Activation of RAF/MEK/ERK and PI3K/AKT/mTOR pathways in pituitary adenomas and their effects on downstream effectors.

Raf/MEK/ERK and phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) cascades are key signalling pathways interacting with each other to regulate cell growth and tumourigenesis. We have previously shown B-Raf and Akt overexpression and/or overactivation in pituitary adenomas. The aim of this study is to assess the expression of their downstream components (MEK1/2, ERK1/2, mTOR, TSC2, p70S6K) and effectors (c-MYC and CYCLIN D1). We studied tissue from 16 non-functioning pituitary adenomas (NFPAs), six GH-omas, six prolactinomas and six ACTH-omas, all collected at transsphenoidal surgery; 16 normal autopsy pituitaries were used as controls. The expression of phospho and total protein was assessed with western immunoblotting, and the mRNA expression with quantitative RT-PCR. The expression of pSer217/221 MEK1/2 and pThr183 ERK1/2 (but not total MEK1/2 or ERK1/2) was significantly higher in all tumour subtypes in comparison to normal pituitaries. There was no difference in the expression of phosphorylated/total mTOR, TSC2 or p70S6K between pituitary adenomas and controls. Neither c-MYC phosphorylation at Ser 62 nor total c-MYC was changed in the tumours. However, c-MYC phosphorylation at Thr58/Ser62 (a response target for Akt) was decreased in all tumour types. CYCLIN D1 expression was higher only in NFPAs. The mRNA expression of MEK1, MEK2, ERK1, ERK2, c-MYC and CCND1 was similar in all groups. Our data indicate that in pituitary adenomas both the Raf/MEK/ERK and PI3K/Akt/mTOR pathways are upregulated in their initial cascade, implicating a pro-proliferative signal derangement upstream to their point of convergence. However, we speculate that other processes, such as senescence, attenuate the changes downstream in these benign tumours.

Novel molecular aspects of pituitary adenomas.

Ghrelin stimulates while somatostatin inhibits GH release and they thus serve as functional antagonists. We have compared their effects on cell proliferation. Ghrelin stimulates while somatostatin inhibits cell proliferation in most tissues and cell lines. Here we show that ghrelin and desoctanoyl ghrelin stimulate cell proliferation in rat pituitary cell line (GH3), and these effects could be inhibited with mitogen-activated protein kinase (MAPK), tyrosine kinase and protein kinase C inhibitors. Somatostatin and its analogs negatively regulate the growth of pituitary cells, and we now show that they inhibit MAPK activation. We hypothesised that one of the mechanisms involved in the somatostatin effect is a stimulation of cell cycle inhibitor p27, as pituitary adenomas have decreased p27 peptide content. Both octreotide and a new somatostatin analog SOM230 treatment resulted in an upregulation of p27 protein levels in human somatotrophinoma cells. In summary, we suggest that ghrelin and somatostatin have opposite effects on somatotroph cells not just at the level of GH release but also in terms of cell proliferation. Ghrelin may play a role in pituitary tumorigenesis via an autocrine/paracrine pathway. Our results also suggest that the antiproliferative effect of somatostatin analogs octreotide and SOM230 involve the up-regulation of p27 and down-regulation of the MAPK pathway in human somatotrophinomas.

The effect of gender and age on growth hormone replacement in growth hormone-deficient patients.

We analyzed the effect of growth hormone replacement therapy (36 months) analyzed at a dose adjusted to maintain serum insulin-like growth factor-I level between the median and the upper end of the age-related reference range on bone mineral density, body composition, and carbohydrate metabolism with respect to gender and age in 20 adult patients (9 women, 11 men, mean age: 43 years, range: 21-61 years). The lumbar and femoral T-score was increased after 12 and after 18 months of therapy respectively in men (p < 0.001 and p = 0.002), but did not changed significantly in women. The increase of femoral T-score was greater in young men (< or = 45 years, n = 6) than old men (> 45 years, n = 5, p < 0.001). Body fat was lower in men than in women after 6 months (p = 0.002). The waist/hip ratio only decreased in women (p = 0.044). The waist circumference decreased in both genders after 6 months of therapy (p < 0.001), but more markedly in females than in males (p < 0.05). The sum of skinfold thicknesses was reduced in males after 6 months of therapy (p < 0.001). Changes in body composition parameters measured were independent of age. The glycosylated hemoglobin increased without sex or age difference after 12 months of initiation of therapy (p < 0.001), but fasting glucose and insulin levels did not change during the therapy. Our results indicate that the effect of growth hormone replacement on bone mineral content in adults is age- and gender-dependent, gender dependent on body composition, but independent of age and gender on carbohydrate metabolism.

