Natural history of gastro-entero-pancreatic and thoracic neuroendocrine tumors. Data from a large prospective and retrospective Italian epidemiological study: the NET management study.

BACKGROUND: The few epidemiological data available in literature on neuroendocrine tumors (NET) are mainly based on Registry databases, missing therefore details on their clinical and natural history. AIM: To investigate epidemiology, clinical presentation, and natural history of NET. DESIGN AND SETTING: A large national retrospective survey was conducted in 13 Italian referral centers. Among 1203 NET, 820 originating in the thorax (T-NET), in the gastro-enteropancreatic tract (GEP-NET) or metastatic NET of unknown primary origin (U-NET) were enrolled in the study. RESULTS: 93% had a sporadic and 7% a multiple endocrine neoplasia type 1 (MEN1)-associated tumor; 63% were GEP-NET, 33% T-NET, 4% U-NET. Pancreas and lung were the commonest primary sites. Poorly differentiated carcinomas were <10%, all sporadic. The incidence of NET had a linear increase from 1990 to 2007 in all the centers. The mean age at diagnosis was 60.0 ± 16.4 yr, significantly anticipated in MEN1 patients (47.7 ± 16.5 yr). Association with cigarette smoking and other non-NET cancer were more prevalent than in the general Italian population. The first symptoms of the disease were related to tumor burden in 46%, endocrine syndrome in 23%, while the diagnosis was fortuity in 29%. Insulin (37%) and serotonin (35%) were the most common hormonal hypersecretions. An advanced tumor stage was found in 42%, more frequently in the gut and thymus. No differences in the overall survival was observed between T-NET and GEP-NET and between sporadic and MEN1-associated tumors at 10 yr from diagnosis, while survival probability was dramatically reduced in U-NET. CONCLUSIONS: The data obtained from this study furnish relevant information on epidemiology, natural history, and clinico-pathological features of NET, not available from the few published Register studies.

Is a five-category reporting scheme for thyroid fine needle aspiration cytology accurate? Experience of over 18,000 FNAs reported at the same institution during 1998-2007.

OBJECTIVE: Fine needle aspiration (FNA) has long been recognized as an essential technique for the evaluation of thyroid nodules. Although specific cytological patterns have been recognized, a wide variety of reporting schemes for thyroid FNA results have been adopted. This study reports our experience with a five-category reporting scheme developed in-house based on a numeric score and applied to a large series of consecutive thyroid FNAs. It focuses mainly on the accuracy of thyroid FNA as a preoperative test in a large subset of histologically distinct thyroid lesions. METHODS: During the 1998-2007 period, 18,359 thyroid ultrasound-guided FNAs were performed on 15,269 patients; FNA reports were classified according to a C1-C5 reporting scheme: non-diagnostic (C1), benign (C2), indeterminate (C3), suspicious (C4), and malignant (C5). RESULTS: Non-diagnostic (C1) and indeterminate (C3) FNA results totalled 2,230 (12.1%) and 1,461 (7.9%), respectively, while suspicious (C4) and malignant (C5) results totalled 238 (1.3%) and 531 (2.9%), respectively. Histological results were available in 2,047 patients, with thyroid malignancy detected in 840. Positive predictive value of FNA was 98.1% with a 49.0 likelihood ratio (LR) of malignancy in patients with a C4/C5 FNA report. CONCLUSIONS: This five-category scheme for thyroid FNA is accurate in discriminating between the virtual certainty of malignancy associated with C5, a high rate (92%) of malignancy associated with C4, and a 98% probability of a histological benign diagnosis associated with C2. Further sub-classifications of C3 may improve the accuracy of the diagnostic scheme and may help in recognizing patients eligible for a 'wait and see' management.

American Association of Clinical Endocrinologists, Associazione Medici Endocrinologi, and European Thyroid Association medical guidelines for clinical practice for the diagnosis and management of thyroid nodules: Executive Summary of recommendations.

American Association of Clinical Endocrinologists, Associazione Medici Endocrinologi, and European Thyroid Association medical guidelines for clinical practice for the diagnosis and management of thyroid nodules are systematically developed statements to assist health care professionals in medical decision making for specific clinical conditions. Most of the content herein is based on literature reviews. In areas of uncertainty, professional judgment was applied. These guidelines are a working document that reflects the state of the field at the time of publication. Because rapid changes in this area are expected, periodic revisions are inevitable. We encourage medical professionals to use this information in conjunction with their best clinical judgment. Any decision by practitioners to apply these guidelines must be made in light of local resources and individual patient circumstances.

