Journal of Endocrinological Investigation

Published by Springer Verlag
Online ISSN: 1720-8386
Publications
Article
Dopamine in humans inhibits the secretion of luteinizing hormone (LH), follicular stimulating hormone (FSH), thyroid stimulating hormone (TSH) and prolactin (PRL), and is a stimulator of growth hormone (GH) secretion. Dopamine-D1 receptor stimulation with fenoldopam increases basal PRL levels, suppresses TSH, and increases gonadotropin releasing hormone (LHRH) induced LH release. We have investigated the effect of a dopamine D1-receptor antagonist, NNC 01-0687, on the secretion of anterior pituitary hormones. In 8 healthy males NNC 01-0687 and placebo were administered orally in a double-blind placebo controlled cross-over study for three days with a wash-out period of 14 days. Hormonal responses (PRL, LH, FSH, GH, TSH, thyroid hormones and testosterone), unstimulated and LHRH/TRH stimulated, were studied on days 1 and 3. No significant difference (p > 0.05) between placebo and active periods was found neither in unstimulated nor in stimulated hormone concentrations expressed in absolute values, percent change of before, incremental values and area under the curve. These results suggest that the neuronal DA-D1 activity is not activated during basal conditions in healthy male subjects.
 
Article
Genes of, or closely associated to, the HLA complex are assumed to contribute to the genetic predisposition of Graves' disease. The aim of this study was to investigate the presence of the HLA DQA1*0501 and DRB1*0301 antigens in Greek patients with Graves' disease. In addition, we tried to establish if there is any association between these antigens and any of the clinical manifestations of the disease. We examined 117 patients with Graves' disease and 104 healthy controls. DNA was extracted from peripheral lymphocytes and the HLA DQA1*0501 and DRB1*0301 genomic regions were amplified by PCR and characterized by hybridization with sequence specific oligonucleotides (SSO). Two of the patients had a positive family history for Graves' disease and 46 had clinical thyroid eye disease (TED). The frequencies of both DQA1*0501 and DRB1*0301 antigens were significantly increased in patients compared to controls (relative risk [RR] 4.2 and 4.5 for each antigen respectively). Neither of these two antigens was an independent risk factor for Graves' disease. However, the combination of both these HLA antigens resulted in a striking increase in the RR for development of Graves' disease especially in females (RR/F=27, RR/M=8.4). No association was found between these antigens and positive family history or the presence of TED. These data suggest that HLA DQA1*0501 and DRB1*0301 antigens are not independent risk factors for the development of Graves' disease. On the contrary, the presence of both these alleles results in a significant increase in the RR for the development of Graves' disease in the Greek population, particularly in females.
 
Article
Parathyroid carcinoma is a rare tumor responsible for 0.5-5% of primary hyperparathyroidism. It is usually small (not more than 27 g) and the precise diagnosis of malignancy is made when local or distant metastases are found. We describe a case of a 37 yr old male presenting with a substernal goiter and no specific symptoms except hypertension. This mass had cysts and calcifications and it was in the anterior upper mediastinum. The patient had severe hypercalcemia (Ca greater than 14 mg/dl), high PTH levels and mild renal failure. Bone scanning showed signs of hyperparathyroidism. The patient was subjected to total thyroidectomy and removal of the mass en block. The tumor was circumscribed lobulated and mostly cystic. It weighed 1,200 g (380 g after evacuation of cysts) and measured 12 x 9 x 4.5 cm. Histologic examination showed a highly differentiated adenocarcinoma of parathyroid with metastasis in a regional lymph node. Almost 4 years later the patient is alive and well without hypercalcemia and without evidence of distant metastases.
 
Article
The effect of 10(-8) M 1,25-dihydroxyvitamin D3 [1,25 (OH)2D3] on the phosphoinositide pathway, was studied on [3H] inositol and 45Ca2+ efflux and on insulin release of islets from vitamin D-deficient rats, during an acetylcholine (Ach) stimulus in perifusion. The insulin release, which was low in vitamin D-deficient rats, was enhanced by this treatment. The 3H flux, reflecting phosphoinositide breakdown, was also increased. The 45Ca2+ flux was stimulated both during the first 14 min peak (mobilization of IP3-sensitive reticular Ca2+ stores) and during the following sustained small elevation of 45Ca2+ flux, reflecting protein kinase C (PKC) activation and consequently increased phosphorylation of Ca2+ channel proteins. These effects were larger during perifusions performed in the presence of glucose which is known to open Ca2+ channels, suggesting a synergistic influence of glucose and 1,25(OH)2D3. This positive influence of 1,25(OH)2D3 in Ca2+ entry by Ca2+ channels was confirmed by the use of nifedipine-a Ca2+ channel blocker-which suppressed the 45Ca2+ flux and lowered insulin secretion. Moreover, the sustained 45Ca2+ flux also disappeared in islets from vitamin D-deficient rats supplemented by 1,25(OH)2D3 but perifused without extracellular Ca2+ supporting the hypothesis of 1,25(OH)2D3-induced activation of PKC. Thus, 1,25(OH)2D3 may provide supplementary calcium to the B cell by regulating the intracellular signalling processes involving phospholipid metabolism, PKC induction, Ca2+ mobilization and Ca2+ entry by Ca2+ channels.
 
Article
The antifungal drug ketoconazole, a cytochrome P450 inhibitor, has been shown to inhibit renal 1,25-dihydroxyvitamin D production in vitro and to lower serum 1,25-dihydroxyvitamin D levels in normal subjects and in patients with primary hyperparathyroidism. To assess the usefulness of this drug in the hypercalcemia of sarcoidosis, a condition thought to result from overproduction of 1,25-dihydroxyvitamin D by sarcoid-involved tissues, two men with sarcoidosis, hypercalcemia, and elevated serum levels of 1,25-dihydroxy-vitamin D were given ketoconazole, 600-800 mg per day, for four to six days. Serum 1,25-dihydroxyvitamin D levels were markedly reduced (by approximately 40%) in both patients during ketoconazole administration, but serum calcium was not affected. In both patients, renal function deteriorated during ketoconazole treatment. We conclude that ketoconazole administration can lower the elevated serum 1,25-dihydroxyvitamin D levels in sarcoidosis. However, deterioration of renal function during ketoconazole administration as well as failure of hypercalcemia to be affected during short-term ketoconazole treatment suggest that this drug might not be appropriate for acute treatment of hypercalcemic sarcoidosis.
 
Article
The aim of the work was to investigate the effect of 1,25 (OH)2 vitamin D3 on beta-endorphin and cortisol secretion in vivo. beta-Endorphin, cortisol, calcium and phosphate in blood were measured in ten healthy unstressed volunteers before and after 4-day oral administration of 1,25 (OH)2 vitamin D3 in doses of 3 micrograms/d. The biological effectiveness of the treatment was proved by a significant increase of calcemia as compared with control values (2.71 +/- 0.03 vs 2.57 +/- 0.02 mmol/l, mean +/- SE, p < 0.01) and phosphatemia (1.18 +/- 0.06 vs 0.89 +/- 0.01 mmol/l, p < 0.01). beta-Endorphin after treatment was 39.1 +/- 9.2 (vs 42.7 +/- 7.6) ng/l and cortisol 369 +/- 35 (vs 377 +/- 31) nmol/l. In conclusion, in spite of the good compliance of the treatment, 1,25 (OH)2-vitamin D3 stimulates neither beta-endorphin nor cortisol secretion in healthy subjects.
 