Effects of 24 months of growth hormone (GH) treatment on serum carboxylated and undercarboxylated osteocalcin levels in GH-deficient adults.

We studied the effect of growth hormone (GH) replacement on bone mineral density (BMD) and some parameters of bone metabolism, including undercarboxylated osteocalcin (ucOC), an independent predictive marker of fracture risk, which has not been previously determined or compared during GH treatment. Measurements were performed at baseline and after 6, 12, 18 and 24 months of the initiation of the GH therapy in 21 adult patients with GH deficiency. Significant increases were observed in BMD after 1 year at the lumbar spine and after 1.5 years at the femoral neck. Serum total OC and carboxylated (c) OC increased and reached the maximum at 6 months, but the values remained over the baseline at both 12 and 18 months. The ucOC:total OC ratio changed contrarily: it decreased at 6 months, then increased again and reached the baseline level during the next 18 months. Serum calcium (Ca), phosphate (P) and total alkaline phosphatase (ALP) levels increased after 6 months, thereafter the Ca and P values decreased, while the total ALP remained elevated until 12 months. Serum parathormone decreased at 12 months and increased again thereafter. GH replacement therapy is associated with improvement of ucOC, a marker of fracture risk, which in addition to the increase of BMD, might contribute to the beneficial effect of GH replacement therapy on bone metabolism.

Efficacy of the new long-acting formulation of lanreotide (lanreotide Autogel) in the management of acromegaly.

Lanreotide Autogel is a new long-acting aqueous preparation of lanreotide for the treatment of acromegaly and is administered by deep sc injection from a small volume, prefilled syringe. The aim of this study was to evaluate the efficacy and safety of this new long-acting formulation in a large population of acromegalic patients previously responsive to lanreotide 30 mg, im (sustained release microparticle formulation). Lanreotide Autogel was administered by deep sc injection every 28 d to 107 patients (54 males and 53 females; mean age, 54 +/- 1.2 yr). All patients had been treated with lanreotide (30 mg) for at least 3 months before study entry and had a mean GH level less than 10 ng/ml after at least 4 subsequent im injections every 14 d (48%), 10 d (32%), or 7 d (20%). Treatment was switched from lanreotide 30 mg injected every 14, 10, or 7 d to 60, 90, or 120 mg lanreotide Autogel, respectively, every 28 d. After three fixed dose injections of lanreotide Autogel, mean lanreotide levels were similar to those obtained at steady state with lanreotide 30 mg. During lanreotide Autogel treatment, the control of acromegalic symptoms was comparable with that previously achieved during lanreotide 30 mg treatment. After 3 injections of lanreotide Autogel, mean GH (2.87 +/- 0.22 ng/ml) and IGF-I (317 +/- 15 ng/ml) values were comparable with those recorded at the end of lanreotide 30 mg treatment (GH, 2.82 +/- 0.19 ng/ml; IGF-I, 323 +/- 16 ng/ml). GH levels below 2.5 ng/ml and age-/sex-normalized IGF-I were achieved in 33% and 39% of patients during lanreotide 30 mg and lanreotide Autogel treatment, respectively. Diarrhea, abdominal pain, and nausea were reported by 38%, 22%, and 18% of patients during lanreotide 30 mg treatment and by 29%, 17%, and 9% of patients, respectively, during lanreotide Autogel treatment. In conclusion, this clinical study shows that lanreotide Autogel is at least as efficacious and well tolerated as lanreotide 30 mg. This new long-acting lanreotide formulation, lanreotide Autogel, which is administered from a small volume, prefilled syringe by deep sc injection, is therefore likely to improve the acceptability of medical treatment for patients requiring long-term somatostatin analog therapy.

[Laparoscopic adrenalectomy with transperitoneal approach]. / Laparoszkópos adrenalektómia transzperitonealis módszerrel.

