Novel DAX1 mutations in X-linked adrenal hypoplasia congenita and hypogonadotrophic hypogonadism.

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.

Cell proliferation and death in the irradiated pituitary gland and its modification by growth stimulants.

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 17beta-estradiol (E2) 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 E2 + 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 E2 + 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 E2 + S. Apoptosis was induced by irradiation and was substantially increased in lactotrophs and in other cell types by withdrawal of the E2 and S stimulus, although the highest observed incidence was only 7 per 10,000 cells. CONCLUSION: Both irradiation and E2 + 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 E2 + 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 E2 + S treatment, indicating that the E2 + S did enhance radiation-induced cell death relative to cell renewal. However, overall, the E2 + 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.

The evolution of radiation-induced growth hormone deficiency in adults is determined by the baseline growth hormone status.

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 hypoglycaemia following external irradiation to the hypothalamic-pituitary 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 5 mU/l) after radiotherapy it took patients with baseline GH peaks of 30, 20 and 10 mU/l approximately 4 years, 3 years and 1 year respectively. Those patients with a baseline GH peak of greater than 50 mU/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.

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 deficiency 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); GHD3, 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 hypopituitarism present and that the greater the number of pituitary hormone deficits the more severe the GH deficiency. These observations will help to clarify the diagnosis of GH deficiency in adult life.

Relationships between insulin-like growth factor-1 levels and growth hormone concentrations during diurnal profiles and following oral glucose in acromegaly.

OBJECTIVE: 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. DESIGN: 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. PATIENTS: 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. MEASUREMENTS: 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. RESULTS: Ninety-four per cent of acromegalic patients with raised plasma IGF-1 levels had serum GH concentrations > 10 mU/l whilst 98% of acromegalic patients with plasma IGF-1 levels in the normal range had serum GH concentrations < 6 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 concentrations > 40 mU/l but maintaining a linear relationship with serum GH levels < 20 mU/l. CONCLUSIONS: 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 to < 6 mU/l.

The effects of CV205-502 in patients with hyperprolactinaemia intolerant and/or resistant to bromocriptine.

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.

The effect of external pituitary irradiation on elevated serum prolactin levels in patients with pituitary macroadenomas.

The response of serum prolactin to external radiotherapy was studied in 58 patients (32 women) with pituitary tumours, aged between 16 and 75 years. Forty-four patients underwent pituitary surgery before radiotherapy. Six patients were irradiated with a regimen of 20 Gy in eight fractions over 10-11 days and the remainder received 35-42.5 Gy in 15 fractions over 20-22 days. Following radiotherapy, 44 patients received additional treatment with dopaminergic agonists. Prolactin levels ranged from 1078 to 491,000 mU/l (median 11,750 mU/l) before radiotherapy and all but three patients showed a fall in serum prolactin (measured 4 weeks after stopping bromocriptine in those on dopamine agonist therapy) during observation over periods of up to 154 months. All patients had evidence of pituitary fossa erosion or expansion at presentation and large tumours (Hardy-Vezina Grade 3-4) were more common in male patients (chi 2 = 10.08, p less than 0.01). The rate of fall of serum prolactin levels was greater in patients with true prolactin-secreting tumours when compared with those who had stalk or hypothalamic damage (p less than 0.005). The rate of decline of serum prolactin was also significantly related to the pre-radiotherapy value (rho = 0.519, p less than 0.01). A serum prolactin level less than 500 mU/l was achieved in 31 out of 44 patients treated with radiotherapy and dopaminergic agonist but only nine remained normoprolactinaemic when medication was discontinued for 4 weeks or more. The serum prolactin level fell permanently to less than 500 mU/l in two of 14 patients treated with radiotherapy only. Actuarial analysis of data from all patients indicated a 50 per cent probability that prolactin would be reduced to less than 500 mU/l by 10 years; this increased to 58 per cent for patients with smaller tumours (Hardy-Vezina grade 2).(ABSTRACT TRUNCATED AT 250 WORDS)

Long-term follow-up of low-dose external pituitary irradiation for Cushing's disease.

