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Insulin treated patients frequently develop insulin-binding antibody. Antisera from some patients, treated with bovine or bovine/porcine insulin mixtures, react differently with bovine and porcine insulin while for others there is no difference: when there is a difference there is greater avidity for bovine than porcine insulin. We studied antisera from 16 patients who had previously been treated with bovine insulin and then were changed to porcine insulin. Dissociation rate constants and association rates were measured with bovine and porcine insulin. Significant differences were found in association rates, which correlated well with binding at equilibrium (r=0.91), but not in dissociation rates. For 11 subjects who stayed on highly purified porcine insulin, long term reduction in insulin requirement correlated with the magnitude of the difference in antibody reaction to bovine and porcine insulin (r=0.74).

Infusion of growth-hormone release inhibiting hormone (G.H.-R.I.H.) in four fasting subjects reduced plasma glucagon and insulin concentrations to undetectable levels and this was associated with a highly significant decline in plasma-glucose (28±S.E.M. 3 mg. per 100 ml. in 1 hour, p

Clinical, laboratory and radiological findings were evaluated in twenty-nine men who had raised serum prolactin concentrations and pituitary tumours. Twenty-one had functionless pituitary tumours ('prolactinomas') and eight had acromegaly. Supraseller extension was detected in twenty of the twenty-six men who had lumbar airencephalography. Three patients were studied before, sixteen before and after and ten only after pituitary ablative therapy. Seventeen of these men complained of complete lack of libido and impotence and six had impaired libido and sexual potency; only six patients in this series denied reproductive symptoms. Thirteen of the impotent subjects had small soft testes, ten reduced facial and body hair and three had marked gynaecomastia. No features of hypogonadism were noted in the six patients without reproductive symptoms and none of the patients had galactorrhoea. Serum prolactin concentrations were higher and serum testosterone concentrations lower in the impotent men compared with those with normal sexual potency. Serum LH and FSH (both basal and in response to LHRH) oestradiol and oestrone concentrations were not different between the two groups and, except in those with post-operative hypopituitarism, were within the normal range. Following successful lowering of prolactin concentrations by surgery or bromocripitine or both, serum testosterone rose and potency returned; by contrast failure to lower prolactin concentrations was associated with persistent impotence and hypogonadism. The endocrine profile of low serum testosterone concentrations with gonadotrophins which had not risen into the range usually seen in primary hypogonadism (together with the parallel increase of LH and testosterone in one patient studied sequentially during treatment which suppressed prolactin levels to normal), suggested that the impaired gonadal function was caused by a prolactin-mediated disturbance of hypothalamic-pituitary function.

Hypoglycaemic and growth hormone responses were studied at different steady-state plasma insulin concentrations during a graded infusion of monocomponent human insulin. The control group consisted of ten volunteer subjects. The other groups studied included women taking oral contraceptives and patients with obesity, thyrotoxicosis, myxoedema, acromegaly, diabetes mellitus (moderate and severe) and liver disease. The hypoglycaemic response was measured in two ways: (i) the percentage reduction in plasma glucose below basal, and (ii) the rate of fall of plasma glucose (Kg-%/min). Insulin sensitivity was greatest in the normal subjects and in the other groups decreased in the order thyrotoxicosis greater than oral contraceptive greater than obesity greater than myxoedema greater than acromegaly greater than liver disease. Insulin sensitivity was difficult to assess in the diabetic patients because basal plasma glucose concentrations were elevated. At any given insulin concentration, the diabetics metabolized approximately the same amount of glucose as the normal subjects but the fact that this rate of glucose turnover occurred at higher plasma glucose concentrations probably indicated insulin resistance. Within each group Kg at each dose level of insulin correlated with the steady state plasma insulin concentration during the same infusion period. Diminishing sensitivity to insulin was reflected in an increasing fasting plasma insulin and insulin/glucose ratio except in patients with diabetes. GH responses to insulin infusion in normal subjects reflected the pattern of fall of plasma glucose. In the diabetic patients GH secretion appeared to be related to the infusion of insulin and occurred before plasma glucose had fallen to hypoglycaemic levels. GH secretory patterns were within normal limits in women taking oral contraceptives and in seven of eleven patients with liver disease but were impaired in three of seven patients with thyrotoxicosis and four of five patients with myxoedema. Four obese patients had a markedly delayed but eventually normal GH response.

SUMMARY The response to the subcutaneous injection of glucagon (1 mg) has been studied as a test of the ability of the pituitary to secrete ACTH and growth hormone (GH). Tests have been performed on fifteen normal subjects or patients with unrelated conditions, nine patients with pituitary tumours and seventeen with acromegaly. It is suggested that a normal response is a peak level of 5 ng/ml or more of GH (standard NIH GH 1216C) and either a rise of plasma cortisol measured by competitive protein binding of at least 4 μg/100 ml or a peak level of 7 μg/100 ml. In seventeen patients the responses were compared with those obtained in the insulin hypoglycaemia test and there was good agreement. Measurement of plasma ACTH showed that the response is at pituitary and not adrenal cortical level. Peak responses of ACTH and GH were obtrained at 150 min and of cortisol at 180 min. Plasma glucagon concentrations were falling steadily by this time although still above the control level. The mechanism of action of glucagon is not clear but does not appear to be related to fall of blood sugar. The subcutaneous injection of glucagon is not without side effects; about half the patients were nauseated and nine vomited. Nevertheless we believe that a subcutaneous glucagon test is of value for testing the pituitary reserve of ACTH and GH in situations where insulin hypoglycaemia cannot be used.