UNLABELLED: The feasibility, safety, and results of 52 laparoscopic transperitoneal adrenalectomies were evaluated. METHODS: A total of 52 patients were included in the study based on thorough endocrinological and imaging assessment. 15 patients with Conn syndrome, 3 with Cushing syndrome, 15 with nonfunctioning adenoma, 14 with pheochromocytoma, 2 with adrenocortical cyst, 2 with adrenocortical lipoma and 1 with metastasis were considered eligible for adrenalectomy. Lesion size ranged from 1 to 12 cm (mean 4.53 cm). Concurrent surgical procedures were performed in 6 patients (11%). RESULTS: There was one conversion (during a left adrenalectomy), because of our learning curve. After we changed the technique, there was no more conversion. There were two (3.8%) postoperative complications: postoperative pancreatitis, one of the patients required re-operation (lavage and drainage). There was one wound infection. We had no postoperative mortality. Mean postoperative hospital stay was 6 days (range, 2-27 days). CONCLUSION: Patients with secreting and non-secreting adrenal lesions can be treated safely and effectively by laparoscopic adrenalectomy.

Leptin and puberty: a review.

Over the last few years, many studies have focused on leptin, the product of the LEP (ob) gene, searching for a possible link between energy balance and reproduction. The involvement of this peptide in the regulation of the hypothalamo-pituitary-adrenal, gonadal, thyroid and somatotroph axes suggests that leptin might play a pivotal role in coordinating the activity of these axes and their relationship with the body's energy balance. The effects of leptin on hypothalamic, pituitary and peripheral hormone levels, as well as the presence of the leptin receptor in a variety of tissues, suggest both an endocrine and a paracrine mode of action. Particular attention was paid to the effect of leptin on the gonadal axis as infertility, a characteristic feature of both the leptin deficient ob/ob mice and the leptin receptor mutant db/db mice, could be corrected in ob/ob mice by leptin administration. Considerable leptin level changes were observed during puberty both in animal and human studies. A matter of controversy is the precise role of leptin in the onset of puberty: is leptin the signal that initiates puberty and the accompanying hormonal changes, or has leptin only a permissive but key role for the onset of puberty, as likely seems to be the case for the maintenance of a functional gonadotroph axis? On current evidence, a mainly permissive role seems most probable.

[Effects of growth hormone replacement therapy in adults with severe growth hormone deficiency]. / Növekedési hormonnal történó hormonpótló kezelés hatásai súlyos növekedési hormonhiányos felnóttekben.

UNLABELLED: The aim of the study was to analyse the effects of GH replacement therapy (1 year duration) on body composition, carbohydrate metabolism, thyroid hormone metabolism and bone mineral density in 8 adults with growth hormone deficiency (5 women, 3 men; mean age 40 years). Mean maintenance dose of GH was 1.5 IU/day-1.76 IU/day for women and 1.07 IU/day for men, respectively--determined according to individual patient requirements. Serum insulin-like growth factor-I standard deviation score increased from -5.4 to 0.0 (p < 0.001). There was a significant negative relationship between serum insulin-like growth factor-I standard deviation score at the start of therapy and the increase in this score (r = -0.85; p < 0.05). The waist:hip ratio decreased after 12 months by 0.039 (p < 0.05). The glycosylated hemoglobin increased (4.43 +/- 0.56% vs. 5.86 +/- 0.27; p < 0.05), and a negative correlation of the baseline glycosylated hemoglobin to the glycosylated hemoglobin increase was found (r = -0.88; p < 0.01). Both the free triiodothyronine and free triiodothyronine:free thyroxine ratio increased (3.09 +/- 0.22 vs. 4.17 +/- 0.40; p < 0.05, and 0.234 +/- 0.02 vs. 0.324 +/- 0.04; p < 0.01), and a positive relationship was observed between this ratio at the start of therapy and the increase in the ratio (r = 0.76, p < 0.05). The bone mineral density of lumbar spine and femoral neck expressed as z-score increased (-1.18 +/- 0.56 vs. -0.75 +/- 0.48; p < 0.01 and -0.06 +/- 0.60 vs. 0.43 +/- 0.43; p < 0.05), while the bone mineral density of forearm was unchanged. CONCLUSIONS: Growth hormone replacement leads to a decrease in visceral fat, modulates the thyroid hormone levels by increasing peripheral conversion of thyroxine to triiodothyronine and probably is a physiological regulator of peripheral thyroxine metabolism, slightly deteriorates the carbohydrate metabolism, and results in an increase of bone mineral density of lumbar spine and femoral neck.

[Aspergillosis of the sphenoid sinus: presentation as a pituitary mass]. / Hypophysistumor képében jelentkezó ritka kórkép: a sinus sphenoidalis invazív aspergillosisa.

