The changing spectrum of TSH-secreting pituitary adenomas: diagnosis and management in 43 patients.

OBJECTIVE: Our aim was to report the recent changes in diagnosis and management of TSH-secreting pituitary adenomas. METHODS: We retrieved 43 consecutive patients with TSH-secreting pituitary tumors (23 male and 20 female) among 4400 pituitary adenomas followed between 1976 and 2001 in six Belgian and French centers. RESULTS: TSH was elevated in 18/43 and alpha subunit in 13/32 patients. In patients with intact thyroid (n=30), mean free tri-iodothyronine was 13.1 pmol/l (range 3.5-23) and mean free thyroxine was 38.4 pmol/l (range 10.2-62.7). Hyperprolactinemia and acromegaly were associated in 9/43 and 8/43 cases. The number of associated hypersecretions was higher in macroadenomas than in microadenomas (Chi square = 11.2, P<0.01). Two women had sporadic multiple endocrine neoplasia type 1-associated syndrome. The proportion of microadenomas versus macroadenomas was 1/11 (period 1974-1986) and 8/32 (period 1987-2001). Bilateral petrosal sinus sampling, (111)In-pentreotide scintigraphy and ((11)C)-l-methionine positron emission tomography scan confirmed diagnosis in four questionable microadenomas. Macroadenomas with extrasellar extension (31 cases) had a tendency to be medially located. Medical treatment with somatostatin analogs was initiated as first-line treatment in 26 patients. TSH levels were reduced by more than 50% in 23/26 cases. A tumoral shrinkage of more than 20% was observed in 5/13 cases. Surgery was performed in 36 patients. After 1 year, 21 of them (58.3%) met the criteria of surgical favorable outcome. Pituitary radiotherapy (n=8) and somatostatin analogs allowed normalization in cases not cured by surgery. CONCLUSION: Ultrasensitive methods for TSH measurement led to an earlier recognition of TSH-secreting pituitary tumors. In this series, we observed that TSH-secreting pituitary tumors are today more frequently found at the stage of microadenomas, medially located, without associated hypersecretions and needing new exploration methods as compared with older series. This changing spectrum in the presentation of TSH-secreting pituitary tumors and the excellent response to somatostatin analogs has been accompanied by an improvement in the prognosis of the disease.

[Partial androgenic deficit in the aging male]. / Le déficit androgénique partiel de l'homme vieillissant.

It is possible to observe in the aging male an hypotestosteronemia below 3 ng/ml. The indications of an androgenic treatment are discussed with their benefits, risks, contra-indications and choices of molecules. Testosterone-gel seems to be now the first choice for this type of patient. In case of normal testosteronemia and erectile dysfunction, the benefits/risks ratio of sildenafil is very favorable, except when contra-indicated.

[The endocrinology department]. / Le Service d'Endocrinologie.

The clinical activities of the department of endocrinology encompass the care and treatment of diabetes, thyroid diseases, hypothalamo-pituitary, adrenal, gonadic and parathyroid diseases, obesity, hypercholesterolemia and paraneoplastic endocrine syndromes. These domains are briefly described. The research activities of the department have investigated the regulation of thyroid metabolism in vitro, the intrathyroid H2O2 generating system, the physiopathology of toxic thyroid nodules and the effects of ageing on the thyreotropic function of the normal ageing male. Studies of "jet lag" conditions have shed a new light on hormonal chronophysiology. Other investigations have considered the regulation of ketone body metabolism, the relationship between nutritional status and glucose metabolism, and some aspects of immunodiabetology.

Slow-release lanreotide in the treatment of acromegaly: a study in 66 patients.

