Ettore degli Uberti

There is increasing evidence that the abdominal obesity phenotype may be associated with multiple alterations of the hypothalamic-pituitary-adrenocortical (HPA) axis activity in both sexes. Our hypothesis is that the lack of adequate cortisol suppression after the dexamethasone test may constitute an indirect marker of HPA axis hyperactivity in the presence of the abdominal obesity phenotype. A total of 34 normal-weight (13 men and 21 women) and 87 obese (36 men and 51 women), healthy, nondepressed subjects therefore underwent four different dexamethasone suppression tests randomly performed at varying intervals of at least 1 wk between each test. After a standard overnight 1-mg dexamethasone test, which served as a reference, three other tests were randomly performed at 1-wk intervals by administering 0.0035, 0.0070, and 0.015 mg oral dexamethasone per kilogram of body weight overnight. Blood samples were obtained for cortisol, ACTH, and dexamethasone. Results were analyzed separately in men and women as well as in normal-weight [body mass index (BMI) < or = 25 kg/m(2)] and overweight or obese (BMI > 25 kg/m(2)) subjects. The waist circumference and the waist to hip ratio (WHR) were used as markers of body fat distribution. After the standard 1-mg test, cortisol suppression was greater than 90% in all subjects. However, after each test, obese women had significantly higher values of percent cortisol and percent ACTH suppression than normal-weight women without any difference between obese and normal-weight men. Considering the response to the three variable-dose tests, a clear dose- response pattern (P < 0.001 for trend analysis) in percent cortisol and percent ACTH suppression was found in all subjects. After each test men had significantly higher dexamethasone levels than women, regardless of BMI. However, obese women, but not men, had significantly higher dexamethasone levels after each test than their normal-weight counterpart. Plasma dexamethasone concentrations were dose related (P < 0.001 for trend analysis) in all subjects, but the dose-related increase was significantly higher in normal-weight men than normal-weight women, whereas it was similar in obese subjects of both sexes. Stepwise multiple regression analysis revealed that both percent cortisol and percent ACTH variations were significantly and negatively influenced by dexamethasone levels, as well as by waist circumference values in men, and independently by BMI and waist circumference in women. However, in contrast to what has been found in men, a divergent contribution of BMI and waist circumference was found in women indicating that, with increasing waist values, a smaller suppression of the HPA axis was found with respect to that expected on the basis of BMI values. In conclusion, this study provides data of both physiological and physiopathological relevance. Overall, our data indicated that adjustment of the dexamethasone dose to body weight does not seem to substantially improve the sensitivity of the test, even in obese individuals, particularly when near-maximal doses are administered. However, this study demonstrated a highly significant effect of dexamethasone blood level concentrations on cortisol and ACTH suppression to low-dose dexamethasone tests. In addition, a significant effect of gender on postdexamethasone cortisol concentrations, suppression of the HPA axis, and dexamethasone levels were found, which may be dependent on related differences in both cortisol and dexamethasone metabolism. We showed that pituitary sensitivity to feedback inhibition by dexamethasone is preserved in obesity in both sexes even at low dosages. On the other hand, our data suggest that, at least in women, abdominal fat distribution may partially counteract the progressively greater suppressibility of the HPA axis that would be expected according to increasing BMI.

Somatostatin (SRIF) analogs interacting with SRIF receptor (SSTR) subtypes SSTR2 and SSTR5 reduce hormone secretion of pituitary adenomas, but their antiproliferative effects are still controversial. We investigated the in vitro effects of SRIF and SSTR-selective agonists interacting with SSTR1 (BIM-23926), SSTR2 (BIM-23120), SSTR5 (BIM-23206), or both SSTR2 and SSTR5 (BIM-23244) on alpha-subunit and chromogranin A secretion and on cell viability of 12 nonfunctioning pituitary adenomas (NFA) expressing SSTR1, SSTR2, and SSTR5, as assessed by RT-PCR. Treatment with SRIF or BIM-23206 did not modify alpha-subunit and chromogranin A secretion, which was significantly inhibited by BIM-23926, BIM-23120, and BIM-23244. SRIF and BIM-23120 did not influence cell viability, which was significantly promoted by BIM-23206 and BIM-23244 and reduced by treatment with BIM-23926. These results demonstrate that, in the selected NFA, the SSTR1-selective agonist inhibits secretory activity and cell viability, the SSTR2-selective agonist inhibits secretion but not cell viability, and the SSTR5-selective agonist does not influence secretion but promotes cell viability. These data can explain the lack of inhibitory effects of currently used SRIF analogs and suggest that drugs acting potently and preferentially on SSTR1 might be useful for medical treatment of NFA.

