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Objective: Acquired hypopituitarism in adults is obviously suspected in patients with primary hypothalamic-pituitary diseases, particularly after neurosurgery and/or radiotherapy. That brain injuries (BI) can cause hypopituitarism is commonly stated and has been recently emphasized but the management of BI patients does not routinely include neuroendocrine evaluations., Aim: To clarify the occurrence of hypopituitarism in patients after traumatic brain injury (TBI) or subarachnoid haemorrhage (SAH) 3 months after the BI., Subjects and Methods: The occurrence of hypopituitarism in conscious patients after traumatic brain injury [TBI, n = 100, 31 women, 69 men; age 37.1 +/- 1.8 years; body mass index (BMI) 23.7 +/- 0.4 kg/m(2); Glasgow Coma Scale (GCS) 3-15] or subarachnoid haemorrhage [SAH, n = 40, 14 men, 26 wpmen, 51.0 +/- 2.0 years; 25.0 +/- 0.6 kg/m(2); Fisher's scale 1-4] was studied in a multicentre study 3 months after the BI. All patients underwent wide basal hormonal evaluation; the GH/IGF-I axis was evaluated by GHRH + arginine test and IGF-I measurement., Results: In TBI patients, some degree of hypopituitarism was shown in 35%. Total, multiple and isolated deficits were present in 4, 6 and 25%, respectively. Diabetes insipidus was present in 4%. Secondary adrenal, thyroid and gonadal deficit was present in 8, 5 and 17%, respectively. Severe GH deficiency (GHD) was the most frequent pituitary defect (25%). In SAH patients, some degree of hypopituitarism was shown in 37.5%. Despite no total hypopituitarism, multiple and isolated deficits were present in 10 and 27.5%, respectively. Diabetes insipidus was present in 7.5%. Secondary adrenal, thyroid and gonadal deficit was present in 2.5, 7.5 and 12.5%, respectively. Severe GHD was the most frequent defect (25%)., Conclusions: TBI and SAH are conditions associated with high risk of acquired hypopituitarism. The pituitary defect is often multiple and severe GHD is the most frequent defect. Thus neuroendocrine evaluations are always mandatory in patients after brain injuries.

In adults, hypopituitarism and growth hormone deficiency (GHD) should be suspected and diagnosed within an appropriate clinical context. It has been demonstrated that all patients with primary hypothalamic-pituitary diseases before and after any medical intervention (defined as neurosurgery, radiotherapy and medical therapy) are at obvious risk - more than just at high risk - for hypopituitarism (greater than 80% had severe GHD). The same obvious risk applies to patients diagnosed as having congenital or acquired GHD in childhood (between 30% and 50% of patients with severe GHD after retesting). Taking into account the fragility of the infundibular-hypothalamic structure, patients with other common pathological conditions of the central nervous system (CNS), such as traumatic brain injury (TBI), subarachnoid haemorrhage (SAH) or primary brain tumours (BT) with related medical intervention could be at risk for developing hypopituitarism, including GHD. GHD is the first and most common sign of pituitary impairment. Despite the risk of pituitary dysfunction and the results of some studies that these risks are greater than previously believed, neuroendocrine evaluations are still not routinely included as part of the clinical management plan for patients with TBI and SAH. Preliminary results of a multicenter study performed under the auspices of the Italian Society of Endocrinology underscore the high risk of hypopituitarism and GHD under these clinical conditions. Thus, careful screening of pituitary function should always be performed in patients following TBI and SAH.