Article
The identification of Gc (vitamin D binding protein) with the anionic polypeptide cochemotaxin has recently been reported. In this paper we investigate its dose dependent cochemotactic activity and report the inhibition of Gc enhanced chemotaxis by vitamin D3. These results further support the role of immunomodulating hormone played by vitamin D.
 
Article
We describe an elderly man who presented with hypercalcemia associated with suppressed intact parathyroid hormone (PTH) levels. Despite renal insufficiency the circulating 1,25-dihydroxyvitamin D (1,25(OH)2D) was in the upper part of the normal range. Known causes of hypercalcemia were absent and mild hypercalcemia with suppression of intact PTH persisted until after bilateral hip replacement for severe arthritis (1 year after presentation). After hip replacement the ionized calcium normalized, intact PTH normalized, and 1,25(OH)2D decreased markedly. We believe the abnormalities in mineral homeostasis were related to production of 1,25(OH)2D by inflammatory mononuclear cells associated with arthritis.
 
Article
To evaluate the role of PTH-related peptide (PTH-rP) and 1,25-dihyhydroxyvitamin D3 in a case of hypercalcemia related to an ovarian adenocarcinoma. We report a case of humoral hypercalcemia in a patient aged 74 yr with a clear cell adenocarcinoma of the right ovary at an early stage of its development (stage T1aN0M0) revealed by moderate and persistent hypercalcemia (variable level between 2.7 and 3.2 mmol/l without any treatment) over six months. PTH-rP and 1,25-dihydroxyvitamin D3 were measured in blood samples taken before and after hysterectomy and bilateral salpingooophorectomy and in blood samples taken intraoperatively from the right ovarian vein and a peripheral vein. High levels of plasma PTH-rP and 1,25-dihydroxyvitamin D3 concomitant with high serum calcium and low PTH levels were found before surgery, which was followed by normalisation of all parameters studied. A concentration gradient was found regarding plasma PTHrP (right ovarian vein 60.4 pmol/l, peripheral vein 4.5 pmol/l), not 1,25-dihydroxyvitamin D3. 1) moderate and persistent hypercalcemia can be observed at an early stage of an ovarian carcinoma; 2) the gradient of PTH-rP concentration between the samples taken from the right ovarian vein and a peripheral vein provides evidence for a direct secretion of PTH-rP by the ovarian tumor; 3) the increased 1,25-dihydroxyvitamin D3 level is not related to a direct ovarian production, but is a consequence of PTH-rP secretion.
 
Article
Basal plasma prolactin (PRL) has been measured in 6 patients with chronic renal failure 3 months before and at monthly intervals during a 3 months 1,25-dihydroxyvitamin D3 [1,25 (OH)2-D] treatment. Plasma PRL decreased rapidly during, 1,25 (OH)2-D treatment, while it remained unchanged during the 3-months control period. There was no correlation between PRL and parathyroid hormone (PTH; measured either with carboxy- or amino-terminal assays) and several other parameters. A direct effect of 1,25 (OH)2-D on PRL secretion may exist.
 
Article
Fatty acid deposition in the liver can activate a number of pro-inflammatory signaling pathways such as the Toll-like receptor 4 (TLR4) pathway, which may be important in the pathogenesis of nonalcoholic steatohepatitis. 1,25(OH)2D3 downregulates the expression of TLR4 and may represent a novel treatment strategy for reducing hepatocyte injury. Therefore, in this study, we investigated the protective effects of 1,25(OH)2D3 on diabetic liver injury in vivo. Streptozotocin (STZ)-induced diabetic rats were randomly divided into five groups and treated with low-dose 1,25(OH)2D3 (0.025 μg/kg/day), medium-dose 1,25(OH)2D3 (0.15 μg/kg/day), high-dose 1,25(OH)2D3 (0.3 μg/kg/day), insulin (protamine zinc insulin 16 U/kg/day, subcutaneous injection), or no intervention (the control group). Sixteen weeks later, the rats were killed, and blood samples were obtained to test lipid profiles and hepatic function. The infiltration of inflammatory cells, the level of fibrosis, and the expression levels of TLR4, nuclear factor-kappa B (NF-κB), and tumor necrosis factor-α (TNF-α) in the liver were analyzed. The hepatocytes were treated with vehicle control, LPS (100 ng), high fat [DMEM + FFA (0.1 mM: palmitic acid, oleic acid, 1:2)], LPS + high fat, vehicle + 1,25(OH)2D3 (10(-7) M), LPS + 1,25(OH)2D3, high fat + 1,25(OH)2D3, or LPS + high fat + 1,25(OH)2D3. RNA and protein were extracted to detect the expression of TLR4 and downstream inflammatory factors such as NF-ΚB, TNF-α, and IL-6. Groups of data were compared by single factor variance analysis. High-dose 1,25(OH)2D3 administration for 16 weeks downregulated the expression of TLR4, NF-κB, and TNF-α in the liver tissue of diabetic rats and attenuated hepatic inflammation and fibrosis, as shown by immunohistochemical staining, hematoxylin and eosin staining, Masson's trichrome staining, reverse transcription polymerase chain reaction (RT-PCR), and western blotting. In vitro, hepatocytes treated with high fat or LPS exhibited significantly increased expression of TLR4, NF-κB, and downstream inflammatory factors (P < 0.05). Intervention with 1,25(OH)2D3 decreased the expression of TLR4, NF-κB, and inflammatory factors (P < 0.05). 1,25(OH)2D3 exhibited protective effects against diabetes-related liver injury, possibly through downregulation of components of the TLR4 signaling pathway.
 
Article
A simple method for extraction, purification and separation of the principal vitamin D metabolites from a single serum sample is described. The method involved extraction of serum with acetonitrile followed by a first purification employing C-18 Sep-pak cartridges eluted with methanol/water and acetonitrile. Final separation before assay was carried out by high pressure liquid chromatography. 1.25-dihydroxy-vitamin D was measured with radioimmunoassay using an antiserum (S11) with high selectivity for 1 alpha-OH function of the hormone at a final dilution of 1:100,000. 24.25-dihydroxy-vitamin D and 25-hydroxy-vitamin D were measured employing a competitive binding assay with normal rat serum at a final dilution of 1:10,000 as source of binding protein. The mean (+/- SD) serum 1.25-dihydroxy-vitamin D, 24.25-dihydroxy-vitamin D and 25-hydroxy-vitamin D concentrations for a group of healthy subjects were 50.4 +/- 17.3 pg/ml, 2.3 +/- 2.6 ng/ml and 20.8 +/- 12.3 ng/ml, respectively. 1.25-dihydroxy-vitamin D concentrations were low or undetectable in patients on dialysis or with mild renal failure. High 1.25-dihydroxy-vitamin D levels were found in 2 out of 17 patients with primary hyperparathyroidism. In 4 normal subjects treated for two weeks with large doses of 25-hydroxy-vitamin D, serum 25-hydroxy-vitamin D rose from 12.5 ng/ml to 119 ng/ml and from 0.89 ng/ml to 15 ng/ml, respectively; no changes in the 1.25-dihydroxy-vitamin D assay were found.
 
