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Purpose To investigate changes in bone mineral density (BMD) following denosumab after previous bisphosphonate therapy and the impact of chronic kidney disease (CKD) on response. Methods A retrospective study of 134 patients (11 M, 123 F) aged [mean (SD)] 72 [11] years on denosumab was undertaken. Ninety-five patients had previously been on oral and 28 on iv bisphosphonate. Lumbar spine (LS), total hip (TH) and femoral neck (FN) BMD were measured before treatment and at 2.7 [1.2] years. GFR was Results BMD improved following denosumab [mean (SEM) % change LS: 6.0 (0.62) p p p = 0.045]. Changes at the TH and FN were lower in patients with GFR 35 ml/min (Group A) [% change TH; Group A: 2.9 (0.72), Group B: − 0.84 (1.28), p = 0.015, FN; Group A: 2.76 (0.86), Group B: − 1.47 (1.53), p = 0.025]. % change in BMD at the FN and PTH were negatively associated (r = − 0.25, p = 0.013). BMD changes were not different at 12–18 months between patients on denosumab compared to zoledronate [% change at LS: denosumab: 3.97% (0.85), zoledronate: 2.6% (0.5), p = 0.19 TH: denosumab: 0.97% (0.58), zoledronate: 0.92% (0.6), p = 0.95). Conclusion Denosumab increases BMD following previous bisphosphonate treatment and is comparable to zoledronate. Lower response seen at the hip in CKD is related to PTH concentrations.

SUMMARY The urinary excretion of thyroid-stimulating hormone (TSH) has been measured by double antibody radioimmunoassay after concentration by dialysis followed by lyophilization. Among 30 normal subjects, the excretion was 5·6 ± 0·31 (s.e.m.) μu./h. No diurnal variation nor differences between sexes were discerned. In 14 primary hypothyroid subjects the urinary excretion was raised (P < 0·001) to 25·1 ± 3·3 μu./h. In 14 hyperthyroid and 7 hypopituitary subjects subnormal levels of 2·6 ± 0·2 and 2·5 ± 0·22 μu./h (P < 0·001) respectively, were found. Serum and urinary TSH concentrations were measured before, during and after an infusion of human pituitary TSH (MRC 70/9) in two subjects and showed a correlation. Urinary TSH measurement is thus a good discriminant between normal and hyperthyroid or hypopituitary patients.

A group of 34 patients with florid diabetic retinopathy are reported. Nine of these had at least one eye untreated and of these only two maintained vision at one year—the others were blind. Ten patients had 11 florid eyes treated by photocoagulation. At one year six were blind and five had good vision. At two years only three could still see. Of 20 pituitary-ablated patients with 29 florid eyes, only three were blind at one year. Even at five years, 12 of 17 eyes could see and only two patients were blind. The one- and two-year visual acuities were significantly better in the pituitary ablated eyes than in the untreated and photocoagulated ones (p = 0.01 – 0.03). It is suggested that for this rare form of retinopathy pituitary ablation remains the treatment of choice if vision is to be maintained.

Observations that insulin-induced stimulation of glycogen synthetase occurs without detectable reduction in cyclic AMP suggests an alternative controlling mechanism. The hypothesis that this stimulation might be mediated through calcium was tested using procaine HC1, a drug whose insulin-like action is not associated with reduction in basal or adrenaline-stimulated cyclic AMP levels. Pretreatment of adipose tissue with insulin or porcaine for 30 minutes increased homogenate glucose-6-phosphate independent ("I") form activity to 58% and 48% respectively with no significant change in total activity. Insulin and procaine also had similar effects on calcium efflux from isolated rat adipocytes. Following an initial displacement of calcium from the adipocytes by insulin (but not by procaine) both agents decreased efflux of calcium, measured following 10, 20 and 30 minutes incubation. In adipose tissue homogenates increasing the free calcium concentration from 10(-8) to 10(-3) M increased "I" form glycogen synthetase activity without significantly altering total activity. A complex interrelationship with ATP and calcium was also observed. In the presence of ATP 0.5 mM maximal activation occurred at 10(-6) M calcium concentration. These findings suggest that insulin-induced activation of glycogen synthetase may be effected by alteration of intracellular free calcium with consequent effects on glycogen synthetase-related enzymes in a mechanism independent of or complementary to effects on cyclic AMP levels.

