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Insulin has been shown to regulate insulin-like growth factor-binding protein-1 (IGFBP-1) in vivo and in vitro. Insulin resistance is a feature of the polycystic ovary syndrome (PCOS). We have studied the relationship between insulin sensitivity (S1) and the circulating concentration of IGFBP-1 in a group of young women and in some who had PCOS. A case-control study has been carried out comparing reproductively normal women with women with PCOS (defined as women with oligo- or amenorrhea associated with androgen excess). Fifteen women with clinical PCOS and ten age- and weight-matched controls were studied. S1 was measured by the frequently sampled intravenous glucose tolerance test (FSIGT) using the minimal model technique. IGFBP-1, insulin-like growth factor-I (IGF-I) and growth hormone levels were measured before and during the FSIGT. Circulating testosterone, dehydroepiandrosterone (DHEA) and its sulfate (DHEAS) levels were measured while the subjects were fasting. S1 and IGFBP-1 levels were significantly lower in the PCOS group than in controls (S1/10(-5) min-1/pM] mean +/- SE 3.8 +/- 0.8 vs. 8.5 +/- 1.3, p < 0.03; IGFBP-1 [ng/ml] mean +/- SE 26.6 +/- 4.2 vs. 56.0 +/- 5.9, p < 0.005). In women with PCOS, IGFBP-1 concentrations related negatively to the body mass index (BMI) (r = -0.77, p < 0.003) and positively to S1 (r = 0.76, p < 0.003). S1 remained a significant predictor of IGFBP-1 concentrations when controlled for BMI (combined r2 = 0.35, p < 0.05). No relationship was found between androgen levels and IGFBP-1. Insulin sensitivity contributed to the difference in IGFBP-1 levels found in women with PCOS. Whether the reduced concentrations of IGFBP-1 play a role in the pathophysiology of PCOS is uncertain, but it may act to alter delivery of IGF to peripheral tissues in insulin-resistant individuals.

Changes in adipose tissue distribution as defined by the waist-to-hip ratio (WHR), were evaluated in 16 android, obese subjects (seven male and nine female) given a very low energy ketogenic diet of 1.72 MJ (411 kcal) for 4 weeks. Total weight loss was significantly greater for the males (11.2 +/- 2.5 kg) compared to females (8.3 +/- 0.8 kg); the relative weight loss however, was similar (9.9 vs 9.3 percent). Female and male losses in percent body fat and lean body mass were not significantly different. For both groups, significant (P less than 0.01) changes in waist and hip circumferences were observed; however, no significant changes were observed in WHR. These results indicate that in obese android male and female subjects, adipose tissue distribution as measured by WHR, does not change in response to rapid weight loss.

This technical note demonstrates that earthquake-induced liquefaction consists of a cyclic instability dominated by heterogeneities in the soil, and as such is a phenomenon that is fundamentally intractable analytically. Consequently it is shown that the liquefaction analyses proposed by the Berkeley school are fundamentally incorrect, not just after zero effective stress has been reached in the soil, but well before that - that is as soon as any pore pressure is generated and any softening of the soil takes place. The method is fundamentally in error in assuming that dynamic stressing of the soil takes place independently of soil softening. A distinction is also made between liquefaction failure and flowslides, which is a phenomenon originally addressed by the Harvard school in its studies of soil behaviour at densities looser than critical. It is argued that the only way in which reliable design procedures against liquefaction can be developed is by the creation of empirical design criteria based on direct experimental data. Where possible this should involve experimentation at full scale, which is by definition the most accurate method. However, such data is necessarily very limited and very expensive, and so it is suggested that these design rules should be developed from the second most accurate experimental method, namely centrifuge modelling, and then calibrated wherever possible against measured full-scale results. It is also suggested that the most accurate form of in situ index testing of soil liquefaction potential will incorporate the self-boring pressuremeter, and some preliminatry recommendations are given in this note. (Author/TRRL)

Summary A 20-year-old patient presented with primary amenorrhoea and growth hormone deficiency caused by a basal encephalocoele. She was found to have developed diabetes insipidus in the 8 years following diagnosis. Gonadotrophin release in response to bolus injection of luteinizing hormone-releasing hormone (LHRH) was normal, as was thyrotrophin and adrenocorticotrophin (ACTH) secretion. Pulsatile administration of LHRH by the subcutaneous route resulted in normal ovulation and subsequent menstruation. The investigation and management of patients with basal encephalocoeles are discussed in the light of these findings.