Influence of thyroid status on serum immunoreactive leptin levels.

Leptin, the product of the ob gene, is a recently discovered hormone secreted by adipocytes. Serum leptin concentrations increase in correlation with the percentage of body fat, but besides that, little is known about the physiological actions of leptin in humans. The aim of this study was to assess the influence of hypo- and hyperthyroidism on serum leptin levels. Thirty-two patients (16 with hypothyroidism and 16 with hyperthyroidism) were studied before and after treatment with replacement doses of T4 (hypothyroid patients) or methimazole (hyperthyroid), when thyroid function was normal. Control serum for each group was obtained from healthy age-, sex-, and body mass index-matched subjects. Plasma leptin levels were measured by specific RIA. The mean leptin level in the hypothyroid patients was lower before treatment (4.7 +/- 0.7 microg/L) than that in the controls (8.6 +/- 1.4 microg/L; P < 0.02) and was lower than that during treatment with T4 and normalization of thyroid function in the same group of patients (6.3 +/- 0.8 microg/L; P < 0.05). Leptin levels in the hyperthyroid patients were similar before (7.2 +.0 1.1 microg/L) and after normalization of thyroid function following treatment with methimazole (6.2 +/- 1.1 microg/L) and were similar to the control value (8.8 +/- 1.4 microg/L). In conclusion, leptin levels are decreased in the hypothyroid patients and unchanged in hyperthyroidism. Whether decreased leptin levels may contribute to the decreased energy expenditure in patients with hypothyroidism merits further investigation.

Evidence against depletion of the growth hormone (GH)-releasable pool in human primary hypothyroidism: studies with GH-releasing hormone, pyridostigmine, and arginine.

We investigated whether the impaired GH secretion of hypothyroid patients could be due to an increase in hypothalamic somatostatinergic tone. Twenty-four patients with primary hypothyroidism [20 females and 4 males; mean age (+/- SE), 47.5 +/- 2.7 yr] and 20 normal subjects (17 females and 3 males; age, 47.6 +/- 3.0 yr) were studied. In the first group of 12 hypothyroid patients, administration of pyridostigmine, a cholinergic agonist drug (120 mg, orally, at -60 min), notably increased GH responses to GH-releasing hormone (GHRH; 1 microgram/kg, iv, at 0 min; peak GH levels for pyridostigmine plus GHRH vs. placebo plus GHRH, 16.6 +/- 4.9 vs. 6.0 +/- 1.8 micrograms/L; P < 0.01). The GH responses to pyridostigmine plus GHRH, however, were considerably lower than those in 10 normal subjects (peak GH levels, 53.0 +/- 3.5 micrograms/L; P < 0.001). In the second group of 12 hypothyroid patients, arginine infusion (30 g, iv, from 0-30 min) markedly increased the GH responses induced by GHRH administration (1 microgram/kg, iv, at 0 min; peak GH levels for arginine plus GHRH vs. placebo plus GHRH, 30.6 +/- 4.7 vs. 5.3 +/- 1.0 micrograms/L; P < 0.001). However, GH release after GHRH plus arginine was greater in 10 normal subjects than in the hypothyroid patients (peak GH levels, 50.9 +/- 5.3 micrograms/L; P < 0.001). Pyridostigmine and arginine inhibit hypothalamic somatostatin tone. The stimulatory effect of both agents on GHRH-induced GH release indicates that reduced GH secretion in hypothyroidism can be reversed to a considerable extent by inhibiting hypothalamic somatostatinergic tone. The relatively greater potency of arginine compared to pyridostigmine suggests that hypothyroid patients may have an impairment of the cholinergic pathways. Furthermore, these data show that hypothyroid patients have a somatotrope secretory capacity much greater than previously thought.

Effects of hypothyroidism and hyperthyroidism on insulin-like growth factors (IGFs) and growth hormone- and IGF-binding proteins.