1. The effect of a high calcium intake (1 mmol day−1 kg−1) alone or with the concomitant administration of oestradiol and testosterone derivatives was monitored by serial calcium balances in 48 patients with osteoporosis of various types. 2. On high calcium alone there was an increase (P < 0.001) in both total calcium balance and net calcium absorption as compared with values on a simulated home intake. This effect was sustained for periods up to 10 years (mean 3.5 years) by the addition of the hormones. 3. Discontinuation of the hormones (only) produced a significant decrease in both calcium balance and nett absorption but both were still increased when compared with the initial values under simulated home calcium intake. 4. No significant change in the urinary calcium output was observed under any of the regimens.

Standardized 4 h intravenous infusions of human follicle stimulating hormone (hFSH) and/or human luteinizing hormone (hLH) were given either separately or combined to 7 normal male volunteers. The infusions raised the serum gonadotrophin levels at least 10 (FSH) and 18 (LH) times above the basal ones. Serum testosterone (T) levels were measured serially before, during and after the infusions and, in 4 subjects, during a corresponding period of another normal day. During a normal or basal 24 h period fluctuations were seen and also a circadian rhythm with lower levels in the evening. The infusion of hFSH alone (3 subjects) did not alter the serum T levels. The infusion of hLH alone in 2 subjects raised serum T levels by 17% and 55% over those of the basal day. The combined FSH/LH infusion caused a significant rise (35–68%) in 4 subjects and greater rise in 2 of them than after infusion of the hLH alone. The serum T responses were gradual, reaching a maximum 7–8 h after the end of the infusion.

A unifying hypothesis is proposed for the mechanism of insulin action in adipose tissue. Insulin both induces displacement of Ca++ from a membrane-bound pool and inhibits efflux of the ion, thereby facilitating a rise in intracellular free Ca++ concentration. The former effect could enhance the transport of substrates and ions into the cell, while the latter modulates the activity of some intracellular enzymes to stimulate glycogenesis, lipogenesis, and decrease lipolysis and glycogenolysis. The calcium ion might act as the missing second messenger for insulin action.

Eighteen patients with Cushing's syndrome (16 pituitary-dependent Cushing's disease, 1 ectopic ACTH syndrome, 1 primary adrenal adenoma) were given a combination of aminoglutethimide and metyrapone, with the object of controlling cortisol overproduction using less toxic doses than would be required with each drug alone. A preliminary trial of this combination using doses of aminoglutethimide of 1 g or more a day was assessed over 2 weeks. Control of cortisol overproduction and clinical improvement was achieved but side effects led to withdrawal of the drugs in 6 out of the 12 patients. A lower dose trial of this combination over 2 weeks, using 750 mg/day of aminoglutethimide also controlled cortisol overproduction and side effects led to drug withdrawal in only 2 out of 6 patients. Four of these patients were successfully controlled with even lower doses (500-750 mg/day of aminoglutethimide) for longer periods (26 days–1 year). This low regimen which consists of aminoglutethimide 500–750 mg daily, metyrapone 2 g daily, dexamethasone 0.5 mg b. d. and fludrocortisone 0.1 mg daily, is useful for preparing patients for operative treatments and may be used as a long-term treatment of milder cases.

Serum-lipid concentrations and their relationship to blood-glucose and serum-insulin were examined in non-insulin-requiring diabetics, 62 with and 45 without retinopathy. The age, sex, body-weight, and duration of known diabetes was comparable in the two groups. All were treated by diet only or diet and oral hypoglycaemic agents. Patients with retinopathy had higher fasting serum- triglyceride and serum-cholesterol levels than those without. Compared with a non-diabetic population, significantly more diabetics with retinopathy had raised serum-lipids. The lipid concentrations did not correlate with body-weight, serum-thyroid-stimulating-hormone levels, renal involvement, or fasting blood-sugar. While the blood-sugar concentrations were similar in the two groups the absolute insulin increment and the relative insulin response to a 50 g oral glucose load were significantly lower in those with retinopathy than in those without. The impairment of insulin response correlated significantly with the frequency of hyperlipidaemia. It is suggested that insulin deficiency with secondary hyperlipidaemia is characteristic of diabetic patients with retinopathy.