The effects of somatostatin, or somatotropin release-inhibiting factor (SRIF), and SRIF analogs in human diseases have been widely investigated to potentially expand the therapeutic applications of commercially available and newly designed compounds belonging to this class of agents. Several preclinical studies and clinical trials have demonstrated the antiproliferative and antisecretory effects of SRIF and its analogs. This review discusses results from studies investigating the secretory activity and cell viability of SRIF analogs, and the potential of new therapeutic applications of these drugs in endocrine diseases and, in particular, as a treatment for endocrine neoplasia.

It has recently been noted that peripheral nerve fibres are involved in the course of chronic liver disease. The existence of hepatic polyneuropathy is still a matter of debate. A series of 29 subjects (not including diabetics or alcoholics) were examined clinically and electromyographically. Signs of distal lower extremity polyneuritis (paresthesia, hypoesthesia and osteotendinous hypo-areflexia) were noted in 31%. Latent neuropathy was observed in the form of slow maximum and minimum motor conduction rates in clinically unimpaired nerves. Electromyographical alterations were more evident in subjects with frankly chronic as opposed to barely chronic liver disease.

Hashimoto's thyroiditis (HT) is a very common autoimmune disease of the thyroid. In addition to genetic background, several viruses, including herpesviruses, have been suggested to play a role as possible environmental triggers of disease, but conclusive data are still lacking. Previous results showed that HT patients have an increased cellular immune response directed against the HHV-6 U94 protein and increased NK activity directed against HHV-6 infected thyrocytes.In this study, we characterized the antiviral antibody response and the NK cells activity and subtype in HHV-6 infected HT patients. The results showed that HT subjects have increased prevalence and titer of anti-U94 antibodies and a higher amount of CD3-CD56(bright)CD16(-)NK cell percentages compared to controls. Furthermore, the cell activation of CD3(-)CD56(bright) NK cells in HT patients significantly correlates with TPO and Tg Ab levels.The results suggest that HHV-6 might contribute to HT development, increasing NK cell secretion of inflammatory cytokines that could sustain the persistence of an inflammatory status in HT patients.

Diagnostic protocols for acromegaly have evolved over time reflecting the refinement of assays for the biochemical assessment of the GH-IGF-I axis and greater understanding of disease process. In February 1999, an International Consensus Conference was held in Cortina, Italy, to define the criteria for cure of acromegaly. This review paper summarizes the diagnostic guidelines proposed in the consensus statement by Giustina et al. In recent years, however, the criteria for both biochemical assessment and long-term monitoring in patients with acromegaly have changed with the development of increasingly sensitive and specific GH assays coupled with the widespread availability of reliable IGF-I assays. For this reason, constant updating of the assessment criteria proposed in the workshop held in Cortina, in 1999, would be advisable.

Medical treatment of adrenocortical carcinoma (ACC) is still far from optimal, since even molecular targeted therapy failed to demonstrate striking results. Clinical trials enrolling ACC patients with high tissue Vascular Endothelial Growth Factor Receptor (VEGFR) expression levels showed controversial results after treatment with Sunitinib, possibly due to variability in the expression of drug targets, which include Epidermal Growth Factor Receptor (EGFR). To better clarify this issue, we evaluated whether VEGFR may play a crucial role in ACC responsiveness to Sunitinib and whether EGFR may represent an alternative target in ACC medical treatment, by employing two ACC cell lines, the NCI-H295 and SW13 cells lines, and adrenocortical tissues primary cultures. Our data show that VEGF/VEGFR system may not be crucial in modulating ACC proliferation and responsiveness to Sunitinib. In addition, by cell viability, proliferation and caspase activation assays we found that Sunitinib inhibi...

