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OBJECTIVE: ACTH is secreted by the pituitary following processing of larger molecular weight precursors, proopiomelanocortin and pro-ACTH. Ectopic ACTH syndrome refers to the secretion of ACTH by non-pituitary tumours, but the predominant circulating form of proopiomelanocortin-related peptides remains unclear. PATIENTS: Fifteen patients with ectopic ACTH syndrome were compared to 20 patients with pituitary-dependent Cushing's syndrome, 22 patients with small cell lung carcinoma but no evidence of Cushing's syndrome, and 25 controls. DESIGN AND MEASUREMENTS: Measurement of plasma ACTH and ACTH precursors using specific monoclonal-based immunoradiometric assays at 0900 h and, in five patients with ectopic ACTH syndrome, at 15-minute intervals for 6-24 hours. RESULTS: ACTH precursors were grossly elevated in patients with ectopic ACTH syndrome (median 2194, range 139-18000 pmol/l) compared to patients with Cushing's disease (median 33, 8-73 pmol/l, P < 0.001), patients with small cell lung carcinomas (38, 8-117 pmol/l, P < 0.001) and controls (26, 10-39 pmol/l, P < 0.001). ACTH levels were also elevated in ectopic ACTH syndrome (0900 h median 34, 11-152 pmol/l) compared to patients with Cushing's disease (0900 h median 8, 3-19 pmol/l), but not to the same degree as ACTH precursors. In contrast with Cushing's disease, ACTH was secreted in a non-pulsatile fashion. ACTH precursors but not ACTH itself correlated with plasma cortisol in patients with ectopic ACTH syndrome (r = 0.65, P < 0.05). Chromatographic analysis of plasma from a patient with ectopic ACTH syndrome confirmed ACTH precursors and not ACTH to be the predominant circulating form. With the cross-reactivity of proopiomelanocortin and pro-ACTH in the ACTH IRMA of < 1 and < 10% respectively, ACTH precursors could represent all the ACTH immunoreactivity in patients with ectopic ACTH syndrome. CONCLUSIONS: Ectopic 'ACTH' is characterized by aberrant processing of proopiomelanocortin and should be more accurately referred to as 'ectopic ACTH precursor syndrome'.

OBJECTIVE We aimed to investigate the pattern of 24-hour ACTH and cortisol secretion in pitultary-dependent Cushing's syndrome and to evaluate the pituitary and hypothalamic contributions to the disease. PATIENTS Five women with Cushing's disease (mean age 35±5 (SEM) years) and five normal female controls (mean age 25±2 years) were studied. DESIGN AND MEASUREMENTS Plasma ACTH and cortisol levels were measured every 15 minutes for 24 hours using established IRMA and RIA respectively. ACTH and cortisol mean and trough levels, pulse number and amplitude were calculated using established computer software, programmed to identify ACTH and cortisol peaks. RESULTS Patients with Cushing's disease had a twofold increase in 24-hour mean cortisol levels and a threefold increase in 24-hour mean ACTH levels (Cushing's 5.9±1.0, controls 1.9±0.2 pmol/l, P

A patient presented with apparent septicaemic shock. Full invasive cardiovascular monitoring revealed systemic hypotension, high normal cardiac output, and a low systemic vascular resistance. Maintenance of systemic vascular resistance and blood pressure was shown to be highly dependent on noradrenaline. Subsequent investigation revealed the presence of a phaeochromocytoma producing adrenaline. The mechanisms by which phaeochromocytomas may produce hypotension are discussed.

The potential importance of the obstructive sleep apnoea syndrome (OSA) has been recognized only in the last few years. Epidemiological studies suggest that symptomatic OSA occurs in 1-2% of middle-aged men and in approximately half that number of women. The relation of OSA to vascular disease is uncertain and the main indication for treatment is the relief of disabling sleepiness. Two recent evidence based analyses have produced diametrically opposed conclusions on the efficacy of treatment with nasal continuous positive airway pressure (CPAP). However, recent controlled studies confirm the overwhelming clinical experience of benefit. Facilities for the investigation and treatment of patients with OSA in the UK are subject to severe financial constraints and the availability of CPAP treatment lags markedly behind that in other countries for which data are available.

