems were common. We draw attention to the importance of early diagnosis and treatment if the long-term sequelae of pituitary gigantism are to be prevented.

The effects of varied doses of bromocriptine on the growth hormonesomatomedin axis have been studied in 6 acromegalic patients. The study last 9 months and during this time a maximum daily dose of bro

The influence of external pituitary irradiation (XRT) on thyrotroph function and PRL secretion was studied in twenty-five patients with pituitary adenomas, of whom eight had acromegaly. Twenty-one patients had undergone subtotal operative removal of their adenomas 8-190 weeks (median 12 weeks) before XRT. Following irradiation there was a significant reduction in peak serum TSH levels in response to i.v. TRH (P less than 0.05, compared with before XRT). Peak TSH levels returned to normal at 3 months. Similarly a transient reduction in TRH-stimulated beta-TSH release was observed. Serum T3 and T4 concentrations also fell after XRT, the levels at 3 months being significantly lower than control values (P less than 0.02), though no difference was seen at 6 and 12 months. A delayed (hypothalamic) serum TSH response to TRH (60 greater than 20-min level) developed at 6 months. In contrast, PRL concentrations (basal and TRH stimulated) were not altered during the 12 months following XRT. These findings demonstrate that thyrotroph function can be transiently impaired following external pituitary irradiation. None of the patients studied required T4 replacement therapy. The development of a delayed TSH response to i.v. TRH may indicate endogenous TRH deficiency. It was not associated with supra-sellar tumour enlargement in our patients and may be due to hypothalamic damage by irradiation.

SUMMARY We have studied growth hormone production in a patient with a bronchial carcinoid and acromegaly. The absence of growth hormone from the carcinoid tumour was demonstrated by extraction, cell culture and immunoperoxidase techniques. Using a linked perfusion culture system, effluent from the bronchial carcinoid tumour culture stimulated a rapid release of growth hormone from a rat pituitary mono-layer. This is the first time evidence of growth hormone releasing activity by a bronchial carcinoid has been demonstrated in a patient with the clinical and biochemical manifestations of excess growth hormone production.

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.