SUMMARY In human urinary concentrates and also in a urinary gonadotrophin standard (2nd IRP-HMG), gel-filtration analysis revealed three main peaks of immunoassayable luteinizing hormone (LH). A similar analysis of LH extracted from human pituitaries showed most of the activity in a peak of larger molecular weight, and only minor fractions in the positions of the urinary peaks. In an extract of normal human serum, analysis showed only one similar peak of large molecular weight, which also emerged before the urinary peaks. During an i.v. infusion of pituitary LH into normal men, the urinary LH activity increased but was still found only in the same three peaks on gel filtration, and all were of a molecular weight smaller than that of the infused material; but a higher proportion of the urinary LH was found in the earliest of these peaks compared with that found before infusion. Conversely, 20–35 h after the i.v. infusion, there was a slightly higher proportion of LH activity in the third peak of smallest molecular weight. These findings suggest that the urinary immunoassayable LH, which is found in three peaks of different molecular weights, is derived from the pituitary or serum LH of higher molecular weight. The changes in the proportions of larger or smaller molecular weight fractions in the urine during and after LH infusion suggest that the earliest peak may be disaggregated serum LH, while the last or smallest molecular weight peak may comprise metabolites of LH.

We have examined the utilisation of glucose and ketone bodies in normal adipose tissue in response to insulin and some drugs used in diabetic therapy. Under basal conditions 14C from acetoacetate was incorporated into long chain fatty acids, while 14C from glucose was found principally in the glyceride glycerol fraction of tissue lipids. Fatty acid synthesis from acetoacetate was stimulated ten-fold by glucose addition up to 20m.M and conversely, acetoacetate enhanced the incorporation of glucose 14C into lipids. The stimulatory effect of glucose was independent of its transport, since it is not reproduced by 2-deoxy-glucose. Insulin further stimulated fatty acid synthesis from acetoacetate, an effect abolished in the absence of glucose. Phenethyl-biguanide (Phenformin) increased tissue glucose uptake, although it decreased glucose 14C and acetoacetate 14C incorporation into triglyceride. Free fatty acids (FFA) and very low density lipoproteins (VLDL) addition at concentrations observed in diabetic ketosis resulted in inhibition of acetoacetate utilisation. We conclude that ketone bodies do not block glucose utilisation in normal human adipose tissue in vitro. The apparent reduction in ketone body metabolism during diabetic ketosis may be related to the high FFA and VLDL levels observed.

The metabolic response to two weeks' fasting and the influence of starvation on glucose tolerance have been studied in obese diabetic and obese nondiabetic subjects. After an overnight fast, mean concentrations of both blood glucose and plasma triglyceride were significantly greater in the diabetics than in the nondiabetics. In neither group, however, were correlations found in any combination between circulating levels of triglyceride, glucose, insulin, free fatty acids, or the degree of obesity. During the fast, concentrations of plasma triglyceride and blood glucose fell slightly in the nondiabetics, but strikingly in the diabetics, and in the latter these reductions were highly correlated. Glucose tolerance was impaired by starvation in the nondiabetics but considerably improved in the diabetics. In the former, the rise in both serum insulin and plasma lactate concentrations was delayed following starvation. In the latter, the most striking change was a reduction in the basal glucose concentration after fasting; a rise in lactate levels was observed prior to starvation but no elevation was detected during the post-fast glucose tolerance test, while serum insulin responses remained unchanged. It is suggested that in some obese diabetics the development of endogenous hypertriglyceridemia is dependent on increased hepatic gluconeogenesis, and that a reduction in gluconeogenesis is the principal mechanism by which both plasma triglyceride levels are decreased, and glucose tolerance improved, in such patients following starvation. It is further suggested that both diminished β-cell responsiveness and decreased muscle glycolysis contribute to the genesis of starvation diabetes.

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.

Oral glucose-tolerance tests were done in 43 patients with acromegaly (38 with normal glucose tolerance and 5 with diabetes). Insulin levels were compared with 45 healthy London controls and levels found in a population survey in Western Australia from which a sixty-minute insulin-response index was derived. Although the mean serum-insulin levels were higher during the oral glucose-tolerance tests in non-diabetic acromegalics than in controls, only 10 out of 38 showed levels clearly outside the normal range. Only 9 were outside two standard deviations from the mean in the population survey. The insulin levels for the diabetics lay in the lower range for the rest of the group and they were less responsive to glucose. Apart from a possible correlation between mean serum-insulin and mean growth-hormone levels during the glucose-tolerance test no correlation was found between serum-insulin and indicators of disease activity. After treatment there was an appreciable fall in insulin levels only in those who initially had high insulin levels. The fall in serum-growth-hormone after treatment did not relate to the fall in insulin levels.

