In patients with insulin-dependent diabetes niellitus (IDDM), microalbuminuria is a predictor of widespread severe microangiopathy and maeroangiopathy. Patients with microalbuniimiria show generalized dysfunction of tiie vascular endothelium, but it Is unknown whether endothelial dysfunction precedes the development of mi croalbuminuria. We examined a cohort of 17 IDDM pa tients at baseline and on three occasions during a follow-up of (median) 64 months (range 51-89 permeability, the balance between coagulation and fibrino lysis, the composition of the subendothelial matrix, and the mitogenesis of vascular smooth muscle and renal mesangial cells (4-6). In cross-sectional studies in IDDM, there is a close association between microalbuminuria and endothelial dysfunction. Thus, in patients with microalbuminuria, the vascular endothelium tends to increase, rather than deerease, vascular resistance (7,8); fails to restrict the passage of macromolecules (1,3); and loses its anticoagulant and profibrinolytic properties (9,10). In addition, there is an increase in the plasma concentration of markers of endothe lial injury and dysfunction, such as von Willebrand factor (vWF) (9,11), a glycoprotein involved in primary hemostasis and secreted mainly by endothelial cells.Some aspects of endothelial function have been reported to be disturbed in IDDM patients with normal urinary albumin excretion (UAE) (12-15), but whether these are of prognostic significance is not known. Answering that ques tion is important because it would increase our knowledge about the pathogenesis of microalbuminuria and allow early recognition of high-risk patients. Therefore, we wished to investigate whether endothelial dysfunction precedes the occurrence of microalbuminuria. To do this, we followed a group of IDDM. patients and measured UAE and plasma vWF concentration at regular intervals (as an estimate of endo thelial function). n insulin-dependent diabetes mellitus (IDDM), mi croalbuminuria predicts the development not only of diabetic nephropathy, but also of severe retinopathy, neuropathy, hypertension, and macro vascular disease (1,2). Microalbuminuria is thought to be a marker of wide spread vascular damage (1,3), which may underlie the pro pensity of microalbuminuria patients to develop severe extrarenal vascular disease.The endothelium is mi important locus of control of vascular functions. It actively regulates vascular tone and Received for publication 10 November UHM and accepted in revised form li)January IW H.ANOVA, analysis of variance; HP, blood pressure; BMI, body mass index; IDDM, iasuliiMlopendent diabetes mellitus; NIDDM, non-insuliiMlepondom diabetes mel litus; UAE, urinary albuntin excretion; vWP, von Willebrand factor.

Recently somatostatin analogues were successfully used to control insulin-induced hypoglycemia in patients with insulinoma. We observed a transient decrease in glucose levels and symptomatic hypoglycemia after administration of the long-acting somatostatin analogue octreotide (Sandostatin\s=r\) in two insulinoma patients. We studied the acute effects of octreotide (administered before breakfast) on blood glucose and glucoregulatory hormones in these patients. In one patient, we studied the effects of glucagon replacement and changing the time of breakfast (relative to octreotide administration) on octreotide-associated changes in blood glucose and glucoregulatory hormones. Compared with control levels, octreotide therapy reduced insulin levels. During hypoglycemia glucagon and growth hormone levels were suppressed, but cortisol levels appropriately increased. The increase in catecholamine levels was normal in one patient, but markedly attenuated in the other. A transient decrease in serum glucose after octreotide was absent after glucagon replacement, but present when breakfast was taken before administration of octreotide. We conclude that in patients with insulinoma, octreotide therapy may be associated with clinically important hypoglycemia, during which counterregulatory hormone secretion may be attenuated.Patients with insulin-secreting islet cell tumours are at risk for severe hypoglycemia. Surgical remo¬ val of the tumour is the treatment of choice. Medi¬ cal therapy is often required in the period preced¬ ing surgery and in patients with metastatic disease. Recently, long-acting somatostatin analogues were successfully used to control insulin-induced hypo¬ glycemia in patients with insulinoma (1-5).Important advantages of long-acting somatos¬ tatin analogues compared with native somatos¬ tatin are their prolonged half life, the possibility of subcutaneous administration, and the lack of a re¬ bound increase in insulin levels after discontinu¬ ing treatment. Furthermore, no clinically import¬ ant adverse effects during short-term therapy have been reported in insulinoma patients (1-5). We re¬ cently observed a transient aggravation of hypo¬ glycemia associated with treatment with the longacting somatostatin analogue octreotide (SMS 201-995, Sandostatin®) in a patient with malignant in¬ sulinoma (6). We here report the acute effects of oc¬ treotide on blood glucose and glucoregulatory hormones in this patient and in a second one in whom we observed a similar worsening of hypo¬ glycemia after administration of octreotide. Patients and MethodsPatient A, a 77-year-old woman, was admitted with a hy¬ poglycémie coma (blood sugar 2.0 mmol/1) at 05.00 h. After iv administration of glucose she regained con¬ sciousness. There was no history of liver disease, alcohol abuse, use of hypoglycémie drugs or prolonged (> 10 h) fasting. Results of diagnostic fasting, abdominal ultra¬ sound and computed tomography were compatible with a diagnosis of fasting hypoglycemia due to a pancreatic insulinoma.