Article
Of the 10,730 neonates born in the period 1978-1997 and examined for cryptorchidism (C) at birth, 1387 were pre-term (gestational age <37 wk), and 9343 were full-term. At birth, a total of 737 neonates (6.9%) were cryptorchid, 487 had bilateral C and 250 unilateral C. The C rate of pre-terms was 10 times higher than that of the full-terms (30.1 and 3.4%, respectively). Comparing the two studied decades, a significant decrease of C rate was found in the second decade in full-term neonates. The rates of C at birth were significantly elevated for low birth weight, babies born from mothers with an age <20 or >35 yr, newborns from mothers with A Rh positive and B Rh positive blood group. Of the 737 cryptorchid newborns at birth, 613 (83%) were re-examined after 12 months from the expected date of delivery, and those born in the period 1988-1997 were also re-evaluated at 6 months of life. Late spontaneous descent occurred in 464 cases (75.7%), while 149 (24.3%) were still cryptorchid. The incidence of C at 12 months from the expected date of delivery, after survival curve calculation, in term and pre-term infants, was 1.53 and 7.31%, respectively, in the period 1978-1987, and 1.22 and 3.13% respectively, in the 2nd decade (1988-1997). In the groups also examined at 6 months of life, spontaneous descent occurred almost completely within the first 6 months of life in term infants, but not in pre-terms. No evidence of seasonal cyclicity was found. Medical and/or surgical treatment was generally started within 2-4 yr of age earlier in the second decade of the study. In conclusion, the main risk factor for C at birth and at 12 months of life seems to be pre-term birth and low birth weight. If this is associated itself to a higher risk of infertility too, it remains to be defined.
 
Article
A neonatal screening for both 21-hydroxylase and 11-beta-hydroxylase deficiencies, responsible for congenital adrenal hyperplasia (CAH), has been conducted in Campania Region, Southern Italy. In 4380 neonates, aged 2-10 days, capillary blood from a heel prick was collected on microfilter paper, and 17-alpha-hydroxyprogesterone (17OHP) measured by radioimmunoassay (RIA) using a highly specific antibody (Ab A). In addition, in 295 of these samples, both 17OHP and 11-deoxycortisol (S) were measured using an anti-deoxycortisol antibody (Ab B) cross-reacting with 17OHP 100%. All results were compared with plasma 17OHP and S levels in 21 patients with diagnosed 21-hydroxylase deficiency and in 5 healthy volunteers on metyrapone test used for blocking the 11-beta-hydroxylase activity. CAH due to 21-hydroxylase deficiency was diagnosed in a female newborn. The assay, based on the antibody reacting with both 17OHP and S, is particularly suitable for wide-scale screening programs enabling the simultaneous detection of two congenital enzyme defects.
 
Article
Serum levels of 11-deoxycortisol were determined in 182 hirsute women. Three patients presented high basal 11-deoxycortisol levels and an exaggerated response of this steroid to ACTH stimulation. A fourth patient had normal basal 11-deoxycortisol but was hyperresponsive to ACTH stimulation. Therefore diagnosis of late-onset 11 beta-hydroxylase deficiency was made in 4 out of 182 hirsute women with a prevalence of 2.2% in the group studied. In these patients, clinical findings and other hormonal patterns were not different from those of other women suffering from hirsutism.
 
Article
Molecular diagnostics of the LHR gene was conducted in a 5-year-old boy with clinical symptoms and hormonal profile typical of precocious puberty. His parents and 4 sisters were also diagnosed. Single-strand conformation polymorphism analysis under temperature gradient conditions (Multitemperature SSCP) of 3 overlapping fragments of exon 11 of LHR gene revealed a mutation in the fragment spanning nucleotides 1072 to 1804. This mutation was found in the patient, in his mother and in his 4 sisters, and was confirmed by digestion with the use of restriction enzyme Bbr Cl. Direct sequencing revealed a heterozygous T1193C transition in the DNA fragment of the patient and in one of the alleles of his mother's and sister's DNA. This mutation causes Met398Thr substitution in the second transmembrane helix and results in a constitutive activation of LH receptor. This is the second identical mutation detected in Poland and one of the 7 identified so far in the world population.
 
Article
The aim of the study was to determine the main metabolic parameters of 11-beta-hydroxy-androstenedione (11 OHAD) in man. Seven normal subjects were investigated at 1-3 months interval by 2 types of isotope dilution techniques using a tritiated tracer: constant infusion and bolus iv injection. 3H-11 OHAD and 3H-11-beta-hydroxy-androsterone (3H-11 OA) were isolated by gel column chromatography, unlabeled 11 OHAD was determined by RIA, unlabelled 11 OA by GLC. The results included computation of free and conjugated catabolite fractions. 3H-11 OHAD MCR determined from the infusion or the injection data averaged ca 1250 ml/min or 1800 L/d (CV: +/- 10%) providing a mean estimation of unlabelled 11 OHAD BPR of 1.5 +/- 0.15 mg/d. UPR estimations gave similar values. 3H-11 OHAD fractional catabolic rate drawn from the postinfusion or the injection curve averaged ca 1.4% per min (CV: +/- 7%). Mean total distribution volume ranged between 90 and 120 L according to the type of experiment. Extrapolation to time zero of the injection curve (2 exponentials) provided an estimation of 32 +/- 5 L for rapid exchange compartment. Urinary recovery of labelled compounds was complete within 24 h whereas the excretion of undegraded 3H-11 OHAD was undetectable; urinary clearance rate of 3H-conjugates approached that of creatinine. The present data show that: the secretion rate of 11 OHAD is equivalent to that of its direct precursor, adrenal androstenedione; its large MCR value results from the size of its exchange volume-equivalents.(ABSTRACT TRUNCATED AT 250 WORDS)
 
Article
Simultaneous comparison of plasma levels of Cortisol, cortisone, corticosterone, and 11-deoxycortisol was performed in healthy adult volunteers of both sexes before, during and after intravenous infusion of corticosterone and 11-deoxycortisol, respectively. Chromatographic separation on Sephadex LH-20 columns was used prior to steroid quantification by specific protein binding assays. Steroids were infused at the dose of 10 mg/h/60 ml saline; 6 subjects underwent corticosterone infusion from 22:00 to 04:00; 4 subjects underwent 11-deoxycortisol infusion from 22:00 to 04:00; 4 subjects underwent 11-deoxycortisol infusion from 24:00 to 08:00. To obtain control data, saline alone was always infused under the same conditions on the preceding day. Blood samples were drawn at different intervals; in each subject, attention was given to obtain samples at the following hours: 04:00, 08:00, 12:00, 16:00, 20:00, and 24:00. Under control conditions, clear circadian fluctuations were observed for Cortisol, cortisone, and corticosterone; levels of 11-deoxycortisol did not show significant changes along the 24-h day. Corticosterone infusion did consistently interfere with the morning rise of plasma Cortisol and cortisone; levels of Cortisol were significantly reduced in comparison to control values at 04:00, 08:00, and 12:00 (pACTH-suppressing potency whereas 11-deoxycortisol under the same conditions has no effect. Displacement of Cortisol molecules from the transcortin binding sites may be a complementary factor in accounting for the effect of corticosterone on the plasma glucocorticoid profile.
 
Article
This report describes a 13-year-old female patient with 11-beta-hydroxylase deficiency who was found to have short fourth metatarsals and pulmonary stenosis. The unusual association between these abnormalities and this rare form of congenital adrenal hyperplasia is presented.
 