The limit equilibrium method is applied to analyse the stability of rockfill embankments. Stability charts that utilize contours of zero critical acceleration factor are generated. These charts are valuable as design aids and are presented in a form amenable for the direct computation of the factor of safety, which is a more familiar parameter of stability analysis. Reliability theory is then applied in the form of a second moment format, to compute the probability of failure of a rockfill embankment. Strength parameters are characterized using three slightly different density functions, to study the effect of truncation on the probability of failure of the system. The use of the logistic distribution is introduced, as a means of computing the failure probability of the structure without the aid of tables. The parameters necessary to compute both the factor of safety and its reliability, have been evaluated and are presented in graphical form, in terms of common design variables. A wide spectrum of practical combinations of geometries and strength parameters are covered by the study. La méthode de l'équilibre limite est employée pour analyser la stabilité des remblais rocheux. On pré-sente des abaques de stabilité qui utilisent des contours de facteur zéro d'accélération critique. Ces abaques sont utilisables pour 1'établissement de projets et prennent une forme qui se prête au calcul direct du facteur de sécurité, qui est un paramètre mieux connu dans 1'analyse de stabilité. La théorie de la fiabilité s'applique alors comme un deuxième moment de force pour calculer la probabilité de rupture d'un remblai rocheux. Des paramètres de résistance sont caractérisés à l'aide de trois fonctions de densitié un peu différentes, afin d'etudier l'effect de la troncature sur la probabilité de rupture du systéme. On introduit l'emploi de la distribution logistique comme moyen de calculer la probabilité de rupture de la construction sans l'aide de d'abaques. Les paramètres nécessaires pour calculer le facteur de sécurité et sa fiabilité ont été évalués et sont présentés en forme de diagrammes selon des variables ordinaires de construction. L'étude comprend une gamme étendue de combinaisons pratiques de géométries avec des paramètres de résistance.

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.

SummaryUnderstanding of the physiology of luteinising hormone-releasing hormone (LHRH) has increased rapidly over the 12 years since the hormone was elucidated and synthesised (Schally et al., 1972). It was initially hoped that the hormone would fulfil a role as an agent for both the stimulation and inhibition of gonadal function. These hopes were not fulfilled until the physiology of release and effect of LHRH was elucidated in greater detail (Knobil, 1980). The role of the hormone appears under normal conditions to be the permissive regulation of the gonadotrophins by pulsatile release every 90-180 minutes. LHRH and its analogues have an effect on the pituitary gland which is dependent on both dose and method of administration. Low doses of the drug given in a pulsatile fashion activate both gonadotrophic responsiveness and gonadotrophin reserve. Continuous infusions or high dose pulsatile infusion cause loss of pituitary sensitivity and loss of gonadotrophin secretion. Long-lasting LHRH analogues cause...

SUMMARY The effects of chronic subcutaneous infusion of luteinising hormone-releasing hormone (LHRH) have been studied in a group of 17 male patients with hypogonadotrophic hypogonadism (HH). Ten of the patients had primary and seven secondary failure of gonadotrophin release, and all but four had previously been treated with gonadotrophin injections. Treatment was continued for between one and 18 months and was well tolerated by all except one patient who became allergic to LHRH. An increase in the basal gonadotrophin concentrations occurred in all except four patients within one week of the initiation of therapy, and this was associated with a rise in the serum testosterone level in eight patients. Increased spermatogenesis was demonstrated in seven cases and three pregnancies have resulted thus far. Pituitary desensitisation to the effects of LHRH was found in five subjects with primary HH who failed to produce any increase in testosterone secretion despite an initial stimulation of gonadotrophin release. We conclude that chronic pulsatile infusion of LHRH is an effective technique for the treatment of some cases of hypogonadotrophic hypogonadism.