Objective Is polycystic ovary syndrome (PCOS) associated with activating autoantibodies (AAb) to the second extracellular loop (ECL2) of gonadotropin-releasing hormone receptor (GnRHR)? Design and Methods We retrospectively screened sera from 40 PCOS patients and 14 normal controls (NC) with regular menses by ELISA for the presence of GnRHR-ECL2-AAb. We obtained similar data from 40 non-PCOS ovulatory but infertile patients as a control group (OIC) of interest. We analyzed GnRHR-ECL2-AAb activity in purified IgG using a cell-based GnRHR bioassay. Results The mean ELISA value in the PCOS group was markedly higher than the NC (P=0.000036) and the OIC (P=0.0028) groups. IgG from a sample of five PCOS subjects, in contrast to a sample of five OIC subjects, demonstrated a dose-dependent increase in GnRHR-stimulating activity qualitatively similar to the acute action of the natural ligand GnRH and the synthetic agonist leuprolide. The GnRHR antagonist cetrorelix significantly suppressed (P<0.01) the elevated GnRHR activity induced by IgG from seven PCOS patients while the IgG activity levels from seven OIC subjects was unchanged. Five other OIC subjects had relatively high ELISA values at or above the 95% confidence limits. On further study, three had normal or low activity while two had elevated IgG-induced GnRHR activity. One suppressed with cetrorelix while the other did not. The co-presence of PCOS IgG increased the responsiveness to GnRH and shifted the dosage response curve to the left (P<0.01). Conclusions GnRHR-ECL2-AAb are significantly elevated in PCOS compared to normal controls. Their presence raises important etiological, diagnostic and therapeutic implications.

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Severe psychosis in patients with Cushing's syndrome is rare and generally difficult to treat. We report a 46-yr-old woman suffering from Cushing's syndrome caused by an inoperable ACTH-producing lung carcinoma. She was initially treated with chemotherapy and radiotherapy. Six months later she presented with severe psychosis. Laboratory findings revealed a severe hypokalemia and metabolic alkalosis, which was caused by extremely high serum ACTH (788 ng/l) and cortisol (4.2 micromol/l). She was unresponsive to treatment with conventional antipsychotic drugs; she was therefore sedated and intubated. Treatment was started i.v. with etomidate, which blocks the cortisol synthesis, and orally by nasogastric tube with mifepristone, which competes with cortisol for binding to their receptors. To counteract adrenal insufficiency, she received corticosteroids. After 5 days there was a normalization of the ACTH, cortisol levels, and the metabolic disorders. After discontinuing etomidate she was extubated; there were no signs of psychosis observed. Computed tomography (CT) scan of the brain showed no metastasis, however CT scan of the abdomen showed liver metastasis and bilateral adrenal enlargement. Unfortunately, the clinical situation worsened and the patient died due to progression of the metastasis. This case report demonstrates the efficacy of a treatment of mifepristone with etomidate in a patient with an ectopic ACTH-producing Cushing's syndrome.