Traumatic brain injury (TBI) may be associated with impairment of pituitary hormone secretion, which may contribute to long-term physical, cognitive, and psychological disability. We studied the occurrence and risk factors of pituitary dysfunction, including growth hormone deficiency (GHD) in 50 patients (mean age 37.6 +/- 2.4 years; 40 males, age 20-60 years; 10 females, age 23-87 years) with TBI over 5 years. Cranial or facial fractures were documented in 12 patients, and neurosurgery was performed in 14. According to the Glasgow Coma Scale (GCS), 16 patients had suffered from mild, 7 moderate, and 27 severe TBI. Glasgow Outcome Scale (GOS) indicated severe disability in 5, moderate disability in 11, and good recovery in 34 cases. Basal pituitary hormone evaluation, performed once at times variable from 12 to 64 months after TBI, showed hypogonadotrophic hypogonadism in 7 (14%), central hypothyroidism in 5 (10%), low prolactin (PRL) levels in 4 (8%), and high PRL levels in 4 (8%) cases. All subjects had normal corticotrophic and posterior pituitary function. Seven patients showed low insulin-like growth factor-I (IGF-I) levels for age and sex. Results of GHRH plus arginine testing indicated partial GHD in 10 (20%) and severe GHD in 4 (8%) cases. Patients with GHD were older (p <0.05) than patients with normal GH secretion. Magnetic resonance imaging demonstrated pituitary abnormalities in 2 patients; altogether pituitary dysfunction was observed in 27 (54%) patients. Six patients (12%) showed a combination of multiple abnormalities. Occurrence of pituitary dysfunction was 37.5%, 57.1%, and 59.3% in the patients with mild, moderate, and severe TBI, respectively. GCS scores were significantly (p <0.02) lower in patients with pituitary dysfunction compared to those with normal pituitary function (8.3 +/- 0.5 vs. 10.2 +/- 0.6). No relationship was detected between pituitary dysfunction and years since TBI, type of injury, and outcome from TBI. In conclusion, subjects with a history of TBI frequently develop pituitary dysfunction, especially GHD. Therefore, evaluation of pituitary hormone secretion, including GH, should be included in the long-term follow-up of all TBI patients so that adequate hormone replacement therapy may be administered.

Somatostatin (SRIF) analogs interacting with SRIF receptor subtype (SSTR) 2 and SSTR5 are known to reduce secretion in GH-secreting pituitary adenomas. We investigated the effects of SRIF and a SSTR1 selective agonist, BIM-23926, on GH and prolactin (PRL) secretion and cell viability in primary cultures deriving from 15 GH- and PRL-secreting adenomas expressing SSTR1. Quantitative RT-PCR showed SSTR1 mRNA mean levels of 6 +/- 2.2 x 10(4) molecules/ microg reverse-transcribed total RNA. SSTR2 and SSTR5 were frequently expressed (93.3%), on the contrary of SSTR3 (53.3%) and SSTR4 (6.7%). GH secretion was significantly reduced by SRIF and BIM-23926 (45 +/- 8.6% and 32 +/- 18.1% inhibition, respectively) as well as PRL secretion (16.1 +/- 4% and 19.7 +/- 3.5% inhibition, respectively). After treatment with SRIF and BIM-23926, cell viability was significantly reduced by 17.5 +/- 5% and 20 +/- 3.9%, respectively. SSTR1 mRNA levels correlated with the degree of GH and PRL secretion inhibition. These results demonstrate that SSTR1 selective activation inhibits hormone secretion and cell viability in GH- and PRL-secreting adenomas in vitro and suggest that SRIF analogs with affinity for SSTR1 may be useful to control hormone hypersecretion and reduce neoplastic growth of pituitary adenomas.

Testosterone (T) is known to affect the growth hormone (GH) axis. However, the mechanisms underlying the activation of GH secretion by T still remain to be clarified. Available data in animals and humans have shown that withdrawal of somatostatin (SRIH) infusion induces a GH-releasing hormone (GHRH)-mediated rebound release of GH, and there is accumulating evidence that SRIH infusion withdrawal may be a useful test to probe the GHRH function in vivo. With the aim of investigating whether the stimulatory effect of androgens on GH release in man could be accounted for by activation of the hypothalamic GHRH tone, we evaluated the plasma GH response to SRIH withdrawal in 10 patients aged 29.6 +/- 2.4 years (mean +/- SEM), diagnosed with hypergonadotropic hypogonadism, before and after a 6-month replacement therapy with T enanthate (250 mg every 3 weeks, i.m.), and in 10 healthy men, aged 26.7 +/- 2.8 years. To verify whether the modulation of GH secretion by T could also be mediated through changes in SRIH tone and/or pituitary releasable pool, we examined GH secretory responses to combined GHRH and L-arginine (ARG) in the same individuals. Basal plasma concentrations of GH (0.48 +/- 0.11 microg/l) and IGF-I (23.79 +/- 1.83 nmol/l) were significantly lower in untreated hypogonadal patients than in healthy men, and significantly increased after T replacement therapy (GH 1.13 +/- 0.28 microg/l; IGF-I 28.71 +/- 1.46 nmol/l). The mean Delta GH peak after SRIH withdrawal recorded in untreated hypogonadal men (2.65 +/- 0.86 microg/l) was significantly (p < 0.05) lower than that observed in healthy men (6.53 +/- 1.33 microg/l) and significantly increased after T replacement therapy (5.52 +/- 1.25 microg/l). The GH responses to GHRH combined with ARG (a functional SRIH antagonist) were not significantly different between healthy men and untreated hypogonadal patients, and were not significantly affected by T treatment. Plasma T and estradiol (E(2)) levels significantly correlated with Delta GH peak after SRIH withdrawal in healthy men and in T-treated hypogonadal patients, whereas in untreated patients they did not. No significant correlation was found between GH areas under the curve after GHRH + ARG test and T and E(2) plasma levels in either healthy men or in hypogonadal patients (both before and after T replacement). These findings are consistent with the view that in humans the stimulatory action of T on the GH axis appears to be mediated at the hypothalamic level primarily by promoting GHRH function., (Copyright 2003 S. Karger AG, Basel)