Article
A 37-yr-old man presented with the classic signs of mineralocorticoid excess hypertension and hypokalemia. The cause was not aldosterone excess, but elevation of plasma 11-deoxycorticosterone (DOC). Computed tomography (CT) scans showed a large right adrenal mass without signs of metastatic disease. The tumor was removed by open laparotomy, and histology revealed an adrenocortical carcinoma. Two yr after diagnosis, the patient is in good general condition and there is no sign of recurrence or metastatic disease, despite the large tumor size. DOC producing adrenocortical carcinomas causing mineralocorticoid hypertension are very rare, so far only 10 cases have been described in the literature.
 
Article
A 26-day-old male was evaluated because on routine follow-up visit his weight was noted to be 3292 g which was not a significant weight gain over his birth weight of 3178 g. His serum electrolytes (NA 107 meq/1, K 8.0 meq/1, Cl 82 meq/1, and HCO2 12 meq/1) were abnormal, urine Na concentration (68 meq/1) was high, and his serum concentrations of 21-deoxycortisol 10, 113 ng/dl (normal 1.2-13), 11-deoxycortisol 15,000 ng/dl (normal 50-250), and 11-deoxycorticosterone 148 ng/dl (normal 2-13) were markedly elevated. Patients having increased levels of the three indicated steroids are diagnosed as having combined 21- and 11 beta-hydroxylase deficiency. On glucocorticoid and mineralocorticoid replacement therapy his electrolytes returned to normal and his weight increased 428 g by the 10th day post initiation of therapy. We hypothesize that the elevated steroid pattern designated as combined 21- and 11 beta-hydroxylase deficiency could result from extraadrenal conversion of 17-hydroprogesterone to 11-deoxycortisol and progesterone to 11-deoxycorticosterone in subjects with adrenal 21-hydroxylase deficiency.
 
Article
Background A fundamental date for the standardization of glycated hemoglobin (HbA1c) measurement in Italy is represented by 1/1/11 because, from this date, according to the recommendations by the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC), all the instruments should report results not more only in percent but also in IFCC units (mmol/mol) and in derived units, as in the NGSP system (%). Aim The present paper is one of the documents issued by the Italian Society of Clinical Biochemistry and Clinical Molecular Biology (SIBioC) and a number of other National Scientific Societies and Associations in order to spread informations about changes in reporting HbA1c results. New units of HbA1c and how to relate old and new units are the main issues discussed.
 
Article
Classic congenital 11-beta-hydroxylase deficiency is a relatively uncommon cause of congenital adrenal hyperplasia and is characterized by virilization and often hypertension. The association of skeletal abnormalities (short metatarsal bone) and pulmonary stenosis in a patient with 11-beta-hydroxylase has been reported by our group. In this report, three new patients with congenital adrenal hyperplasia due to a defect in 11-beta-hydroxylase enzyme with short fourth metatarsals are described. Gynecomastia was noted in one patient. The relative rarity of 11-beta-hydroxylase deficiency and the association of skeletal abnormalities suggest the possibility that this is more than a mere coincidental finding.
 
-Summary of main laboratory and instrumental findings in von Hippel-Lindau patients. 
Patient 1: Contrast-enhanced helical computed tomography (A) and single photon emission computed tomography (B) of the upper abdomen obtained after iv injection of 150 cc of non-ionic iodinated contrast-media and 111 MBqof 111-indium-diethylenetriaminepentaacetic acid octreotide, respectively. A) Two hypervascularfocal lesions are depicted at the level of the II and the V hepatic segments, the latter is associated with segmental arterialization. A small (< 1 cm) hypervascularnodule can be seen in the pancreatic tail. B) Both hepatic lesions show significant uptake of the radiolabeledsomatostatinanalogue. Physiologic kidney accumulation is also depicted. 
Patient 1: transaxial, coronal, and sagittal [ 111 Indium/ 90 Y1,4,7,10-Tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid ]-Tyr 3-octreotide/computed tomography fused sections, obtained 16 h after the first cycle of receptor radionuclide therapy, showing huge uptake to one lesion in the right liver. 
Patient 2: Posterior whole-body views of 131 I-metaiodobenzylguanidine (A) and 111-indium-diethylenetriaminepentaacetic acid octreotide scintigraphy (B) acquired at 48 and 24 h post-injection, respectively and contrast-enhanced helical computed tomograohy (CT) of the pelvis (C) and the neck (D). A) Pathologic uptake (grade 2) of the radiotracer in both adrenal glands (black double-arrow) and in the right sub-mandibularregion (black arrow). The latter is also seen in B, which shows 2 areas of symmetric uptake of the radiolabeledsomatostatinanalogue in the sacral region (black double-arrow). These areas were confirmed to be intraforaminalparagangliomas (asterisks) by CT (C), which also depicted a hypervascularmass in the right carotid region consistent with an inter-carotid paraganglioma (D) (asterisk). 
Patient 3: Whole-body views of 131 I-metaiodobenzylguanidine (A) and 111-indium-diethylenetriaminepentaacetic acid octreotide scintigraphy (B) acquired in the posterior and anterior projections at 48 and 24 h post-injection, respectively, and contrast-enhanced helical computed tomography (CT) of the upper abdomen (C). A) Pathologic uptake (grade 3) of the radiotracer in the left adrenal region (white arrow). B) Note the illdefined area of increased activity near the splenichilus (white arrow). Both findings were confirmed by helical CT (C) that shows a hypervascularmass in the left adrenal region, consistent with a pheochromocytoma (asterisk) as well as a solid inhomogeneous mass in the pancreatic tail consistent with an endocrine pancreatic tumor (white arrow). 
Article
The identification of patients with von Hippel-Lindau (VHL) disease dictates accurate genetic counseling of family members, whereas screening for early detection of visceral and neurological involvement is usually performed by a combination of radiological and nuclear medicine techniques such as ultrasonography or contrast-enhanced computed tomography of the upper abdomen, magnetic resonance imaging of the central nervous system and 131I-metaiodobenzylguanidine-scintigraphy. The role of 111-indium-diethylenetriaminepentaacetic acid [111In-DTPA0] octreotide scintigraphy in this clinical context has never been investigated. Here, we report imaging findings in a VHL patient and in 3 consecutive family members undergoing clinical and radiological screening that included [111In-DTPA0] octreotide scintigraphy in addition to the above-mentioned procedures. Somatostatin receptor expression was investigated in vitro by immunohistochemistry in pancreatic tumor sections. On the basis of in vivo and in vitro findings, octreotide long-acting release treatment followed by 90Y-1,4,7,10-Tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA0)-Tyr3-octreotide led to a lack of progression in this patient although this result is a possibility which needs to be proved by further investigation and longer follow-up. The results of this study suggest that [111In-DTPA0] octreotide scintigraphy may be helpful in the routine work-up of VHL patients for diagnostic and therapeutic purposes.
 
Article
Bronchial carcinoid tumor is the most frequent occult source of ectopic ACTH-dependent Cushing's syndrome, but its initial localization may be very difficult, as well as its postoperative follow-up. We here present the case of a 21-year-old man with Cushing's syndrome and biochemical findings suggesting an ectopic source of ACTH (lack of inhibition of cortisol after overnight 8-mg dexamethasone suppression test, and lack of response to h-CRH challenge). Chest CT-scan showed a node adjacent to the left lung hilium whose nature was confirmed by uptake of 111Indium-DTPA labelled octreotide scintigraphy. Surgical resection of the tumor consisted in an upper lobectomy of the left lung. Microscopic examination identified a typical carcinoid tumor. After surgery pituitary-adrenal function normalized and a second scintigraphy offered additional data on the absence of tumor remnants.
 
