The efficacy and safety of lanreotide Autogel in patients with acromegaly previously treated with octreotide LAR.

OBJECTIVE: Lanreotide Autogel is a sustained-release aqueous gel formulation supplied in a prefilled syringe, with injection volume <0.5 ml. The aim of this study was to establish the efficacy and safety of Autogel in patients with acromegaly previously treated with octreotide LAR. DESIGN: A 28-week, open, multicentre study. PATIENTS: Twelve patients with acromegaly, treated with 20 mg octreotide LAR for >4 months, with serum GH levels <10.0 mU/l. METHODS: Autogel (90 mg) was given every 28 days during weeks 0-12. At week 16 the dose was titrated based on GH levels at weeks 8 and 12. If GH levels were <2.0, 2.0-5.0, or >5.0 mU/l, Autogel was reduced to 60 mg, maintained at 90 mg, or increased to 120 mg respectively, for the next three injections. GH and IGF-I levels were reassessed at weeks 24 and 28. RESULTS: Ten patients completed the study. Five remained on 90 mg Autogel throughout the study; in two patients the dose was reduced to 60 mg from week 16; in three patients it was increased to 120 mg. Mean GH levels were: baseline, 3.0+/-1.7 mU/l; week 12, 3.5+/-1.8 mU/l; week 28, 3.3+/-1.6 mU/l (NS). Mean IGF-I levels were: baseline, 212+/-70 microg/l; week 12, 185+/-91 microg/l; week 28: 154+/-61 microg/l (P=0.027). Six patients at baseline and eight at week 28 had normalised GH and IGF-I levels. Three patients reported adverse events: musculoskeletal pain (n=2) and injection-site symptoms (n=1). CONCLUSIONS: Lanreotide Autogel is effective and well tolerated in patients with acromegaly. This study in a small group of patients with well-controlled acromegaly suggests that the majority of patients switched from 20 mg LAR to 90 mg Autogel will have equivalent or better disease control.

Absolute level and rate of change of albuminuria over 1 year independently predict mortality and cardiovascular events in patients with diabetic nephropathy.

AIMS: To determine the nature of the association between baseline albuminuria and risk of all-cause mortality and cardiovascular disease, and to determine if the rate of change of albuminuria from baseline over 1 year predicts these endpoints in patients with diabetic nephropathy. METHODS: Cohort study of 427 patients (161 Type 1 and 266 Type 2) with diabetic nephropathy defined as urinary albumin excretion (UAE) > or = 30 mg/24 h at baseline (mean age 53.4 years). Patients were recruited at the time of referral to a diabetic nephropathy clinic and followed up annually for an average of 5 years. UAE rate was re-measured at 1 year and the rate of change from baseline calculated. RESULTS: All-cause mortality and cardiovascular disease increased significantly and continuously across quintiles of baseline UAE (P for linear trend < 0.001 in both outcomes). The rate of change of albuminuria over 1 year (log10) independently predicted all-cause mortality (hazard ratio (95% confidence interval) 1.76 (1.39, 3.11)) and cardiovascular mortality (1.57 (1.13, 5.22)). Taken as a categorical variable, a rate of change of albuminuria > or = 30% independently predicted mortality and cardiovascular events (2.07 (1.5, 4.30) and 1.89 (1.33, 4.06), respectively). CONCLUSIONS: The rate of change of albuminuria over 1 year independently predicts mortality and cardiovascular disease in diabetic nephropathy and may have clinical utility as a risk marker in identifying a subgroup of patients at particular risk. The risk of these outcomes is continuous across the range of baseline albuminuria in patients with diabetic nephropathy.

Excessive secretion of insulin precursors characterizes and predicts gestational diabetes.

Using assays that specifically measure insulin, intact proinsulin, and 32,33 split proinsulin, we examined the beta-cell secretory response to an oral glucose tolerance test (OGTT) in 64 women with gestational diabetes mellitus (GDM) and 154 pregnant normoglycemic control subjects of comparable age and body mass index. Women with GDM were characterized by a lower 30-min insulin increment (40.8 [34.9-47.6] vs. 58.6 [53.6-64] pmol insulin/mmol glucose, P < 0.001; geometric mean [95% confidence interval]) and a higher plasma insulin level at 120 min (702 [610-808] vs. 444 [400-492] pmol/l, P < 0.001). 32,33 split proinsulin levels were elevated in GDM patients in both fasting (9.1 [7.3-11.4] vs. 6.7 [6.0-7.5] pmol/l, P < 0.02) and 120-min (75.2 [62.9-90.0] vs. 52.2 [46.7-58.3] pmol/l, P < 0.001) samples, respectively. Intact proinsulin levels were significantly elevated at 120 min in the women with GDM (21.3 [18.1-25.1] vs. 14.8 [13.4-16.3] pmol/l, P < 0.001). Thus, the qualitative abnormalities of insulin secretion in GDM patients (low 30-min insulin increment, high 120-min plasma insulin, and elevated 32,33 split proinsulin) are similar to those seen in nonpregnant subjects with impaired glucose tolerance. To determine whether measures of proinsulin-like molecules (PLMs) might assist in the prediction of GDM, women who had a 1-h glucose level of > 7.7 mmol/l after a 50-g glucose challenge at 28-32 weeks' gestation had insulin and PLMs measured in the 1-h sample.(ABSTRACT TRUNCATED AT 250 WORDS)

Treatment of Graves' disease with the block-replace regimen of antithyroid drugs: the effect of treatment duration and immunogenetic susceptibility on relapse.