Severe traumatic head injury has been recognized to be associated with hypothalamo-hypophyseal impairment and subsequent abnormalities in hormone secretion, which can contribute to a prolonged clinical course and to hampered recovery in many head-injured patients. Most of the data on the growth hormone/insulin-like growth factor -1 (GH/IGF-1) axis function have been obtained early after head injury, whereas GH secretory pattern has not been fully elucidated after patients had left the intensive care unit. We examined the activity of the GH/IGF-1 axis in 16 severely closed head-injured (CHI) patients (14 males; age range, 17 to 47 years; body mass index [BMI], 21.4 +/- 0.8 kg/m(2)) during the rehabilitation period at least 1 month after leaving the intensive care unit and in 12 sex-, age-, and weight-matched healthy controls. The severity of trauma was assessed by the Glasgow Coma Scale (GCS) score (8 or less), posttraumatic amnesia (PTA, more than 24 hours), and initial computed tomography (CT) scan. The clinical picture at time of the study was evaluated by the Rancho Los Amigos Scale of Cognitive Functioning (CFS) and the Functional Independence Measure (FIM). In all subjects, we evaluated basal levels of anterior pituitary hormones, IGF-1, insulin-like growth factor-binding protein (IGFBP)-3, and IGFBP-1, as well as the GH responses to intravenous (IV) infusion of growth hormone-releasing hormone (GHRH) alone, GHRH plus arginine (ARG), and the GH release evoked by somatostatin (SRIH) infusion withdrawal, which is related to endogenous GHRH tone. In all subjects, nutritional parameters and nitrogen balance were normal. Basal plasma concentrations of GH, IGF-1, IGFBP-3, and IGFBP-1 did not significantly differ between CHI patients and controls. The GH responses to GHRH and GHRH plus ARG did not significantly differ between CHI patients (GH peak, 10.7 +/- 3.0 microg/L; area under the curve [AUC], 5.9 +/- 1.5 microg/L. min; and GH peak, 34.7 +/- 6.1 microg/L; AUC, 20.25 +/- 3.3 microg/L. min, respectively) and normal subjects (GH peak at 30 minutes, 7.23 +/- 1.35 microg/L; AUC, 4.7 +/- 0.8 microg/L. min; and GH peak at 60 minutes, 41.0 +/- 5.1 microg/L; AUC, 24.3 +/- 1.7 microg/L. min, respectively). SRIH withdrawal resulted in an unequivocal increase in plasma GH concentrations both in CHI patients and in controls, without any significant difference between the 2 groups. A negative correlation was found between the GH response (deltaGH peak) to SRIH withdrawal and CFS (r = -.615, P <.005). In conclusion, our study indicates that patients receiving rehabilitation after leaving the intensive care unit for severe traumatic head injury have no significant changes of GH secretion with normal central regulation of the GH-IGF-1 axis., (Copyright 2002, Elsevier Science (USA). All rights reserved.)

Background: 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., Methods: 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., Results: 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., Conclusions: 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.