Twenty-four patients (three male) with Cushing's disease, aged between 11 and 67 years, were treated with low-dose external pituitary irradiation (20 Gy in eight fractions over 10-12 days) and followed for between 13 and 171 months (median 93 months). Eleven patients (46%) went into remission 4-36 months after irradiation, but five subsequently relapsed. Two of these received no further active treatment, one underwent successful pituitary surgery, one underwent a second course of low-dose external irradiation (as yet unsuccessful) and one has been treated with metyrapone for a total of 75 months. One of the 13 patients who did not respond received a further course of low-dose pituitary irradiation with prompt remission and two have received metyrapone for 41 months and 15 years without ill effect. One patient died from cerebrovascular disease. The remaining nine patients underwent bilateral adrenalectomy (one after unsuccessful pituitary surgery) with rapid resolution of hypercortisolism. Five of these patients have developed hyperpigmentation and elevated ACTH levels (range 505-1150 ng/l). A pituitary microadenoma has been demonstrated on CT scan in three and successfully removed by microadenomectomy. In the present series, the low incidence of radiation-induced hypopituitarism and absence of other complications attributable to radiotherapy suggest that low-dose pituitary irradiation may be a useful treatment option in selected patients. However, long-term follow-up has demonstrated a high relapse rate and failure to prevent Nelson's syndrome in adrenalectomized patients, indicating that it should not be used as primary treatment in preference to selective adenomectomy.

Radiation and hypothalamic-pituitary function.

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.

Low-dose pituitary irradiation for acromegaly.

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.

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% 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.

Hypopituitarism following external radiotherapy for pituitary tumours in adults.

The development of anterior pituitary hormone deficiencies has been studied in a group of 165 patients who underwent external radiotherapy for tumours of the pituitary or closely related anatomical sites, and who have been observed for up to 10 years. One hundred and forty had undergone pituitary surgery before radiotherapy. All patients received external radiotherapy by a three-field technique, giving 3750-4250 cGy in 15 or 16 fractions over 20-22 days. A combined test of anterior pituitary function using insulin hypoglycaemia or glucagon stimulation in conjunction with thyrotrophin and gonadotrophin releasing hormone tests and basal estimations of prolactin, thyroid hormones and testosterone or oestradiol was performed before radiotherapy. This was repeated six and 12 months later and subsequently annually. Before radiotherapy, 18 per cent of patients had normal growth hormone secretion, 21 per cent had normal gonadotrophin secretion, 57 per cent had normal corticotrophin reserve and 80 per cent had normal thyrotrophin secretion. Life table analysis demonstrated increasing incidences of all anterior pituitary hormone deficiencies with time: by five years all patients were growth hormone deficient, 91 per cent were gonadotrophin deficient, 77 per cent were corticotrophin deficient and 42 per cent were thyrotrophin deficient. At eight years, respective incidences of deficiencies were 100, 96, 84 and 49 per cent. Radiation-induced hyperprolactinaemia was seen in 73 patients; mean serum prolactin concentration rose from 227 +/- 11 mU/l to a peak of 369 +/- 60 mU/l at two years and subsequently declined towards the basal value. The primary diagnosis, patient age, sex, irradiated tissue volume and previous surgery were examined as variables that might influence the rate of development of anterior pituitary hormone deficiencies, but none of these factors had a significant effect. The radiation induced hyperprolactinaemia was however more marked in female patients. Although anterior pituitary hormone deficiencies most commonly developed in the order growth hormone, gonadotrophin, corticotrophin, thyrotrophin (61 per cent of patients), other sequences were evident. Most notably corticotrophin deficiency occurred before gonadotrophin deficiency. There is a high incidence of anterior pituitary hormone deficiencies in patients treated surgically for pituitary tumours and the incidence increases after external radiotherapy. Deficiencies may occur in an unpredictable sequence and endocrine testing is recommended on an annual basis.

Adrenocorticotrophin (ACTH) deficiency undetected by standard dynamic tests of the hypothalamic-pituitary-adrenal axis.

