Role of contrast-enhanced ultrasound to define prognosis and predict response to biotherapy in pancreatic neuroendocrine tumors.

PURPOSE: The incidence of neuroendocrine tumors (NETs) is progressively increasing. Most cases arise from the digestive system, where ileum, rectum and pancreas represent the commonest site of origin. Liver metastases are frequently detected at diagnosis or during the follow-up. Contrast-enhanced ultrasound (CEUS) is used in patients with pancreatic NETs (P-NETs) and liver metastases from P-NET but its role has not been standardized. The aim of this retrospective study was to investigate CEUS in patients with P-NETs and liver metastases from P-NET both as prognostic factor and predictor of response to therapy with somatostatin analogues (SSAs). METHODS: CEUS was performed at the diagnosis of NET and 3, 6 and 12 months after the beginning of SSAs. CEUS pattern was compared with contrast-enhanced computed tomography (CT) pattern. RESULTS: There was a significant association between CEUS and CT pattern (X 2 = 79.0; p < 0.0001). A significant association was found between CEUS pattern and Ki-67 index (X 2 = 24.6; p < 0.0001). The hypervascular homogeneous CEUS typical pattern was associated with low tumor grading (G1 or G2) (X 2 = 24.0; p < 0.0001). CEUS pattern changed from hypervascular homogeneous in baseline to hypovascular/hypervascular inhomogeneous after SSA therapy, with a significant association between tumor response at CT scan and appearance of hypervascular inhomogeneous pattern at CEUS evaluation (6 months: X 2 = 57.0; p < 0.0001; 12 months: X 2 = 49.8; p < 0.0001). CONCLUSIONS: In patients with P-NET, CEUS pattern correlates with tumor grading, being homogeneous in G1-G2 but not in G3 tumors. After therapy with SSAs, CEUS is predictive of response to SSAs. These findings seem to support a role of CEUS as prognostic and predictive factor of response.

Delineating physiologic defensive reactivity in the domain of self-report: phenotypic and etiologic structure of dispositional fear.

BACKGROUND: Individual differences in fear and fearlessness have been investigated at their extremes in relation to markedly different forms of psychopathology--anxiety disorders and psychopathy, respectively. A documented neural substrate of fear-related traits and disorders is defensive reactivity as reflected in aversive startle potentiation (ASP). METHOD: The current study extended prior work by characterizing, in a sample of adult twins from the community (n = 2511), the phenotypic and etiologic structure of self-report measures of fear and fearlessness known to be associated with ASP. RESULTS: Analyses revealed a hierarchical structure to the trait fear domain, with an overarching, bipolar fear/fearlessness dimension saturating each measure in this domain, and subfactors labeled 'distress,' 'stimulation seeking' and 'sociability' accounting for additional variance in particular measures. The structure of genetic and non-shared environmental associations among the measures closely mirrored the phenotypic structure of the domain. CONCLUSIONS: The findings have implications for proposals to reconceptualize psychopathology in neurobiological terms.

Insulin-like growth factor (IGF)-I and IGF-binding protein-3 serum levels in relapsing-remitting and secondary progressive multiple sclerosis patients.

BACKGROUND: Insulin-like growth factor (IGF)-I has a role in remyelination, and insulin-like growth factor-binding protein-3 (IGFBP-3) might reduce its bioavailability. A role of IGFBP-3 in multiple sclerosis (MS) progression was hypothesized in patients with primary progressive (PP) MS. OBJECTIVE: To evaluate serum levels of IGF-I and IGFBP-3 in patients with relapsing-remitting (RR) and secondary progressive (SP) MS and their correlations with disease activity and progression. METHODS: Sixty-three (41 RR and 22 SP) 'naive' MS patients and 60 age-matched healthy controls were enrolled. Patients were assessed through clinical [Expanded Disability Status Scale (EDSS), Multiple Sclerosis Severity Scale (MSSS), number of relapses] and laboratory investigations. IGF-I and IGFBP-3 were measured by ELISA. RESULTS: Levels of IGF-I and IGFBP-3 were similar in the two MS groups. IGFBP-3 levels were higher in patients with MS than in controls (P < 0.001), with a reduction in IGF-I/BP3 ratio (P < 0.001). Patients showing IGFBP-3 levels higher than 2SD of the normal population had a higher EDSS (mean EDSS 3.7 vs. 2.8, P = 0.021). MSSS was not related to IGF-I or IGFBP-3 serum levels. CONCLUSIONS: Our patients showed high IGFBP-3 serum levels respect to controls and higher serum levels were associated with a higher EDSS, despite of comparable disease duration. Therefore, MS and higher disability seem to be associated with a reduction in bioavailability of IGF-I. MSSS score was not related to IGFBP-3 levels, suggesting that IGFBP-3 might not have the pathogenetic role previously suggested for PP MS, in the mechanism of progression in the SP form of disease.