Highly purified insulins offer the possibility of reducing insulin antibody levels and insulin requirement. Those likely to respond cannot be predicted on clinical grounds and a simple laboratory test is recommended for this purpose. This is based on insulin binding capacity (IBC) of plasma and has been used to follow a group of 47 patients over six months. 47 patients previously treated with British soluble and isophane insulins were changed to highly purified Leo Neutral and Leo Retard. 36 showed a reduction of insulin requirement and two groups could be identified. An IBC of greater than 40 muU/ml was associated in 94% with a reduction of insulin dose; if the IBC was less the response was unpredictable. The initial IBC was related to the initial insulin requirement and to the eventual percentage reduction. Serial measurements in patients with high initial IBC showed a steady fall. Measurement of the IBC is a simple investigation; if the level is greater than 40 muU/ml changing to a highly purified insulin is likely to be associated with reduction of insulin requirement.

A group of 14 patients with skin reactions to insulin have been treated with highly purified insulin over a period of 5--14 months while continuing to inject into the abnormal areas. Fat atrophy improved in all cases, coincident with a reduction in insulin requirement and insulin binding capacity. The response of patients with fat hypertrophy was less predictable, but there was an improvement in 3 out of 6 cases. Measurements of insulin binding capacity of the plasma suggested that fat atrophy and hypertrophy are immunologically distinct and some explanations for this are discussed. It is concluded that highly purified insulin benefits some patients with skin reactions to insulin.

Summary Results of treatment of 52 patients with amenorrhoea associated with hyper-prolactinaemia are presented. All patients had a detailed radiological examination of the pituitary fossa, including lateral tomography in every patient and air encephalography in those in whom a pituitary tumour was suspected. There were 17 patients with untreated pituitary tumours, 5 patients with previously treated pituitary tumours and persisting hyperprolactinaemia, and 30 patients with normal pituitary radiology. Patients with pituitary tumours were treated either by transsphenoidal or transfrontal surgical extirpation of the tumour, followed, if necessary, by external irradiation and/or bromocriptine. Four patients were treated with external irradiation as primary therapy, and three patients who did not wish to conceive were treated with bromocriptine as primary therapy. Patients with normal radiological appearances were treated with bromocriptine as primary treatment. Ovulatory menstrual cycles developed in 42 patients and there were 19 pregnancies. Those ovulating but not conceiving had adequate non-endocrine factors to account for the disparity. Failure of response was seen in 10 patients and was due to inadequate fall of prolactin in response to surgery (2 patients), external irradiation (3 patients) and bromocriptine (1 patient), and gonadotrophin deficiency which developed after surgery in 3 patients but was present pre-operatively in 1. The relative merits of treatment by surgery, external irradiation and bromocriptine are discussed and a policy of treatment outlined.

Summary A series of 26 patients diagnosed as having an insulin-secreting, islet-cell tumour of the pancreas is described. Three patients were treated medically, but in the remaining 23 the tumour was found at operation; 1 patient had a carcinoma with hepatic metastases, but in the other 22 the tumour was apparently benign and the subsequent course of these patients has confirmed this conclusion. The tumour was found at the initial operation in 19 of the 22 patients with a benign tumour treated surgically. Of the other 3, the tumour was removed at a second operation in 2 and at a third operation in 1. Two of the 22 patients died following the operation. Diazoxide was administered to 21 patients, before and/or after operation. It was given preoperatively to 17 patients, in all of whom it prevented the development of hypoglycaemic symptoms, but in 2 it caused serious fluid retention and had to be discontinued. Seven patients have been successfully treated with long term diazoxide, either as an alternative to surgery or following an unsuccessful operation, 1 of these being the patient with an islet-cell carcinoma. In these patients diazoxide has been given for up to 12 years without apparent side effects. Selective coeliac angiography was performed in 13 patients. In no patient did it provide critical information that significantly influenced the treatment of the patient. Percutaneous, transhepatic portal venous catheterization was performed in 4 patients and indicated the site of the tumour in 3, 2 of whom had had 1 previous operation and 1 had had 2 previous operations, at none of which was a tumour found: in all 3 patients the tumour was removed at a subsequent operation. The application of these findings to the management of patients with an insulinoma is discussed and a scheme of management is proposed.