A rare manifestation of aspergillosis in the central nervous system is its invasion through the sphenoidal wall into the sella turcica representing itself as a pituitary mass. The symptoms may be headache, visual defect caused by compression of the chiasma, hypopituitarism and diabetes insipidus. In the majority of cases only the postoperative histology leads to the correct diagnosis. A case of invasive aspergillosis was reported here with the clinical picture of a pituitary tumor and without underlying immunodeficiency.

Changes of serum calcium level following thyroid surgery--reasons and clinical implications.

The reasons of transient hypocalcemia, frequently occurring after thyroid surgery, were investigated. Serum total calcium (seCa) and phosphorus (seP) levels were determined in 185 patients with benign nodular goiter before and after thyroid surgery. Beside these, in 27 additional patients, serum magnesium (seMg), total protein, albumin, calcitonin, parathormone (PTH) and 25-OH-D3 vitamin (25-OH-D3) levels were determined; corrected calcium (cCa) values, reflecting ionized calcium concentrations, were calculated. The daily changes of seCa and protein levels were measured in 20 patients. Another twenty patients, undergoing non-endocrinological surgery served as controls. Transient, mild but significant decrease of seCa was observed after surgery, while seP values were increased. Mild hypocalcemia (seCa<2.12 mmol/l) developed in 18.4%, severe hypo-calcemia (seCa<1.9 mmol/l) in 5.4% of the patients. The reduction of seCa levels was more pronounced in elderly, female patients. SeMg, total protein and albumin decreased, while cCa, PTH, calcitonin and 25-OH-D3 values did not change. Positive correlation was demonstrated between the change of seCa and albumin levels. Similar results were obtained in the general surgery group. In the thyroid operated group, in case of severe hypocalcemia, PTH levels decreased significantly into the pathological range. It may be concluded that transient, mild postoperative hypocalcemia is not a thyroid surgery-dependent phenomenon; it can also be observed after other operations accompanied by similar blood loss; in its development hypoalbuminemia plays a role. The causal role of PTH, calcitonin and 25-OH-D3 could not be proved in this study. Hypoparathyroidism can be responsible for the development of severe, prolonged hypocalcemia occurring at rare occasions.

Evaluation of the treatment of thyrotropin-secreting pituitary adenomas with a slow release formulation of the somatostatin analog lanreotide.

Somatostatin analogs have been shown to be effective for the treatment of TSH-secreting pituitary adenomas. However, their use in this indication is limited by the fact that available analogs require several daily sc injections. The present study was performed to evaluate the effects of a slow release formulation of the somatostatin analog lanreotide (SR-L) on both hormone secretion and tumor size and to assess the tolerance in a series of thyrotropinomas treated for 6 months. Eighteen patients with hyperthyroidism related to a TSH-secreting pituitary adenoma, evidenced by pituitary magnetic resonance imaging, were studied. After a basal assessment, each patient received 30 mg SR-L, im, every 14 days for 1 month. Then, according to the free T3 (fT3) plasma level measured, 9 of 18 patients were injected twice monthly, and 7 of 18 patients received SR-L every 10 days for 5 additional months. One patient was dismissed from the study in month 1 of the study for side-effects and another in month 3 for noncompliance to the protocol. Clinical and biological evaluations (plasma TSH, free alpha-subunit, fT4, fT3, and lanreotide levels) were performed before and in months 1, 3, and 6 of treatment. Pituitary magnetic resonance imaging and gallbladder ultrasonography were performed both at entry and at the end of the study. Clinical signs of hyperthyroidism improved within 1 month in all 16 evaluable patients. Mean (+/- SEM) plasma lanreotide levels reached 1.11 +/- 0.43 and 1.69 +/- 0.65 ng/mL in month 3 using 2 and 3 injections/month, respectively, then remained stable until the end of the study. During therapy, the plasma TSH level decreased from 2.72 +/- 0.32 to 1.89 +/-0.27 mU/L (P < 0.01), with parallel significant changes in free alpha-subunit. During the same period, plasma fT4 and fT3 levels decreased from 37.9 +/- 2.9 to 19.7 +/- 2.3 pmol/L (P < 0.01) and from 14.6 +/- 1.1 to 8.3 +/- 0.8 pmol/L (P < 0.01), respectively. No statistically significant change in mean adenoma size was observed after 6 months of treatment. Side-effects, including pain at the injection point, abdominal cramps, and diarrhea, were mild and transient and did not lead to interruption of the treatment. No gallstones occurred during the study. SR-L appears to be able to suppress clinical signs of hyperthyroidism in our series of patients with TSH-secreting pituitary adenomas. The analog also reduces plasma TSH and thyroid hormone levels, which were normalized in 13 of 16 cases. The effect was maintained throughout the treatment using 2 or 3 SR-L injections monthly without any problem of tolerance. We conclude that SR-L is a safe and effective treatment of thyrotropinomas and avoids the drawbacks of the modes of administration of other somatostatin analogs, given three times daily.