Vitamin D status may contribute to serum insulin-like growth factor I concentrations in healthy subjects.

OBJECTIVE: The aim of the study was to evaluate whether vitamin D [25-(OH) D3] status affects serum IGFI concentrations in healthy subjects. DESIGN AND PATIENTS: Two hundred and forty-one consecutive healthy subjects were included in the present study. MEASUREMENTS: Serum IGF-I and 25-(OH) D3 concentrations. RESULTS: As expected, serum IGF-I concentrations progressively decreased with age (r=-0.55, p<0.0001); on the contrary, gender was not related to serum IGF-I levels. A positive relationship was identified between serum 25-(OH) D3 and IGF-I concentrations (r=0.33, p<0.0001); the 25-(OH) D3-dependent changes of serum IGF-I concentrations were observed also when subjects were divided on the basis of vitamin D deficiency; in fact, those with severe 25-(OH) D3 deficiency (<20 ng/ml) had lower (185 ± 83 µg/l) IGF-I values than those with mild-to absent 25-(OH) D3 deficit (225 ± 83 µg/l, p=0.0004). CONCLUSIONS: 25-(OH) D3 status may contribute to determine serum IGF-I levels in healthy population.

Pituitary autoimmunity is associated with hypopituitarism in patients with primary empty sella.

OBJECTIVE: Some evidence suggests that late stage autoimmune hypophysitis (AH) may result in empty sella (ES). Aim of the study was to assess the prevalence of serum pituitary antibodies (PitAb) and their correlation with pituitary function in patients with ES. DESIGN: In this casecontrol study 85 patients with primary ES, 16 patients with ES secondary to head trauma, 214 healthy controls, and 16 AH were enrolled in a tertiary referral center. METHODS: PitAb were assessed in all cases and controls. Endocrine function was assessed by basal hormone measurement and dynamic testing in all ES cases. RESULTS: PitAb prevalence was higher in primary ES (6%) than in healthy subjects (0.5% p=0.003) and lower than in AH patients (50%, p<0.0001). PitAb were not found in patients with secondary ES. Hypopituitarism was found in 49% of primary ES and in 62% of secondary ES (p=0.34). A positive correlation between the presence of PitAb and hypopituitarism was found in primary ES (p=0.02). CONCLUSIONS: The significant association between pituitary autoimmunity and hypopituitarism suggests that ES, in selected cases, could be the final result of AH.

Growth hormone/insulin-like growth factor I axis in neurodegenerative diseases.

Neurodegenerative diseases (ND) are a group of heterogeneous disorders characterized by unknown etiology, subtle onset, and progressive involvement of neuronal systems leading to degeneration and dysfunction. They represent a challenge for basic science and clinical medicine because of increasing prevalence, social cost, complex biochemistry and pathology, and lack of mechanism-based treatments. Endocrine modifications may accompany the progression of ND, due to the intimate connections between central nervous and endocrine systems. Reported data on endocrine changes in different ND have often been non-conclusive or conflicting. GH/IGF-I axis is involved in the regulation of brain growth, development, and metabolism. Dysfunctions in GH/IGF-I axis in most of ND are therefore reviewed. Whether GH deficiency, when present, may act as a contributory factor in the pathogenesis of these diseases, or might represent a consequence of it is presently unknown. A thorough effort in investigating every possible involvement of GH/IGF-I axis is warranted, in the light of future possible therapeutic strategies.