Comparisons are made between the incidence, prognosis and treatment of juvenile-onset diabetes and other endocrinopathies in the young. 548 patients with insulin deficient diabetes diagnosed before 20 years of age have been reviewed. Excess mortality, especially at 35--40 years of age was found. Profiles of blood glucose and serum insulin have been studied and compared to those of normal subjects. The variation of insulin absorption and effect of insulin antibodies on the free insulin levels achieved after exogenous insulin injections have been demonstrated. The common occurrence of nocturnal subclinical hypoglycaemia following intermediate or long-acting insulin was often found to be the cause of poor diabetic control. Five out of 33 patients with 'difficult' diabetes had an unexplained resistance to high levels of free-insulin. The value of self-monitoring and HbAl measurements in the improvement of diabetic control and possibly life expectation is reviewed. The incidence of thyroid disease was found to be increased in 1779 insulin deficient diabetics of all ages and persistence of islet-cell antibodies suggests that the diabetes may be due to autoimmunity in some of these patients.

In patients with hyperosmolality as the sole cause or as an important factor in the production of the coma, therapy with hypotonic or isotonic fluids and with insulin, often in amounts less than those generally used in diabetic ketoacidosis, has proved effective in restoring consciousness in many, but not all, instances of hyperosmolar coma. The mortality, however, has been high, usually because of uremia, stroke, massive infection, pancreatitis, etc.

A method for the quantitative assessment of rapid changes in the delivery rate of hormones into the systemic circulation is reported. Plasma hormone levels are examined in relation to the “non-steady-state” disappearance rate measured following an intravenous infusion of the hormone. The insulin delivery rate in response to iv glucose has been measured; a biphasic insulin response has been confirmed; and the amount of insulin entering the systemic circulation in each phase can be examined.

Intravenous glucose and xylitol tests have been performed on normal, diabetic and obese subjects. In normal and obese subjects glucose is considerably more effective than xylitol in stimulating the first phase of insulin release. In diabetic subjects the initial response to xylitol is not reduced to the same extent as the response to glucose, and the 2 stimuli are equally effective in stimulating the reduced first phase response. Xylitol and glucose equally stimulate the second phase in all groups, but xylitol gives a less prolonged response. Neither xylitol nor glucose stimulates either phase in severely diabetic subjects. The equal stimulation of the second phase suggests xylitol and glucose may share a common stimulatory mechanism, possibly via the pentose phosphate pathway. The less prolonged xylitol response is probably due to lack of stimulus to insulin synthesis. Glucose appears to stimulate the first phase by a mechanism which is not equally available to xylitol; a deficiency of this “glu...

Plasma testosterone values in the basal state were within normal range (0.03–0.20 μg/100 ml) in 40 women with idiopathic hirsutism. Corticotropin stimulation tests were done in 8 patients; in 7, plasma testosterone increased significantly, and 1 patient tested at 4-hr intervals after 1 injection of ACTH gel showed maximal increase at 4 hr. Stimulation tests resulted in elevation of plasma testosterone in 3 of 4 nonhirsute female control subjects. Dexamethasone suppression tests resulted in significant reduction in plasma testosterone in 5 of 9 patients. HCG was given to 10 patients. No response in plasma testosterone was seen in the first 24 hr after 1500 U was given to 2 patients on 3 successive days, or after 12,000 U to 1 patient on 2 successive days, the adrenals being suppressed in all 3. A single injection of 24,000 U given to 1 patient while adrenal suppression was maintained resulted in a significant rise only after 72 hr. A single injection of 12,000 U was given, without adrenal suppress...

Aldosterone secretion rates have been measured in six patients with cirrhosis of the liver using 16–3H aldosterone. The proportion of administered radioactivity excreted as pH 1 extractable conjugates and as a glucuronide has also been determined. On unrestricted diets the aldosterone secretion rates were 19, 85 and 94 μg/day in three patients with ascites and oedema, and 140, 170 and 386 μg/day in three without fluid retention. Five of these patients were restudied after at least seven days on a low sodium diet (20 – 30 meq./day) and slight increases of secretion rate observed. The levels obtained were much lower than those previously reported for normal subjects on a low sodium diet. One patient was studied on a subsequent occasion after a haematemesis (urine sodium 1 meq./day), the secretion rate was 1130 μg/day. The proportion of administered radioactivity excreted as glucuronide was below normal in at least one determination on four of the six patients and there was an increase of the proportion excreted as pH 1 extractable conjugates. There was a striking variation of the proportion of radioactivity excreted as pH 1 extractable conjugates. One patient was studied on five occasions and the range was from 6.0 to 25.2 % of the administered radioactivity. This suggests that in patients with cirrhosis of the liver the urinary pH 1 extractable aldosterone may have a variable relationship to the actual secretion rate.

Stimulation tests have been performed on 26 patients with normal adrenal function, 23 hirsute women, 13 patients with Cushing's syndrome (liypcrplasia 11, adenoma 1, carcinoma 1), and 3 patients with hormone-secreting adrenocortical carcinoma without Cushing's syndrome. Suppression tests have been performed on 11 patients with Cushing's syndrome (hyperplasia 9, adenoma 1, carcinoma 1). Corticotropin-gel was used for stimulation and α fluorohydrocortisone for suppression. Response was assessed from changes in urinary 17-hydroxycorticosteroid and 17-ketosteroid excretion. In the stimulation tests an abnormal increase of urinary 7-hydroxycortieosteroid excretion was noted in 1 obese male, 1 normal male, 15 hirsute females and 7 of the patients with Cushing's syndrome due to adrenocortical hyperplasia. There was a moderate increase of urinary 17-hydroxycorticosteroids in the patient with an adenoma and a very slight increase in the patient with Cushing's sjaidrome due to a carcinoma. In 2 of the patients with...