The effects of somatostatin, or somatotropin release-inhibiting factor (SRIF), and SRIF analogs in human diseases have been widely investigated to potentially expand the therapeutic applications of commercially available and newly designed compounds belonging to this class of agents. Several preclinical studies and clinical trials have demonstrated the antiproliferative and antisecretory effects of SRIF and its analogs. This review discusses results from studies investigating the secretory activity and cell viability of SRIF analogs, and the potential of new therapeutic applications of these drugs in endocrine diseases and, in particular, as a treatment for endocrine neoplasia.

Mild or subclinical hypothyroidism is characterized by normal serum free thyroxine concentrations with elevated serum thyroid-stimulating hormone concentrations. Subclinical hypothyroidism is relatively prevalent in the general population, especially among women and the elderly. The main cause of subclinical hypothyroidism is autoimmune chronic thyroiditis. The present report reviews the most important and recent studies on subclinical hypothyroidism, and discusses the most controversial aspects of this topic. Several studies have demonstrated that subclinical hypothyroidism may affect both diastolic and systolic cardiac function. It may also worsen many risk factors for cardiovascular disease, including hypertension, abnormal endothelial function, and elevated low-density lipoprotein cholesterol concentrations. Furthermore, a growing body of evidence suggests that subclinical hypothyroidism may cause symptoms or progress to symptomatic overt hypothyroidism. Prompt treatment of subc...

Dermorphinoyl(DMR)-glycine, DMR-sarcosine and DMR-glycyl-arginine have been prepared in order to examine the effect of C-terminal extension of dermorphin (H-Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2) on opioid activity. On GPI preparation the addition of Gly, Sar, or Gly-Arg to the carboxyl terminus of dermorphinoic acid was detrimental to mu activity: dermorphinoyl-derivatives, in fact, retain only 5-20% of dermorphin potency. Following intracerebroventricular administration (tail-flick test), whereas the analgesic activities of compounds showed the trend dermorphin greater than DMR-Sar greater than DMR-Gly-Arg greater than DMR-Gly greater than morphine, the nonapeptide displayed highest activity after subcutaneous injection in mice: DMR-Gly-Arg was 2.5 and 10 times more potent than dermorphin and morphine, respectively.

A possible role of the c-myc oncogene in the neoplastic transformation of the human thyroid has been investigated. The structure, the methylation status, and the copy number of this oncogene have been analyzed in normal and in tumor thyroid DNAs by Southern blotting technique and dot blot hybridization. Among six carcinomas, four presented abnormal c-myc DNA structure: Three cases showed a mutation in the 5' flanking region of the gene, originating a new EcoRI site; the other case showed a deletion of 5 kb involving the first exon of the gene. This deletion was also observed in the white blood cells of the same individual. In addition, in three carcinomas a double dose of the oncogene has been demonstrated. In all the carcinomas examined, undermethylation of the c-myc oncogene has been observed. These findings suggest that c-myc oncogene alterations might be involved in the malignant transformation of the human thyroids and can be considered as tumor markers.

In this paper are reported the results obtained by a simple, reproducible and sensitive rT3 RIA, in unextracted serum, using the PEG separation technique. The linear correlation coefficient of the results obtained from extracted and unextracted sera, in a population of 60 adults and 35 child controls was 0.984, with a minimal spread of the data.

Five patients with severe hypothyroidism were studied to determine diurnal variations in serum TSH and thyroid hormones. The results were based on blood samples withdrawn at 1-h intervals during a 24-h period. A statistically significant circadian rhythm in TSH was detected with the acrophase at 23(30); no significant diurnal periodicity was observed for serum T3. The TSH pattern was similar to that observed in normal and midly hypothyroid subjects, with low levels during the day and higher levels at night. The findings are consistent with the following concepts: a. the TSH circadian rhythm is retained in patients with severe hypothyroidism; b. the abnormality in thyroid function does not effect the regulation of the TSH periodicity.