Normal thyroid status is a prerequisite for the normal growth and development of many tissues. The interrelationships between the thyroid and pituitary-GH-insulin-like growth factor (IGF) axes are complex and not yet fully understood. We have studied the effects of hypothyroidism (n = 22) and hyperthyroidism (n = 17) on levels of serum immunoreactive IGF-I and II, IGF-binding proteins (IGFBP-1 and -3), and IGF bioactivity before and during treatment. We have also assessed changes in GH-binding activity (GHBP). Mean immunoreactive (IR) IGF-I levels in the hypothyroid group rose from 106.6 +/- 10.6 micrograms/L at diagnosis to 139.9 +/- 12.7 micrograms/L (P = 0.009) on normalization of thyroid function. In hyperthyroidism, mean IGF-I levels (258.9 +/- 33.9 micrograms/L) were high initially and fell to 188.7 +/- 14.8 micrograms/L (P = 0.04) after treatment. IR IGF-I levels correlated positively with free T3 and free T4 and negatively with TSH levels. Mean serum IGF-II levels were low in hypothyroid patients (375.2 +/- 37.3) and rose during treatment (516.9 +/- 59.4 micrograms/L; P = 0.04). In the hyperthyroid subjects, however, there was no significant change during therapy (625.0 +/- 66.9 vs. 621.9 +/- 120.8 micrograms/L; P = 0.98). IGF bioactivity potency ratios were low in the hypothyroid group (0.26 +/- 0.03 U/mL) and rose to 0.71 +/- 0.10 U/mL (P = 0.01) during treatment. IGF bioactivity in the hyperthyroid group was also low (0.38 +/- 0.05 U/mL) and rose significantly during treatment (0.81 +/- 0.06 U/mL; P = 0.003). Mean IGFBP-1 levels (29.8 +/- 5.7 micrograms/L) were unaltered by treatment of hypothyroid subjects (28.4 +/- 4.8 micrograms/L). In contrast, IGFBP-1 levels in the hyperthyroid subjects were high at diagnosis (134.6 +/- 26.6 micrograms/L) and fell significantly (71.3 +/- 14.3 micrograms/L; P = 0.04) during treatment. In the hypothyroid group, IGFBP-3 levels rose from an initial mean of 1.98 +/- 0.17 to 2.67 +/- 0.27 mg/L (P = 0.04) during treatment. The higher mean pretreatment levels in the thyrotoxic group (3.46 +/- 0.32 mg/L) were unaltered by treatment (3.20 +/- 0.51 mg/L; P = 0.71). GHBP was low in the hypothyroid group at diagnosis (28.5 +/- 2.5%) and rose during treatment to 40.6 +/- 3.9% (P = 0.02). We have confirmed that IR IGF-I levels are low in hypothyroidism and have demonstrated a reduction in IGF bioactivity and IGF-II and IGFBP-3 levels, and low GH-binding activity, which may reflect a reduction in the processing of GH receptors.(ABSTRACT TRUNCATED AT 400 WORDS)

Reversible effects of cessation and recommencement of thyroxine treatment on insulin-like growth factors (IGFs) and IGF-binding proteins in patients with total thyroidectomy.

There is a complex relationship between the thyroid and pituitary GH/insulin-like growth factor (IGF) axes. IGFs circulate in association with six specific high affinity binding proteins (IGFBPs) that modulate their bioactivity and bioavailability. Recent evidence suggests that gene expression and circulating levels of IGFBPs are related to prevailing thyroid hormone status. We have investigated the effects of both withdrawal and reinstitution of thyroid hormone replacement on circulating IGF and IGFBP levels in athyreotic patients (n = 10). The mean IGF-I concentration fell from a basal level of 191.8 +/- 12 micrograms/L to a nadir of 136.4 +/- 17.8 micrograms/L (P = 0.026) 5 weeks after stopping T4 treatment and returned to normal values 3 weeks after recommencement of replacement treatment. The fall in IGF-II levels followed a similar pattern from a basal mean level of 649 +/- 33.7 to 547 +/- 42.7 micrograms/L (P = 0.026) at 5 weeks. These changes paralleled the fall in free T3 and free T4. Similarly, IGFBP-1 levels fell after stopping T4 treatment from a basal level of 54.8 +/- 4.0 to 24.6 +/- 7.0 micrograms/L (P = 0.001) 5 weeks later. After T4 treatment was restarted, IGFBP-1 levels rose and were not significantly different from basal values by week 8. There were strong positive correlations between paired data sets for IGFBP-1 and free T3 (r = 0.488; P = 0/0037) and free T4 (r = 0.56; P = 0.0006), and a strong negative correlation with TSH (r = -0.515; P = 0.0001). Insulin is known to be important in the regulation of IGFBP-1, but no changes in fasting insulin levels during T4 withdrawal were noted, and levels of IGFBP-1 did not exhibit the normal inverse relationship with circulating insulin levels. Levels of IGFBP-2, assessed by Western ligand blotting, increased during the development of hypothyroidism, peaked 5 weeks after stopping T4 replacement, and declined on reinstitution of replacement treatment. A further level of regulation of the IGF-IGFBP axis is afforded by the presence of specific circulating IGFBP proteases. Proteases directed against IGFBP-3 proteolytically cleave the major carrier BP in the circulation and reduce its binding affinity, possibly resulting in increased tissue IGF bioavailability. Despite the marked reduction in circulating IGF levels and the generation of significant biochemical hypothyroidism, IGFBP-3 protease activity was not apparent during the 10-week period of the study.(ABSTRACT TRUNCATED AT 400 WORDS)

Effects of oral glucose administration on spontaneous and growth hormone (GH)-releasing hormone-stimulated GH release in children and adults.