It has been suggested that prolactin is in some way involved in the development of migraine attacks. This hypothesis was tested in two series of experiments. In patients prone to early-morning migraine, fasting followed by intravenous glucose did not precipitate an attack even when prolactin concentrations were raised by chlorpromazine, nor were attacks precipitated when prolactin levels were lowered by a synthetic ergot derivative. Alcohol, on the other hand, did precipitate a migraine attack in patients known to be susceptible to this agent, but the development of an alcohol-induced attack was not influenced by pretreatment with the ergot derivative. Furthermore, alcohol had no effect on prolactin concentrations when administered to controls, nor did it precipitate a migraine attack. Both sets of experiments cast doubts on the notion that prolactin is a permissive factor in migraine.

Seven patients with anorexia nervosa were studied, three during the acute stages of the illness, and four in whom weight gain had been achieved, but who suffered from persistent amenorrhoea of 18 to 79 months' duration.In the acute stage all patients had low serum luteinizing hormone (LH) levels which were unresponsive to clomiphene citrate. In those who had regained weight the mean basal LH levels were normal, and they responded to clomiphene with an initial doubling of serum LH during administration of the drug, followed by a second peak of serum LH four to seven days after the drug was stopped. Menstruation occurred in these patients 13 to 19 days after the clomiphene was discontinued, and in two patients regular spontaneous menstruation was initiated.The low LH levels unresponsive to clomiphene in the acute stage provide evidence for a hypothalamic abnormality in anorexia nervosa. After regain of body weight the drug seems to be effective in treating the amenorrhoea which may be persistent.

Nine normal women were examined in the first 11 days of the puerperium. Serum prolactin, oestradiol and follicle simulating hormone (FSH) levels were measured and the FSH response to 100 mug of intravenously administered follicle stimulating hormone/lutenizing hormone-releasing hormone (LH/FSH-RH) was assessed on day 1 post partum in five subjects and on days 4 (two subjects), 6 and 7 post partum in the other four subjects. Bromocriptine therapy was given to six of these women and four to seven days after the start of such therapy, when prolactin levels had fallen to normal non-pregnant levels, these women were retested. Before bromocriptine treatment, the basal FSH levels were unmeasurable in six and low in one other of the nine subjects. After bromocriptine treatment, the basal FSH levels were measurable in four out of six patients and were higher than in the untreated patients (P less than 0-01). The FSH response to LH/FSH-RH was unmeasurable in eight out of nine before treatment, which is less than the response seen in 26 normal men and women (P less than 0-01). There was also no discernible FSH response to LH/FSH-RH after treatment with bromocriptine. Before treatment with bromocriptine, the serum prolactin levels were elevated in all nine women but were within the normal range for non-pregnant women after three days of bromocriptine therapy. Thus postpartum gonadotrophin suppression seemed to depend on high prolactin levels and at least part of the antigonadotrophic action of prolactin seemed to be at pituitary level.

Ninety-four growth hormone deficient New Zealand children were treated with thrice weekly intramuscular injections of human pituitary growth hormone (GH) from 1979 to 1985 and the results from 43 children were analysed in detail. Their height velocity was mean (SD) 4.0 (1.9) cm/yr immediately prior to treatment and 8.5 (3.1) cm/yr in the first year of treatment. In each of the first three years of treatment the height velocity was significantly increased (p less than 0.001), but there was a significant decline in height velocity between the first and second, and second and third years. Nevertheless each year of treatment gave a highly significant gain in relative height. Bone age did not advance more rapidly than chronological age during the first two years of treatment, but did so subsequently. The response to GH, as assessed by the increase in relative height, was negatively correlated with the relative height at the start of treatment and with the maximum pretreatment plasma GH response to insulin hypoglycaemia. There was no correlation with pretreatment relative height velocity or aetiology of GH deficiency. Height velocity improved in five of 14 children treated with thyroxine after starting GH. Discontinuation of GH for one year in 34 children resulted in a highly significant reduction in growth rate from 7.5 (2.4) cm/yr to 2.5 (2.0) cm/yr, however four prepubertal children continued to grow at a rate exceeding 4 cm/yr.

Previously, TSH metabolism and tissue distribution in the rat were studied using heterologous hormone and/or unphysiological doses. We injected iv [131T]rTSH (S.A. 100 μCi/μg) in physiological doses (10 ng) to KI blocked male rats. Two to 180 min after which TCA precipitable 131I was measured in the kidney, liver, muscle, fat and testis. The highest TCA precipitable radioactivity concentration, peak value 12 % at 30 min; organ/blood ratio, 16, was found in the kidney. With the kidney validated as the major site of localization of TSH, the renal localization and handling of [125I]rTSH was studied by autoradiography. Radioactivity was confined to the cortex. Two to 30 min samples showed 125I in Bowman's space and luminal parts of the proximal tubular cells while samples from 60 to 180 min revealed activity in contraluminal areas, suggesting glomerular filtration and tubular re-absorption. Gel-filtration of supernatants of kidney homogenates revealed progressive diminution of the TSH peak and the appearance of a smaller MW peak. We conclude that (1) the kidney is the major site of localization and metabolism of homologous TSH, (2) the renal handling of TSH involves both glomerular filtration and tubular re-absorption.