OBJECTIVE: Slow-release (SR) lanreotide is a long-acting somatostatin analog that has been developed in order to overcome the inconvenience of multiple daily subcutaneous injections of octreotide, required for metabolic control in acromegaly. Lanreotide SR has been found to be well tolerated and effective in reducing GH and IGF-I levels but clinical data are still limited compared with those with subcutaneous octreotide treatment. DESIGN: Sixty-six unselected patients with active acromegaly were therefore evaluated in a multi-center, prospective, open label study. Lanreotide SR was given at a dose of 30mg intramuscular every 7-14 days. METHODS: At baseline and after 2, 4, 8, 12, 24, 36 and 48 weeks patients underwent a clinical examination with assessment of acromegaly related symptoms, and blood was sampled for serum GH, IGF-I, prolactin, glycosylated hemoglobin, fasting glucose, hematology, kidney function and liver function tests. Biliary ultrasonography and pituitary magnetic resonance imaging were performed at baseline and after one year. RESULTS: Treatment resulted in a significant improvement in the symptom score from 2.69+/-0.27 to 1.06+/-0.17 (P<0.0001). Serum IGF-I levels fell from 699+/-38microg/l at baseline to 399+/-26microg/l (P<0.0001, n=60) after one month, after which levels remained stable: 480+/-37microg/l after 6 months (n=54) and 363+/-32microg/l after one year (n=46). GH levels dropped from 13.8+/-3.2microg/l to 4.3+/-0.7microg/l after one month (P<0.0001, n=60) and remained stable thereafter: 3.9+/-0.4microg/l (n=54) after 6 months and 3.5+/-1.1microg/l after one year (n=46). Twenty-nine out of 66 patients (44%) attained a normal age-corrected IGF-I level and 30 patients (45%) attained a GH level below 2.5microg/l. Pituitary adenoma shrinkage of at least 25% was found in 5 of 14 patients (36%) after one year. Side effects were mainly transient gastrointestinal symptoms and pain at the injection site, resulting in drug discontinuation in only 6 patients (9%). Two patients developed new gall stones. No difference was found between subcutaneous octreotide and lanreotide SR in efficacy and almost all patients preferred the easier dose administration of lanreotide SR. CONCLUSIONS: Long-term treatment of acromegaly with SR-lanreotide is effective in controlling GH and IGF-I levels and symptoms and is well tolerated in the majority of patients. Compared with subcutaneous octreotide, lanreotide SR considerably improves patient's acceptance of therapy while having the same overall efficacy.

Metabolic effects of short-term elevations of plasma cortisol are more pronounced in the evening than in the morning.

To determine whether elevations of cortisol levels have more pronounced effects on glucose levels and insulin secretion in the evening (at the trough of the daily rhythm) or in the morning (at the peak of the rhythm), nine normal men each participated in four studies performed in random order. In all studies, endogenous cortisol levels were suppressed by metyrapone administration, and caloric intake was exclusively under the form of a constant glucose infusion. The daily cortisol elevation was restored by administration of hydrocortisone (or placebo) either at 0500 h or at 1700 h. In each study, plasma levels of glucose, insulin, C-peptide, and cortisol were measured at 20-min intervals for 32 h. The initial effect of the hydrocortisone-induced cortisol pulse was a short-term inhibition of insulin secretion without concomitant glucose changes and was similar in the evening and in the morning. At both times of day, starting 4-6 h after hydrocortisone ingestion, glucose levels increased and remained higher than under placebo for at least 12 h. This delayed hyperglycemic effect was minimal in the morning but much more pronounced in the evening, when it was associated with robust increases in serum insulin and insulin secretion and with a 30% decrease in insulin clearance. Thus, elevations of evening cortisol levels could contribute to alterations in glucose tolerance, insulin sensitivity, and insulin secretion.

Cabergoline in the treatment of hyperprolactinemia: a study in 455 patients.