Summary OBJECTIVE We explored the hypothesis that activation of the hypothalamo-pituitary-adrenal axis is involved in the pathogenesis of hyperandrogenism in the polycystic ovary syndrome. PATIENTS Seven women with polycystic ovary syndrome (mean age 27.6 ± 1.6 (SEM) years) (hirsutism, oligo/ amenorrhoea and elevated serum testosterone and dehydroepiandrosterone sulphate) and nine normal female controls (mean age 24.6 ± 15 years) were studied. To exclude anovulation as a confounding factor, four of these normal women were studied in both the follicular and luteal phase of the menstrual cycle. DESIGN AND MEASUREMENTS Plasma ACTH and Cortisol levels were measured at 15-minute intervals between 0600 h and 1800 h. ACTH and Cortisol mean levels, pulse number and amplitude were calculated using established computer software, programmed to identify ACTH and Cortisol peaks. RESULTS With the exception of mean plasma levels of ACTH over the 12-hour period, which were reduced in the luteal phase of the menstrual cycle (1.8 ± 0.3 pmol/l) compared to the follicular phase (2.3 ± 0.2 pmol/l, P < 005), there were no differences in the pattern of ACTH or Cortisol secretion across the normal cycle. In polycystic ovary syndrome, 12-hour ACTH pulse frequency was reduced (3.6 ± 0 7) compared with controls (5.9 ± 0.6, P

Only five cases of growth hormone secreting pituitary carcinoma have been documented. We present a 49-year-old West Indian male with grossly elevated plasma growth hormone (760–10 400 mU/l), and a large aggressive pituitary tumour that continued to grow despite repeated pituitary surgery, radiotherapy and medical therapy (bromocriptine and somatostatin analogue). Thirteen years after diagnosis the patient died secondary to left ventricular failure. A post-mortem revealed a large locally invasive pituitary tumour, but in addition numerous tumour seedlings within the cerebrospinal fluid space, and a solitary intraparenchymal tumour deposit within the right temporal lobe, clearly separate from the primary tumour. Pituitary carcinoma should be considered in any acromegalic with grossly elevated plasma growth hormone levels who falls to respond to conventional therapy.

General physicians not a thing of the past Editor,--Stuart Handysides states that “the general physician in hospital practice is a thing of the past,”1 quoting a speculative article written some 10 years ago. Neither the statement nor the speculation is correct. Most posts advertised for consultant physicians, even though a …

The case reported is of a 46-year-old woman who had congenital adrenal hyperplasia due to a 21-hydroxylase deficiency, and in whom there was the development of an ACTH secreting pituitary tumour. The patient was untreated with glucocorticoids until the age of 32 years when she presented with infertility. She next presented with amenorrhoea at the age of 44 years when she was found to have an enlarged pituitary fossa. Despite treatment with bromocriptine and adequate doses of dexamethasone, the tumour enlarged and required operative treatment 1 year later. Before and after operation, plasma ACTH levels were between 300 and 400 ng/l, immunocytochemistry showed staining for ACTH and other structurally related pro-opiocortin peptides but for no other hormones, and the tumour secreted large amounts of ACTH in vitro. The report of this case is to our knowledge the first account of a feedback tumour in congenital adrenal hyperplasia and provides yet another reason why patients with this condition should be treated, and good control achieved.

We have followed nine adult patients with congenital adrenal hyperplasia (CAH) for between 7-77 months on dexamethasone (DXM) 0.5 mg mane and 0.25 mg nocte, reducing to 0.5 mg mane. Twenty-four hour profiles of ACTH, 17-hydroxyprogesterone (17OHP), and androstenedione were performed; the areas under the curves (AUC) and the heights of the morning peaks were used to assess biochemical control. Comparisons were made between treatment before DXM (pre-DXM), 0.75 mg for 2 weeks (DXM-ST), 0.75 mg for at least 3 months (DXM-LT), and 0.5 mg for at least 3 months (DXM-0.5). None of the three males suffered any significant side-effects. All women had menstrual disturbance but in three ovulation was induced. One female developed Cushing's syndrome and two developed hirsutism which resolved on stopping DXM. Overall there was no significant difference between DXM-ST and DXM-LT (mean AUCs for ACTH: DXM-ST 660, DXM-LT 383, for 17OHP: DXM-ST 1177, DXM-LT 587, for androstenedione DXM-ST 232, DXM-LT 121). Reduction of the dose from 0.75 mg to 0.5 mg led to significant deterioration in control (Mean AUC's for ACTH DXM-0.5, 1123 (P less than 0.02), for 17OHP DXM-0.5, 2068 (P less than 0.002), for androstenedione DXM-0.5, 213 (P less than 0.5). We conclude that DXM is a satisfactory regime but the dose must be adjusted for each patient.