Article
The aim of this study was to compare the pituitary (111)In-DTPA-D-Phe1-octreotide uptake measured in 49 patients subjected to the scintigraphy for SS-R expressing tumors not located in the sellar region with that measured in 38 patients with pituitary adenomas. The 87 subjects enrolled in this study were divided into two groups: the first included SSR-expressing tumors (SS-ET), 10 thymomas, 13 differentiated thyroid carcinomas, 4 carcinoids, 5 neuroendocrine tumors, 5 insulinomas, 6 melanomas, 2 renal carcinomas, 2 pheocromocytomas, and 2 parathyroid tumors, while the second included pituitary adenomas, 25 GH-secreting, 4 GH/PRL-mixed and 9 clinically nonfunctioning adenomas (NFA). Planar and single-photon-emission tomography images of the head were obtained 2-4 and 24 hours after the injection of 77-103 MBq of (111)In-DTPA-D-Phe1-octreotide and pituitary uptake was measured by the region of interest method. A 4 point score was used to grade the pituitary-to-blood (T-to-B) ratios: 0=negative; 1 =faint (T-to-B=<1.5); 2=moderate (T-to-B=1.6-3.5); 3=intense (T-to-B=>3.5). In patients with pituitary adenomas, the percent suppression of GH and alpha-subunit levels after 6-12 months of octreotide treatment (0.3-0.6 mg/day) was correlated to T-to-B ratios. After 2-4 hr from injection, pituitary (111)In-DTPA-D-Phe1-octreotide uptake was moderate/intense in 2 out of 49 SS-ET (4%), 18 out of 29 acromegalics (62%) and 6 NFA (66.6%), while a faint uptake was detected in 4 SS-ET (8%), 8 GH-secreting adenomas (27.5%) and 3 NFA (33.3%). Negative scan was detected in the remaining 43 SS-ET (87.7%) and 3 GH-secreting microadenomas (10.3%). 24 hr after injection, pituitary (111)In-DTPA-D-Phe1-octreotide uptake was moderate/intense in SS-ET (10.2%), 21 GH-secreting adenomas (72.4%), and 9 NFA (100%) while a faint uptake was detectable in 15 SS-ET (30.6%), and 6 GH-secreting adenomas (20.7%). No uptake was visualized in 29 SS-ET, and 2 GH-secreting adenomas. By MRI a pituitary tumor was shown in the 2 SS-ET with early moderate tracer uptake. Normalization of circulating GH/IGF-I levels and suppression of alpha-subunit levels was achieved in 16 of 18 acromegalics (88.9%) and 5 of 6 NFA-bearing patients, respectively, with scan scored 2-3 at early images. Eleven acromegalics (37.9%) and 2 NFA (22.2%) displayed significant tumor shrinkage (> or =30% of baseline size) during long-term octreotide therapy. Both in GH-secreting and in NFA, a significant correlation was found between percent GH or alpha-subunit suppression after 6-12 months of octreotide therapy and T-to-B ratios both in early (r=0.626; p<0.0001 and r=0.738, p=0.003, respectively) and late images (r=0.569; p=0.002 and r=0.8, p=0.01, respectively). In conclusion, the (111)In-DTPA-D-Phe1-octreotide uptake in pituitary adenomas was significantly correlated to octreotide treatment. However, since pituitary (111)In-DTPA-D-Phe1-octreotide uptake was clearly detectable in 40% of patients with SS-ET not located in the pituitary region at 24 hr post-injection, (111)In-DTPA-D-Phe1-octreotide scintigraphy with late pituitary images can not be considered an useful method to predict the chronic responsiveness to octreotide in individual patients. Caution should also be taken in evaluating the results of the scintigraphy with early images in patients with scant uptake before excluding them from treatment.
 
Article
Intraoperative [111In]-pentetreotide scintigraphy with a hand-held gamma detector probe has recently been proposed to increase the intraoperative detection rate of small neuroendocrine tumors and their metastases. We report a case of a 28-yr-old woman with ectopic Cushing's syndrome due to an ACTH-secreting bronchial carcinoid, in whom the use of radioguided surgery improved disease management. At presentation, radiolabeled pentetreotide scintigraphy was the only procedure able to detect the ectopic source of ACTH. After radiologic confirmation, the patient underwent removal of a bronchial carcinoid, with disease persistence. After surgery, pentetreotide scintigraphy showed pathologic uptake in the mediastinum not previously detected at surgery and only subsequently confirmed by radiologic studies. Despite a second thoracic exploration, hormonal, scintigraphic, and radiological evidence of residual disease persisted. Radioguided surgery was then performed using a hand-held gamma probe 48 h after iv administration of a tracer dose of radiolabeled [111In-DTPA-D-Phe1]-pentetreotide, which permitted detection and removal of multiple residual mediastinal lymph node metastases. Clinical and radiologic cure, with no evidence of tracer uptake at pentetreotide scintigraphy, was subsequently observed. The use of an intraoperative gamma counter appears a promising procedure in the management of metastatic ACTH-secreting bronchial carcinoids.
 
Article
GH secreting pituitary adenomas are frequently visualized by scintigraphy with the somatostatin analogue 111Indium-pentetreotide. We studied 111Indium-pentetreotide scintigraphy and hormonal responses to octreotide in 12 acromegalic patients. Nine patients with active acromegaly were studied before pituitary adenomectomy; 6 of these and 3 other patients were studied after operation. GH was measured after a single s.c. dose of 100 micrograms of octreotide (acute test). The patients were preoperatively treated with 100 micrograms s.c. tid octreotide for 3 months as were patients who had been unsuccessfully operated; GH and IGF-I were measured at the end of this period (chronic treatment). A decrease of the hormones higher than 50% of basal values was considered a positive response in both acute test and chronic treatment. Eight/nine unoperated patients had a pituitary adenoma visualized by scintigraphy and a positive response to both the acute test and chronic treatment; one patient had no evidence of tumor at scintigraphy and he did not respond to octreotide. Scintigraphy was negative in all of the three patients cured by surgery. Six patients still had active disease after adenomectomy: scintigraphy was positive only in one case, although GH responded to octreotide treatment in all patients. Conclusions. 111In-pentetreotide scintigraphy frequently visualizes pituitary adenomas and predicts GH responses to octreotide in unoperated acromegalic patients. In unsuccessfully operated patients scintigraphy is infrequently positive and does not predict which patients will respond to octreotide. These data and the cost of 111In-pentetreotide scintigraphy do not warrant its extensive clinical use in acromegaly.
 