... Hypertension Francesco Portaluppi, Loris Montanari, Ettore degli Uberti, Giorgio Trasforini and Raffaele Pansini (Clinica Medica, University of Ferrara, 1-44100 Ferrara, Italy) ... hypertension REFERENCES 1. Zimmerman, BG, Clin. Sci. ...

Prospective uncontrolled study to investigate in papillary thyroid carcinoma (PTC) patients: (1) Distribution of lymph node metastases within the neck compartments, (2) factors predicting lymph nodes metastases, and (3) disease recurrence after thyroidectomy associated with radio-guided selective compartment neck dissection (RSCND). We studied 345 consecutive PTC patients operated on between February 2004 and October 2011 at the S. Anna University Hospital, Ferrara (Italy). Patients with cervical lymph node metastases on preoperative ultrasonography and fine needle aspiration cytology were excluded. All patients underwent total thyroidectomy associated with SLN identification followed by RSCND in the SLN compartment, without SLN frozen section. In patients with lymph node metastases, metastatic nodes were not in the central neck compartment in 22.6% of the cases. The presence of infiltrating or multifocal PTC was a predicting factor for lymph nodes metastases. The median follow-up was 35.5 months. RSCND was associated with a false-negative rate of 1.1%, a persistent disease rate of 0.6%, and a recurrent disease rate of 0.9%. The permanent dysphonia rate was 1.3%. RSCND associated with total thyroidectomy may improve: (1) the locoregional lymph node staging, and (2) the identification of the site of lymphatic drainage within the neck compartments. Thus, considering the high false-negative rate of sentinel lymph node biopsy (SLNB), a radio-guided technique in PTC patients may guide the lymphadenectomy (ie, RSCND) to increase the metastatic yield and improve staging of the disease rather than avoid prophylactic lymphadenectomy (ie, SLNB).

Genetic alterations frequently are involved in the development of a pituitary adenoma in young age. We here characterize the functional role of a deletion in CDKN1B 5'-UTR region (c.-29_-26delAGAG) identified in an acromegalic patient that developed a growth hormone in pituitary adenoma during childhood. Our results show that the identified novel heterozygous deletion in the CDKN1B 5'-UTR region associates with a reduction in CDKN1B mRNA levels, a predicted altered secondary mRNA structure, and a reduced CDKN1B 5'-UTR transcriptional activity in vitro. The patient displayed loss of heterozygosity in the same CDKN1B 5'-UTR region at tissue level and the 5'UTR region containing the deleted sequence encompasses a GRE. These findings indicate that the identification of functional alterations of newly discovered genetic derangements need to be fully characterized and always correlated with the clinical manifestations.

Dopamine (DA) therapy of non-functioning pituitary adenomas (NFA) can result in tumor stabilization and shrinkage. However, the mechanism of action is still unknown. Previous evidence showed that DA can inhibit pituitary vascular endothelial growth factor expression (VEGF), that may be involved in pituitary tumor growth. The aim of our study was to clarify whether VEGF secretion modulation might mediate the effects of DA agonists on cell proliferation in human NFA. We assessed DA receptor subtype 2 (DR2) expression in 20 NFA primary cultures, where we also investigated the effects of a selective DR2 agonist, cabergoline (Cab), on VEGF secretion and on cell viability. All NFA samples expressed α-subunit and DR2 was expressed in 11 samples. In DR2 expressing tumors, Cab significantly reduced cell viability (-25%; P < 0.05) and VEGF secretion (-20%; P < 0.05). These effects were counteracted by treatment with the DA antagonist sulpiride. Cab antiproliferative effects were blocked by VEGF. Our data demonstrate that Cab, via DR2, inhibits cell viability also by reducing VEGF secretion in a selected group of NFA, supporting that DA agonists can be useful in the medical therapy of DR2 expressing NFA.