SUMMARY The hormonal effects of tamoxifen (10 mg daily for 6 months) have been studied in nine men with oligospermia. Basal concentrations of serum LH (1·7 ± 0·1 (s.e.m.) i.u./l) increased to a maximum of 4·1 ± 1·3 i.u./l (P < 0·001) after 6 months, and FSH rose from 4·9 ± 1·0 to a maximum of 7·7 ± 1·3 i.u./l after 4 months of treatment (P < 0·01). The response to luteinizing hormone releasing hormone (LH-RH) was studied at monthly intervals. Sums of increments of serum LH increased from 35 ± 4 to 92 ± 17 i.u./l at 4 months (P < 0·001) and of FSH from 14 ± 3·4 to 23 ± 3·5 i.u./l at 4 months (P < 0·01). Basal serum androgens rose from 25 ± 2·7 to 38 ± 2·4 nmol/l after 4 months of treatment (P < 0·05), and serum oestradiol-17β increased from 185 ± 25 to 631 ± 90 pmol/l by 6 months (P < 0·001). No significant changes occurred in sperm counts. Five normal men acted as controls: they were given tamoxifen for 1 week. No significant changes were observed in serum LH, FSH or release of these hormones following administration of LH-RH. Serum androgens and oestrogens however, increased significantly by day 4 of treatment (P < 0·05).

The oestrogen feedback and gonadotrophin release in ten amenorrhoeic women were investigated, using intramuscular injection of 1 mg oestradiol benzoate. Serial estimations of serum oestradiol and gonadotrophins (LH and FSH) were made over a period of 72 h following the injection. Five patients demonstrated positive feedback release of LH to the oestrogen stimulus with elevated levels of LH significantly above baseline (P less than 0.001), which occurred between 48 and 72 h after the injection. Two of the five patients also demonstrated elevated FSH levels accompanying these LH peaks, The hypothalamic-pituitary axis was postulated to be intact in these five patients, and all ovulated on clomiphene. None of the remaining five subjects showed any increase in serum gonadotrophin levels in response to oestradiol and none ovulated on clomiphene when given a dose of up to 200 mg daily x5 days. This 'oestrogen provocation test" seems to be a useful means of evaluating the functional capacity of the hypothalamic-pituitary axis for gonadotrophin release and has proved useful in predicting responsiveness to clomiphene in amenorrhoeic women.

Growth hormone was shown in histological sections of 25 pituitary adenomas from acromegalic patients by means of the unlabelled peroxidase-antiperoxidase (PAP) technique. On the basis of the numbers of cytoplasmic granules, the cells of the adenomas were of two types: densely granulated and sparsely granulated. The densely granulated cells had abundant cytoplasm containing numerous granules, whereas the sparsely granulated cells had little cytoplasm with scanty granules. Depending on the predominant cell type the adenomas were also classified as densely granulated or sparsely granulated: 21 of the 25 adenomas (84%) were densely granulated and four (16%) sparsely granulated. There was some variation, however, in the relative numbers of the two types of cell from one part of an adenoma to another, a feature consistent with one type of cell in different phases of activity. There was no significant difference in mean serum growth hormone concentrations between the two groups, and granularity of the adenomas in histological sections did not therefore correlate with secretory activity. Nine adenomas showed extrasellar extension. The mean serum growth hormone concentration in these cases was lower than the mean of the adenomas confined to the sella turcica. Thus the size of the tumour did not correlate with the serum growth hormone concentration. Three of the four adenomas in the sparsely granulated group showed extrasellar extension, compared with 6 of 21 classified as densely granulated. This suggests that sparsely granulated adenomas have a more aggressive pattern of behaviour, but histological evidence for this was lacking.

Twenty-two normal, regularly menstruating female subjects had an LHRH test performed before and after pretreatment with 0.5 mg, 1 mg. or 2.5 mg of oestradiol benzoate during the follicular phase of their menstrual cyclees (days 4-8). Two further women acted as controls and received no oestrogen; they showed identical responses for both LH and FSH release when LHRH tests were performed at intervals of 48 h. Oestrogen pretreatment induced a biphasic effect upon subsequent LHRH response. Four subjects retested 20 h after 0.5 mg oestradiol benzoate showed either no change or a slight suppression of LH and FSH release. Fifteen of the eighteen women pretreated with oestradiol benzoate and retested 44 h later showed significantly increased LH release and fourteen significantly increased FSH release when compared to their control responses. The responses appeared to be dose related with a positive correlation between sum of LH increments and basal oestradiol levels (R = 0.61; P less than 0.001) and a similar correlation (r = 0.67; P less than 0.001) between sum of FSH increments and basal oestradiol levels. The physiological significance of this biphasic action of oestrogen upon pituitary sensitivity is discussed in relation to the control of the menstrual cycle.