This study was planned to investigate the pathogenesis of diabetes in acromegaly. Standard intravenous glucose tolerance tests were done with measurements of blood sugar, plasma insulin, growth hormone and free fatty acids. Sixteen patients were studied, and 10 had more than one glucose tolerance test. Seven of the patients had impaired carbohydrate tolerance, including 2 with symptomatic diabetes. In 6 patients serial tests showed the change that may occur as carbohydrate tolerance deteriorates, and in 5 the response to surgical hypophysectomy was observed. Fasting hyperinsulinism was present in 6, and insulin response to intravenous glucose was increased in 10. The pattern of this response varied—in 10 there was a peak in the first 15 min, in 4 the pattern resembled that of maturity onset diabetes, with a gradual rise of plasma insulin concentration toward a peak at 60 min. In the 2 patients with symptomatic diabetes, there was no response to intravenous glucose although the fasting plasma insu...

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Early "prophylactic" oophorectomy and adrenalectomy has been performed on 12 patients with carcinoma of the breast. The patients selected were considered to have a very bad prognosis on account of axillary node involvement associated with internal mammary chain deposits (9 patients), supraclavicular nodes (2 patients) and a parasternal mass (1 patient). Five patients had evidence of spread beyond the primary lymph drainage area (axillary and internal mammary nodes), and all had died within 4 years. In 7 patients the disease was confined to the primary lymph drainage area and 4 lived for more than 10 years, 3 being alive and well at 11 to 12 years. This is a higher proportion than in a control series but does not quite reach the level of statistical significance. In the 7 patients with disease confined to the axillary and internal mammary nodes prognosis was not apparently related to malignancy determined histologically, but did have an association with the extent of invasion of the axillary nodes. Urinary oestrogen estimations performed in 4 patients did not give any evidence that outcome was related to persistence of oestrogen production. Details of the patients' management and replacement therapy are given and from prolonged personal follow-up of these patients it is concluded that women who have undergone oophorectomy and adrenalectomy are able to lead full and active lives.

1. The metabolism of unlabelled monocomponent human insulin and porcine proinsulin was studied in ten normal subjects (five males and five females) by using a priming dose-constant-infusion technique. In each subject, the metabolic clearance rate (MCR) was measured at four separate steady-state hormone concentrations averaging 16–216 μunits/ml (insulin) and 4·2–42·8 ng/ml (proinsulin). 2. For insulin the MCR fell progressively from 34 ml kg−1 min−1 at a mean fasting insulin concentration of 3·8 μunits/ml to 11·4 ml kg−1 min−1 at the highest concentration achieved (280 μunits/ml); for proinsulin MCR averaged 3·7 ml kg−1 min−1 at a mean plasma concentration of 4·2 ng/ml and fell to 2·71 ml kg−1 min−1 at 10·7 ng/ml, remaining constant thereafter at concentrations up to 71 ng/ml. 3. The half-disappearance time (T½) from the plasma, after the end of the infusion, averaged 4·3 min for insulin and 25·6 min for proinsulin. 4. The apparent distribution space (DS) was similar for both hormones (83 ml/kg of insulin and 98·9 ml/kg of proinsulin). 5. There was a direct correlation between T½ and DS for both hormones. 6. Although the higher MCR of insulin was reflected in its shorter T½ there was, for each hormone, no relationship between MCR and T½. 7. The biological potency of porcine proinsulin, as judged by its effect on plasma glucose, was approximately 5% of that of insulin. 8. The responses of serum growth hormone and Cortisol were shown to be directly related to the degree of hypoglycaemia induced.

A method is described for the estimation of urinary testosterone excretion. After hydrolysis, the urine is fractionated on a Sephadex column, the appropriate fractions are extracted and the testosterone separated from other steroids by paper and thin-layer chromatography. The final quantitation is performed by sulpliuric acid fluorescence using a highly sensitive spectrophotofluorimeter. [14C]Testosterone is added to the urine after hydrolysis. It serves as a marker on the paper chromatogram and thin-layer plate and is used for correction of extraction losses. The specificity of the method has been confirmed by study of possible interfering steroids by bisection of the radioactive spots on the paper chromatogram and by biological data on normal men and women, hypogonad men, hirsute women and adrenalectomised, oophorectomised women. Satisfactory reproducibility and recovery of added testosterone glucuronide have been demonstrated. The method is extremely sensitive. Urine aliquots of 10 ml are used and it is possible to measure a urinary testosterone excretion of 1.0 μg per 24 h in a urine volume of one litre.