Short- and long-term changes of quality of life in patients with acromegaly: results from a prospective study.

Quality of life (QoL) may be affected in acromegalic patients, although the role of disease activity is still unsettled. The aim of the study was to assess the QoL of acromegalic patients with a specific questionnaire (ACROQOL). ACROQOL was evaluated in a prospective study (at baseline, at 6 and 24 months) in 23 active untreated acromegalic patients. Control of acromegaly was defined by normal age-matched serum IGF-I concentrations. Patient groups were defined as controlled or uncontrolled at 6 months and at 24 months: controlled or uncontrolled during the entire study period (ACRO(CC) or ACRO(NC), respectively) or uncontrolled at 6 months and controlled thereafter (ACRO(C)). At 6 months, ACROQOL scores improved globally (from 54.3+/-21 to 65.1+/-19, p=0.04) as did subdomains and were inversely related to IGF-I variation (r=-0.50, p=0.052). At 24 months, ACROQOL improved globally (from 54.3+/-21 to 65.7+/-18.0, p=0.04) and this was also seen in the appearance subdomains; however, no correlation was revealed between variation of serum IGF-I concentrations and changes in ACROQOL total score (r=0.008, p=0.87). ACROQOL scores did not significantly change in ACRO(NC) (p=0.310) and in ACRO(C) (p=0.583), whereas it improved globally (from 42.1+/-22.1 to 58.8+/-16.04, p=0.021) and in psychological subdomains in ACRO(CC); however, it reflected the improvement occurred within the first 6 months of disease control. In conclusion, successful treatment, which normalizes disease activity, improves QoL in acromegaly in the short term. However, the lack of correlation between the ACROQOL score in the long term might suggest that factors other than serum IGF-I participate in the well-being of acromegalic patients; however, due to the small sample size, our results need to be confirmed in larger studies.

Clinical aspects and therapeutic outcome in thyrotropin-secreting pituitary adenomas: a single center experience.

BACKGROUND AND AIM: The management of pituitary adenomas secreting TSH has evolved considerably over the last decades.We report the clinical features, management, and outcome of a large monocentric series. MATERIAL AND METHODS: A monocentric retrospective cohort of 26 patients admitted to our Department of Endocrinology between 1983 and 2007, followed for a period up to 204 months. The diagnosis of TSH-secreting adenoma was based on clinical and biochemical findings of central hyperthyroidism. Evaluation of basal and dynamic pituitary function, magnetic resonance imaging or computerized tomography scan were performed in all patients. Twenty-two patients, of whom 15 pre-treated by somatostatin analogs (SSA), underwent trans-sphenoidal surgery and were regularly re-evaluated. RESULTS: The number of cases increased over the years. Age at diagnosis, micro- to macroadenoma ratio, and mean estimated latency between first symptoms and diagnosis did not appreciably change over time. Latency was significantly shorter in macroadenomas. Following surgery, 55% of patients obtained remission (success rate of 40 and 67% in macro- and microadenomas, respectively). SSA pre-treatment led to an apparent although not statistically- significant increase in success rate in micro- but not in macroadenomas. CONCLUSIONS: In a monocentric group of 26 TSH-secreting adenomas the high ratio between micro- and macroadenomas remained stable over time with a significantly shorter diagnosis latency in macroadenomas. A more precocious recognition of the tumors and possibly the use of presurgical SSA allowed a high remission rate. A varied combination of neurosurgery, SSA, radiotherapy, and thyroid ablation led to the control of the disease in all the patients studied.

Acceptance and commitment therapy as an adjunct to the MOVE! programme: a randomized controlled trial.