It has been suggested that hypothalamic regulation of GH secretion in children may differ from that in adults. On the other hand, there is evidence that oral glucose administration affects GH secretion through hypothalamic mechanisms. Therefore, we investigated spontaneous and GHRH-stimulated (1 microgram/kg BW) GH responses after oral glucose administration (children, 1.75 g/kg BW; adults, 75 g) in peripubertal normal children (13 girls and 13 boys, aged 11.7 +/- 0.4 yr; range, 8-13) and healthy adults (12 males and 14 females, aged 25.7 +/- 1.2 yr; range, 18-39). Three studies were carried out. In study 1, serum GH levels in 8 children were suppressed (< 1 microgram/L) for 135 min after oral glucose administration. Afterward, there was a rise in serum GH levels. In 8 adults, the suppressive effect of glucose persisted throughout the 210-min study period, and no GH rebound appeared. In study 2, the GH responses to iv GHRH boli in 10 adults and 10 children were, respectively, inhibited, unchanged, or augmented by an oral glucose load administered 30, 60, or 120 min before GHRH challenge. In study 3, oral glucose administration to 8 adults greatly enhanced the GH response to GHRH given 180 min after the glucose, whereas in 8 children, the GH response to GHRH was unchanged. In conclusion, glucose affects basal and GHRH-stimulated GH release in a similar manner in adults and children, indicating that neuroregulatory influences of glucose on the GH axis may not differ in the two age groups. In children, however, the duration of both the initial inhibitory and subsequent stimulatory effects of glucose administration on GH secretion is shorter.

Sinus node function in hyperthyroid patients.

We have studied the electrophysiology of the sinus node and the role of the autonomic nervous system on sinus node function in 8 thyrotoxic patients of both sexes, 37.5 +/- 4.3 (mean +/- SE) yr old. The resting heart rate (RHR), the sino-atrial conduction time (SACT), and the sinus node recovery time (SNRT) were measured in the untreated condition (basal), after sympathetic blockade with propranolol 0.2 mg/kg body weight (BW) i.v. infusion, and after complete autonomic blockade with the additional administration of atropine 0.04 mg/kg BW i.v. bolus. 1) In the thyrotoxic patients the RHR was higher [117 +/- 6 beats per min (bpm)] than in 20 normal subjects (73 +/- 1 bpm, P less than 0.001), whereas the SACT and SNRT values were not different. 2) After sympathetic blockade with propranolol, the RHR decrement and SACT increase were greater in the hyperthyroid patients than in normal subjects, whereas there was no difference in SNRT values between the two groups. 3) In the thyrotoxic patients the complete autonomic blockade reestablished the electrophysiological parameters to values similar to those observed in basal condition. In conclusion, in thyrotoxic patients the intrinsic activity of the sinus node is increased. It appears that this is a direct consequence of thyroid hormone excess, rather than an effect of extrinsic influences exerted by the autonomic nervous system on sinus node activity.

Cardiac performance and mass in adults with hypopituitarism: effects of one year of growth hormone treatment.