Recently, a new slow-release (SR) formulation of lanreotide (LAN) comprising 60 mg of the drug incorporated in microspheres of biodegradable polymers (SR-LAN 60) has become available. The aim of our study was to assess the effectiveness of SR-LAN 60, administered every 21 to 28 days, as well as its tolerability in the long-term treatment of acromegalic patients treated with SR-LAN 30. Twenty patients with acromegaly (10 males and 10 females) were enrolled in this open study. Thirteen patients had undergone surgery, but with incomplete resection of the pituitary tumor. All patients, treated with intramuscular (IM) SR-LAN 30 injections every 10 days for 12 to 24 months, started SR-LAN 60 (Ipsen-Beaufour, Milan, Italy) administration 10 days after the last injection of SR-LAN 30. Growth hormone (GH) levels were determined on the day of the first injection of SR-LAN 60, and 10, 20, and 30 days after. According to the GH levels reached on day 30, patients received SR-LAN 60 every 28 days if GH levels were below 2.5 microg/L (group A) and every 21 days if GH levels were above 2.5 microg/L (group B). In group A, after the 8th month, SR-LAN 60 treatment resulted in well-controlled GH levels in 9 of 10 patients in comparison to SR-LAN 30 treatment every 10 days (6 of 10 patients). Normal age-adjusted insulin-like growth factor-I (IGF-I) levels were achieved in 4 of 10 patients, as in treatment with SR-LAN 30. In group B, SR-LAN 60 treatment resulted in well-controlled GH levels in 4 of 10 patients, as in treatment with SR-LAN 30 every 10 days. Normal age-adjusted IGF-I levels were achieved in 3 of 10 patients after SR-LAN 60 in comparison to SR-LAN 30 treatment every 10 days (1 of 10 patients). During SR-LAN 60 therapy, an improvement was also observed in signs and symptoms of active acromegaly and no relevant side effects were detected. In conclusion, this study shows that SR-LAN 60 treatment is able to induce a good control of circulating GH and IGF-I levels in most acromegalic patients. The first injections of SR-LAN 60 are very helpful in predicting the optimal long-term injection frequency. Patients on SR-LAN 30 can be safely and effectively shifted to SR-LAN 60., (Copyright 2002 by W.B. Saunders Company)

Hypertension is an important complication of acromegaly, contributing to the increased morbidity and mortality of this condition. Prevalence of hypertension in acromegalic patients is about 35%, ranging from 18 to 60% in different clinical series, and the incidence is higher than in the general population. The lowering of blood pressure observed concomitantly with the reduction in GH levels after successful therapy for acromegaly suggests a relationship between GH and/or IGF-I excess and hypertension. The exact mechanisms underlying the development of hypertension in acromegaly are still not clear but may include several factors depending on the chronic exposure to GH and/or IGF-I excess. Experimental and clinical studies suggest that the anti-natriuretic action of GH (due to direct renal action of GH or IGF-I and/or to indirect, systemic GH or IGF-I-mediated mechanisms) may play a role in the pathogenesis of hypertension. Acromegaly is frequently associated with insulin resistance and hyperinsulinaemia which may induce hypertension by stimulating renal sodium absorption and sympathetic nervous activity. Whether sympathetic tone is altered in acromegalic hypertensive patients remains a matter of debate. Recent studies indicate that an increased sympathetic tone and/or abnormalities in the circadian activity of sympathetic system could play an important role in development and/or maintenance of elevated blood pressure in acromegaly, and may partially account for the increased risk of cardiovascular complications. Acromegalic cardiomiopathy may also concur to elevate blood pressure and can be aggravated by the coexistence of hypertension. Finally, a role of GH and IGF-I as vascular growth factors cannot be excluded. In conclusion, acromegaly is associated with hypertension, but there is still no real consensus in the literature on the mechanisms behind the development of the high blood pressure.

The aim of this study was to review our experience with endocrine tumours of the gastrointestinal tract and pancreas (ETGIP). Between February 1991 and March 2000, sixteen patients with ETGIP were operated on at our institution. Of these patients we reviewed preoperative symptoms, diagnostic techniques (ultrasound, CT, MRI, radiolabelled octreotide scintigraphy, angiography, immunohistochemical study), treatment (surgical operation, neoadjuvant and adjuvant chemotherapy, and radiometabolic therapy) and survival. Nine patients (56%) had a carcinoid tumour, three (19%) an unspecified endocrine tumour, and four (25%) an endocrine tumour associated with a non-endocrine neoplasm. Only five patients (31%) had a preoperative diagnosis of endocrine tumour. Eight patients (50%) had metastatic disease at the time of the operation. All patients without preoperative metastasis (eight patients, 50%) are still alive without recurrent disease, with a mean postoperative survival of 36 months (12-60 months). Of eight patients with metastatic disease, six (75%) died after a mean of 20.5 months (3-60 months) and two (25%) are still alive with the disease after 3 and 6 months, respectively. These data show that presence of metastasis strongly influence survival. Furthermore, survival of patients with metastatic disease seems to be longer as compared to other gastrointestinal tract malignancies. ETGIP are more common and aggressive than previously believed and, therefore, early diagnosis is crucial for cure. Nowadays, however, new diagnostic tools such as radiolabelled octreotide scintigraphy are available for diagnosis and postoperative follow-up. The optimal treatment for ETGIP is a multimodal approach with surgical operation, chemoradiation, radiometabolic, and genetic therapies.