OBJECTIVE: The current study tested the efficacy of an acceptance and commitment therapy (ACT) group intervention for disinhibited eating behaviour as an adjunct to the Veterans Affairs MOVE!© weight management programme. METHODS: Veterans (N = 88) with overweight or obesity who completed the MOVE! weight management programme and self-identified as having problems with 'stress-related eating' were randomized to four 2-h weekly ACT sessions or a continued behavioural weight-loss (BWL) intervention. Assessments were completed at baseline, post-treatment and 3- and 6-month follow-up on outcomes of interest including measures of disinhibited eating patterns, obesity-related quality of life, weight-related experiential avoidance and weight. RESULTS: The BWL group exhibited significantly greater reductions in binge eating behaviour at post-treatment compared with the ACT group. Significant improvements in other outcomes were found with minimal differences between groups. In both groups, decreases in weight-related experiential avoidance were related to improvements in binge eating behaviour. CONCLUSIONS: Taken together, the continued BWL intervention resulted in larger improvements in binge eating behaviour than the ACT intervention. The two groups showed similar improvements in other disinhibited eating outcomes. Future studies are encouraged to determine if more integrated or longer duration of ACT treatment may maximize eating outcomes in MOVE.Trial Registration Number: This trial was registered with ClinicalTrials.gov database (NCT01757847).

Dopamine D2 receptor gene polymorphisms and response to cabergoline therapy in patients with prolactin-secreting pituitary adenomas.

Dopamine-agonist cabergoline (CB) reduces prolactin (PRL) secretion and tumor size in 80% of patients with prolactin-secreting adenomas (PRL-omas) by binding type 2 dopamine receptor (DRD2). The mechanisms responsible for resistance to CB remain largely unknown. To assess the association of DRD2 with sensitivity to CB, TaqI-A1/A2, TaqI-B1/B2, HphI-G/T and NcoI-C/T genotypes were determined in a cross-sectional retrospective study, including 203 patients with PRL-oma. DRD2 alleles frequencies did not differ between patients and 212 healthy subjects. Conversely, NcoI-T allele frequency was higher in resistant rather than responsive patients, considering both PRL normalization (56.6 vs 45.3%, P=0.038) and tumor shrinkage (70.4 vs 41.4%, P=0.006). Finally, [TaqI A1-/TaqI B1-/HphI T-/NcoI T-] haplotype was found in 34.5% of patients normalizing PRL with < or =3 mg/week of CB vs 11.3% of resistants (P=0.021). In conclusion, resistance to CB was associated with DRD2 NcoI-T+ allele, consistent with evidence suggesting that this variant may lead to reduction and instability of DRD2 mRNA or protein.

Primary hyperparathyroidism is associated with marked impairment of GH response to acylated ghrelin.

BACKGROUND: Impaired GH secretion is a common finding in patients with primary hyperparathyroidism (PHP). Ghrelin displays strong GH-releasing action, mainly at the hypothalamic level. OBJECTIVE: To evaluate secretory response of GH to ghrelin in PHP patients. PATIENTS: Fifteen patients [11 women/4 men, mean age 54 years, range 32-70 years, body mass index (BMI) 25.0 +/- 0.7 kg/m(2)] affected with PHP due to single parathyroid adenoma and 35 normal age-matched subjects (23 women/12 men, mean age 58 years, range 35-68 years, BMI 24.1 +/- 1.1 kg/m(2)). METHODS: A measure of 1 microg/kg body weight i.v. acylated ghrelin or 1 microg/kg body weight i.v. GH releasing hormone (GHRH) followed by 0.5 g/kg body weight i.v. arginine (ARG) hydrochloride were administered to all subjects on alternate days in order to evaluate GH response. RESULTS: Mean serum GH peak after GHRH + ARG was 32.6 +/- 7.8 and 17.4 +/- 4.0 microg/l, in controls and PHP patients, respectively (P < 0.05). Mean serum GH peak after ghrelin was 70.4 +/- 31.5 and 16.8 +/- 1.9 microg/l, in controls and PHP patients, respectively, (P < 0.001). Using ROC curves, a serum GH peak > 22 microg/l after ghrelin stimulation might be considered as a cut-off value for identifying normal subjects. Ten (67%) PHP patients have impaired GH response to GHRH + ARG and 13 (87%) to ghrelin. Serum GH peak after ghrelin or GHRH + ARG was unrelated to serum IGF-1, PTH or ionized calcium concentrations. CONCLUSIONS: The present data confirm that GH secretion is impaired in PHP patients using the potent GH secretagogue ghrelin and suggest that impaired GH secretion is likely due to a deleterious effect of hypercalcaemia at the hypothalamic level in PHP patients.

