Somatostatin receptors on thyrotropin-secreting pituitary adenomas: comparison with the inhibitory effects of octreotide upon in vivo and in vitro hormonal secretions.

The in vivo and in vitro inhibitory effects of a somatostatin (SRIH) analog, octreotide, upon TSH, alpha-subunit, GH, and PRL have been studied, as well as SRIH receptors and their coupling to adenylate cyclase, in nine TSH-secreting pituitary adenomas. From in vivo and cell culture studies, the TSH- and alpha-subunit-secreting adenomas appeared heterogeneous, with four out of the nine tumors cosecreting GH and/or PRL. A single sc injection of octreotide (100 micrograms) lowered plasma concentration of TSH by 40 +/- 5% (mean +/- SE of 5), of alpha-subunit by 27 +/- 9% (n = 5), of GH by 60 +/- 5% (n = 4), and of PRL by 27 +/- 9% (n = 4). In cells cultures, octreotide (10(-8) mol/L) inhibited equally TSH, alpha-subunit, and GH release. 125I-Tyr0-DTrp8-SRIH binding sites were measurable in the nine TSH-secreting adenomas either on membrane preparations (n = 6; Bmax: 152 +/- 73 fmol/mg protein) or on frozen sections by radioautography (n = 3). Their density was variable among TSH adenomas and was lower than that measured in GH-secreting adenomas but higher than in nonfunctioning tumors. Two out of three TSH-secreting adenoma displayed an heterogeneous distribution of 125I-Tyr0-DTrp8-SRIH binding sites. 125I-Tyr0-DTrp8-SRIH specific binding was inhibited by guanosine triphosphate (GTP: 10(-4) mol/L). SRIH inhibited adenylate cyclase in 5/5 TSH-secreting adenomas and a good correlation (r = 0.92, P less than 0.02) was found between 125I-Tyr0-DTrp8-SRIH binding capacity (Bmax) and maximal adenylate cyclase inhibition by SRIH. These results demonstrate in vivo and in vitro inhibition of TSH, alpha-subunit, PRL, and GH secretion by octreotide in TSH-secreting pituitary adenomas. Functional SRIH receptors are present on these tumors and the effect of SRIH on hormonal secretion could be mediated, at least in part, by inhibition of adenylate cyclase. These findings support the medical treatment of this rare type of tumors by SRIH analogs.

Plasma levels of aldosterone versus aldosterone precursors: a way to estimate the malignancy of asymptomatic and nonsecretory adrenal tumors: a French Retrospective Multicentric Study.

The aim of this study was to find out whether the dysfunction of aldosterone pathway, previously proposed as a marker of secretory adrenal carcinoma, is also found in nonsecretory adrenal carcinomas, which pose even more difficult diagnostic problems even for patients with hypertension accompanied or not by hypokalemia. The exploration consisted of using the same method (RIA preceded by a chromatographic step) to determine the plasma levels of the following steroids in the mineral corticosteroid pathway: deoxycorticosterone (DOC), 18-hydroxydeoxycorticosterone (18-OHDOC), corticosterone (B), 18 hydroxycorticosterone (18 OH B), and aldosterone. The subjects included 16 adults, each presenting with an endocrinologically asymptomatic adrenal mass associated for some patients with hypokalemia and hypertension (8 with adrenal carcinoma, 2 with adrenal metastasis from other forms of cancer, and 6 adenomas). These results show that even in nonsecretory adrenal carcinoma, there is a dysfunction of the aldosterone pathway, which can be evaluated from the ratio between aldosterone and the substrate of 11 beta hydroxylase (DOC) and its derivative (18-OH DOC). This study suggests that exploration of mineralocorticosteroid pathway can be used as a hormonal marker of adrenal carcinoma for both secretory and non-secretory malignant masses.

Cerebrotendinous xanthomatosis: treatments with simvastatin, lovastatin, and chenodeoxycholic acid in 3 siblings.

We report 3 sisters treated for cerebrotendinous xanthomatosis. We treated one, with a severe neurologic form of the illness, with chenodeoxycholic acid, then lovastatin and simvastatin. These drugs had different efficacy and tolerance, but induced no clinical improvement. Her sisters, without neurologic symptoms, received chenodeoxycholic acid, which normalized the cholestanol level. Optimal treatment of this illness must begin before there is significant clinical symptomatology.