Cabergoline is a new long-acting dopamine agonist that is very effective and well tolerated in patients with pathological hyperprolactinemia. The aim of this study was to examine, in a very large number of hyperprolactinemic patients, the ability to normalize PRL levels with cabergoline, to determine the effective dose and tolerance, and to assess the effect on clinical symptoms, tumor shrinkage, and visual field abnormalities. We also evaluated the effects of cabergoline in a large subgroup of patients with bromocriptine intolerance or -resistance. We retrospectively reviewed the files of 455 patients (102 males and 353 females) with pathological hyperprolactinemia treated with cabergoline in 9 Belgian centers. Among these patients, 41% had a microadenoma; 42%, a macroadenoma; 16%, idiopathic hyperprolactinemia; and 1%, an empty sella. The median pretreatment serum PRL level was 124 microg/L (range, 16-26,250 microg/L). A subgroup of 292 patients had previously been treated with bromocriptine, of which 140 showed bromocriptine intolerance and 58 showed bromocriptine resistance. Treatment with cabergoline normalized serum PRL levels in 86% of all patients: in 92% of 244 patients with idiopathic hyperprolactinemia or a microprolactinoma and in 77% of 181 macroadenomas. Pretreatment visual field abnormalities normalized in 70% of patients, and tumor shrinkage was seen in 67% of cases. Side effects were noted in 13% of patients, but only 3.9% discontinued therapy because of side effects. The median dose of cabergoline at the start of therapy was 1.0 mg/week but could be reduced to 0.5 mg/week once control was achieved. Patients with a macroprolactinoma needed a higher median cabergoline dose, compared with those with idiopathic hyperprolactinemia or a microprolactinoma: 1.0 mg/week vs. 0.5 mg/week, although a large overlap existed between these groups. Twenty-seven women treated with cabergoline became pregnant, and 25 delivered a healthy child. One patient had an intended abortion and another a miscarriage. In the patients with bromocriptine intolerance, normalization of PRL was reached in 84% of cases, whereas in the bromocriptine-resistant patients, PRL could be normalized in 70%. We confirmed, in a large-scale retrospective study, the high efficacy and tolerability of cabergoline in the treatment of pathological hyperprolactinemia, leaving few patients with unacceptable side effects or inadequate clinical response. Patients with idiopathic hyperprolactinemia or a microprolactinoma, on average, needed only half the dose of cabergoline as those with macroprolactinomas and have a higher chance of obtaining PRL normalization. Cabergoline also normalized PRL in the majority of patients with known bromocriptine intolerance or -resistance. Once PRL secretion was adequately controlled, the dose of cabergoline could often be significantly decreased, which further reduced costs of therapy.

A pilot study for identifying at risk thyroid lesions by means of a decision tree run on clinicocytological variables.

Fine-needle aspiration biopsy (FNAB) is safe, inexpensive, minimally invasive, and highly accurate in the diagnosis of nodular diseases of the thyroid. However, FNAB does not provide a reliable benign versus malignant diagnosis for 100% of the cases analysed. It is possible to increase the accuracy of the cytological diagnosis by means of information contributed by different clinical variables. In the present study we evaluate the diagnostic value of 10 variables in addition to FNAB on a series of 218 specimens for which we obtained histological diagnoses including 37 cancers (17%). The diagnostic information contributed by these variables was analyzed by means of the Decision Tree technique, an artificial intelligence-related method which forms part of the Supervised Learning algorithms. The results show that Decision Trees enable some subpopulations of patients with uncertain FNAB results to be characterized.

Ectopic Cushing's syndrome and pulmonary carcinoid tumour identified by [111In-DTPA-D-Phe1]octreotide.

The differential diagnosis and management of Cushing's syndrome remain difficult, particularly for ectopic adrenocorticotropin (ACTH) syndromes resulting from small bronchial carcinoids. We report the case of a 41-year-old man with ectopic ACTH-dependent Cushing's syndrome. Two computed tomography scans of the thorax were normal and magnetic resonance imaging of the chest showed a 6-mm hyperintense T1-weighted area close to the left pulmonary hilus, interpreted as probably vascular by the radiologists. An [111In-DTPA-D-Phe1]octreotide scintigraphy scan demonstrated a positive image for somatostatin receptors in exactly the same location and surgery confirmed the presence of a small ACTH-secreting carcinoid tumour in the upper left lung lobe which was resected. Surgery cured the hypercorticism of the patient. The differential diagnosis of Cushing's syndrome and the procedure for localisation of an ACTH source are discussed.

[Growth hormone treatment in adults: legitimate and illegitimate indications]. / L'hormone de croissance chez l'adulte: vraies et fausses indications.

Growth hormone replacement therapy of hypopituitary adult patients has demonstrated its usefulness during the last 12 years: it decreases excess body fat while raising lean mass and basal metabolic rate, it ameliorates the lipid profile of the patients and decreases their peripheral vascular resistance, it increases bone mineralization and ameliorates the quality of life of treated individuals. Based on these results, many other applications of growth hormone have been developed: treatment of old age, of simple and android obesities, of osteoporosis and extreme catabolic situations. The data collected have been of great pathophysiological interest, but do not lead for the present towards therapeutic indications.