We studied the effects of GH administration on myocardial structure and function in 20 patients with hypopituitarism (14 males and 6 females; mean +/- SE age, 47.2 +/- 2.6 yr; range, 31-59 yr) developed in adulthood because of pituitary or parapituitary tumors. All patients had GH deficiency (GHD), as assessed by a GH response of less than 4 micrograms/L to a standard insulin tolerance test (0.05 U kg, iv) and the combined pyridostigmine (120 mg, orally, at -60 min) plus GHRH (1 microgram/kg, iv, at 0 min) test. Patients received either placebo (n = 10) or GH substitution therapy (n = 10; 0.05 U/kg.day GH for 1 yr; 0.03 U/kg.day during the first month). M- and B-mode echocardiography and pulsed Doppler examination of transmitral flow were performed before treatment, 6 months and 1 yr after starting GH or placebo administration, and 15 days and 3 months after GH or placebo withdrawal. Twenty healthy subjects, matched for age, sex, body mass index, and physical activity, served as controls. Left ventricular dimensions, mass, and systolic function were normal in patients with adult-onset GHD; however, diastolic function, specifically E wave deceleration time, was altered. GH administration markedly increased left ventricular performance and reversed diastolic abnormalities at 6 and even more so at 12 months. On the other hand, a clear increase in left ventricular mass was seen after 12, but not after 6, months of GH administration (P < 0.01 vs. pretreatment values). In addition, although all changes induced by GH treatment disappeared within 3 months after GH withdrawal, at that time the increase in left ventricular mass was still detectable (P < 0.05 vs. pretreatment values). These data indicate that augmented left ventricular contractility is not strictly related to cardiac muscle growth, supporting the hypothesis that GH treatment increases the inotropic activity of myocardial fibers. In conclusion, GH treatment enhances cardiac function, increases cardiac mass, and reverses diastolic abnormalities in adults with hypopituitarism and GHD. However, long term studies are required to demonstrate that GH replacement therapy reduces cardiac death rate in these patients.

Pyridostigmine potentiates growth hormone (GH)-releasing hormone-induced GH release in both men and women.

It has been recently reported that pyridostigmine (PD), an indirect cholinergic agonist, probably acting via inhibition of hypothalamic somatostatin, potentiates the GH-releasing hormone (GHRH)-induced GH rise in men, but not in women. The aim of this study was to verify the sex-related, if any, GH response to GHRH (1 microgram/kg, i.v., as a bolus) both alone and preceded by two different doses of PD (120 mg, group A, and 60 mg, group B, given orally 60 min before GHRH) in a large group of volunteers (36 women, aged 18-35 yr, and 48 men, aged 18-35 yrs). In group A, 120 mg oral PD potentiated the GH response to GHRH in both men [area under the curve (AUC), 2579.3 +/- 264.5 vs. 806.2 +/- 99.7 micrograms/L.h; P < 0.00001] and women (AUC, 2273.2 +/- 248.7 vs. 792.6 +/- 72.7 micrograms/L.h; P < 0.00001). Similarly, in the group B, 60 mg oral PD potentiated the GH response to GHRH in both men (AUC, 1929.6 +/- 157.2 vs. 568.2 +/- 81.3 micrograms/L.h; P < 0.01) and in women (AUC, 1655.9 +/- 146.9 vs. 738.2 +/- 105.7 micrograms/L.h; P < 0.01). The GH responses to GHRH, both alone and after 120 and 60 mg oral PD, did not significantly differ in men and women. No sex-related difference was observed in the cholinergic side-effects (mild abdominal pain and muscle fasciculations) that occurred in nearly 30% of the subjects. In conclusion, our results clearly show that there is no sex-related difference in the potentiating effect of PD on GHRH-induced GH release, ruling out the suggestion that women have increased cholinergic activity, leading to reduced somatostatinergic tone.

In obesity, glucose load loses its early inhibitory, but maintains its late stimulatory, effect on somatotrope secretion.

Glucose load has a biphasic effect on GH secretion. In fact, in normal subjects, glucose load has a prompt inhibitory and a late stimulatory effect on both spontaneous and GHRH-induced GH levels. The mechanism underlying the inhibitory effect is probably mediated by the increase in hypothalamic somatostatin, whereas that underlying the stimulatory effect is unclear. On the other hand, in obesity, a reduced somatotrope responsiveness to all GH secretagogues is well known, whereas recently, we found that glucose load, but not pirenzepine and somatostatin, fails to inhibit the GHRH-induced GH rise. Thus, the inhibitory effect of hyperglycemia on GH secretion is selectively lacking in obesity. The aim of the present study was to verify whether in obesity the late stimulatory effect of glucose on GH secretion is preserved. We studied 15 female obese patients (OB; age, 33.9 +/- 2.6 yr; body mass index, 36.4 +/- 1.5 kg/m2; waist/hip ratio, 0.9 +/- 0.1) and 12 normal female subjects (NS; 26.5 +/- 1.0 yr; 21.4 +/- 0.3 kg/m2) as controls. Two studies were performed. In study A (six OB and six NS) we evaluated the somatotrope response to GHRH (1 microgram/kg, i.v., at 0 min) alone or preceded by oral glucose (OGTT; 100 g, orally, at -45 min). In study B (nine OB and six NS) we studied the somatotrope response to OGTT (100 g, orally, at 0 min), saline plus GHRH (1 microgram/kg, iv, at 150 min), and OGTT plus GHRH. In study A, the GHRH-induced GH rise in NS was higher (P < 0.01) than that in OB. OGTT blunted the GHRH-induced GH rise in NS (0-90 min area under the curve, 318.9 +/- 39.1 vs. 696.3 +/- 110.8 micrograms/min-L; P < 0.05), but failed to modify it in OB (289.1 +/- 51.7 vs. 283.9 +/- 44.0 micrograms/min-L). In study B, the GHRH-induced GH rise in NS was higher (P < 0.01) than that in OB. OGTT induced a late GH increase in both NS (150-240 min area under the curve, 249.6 +/- 45.2 micrograms/min-L) and OB (103.2 +/- 31.4 micrograms/min-L). Moreover, OGTT enhanced the GHRH-induced GH rise in NS as well as in OB [1433.0 +/- 202.0 vs. 967.9 +/- 116.3 micrograms/min-L (P < 0.03) and 763.8 +/- 131.0 vs. 278.1 +/- 52.3 micrograms/min-L (P < 0.01), respectively]. The GH responses to OGTT alone and combined with GHRH in OB were lower (P < 0.03) than those in NS. Our data show that in human obesity, the oral glucose load loses its precocious inhibitory effect on the GHRH-induced GH rise but maintains its late stimulatory effect on somatotrope secretion. These findings suggest that the inhibitory and stimulatory effects of glucose load on GH secretion are unlikely to be due to biphasic modulation of hypothalamic somatostatin release, which seems selectively refractory to stimulation by hyperglycemia in obesity.