Article
Iodine-131 metaiodobenzylguanidine (131I-MIBG), a radiopharmaceutical agent used for scintigraphic localization of pheochromocytomas, has been employed to treat malignant pheochromocytomas since 1983 in a few specialized centers around the world. We review our clinical experience together with the published experience of 23 other centers in 10 countries, regarding the use of 1311-MIBG for treating patients with malignant adrenal pheochromocytomas or extra-adrenal paragangliomas. There were a total of 116 evaluable patients: 3 were from our current report and another 113 were reported in the literature from 1983 to 1996. A majority of the patients were selected for treatment based upon positive tracer uptake studies. The cumulative dose of 131I-MIBG administered ranged from 96 to 2,322 mCi (3.6 to 85.9 GBq), with a mean (+/-SD) of 490+/-350 mCi (18.1+/-13.0 GBq). The subjects received a mean single therapy dose of 158 mCi (5.8 GBq) and the number of doses administered ranged from 1 to 11, with a mean of 3.3+/-2.2 doses. Initial symptomatic improvement was achieved in 76% of patients, tumor responses in 30%, and hormonal responses in 45%. Five patients had complete tumor and hormonal responses, ranging from 16 to 58 months, which were sustained at the time of reporting. Patients with metastases to soft tissue had more favorable responses to treatment than those with metastases to bone. No difference was noted in the age between the responders and non-responders. Adverse effects, recorded in 41% of the treated patients, were generally mild except for one fatality from bone marrow aplasia. Among 89 patients with follow-up data, 45% of the responders had relapsed with recurrent or progressive disease after a mean interval of 29.3+/-31.1 months (median 19 months). Of patients with an initial response to 1311-MIBG, death was reported in 33% after a mean of 23.2+/-8.1 months (median 22 months) following treatment. Of non-responders, death was reported in 45% after a mean of 14.3+/-8.3 months (median 13 months). In conclusion, this review suggests that 131I-MIBG therapy may be a useful palliative adjunct in selected patients with malignant pheochromocytoma or paraganglioma. Although controlled studies are lacking, our review raises the hope that this therapeutic modality may prolong survival with an occasional sustained complete remission or possible cure.
 
Article
Age of thelarche presentation, breast evolution, growth and puberty patterns were retrospectively evaluated in 119 girls with premature thelarche (PT). Thelarche spontaneously presented before 2 yr of chronological age in 80% of girls and completely regressed in 60% of them. Breast regression was significantly more frequent in the patients with more precocious thelarche presentation. In 40% of the girls breast size did not significantly change during a follow-up period ranging from 12 to 134 months (40.6 +/- 32.5). Among the 38 girls who were followed up to an age greater than 8 yr, seven (18.4%) developed central precocious puberty (PP). These 7 patients who progressed into true PP were indistinguishable from girls with normal puberty for age of thelarche presentation, breast size, evolution and auxological features. On the contrary, a subgroup of patients (28.5%) with accelerated height velocity and/or bone age at diagnosis of PT showed an auxological pattern different from normally growing girls during a 3-yr follow-up, but they did not seem to have higher risk of progressing into precocious puberty. In conclusion, PT encompasses different clinical, and perhaps hormonal situations, therefore requiring careful clinical follow-up.
 
Article
Until recently it was assumed that there was a direct relationship between the level of glucocorticoids in the circulation and the levels within tissue. The identification and characterisation of local glucocorticoid modifying enzymes in a range of tissues however demonstrated that tissue levels of glucocorticoids can be regulated independently of circulating levels. This appears to be the case in bone where the 11beta-hydroxysteroid dehydrogenase (11beta-HSD) enzymes are expressed. Glucocorticoids are actively generated within osteoblasts by the 11beta-HSD1 enzyme and this generation increases with proinflammatory cytokines, glucocorticoids, and probably with age. Measures of enzyme activity can predict the response of bone formation markers to therapeutic glucocorticoids. This review summarises the data relating to 11beta-HSD expression and activity in human bone and describes how this has implications for age-related, inflammation-associated, and glucocorticoid-induced osteoporosis.
 
Article
Many neuroendocrine tumors (NET) are small and may escape localization by conventional imaging techniques. In such cases, 11C-5-hydroxy-tryptophan (11C-5-HTP) positron emission tomography (PET) has been tested as an additional diagnostic tool. Nine patients with clinically, biochemically and/or histologically confirmed NET and negative computerized tomography (CT) or magnetic resonance imaging (MRI), and 111In-pentetreotide (Octreoscan) scintigraphy underwent imaging with 11C-5-HTP-PET/CT in order to: 1) detect the primary tumor lesion in three patients; 2) detect residual disease in two patients with appendiceal carcinoid, one with rectal carcinoid, one with midgut carcinoid, and one with ectopic ACTH secretion (EAS) due to residual pulmonary carcinoid; and 3) restage a patient with medullary thyroid carcinoma (MTC) and hepatic metastases. 11C-5-HTP-PET/CT detected lesions in the mediastinum in a patient with EAS due to a pulmonary carcinoid, further hepatic metastases in a patient with carcinoid syndrome (CS) from a NET of unknown primary, further hepatic metastases in the patient with MTC, and hepatic metastases in the patient with midgut carcinoid. The 11C-5-HTP-PET/CT findings contributed to radical cure of the patient with recurrent EAS, and pointed towards bilateral adrenalectomy in the patient with EAS without evident primary tumor. In addition, 11C-5- HTP-PET/CT directed towards combined surgical and medical treatment in the patient with CS and multiple rather than single hepatic metastases and in the patient with midgut carcinoid, and towards continuation of medical treatment in the patient with MTC. 11C-5-HTP-PET/CT is a useful imaging technique, providing additional information for the diagnosis, staging and decision-making regarding management of patients with NET.
 
The pedigree of the families with 11β-hydroxylase deficiency. Filled circles indicate patients presenting 11β-hydroxylase deficiency with R448C/R448C genotype. Half-filled circles and squares indicate individuals with R448C/WT genotype, but without 11β-hydroxylase deficiency. Besides; IV.2, IV.3 and probands have a pericentric inversion of chromosome 3 [inv(3)(p13q24)]. Empty circles and squares are for homozygote wild type. A diagonal line through the symbol indicates deceased individuals. Empty circles and squares were not tested. 
Fluorescence in situ hybridisation (FISH) results of patient (V.13). A) FISH using bacterial artificial chromosome (BAC) RP11-286L5, with one signal on arm of normal chromosome 3 and two signals on both arm of the inverted chromosome 3. B) Figure prepared according to FISH results and human genome browser shows the position of the proximal and the distal clones and known genes on the spanning BAC clone RP11-286L5. RP11-349E6 is the proximal BAC clone, and BAC RP1124E1 is the distal BAC clone. 
-Clinical, hormonal, molecular, and cytogenetic data of the patients with 11β -hydroxylase deficiency. 
Sequence electropherograms showing C→T transitions resulting in arginine to cysteine substitution at position 448 (R448C). Both fathers (IV.1, IV.3) and mothers (IV.2, IV.4) are heterozygous for the mutant allele in two families. Index patients (V.13, V.6) are homozygous mutants whereas the control (C) is homozygous for the wild type allele at the corresponding region. Arrows indicate the nucleotide involved in the mutation. 
Article
11beta-hydroxylase deficiency is the second most common cause of congenital adrenal hyperplasia (CAH). This isoenzyme is coded by two highly homologous genes of cytochrome P450: CYP11B1 and CYP11B2 which were mapped to the chromosomal band 8q24. The aim of this study was to perform a series of molecular and cytogenetic analyses in two families with 11beta-hydroxylase deficiency of the Turkish kindred. Mutational analysis was carried out by directly sequencing the PCR products of CYP11B1 gene. We performed fluorescence in situ hybridisation (FISH) experiments with consecutive bacterial artificial chromosome (BAC) clones to map the breakpoints of the inversion of chromosome 3 which was detected during the karyotypic analysis of the propositus. Homozygous R448C mutations were detected in 2 individuals with 11beta-hydroxylase deficiency. Interestingly, karyotypic change of pericentric inversion [inv(3)(p13q24)] was detected in both individuals who are cousins, one transmitted paternally and the other maternally. The breakpoint at 3p included one interesting gene PPP4R2. Here we present the data of two Turkish families' members having 11beta-hydroxylase deficiency coupled with the familial chromosomal aberration of inv(3)(p13q24). Our data suggest that codon 448, which is a mutational hot spot in CYP11B1 causing 11beta-hydroxylase deficiency, is not restricted to Jews of Moroccan origin. Phenotypic variations observed in former studies in patients homozygous for R448H were stated to be due to other factors outside the CYP11B1 locus. The breakpoint in 3p might be a candidate region affecting variations in phenotypes of 11beta-hydroxylase deficiency.
 