The kinetic profile of diltiazem, a novel calcium antagonist, was studied in 12 volunteers following oral (60 mg) and intravenous (15 mg) administration. After i.v. administration biphasic elimination was observed, with a distribution half-life of 0.3 +/- 0.2 h and an elimination half-life of 3.1 +/- 1.0 h; the apparent volume of distribution was 5.3 +/- 1.71/kg and the total clearance was 1.28 +/- 0.48 l/kg/h. After the oral dose the elimination had a half-life of 3.2 +/- 1.3 h. The absolute bioavailability of diltiazem ranged from 24 to 74% (mean 42 +/- 18%). The interindividual variation may be explained by a variable first pass effect.

The effect of castration and gonadal steroid replacement on the concentrations of LH-β and α subunit and prolactin mRNA was examined in mice. Mouse LH-β, α and prolactin mRNAs were approximately 0·8, 0·7 and 1·1 kb in size respectively. After ovariectomy, LH-β mRNA levels increased 2- to 2·5-fold, while α mRNA levels increased 2·5-fold 6 and 10 days after ovariectomy. Serum LH rose after 2 days to reach six times control values at 10 days. Pituitary LH content doubled by 8 days after ovariectomy. Prolactin mRNA levels decreased to 50–60% of control at 3, 6, 8 and 10 days after ovariectomy and parallelled the fall in serum prolaction. Pituitary prolactin content fell more slowly, to 50% of intact control values by 10 days. The increase in both LH-β and α subunit mRNA, and decrease in prolactin mRNA, and serum and pituitary hormone changes, after ovariectomy were prevented by oestradiol or oestradiol plus progesterone replacement. Levels of LH-β mRNA increased more quickly in male than in female mice, theearliest change being seen 24 h after orchidectomy. Maximum values (two- to threefold) were found on day 6 after orchidectomy. Concentrations of α mRNA increased by 12 h to between 2 and 2·5 times control from 3 to 10 days after orchidectomy. Serum LH doubled by 12 h and was three to five times greater than control values up to 10 days. Pituitary LH content fell by 48 h before gradually increasing to intact values after 10 days. Prolactin mRNA levels decreased progressively from 2 days after orchidectomy, and this decrease was preceded by a fall in serum and pituitary prolactin which remained low throughout the experiment. Testosterone treatment attenuated the rise in α mRNA, prevented the rise in LH-β mRNA and serum LH and partially restored the decrease in prolactin mRNA seen after orchidectomy. We conclude that in mice, as in rats and ewes, both LH-β and α subunit mRNAs are negatively regulated by gonadal steroids, whereas prolactin mRNA is positively regulated, although there are temporal differences in patterns of mRNA responses between males and females. By comparison with female rats the rise in LH-β mRNA after ovariectomy was slower in mice. Moreover, the discordant changes in pituitary LH content and LH subunit mRNAs seen in mice after castration were not observed in rats. Furthermore, pituitary prolactin and prolactin mRNA do not fall after orchidectomy of rats. The modest (50%) increase of LH-β mRNA after castration of mice suggests that an increase in mRNA is not necessarily required for increased LH production.

SUMMARY We have compared three glucocorticoids, hydrocortisone (HC) (20 mg mane & 10 mg nocte), cortisone acetate (CA) (25 mg mane & 12.5 mg nocte), dexamethasone (DXM) (0.5 mg mane & 0.25 mg nocte), for their effect on the biochemical control of adult patients with congenital adrenal hyperplasia (CAH). Twenty-four-hour profiles of plasma concentrations of ACTH, 17-hydroxyprogesterone (170HP) and androstenedione (Δ4A), and 09.00 h dehydroepiandrosterone sulphate (DHAS) plasma concentrations were used to assess control. The patients were studied after 2 weeks on each glucocorticoid. The areas under the curves, the heights of the morning peaks of each hormone, the midnight concentrations, and the concentrations of hormones just before the evening dose were analysed. The results show that all the indices, except the midnight concentrations which were uniformally low, were significantly lower on DXM than on either HC or CA. There were no significant differences between HC and CA for any of the indices. The DHAS concentrations were low on all three glucocorticoids but again significantly lower on DXM. DXM (0.5 mg mane & 0.25 mg nocte) is therefore, in the short term, a better suppressor of the pituitary-adrenal axis in adults with CAH than either HC or CA, and in the dose used did not suppress ACTH to undetectable levels, nor the steroids to below levels found in normal subjects.