Alpha-adrenoreceptor blockade with thymoxamine reduces basal thyrotrophin levels but does not influence circadian thyrotrophin changes in man.

We have tested the hypothesis that alpha-adrenergic drive is involved in the nocturnal increase in TSH in man. Seven mildly hypothyroid women (basal TSH levels 5.0-11.0 mU/l), aged 38-60 years, and nine euthyroid women, aged 27-60 years, were studied. Subjects underwent alpha-adrenergic blockade by infusion of thymoxamine (210 micrograms/min from 19.00 to 24.00 h); the same women were used as controls, with saline infused on different nights. Subjects were not allowed to sleep during the study period. A clear evening rise in basal TSH levels was apparent in both normal subjects and patients. Although overall secretion of TSH was slightly decreased in normal subjects (mean +/- S.E.M. area under the curve, 29.93 +/- 0.96 vs 30.71 +/- 0.80 mU/l per h; P less than 0.05), thymoxamine infusion did not produce any major alteration in the gradual rise in TSH levels during the evening (incremental change above baseline +0.96 +/- 0.21 during control infusion and +0.97 +/- 0.27 mU/l during thymoxamine infusion). In mildly hypothyroid patients the TSH changes were exaggerated and alpha-adrenergic blockade caused a reduction in basal TSH levels and a delayed rise in TSH (incremental change above baseline +2.93 +/- 1.42 during control infusion and +2.26 +/- 0.73 mU/l during thymoxamine infusion; P less than 0.02). Overall TSH secretion was significantly decreased by thymoxamine (mean +/- S.E.M. area 106 +/- 2.45 mU/l per h vs 123.32 +/- 3.68 in the control study; P less than 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of 15-day treatment with growth-hormone-releasing hormone alone or combined with different doses of arginine on the reduced somatotrope responsiveness to the neurohormone in normal aging.

It is well known that both spontaneous and growth hormone-releasing hormone (GHRH)-stimulated GH secretion undergo an age-related decrease; in addition, there is supportive evidence that the GH hyposecretory state of aging is of hypothalamic origin. The aims of the study in 35 normal elderly subjects (20 males and 15 females aged 65-89 years) were to verify whether the low somatotrope responsiveness to GHRH (1 microgram/kg) can be primed by a daily GHRH treatment and whether the potentiating effect of both high intravenous (0.5 g/kg) and low oral (8 g) doses of arginine (ARG) on GH response to GHRH is maintained with time. In group A (N = 14) the GH response to GHRH on day 1 (AUC: 373.5 +/- 78.5 micrograms.l-1.h-1) was unchanged after 7 (3720 +/- 38 micrograms.l-1.h-1) and 15 days (377.9 +/- 63.8 micrograms.l-1.h-1) of daily GHRH administration. In group B (N = 6) the GH response to GHRH co-administered with iv ARG on day 1 (1614.2 +/- 146.2 micrograms.l-1.h-1) was higher (p < 0.05) than that of GHRH alone (group A) and persisted unchanged after 7 (1514.7 +/- 366.5 micrograms.l-1.h-1) and 15 days (1631.7 +/- 379.1 micrograms.l-1.h-1) of treatment. In group C (N = 15) the GH response to GHRH co-administered with oral ARG on day 1 (950.6 +/- 219.4 micrograms.l-1.h-1) was higher (p < 0.03) than that of GHRH alone (group A) but lower (p < 0.05) than that to GHRH plus iv ARG (group B).(ABSTRACT TRUNCATED AT 250 WORDS)

Triiodothyronine administration reduces serum growth hormone levels and growth hormone responses to thyrotropin-releasing hormone in patients with anorexia nervosa.