Two years of replacement therapy in adults with growth hormone deficiency.

OBJECTIVES: Although several studies have shown beneficial short-term effects of recombinant human growth hormone (rhGH) therapy in adult GH deficient (GHD) patients, few data are available on large groups of patients treated for more than one year. In addition, the optimal dose of rhGH for each patient and the baseline parameters that predict which patients will benefit most from therapy or will have adverse events are not entirely elucidated. DESIGN: 148 adult GHD patients were enrolled in a multicentre 2-year rhGH replacement study which was placebo controlled for the first six months. rhGH (Genotropin/Genotonorm Pharmacia & Upjohn) was given in a dose of 0.25 IU/kg/week sc (1.5 IU/m2/day). MEASUREMENTS: Every 3-6 months body composition was measured using body impedance analysis and general well being was assessed using the Nottingham Health Profile (NHP) and social self-reporting questionnaire. At the same time patients had a full clinical examination and blood was sampled for glucose, HbA1c, IGF-1, creatinine, full blood count, thyroid hormones and liver function tests. RESULTS: With rhGH therapy IGF-1 levels increased from -2.00 +/- 2.60 SDS to 1.47 +/- 2.6 SDS after six months (P < 0.001), continued to rise despite no change in dose to 1.84 +/- 2.8 SDS after one year and remained constant thereafter (1.98 +/- 2.4 after 2 years). 56% of patients ultimately attained supranormal IGF-1 levels (+2 SD), 22% had levels below the mean, of which 9% were below -2 SD. Within 3 months lean body mass (LBM) increased by +5.09% (P < 0.001), total body water (TBW) by +5.40% (P < 0.001), while body fat (BF) dropped by -10.89% (P < 0.001) and waist circumference by -1.42% (P < 0.004). These effects were maintained during the first year of therapy, but the effect was attenuated after 24 months: LBM, +3.91% (P < 0.001); TBW, +3.28%, P < 0.001, BF, -6.42% (P < 0.001) and waist -2.22% (P < 0.009). Individual differences in response were large and could not be predicted by any of the baseline parameters, except for a better response in males. Treatment resulted in a large and progressive improvement on the NHP scale, especially energy, emotions and sleep, but a similar change was also found in patients during placebo treatment. With rhGH the number of full days of sick leave/6 months decreased from 12.17 +/- 3.90 days (SEM) to 7.15 +/- 3.50 days after six months (P = 0.009), 2.93 +/- 1.55 days after 12 months (P = 0.01), 0.39 +/- 0.17 days after 18 months (P < 0.001) and 3.3 +/- 2.51 days after 24 months (P = 0.026). Similarly, the hospitalization rate went down from 14.9 to 7% after 6 months and remained at this level thereafter (P = 0.12). About one third of patients on rhGH experienced fluid-related adverse events, most often within the first 3 months. They usually disappeared spontaneously or responded well to dose reduction. Cumulative dropout rates were 29% after 1 year and 38% after two years. Two thirds of these patients stopped treatment because of insufficient subjective improvement. Neither drop-outs nor fluid retention could not be predicted by any of the baseline parameters. CONCLUSIONS: We confirmed in a large group of patients the beneficial effects of rhGH therapy on body composition, metabolic parameters and general well-being and found a consistent drop in number of sick days and hospitalization rate. These effects were maintained during two years of therapy, except for an attenuation in body composition changes after 24 months. The high incidence of fluid-related adverse events suggests that it may be better to start with lower doses of rhGH and to increase the dose more slowly over a number of weeks. The finding of suboptimal high or low IGF-1 levels in many patients reinforces guidelines not to give rhGH in a weight-dependent dose but to titrate it individually for each patient.

Regulation and metabolic role of phospholipase D activity in human thyroid and cultured dog thyrocytes.