The diagnostic value of fine-needle aspiration biopsy under ultrasonography in nonfunctional thyroid nodules: a prospective study comparing cytologic and histologic findings.

Fine-needle aspiration biopsy (FNAB) of thyroid nodules has been proposed as a preoperative screening method to reduce the number of patients with benign nodules referred for surgery. Only a few previously published studies have compared cytologic results with a systematic surgical control; furthermore, the role of ultrasound guidance for FNAB in obtaining representative material has been poorly evaluated. The authors tried to assess the diagnostic value of FNAB performed under ultrasonography in a series of patients with a cold nodule and a systematic surgical control. This prospective study included 132 consecutive patients, 19 men and 113 women, aged from 18 to 82 years. The rate of carcinomas was 13.8%. A very high rate of adequate material was obtained (96.2%). Sensitivity, specificity, and global accuracy were 95%, 87.7%, and 89%, respectively. These results, which are equivalent to those previously published but associated with a low level of insufficient material, emphasize the diagnostic value of thyroid FNAB.

Somatostatin receptor scintigraphy in pituitary adenomas: a somatostatin receptor density index can predict hormonal and tumoral efficacy of octreotide in vivo.

UNLABELLED: Previous studies have failed to predict somatostatin analog response with somatostatin receptor scintigraphy in pituitary adenomas. In vitro studies have shown that the density of somatostatin receptors in pituitary tumors might be critical for octreotide response. METHODS: The density of somatostatin receptors was calculated in vivo combining the uptake index obtained from somatostatin receptor scintigraphy and the tumor volume obtained by MRI. The ratio of these two values, called density index (DI), was established in 32 of 37 consecutive patients with pituitary adenomas (11 had growth hormone-secreting adenomas, 4 thyroid-stimulating hormone-secreting and 17 nonfunctioning). It was compared with hormonal response, assessed in 15 secreting adenomas on growth hormone or thyroid stimulating hormone suppression (which was considered significant when it reached at least 50% of basal level), and with tumor shrinkage (which was considered significant when > or =20% of pretherapeutic value) in 12 secreting and 14 nonfunctioning adenomas. RESULTS: In agreement with previous reports, uptake index is not predictive of octreotide response. In contrast, DI predicts both hormonal suppression and tumor shrinkage (P = 0.009 and P = 0.0002, respectively) obtained with octreotide therapy. DI sensitivity, specificity and accuracy were 92% each, and a positive correlation was found between DI and the percentage of tumor shrinkage (r = 0.54, P = 0.004). CONCLUSION: The combination of scintigraphic and MRI data allows the computation of a DI for somatostatin receptors that points out patients who can profit from somatostatin analog treatment.

The role of octreotide (Sandostatin) in non-growth hormone-, non-thyroid-stimulating hormone-, and non-prolactin-secreting adenomas.

Octreotide may act on non-growth hormone-, non-thyroid-stimulating hormone, and non-prolactin-secreting adenomas. Its efficacy was reported in some corticotropin-secreting adenomas from Nelson's syndrome and from Cushing's disease. In gonadotropin-secreting adenomas, octreotide was shown to be effective in two of eight cases. In nonfunctioning adenomas, visual improvement was observed with octreotide in 14 of 23 cases in a French multicenter study. Among the 33 patients whose tumor volume was checked, shrinkage occurred in seven, but an increase in tumor volume was observed in another seven patients. Mechanism(s) and prediction of efficacy of octreotide remain to be documented.

Treatment of thyroid-stimulating hormone-secreting adenomas with octreotide.

From data collected in the literature, the effects of octreotide therapy in 37 patients with thyroid-stimulating hormone (TSH)-secreting adenomas who received short-term (1 to 2 weeks, n = 23) and long-term treatment (3 to 36 months) are reviewed. In 20 of 21 patients studied, short-term administration of octreotide (50 or 100 micrograms subcutaneously [SC] produced a 25% to 100% (mean +/- SD, 55.3% +/- 29%) decrease in TSH levels, with the nadir being obtained between the third and sixth hour following injection. After 1 to 2 weeks therapy with 50 to 100 micrograms twice or three times a day, 21 of 23 patients studied demonstrated a 66% (+/- 30%) decrease in TSH levels and 14 of 16 showed a 64% (+/- 27%) decrease in alpha-subunit levels. In approximately two thirds of the patients, the response was better than after short-term administration. The effect of octreotide on clinical and biological thyroid status was significant in all patients studied. After 1 week or 1 month of treatment, thyroid hormone levels were reduced in all patients and were normalized in 78%. Response to therapy was similar whether TSH secretion was pure or mixed (growth hormone [GH]-TSH adenomas). Fourteen patients received long-term treatment (3 to 36 months; mean, 12 +/- 10) with daily doses ranging from 200 to 1,500 micrograms. The response was better than or similar to that with short-term treatment. An escape occurred in TSH levels in two patients and in thyroid hormone levels in three patients, leading to an adjustment of dose or frequency of injection.(ABSTRACT TRUNCATED AT 250 WORDS)

Insulin autoimmune syndrome: a rare cause of hypoglycaemia not to be overlooked.