Serum growth-hormone (G.H.), insulin, and cortisol and plasma-glucose were measured serially in peripheral venous blood, before and during slow continuous infusions of mono-component human insulin in four patients with severe and nine patients with moderate uncontrolled diabetes mellitus. The results were compared with similar studies in nine healthy controls. In the controls serum G.H. and cortisol rose in direct proportion to the degree of hypoglycaemia achieved. In the diabetic patients there was a striking rise in serum G.H. and cortisol within 30 minutes of the start of the insulin infusion. In these patients the G.H. and cortisol responses did not seem to be related to a fall in plasma-glucose but to be directly related to the administration of insulin. No rise in serum-levels of thyroid-stimulating hormone was observed. The results are compatible with the hypothesis that the abnormal responses were due to direct stimulation of glucose metabolism within the pituitary gland, with subsequent release of G.H. and corticotrophin in response to pre-existing stimulation by G.H. and corticotrophin-releasing hormones. Slow infusions of small amounts of insulin were found to be highly effective in correcting the biochemical abnormalities of uncontrolled diabetes mellitus.

Serum-prolactin concentrations were measured in 111 patients who had radiological abnormalities of the pituitary but no evidence of acromegaly, Cushing's syndrome, or Nelson's syndrome. Raised prolactin levels were found in 45 of 64 (70%) patients studied before treatment and in 15 of 47 patients studied after pituitary surgery. The majority of hyperprolactinaemic patients presented with amenorrhœa or impotence; galactorrhœa was uncommon. By contrast, reproductive disorders were rare in patients with normal prolactin levels. It is concluded that pituitary tumours previously described as "functionless" are frequently associated with hypersecretion of prolactin and that such tumours usually present as reproductive disorders. In the investigation of patients with amenorrhœa or impotence serum-prolactin should be measured and skull radiology performed if the prolactin level is raised. Prolactin should be measured in all patients with abnormal pituitary X-rays both before and after pituitary surgery.

A case of factitious diabetes is reported. The patient gave herself insulin intermittently over a four year period. A high concentration of insulin binding antibody was found with the antibody showing much greater avidity towards beef than human insulin. There was resistance to intravenously administered beef insulin with low concentrations of free insulin and high concentrations of bound insulin. In contrast, in response to a glucose tolerance test, both the free insulin and C-peptide responses were normal as was glucose tolerance. The clinical difference in responsiveness to the human and beef insulins is well illustrated in vitro by insulin binding differences and is probably a function not only of different equilibrium constants of the antibody for human and beef insulins but also of different high affinity binding site concentrations.

Insulin administration often causes the development of insulin antibodies. Plasma insulin-binding capacity was assessed and free and total plasma insulin were measured in 96 insulin-dependent diabetic patients. Patients with the highest insulin binding capacity not only had the highest total insulin but also had the lowest free insulin. It is concluded that bound insulin is not unavailable to cells, that sufficient dissociation can occur for this insulin source to make a sizeable contribution to insulin delivery to the cell receptors, and that this can happen at a very low free insulin concentration.

The clinical, radiological and endocrine findings in thirty-five women with hyperprolactinaemia and amenorrhoea are described. Twelve patients had radiological evidence of a pituitary tumour and six were tested after pituitary ablation. Seventeen patients with hyperprolactinaemia and normal pituitary X-rays were also studied. None was on any drug known to increase prolactin secretion and all patients were euthyroid when tested. Basal serum prolactin concentrations were high in the group with untreated pituitary tumours and in those with normal X-rays. The levels were variable in the post-ablation cases. The increase of prolactin after TRH was subnormal in all of the groups. Serum oestradiol concentrations were low in most patients and nineteen of twenty-one patients tested had no withdrawal bleeding after treatment with a progestogen. Mean serum gonadotrophin concentrations (basal and after LHRH) were normal in twenty-nine patients but subnormal in four post-ablative cases. Anovulatory responses to clomiphene were obtained in nineteen of twenty patients tested. Fifteen patients were treated with bromocriptine; twelve ovulated and eight became pregnant; two not responding had impaired LH and FSH production. Hyperprolactinaemic amenorrhoea is a common disorder with characteristic endocrine features. Galactorrhoea is unusual (30%). Treatment with bromocriptine lowers prolactin concentrations and rapidly repairs the reproductive defect.

The sera of 30 patients who had been treated with conventional beef insulin were tested for binding of insulin and other pancreatic hormones. All showed antibody binding of insulin, 29 binding of proinsulin, 29 binding of pancreatic polypeptide, two binding of glucagon but none of the sera bound vasoactive intestinal peptide or somatostatin. After changing therapy to highly purified pork insulin the binding capacity of sera for insulin and the other hormones was monitored for up to 35 months and a steady fall was found in nearly all cases. In eight of the patients conventional beef insulin treatment was resumed: in one month binding of insulin and of the other hormones increased back to the initial levels. In eighteen subjects who had only received highly purified pork insulin low levels of insulin binding were found with no binding of proinsulin or other hormones. The amounts of proinsulin and contaminating hormones in highly purified pork insulin are so low that they are not immunogenic; conventional beef insulin not only contains immunogenic amounts of proinsulin and the contaminating hormones pancreatic polypeptide and glucagon but also is more immunogenic than purified pork insulin.