The aim of this study was to test the hypothesis that low serum T3 concentrations may promote an abnormal growth hormone (GH) response to thyrotropin-releasing hormone (TRH) in patients with anorexia nervosa. Eight anorexic women and two anorexic men, ages 15-25 years, with low free T3 circulating levels (mean +/- SEM = 2.8 +/- 0.3 pmol/l) were studied. A TRH test (200 micrograms IV) was carried out under basal conditions and repeated following treatment with oral T3 (1.5 micrograms/kg BW/day) for eight days. Following T3 administration, GH levels dropped significantly from a baseline of 7.1 +/- 1.3 micrograms/l to 3.1 +/- 0.7 micrograms/l (p less than 0.02), as did GH peak responses to TRH (9.0 +/- 1.0 micrograms/l vs 4.4 +/- 0.8 micrograms/l, p less than 0.01). ANOVA and analysis of area under the curve (AUC) confirmed that after T3 treatment there was a significant reduction in TRH-induced GH release in these patients (GH AUC: 902 +/- 132 micrograms/l vs. 456 +/- 91 micrograms/l, p less than 0.02). TSH responses to TRH, which were normal prior to T3 treatment, completely disappeared following it, and PRL responses to TRH also were diminished. Although our experimental approach does not permit a conclusion that low T3 levels were the primary reason for these changes, the data support the theory that low T3 circulating levels may facilitate abnormal GH secretion and the GH-releasing activity of intravenous TRH.

Role of thyroglobulin measurement in fine-needle aspiration biopsies of cervical lymph nodes in patients with differentiated thyroid cancer.

The identification of metastatic neck lymph nodes in patients awaiting surgery for differentiated thyroid tumor permits their excision during thyroidectomy. In order to detect thyroid cancer lymphatic metastasis before surgery, we measured thyroglobulin (Tg) in the needle wash-out of fine-needle aspiration biopsy (FNAB). Ultrasound-guided FNAB on enlarged neck nodes was performed in 23 patients awaiting surgery for differentiated thyroid tumor (n = 33 lymph nodes), 47 patients previously thyroidectomized for thyroid tumor (n = 89 lymph nodes), and 60 patients without thyroid disease (n = 94 lymph nodes). Immediately after aspiration biopsy, the needle was rinsed with 1 mL of normal saline solution and Tg levels were measured on the needle wash-out (FNAB-Tg). FNAB-Tg levels were markedly elevated in metastatic lymph nodes both in patients awaiting thyroidectomy (metastatic vs. negative lymph nodes, mean +/- SEM, 16,593 +/- 7,050 ng/mL vs. 4.91 +/- 1.61 ng/mL; p < 0.001) and in thyroidectomized patients (11,541 +/- 7,283 ng/mL vs. 0.45 +/- 0.07 ng/mL; p < 0.001). FNAB-Tg sensitivity, evaluated through histological examination in 69 lymph nodes, was 84.0%. The combination of cytology plus FNAB-Tg increased FNAB sensitivity from 76% to 92.0%. In conclusion, FNAB-Tg measurement is a useful technique for early diagnosis of lymph node metastasis originating from differentiated thyroid cancer.

[Epidemiologic investigation on the prevalence of goiter and urinary excretion of iodine in the school population of the province of Reggio Emilia]. / Indagine epidemiologica sulla prevalenza del gozzo e sulla escrezione urinaria di iodio nella popolazione scolastica della provincia di Reggio Emilia.