One hundred and fifty-five acromegalics, 76 males (mean age 44 +/- 1.3 years) and 79 females (45 +/- 1.4 years) were studied. The frequency of clinical features were: acral enlargement 100 per cent, hyperhidrosis 65 per cent, headache 55 per cent, paraesthesiae 49 per cent, cardiac problems 34 per cent, hypertension 32 per cent, diabetes mellitus (clinical and chemical) 27 per cent, and visual field defects 6 per cent. Signs and symptoms, and particularly headache, did not show any relation with the size or shape of pituitary tumours, nor with growth hormone (GH) values, age, sex or weight. Mean of GH values at 60, 90 and 120 minutes during a GTT averaged 135 mIU/l, range 8-1833. Diabetes mellitus was more frequent and severe in patients with higher GH values, occurring in 32 per cent of patients with mean GH values greater than or equal to 50 mIU/l and only in 16 per cent of the rest (p less than 0.05). GH values correlated positively with size of tumours. Forty-nine per cent of patients presented with entirely intrasellar tumours, 27 per cent with suprasellar extensions and 23 per cent with partially empty sellae. The mean GH (238 mIU/l) of patients with suprasellar extensions was significantly higher (p less than 0.004) than those of the others. Younger acromegalics showed a tendency to larger tumours. Early treatment of acromegaly, particularly in young patients and those presenting with high GH values, is recommended.

Summary The hormonal criteria of a “normal” or “ovulatory” response, and three grades of subnormal anovulatory responses, were defined during a first course of treatment with clomiphene citrate in twenty patients with amenorrhoea for which no organic cause could be found. The hormonal responses were estimated by frequent serum measurements and by the menstrual response. Seven patients had a normal or ovulatory response with a late rise of serum progesterone and subsequent menses. Their serum luteinizing hormone (LH) and oestradiol (E2) responses were greater than in spontaneous menstrual cycles. Five patients gave only partial responses, with menstruation and no prior rise of progesterone. Their serum LH and E2 responses were generally lower than in the normal group but had the same pattern except for an absence of the luteal phase rise in E2. Five patients who did not menstruate showed smaller and more variable responses. The remaining five showed no hormonal rerponses. The second and third groups had ovulatory responses on subsequent clomiphene courses, whereas no improvement was shown by the last group. The serum E2 responses offered the most sensitive index of the responsiveness to clomiphene. Response values in our normal group suggested that higher progesterone levels need to be reached after clomiphene administration than in spontaneous cycles for ovulation to be inferred. The serum prolactin showed no consistent response during the clomiphene test; three patients with moderately raised basal prolactin levels had “normal” responses.

SUMMARY To assess whether urinary immunoassayable thyroid-stimulating hormone (TSH) differed from pituitary and serum TSH, urinary concentrates from two hypothyroid subjects were analysed by Sephadex G-100 gel filtration. The elution profiles, measured by radioimmunoassay, were then compared with those of neat sera from hypothyroid patients and human pituitary TSH preparations. The pituitary preparations and the hypothyroid serum were eluted as a comparable single symmetrical peak corresponding to that obtained from a highly purified radio-iodinated human TSH of pituitary origin; no evidence of 'big' TSH emerged. In contrast, however, the material eluted from the hypothyroid urine concentrates not only revealed an asymmetrical peak corresponding to that described above but several other minor peaks eluting later and probably corresponding to fragments of TSH. When human pituitary TSH was infused into two normal subjects, gel filtration analysis of concentrates from urinary samples obtained during and at fixed periods after the infusion revealed a single peak during the infusion but more peaks appeared with the later samples.