The actions of TSH, ATP, the ionophore A23187, the endoplasmic reticulum Ca(2+)-ATPase inhibitor thapsigargin, and phorbol dibutyrate (PDBu) on 3H-cytidine-monophosphate phosphatidic acid (3H-CMP-PA) accumulation were studied in human thyroid slices to evaluate PA generation and inositol recycling towards phosphatidyl-inositol synthesis. The effects of the same agonists also were measured on phosphatidylbutanol (PtdBut) generation in 3H-palmitate or 3H-myristate prelabeled slices to assess the activity of phospholipase D (PLD). The phospholipid target of this PLD was determined on 3H-choline prelabeled human thyroid slices by measuring 3H-choline release in incubation medium and slices and 3H-choline incorporation in phospholipids. TSH (10 U/L) stimulated 3H-CMP-PA accumulation in an LiCl-and propranolol-insensitive way, as well as 2H-fatty acids incorporation into PA, diacylglycerol, and phosphatidylcholine (PtdCho) with on evidence of dose-dependent effects and had no detectable action on PLD activity. The effects of TSH were not reproduced by Bu2cAMP or forskolin. Thapsigargin and A23187 both increased CMP-PA accumulation and PtdBut generation, whereas ATP only stimulated PLD activity. The phorbol ester PDBu (5 x 10(-7) mol/L) increased PtdBut formation and 3-H-fatty acid incorporation into PtdCho, but had no effect on CMP-PA generation. Staurosporine (STSP) (5 x 10(-6) mol/L), a nonspecific inhibitor of protein kinase C, unexpectedly reproduced the effects of PDBu. The increase of 3H-choline in slices' supernatant and the decrease of 3H-choline-labeled PtdCho induced by PDBu, ATP, thapsigargin, and STSP indicate that the activated PLD hydrolyzed PtdCho. We suggest that the PA generation induced by PLD stimulation could contribute to the stimulated H2O2 formation and iodide organification observed with the agonists inducing PtdBut accumulation. Indeed, Bu2cAMP and forskolin, known to decrease iodide organification in human thyroid, inhibited the PLD stimulation induced by ATP and PDBu. In cultured dog thyrocytes, phorbol esters, and STSP induced DNA synthesis and dedifferentiation, whereas thapsigargin inhibited TSH-induced growth and killed phorbol esters stimulated cells, suggesting a positive role of PLD stimulation towards dedifferentiated growth and of simultaneously raised [Ca2+)i and stimulated protein kinase C-PLD towards growth arrest and cellular death.

Effects of morning cortisol elevation on insulin secretion and glucose regulation in humans.

The time course of the effects of an acute elevation in morning plasma cortisol on the daytime profiles of plasma glucose, serum insulin, and insulin secretion under constant glucose infusion was determined using a placebo-controlled design in two groups of eight normal men. In one group, the elevation of plasma cortisol was obtained by oral administration of 100 mg hydrocortisone. In the other group, the elevation was obtained by intravenous administration of 25 micrograms of corticotropin-releasing hormone. In both studies, the immediate effect of the increase in plasma cortisol, even when of very small amplitude, was an abrupt inhibition of insulin secretion without change in glucose concentration. Larger cortisol elevations, such as occurred after hydrocortisone administration, were additionally associated with the appearance of insulin resistance, which developed 4-6 h after the cortisol elevation and persisted for > 16 h. These observations support the concept that the 24-h cortisol rhythmicity is responsible, at least in part, for the normal diurnal variation in glucose tolerance.

Analysis of particle size generated during plaque ablation with a flashlamp pumped pulsed dye laser.

PURPOSE: To examine debris size generated during in vitro plaque ablation by laser energy and estimate the risk of peripheral embolization following laser angioplasty. METHODS: A flashlamp pumped pulsed dye laser of 480-nm wavelength was used to ablate calcified arteriosclerotic plaque, fibrous fatty plaque, and normal aortic wall on samples of human cadaver aortas. Each tissue sample was immersed in saline solution and treated with the same amounts of laser energy transmitted by a 320 microns-diameter glass fiber in direct tissue contact. The debris generated during plaque ablation was then separated from the supernatant and the particles were counted and analyzed for size. RESULTS: Depending on the underlying type of tissue and the setting of laser energy, a wide range of particles with sizes between 5.3 mm2 and 64 microns 2 was found in samples. The largest particles were found after ablation of calcified atherosclerotic plaque, whereas fibrous, fatty plaque and normal aortic wall showed smaller particles and a lesser amount of debris. CONCLUSION: Our study demonstrates that a considerable amount of debris is generated during laser angioplasty at 480 nm and that particle size is sufficient to cause potentially symptomatic embolic occlusions of mid- and small-sized peripheral arteries.