A personal series of 256 cases of acromegaly/gigantism seen over a 20-year period from 1963 is described. The insidious nature of the condition resulted in delay in diagnosis which was often made by a doctor when seeing the patient for an unrelated problem. Other features which commonly led to the diagnosis being made were headache, change in appearance, carpal tunnel syndrome, amenorrhoea and diabetes. The Hardy system for grading the radiological appearance of the pituitary tumour was used. Widely invasive tumours were not common but tended to occur in patients with younger age of onset and high GH levels. The occurrence of various symptoms and clinical features was noted and the changes resulting from reducing the GH level to normal. The incidence of hypertension, but not of coronary artery disease, is increased and the blood pressure may be reduced following successful treatment. The effects on the upper and lower respiratory tract are reported as well as sleep apnoea and problems associated with anaesthesia. Skin manifestations included sweating, pigmented skin tags, acanthosis nigricans and cutis verticis gyrata. In the skeletal system the incidence of kyphoscoliosis and osteoarthritis especially of the hip is reported: the question of hip replacement is discussed. Diabetes mellitus disappeared in most cases if the acromegaly was cured. In men but not in women the incidence of colloid nodular goitre was increased as was hyperthyroidism in middle-aged women. In two patients a parathyroid adenoma was present: hypercalcaemia was present in five additional patients, but the cause was not determined. The common occurrence of amenorrhoea in the younger women was noted, it was not always associated with hyperprolactinaemia, and often responded to successful treatment of the acromegaly. The association of acromegaly with hirsutism and galactorrhoea is confirmed. The incidence of impotence and loss of libid in the men is discussed: in a proportion of those in whom the acromegaly was cured, potency returned, but in a number depression occurred and what was believed to be psychogenic impotence persisted. Hyperprolactinaemia was found in 49 out of 151 patients with active acromegaly in whom the prolactin level was measured. Previous reports have indicated a doubling of death rates in acromegalics. In this series there were 47 deaths observed compared to 37.2 expected. The increased death rate was in women of all ages and in men under the age of 55, The increased deaths in the women were from cardiovascular and cerebrovascular causes and from breast cancer.(ABSTRACT TRUNCATED AT 400 WORDS)

Hypothalamo-pituitary--adrenal (HPA) function was studied using tetracosactrin and insulin hypoglycemia tests in eleven asthmatic patients who were receiving or had taken oral steroids. The patients had been on prednisone, 5--20 mg/day for 2--17 years. As the dose was reduced they used beclomethasone inhalation, up to 800 micrograms/day. Seven insulin hypoglycemia tests were performed when the patients had been off oral steroids for 15--37 months. Plasma cortisol responses were normal in all seven, three had subnormal responses of ACTH. In five patients serial tetracosactrin and insulin hypoglycaemia tests were performed during reduction of steroid dose. Two patterns of recovery of HPA function were observed. In one, both hypothalamo--pituitary and adrenal function seemed to return simultaneously, in the other normal response to tetracosactrin appeared before that to insulin hypoglycaemia. One patient had normal ACTH and cortisol responses to the stress of a vasovagal attack, but failed to respond to subsequent hypoglycaemia. We conclude that a normal response to tetracosactrin does not indicate recovery of the HPA axis after stopping prolonged oral steroid therapy for asthma, and that patients should continue to carry steroid therapy cards for at least 5 years after such treatment has been discontinued.

To investigate further the "hyperglucagonaemia" of diabetes mellitus, the metabolic clearance rate (MCR) and acute disappearance time (t1/2) of unlabelled pancreatic glucagon were estimated in 9 normal subjects and 7 insulin-dependent diabetics, using a constant infusion technique. The mean MCR (+/-SE) was similar for both groups (control: 9.0 +/- 0.6; diabetics: 11.4 +/- 1.0 ml/kg/min). The MCR was not influenced by the concentration of glucagon at the time of plateau, and the exogenous hormone appeared to be handled similarly to endogenous glucagon. On the other hand, t1/2 calculated from the fractional decay rate of glucagon from plateau was significantly prolonged in the diabetics (t1/2 6.6 +/- 0.5 min) compared with the control group (t1/2 4.8 +/- 0.2 min, P less than 0.01). Furthermore, there was no correlation between MCR and t1/2, for the control, diabetic, or combined group. It therefore appears that the MCR of glucagon is similar in normal and diabetic subjects. However, since the acute disappearance time (t1/2) of glucagon is not identical in these two groups, it appears that the kinetics of the overall in vivo metabolism of pancreatic glucagon are not similar in diabetic and control subjects.