The in-vitro antilipolytic response to insulin and procaine hydrochloride by adipose tissue from young rats (150 - 180 g) and lean mice has been compared with that from aged Wistar rats (600 g) and obese (ob/ob) hyperglycaemic mice. 1. The adipose tissue from the obese mice showed diminished responsiveness to insulin and to procaine hydrochloride. Response to these agents, however, was restored by prewashing the tissue, suggesting that the apparent resistance in this tissue reflected saturation of the insulin receptors to endogenous insulin. 2. In adipose tissue of old Wistar rats the antilipolytic effect of insulin was also impaired, but this was not restored after extensive washing. Unlike adipose tissue ghosts prepared from young rats, insulin did not decrease the binding of calcium to ghost membrane preparations from old rats. Neither did insulin inhibit the adrenaline stimulated 45 calcium efflux from perifused isolated fat cells prepared from old rats. These results suggest that the insulin response of fat cells from old rats is impaired because of a defect either in their insulin receptors or in their post-receptor responses. 3. Procaine-hydrochloride, however, when added to the medium perifusing fat cells of these old rats inhibited the adrenaline stimulated lipolysis, reduced the Ca efflux and decreased the binding of Ca to fat cell ghosts; as it did with similar preparations of young rats. Thus the cells from old rats still show full post-receptor responsiveness to an insulin-like stimulus, provided the stimulus for such a response is given at a point beyond the insulin receptor itself. The results suggest that the insulin resistance observed in old rat fat cells may be related to some by deficiency in the insulin receptors, possibly due to their lower replacement with age.

The role of the adrenal cortex in the pathogenesis of hypertriglyceridaemia associated with the intake of oral contraceptive agents containing oestrogen has been investigated in rats. Bilateral adrenalectomy reduced the activity of hepatic enzymes regulating lipogenesis (acetyl CoA carboxylase, fatty acid synthetase) and decreased plasma triglyceride concentrations. On the other hand, the administration of high dosage corticosterone induced the activity of hepatic enzymes with consequent elevation in serum triglyceride levels. In animals with intact adrenals the administration of oestradiol: (a) raised plasma triglyceride levels, (b) enhanced the activity of hepatic enzymes, and (c) increased the adrenal cortex:body weight ratio. The effects (a) and (b) were not observed when both adrenals were removed prior to oestrogen therapy. High dosage corticosterone replacement was found to be essential for the oestradiol to produce its effects on hepatic enzymes and plasma triglyceride levels. The results suggest a regulatory role for the adrenal cortex in the homeostasis of plasma triglyceride concentration and that the hypertriglyceridaemia induced by the oestrogen containing preparations might be secondary to alterations in adrenocortical function.

SUMMARY Serum thyrotrophin response to thyrotrophin releasing hormone was impaired in all of eight subjects with untreated Cushing's disease; while all of six similar subjects tested after adequate treatment by a pituitary implant of 198 Au then showed a normal response. In all five of the untreated patients studied, the serum prolactin response to TRH was normal. Thus chronically excessive cortisol levels as seen in Cushing's disease inhibit pituitary TSH responsiveness to TRH without affecting the prolactin response to TRH Evidently the release of TSH and of prolactin by TRH are governed by independent mechanisms.

Hyperprolactinaemia was found in all 17 women and in one out of six men who presented with hypogonadism and a radiologically enlarged sella turcica but no other clinical endocrine dysfunction. Some of the women also had galactorrhoea. The greater the level of hyperprolactinaemia in these 18 patients the larger their sellae turcica except in two patients with unusual features. The sella turcica was usually asymmetrically enlarged and there was rearly an upward extension of tumour, though the sella floor often showed some erosion on tomography. An oral dose of bromocriptine suppressed the hyperprolactinaemia in mose patients at the same rate as in normal post-partum women. Nine of the 18 patients with hyperprolactinaemia had low basal luteinizing hormone (LH) levels. The LH responsiveness to 100 mug of LH-releasing hormone (LHRH) was tested in 12, and eight showed subnormal values. Of eight biopsy specimens obtained four showed acidophil granules on light microscopy, and in five granules of various sizes were seen on electron microscopy.

The reaction steps involved in the activation and inactivation of the hormone sensitive lipase have been studied in human adipose tissue. Homogenates prepared from adipose tissue shreds or isolated fat cells contained a cyclic-AMP dependant protein kinase. This enzyme was partially purified from the 100,000 g supernatant using DEAE Cellulose Column Chromatography. The activity of the purified preparation was stimulated 3-4 fold with cyclic-AMP and inhibited with progressive increases in free calcium concentration in the reaction mixture. Calcium seems to inhibit the binding of cyclic-AMP to the protein kinase regulatory units and thus abolishes cyclic-AMP stimulation. In the presence of cyclic-AMP and ATP the protein kinase phosphorylates a lipase preparation partially purified from the same tissue with synchronous increase in the lipolytic activity. Inactivation of the lipase is preceeded by its dephosphorylation by a phosphatase(s) which is present in 105,000 g supernatant. Increasing free calcium concentration between 10-8 and 10-3M produced progressive inhibition of the lipase activity. This inhibition can be attributed to a dual mechanism. First, calcium ions inhibited the protein kinase activation of the lipase. Second, calcium ions stimulated the adipose tissue phosphatase(s) and this increased the rate of inactivation of the hormone sensitive lipase. A role for calcium ions as well as cyclic-AMP in the control of lipolysis is postulated.