Relative contribution of phosphoinositides and phosphatidylcholine hydrolysis to the actions of carbamylcholine, thyrotropin (TSH), and phorbol esters on dog thyroid slices: regulation of cytidine monophosphate-phosphatidic acid accumulation and phospholipase-D activity. I. Actions of carbamylcholine, calcium ionophores, and TSH.

The actions of carbamylcholine (Cchol), the ionophores A23187 and thapsigargin, and TSH on [3H]cytidine monophosphate-phosphatidic acid ([3H]CAMP-PA) accumulation were studied in prelabeled dog thyroid slices to evaluate phosphatidic acid (PA) generation and inositol recycling by phosphatidylinositol (PtdIns) synthesis. The effects of the same agonists were also measured on phosphatidylbutanol generation in [3H]palmitate- or [3H]myristate-prelabeled slices to assess the activity of phospholipase-D (PLD) and on the effluxes of myo-[3H]inositol and [3H]choline induced by these agents from prelabeled slices. Cchol (10(-6)-10(-4) M) increased inositol phosphate (InsP) generation, with no change in inositol efflux, and contracted the intracellular inositol pool. This suggests a stimulation of PtdIns synthesis as well as hydrolysis. The muscarinic agonist provoked a dramatic accumulation of CMP-PA in the presence of lithium chloride (10 mM), which suggests that when InsP hydrolysis is inhibited, inositol limits the rate of CMP-PA incorporation into PtdIns. Cchol also increased phosphatidylbutanol formation. The latter two actions of Cchol were reproduced by A23187 (10(-5) M) and thapsigargin (2 x 10(-6) M) and were inhibited by calphostin-C, an inhibitor of the regulatory site of protein kinase-C. Cchol also induced increased free choline efflux, with a decreased choline phosphate relative content of the medium. TSH (10 mU/ml) stimulated free inositol efflux and induced a slight and proportional increase in [3H]inositol incorporation in phosphoinositides and InsP. The hormone also increased PA and CMP-PA accumulation exclusively in the presence of the PA phosphatase inhibitor propranolol (10(-4) M), but had no detectable action on PLD activity. None of these effects of TSH was reproduced by forskolin or potentiated by lithium chloride (10 mM). The data demonstrate the existence in thyroid tissue of a PLD-hydrolyzing phosphatidylcholine that was stimulated by Cchol and increased intracellular Ca2+, but not by TSH. The results obtained, besides confirming that TSH does not stimulate PtdInsP2-PLC or affect phosphatidylcholine hydrolysis, suggest that the hormone, instead, stimulates de novo PtdIns synthesis and/or inositol transport. The physiological relevance of these actions of Cchol, increased intracellular Ca2+, and TSH in thyroid metabolism could be related to their divergent effects on thyroid cell metabolism.

Relative contribution of phosphoinositides and phosphatidylcholine hydrolysis to the actions of carbamylcholine, thyrotropin, and phorbol esters on dog thyroid slices: regulation of cytidine monophosphate-phosphatidic acid accumulation and phospholipase-D activity. II. Actions of phorbol esters.

The effects of phorbol dibutyrate (PDBu) on phosphatidylbutanol (PtdBut) generation in [3H]palmitate- or [3H]myristate-prelabeled dog thyroid slices were measured to assess the activity of phospholipase-D (PLD) in the presence or absence of the two inhibitors of protein kinase-C (PKC), staurosporine (STSP) and calphostin-C. The actions of the same agents on [3H]cytidine monophosphate-phosphatidic acid accumulation were also determined to evaluate phosphatidic (PA) generation and inositol recycling to phosphatidylinositol. The effluxes of [3H]choline and [3H]ethanolamine induced by the phorbol ester from prelabeled slices were also evaluated. PDBu (5 x 10(-9) to 5 x 10(-6) M) potently stimulated PLD activity, with a concomitant increase in fatty acids incorporation in phosphatidylcholine (PtdCho). However, under no condition did the phorbol ester result in cytidine monophosphate-phosphatidic acid accumulation. It stimulated the efflux of choline and ethanolamine while decreasing choline and ethanolamine phosphates in the slices and incubation medium. Calphostin-C, inhibiting PKC, decreased PtdBut and PtdCho formation induced by the phorbol ester, as opposed to STSP (5 x 10(-6) M), which did not affect these actions of PDBu and, moreover, reproduced by itself the effects of the phorbol ester on choline efflux and PtdBut generation despite efficient inhibition of other effects of PKC. These data demonstrate the existence in thyroid tissue of a PLD-hydrolyzing PtdCho, which was stimulated by phorbol esters and STSP. They also suggest that the PA formed after PKC stimulation and subsequent PLD activation is channeled toward PtdCho resynthesis when intracellular Ca2+ is not increased, whereas the PA accumulated with a concomitant increase in intracellular Ca2+ is diverted toward phosphatidylinositol synthesis. The physiological relevance of this Ca-independent stimulation of a PKC-coupled PLD in thyroid metabolism could be related to the growth-inducing and dedifferentiating effects of the phorbol esters.