During the past 20 years 33 patients suspected of harbouring an insulinoma have been investigated. 29 had laparotomy, and tumours were removed from 27.2 of the 29 and 1 other proved not to have an insulinoma, although preoperative imaging had suggested a tumour. Four different localisation procedures were used, and in some patients more than one technique was applied. Selective arteriography of branches of the coeliac axis showed the position of the insulinoma correctly in 9 out of 18 cases, but in all of these the tumour was felt at operation, so that the information provided was unnecessary. Arteriography gave false localisation in 4 patients and missed the tumour completely in 4 but was also negative in 1 patient not harbouring a tumour. Ultrasonic examination provided correct localisation in only 2 out of 11 instances and computer-assisted tomography in 1 out of 8. Insulin estimation in blood obtained at percutaneous transhepatic portal-venous sampling (THPVS) provided correct localisation in 2 out of 8 cases, but in only 1 of these was it needed to guide pancreatic resection. Localisation was spurious in 5 patients, and in 1 there was no evidence of a tumour at all. In 23 patients the surgeon felt and removed the insulinoma at the first operation. In 3 tumour was palpable at a second laparotomy some years later. In only 1 was no tumour felt at operation. The false-positive findings in the THPVS were caused by misinterpretation of data. For a peak of insulin concentration in the portal vein to be meaningful, it should exceed 200 mU/l and to be fully diagnostic it should be greater than 500 mU/l. Present imaging techniques are not precise enough to localise an insulinoma. An experienced surgeon has a very high probability of being able to palpate the tumour at operation, and preliminary localisation is therefore not needed in most cases.

Non-specific plasma effects may produce major errors in the estimation of true plasma pancreatic glucagon concentrations by radioimmunoassay. This has been circumvented by the production of glucagon-free plasma for each individual investigated, by means of glucagon antibody, coupled to sepharose beads. True fasting pancreatic glucagon levels (mean+/-SEM) in 18 healthy subjects (24+/-3 pg/ml) were significantly lower (p less than .005) than in 10 non-ketotic non-obese diabetics (38+/-3 pg/ml). It is suggested that, in the presence of decreased insulin-effect in the diabetic, this 55% glucagon elevation in diabetics may be of biological importance and contribute to the fasting hyperglycaemia.

SUMMARY To determine whether the fluctuations in the concentration of prolactin in plasma of man affect diagnostic procedures, the integrated concentration of prolactin has been compared with a basal concentration. A continuous sampling apparatus was used to study nine normal subjects and 12 subjects with features of the hyperprolactinaemia syndrome. Small differences were demonstrated, which were, however, neither statistically significant nor likely to influence clinical decisions. It is concluded that single estimations of the concentration of prolactin in blood, taken under resting conditions, are adequate for routine diagnostic use.

Thirty-eight patients in diabetic coma from four different centres were treated with a continuous low-dose intravenous infusion of insulin at an average dose of 7·2 IU/hr. All patients recovered rapidly except for one profoundly shocked patient who died. The mean fall in plasma glucose was 58% four hours after the start of insulin. Blood ketone bodies and plasma free fatty acids showed a similar response. There was no significant difference in plasma glucose response according to severity of acidosis or previous treatment with insulin. Hypokalaemia was uncommon. In the treatment of diabetic coma this technique has proved simple, safe, and effective.

Insulin was first used in the treatment of diabetic patients in 1921 and the first immunological problem associated with its use was reported in 1922 [1]; a patient developed anaphylaxis after the injection of a porcine, but not of a bovine insulin preparation. At that time insulin preparations were very impure and the antigen was probably a contaminating substance rather than insulin. In subsequent years a small number of patients were found to have developed insulin resistance after treatment with insulin [2]. In

SUMMARY The integrated concentration of growth hormone (ICGH) has been measured in fourteen acromegalic patients, and compared with the basal plasma growth hormone concentration (BGH). Seven patients were treated by trans-sphenoidal pituitary surgery, and in these, similar percentage reductions of BGH and ICGH occurred after treatment. The other seven patients were treated with bromocriptine alone, and in these the percentage reduction of ICGH was significantly less than that of BGH. Measurements of basal plasma growth hormone concentration may be unreliable in assessing the response of acromegalic patients to treatment with bromocriptine. The ICGH can be measured easily on a single blood specimen obtained by continuous sampling over 24h, and may be more reliable for this purpose.

Serum prolactin and gonadotrophin concentrations were measured by radioimmunoassay in 106 women with amenorrhoea. Prolactin was normal in those with weight related disorders, primary ovarian failure, those with a variety of systemic diseases and in those in whom amenorrhoea followed treatment with the oral contraceptive and in unexplained primary amenorrhoea. Gonadotrophin concentrations in the above patients were normal except in those with primary ovarian failure. Prolactin was elevated in eight of forty patients (20%) with functional secondary amenorrhoea and was greatly raised in all but one of the thirteen women in this series with pituitary tumours (five of whom were studied only after treatment). Only three patients in each of the last two groups had galactorrhoea. Gonadotrophin levels were normal or slightly raised in all of the hyperprolactinaemic patients apart from those studied after hypophysectomy. Four hyperprolactinaemic patients (three with pituitary tumours and one with functional amenorrhoea) who did not have galactorrhoea have been treated with bromocriptine. Prolactin secretion was reduced in all patients and, in the two with normal gonadotrophins, ovulatory menstruation was resumed. One became pregnant in the second ovulation cycle after starting treatment. We conclude that, despite the rarity of galactorrhoea, hyperprolactinaemia is common in patients with functional amenorrhoea and in those with pituitary tumours. Treatment with bromocriptine in patients with normal gonadotrophins restores ovulation when the infertility is due to prolactin excess.