Twenty-seven women with secondary amenorrhoea have been treated with pulsatile subcutaneous luteinising hormone releasing hormone (LHRH). Serial ultrasonic observations of increasing follicular diameters and changes in the size of the uterus have been recorded. The rate of the increase of the diameter of dominant follicles in LHRH induced cycles is identical to that observed in women undergoing spontaneous cycles. An interesting correlation was observed between follicular diameter and uterine size. The correlation suggests that uterine size measured ultrasonically can be used as a bio-assay of follicular oestradiol production. Uterine growth continues throughout the luteal phase of conception cycles and can be used as a very early sign of pregnancy.

SUMMARY A 46XY individual with incomplete male pseudohermaphroditism was studied. The phenotype was distinctive, with a masculine habitus despite a small phallus, gynaecomastia and diminished virilization. Plasma levels of testosterone, oestrogens, gonadotrophins and sex-hormone binding globulin were elevated. It is proposed that this syndrome is a variant of Type I incomplete male pseudohermaphroditism.

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.

Erythrocyte carbonic-anhydrase-I (C.A.I.) concentration was measured by radial immunodiffusion in 30 thyrotoxic patients and 15 myxœdemic patients, the results being compared with those found in a control group of 90 euthyroid individuals. In thyrotoxicosis the erythrocyte-C.A.I. concentration was found to be below 10·29 mg/g haemoglobin, whereas the normal range varied from 11·1 to 22·5 mg C.A.I./g Hb. Low values were found in 4 patients with triiodothyronine(T3)-toxicosis. In myxœdema, the mean erythrocyte-C.A.I. concentration, though elevated at 20·37 mg/g Hb, fell within the normal range. In pregnancy, the erythrocyte-C.A.I. concentration rose with time, the mean value at term being 20·6±S.D. 3·3 mg/g Hb. In a group of women taking oral contraceptives, a low erythrocyte-C.A.I. concentration was noted—an effect which was most obvious among those taking low-œstrogen contraceptives. It is suggested that erythrocyte-C.A.I. estimation provides a rapid screening test for thyrotoxicosis.

Summary A patient is described who had a long history of abuse of kaolin and morphine mixture which ultimately proved fatal.

The endocrine abnormalities associated with the development of androgen-dependent hirsutism have been presented and discussed in the light of the frequent finding of ultrasonographic abnormalities suggestive of polycystic ovary syndrome. A simple protocol of investigation, which should ideally include pelvic ultrasonography, has been presented. The treatment of hirsutism by combined anti-androgen and oestrogen therapy has been detailed and other approaches discussed.

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.

The effects of treatment by argon laser and xenon arc photocoagulation in 165 diabetic patients with optic disc new vessel formation have been studied retrospectively. Visual acuity and degree of new vessel formation have been assessed over a period of between six months and seven years of follow-up (mean 23 months). Visual acuity improved in 36% of treated eyes and remained unchanged in 34%. Improvement was most marked in those with initially poor acuity (less than 6/36). There was no association between improvement in visual acuity and regression of disc vessels, the latter occurring in 79% of treated eyes. Only 6% of eyes became blind during the period of follow-up, principally as a result of vitreous haemorrhage and retinal detachment. There was no difference between the results produced by the use of separate or combined argon laser and xenon arc photocoagulation on the regression of disc new vessels. However, our results suggest that argon laser treatment was more effective than xenon arc photocoagulation in improving visual acuity. These findings suggest that either form of treatment or a combination offers considerable benefit in the management of proliferative diabetic retinopathy, even when very severe at presentation.

Seventy-three patients with active acromegaly were treated for three to 25 months with bromocriptine 10-60 mg/day. Seventy-one patients showed symptomatic and objective clinical improvement. This included reduction in excessive sweating, hand and foot size, and the number of headaches; improved facial appearance; and increased energy and libido. Abnormal visual fields became normal in two patients, one of whom had concomitant radiotherapy. Mean circulating growth hormone levels, obtained by averaging serial samples through the day, fell by more than 7 microng/l or became undetectable in 58 patients (79%) but did not reach normal values: only 15 patients had mean levels on treatment of 5 microng/l or less. Twenty-three patients were diabetic before treatment, and glucose tolerance became normal in 15 and improved in a further five. Provided the drug was started slowly side effects were minor when compared with the considerable clinical benefit obtained.