The blood spot thyrotropin method is not adequate to screen for hypothyroidism in the elderly living in abundant-iodine intake areas: comparison to sensitive thyrotropin measurements.

We investigated whether the blood spot thyrotropin (TSH) method was adequate for screening elderly subjects with abundant iodine intake (median excretion 330 microg/g creatinine) for hypothyroidism. In 97 healthy adults (group A), 210 nursing home residents (group B) and 265 elderly subjects living at home (group C) serum (sensitivity < 0.02 mU/L, cost 1.2 U.S. dollars [USD]) and blood spot TSH (sensitivity < 1.0 mU/L, cost 0.4 USD) were measured, and the sensitivity and specificity of different blood spot TSH cutoff points to detect cases with elevated serum TSH were calculated. Elevated (> 3.5 mU/L) serum TSH levels (group A, 6.2%; group B, 16.2%; group C, 22.3%; B > A, p = 0.025; C > A, p < 0.001) were detected with the required sensitivity of greater than 0.9 only if the cutoff point of the blood spot TSH was set as low as 2.5 mU/L, but this led to a considerable loss of specificity. At cutoff point 2.5 mU/L, the rate of positivity was 39.3% and the cost of blood spot screening/person increased to 0.88 USD, considering that positive cases have to be rechecked by serum TSH to exclude false positivity. Cases with significantly elevated (> 10.0 mU/L) serum TSH (group A, 1.03%; group B, 2.85%; group C, 2.20%) were detected at blood spot cutoff points 10.0-4.0 mU/L with a sensitivity of 1.0 and without considerable loss of specificity. We conclude that while screening for hypothyroidism in the elderly population with abundant iodine intake is justified by the high prevalence of elevated ultrasensitive serum TSH values, the sensitivity of the blood spot method is insufficient to detect the subclinical hypothyroidism accurately and would, therefore, fail to detect most affected subjects.

[The role of insulin-like-growth-factor-binding protein 3 in the evaluation of disease activity in acromegaly]. / Az inzulinszerü növekedési faktort kötö fehérje-3 helye az acromegalia aktivitásának megítélésében.

Studied the diagnostic value of measurements of insulin-like growth factor binding protein-3 compared to insulin-like growth factor-1 as a parameter of disease activity in patients with active (n = 12, 8 females, 4 males, 29-69 years old) and inactive (n = 14, 11 females, 3 males, 28-58 years old) acromegaly. Patients were assigned to the active group if they had GH levels > or = 2 ng/ml, to the inactive group if they had growth hormone levels < 2 ng/ml after 75 g glucose challenge. The absolute serum insulin-like growth factor-1 concentration (526 +/- 66 ng/ml vs. 272 +/- 61 ng/ml, p = 0.015; mean +/- SE) and the insulin-like growth factor-1 standard deviation score (3.23 +/- 0.33 vs. 0.67 +/- 0.58, p = 0.0013) was higher in the active than in the inactive group, but no significant difference was seen between the corresponding insulin-like growth factor binding protein-3 values (7270 +/- 1500 vs. 5340 +/- 1050 ng/ml). Positive significant correlation was found between insulin-like growth factor-1 and insulin-like growth factor binding protein-3 both in the active (n = 12, r = 0.55, p < 0.05) and in the inactive (n = 14, r = 0.61, p < 0.05) group. A significant negative correlation existed between insulin-like growth factor binding protein-3 and age in the inactive (r = 0.58, n = 14; p < 0.05), but not in the active (r = 0.35, n = 12) group. The diagnostic value of insulin-like growth factor binding protein-3 is less than that of the insulin-like growth factor-1. Conclude that the insulin-like growth factor binding protein-3 has smaller suitability to determine the activity of acromegaly than the insulin like-growth factor-1 measurement.

[Insulin-like growth factor proteins]. / Az inzulinszerü növekedési faktorokat kötö fehérjék.