The long term effects of bromocriptine in 12 acromegalics treated for a mean duration of 10.2 months are reported. Seven showed a significant (P less than 0.05) and sustained fall in serum immunoreactive growth hormone (GH) levels throughout 24 h, 6 of whom had a 50% or greater reduction in mean circulating GH during glucose tolerance testing. Only one patient had mean serum GH levels throughout the day suppressed to normal (less than 5 mIU/l) but 3 had suppression of mean serum GH during GTT to normal or very near normal (less than 10 mIU/l). The effective dose was 20 mg daily. Only 4 patients reported any improvement in soft tissue swelling and acral features, which was unrelated to the GH response. Possible reasons for the discrepancy between clinical and biochemical responses are discussed. In 9 of the 12 patients bromocriptine was discontinued and pituitary ablative therapy offered. Three out of 4 patients who underwent trans-sphenoidal hypophysectomy had mean GH levels during GTT reduced to less than 7 mIU/l. In the three who continued bromocriptine treatment GH suppression was maintained at less than 10 mIU/l for up to 3 years but with little change in acral features. Although bromocriptine is safe and was well tolerated it is not as effective as existing forms of pituitary ablative therapy and should be reserved for those cases where ablation is contraindicated or unsuccessful.

Fifteen patients with the polycystic ovarian (PCO) syndrome were classified into Group A (n = 6) and Group B (n = 9) based on their LH responses to LHRH before and at 44 and 92h after administration of oestradiol benzoate. Adrenal function in both groups was assessed by comparing the hormone responses to ACTH (0.5mg twice daily for 4 days) with those obtained in nine normally ovulating women during the early follicular phase of their cycles. In Group A patients there was no significant difference from normals in the serum concentration of dehydroepiandrosterone sulphate (DHAS), 17 alpha-hydroxy-progesterone (17-OHP) or androgens (testosterone and dihydrotestosterone). In contrast, the serum concentrations in Group B were significantly higher (P less than 0.01) for each of these steroids before ACTH, and remained higher at 2 and 4 days for DHAS, but not for the other two steroids. The concentration of oestrone was significantly higher (P less than 0.05) in Group B patients before, and 2 days after, ACTH, while in Group A patients higher concentrations (P less than 0.02) were found only after 2 days. The concentrations of oestradiol, on the other hand, were not different from normal in either group before ACTH and became lower than normal in both groups at 2 days and remained lower at 4 days in Group B. The concentration of cortisol was within the normal range throughout in Group A, but was lower than normal after 4 days in Group B patients (P less than 0.05). The ratios between the sums of concentrations of DHAS to cortisol on days 2 and 4 (P less than 0.001) or 17-OHP to cortisol (P less than 0.05) were elevated in Group B compared with normal subjects. LH, FSH and prolactin values were normal throughout in Group A, but in Group B patients the mean value for LH was significantly elevated before ACTH and at 4 days after ACTH (P less than 0.02).

Summary Synthetic luteinizing hormone-releasing hormone (LH-RH) was given intravenously in a dose of 100μg. to 24 normal regularly menstruating women at various stages of the same menstrual cycle. The luteinizing hormone (LH) response was always greater during the luteal phase (days 22 to 24) than during the early follicular (days 4 to 6) or mid-follicular phases (days 8 to 10). No statistical difference was shown between the two groups studied in the early and mid-follicular phases for LH release, but in four subjects, studied on four occasions in the same cycle, the greatest release of LH occurred on day 14. The follicle stimulating hormone (FSH) responses were more variable although every patient showed a significant rise in circulating FSH after the injected LH-RH. The luteal phase response was greater in all but four of the subjects tested. However, a significantly larger response (0.1 0.05) was seen in the early follicular phase when compared with the mid-follicular phase responses. No correlation between LH or FSH responses and circulating progesterone levels could be demonstrated in any of the subjects. A negative correlation (r=−0.55; 0.1>p>0.05) was found between sum of FSH increments and circulating oestradiol during the early follicular phase, but no such correlation was seen in the mid-follicular phase responses. Similarly, a negative correlation between sum of FSH increments and oestradiol (r=−0.70; 0.05>p>0.02) was demonstrated in the luteal phase responses, but no correlation with LH response was apparent.

Serum androgen levels, including dehydroepiandrosterone sulphate (DHAS) which is thought to be solely of adrenal origin, are elevated in women with the polycystic ovarian syndrome. We have investigated the possibility that this may be due to a mild form of congenital adrenal hyperplasia by measuring basal and stimulated levels of ACTH in women with this condition and have compared them to levels in normal women. We found no difference in the diurnal rhythm of ACTH between patients and normal subjects nor any difference in stimulated levels achieved after a single-dose oral metyrapone test. Thus there is no evidence from this study to support the idea that these patients might have congenital adrenal hyperplasia. There are two alternative hypotheses to explain the elevated DHAS levels. They may be associated with the high oestrogen levels, which interfere with the enzyme 3 beta-hydroxysteroid dehydrogenase, or there may be alteration of the factors controlling adrenal androgen secretion.