We report the case of a Caucasian patient with insulin autoimmune syndrome (IAS), defined as the association of hypoglycaemic attacks with insulin autoantibodies in individuals not previously treated with exogenous insulin. This rare syndrome (more than 200 published cases) has been reported mainly in Japan. Most affected patients present with other autoimmune disorders, most often Graves' disease. In most cases, insulin autoantibodies appear a few weeks after the beginning of treatment with a drug containing a sulphyldryl group. A significant increase in insulin and C-peptide plasma concentrations and the presence of other antiorgan antibodies are observed. The susceptibility haplotype is present in the Japanese population, which may account for the high frequency of IAS. Spontaneous remission is observed in 80% of cases, with cessation of hypoglycaemic attacks and disappearance of insulin autoantibodies some months after withdrawal of the drug. This rare cause of hypoglycaemia in Caucasian subjects should be considered in aetiologic investigation of spontaneous hypoglycaemia.

Chronic diarrhoea and diabetes mellitus: prevalence of small intestinal bacterial overgrowth.

The mechanisms of chronic diarrhoea, a frequent symptom in diabetes mellitus, are multifactorial and complex, although small intestinal bacterial overgrowth and autonomic neuropathy seem to play a major role. This study evaluated the prevalence of small intestinal bacterial overgrowth and the effects of antibiotic treatment in a population of diabetic patients with chronic diarrhoea (defined as > 3 stools/24 h, weight > 200 g/24 h, duration > 3 weeks). Small intestinal bacterial overgrowth syndrome was diagnosed by glucose-hydrogen breath testing (sensitivity: 78%, specificity: 89%). The characteristics of diarrhoea (duration, number of stools per day, and gastrointestinal symptoms) were noted. Autonomic neuropathy was assessed by cardiac parasympathetic tests. A total of 35 patients were included, 15 with small intestinal bacterial overgrowth syndrome (43%, group 1) and 20 with no bacterial overgrowth (group 2). Age (52.9 +/- 13.5 vs. 53.9 +/- 11.8 years, NS), duration of diabetes (13.8 +/- 9.1 vs. 10.6 +/- 7.8 years, NS), and HbA1c level (10 +/- 2.9 vs. 10.9 +/- 2.4%, NS) were not different between the two groups. In group 1, duration of diarrhoea was longer (18.1 +/- 18.5 vs. 7.75 +/- 4.02 months, P = 0.05), the number of stools higher (7.1 +/- 5.7 vs. 4.6 +/- 2.6/24 h, P < 0.05), and gastrointestinal symptoms more frequent (13 vs. 10, P < 0.05). The prevalence of small intestinal bacterial overgrowth syndrome and gastrointestinal symptoms was not different in patients with and without autonomic neuropathy (9 vs. 8 and 12 vs. 11 respectively, NS). Eight patients with bacterial overgrowth received antibiotics (amoxicillin-clavulanic acid, 1.5 g/24 h for 10 days). Dramatic clinical improvement was observed in 6 out of 8 of these patients. It is concluded that small intestinal bacterial overgrowth should be considered in case of chronic diabetic diarrhoea because of its frequency (43%), facility of diagnosis, and often successful treatment with antibiotics.

Enhanced susceptibility of low-density lipoprotein to in vitro oxidation in type 1 and type 2 diabetic patients.