The insulin-like growth factors circulate in plasma complex with a family of binding proteins that extend the serum half-life of the IGF peptides, transport the insulin-like growth factors to target cells, and modulate the interaction of the insulin-like growth factors with surface membrane receptors. The binding proteins have insulin-like growth factor-independent actions too, possibly by interacting with their own receptors on the cell membrane. The insulin-like growth factor binding protein superfamily consists of six classical binding proteins (-1, -2, -3, -4, -5, -6), and insulin-like growth factor binding protein-related proteins (-1, -2, -3, -4). Specific radioimmunoassays have been developed for the six classical binding proteins, the measurement of insulin-like growth factor binding protein-3 appears to have the greatest clinical value because it is growth hormone dependent.

[Ganglioneuroma of the adrenal gland]. / Mellékvese ganglioneuromák.

149 patients with adrenal incidentalomas were examined. Sixty-eight cases were histologically confirmed, five of them had ganglioneuromas. On the basis of these patients history current knowledge of this benign tumour was summarized. Histological and pathological characteristics of one tumour suggest that ganglioneuromas may develop by maturing of malignant neuroblastic tumours. The clinical symptoms (abdominal pain, meteorism) were local. In 2 of 5 cases mildly elevated levels of urinary vanillylmandelic acid and catecholamine could be measured. One patient had persisting hypertension after surgery. In an other patient previous diarrhoea stopped after the removal of tumour. On the basis of ultrasound and computertomographic features, the size and origin of a tumour and its relation to the surrounding organs can be well characterized. One patient was inoperable because of an infiltratively spreading tumour, but during five years of follow-up no tumour progression could be observed with computertomography. After surgery we could follow only 2 of 4 patients. Until now no recurrence of tumour were detected.

The efficacy of long term thyrostatic treatment in elderly patients with toxic nodular goitre compared to radioiodine therapy with different doses.

The objective of the study was to investigate the efficacy of long term thyrostatic versus radioiodine treatment of hyperthyroidism in old age. Our study is a retrospective analysis of the therapeutical outcome in 66 patients over 60 years of age with toxic nodular goitre. The patients were divided in two groups: Group A: 28 patients on methimazole treatment: starting dose 5-30, median (M) 10 mg, maintenance dose 2.5-15 (M = 5) mg, follow up 6 to 240 months (M = 23.5 months). Group B: 38 patients treated by either 100-300 MBq (N = 14, subgroup B1) or 325-1000 MBq (N = 24, subgroup B2) 131I, follow up: 18 to 156 months (M = 48 months). The efficacy of the different therapeutical approaches were compared by calculating the occurrence rate of persisting and relapsing thyroid dysfunctions and associated side effects. The 28 patients on methimazole treatment became euthyroid after 1-16 (M = 5) months but numerous relapses occurred in the follow up: hyperthyroidism, clinical: 5, subclinical 13, (relapse duration: M = 8 months; associated symptoms: hypertension in 4, cardiac arrhythmia in 3, cerebral embolism in 1, angina pectoris in 2, weight loss in 2 cases). Poor patient's compliance (9/28) or dose reduction by the physician (5/28) were the main causes of the relapses. Transient clinical (3 cases) or subclinical (6 cases) hypothyroidism also occurred (duration: 1-3 M = 2 months, no clinical symptoms). In 7 out of 14 (50%) patients receiving 100-300 MBq 131I (Group B1) hyperthyroidism persisted (versus 4/24 -16.7%- in Group B2 following 325-1000 MBq 131I; chi2(1) = 4.78 P = 0.028), methimazole treatment had to be continued in 9/14 patients (64.3%) (versus 5/24 -20.8%)- in Group B2., chi2(1) = 7.18 P = 0.0074) and in 5/14 (35.7%) the radiotherapy had to be repeated (versus 5/24 -020.8%- in Group B2, not sign.). Our conclusions are: 1) long term thyrostatic treatment is not safe in elderly patients with toxic nodular hyperthyroidism, mainly because of poor compliance or dose reduction by the physician; 2) radioiodine treatment as the first choice should be recommended for these patients and higher doses should be preferred.

The effect of surgical treatment on secondary hyperaldosteronism and relative hyperinsulinemia in primary hyperparathyroidism.