One hundred and fifty-five acromegalics, 76 males (mean age 44 +/- 1.3 years) and 79 females (45 +/- 1.4 years) were studied. The frequency of clinical features were: acral enlargement 100 per cent, hyperhidrosis 65 per cent, headache 55 per cent, paraesthesiae 49 per cent, cardiac problems 34 per cent, hypertension 32 per cent, diabetes mellitus (clinical and chemical) 27 per cent, and visual field defects 6 per cent. Signs and symptoms, and particularly headache, did not show any relation with the size or shape of pituitary tumours, nor with growth hormone (GH) values, age, sex or weight. Mean of GH values at 60, 90 and 120 minutes during a GTT averaged 135 mIU/l, range 8-1833. Diabetes mellitus was more frequent and severe in patients with higher GH values, occurring in 32 per cent of patients with mean GH values greater than or equal to 50 mIU/l and only in 16 per cent of the rest (p less than 0.05). GH values correlated positively with size of tumours. Forty-nine per cent of patients presented with entirely intrasellar tumours, 27 per cent with suprasellar extensions and 23 per cent with partially empty sellae. The mean GH (238 mIU/l) of patients with suprasellar extensions was significantly higher (p less than 0.004) than those of the others. Younger acromegalics showed a tendency to larger tumours. Early treatment of acromegaly, particularly in young patients and those presenting with high GH values, is recommended.

Serial serum assays of immunoreactive FSH before, during and after a 4 h intravenous infusion of human follicle stimulating hormone (hFSH) in five healthy men revealed two disappearance rate constants with corresponding mean half-lives of 2.9 and 50.6 h. The mean distribution spaces calculated for the fast and slow component were 4.36 1 and 75.9 1 respectively. The average value for the metabolic clearance rate was 17.2 ml/min and for the endogenous production rate 50.9 mU/min. Two of the subjects had human luteinizing hormone (hLH) added in the infusions without the FSH kinetics changing.

Ten patients with severe Paget's disease of bone and serum alkaline phosphatase (sAP) greater than 900 IU/l were treated for six months with the oral diphosphonate APD, (3-amino-1-hydroxypropylidene-1, 1-bisphosphonate). By the end of the treatment period there was a reduction in the log mean urine hydroxyproline (uHP) and the log mean sAP of 92% and 87% respectively. In four patients both sAP and uHP fell to within the normal range and remained normal for at least six months after therapy was stopped. Bone scintigraphy showed a fall in 99mTc-MDP uptake in sites of active Paget's disease in all patients and histomorphometry showed no increase in osteoid. Repair of radiological osteolytic lesions was observed in 6/6 patients and progression of tibial osteolytic wedges was arrested in 5/5 patients and reversed in four. This improvement persisted six months after completion of therapy but further wedge progression occurred in one patient whose urine HP remained elevated. There were no serious effects though five patients complained of nausea. The clinical and biochemical responses to APD were equivalent to those observed in the same patients during a previous six month course of combined therapy with human calcitonin (CT) + EHDP except that there was additional biochemical and radiological evidence of bone healing. This study confirms PAD as an effective treatment of severe Paget's disease of bone.

Eighteen patients with Cushing's syndrome (16 pituitary-dependent Cushing's disease, 1 ectopic ACTH syndrome, 1 primary adrenal adenoma) were given a combination of aminoglutethimide and metyrapone, with the object of controlling cortisol overproduction using less toxic doses than would be required with each drug alone. A preliminary trial of this combination using doses of aminoglutethimide of 1 g or more a day was assessed over 2 weeks. Control of cortisol overproduction and clinical improvement was achieved but side effects led to withdrawal of the drugs in 6 out of the 12 patients. A lower dose trial of this combination over 2 weeks, using 750 mg/day of aminoglutethimide also controlled cortisol overproduction and side effects led to drug withdrawal in only 2 out of 6 patients. Four of these patients were successfully controlled with even lower doses (500-750 mg/day of aminoglutethimide) for longer periods (26 days-1 year). This low regimen which consists of aminoglutethimide 500-750 mg daily, metyrapone 2 g daily, dexamethasone 0.5 mg b.d. and fludrocortisone 0.1 mg daily, is useful for preparing patients for operative treatments and may be used as a long-term treatment of milder cases.