Adrenal morpho-functional alterations in patients with acromegaly.

Acromegaly is associated with a greater morbidity and higher incidence of tumors, possibly due to the permissive role of elevated GH and IGF-I levels. In the general population, adrenal masses are frequently discovered (prevalence 1-5%) at computed tomography (CT). We evaluated the prevalence of adrenal lesions in patients with acromegaly. We studied 94 acromegalic patients, 54 females (mean age 55.0+/-16.0 yr) and 40 males (mean age 50+/-14 yr) referred to 5 Endocrinology Units between 2001-2003; 49 had active disease and 45 had been treated with surgery and/or were controlled with medical therapy. Abdominal CT showed adrenal lesions in 27 patients; 9 of them had unilateral masses (10%) with benign features (diameter 0.5-3 cm) and 18 had hyperplasia (14 monolateral and 4 bilateral), with no significant differences between patients with active vs controlled disease, and with no correlation between prevalence of masses and duration of disease, GH and IGF-I levels. Hormone study (urinary free cortisol, catecholamines/metanephrines, upright plasma renin activity and aldosterone, morning plasma ACTH and low-dose dexamethasone suppression test) disclosed no major endocrine alterations. During a 1-yr follow-up, the adrenal masses increased in size in 3 cases and 1 patient also developed subclinical Cushing's syndrome. Adrenal lesions seem more frequent in acromegaly than in the general population, but no single factor (GH/IGF-I levels or disease duration) predicts them. The masses appear to be benign and nonhypersecreting, but a longer follow-up is recommended to disclose any changes in their morphofunctional state.

Potassium perchlorate only temporarily restores euthyroidism in patients with amiodarone-induced hypothyroidism who continue amiodarone therapy.

CONTEXT: Amiodarone-induced hypothyroidism (AIH) may occur in patients with or without underlying thyroid disorders. In the latter, restoration of euthyroidism, after amiodarone discontinuation, can be facilitated and accelerated by a short course of potassium perchlorate (KClO4). However, it is unknown whether KClO4 may exert similar effects on thyroid function of AIH patients if amiodarone treatment is continued. OBJECTIVE: To evaluate the effects of KClO4 on thyroid function in AIH patients (without underlying thyroid disease) while continuing amiodarone treatment. DESIGN AND PATIENTS: An open, prospective study of 10 consecutive AIH patients without underlying thyroid abnormalities referred to a tertiary referral center, and treated with KClO4 (600 mg/day) for a period of 26+/-13 days (range, 15-45 days). An additional, historical group of 12 consecutive patients with subclinical AIH left untreated while continuing or after withdrawing amiodarone was retrospectively evaluated as to the outcome of thyroid function. MEASUREMENT: Serum free T4, free T3, and TSH concentrations were measured at booking, during KClO4 treatment and after withdrawing the drug. RESULTS: In the prospective study, KClO4 treatment restored euthyroidism in all patients within 28+/-11 days (range, 15-45 days). After KClO4 withdrawal, however, all patients became hypothyroid again after 45+/-15 days (range, 30-60 days). Two patients developed mild leukopenia (1 case) or a slight increase in serum creatinine levels (1 case), which promptly normalized after KClO4 withdrawal. In the historical group, followed for at least 12 months, euthyroidism was spontaneously and stably achieved after an average of 6 months in 5 patients in whom amiodarone could be discontinued, while subclinical hypothyroidism persisted in 7 patients in whom amiodarone had to be continued. CONCLUSIONS: KClO4 very effectively restores normal thyroid function in AIH patients without underlying thyroid abnormalities, despite the fact that amiodarone therapy is continued. However, euthyroidism does not persist after KClO4 is withdrawn; in addition, spontaneous recovery of euthyroidism does not seem to occur in this subset of AIH patients, unless amiodarone is discontinued. Therefore, also in view of its potential side-effects, KClO4 cannot be recommended as a first-line treatment for AIH if amiodarone needs to be continued, while LT4 replacement is recommended under these circumstances, with periodical reassessment of thyroid function.