SUMMARY The response to synthetic luteinizing hormone-releasing hormone was studied in eighteen patients with the polycystic ovary syndrome. The release of follicle-stimulating hormone was similar to that found in normal women. The mean response of luteinizing hormone was similar to that found in the luteal phase, but significantly greater (P

SUMMARY In castrated animals and hypogonadal men other workers have shown an LH surge following oestrogen administration similar to that found in the normal female. However, there is no evidence that this can be achieved in intact males. We have therefore studied male transsexual patients before and after chronic oestrogen therapy given for at least three months to feminise the body habitus before undergoing plastic surgery. Subjects were assessed for the acute effects of oestradiol valerate on sex steroid hormone levels and gonadotrophin responses to gonadotrophin releasing hormone. The results showed that longterm treatment could transform the normal male pattern of a suppressive eifect of oestrogen on gonadotrophin release to one where the oestrogen increased LH levels and amplified the effect of LHRH on gonadotrophin release. This pattern is similar to that found in normal women and indicates that longterm oestrogen treatment to males can feminise gonadotrophin responses.

SUMMARY Ovarian metabolism of C19-steroids and oestrogens has been assessed at ovarian wedge resection in 22 patients with polycystic ovaries. There were marked variations between different patients. High concentrations of androstenedione were found in ovarian vein plasma in some patients, and always after stimulation with human pituitary follicle-stimulating hormone (HP-FSH) in vivo. Its contribution to the daily production of testosterone has been considered. No measurable amounts of testosterone or dehydroepiandrosterone were found. Oestradiol concentration was sometimes normal or above. Large amounts of androstenedione were generally isolated from cyst fluid. Occasionally testosterone was found and also epitestosterone after FSH. That concentrations of oestrogens in cyst fluid are low was confirmed, but sometimes higher levels were found after FSH. Slices of ovarian tissue generally converted progesterone or pregnenolone to androstenedione in high yield but conversion to oestrogen appeared to be low. However, the difficulty of making quantitative comparisons by this method, in the absence of knowledge of the sizes of the pools of endogenous steroids in the tissue, has been recognized. No evidence was found in any of the 18 cases examined for a lack of 3β-hydroxysteroid dehydrogenase. In vitro synthesis of epitestosterone by both normal and polycystic ovaries has been observed. A coincidental granulosa cell tumour in one patient synthesized testosterone in high yield.

A combined test consisting of the simultaneous administration of insulin, thyrotrophin-releasing hormone (TRH), and luteinizing hormone and follicle stimulating hormone-releasing hormone (LH/FSH-RH) was performed in 24 people. Eleven of these also had the three individual tests performed separately, and the remaining 13 had a separate test of either LH/FSH-RH and TRH together or singly at a later date. In both normal people and patients, whether the tests were performed alone or in combination, no difference was found between the hormone responses (growth hormone, cortisol, LH, FSH, thyroid-stimulating hormone) seen to these stimuli. It is proposed that combined administration of insulin and the hypothalamic releasing hormones may be used as a single test for the assessment of anterior pituitary function. The test is convenient and time saving, and with care can be performed in outpatients.

SUMMARY C19-steroids, testosterone and oestrogen production rates have been measured simultaneously by urinary isotope dilution in a group of 18 patients with polycystic ovaries and in two normal women. The production of total C19-steroids remained high in seven patients under dexamethasone suppression, suggesting a major ovarian contribution. In eight it did not remain high, suggesting a major adrenal contribution. The rate of testosterone production was usually normal under dexamethasone. The rate of oestrogen production was not subnormal and even occasionally raised. Ovarian wedge resection produced a good clinical response in 75% of the observations, and C19-steroid production fell. The latter was not so evident if there was no clinical response. Testosterone production was usually reduced. Oestrogen production rate changed irregularly. Administration of human pituitary follicle-stimulating hormone caused a concurrent increase in C19-steroids, testosterone and oestrogen production in four out of five patients. The inadequacy of the urinary isotope dilution technique, in attempting to measure testosterone secretion and interconversion of testosterone and androstenedione in these patients, has been stressed and discussed. Some correlations have been established with direct observations on ovarian steroid metabolism in certain patients reported elsewhere.

SUMMARY A patient is described who showed evidence of 25 years' duration of intermittent hyperadrenocorticalism due to adrenocortical hyperplasia. The most pronounced clinical symptom was oedema formation, which was shown to be associated with phases of increased adrenocortical activity. Cortisol secretion rates, for example, ranged from 24 to 161 mg./24 hr. There was also potassium depletion. The response to dexamethasone was repeatedly anomalous, there being a tenfold increase in excretion of urinary 17-hydroxycorticosteroids. Responses to metyrapone and pyrogen were absent but the response to insulin appeared excessive. There was no alteration by dexamethasone in vitro of synthesis of cortisol or corticosterone. Binding of plasma cortisol and corticosteroid-binding globulin were decreased.