To compare characteristics and outcomes of differentiated thyroid cancers < or =10 mm with those 11-20 mm in diameter. Retrospective chart review of 426 patients with thyroid carcinoma < or =20 mm diagnosed and treated between 1990 and 2004 in one university clinic. Lymph node metastases were more frequent at diagnosis in 11-20 mm than in < or =10 mm cancers (p < 0.001). The prevalence of distant metastases did not differ between < or =10 mm and 11-20 mm cancers. One hundred and thirty-three patients (73%) with tumors 11-20 mm were disease free 2 years after 131I treatment, and no recurrence has been observed over 2-14 years of follow-up. Forty-one patients (22%) with cancers 11-20 mm (N1 or M1) required 2-4 years to become disease free. Neck lymph node recurrence was observed in nine patients (4.9%) 4 months to 14 years after surgery and (131)I therapy. Four patients (1.6%) with cancers < or =10 mm in diameter had cancer recurrence (p = 0.05 compared to the 11-20 mm cancers). Based on the presence of distant metastases at diagnosis and recurrence of disease during follow-up, cancers 11-20 mm in diameter seemed more aggressive than those < or =10 mm (p < 0.05). Cancers 11-20 mm seem more aggressive than those < or =10 mm.

RET proto-oncogene germ line mutations are associated with the inherited multiple endocrine neoplasia type 2 syndromes (MEN 2), as well as with familial and sporadic Hirschsprung's disease (HSCR). In this study, we report a family in which the MEN 2A and the HSCR phenotypes are associated with a single point mutation in exon 10 of the RET proto-oncogene. Furthermore, we have investigated polymorphic sequence variants of the RET proto-oncogene. Family members were tested for RET proto-oncogene mutations in exons 10, 11, 13, 14, 15, and 16 by double-gradient denaturing-gradient gel electrophoresis, nucleotide sequence analysis, and restriction endonuclease digestion of polymerase chain reaction products. The status of exon 2 and 13 polymorphic sites was investigated by EagI and TaqI digestion in 12 selected patients. A heterozygous C618R mutation of RET exon 10 was identified in 12 family members. Five out of 7 children with mildly elevated pentagastrin-stimulated calcitonin levels who carried the mutation underwent prophylactic thyroidectomy before the age of 12. C-cell hyperplasia (CCH) was found in 4 children and a microscopic medullary thyroid carcinoma (MTC) in an 8-year-old female. Neither CCH nor MTC was found in the only family member affected with HSCR, an 8-year-old male. This patient inherited the mutated RET allele from his mother, who had MTC but not HSCR, together with a rare allelic variant at codon 45 of RET exon 2. This report of a newly-described kindred with the infrequent clinical association between MEN 2A and HSCR confirms the risk of the latter phenotype among carriers of RET exon 10 cysteine codon mutations. Nevertheless, the influence of other genetic or environmental factors cannot be excluded.

We have previously found that the androgen receptor gene is expressed both in normal and adenomatous human adrenal cortex and in the NCI-H295 human adrenocortical cancer cell line. Furthermore, we have observed that dihydrotestosterone (DHT) at physiological concentrations (10−11 M) inhibits human adrenocortical cell growth in vitro and slightly decreases c-myc RNA levels in NCI-H295 cells. As c-myc is probably not the main mechanism mediating DHT-induced inhibition of cell growth, other genes controlling cell proliferation may be involved. Transforming Growth Factor beta (TGF β) is a regulatory peptide that acts by both autocrine and paracrine mechanisms to control proliferation and differentiation, and there is previous evidence that TGF β may exert an antimitotic effect on human fetal adrenal cells in vitro. This study examines a possible role for TGF β 1 in mediating the DHT-induced reduction of human adrenocortical cell growth. TGF β1 and its receptor (TGF β RII) are expressed in DHT-treated and nontreated NCI-H295 cells; on Northern blot analysis 24-h treatment with DHT (10−11 M) produced a small increase in TGF β RII RNA, and quantitative RT-PCR showed a 1.5-fold increase in TGF β 1 RNA levels. These findings suggest that TGF β 1 and its receptor may be involved in DHT-induced inhibition of human adrenocortical cell growth.