OBJECTIVE: To evaluate the renin-aldosterone system and insulin secretion in hyperparathyroidism and their effects on blood pressure regulation. DESIGN: Studies were carried out on patients with primary hyperparathyroidism (PHPT) prior to and following removal of the parathyroid tumor. METHODS: Sixteen normotensive and euglycemic patients with PHPT were studied. The following parameters were measured: basal and stimulated plasma renin activity (PRA) and aldosterone (ALD) secretion: parathormone (PTH) and serum electrolytes. Insulin and glucose levels were measured during an oral glucose tolerance test. RESULTS: Systolic but not diastolic blood pressure showed a decrease following surgery, from 123.3+/-13.0/80+/-8.6 to 116.7+/-13.5/77.3+/-8.8 mmHg. The decrease in the systolic pressure was not clinically significant. After surgery, both the basal and stimulated PRA and ALD values decreased, and the preoperative pathological values returned to normal: PRA basal: 1.79 --> 0.70 ng/ml/h, P=0.0049; PRA stimulated: 7.76 --> 1.90 ng/ml/h, P=0.0031; ALD basal: 111.5 --> 73.0 pg/ml, P=0.0258; ALD stimulated: 392.5 --> 236.0 pg/ml, P=0.0157. The postoperative decrease in the PRA correlated with the changes in PTH levels (r=0.5442, P < 0.05, n=16) but did not correlate with the changes in serum calcium concentrations. Both the fasting and stimulated insulin levels decreased after surgery but remained within the normal range: insulin fasting: 10.2 --> 5.0 mIU/l, P=0.0218; insulin area under the curve: 5555 --> 3296 mIU/l*min, P=0.0218. There was no correlation between the changes in insulin levels and PTH or ion levels. Sodium, potassium and blood glucose levels remained unaffected by parathyroid surgery. CONCLUSIONS: In a population of normotensive hyperparathyroid patients an increased activity of the renin-aldosterone system related to PTH was found and surgery resulted in a small and insignificant decrease in blood pressure. This change was accompanied by a significant decrease in the activity of the renin-aldosterone system indicating the role of the renin-aldosterone system in the regulation of blood pressure in PHPT. Both fasting and stimulated insulin values decreased following removal of the parathyroid tumor, but with no individual correlation with PTH and calcium levels.

[Multiple endocrine adenomatosis IIB]. / Multiplex endokrin adenomatosis IIB.

The first Hungarian MEN IIB (multiplex endocrine neoplasia) syndrome is reported with the short summary of the literature about the pathogenesis and diagnosis of medullary thyroid carcinoma, presenting 80% in sporadic, 20% in hereditary form. The appearance of the patients alone (marfanoid stature, bulky lips, and ganglioneuromatosis of the tongue) may be almost enough for the presumption for the diagnosis of MEN IIB: For screening and preventing the clinical manifestation of the very aggressive medullary carcinoma in the relatives of the patient, the genetic screening is indispensable. The costs of the genetic screening and early treatment of the patients are much lower than the expenses of the traditional annual biochemical screening and the--delayed, often only supportive--treatment of the clinically manifested illness.

[Glycoprotein hormone alpha-subunit secretion in non-functioning pituitary adenomas]. / Glikoprotein hormon alpha-alegység elválasztás nem funkcionáló hypophysisdaganatokban.

The aim of the present study was to investigate the prevalence of elevated free glycoprotein hormone alpha-subunit in different pituitary adenomas, to establish the diagnostic value of the basal and stimulated free alpha-subunit secretion in non-functioning adenomas. Serum basal levels of alpha-subunit were increased in 1 of 22 untreated, in 1 of 16 operated patients with non-functioning adenoma, in 6 of 28 untreated, in 1 of 7 operated patients with acromegaly, in 0 of 5 untreated prolactinomas and in 0 of 1 untreated gonadotrop adenoma. Overall free alpha-subunit levels were increased in 9 of 79 cases (11.4%). In 6 of 9 patients with untreated non-functioning adenoma thyrotrop hormone releasing hormone caused an abnormal--paradox--elevation of serum alpha-subunit. These data indicate that measurement of basal and stimulated alpha-subunit is of relatively poor value in the diagnosis of non-functioning pituitary adenomas. The transsphenoidal surgery did not resulted in a change of alpha-subunit secretion neither in patients with non-functioning adenoma nor with acromegaly. The present data confirm the view that non-functioning pituitary adenomas are not homogeneous since this subset of tumors includes adenomas that either do not secrete measurable amounts of free alpha-subunit or produce normal or supranormal amounts of subunits as consequence of still undefined biosynthetic abnormalities.