In a series of 6,500 patients with diabetes mellitus there were 37 cases of primary carcinoma of the pancreas which significantly exceeded the expected number for the patient years at risk in both males and females (p less than 0.01). There was no evidence that pancreatic cancer was more common in patients with long-standing diabetes. The increased incidence of pancreatic cancer in diabetic patients is probably the result of patients presenting with the symptoms of diabetes as long as four years before the cancer becomes manifest. An underlying pancreatic tumour should be suspected when an elderly diabetic proves difficult to control and loses weight despite adequate treatment.

Sera from patients with different types of protamine-insulin were assayed for IgG antibody to protamine. A high prevalence of circulating antibody was found in patients treated with either bovine isophane insulin (26 out of 28 patients; 26 of whom also had antibodies to insulin), or bovine protamine zinc insulin (27 out of 30 patients; all 30 had antibodies to insulin). In sera from 24 patients treated with highly purified porcine isophane insulin, protamine antibody was detected in nine; circulating insulin-antibody was detected in 12 patients, eight of whom had protamine-antibody; in the 12 patients with no detectable antibody to insulin, antibody to protamine was detected in only one (x2 = 8.7, p less than 0.01). This relationship between insulin and protamine antigenicity is of interest as it suggests that the protamine-insulin complex is itself immunogenic.

The use of pituitary surgery for patients with over-production of growth hormone, corticotrophin and prolactin is reviewed. The value of specialized neuroradiological techniques is discussed including computerized tomography, air-encephalography and cavernous sinus venography. The indications for transcranial as opposed to trans-sphenoidal surgery are considered. The place of trans-sphenoid surgery in the treatment of acromegaly is emphasized and the indications for surgical treatment are reviewed. The two syndromes due to over-production of ACTH are considered--Cushing's disease and Nelson's syndrome. The increasing use of pituitary surgery for the treatment of Cushing's syndrome due to increased ACTH production is noted, but a warning is given about the small ACTH-secreting pulmonary carcinoid tumour that may closely mimic Cushing's disease. The difficulties encountered in trying to treat patients with Nelson's syndrome are stressed. It is recommended that in the rate case where total adrenalectomy is required in Cushing's disease, pituitary irradiation should be given before or shortly after adrenalectomy. The present position relating to the surgical treatment of the small prolactin-secreting pituitary tumour is reviewed. Published data and personal experience suggests that for many of these patients, treatment with bromocriptine is preferable to trans-sphenoidal surgery. Large prolactinomas usually need transfrontal surgery and X-ray therapy, sometimes followed by bromocriptine treatment. The need for steroid cover for pituitary surgery is discussed and it is suggested that a glucocorticoid with less salt-retaining action than cortisol should be used. The importance of post-operative endocrine assessment is emphasized and a convenient method suggested. The incidence of complications after transsphenoidal surgery is low, although panhypopituitarism occurred in 14% of the cases reported.

The metabolic clearance rate (MCR), half-disappearance time (T½ and apparent distribution space (DS) of unlabelled human growth hormone (HGH) have been studied using the priming dose – constant infusion technique. In 11 normal subjects MCR averaged 2.99 ml/kg/min., T½ 19.0 min. and DS 79.3 ml/kg. There were no differences between males and females and MCR was constant at HGH levels ranging from 5 to 50 ng/ml. In 10 out of 17 patients with chronic liver disease of varying severity MCR/kg was reduced below the lower limit of normal. TV2 was prolonged in 15 of these patients. There was a very close correlation between MCR/kg and DS/kg in liver disease (r = 0.8219). Increased DS/kg accounted for the normal MCR/kg seen in some patients with severe hepatocellular failure. MCR/kg was markedly reduced in three patients'with chronic renal failure. T72 and DS/kg were both significantly increased in this group (48.0 min. and 117.0 ml/kg, respectively). MCR/kg and T72 were normal in one patient with the nephrotic syndrome but normal glomerular filtration rate. MCR/kg was not significantly different from normal in patients with thyrotoxicosis, myxoedema and uncontrolled diabetes mellitus, despite the fact that T½ shorter than normal in thyrotoxicosis and longer than normal in myxoedema. It is suggested that HGH does not normally diffuse freely from the vascular to extravascular extracellular fluid, and that normally a substantial concentration gradient exists between the vascular and extravascular compartments; under these circumstances, the liver and kidneys are the major sites of HGH metabolism. In hepatic and renal failure, this gradient is reduced and extravascular degradation sites may assume more importance in the metabolism of growth hormone. Acute fluctuations in the peripheral blood concentrations of growth hormone indicate alterations in secretion rate and not alterations in metabolism.