In an attempt to examine the effect of prolonged physical activity on the function of the GH/IGF-1 axis during the aging process in man, we have evaluated basal and GHRH (GHRH-29: 1 microgram/kg i.v. as a bolus) stimulated GH secretion as well as basal plasma IGF-1 levels in a group of 25 healthy runners (50-60 years, mean age 55.5 +/- 0.6) and 24 age-matched relatively sedentary normal controls (mean age 55.8 +/- 0.7). The runners had a minimum distance in kilometers of 26 km/week for at least 15 years, and competed in distances ranging from 16 km to the marathon. In runners, GHRH induced an increase of GH which was significantly higher (p < 0.001) than that observed in the age-matched controls. Baseline IGF-1 levels were significantly higher (p < 0.001) in trained runners (171 +/- 8.4 micrograms/1) compared to the controls (91.1 +/- 5.5 micrograms/1). These data show that in middle-age prolonged physical activity increases the function of the GH/IGF-1 axis. To clarify the possible mechanisms underlying the GH/IGF-1 secretory pattern in the runners, the GH responses to both single and combined administration of GHRH and arginine (ARG: 30 g infused over 30 min), a GH secretagogue likely acting via inhibition of hypothalamic somatostatin release, were investigated in 6 runners (mean age 55 +/- 1.9 years) and 6 controls (mean age 55 +/- 0.9 years). ARG clearly increased the GH response to GHRH in the controls, whereas it was unable to further potentiate the GH-releasing effect of GHRH in runners, thus suggesting that the increased GH responsiveness to GHRH might be due to an exercise-related decrease in endogenous hypothalamic somatostatinergic activity.

The neuropeptide galanin (GAL) is widely distributed in the central and peripheral nervous systems where it often coexists with catecholamines and acetylcholine. Recently we have reported that human GAL (hGAL) in man depresses the release of norepinephrine (NE) and the responses to both assumption of upright posture and insulin-induced hypoglycemia. To gain an insight into the action of hGAL on sympathetic nervous system activity in man, we investigated the effects of a 60-min infusion (80 pmol/kg/min) of hGAL or saline on the release of NE, epinephrine (E) and pancreatic polypeptide (PP) induced by an acetylcholinesterase inhibitor, pyridostigmine bromide (PD), in nine healthy volunteers. PD (120 mg orally) induced a significant rise in plasma concentrations of NE (1.6 +/- 0.04 vs. 1.08 +/- 0.06 nmol/l), E (0.34 +/ 0.05 vs. 0.12 +/- 0.04 nmol/l) and PP (178.06 +/- 33 vs. 37.57 +/- 7.35 pmol/l), whilst it significantly reduced heart rate (HR; 61 +/- 2 vs. 71 +/- 4 beats/min). Changes in plasma levels of PP were determined as an indirect measure of amplification of endogenous cholinergic activity produced by PD. Administration of hGAL blunted the release of NE and PP evoked by PD. The mean (+/- SEM) area under the curve produced by PD of NE (50.05 +/- 3.97 nmol/l.90 min) and PP (8,692.87 +/- 1,724 pmol/l.90 min) was significantly (p < 0.001) reduced by hGAL infusion (2.65 +/- 1.57 nmol/l.90 min and 248.1 +/- 148 pmol/l.90 min, for NE and PP, respectively). hGAL failed to affect significantly the E release evoked by PD. hGAL was able to enhance HR significantly (104 +/- 5 vs. 69 +/- 3 beats/min), and completely prevented the PD-induced slowing of HR. Both PD and hGAL did not alter supine systolic and diastolic blood pressure. We conclude that hGAL significantly reduces the release of NE and PP stimulated by PD-induced enhancement of cholinergic activity. These findings are consistent with a functional interrelationship between GAL and the cholinergic system in man, and may suggest the participation of a cholinergic pathway in the galaninergic modulation of the autonomic nervous system.