The excretion of pethidine and its metabolite norpethidine is increased in acid urine and decreased in alkaline urine. Excretion of these two bases is the main route of removal of pethidine from the body if the urine is highly acid. If the urine is alkaline, excretion of the hydrolysis products meperidinic and normeperidinic acids, both as free acids and as conjugates, is the more important means of elimination of the drug. Acidification of the urine with ammonium chloride is indicated in the therapy of cases of pethidine poisoning in patients with reduced metabolic breakdown of the drug by the microsomal enzyme systems within liver cells. Reversed-phase chromatography of the dinitrophenyl derivative of norpethidine may prove to be of forensic importance in the diagnosis of pethidine poisoning or of pethidine addiction. Norpethidine can be detected in the urine by this method for at least 3 days after the last dose of pethidine. Analytical sensitivity is increased by acidification of the urine which produces a temporary rise of the excretion rate.

The in vitro uptake of cycloleu-cine, histidine, valine and α-methyl-d-glucopy-ranoside into intestinal segments of hypothyroid rats has been studied. Pieces of jejunum were obtained from animals that had been rendered hypothyroid by thyroidectomy followed by administration of 0.5 me 131I, as well as from control euthyroid animals. With each substance, and at all time points studied, there was an increased intracellular accumulation in the hypothyroid group. This effect was diminished by treating the animals with parenteral triiodothyronine 15 μg for 4–5 days. When valine accumulation was investigated in more detail, it was demonstrated that there was no difference in the efflux of amino acid from the segments in the hypothyroid and control animals. Michaelis-Menten studies showed that intestine from hypothyroid animals had a higher velocity of transport than either the control or treated hypothyroid group. Thyroxine added to incubation flasks containing tissue from the hypothyroid rats did not alter the ...

SUMMARY 1. Various parameters of androgen metabolism have been studied in a group of 11 hypogonadal men. They included the rates of: 17-oxosteroid excretion, total production of C-19 steroids, secretion of testosterone and total production of testosterone (including testosterone converted peripherally from other steroids). The concentrations of testosterone and androstenedione were also measured in peripheral and testicular venous plasma. In addition the effects of stimulation and suppression of adrenocortical function and of testicular stimulation were studied. 2. The patients were divided into three groups according to clinical features, gonadotrophin excretion and testicular histology and an attempt was made to correlate these tests with the steroid studies. 3. Patients with poorly developed secondary sexual characteristics had a low testicular secretion of testosterone. There was also an indication that in these cases the adrenal gland contributed significantly to the plasma testosterone. 4. Methods involving estimations of androgens in blood are shown to be of more value than estimations in urine. In some instances anomalous results were obtained for the rates of secretion of testosterone. The possible significance of these anomalies is discussed.

The intranasal administration of LRH produces rises in serum gonadotrophin concentration similar to those found after 100 μg i.v. LRH. The maximum effect on LH was seen at a dose of 2.5 mg. PSH responses were much smaller and did not display the dose dependence of the LH changes. The results of this study have important implications for the treatment of anovulatory infertility in the female and isolated gonadotrophin deficiency in the male.

Although many studies have been devoted to a delineation of the clinical syndrome of isolated lactase deficiency in the adult (Cuatrecasas et al., 1965 ; Haemmerli et al., 1965 ; McMichael et al., 1965 ; Peternel, 1965 ; Sheehy and Anderson, 1965 ; Cook and Kajubi, 1966), to the in-vivo metabolism of lactose in this syndrome (Durand, 1964 ; Cuatrecasas et al., 1965), and to the characteristics of the enzymes whose absence is respon sible for the disorder (Dahlqvist et al., 1963 ; Semenza et al., 1965 ; Hsia et al., 1966), there have been no investigations of the cellular transport and metabolism of lactose by the small intestine in lactase deficiency. Miller and Crane (1961a, 1961b) have shown that disaccharides, particularly sucrose and maltose, are hydrolysed at the brush border of the hamster intestinal epithelial cell and that the products of hydrolysis are either actively transported into the cell or diffuse into the intracellular compartment. These workers were unable to show that intact disaccharides could be concentrated in the mucosal cell. On the other hand, Escherichia coli possess transport systems which facilitate the entry of unchanged galactosides without the necessity for prior hydrolysis (Rickenberg et al., 1956 ; Cohen and Monod, 1957). It therefore seemed important to study the cellular handling of lactose in isolated lactase deficiency to determine if disaccharide accumulation could occur in the mucosal cell of the human small intestine in the absence of the hydrolytic enzyme.