Article
Ectopic ACTH secretion is characterized by a high incidence of hypokalemia. The pathophysiology of hypokalemia has not been totally clarified, although it has been postulated that excessive amounts of adrenal steroids may play a role, as well as a possible role of the inhibition of the enzyme 11beta-hydroxysteroid dehydrogenase (11beta-OHSD). This enzyme normally converts cortisol to cortisone avoiding the mineralocorticoid action of cortisol. We present a patient with ectopic ACTH secretion due to a metastatic carcinoid tumor. The clinical picture was characterized by maintained hypokalemia (1.4 mmol/l) resistant to potassium, spironolactone and ketoconazole administration. A bilateral adrenalectomy was performed but the hypokalemia persisted while he was receiving a physiological dose of cortisol. Eight days after adrenalectomy cortisol was replaced by an equivalent dose of dexamethasone. This change was followed by a rapid and persistent normalization of hypokalemia suggesting a mineralocorticoid effect of cortisol. In conclusion, the origin of hypokalemia in our patient with ectopic ACTH secretion was secondary to cortisol. We postulate that this peculiar effect of cortisol could have happened if an inhibition of 11beta-OHSD occurred.
 
Article
Glucocorticoids are important regulators of glucose, lipid and protein metabolism, acting mainly in the liver, adipose tissue and muscle. Chronic glucocorticoid excess is associated with clinical features, such as insulin resistance, visceral obesity, hypertension, and dyslipidemia, which also represent the classical hallmarks of the metabolic syndrome. Elevenbeta-hydroxysteroid dehydrogenase type 1 (11beta-HSD-1), a key intracellular enzyme which catalyses the conversion of inactive cortisone to active cortisol, has been implicated in the development of the metabolic syndrome. The shift of this reaction towards cortisol generation may lead to tissutal overexposure to glucocorticoids even with normal circulating cortisol levels. The most robust evidence in support of a pathogenetic role of this enzyme in the development of the metabolic syndrome has been reported in experimental animals, whereas results of human studies are less convincing with several case control and cross-sectional studies showing an association between with 11beta-HSD-1 setpoint and individual features of the metabolic syndrome. However, recent data suggest a tissue-specific rather than systemic alteration of this shuttle, with down-regulation in liver but up-regulation in adipose tissue and skeletal muscle of obese subjects. New techniques based on direct tissutal estimates of cortisol/cortisone ratios are clearly needed to precisely assess the role of enzyme in all target tissues. If confirmed, these results would prompt the development of selective and tissue-specific 11beta-HSD-1 inhibitors to decrease insulin resistance and treat the metabolic syndrome, thus contrasting the harmful effects of glucocorticoid excess in peripheral tissues.
 
Article
To investigate the relationship between 11β-hydroxysteroid dehydrogenase (HSD11B) gene type 1 and 2 and obesity in Chinese children. A total of 400 obese and 200 healthy adolescents were enrolled as obese and control groups. Seven SNPs in HSD11B1 (rs4393158, rs2235543, rs10082248, rs10863782, rs2236903, rs2298930, rs4545339) and four variants in HSD11B2 gene (rs28934592, rs28934591, rs28934594 and rs28934593) were measured by automated platform MassArray. The rs28934592 in HSD11B2 and rs10863782 in HSD11B1 were excluded as false positive or HWE P < 0.05. Moreover, one allele type was found in the other three locations of HSD11B2. The minor allele frequency of rs2235543 and rs10082248 was higher in patients than that in controls (P = 0.045, P = 0.041, respectively). The rs10082248, rs2298930 and rs4545339 were associated with the risk of obesity in the recessive model (P < 0.05, respectively). Moreover, the total cholesterol in patients with GG or AG genotype was significantly higher than that in patients with AA genotype in rs10082248. The rs4393158 was associated with the hypertension in log-additive model test (P = 0.037), and glucose abnormal and hypercholesteremia in dominant model test (P < 0.05, respectively), while the rs2235543 was associated with hypercholesteremia in overdominant model test (P = 0.017). The polymorphism of HSD11B1 may be a cause of childhood obesity, or even associated with the complication of childhood obesity. However, variants of HSD11B2 may be not a cause of obesity.
 
Article
The syndrome of apparent mineralocorticoid excess (AME) is an inherited form of hypertension. This disorder results from an inability of the enzyme 11β-hydroxysteroid dehydrogenase (11β-OHSD) to inactivate cortisol to cortisone. The diagnosis of AME is usually based on an elevated ratio of cortisol to cortisone reduced metabolites in the urine [tetrahydrocortisol plus allotetrahydrocortisol to tetrahydrocortisone (THF+alloTHF/THE)]. The principal site of “A” ring reduction is the liver, But AME arises from mutation in the gene encoding 11β-OHSD2 in the kidney. We used a gas chromatographic/mass spectrometric method to measure the urinary free cortisol (UFF) and free cortisone (UFE) in 24 patients affected by the two variants of AME [19 with the classical form (type I) and 5 with the mild form called AME type II] in order to provide a more reproducible in vivo measure of the renal enzymatic activity. Type I patients were divided into two groups: children under 12 and adults. UFF levels (μg/24 h) did not differ between under-12 controls and AME type I children (mean±SD, 9±4 and 15±12, respectively), But was significantly higher in affected adults compared to controls: (62±32 vs 29±8, ppppvs 0.54±0.3, p
 
Article
1-123 metaiodobenzylguanidine (1-123 MIBG) scintigraphy is known for its high specificity in detecting pheochromocytoma and other tumors of neural crest origin. In this rare case report, we describe a definite adrenocortical adenoma that demonstrated false-positive uptake at I-123 MIBG scintigraphy and a remarkable accumulation of 75-SE-6-beta-selenomethyl-norcholesterol.
 
Clinical and demographic characteristics of the patients 
Efficacy of cabergoline on the normalization of prolactin levels in 238 patients with microprolactinomas (BCR = bromocriptine)  
Article
The aim of the study was to evaluate clinical and laboratorial features of 1234 patients with different etiologies of hyperprolactinemia, as well as the response of 388 patients with prolactinomas to dopamine agonists. A total of 1234 hyperprolactinemic patients from 10 Brazilian endocrine centers were enrolled in this retrospective study. PRL measurement, thyroid function tests, and screening for macroprolactin were conducted. Patients were subdivided as follows: 56.2% had prolactinomas, 14.5% drug-induced hyperprolactinemia, 9.3% macroprolactinemia, 6.6% non-functioning pituitary adenomas, 6.3% primary hypothyroidism, 3.6% idiopathic hyperprolactinemia, and 3.2% acromegaly. Clinical manifestations were similar irrespective of the etiology of the hyperprolactinemia. The highest PRL levels were observed in patients with prolactinomas but there was a great overlap in PRL values between all groups. However, PRL>500 ng/ml allowed a clear distinction between prolactinomas and the other etiologies. Cabergoline (CAB) was more effective than bromocriptine (BCR) in normalizing PRL levels (81.9% vs 67.1%, p<0.0001) and in inducing significant tumor shrinkage and complete disappearance of tumor mass. Drug resistance was observed in 10% of patients treated with CAB and in 18.4% of those that used BCR (p=0.0006). Side-effects and intolerance were also more common in BCR treated patients. Prolactinomas, drug induced hyperprolactinemia, and macroprolactinemia were the 3 most common causes of hyperprolactinemia. Although PRL levels could not reliably define the etiology of hyperprolactinemia, PRL values >500 ng/ml were exclusively seen in patients with prolactinomas. CAB was significantly more effective than BCR in terms of prolactin normalization, tumor shrinkage, and tolerability.
 