Somatic mutations in the thyrotropin receptor gene cause hyperfunctioning thyroid adenomas.

The pituitary hormone thyrotropin stimulates the function, expression of differentiation and growth of thyrocytes by cyclic AMP-dependent mechanisms. Tissue hyperplasia and hyperthyroidism are therefore expected to result when activation of the adenylyl cyclase-cAMP cascade is unregulated. This is observed in several situations, including when somatic mutations impair the GTPase activity of the G protein Gsa (ref 6, 7). Such a mechanism is probably responsible for the development of a minority of monoclonal hyperfunctioning thyroid adenomas. Here we identify somatic mutations in the carboxy-terminal portion of the third cytoplasmic loop of the thyrotropin receptor in three out of eleven hyperfunctioning thyroid adenomas. These mutations are restricted to tumour tissue and involve two different residues (aspartic acid at position 619 to glycine in two cases, and alanine at position 623 to isoleucine in one case). The mutant receptors confer constitutive activation of adenylyl cyclase when tested by transfection in COS cells. This shows that G-protein-coupled receptors are susceptible to constitutive activation by spontaneous somatic mutations and may thus behave as proto-oncogenes.

Zero-order drug release from hydrocolloid matrices.

Matrices are manufactured by direct compression of a powder mixture of a polymer, e.g., methylhydroxypropyl cellulose (MHPC) or polyvinylalcohol (PVAI), and a drug. The following factors that can influence the drug release mode were investigated at constant surface: (i) polymer solution viscosity, glass transition temperature, and swelling; (ii) drug concentration in the matrix and solubility; and (iii) conditions of release experiment (hydrodynamics). In the case of zero-order release profiles (hydrocolloids with low viscosities), only the dissolution of the polymer appears to control the drug release rate. Factors accelerating polymer dissolution resulted in higher release rates. Comparison of swollen and dry hydrocolloid matrices shows that the duration and kinetics of drug release were not controlled by the swelling front moving into the dry polymer, and water penetration and relaxation were not rate controlling. Therefore, the glass transition temperature had no effect on drug release from these hydrocolloids. The higher the hydrodynamic stress exerted on the eroding hydrocolloid, the faster the resulting drug release as a result of accelerated polymer dissolution. With hydrocolloids of very high viscosity the polymer dissolution is slow, and drug release from the swollen gel appears to be controlled by diffusion according to kinetics of the Higuchi type.

Thyroid stimulating immunoglobulins, like thyrotropin activate both the cyclic AMP and the PIP2 cascades in CHO cells expressing the TSH receptor.

In human thyrocytes and in a permanent CHO cell line expressing the human thyroid stimulating hormone (TSH) receptor cDNA (JP09 cells), TSH activates both the cyclic AMP and the phosphatidylinositol 4,5-bisphosphate (PIP2) cascade, although the latter effect requires higher TSH concentrations. Thyroid stimulating autoantibodies (TSAb) activate also the human thyroid leading to the hyperthyroidism of Graves' disease. They bind to the TSH receptor and mimic the TSH stimulation of the gland by increasing intracellular cyclic AMP, but they do not enhance PIP2 hydrolysis in human thyroid slices. We show in this study that TSAb are able to activate the PIP2 cascade in JP09 cells, a cell line expressing high levels of TSH receptor. This suggests that the mechanism of action of TSAb on the TSH receptor is qualitatively similar to that of TSH.