Antithyroid drugs are commonly used as first-line treatment for Graves' disease, but the optimum regimen for inducing remission remains unclear. We gave the block-replace regimen of carbimazole plus thyroxine to 100 patients for 6 or 12 months, to determine whether prolonged treatment is associated with fewer relapses. The remission rate one year after cessation of treatment was 59% with the 6 month course and 65% with 12 months; this was not significantly different. We also analysed HLA markers identified by restriction fragment length polymorphisms and could not confirm the recently reported associations of outcome with HLA-DR4 or with an HLA-DQA2 allele. These results show that six months treatment with a block-replace regimen of antithyroid drugs is probably sufficient, in the UK, to achieve maximum remission of Graves' disease and that there are no HLA markers which clearly predict outcome.

Abnormalities of the hypothalamo-pituitary-gonadal axis after head injury.

OBJECTIVE: We aimed to investigate the mechanisms of hypogonadism which develops after head injury. DESIGN: Pulsatile secretion of LH was studied in subjects 6-10 days after major head injury. PATIENTS: We studied five male subjects admitted with major head injuries and six healthy age-matched control subjects. MEASUREMENTS: During the pulsatility study, LH was measured at 5-minute intervals for 4 hours and 15-minute intervals for a further 2 hours. In addition, testosterone and LH were measured on Days 1-5, 14 and after 3-6 months. RESULTS: The analysis of pulsatile secretion of LH demonstrated an LH pulse frequency similar to control subjects, but a significantly reduced LH pulse amplitude (P less than 0.001, fixed threshold method; P less than 0.02, Detect method). Both testosterone and LH levels were reduced after injury with the nadir occurring on Day 4. CONCLUSIONS: Hypogonadism after head injury is due to defective LH secretion, with normal pulse frequency but a reduced pulse amplitude.

Association between Graves' ophthalmopathy and smoking.

Patients with Graves' disease were questioned by postal survey about their smoking history. There were significantly more smokers in the group with ophthalmopathy than in the group with Graves' thyrotoxicosis or controls. Patients with severe eye signs smoked significantly more tobacco than did those with less serious signs.

Hypothalamic hypogonadism following major head injury.

Endocrine studies, using the four hypothalamic releasing hormones, gonadotrophin releasing hormone, thyrotrophin releasing hormone, corticotrophin releasing hormone and growth hormone releasing hormone, were performed in 33 males after admission with a major head injury. The test was repeated 7 days later in all 33 patients and after 3-6 months in 21 patients. All patients had a period of unconsciousness followed by post-traumatic amnesia of greater than 24 h. The results obtained from investigating the gonadal axis are reported in this paper. The levels of total and free testosterone, basal FSH and basal LH fell significantly during the first 3 days after injury, when the LH and FSH responses to GnRH achieved their highest peak levels. This hormone pattern has not previously been reported in the gonadal axis and may be a consequence of hypothalamic dysfunction. The severity of the injury was negatively correlated to the testosterone concentration on admission and to the basal and peak FSH concentrations 1 week later. Persistent hypogonadism was found in five of the 21 patients retested after 3-6 months, with low testosterone concentrations and three continued to have an exaggerated LH response to GnRH. Thus major head injury frequently results in hypogonadism shortly after injury, with an increased gonadotrophin response to GnRH. In addition, a substantial minority of patients continue to be hypogonadal after 3-6 months. In view of these findings we strongly suggest that all patients should be endocrinologically assessed at intervals following severe head injury.

Computerized and telemetric management of diabetic pregnancy in Cambridge.

In order to optimize the quality of our care, we have used the Ames Memory Glucometer in our computerized management of 17 insulin-dependent diabetic pregnancies. Patients measured their own blood glucose levels on 4.5 +/- 1.2 (SD) occasions per day, and six of them transmitted their blood glucose measurements telemetrically from home into a hospital-based computer on a total of 42 occasions. We achieved near-optimal blood glucose levels and normal HbA1 levels throughout most of these 17 pregnancies. Average blood glucose levels were 6.4 +/- 0.9 mmol/l in the first, 5.9 +/- 1.2 mmol/l in the second, 5.4 +/- 1.0 mmol/l in the third trimester. Corresponding values for HbA1 were 8.0 +/- 1.5%, 6.5 +/- 0.8%, and 6.2 +/- 0.4%. Average insulin requirement doubled during pregnancy, but fell to 74% of the pre-pregnancy dosage by one week after delivery. The average gestational age at delivery was 38.9 +/- 1.3 weeks, and we had no perinatal deaths. Two of the babies were macrosomic, even though their mothers had good diabetic control. Four patients were delivered by Caesarean section. However we achieved a vaginal delivery in 93% of those in whom it was planned. Our computerized system of managing diabetic pregnancies was efficient, safe, and popular with our patients.