Article
Struma ovarii is the most common monodermal ovarian teratoma and consists mainly of thyroid tissue. Only 5% of patients with this tumor have features of hyperthyroidism. The pathophysiology of hyperthyroidism in struma ovarii is not clear. We describe a case of benign struma ovarii, presenting with the clinical features of an ovarian cancer: large complex pelvic mass, large amount of ascites and markedly elevated CA-125 serum levels. The patient was initially treated for Graves' disease, on the basis of ultrasonographic, laboratoristic and scintigraphic evidence. The resistance to the medical treatment led to thyroidectomy. After surgery the hyperthyroidism persisted and, suddenly, the patient presented ascites. A large pelvic mass was then diagnosed which, at the pathologic examination, was diagnosed as a struma ovarii. The struma ovarii always has to be considered when a pelvic mass is associated with features of hyperthyroidism.
 
Article
Thirty-four patients with moderate-severe hirsutism were enrolled in this study. The patients received 125 mg/day flutamide for a period of 6 months. Hirsutism score and hormone parameters including FSH, LH, T, free T, androstenedione (A), DHEAS, PRL and sex hormone-binding globulin (SHBG) levels were evaluated in all patients before treatment and repeated at every three-monthly intervals. Hirsutism greatly improved during flutamide therapy, and the hirsutism score significantly decreased at month 3 and 6 from a mean (+/-SD) of 17.19+/-4.55 to 10.75+/-3.84 (p<0.001) and 17.19+/-4.55 to 5.91+/-2.53 (p<0.001), respectively. A significant reduction in hirsutism score (mean%+/-SD) as compared to baseline was observed at 3 months (37.78+/-13.30, p<0.001) and at 6 months (65.47+/-13.49, p<0.001). No significant changes in the levels of hormone and no serious side effects were observed in the patients. The lower dose flutamide, 125 mg/day, is a safe and cost-effective drug in the treatment of hirsutism. Lower dose flutamide may be used in place of high dose flutamide, 250 to 750 mg/day.
 
Article
CA 125 is a cell surface antigen expressed in some derivatives of celomic epithelium, predominantly in ovarian cancer cells. However, it has also been detected in serum of healthy women and in patients with benign gynecologic diseases. The exact source or sources of the circulating levels of CA 125 and their elevations are not known. In the present study, the relationship between serum CA 125 levels, ovarian steroidogenesis and endometrial thickness is investigated at different periods: 1) mid-follicular, 2) midcycle, and 3) midluteal phases in normal cycles of fertile women, in patients stimulated for intrauterine insemination (IUI) and in patients stimulated for in vitro fertilization (IVF). Only in patients with mild and moderate ovarian hyperstimulation (OHSS) of the IVF group were luteal phase CA 125 levels (149.7 +/- 24.4 U/ml) significantly higher than midfollicular (21.2 +/- 1.9 U/ml) and midcycle phase levels (24.4 +/- 2.5 U/ml) (p < 0.001). The mean midcycle estradiol and midluteal progesterone concentrations in patients stimulated for IUI and IVF were significantly higher than those of normally cycling women (p < 0.001). Mean endometrial thickness in patients stimulated for IVF was significantly higher than in patients stimulated for IUI and normally cycling women (p < 0.001). Midluteal CA 125 levels correlated with midcycle endometrial thickness (r = 0.585, p < 0.05) and midluteal P levels (r = 0.497, p < 0.05) in patients with OHSS of IVF group. This correlation was not observed in patients who had no signs and symptoms of OHSS during stimulation for IVF and in patient stimulated for IUI and the controls.(ABSTRACT TRUNCATED AT 250 WORDS)
 
Article
The levels of the oncofetal antigens CA-125, CA 19-9 and CA 15-3 were measured in serum samples taken from 8 women, aged 21 to 37 yr, before treatment, during the last fifteen days of a 6-month administration of danazol and finally three months after treatment withdrawal. The purpose of the study was to investigate: i) whether endometriosis belongs to the pathologic conditions which induce a concomitant increase in the values of CA-125, CA 19-9 and CA 15-3, and ii) the effect of danazol on the levels of these antigens. Our results indicate that before danazol treatment, three women showed pathologic levels of all three antigens, one of CA 19-9 and CA 15-3, one of CA 19-9 alone, and two of CA 15-3 alone. Administration of the drug significantly reduced the levels of CA-125 (p less than 0.001) and CA 19-9 (p less than 0.05) and to a lesser degree the levels of CA 15-3. Three months after danazol treatment discontinuation, the levels of these three antigens remained significantly lower (p less than 0.05) than the respective pretreatment values. Our findings substantiate the view that endometriosis must be classified with the pathologic conditions which induce a rise in the levels of all three antigens, and that ovarian function mainly influences the levels of CA-125 and CA 19-9.
 
Article
Polychlorinated biphenyls (PCBs) are environmental contaminants which may affect thyroid function. PCBs may reduce serum thyroid hormone (TH) concentrations by either displacing T4 from TH transport proteins or increasing its hepatic metabolism. The reduced serum T4 causes neurological and growth defects in animals exposed to PCBs during the perinatal period, which can partially be reverted by T4 administration. In addition to a hypothyroid-like syndrome, a direct action of PCBs on TH-sensitive genes has been postulated. In the present study the effects of Aroclor 1254 (ARO), a mixture of PCBs, on transcription of TH-dependent genes were investigated. A reporter plasmid containing the TH-responsive element (TRE) of malic enzyme (ME) gene was used in transient transfections to assess the responsiveness to ARO. ARO (10 microM) reduced the CAT activity by about 50% and competed with T3 to reduce the induction of transcription. Cotransfection of TH receptor (TR) and a wild type TRE was required to reveal ARO inhibitiry effect, which was abolished by a mock reaction not containing TR or by a mutated TRE. ARO reduced the 125I-T3 binding to TR by 30%, but did not affect the interaction of TR with a 32P-labeled TRE in gel shift assay. ARO is likely to produce a conformational change in in vitro translated TR, leading to its increased proteolysis by trypsin. These results demonstrate that ARO interacts with TR, thereby affecting the transcription of TH-sensitive genes, and provide a molecular basis to further explain the complex effects of PCBs on TH disruption.
 
Top-cited authors
Andrea Lenzi
  • Sapienza University of Rome
Mario Maggi
  • University of Florence
Paolo Vitti
  • Università di Pisa
Annamaria Colao
  • University of Naples Federico II
Giovanni Corona
  • Endocrinology Unit