Impairment of GH secretion in amyotrophic lateral sclerosis is not affected by riluzole treatment.

Amyotrophic lateral sclerosis (ALS), the most common motor neurone disorder in human adults, is characterized by selective and progressive degeneration of upper and lower motor neurones in the central nervous system. The main currently available drug for ALS treatment is riluzole, a compound that acts through inhibition of glutamate release, postsynaptic receptor activation, and voltage-sensitive channel inhibition. GH secretion, evaluated by GHRH+arginine (ARG) test, has recently been reported to be impaired in most untreated ALS patients. The aim of the present study was to evaluate whether riluzole administration could interfere with GH secretion and therefore with the diagnosis of adult GH deficiency. Ten patients (6 males, 4 females, mean age 59+/-11 yr) were studied performing GHRH+ARG test before and 3 months after starting riluzole treatment (100 mg/day). Blood samples for GH were collected at baseline, at 30 and 60 min. Both before and during riluzole treatment, 5 patients showed GH deficiency and 5 patients had a normal GH response according to body mass index (BMI). Mean peak GH levels were similar before and during riluzole treatment (13.4+/-10 vs 14.2+/-10.1 microg/l, p=ns). No significant correlation was observed between GH concentrations and age, BMI, disease duration, severity or clinical (bulbar/spinal) form. In conclusion, the present data confirm that GH secretion is impaired in a new series of ALS patients and indicate that riluzole treatment does not interfere with GH secretion. Thus, evaluation of GH secretion in ALS patients can also be performed without withdrawing riluzole treatment.

Kinetics of the T-cell receptor CD4 and CD8 V beta repertoire in HIV-1 vertically infected infants early treated with HAART.

OBJECTIVES: To determine the kinetics and the relationship between the T-cell receptor V beta (TCRBV) complementary determining region 3 length, the CD4 T-cell count and HIV viral load changes in HIV-1 infected infants treated early with highly active antiretroviral therapy (HAART) during 1 year of follow-up. DESIGN: Two HIV-1 vertically infected infants, two HIV-1 vertically exposed uninfected and two healthy controls were analysed by spectratyping. Evaluation of viral load, CD4 naive and memory cell counts and a proliferation test were also carried out. METHODS: Twenty-six families and subfamilies of the TCR on CD4 and CD8 T cells were analyzed by spectratyping. Flow cytometric analysis on peripheral blood mononuclear cells for CD4CD45Ra, CD4CD45Ro, CD8CD38, proliferation tests and plasma viral load measurements were performed at baseline, 1, 6 and after 12 months of therapy. RESULTS: HAART induced a marked reduction of viral load in both HIV-1 infected infants and an increase to normal CD4 T-cell count in the symptomatic infant. At baseline the TCRBV family distribution in the majority of CD8 and a few of the CD4 T cells was highly perturbed, with several TCRBV families showing a monoclonal/oligoclonal distribution. During HAART a normalization of the TCR repertoire in both CD8 and CD4 subsets occurred. TCR repertoire normalization was associated with a good virological and immunological response. CONCLUSION: These results suggest that complete and early virus replication control as a result of early HAART leads to a marked reduction of T-cell oligoclonality and is an essential prerequisite to the development of a polyclonal immune response in HIV-1 infected infants.

Low dose hexarelin and growth hormone (GH)-releasing hormone as a diagnostic tool for the diagnosis of GH deficiency in adults: comparison with insulin-induced hypoglycemia test.