The prevalence of goiter was evaluated in a sample from the schoolchildren population of Reggio Emilia district. 1020 children underwent physical examination of thyroid gland and thyroid ultrasonography for determination of thyroid volume. Urinary iodine excretion (UIE) was measured in 837/1020 (82.1%). Iodine content was measured in water samples collected from 65 wells and 12 springs all around the district. The prevalence of goiter according to thyroid gland palpation was 26.2%. Thyroid volume was 4.74 +/- 1.87 ml, and the median UIE value 85 micrograms/l. According to the UIE classes as defined by WHO, 57.8% of all subjects showed a UIE less than 100 micrograms/l. In 57 out of 65 wells and in all the 12 springs examined, iodine was completely absent. In the remaining 8 wells, only iodine traces were found. Based on the results of physical examination of the thyroid gland, Reggio Emilia district should be regarded as an endemic goiter area. Nevertheless, thyroid volume measurement by ultrasound indicates that goiter prevalence may be markedly overestimated by palpation. The high prevalence of subjects featuring an increased thyroid volume, the low median UIE value and the poor iodine content in the local reservoirs of drinkable water suggest the opportunity for iodine prophylaxis in the Reggio Emilia district.

Long-term efficacy of ultrasound-guided laser ablation for benign solid thyroid nodules. Results of a three-year multicenter prospective randomized trial.

BACKGROUND: The aim of the present trial on ultrasound (US)-guided laser ablation therapy (LAT) of solid thyroid nodules is to assess long-term clinical efficacy, side effects, and predictability of outcomes in different centers operating with the same procedure. PATIENTS: Two hundred consecutive patients were randomly assigned to a single LAT session (group 1, 101 cases) or to follow-up (group 2, 99 cases) at four thyroid referral centers. Entry criteria were: solid thyroid nodule with volume of 6-17 mL, repeat benign cytological findings, normal thyroid function, no autoimmunity, and no thyroid gland treatment. METHODS: Group 1: LAT was performed in a single session with two optical fibers, a 1064 nm Nd-YAG laser source, and an output power of 3 W. Volume and local symptom changes were evaluated 1, 6, 12, 24, and 36 months after LAT. Side effects and tolerability of treatment were registered. Group 2: Follow-up with no treatment. RESULTS: One patient was lost to follow-up in each group. Group 1: Volume decrease after LAT was -49 ± 22%, -59 ± 22%, -60 ± 24%, and -57 ± 25% at 6, 12, 24, and 36 months, respectively (P < .001 vs baseline). LAT resulted in a nodule reduction of >50% in 67.3% of cases (P < .001). Local symptoms decreased from 38 to 8% of cases (P = .002) and cosmetic signs from 72 to 16% of cases (P = .001). Baseline size, presence of goiter (P = .55), or US findings (fluid component ≤ 20% [P = .84], halo [P = .46], vascularization [P = .98], and calcifications [P = .06]) were not predictive factors of a volume decrease > 50%. The procedure was well tolerated in most (92%) cases. No changes in thyroid function or autoimmunity were observed. In group 2, nodule volume increased at 36 months (25 ± 42%; P = .04). The efficacy and tolerability of the procedure were similar in different centers. CONCLUSIONS: A single LAT treatment of solid nodules results in significant and persistent volume reduction and local symptom improvement, in the absence of thyroid function changes.

American Association of Clinical Endocrinologists, Associazione Medici Endocrinologi, and European Thyroid Association medical guidelines for clinical practice for the diagnosis and management of thyroid nodules.

American Association of Clinical Endocrinologists, Associazione Medici Endocrinologi, and European Thyroid Association medical guidelines for clinical practice for the diagnosis and management of thyroid nodules are systematically developed statements to assist health care professionals in medical decision making for specific clinical conditions. Most of the content herein is based on literature reviews. In areas of uncertainty, professional judgment was applied. These guidelines are a working document that reflects the state of the field at the time of publication. Because rapid changes in this area are expected, periodic revisions are inevitable. We encourage medical professionals to use this information in conjunction with their best clinical judgment. Any decision by practitioners to apply these guidelines must be made in light of local resources and individual patient circumstances.

American Association of Clinical Endocrinologists, Associazione Medici Endocrinologi, and European Thyroid Association medical guidelines for clinical practice for the diagnosis and management of thyroid nodules: executive summary of recommendations.

American Association of Clinical Endocrinologists, Associazione Medici Endocrinologi, and European Thyroid Association medical guidelines for clinical practice for the diagnosis and management of thyroid nodules are systematically developed statements to assist health care professionals in medical decision making for specific clinical conditions. Most of the content herein is based on literature reviews. In areas of uncertainty, professional judgment was applied. These guidelines are a working document that reflects the state of the field at the time of publication. Because rapid changes in this area are expected, periodic revisions are inevitable. We encourage medical professionals to use this information in conjunction with their best clinical judgment. Any decision by practitioners to apply these guidelines must be made in light of local resources and individual patient circumstances.