Macrovascular disease represents a major cause of morbidity and mortality in patients with diabetes mellitus. Low-density lipoprotein (LDL) is involved in the pathogenesis of atherosclerotic lesions, through modifying processes such as oxidation. We examined the in vitro susceptibility to oxidation and the oxidizability of LDL isolated from the plasma of Type 1 and Type 2 diabetic patients. Two groups of diabetic patients (20 Type 1, 20 Type 2) were compared with sex- and age-matched non-diabetic control groups. In vitro oxidation of the purified LDL preparations was assessed by determination of the kinetics for the formation of conjugated dienes (lag phase duration, maximal rate and maximal dienes concentration) and by measurement of thiobarbituric acid-reacting substances (TBARS) in the presence of copper ions. LDL from both Type 1 and Type 2 diabetic patients exhibited a shorter lag phase duration for conjugated dienes formation (94 +/- 14 vs. 108 +/- 20 and 97 +/- 26 vs. 112 +/- 18 min for Type 1 and Type 2 diabetic groups vs. respective control groups, P < 0.05). We also observed an increase in maximal rate of conjugated dienes formation (2.21 +/- 0.55 vs. 1.52 +/- 0.31 and 2.02 +/- 0.55 vs. 1.52 +/- 0.31 nmol/mg LDL/min, P < 0.01) and of maximal production of TBARS (77.9 +/- 11.8 vs. 65.5 +/- 10.4 and 76.7 +/- 9.9 vs. 65.3 +/- 9.4 nmol/mg LDL protein, P < 0.05) in diabetic groups. Our results demonstrate both a higher susceptibility to oxidation and a higher oxidizability of LDL from diabetic patients, as much for Type 1 as Type 2 diabetic subjects with or without pre-existent vascular complications. This enhanced propensity of LDL oxidation in patients with diabetes mellitus could at least partly be attributable to quantitative and qualitative alterations in the chemical composition of LDL and to the glycoxidation process occurring on these lipoproteins.

A prospective multicenter trial of octreotide in 24 patients with visual defects caused by nonfunctioning and gonadotropin-secreting pituitary adenomas. French Multicenter Octreotide Study Group.

OBJECTIVE: The somatostatin analog octreotide has been demonstrated to improve optic tract compression caused by pituitary macroadenomas within hours of its administration and/or reduce tumor size in some patients. We report the results of a prospective multicenter study of the effects of octreotide on visual function and tumor size in patients with nonfunctioning pituitary adenomas or gonadotropin-secreting adenomas. METHODS: Twenty-four patients with visual defects caused by histologically confirmed macroadenomas were administered octreotide via continuous subcutaneous infusion, as follows: 100 micrograms the 1st day and, if necessary, 200 micrograms the 2nd and then 100 or 200 micrograms three times daily if visual function improved. Vision was assessed after 4 days, 1 month, and 2 months, including tumor size evaluation. Visual improvement was defined by a net gain of at least 2/10 in acuity and/or of more than 20% of the surface of one isopter (a reduction in tumor volume of > or = 20% of the initial measurement); opposite changes were defined as deterioration. RESULTS: Visual improvement was noted in 13 of 24 patients, 10 of 23 patients and 9 of 22 patients, and was not noted in 11 of 24 patients, 14 of 23 patients, and 13 of 22 patients after 4 days, 1 month, and 2 months, respectively. After 2 months, three adenomas had shrunk, three had not changed in size, and one had increased; visual function improved in the seven patients with these adenomas. Octreotide was discontinued in 13 patients for lack of efficacy. CONCLUSION: The incidence of visual improvement and tumor shrinkage noted in this study was higher than previously reported. Our data suggest that early onset of visual improvement might help in deciding which patients profit from octreotide. However, concomitant gain in visual acuity with deterioration in visual fields or visual improvement with an increase (moderate) in tumor size can occur.

The effect of somatostatin analogue on chiasmal dysfunction from pituitary macroadenomas.

The long-acting somatostatin analogue SMS 201-995 has been shown to be efficient in the treatment of somatotropic and thyrotropic adenomas. In some cases, it can suppress adenoma secretion and lead to tumor shrinkage. Pituitary macroadenomas are often associated with a vision-threatening chiasmal syndrome. In this series, SMS 201-995 was administered subcutaneously to eight patients with pituitary macroadenomas of various types responsible for severe long-lasting visual defects. An obvious improvement of both visual fields and acuity occurred in six patients, in two of these during the first 4 to 6 hours of treatment; in two patients, gonadotropic adenomas were unresponsive. Maximal improvement (normalization of visual fields in three cases) occurred within 6 to 45 days and was sustained during the 1- to 12-month follow-up period. This effect seems independent of the type of adenoma since the adenomas secreting growth hormone (GH) and thyroid-stimulating hormone and silent corticotropic-secreting adenomas responded as well as did two of the non-functioning adenomas. In one acromegalic patient visual improvement was obtained while the abnormal GH secretion remained unaltered. In all cases but one, no tumor shrinkage could be demonstrated. These data demonstrate that SMS 201-995 can rapidly improve the chiasmal syndrome due to pituitary macroadenoma, and suggest that this effect might be independent of a reduction in tumor volume.