Six patients (four females, two males; aged 18-65 years), previously treated by external pituitary irradiation (2000-4000 cGY in 8-15 fractions over 10-20 days) for pituitary tumours, presented with the symptoms of excessive and inappropriate tiredness suggestive of ACTH deficiency, despite a normal peak cortisol response to an insulin tolerance test (four cases) or to a glucagon stimulation test (two cases). These six patients were found to have significantly lower mean 24 h urinary free cortisol levels (100 +/- 40 nmol; mean +/- SD) compared with the mean value of 31 normal controls (210 +/- 70.8 nmol; P less than 0.01). In addition serum cortisol profiles based on a series of four timed samples between 0900-2300 h were subnormal (mean 130 nmol/l) in comparison with profiles obtained from 12 normal controls (mean 270 nmol/l) (P less than 0.001). Glucocorticoid replacement therapy promptly abolished their symptoms. These results suggest that a discordance between ACTH secretion under basal circumstances and ACTH response to pharmacological tests may exist in patients with ACTH deficiency. We speculate that defective endogenous corticotrophin-releasing hormone (CRF) secretion, due to radiation-induced damage at hypothalamic level, is one cause of this phenomenon.

Familial dysalbuminaemic hyperthyroxinaemia.

Familial dysalbuminaemic hyperthyroxinaemia (FDH) can be confused with thyrotoxicosis if clinical signs and laboratory tests are misinterpreted. We describe three members of the same family with FDH who were erroneously treated for thyrotoxicosis. Screening of other family members resulted in the discovery of a further six patients at risk of being misdiagnosed as thyrotoxic. Clinical and biochemical findings relevant to the diagnosis of FDH are discussed.

The effects of cranial irradiation on growth hormone secretion.

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 less than 0.002), the total 24 hour GH output (mean 105.7 mU vs. 391.7 mU; p less than 0.002) and the mean GH output during the first six hours of sleep (mean 48.2 mU vs. 226 mU; p less than 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.(ABSTRACT TRUNCATED AT 250 WORDS)

Hormonal changes in postmenopausal women with breast cancer treated with trilostane and dexamethasone.

Postmenopausal women with metastatic breast cancer were treated with trilostane, initially 240 mg daily increasing after 3 days to 480 mg daily and after a further three days to 960 mg daily. After 3 days at this dose dexamethasone 1 mg daily was added and this combination was continued until disease progression occurred. Partial remission was seen in 26% and stabilization of previously progressive disease in a further 13% of the first twenty-three patients studied. During therapy with trilostane alone significant increases in DHEAS, androstenedione, 17-hydroxypregnenolone, progesterone, testosterone and oestradiol were seen. A significant fall in oestrone concentration occurred at the same time. After dexamethasone was added the elevated steroid concentrations fell back to the baseline while oestrone remained depressed below this and testosterone was also significantly lowered. No change was seen in cortisol or ACTH concentration while patients were on trilostane alone but cortisol levels were undetectable after dexamethasone was added though, in most patients, ACTH remained detectable. There was no change in the ratio of delta 5:delta 4 steroids at any stage of therapy but a highly significant increase in the androstenedione: oestrone ratio was seen. We conclude that in long-term use in vivo it is difficult to demonstrate that trilostane inhibits 3 beta-hydroxysteroid dehydrogenase but it may produce inhibition of aromatase.

Lack of binding of serum glycoprotein hormone alpha subunit to concanavalin A-Sepharose reflects increased branching of the oligosaccharide chains.

The lectin-binding properties of serum alpha subunit were studied by lectin affinity chromatography. Normal individuals and most patients with pituitary tumours produced alpha subunit which bound specifically to Concanavalin A-Sepharose (Con A). Some patients with pituitary tumours produced both Con A-reactive alpha subunit and alpha subunit which did not bind to Con A. Concanavalin A-Sepharose-binding alpha subunit from all sources bound strongly to Ricinus communis agglutinin-Sepharose after treatment with neuraminidase. Serum alpha 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 alpha 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 alpha 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 alpha subunit from normal controls is a Con A-reactive, biantennate complex oligosaccharide and (b) that the structural alteration which results in serum alpha subunit which does not bind to Con A in some patients with pituitary tumours is not an absence of carbohydrate, rather the alpha subunit contains highly branched, either complex or hybrid oligosaccharides.