To investigate the role of ∂-opioid receptors in the modulation of growth hormone (GH) secretion, we compared in normal subjects the effect of the highly selective ∂-opioid receptor agonist Deltorphin (DT) on the GH secretion responses to pituitary (GH-releasing hormone, GHRH)- and hypothalamic (insulin-induced hypoglycemia, ΠH)-mediated stimuli. DT blunted the GH response to IIH, whereas it had no effect on the GH response to GHRH. It is concluded that in man DT-induced activation of ∂-opioid receptors exerts an inhibitory action on hypoglycemia-stimulated GH secretion. Based on the lack of an effect of DT on the GH response to GHRH, we suggest that DT may modulate the secretion of GH through suprapituitary mechanisms.Copyright © 1992 S. Karger AG, Basel

Two new related heptapeptides (dermorphins) with potent central and peripheral opiate-like activity have been isolated from the skin of South American frogs, and have been chemically characterized as H-Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2 (dermorphin) and H-Tyr-D-Ala-Phe-Gly-Tyr-Hyp-Ser-NH2 (Hyp6-dermorphin). The response of GH to infusion of a synthetic dermorphin (5.5 micrograms/kg/min for 30 min) was studied in 9 healthy men. Dermorphin (D) significantly increased plasma growth hormone (GH) concentrations. The GH response to D was blunted by prior administration of naloxone, suggesting that D interacts with mu-type opiate receptors. However, the evaluation of the physiological significance of D-induced GH release in humans requires further study.

In this study we explored, in man, the effect of acute attenuation of growth hormone (GH) release induced by somatostatin (SRIH) on ACTH and cortisol plasma levels. Sixteen young (8 women, aged 23–32 years, and 8 men, aged 18–27 years) and 14 elderly (8 women, aged 65–82 years, and 6 men, aged 65–70 years) healthy subjects volunteered to participate in this investigation. Each subject was tested on two separate occasions by: (1) a 90-min i.v. infusion of SRIH given in 50 ml 0.9% saline delivered at a rate of 9 µg/kg/h, and (2) a 90-min i.v. infusion of isovolumetric amounts of 0.9% saline. Plasma GH, ACTH, cortisol and glucose concentrations were determined prior and up to 180 min after SRIH or saline infusion. SRIH induced a significant (p < 0.05) decrease in plasma GH levels from basal values of 0.6 ± 0.15 and 0.5 ± 0.15 µg/l to nadir values 0.25 ± 0.1 and 0.2 ± 0.1 µg/l in young and elderly subjects, respectively. The administration of SRIH was associated with a clear-cut increase in plasma ACTH levels both in young (peak, 10.6 ± 1.6 pmol/l; AUC, 558.6 ± 147.5 pmol/l/h) and in elderly (peak, 21.3 ± 5.6 pmol/l; AUC, 841.9 ± 153.8 pmol/l/h) subjects with a significant (p < 0.01) difference as compared to saline infusion. Consistent with these results, SRIH infusion resulted in an unequivocal rise in plasma cortisol levels both in young (peak, 394.8 ± 36.4 nmol/l; AUC, 18,591.62 ± 1,372.45 nmol/l/h) and in elderly (peak, 585.6 ± 51.5 nmol/l; AUC, 24,871.05 ± 1,837.03 nmol/l/h) subjects. The ACTH and cortisol responses to SRIH were significantly (p < 0.05 and p < 0.01) higher in elderly than in young subjects. No sex-related differences occurred in the SRIH-induced activation of hypothalamic-pituitary-adrenocortical (HPA) axis. We conclude that (1) infusion of SRIH, at a dose that inhibited basal GH secretion, was associated with an activation of HPA axis, and (2) this response was higher in elderly individuals compared with younger adults. The reason for this novel and unexpected SRIH effect is presently unclear; however, the latter may be mediated, at least in part, by some central nervous system ACTH-releasing mechanisms activated by SRIH-induced decrease in GH secretion.