GH deficiency (GHD) in adults must be shown by provocative testing of GH secretion. Insulin-induced hypoglycemia (ITT) is the test of choice, and severe GHD, treated with recombinant human GH replacement, is defined by a GH peak response to ITT of less than 3 microg/L. GHRH plus arginine (ARG) is a more provocative test and is as sensitive as ITT provided that appropriate cut-off limits are assumed. GH secretagogues are a family of peptidyl and nonpeptidyl GH-releasing molecules that strongly stimulate GH secretion and, even at low doses, truly synergize with GHRH. Our aim was to verify the diagnostic reliability of the hexarelin (HEX; 0.25 microg/kg, iv) and GHRH (1 microg/kg, iv) test for the diagnosis of adult GHD. To this goal, in the present study we 1) defined the normal ranges of the GH response to GHRH+HEX in a group of normal young adult volunteers (NS; n = 25; 18 men and 7 women; age, 28.5+/-0.6 yr) and in 11 of them verified its reproducibility in a second session, and 2) compared the GH response to GHRH+HEXwith that to ITT in a group of normal subjects (n = 33; 12 men and 21 women; age, 34.1+/-1.5 yr) and hypopituitaric adults with GHD (n = 19; 10 men and 9 women; age, 39.9+/-2.2 yr; GH peak <5 microg/L after ITT). The GH response to GHRH+ARG was also evaluated in all GHD and in 77 normal subjects (40 men and 37 women; age, 28.1+/-0.6 yr). The mean GH peak after GHRH+HEX in NS was 83.6+/-4.5 microg/L; the third and first percentile limits of the normal GH response were 55.5 and 51.2 microg/L, respectively). The GH response to GHRH+HEX in NS showed good intraindividual reproducibility. In GHD the mean GH peak after GHRH+HEX (2.6+/-0.7 microg/L) was similar to that after GHRH+ARG (3.6+/-1.0 microg/L), and both were higher (P < 0.001) than that after ITT (0.6+/-0.1 microg/L); the GH responses to GHRH+HEX were positively associated with those to ITT and GHRH+ARG. Analyzing individual GH responses, 100% had severe GHD after ITT (GH peak, <3 microg/L). After GHRH+HEX all GHD had GH peaks below the third percentile limit of normality appropriate for this test (i.e. 55.5 microg/L). Thirteen of 19 (68.4%) GHD subjects had GH peaks below 3 microg/L after GHRH+HEX but all 19 (100%) had GH peaks below the first percentile limit of normality (i.e. 51.2 microg/L). The GH responses to GHRH+HEX were highly concordant with those after GHRH+ARG. In conclusion, the present results define normal limits of the GH response to stimulation with low dose HEX+GHRH in normal adults and show that this test is as sensitive as ITT for the diagnosis of adult GHD provided that appropriate cut-off limits are considered.

GH secretion is impaired in patients with primary hyperparathyroidism.

The activity of the GH/IGF-I axis as a function of parathyroid activity and calcium metabolism in humans has never been assessed. To address this issue, we studied 18 patients (5 men, 13 women; age range, 23-76 yr; mean, 61 yr) with primary hyperparathyroidism (PHP) due to solitary parathyroid adenoma. GH secretion was evaluated by serum IGF-I levels, spontaneous mean GH secretion over two morning hours, and GH response to arginine (ARG) alone or combined with GHRH. In five patients, serum GH concentrations were measured every 20 min for 24 h, and deconvolution analysis was performed. A group of 35 age- and sex-matched normal subjects served as controls. Mean serum IGF-I levels in PHP were lower than in normal controls, and in six PHP patients individual serum IGF-I levels were below the age-related normal range. The mean (+/-SE) peak GH response to ARG alone in PHP patients was significantly lower than in normal subjects (4.0 +/- 1.0 vs. 22.0 +/- 1.3 microg/liter; P < 0.001). Likewise, the mean (+/-SE) peak GH response to ARG plus GHRH was reduced in PHP patients (9.9 +/- 0.9 vs. 38.0 +/- 3.5 microg/liter; P < 0.001). The mean GH concentration over two morning hours in PHP was lower (0.20 +/- 0.05 vs. 1.34 +/- 0.31 microg/liter; P < 0.001). The mean GH concentration over 24 h in five PHP patients was lower than in six normal controls (0.3 +/- 0.1 vs. 0.7+/- 0.1 microg/liter; P < 0.05); the deconvolution analysis showed that 24-h GH production rate (3.0 +/- 1.7 vs. 28.2 +/- 4.7 microg/liter.d; P < 0.05) and mean secretory burst mass (1.2 +/- 0.7 vs. 10.5 +/- 2.6 microg/liter; P < 0.05), but not pulse frequency, were lower in PHP patients than in normal controls. GH half-life and approximate entropy values of 24-h GH profiles were similar in PHP patients and normal controls. No correlation was found between serum-ionized calcium or PTH levels and spontaneous or stimulated GH levels in PHP patients. In conclusion, this study demonstrates that PHP patients have a reduction in both spontaneous and stimulated GH secretion. Accordingly, PHP should be mentioned as a further example of a metabolic condition in which GH secretion in adults is reduced.