[Hypophyseal adenomas: functional and tumor evaluation and therapeutic approaches]. / Adénomes hypophysaires: bilan tumoral et fonctionnel et abords thérapeutiques. therapeutic approaches]

Patients with pituitary adenomas present with hypersecretion syndrome(s), and/or pituitary failure(s), and/or signs of mass effect, or incidentally. Pituitary function evaluation, visual acuity and field check-up, and MRI or at least CAT are compulsory for diagnosis, and for therapeutic approach; surgery for Cushing's disease, dopamine agonists for prolactinomas, somatostatin analogs or surgery for thyrotroph adenomas, surgery and/or somatostatin analogs and/or radiotherapy in acromegaly, surgery with additional irradiation in most adenomas of other types, or even expectation in some instances.

[Mesenchymal tumor associated with hypoglycemia and an elevated NSILP (author's transl)]. / Tumeur mésenchymateuse hypoglycémiante de la cuisse avec NSILP élevé.

An unusually located mesenchymal tumor with hypoglycemia is observed. Insulin, cortisol, growth hormone, glucagon levels are within the normals. The glucogenic aminoacids have also been measured, as well as the NSILP which was three times as high as the upper limit of normal values. The various processes which might have brought about the patient's hypoglycemia are discussed.

[Two cases of FSH secreting adenomas (author's transl)]. / Deux cas d'adénome hypophysaire à FSH.

The authors report two cases of FSH secreting adenomas in men and attempt to draw out some features of these very uncommon pituitary tumors. Absence of gynecomastia is emphasized. Diagnosis proceeds from systematic radio-immunoassay of pituitary hormones. Evidence of FSH secretion results from paradoxical gonadotropin stimulation by TRH and secretory granules seen by electronic microscope. Immunofluorescence studies are still to perform. Dynamic testicular secretion and, in one case, histologic examination were performed.

[Long-term treatment of Cushing's disease using ketoconazole. Possibility of therapeutic escape]. / Traitement prolongé de la maladie de Cushing par le kétoconazole. Possibilité d'un échappement thérapeutique.

Five women suffering from Cushing's disease were treated with ketoconazole 800 mg per day for 2 to 28 months (mean 12.4 months). Four of them had full clinical and biochemical regression. However, after 8 months of therapy the disease failed to respond in three of these four women. Increasing the ketoconazole dosage up to 1,200 mg per day was ineffective in two patients. Such an escape phenomenon, not described until now, will restrict the use of ketoconazole in the treatment of Cushing's disease, although the drug is easy to administer and well tolerated globally and by the liver in most cases.

[Diabetic thoracoabdominal neuropathy. Clinical and electrophysiological study with evaluation of the autonomic nervous system]. / Neuropathie diabétique thoraco-abdominale. Etude clinique et électrophysiologique avec évaluation du système nerveux autonome.

We report on eight patients with diabetic thoracoabdominal neuropathy in whom careful evaluation of peripheral and autonomic nervous system function was performed. All patients had non insulin-dependent diabetes mellitus of 10.5 +/- 6.7 years mean (+/- SD) known duration with poor glycemic control. Thoracic (n = 7) or abdominal (n = 1) pain of sudden onset involved several adjacent dermatomal segments and was bilateral and asymmetrical in 7/8 patients. Four patients had hypoesthesia in the painful zone and six presented with significant weight loss (6.2 +/- 4.3 kg) which reversed after the relief of pain. Truncal electromyogram was abnormal in 7/7 patients. Nerve damage was not limited to thoracic nerves since electrophysiological studies evidenced distal polyneuropathy in all patients. The autonomic nervous system was also involved. Sympathetic skin response was abnormal in 7/7 patients and autonomic cardiovascular function tests demonstrated cardiac denervation in 5/5 patients. In 4/4 patients a marked relief of pain was noted within one week with amitriptyline treatment. This report confirms the characteristic clinical presentation of diabetic thoracoabdominal neuropathy. Moreover, it suggests that this neuropathy is part of a diffuse damage that also involves peripheral nerves of the limbs and autonomic nervous system.