Thyroid stimulating hormone measurement by an ultrasensitive assay during thyroxine replacement: comparison with other tests of thyroid function.

Serum thyroid stimulating hormone (TSH) was measured using a highly sensitive enzyme-amplified immunoassay in 37 clinically euthyroid patients receiving thyroxine replacement therapy and compared with other biochemical tests of thyroid function. A highly significant correlation (P less than 0.001) was found between the basal serum TSH and the increase in serum TSH concentration 20 min after the administration of thyrotropin releasing hormone (TRH). The basal serum TSH was negatively correlated with the serum total thyroxine (P = 0.05). When patients results were classified as abnormal or normal many discrepancies were noted between the various thyroid tests. A suppressed serum TSH was found in 65% of patients with a normal serum total thyroxine. However, in patients on thyroxine replacement therapy a basal TSH measured by enzyme-amplified immunoassay provides the same information as a TRH test.

Retinal haemorrhages and papilloedema due to benign intracranial hypertension in a pregnant diabetic.

A case of benign intracranial hypertension associated with generalized oedema is reported in a normotensive pregnant patient with long-standing insulin-treated diabetes mellitus. Following treatment with bed rest, chlorthalidone and dexamethasone the condition resolved and a healthy infant was delivered. This condition, not previously reported in a diabetic pregnancy, must be differentiated from other causes of bilateral optic nerve abnormalities associated with retinal haemorrhages and oedema, including diabetic retinopathy, diabetic optic neuropathy, accelerated hypertension and cerebral mass lesions. Treatment is required to prevent permanent visual impairment due to pressure on the susceptible optic nerve of the diabetic patient and to avoid the metabolic consequences to both mother and fetus of poor nutritional intake due to nausea.

Post-traumatic hypopituitarism. Six cases and a review of the literature.

The typical patient with post-traumatic hypopituitarism is a young adult male presenting months to years after an automobile accident, following which he was unconscious for several days. He will probably have sustained a fracture of the base of the skull and on recovery is likely to have permanent visual or other neurological sequelae. Temporary or permanent diabetes insipidus may have occurred. The features of panhypopituitarism such as weight loss, fatigue, faintness, loss of libido, and impotence may have been ascribed to depression or the "postconcussion syndrome" and often inappropriate treatment and rehabilitation advised. The striking feature on review of the literature is that the pathological consequences of head injury to the pituitary and hypothalamus have been well described, while only 47 cases of traumatic hypopituitarism have been reported. The most likely reason for this disparity is that head injury of sufficient severity to cause hypothalamic and pituitary damage commonly led to death. More patients now survive, owing to the availability of intensive care; accordingly, most cases have been reported in the last 15 years. However, several patients are described in whom the initiating head injury was not associated with a skull fracture or followed by coma. We recommend that patients with major head injury (defined by post-traumatic amnesia greater than 24 hours), and in particular those with fractures of the base of the skull or diabetes insipidus should be closely monitored for symptoms and signs of endocrine dysfunction and appropriate dynamic pituitary-function tests performed.

Insulin oedema and its clinical significance: metabolic studies in three cases.

Three patients with insulin-dependent diabetes mellitus are described in whom generalized oedema and weight gain followed the administration of excessive monocomponent insulins, in two cases associated with symptomatic hypoglycaemia. Serial measurements of plasma volume and transcapillary escape rate of albumin (TERA) using 125I-labelled albumin, serum colloid osmotic pressure (COP) using a membrane colloid osmometer, packed cell volume (PCV), and serum proteins, showed that oedema was associated with an increased plasma volume and TERA, while serum albumin and total protein concentration and serum COP were reduced. A reduction in daily insulin dose abolished hypoglycaemia and resulted in weight loss, natriuresis, diuresis, a reduction in plasma volume and TERA, and an increase in serum albumin, total protein, and COP. Strict metabolic control in previously poorly controlled patients may cause insulin-induced increments in plasma volume and albumin escape rate.

Toxic shock: clinical presentation and management. II.

The management of toxic shock syndrome poses a challenge to clinicians because the syndrome has only been recently recognized and new complications are still being described. This report describes the major complications which arose in our case and highlights a severe bleeding disorder which was the cause of the patient's death. The bleeding disorder was characterized by normal in vitro coagulation screens, normal platelet aggregation tests, but prolonged skin bleeding time. It was not improved by haemodialysis, platelet transfusion or steroid therapy. We conclude that in cases with severe toxaemia, despite early recognition and appropriate treatment, there is still no effective method of preventing complications. Current avenues for investigation include plasmapheresis, the administration of fresh frozen plasma, and the development of a specific anti-toxin.