Forty-five post-menopausal women with recurrent breast cancer were treated with the antioestrogen, tamoxifen, 20 mg twice daily. Clinical assessment after 12 weeks indicated that 18 (40%) showed some remission. Gonadotrophins were suppressed within two weeks to relatively constant concentrations within the post-menopausal range, responses to luteinising hormone-releasing hormone (LH-RH) did not change, and androgen concentrations remained within the normal range in all patients. Oestradiol concentrations rose steadily only in women in whom treatment failed. Serum prolactin concentrations were raised in 18 out of the 44 (41%) patients in whom they were measured; 13 of these did not respond to treatment. Treatment did not change the average prolactin concentration when this was within the normal range, but it significantly reduced prolactin concentrations in hyperprolactinaemic patients--within two weeks (P less than 0-01) in those who responded well and by six weeks (P less than 0-05) in those who showed no remission. Among patients with normal prolactin values the release of prolactin after thyrotrophin-releasing hormone was significantly greater in those with no remission than in those who responded to tamoxifen. Responses in those with hyperprolactinaemia were reduced to about half the control values, and again this change occurred faster in those who were successfully treated. Patients therefore seem to have a better chance of responding to anti-oestrogen treatment if prolactin secretion is low.

SummaryHirsutism is usually caused either by an increase in androgen production by the ovary or adrenal or it may be due to increased sensitivity of the hair follicle to normal amounts of circulating androgens. The diagnostic possibilities can be resolved on clinical grounds by laparoscopy and by hormone measurements. The commonest causes of this symptom are ‘idiopathic hirsutism’ and the polycystic ovary syndrome. Treatment is of the underlying condition or, when that is not possible, by local removal of hair or by the administration of oral contraceptives or glucocorticoids.

Summary Basal prolactin concentrations were measured in 77 patients presenting with amenorrhoea; 17 per cent were found to have hyperprolactinaemia. The release of prolactin in response to a standard dose of thyrotrophin releasing hormone for amenorrhoeic subjects with normal basal levels of prolactin was within the normal range. However, patients with hyperprolactinaemic amenorrhoea and no evidence of pituitary tumour were found to have a blunted response.

An LHRH test was performed before and at both 44 and 92 h after the administration of 2.5 mg oestradiol benzoate in eleven patients with hyperprolactinaemia, eight with idiopathic secondary amenorrhoea and seven with oligomenorrhoea. The basal serum hormone concentrations and the responses to LHRH were compared with the same tests performed on ten normal subjects during the early follicular phase of their menstrual cycles (days 4--6). Mean basal concentrations of oestradiol in each group of patients and oestrone in those with hyperprolactinaemia were significantly lower than in the normal subjects. The mean concentration of prolactin in women with secondary amenorrhoea remained lower than in the normal women throught the tests (P less than 0.05). The LH and FSH responses to LHRH before oestrogen in patients with hyperprolactinaemia and of FSH in those with secondary amenorrhoea, were greater than in the normal subjects (P less than 0.001). After oestrogen treatment the responses were similar in all groups except in those with oligomenorrhoea where LH and FSH responses at 44 h (P less than 0.05 and P less than 0.01 respectively) and LH responses at 92 h (P less than 0.01) were lower than in normal controls. The responses at 92 h in all groups were greater than at 44 h (amplification) but the amplification at 92 h and at 44 h compared to the pre-treatment responses, tended to be lower in each group of patients compared to the normal controls. In the hyperprolactinaemic group of patients there was a negative correlation between the basal prolactin concentration and the gonadotrophin amplifications at 92 h (P less than 0.01), and a positive correlation between the basal oestrone levels and the amplifications at 92 h (P less than 0.01). The results of the oestrogen amplification test in eleven of the non-hyperprolactinaemic anovular patients were compared with the ovulatory response to 100 mg clomiphene given for 5 days. Six showed a normal oestrogen amplification and they all ovulated. Two patients failed to show greater amplification at 92 than at 44 h and required human chorionic gonadotrophin (HCG) as well as clomiphene to ovulate. The other three showed a diminished LH amplification at 92 h; they required 200 mg clomiphene and showed a prolonged follicular phase. The responses of the hyperprolactinaemic patients to clomiphene were poor and there was a negative correlation between prolactin concentration and oestrogen production (P less than 0.01). All ten hyperprolactinaemic patients treated with bromocriptine ovulated and eight conceived. The oestrogen amplification test appears to have some value in predicting the subsequent response to clomiphene in non-hyperprolactinaemic anovular women.