Standardized 4 h intravenous infusions of human follicle stimulating hormone (hFSH) and/or human luteinizing hormone (hLH) were given either separately or combined to 7 normal male volunteers. The infusions raised the serum gonadotrophin levels at least 10 (FSH) and 18 (LH) times above the basal ones. Serum testosterone (T) levels were measured serially before, during and after the infusions and, in 4 subjects, during a corresponding period of another normal day. During a normal or basal 24 h period fluctuations were seen and also a circadian rhythm with lower levels in the evening. The infusion of hFSH alone (3 subjects) did not alter the serum T levels. The infusion of hLH alone in 2 subjects raised serum T levels by 17% and 55% over those of the basal day. The combined FSH/LH infusion caused a significant rise (35-68%) in 4 subjects and greater rise in 2 of them than after infusion of the hLH alone. The serum T responses were gradual, reaching a maximum 7-8 h after the end of the infusion.

The effects of adrenaline, insulin and procaine-HCl on Ca distribution in intact fat cells and on Ca binding to fat cell ghost membranes have been investigated. 1. Fat cells incubated in 45ca containing media till isotopic equilibrium indicated that the exchangeable Ca in these cells averages 25. 7 ± 3. 2 nmol/mg protein, which represents approximately 9. 8 % of their total Ca content. 2. Perifusion of 45Ca prelabelled fat cells gave washout curves whose analysis conformed with three kinetically distinct Ca pools (Fig. 1). The fast exchangeable pool (Compartment A) had an efflux rate constant of 0. 193 ± 0. 013 min. -1. The release of Ca from the second and third pools (Compartments B and C) was much slower with efflux rate constants of 0. 032 ± 0. 0018 min. -l and 0. 0042 + 0. 0006 min. -l respectively. Changing the Ca concentration in the perifusing medium modified the initial fast phase and its rate constant, while added dinitrophenol (DNP) inhibited the efflux rate from the latter compartments. The results suggest that the initial fast component of the 45ca washout represents Ca exchange from an extracellular pool probably present on the outer surface of cell membranes, while the release of Ca during the second and third slow phases represent Ca derived from two distinct intracellular compartments. The rate constant for 45Ca efflux from compartment (B) is of the same order of magnitude as the transmembrane fluxes measured in other cells and presumably represents Ca efflux from the cytoplasmic pool. The efflux of Ca from compartment (C), on the other hand, occurs at a much slower rate and probably reflects the release of Ca from a storage pool bound to the plasma membrane and/or endoplasmic reticulum. 3. Analysis of Ca binding to fat cell ghosts suggests that the membrane structures in these preparations contain two classes to Ca binding sites, a high affinity site with K (assoc) of 1. 4 times 10-6 M and a low affinity site with K (assoc) of 1. 3 × 10-5 M. The maximum amount of Ca that could be stored in these membranes would be approximately 60 nmol/mg protein. 4. In perifused 45Ca prelabelled fat cells adrenaline increased the 45Ca efflux from intracellular compartments prior to its stimulation of lipolysis. Previous perifusion with insulin or procaine-HCl prevented the effects of adrenaline on 45ca efflux and lipolysis. Moreover, both insulin and procaine-HCl decreased the binding of Ca by ghost membranes. The dose response of these effects compared with that for their effects on lipolysis in isolated fat cells. Pretreatment of fat cells with trypsin to delete the insulin receptor abolished the effects of insulin both on Ca binding and on lipolysis while the insulin like response for procain-HCl remained. The experiments suggest that the effects of insulin and procaine-HCl on fat cells could be mediated by increasing mobilisation of Ca from membrane bound stores and inhibition of Ca efflux thereby facilitating an increase in intracellular Ca concentration These effects of insulin require the presence of an intact insulin receptor while procaine-HCl operates beyond the insulin receptor site.

The effects of administration of methyldopa on serum prolactin and growth hormone (GH) concentrations in hypertensive patients were studied. Single doses of methyldopa (750 or 1000 mg) significantly increased serum prolactin levels, peak concentrations occurring four to six hours after drug administrations. Long-term methyldopa treatment was associated with threefold to fourfold increases in basal prolactin levels compared with those in normal subjects. In patients treated with methyldopa for two to three weeks the GH response to insulin hypoglycaemia was significantly greater than in normal subjects and untreated hypertensive patients. In contrast, patients treated for prolonged periods (mean 13-4 months) had a GH reponse indistinguishable from normal.