Testicular function in patients with differentiated thyroid carcinoma treated with radioiodine.

UNLABELLED: The aim of the present study was to assess whether 131I therapy for differentiated thyroid carcinoma (DTC) can affect endocrine testicular function. METHODS: Serum follicle-stimulating hormone (FSH) and testosterone (T) concentrations were measured in 103 patients periodically submitted for radioiodine therapy for residual or metastatic disease. Mean follow-up was 93.7 +/- 54 mo (range 10-243 mo). RESULTS: Mean FSH values in 131I-treated patients tested after their last treatment were 15.3 +/- 9.9 mU/ml, significantly higher than those of 19 untreated patients (6.5 +/- 3.1 mU/ml). Considering the mean +3 s.d. FSH of untreated subjects as the upper limit of normal range, 36.8% of the patients had an abnormal increase in serum FSH. Longitudinal analysis performed in 21 patients showed that the behavior of FSH in response to 131I therapy was not universal. Six patients had no change or a slight increase in serum FSH after 131I administration; eleven patients had a transient increase above normal values 6-12 mo after 131I treatment, with return to normal levels in subsequent months. The administration of a second dose was followed by a similar increase in FSH levels. Finally, four patients, followed for a long period of time and treated with several 131I doses, showed a progressive increase in serum FSH, which eventually became permanent. Semen analysis, performed in a small subgroup of patients, showed a consistent reduction in the number of normokinetic sperm. No change was found in serum T levels between treated and untreated patients. CONCLUSIONS: Our results indicate that 131I therapy for thyroid carcinoma is associated with transient impairment of testicular germinal cell function. The damage may become permanent for high-radiation activities delivered year after year and might pose a significant risk of infertility.

Radiation dose to the testes after 131I therapy for ablation of postsurgical thyroid remnants in patients with differentiated thyroid cancer.

UNLABELLED: Radioiodine-131 is used in differentiated thyroid cancer (DTC) for ablation of postsurgical thyroid remnants and destruction of metastases. The question may be raised of whether 131I treatment of DTC in male patients may give an irradiation dose to the testes that could impair fertility. Few data in the literature concern the dose absorbed by the testes after 1311 therapy for DTC. Because 131I kinetics may be altered by the hypothyroid condition commonly present at the time of treatment and by the radioiodinated iodoproteins released by the damaged thyroid tissue, the dose values reported in the International Commission on Radiological Protection (ICRP) tables for euthyroid men may not be appropriate. To clarify this problem, three male subjects undergoing 131I therapy for ablation of thyroid remnants shortly after thyroidectomy for DTC were studied. METHODS: The mean administered activity was 1256 MBq, and the duration of the study was 2 wk. The gamma dose was measured by thermoluminescent dosimeters (TLDs) applied to the lower poles of the testes. Correction factors were calculated for the distance of the TLD from the center of the testes and for attenuation by the testes of the gamma rays reaching the TLD. After correction, the gamma dose to the testes ranged from 21 to 29 mGy. The gamma dose calculated by the Medical Internal Radiation Dose (MIRD) method from blood and urine samples was similar (18-20 mGy) to that measured by TLDs. The beta dose was estimated by the MIRD method from blood activity and testicular volume and ranged between 14 and 31 mGy. RESULTS: The total (beta and gamma) doses to testes were 30, 33 and 43 microGy/MBq in the three subjects. CONCLUSION: These values are close to those derived from the ICRP tables (26-37 microGy/MBq 131I) for euthyroid subjects. The present data indicate that significant irradiation is delivered to the testes after the administration of the 131I ablative dose to thyroidectomized patients. The relevance of the radiation absorbed by testes on fertility remains to be established.