Both IGF-I and DHEA-S undergo an age-related decrease and their decrease could be involved in age-related changes in body composition, structure functions and metabolism. On the other hand, it is well known that mean IGF-I levels are clearly reduced in hypopituitaric patients with GH deficiency (GHD) while data about dehydroepiandrosterone sulfate (DHEA-S) levels in hypopituitarism are scanty. We evaluated DHEA-S and IGF-I levels and their relationship in 90 patients with panhypopituitarism (HYPOPIT) with severe GHD [49 women and 41 men; age, mean+/-SE: 47.9+/-1.49 yr, range: 20-80 yr, BMI: 26.4+/-0.6 kg/m2; 21 with childhood-onset (CO) and 69 with adult-onset (AO) HYPOPIT]. DHEA-S and IGF-I levels were also evaluated in 24 HYPOPIT with GHD after 3-month recombinant human GH (rhGH) replacement. Data in HYPOPIT were compared with those in a large group of healthy controls (NS, 233 women and 103 men, aged 20-80 yr; all subjects were within +/-15% of their ideal body weight). In NS both DHEA-S levels and IGF-I were gender-independent while showed a strong, inverse correlation with age (r=-0.6; p<0.001 and r=-0.56; p<0.0001, respectively). Nevertheless, no relationship was found between DHEA-S and IGF-I levels in NS. In HYPOPIT, age-adjusted mean DHEA-S and IGF-I levels were clearly lower than those in NS (2.3+/-0.4 vs 16.0+/-0.7 microg/l, p<0.005; 71.1 +/- 4.5 vs 170+/-4.7 microg/l, p<0.005). IGF-I levels in CO-HYPOPIT were lower (p<0.01) than those in AO-HYPOPIT (49.6+/-4.8 vs 77.0+/-5.4 microg/l), while DHEA-S levels were similar in both subgroups (2.6+/-0.7 vs 2.3+/-0.4 microg/l). In HYPOPIT both DHEA-S and IGF-I were independent of age and gender while there was a trend toward a positive association between each other (r=0.45; p<0.003). Analyzing individual levels in HYPOPIT with respect to age-adjusted normal ranges, IGF-I levels were below normal in 84, 62 and 0% between 20-40, 40-60 and 60-80 yr, respectively. On the other hand, DHEA-S levels were below normal in 84, 86 and 67% between 20-40, 40-60 and 60-80, respectively. In HYPOPIT rhGH treatment strikingly increased IGF-I levels (150+/-3.2 vs 85.3+/-4.1 microg/l, p<0.005) while did not modify DHEA-S levels (1.7+/-0.2 vs 1.6+/-0.2 microg/l). In conclusion, our results demonstrate that DHEA-S and IGF-I are negatively and independently associated to age in physiological conditions but not in hypopituitaric patients in whom both are strikingly reduced. Both DHEA-S and IGF-I levels in HYPOPIT show some overlap with those in normal subjects; thus the assay of these parameters is not diagnostic for hypopituitarism. DHEA-S reduction in HYPOPIT does not depend on IGF-I as indicated also by evidence that GH replacement restores IGF-I but does not modify DHEA-S levels.

We investigated the 24-h profiles of the circulating levels of norepinephrine (NE) and epinephrine (E), blood pressure (BP), and heart rate in 14 acromegalic patients, before (A) and 3-6 months after transsphenoidal surgery (C-A, cured; A-A, active), and in 8 age-matched normal subjects (N). In addition, the responses of NE, E, PRA, and aldosterone to upright posture were investigated. No significant differences in the mean 24-h plasma NE and E levels were observed between either group of acromegalics and the N subjects. Analysis of the 24-h profiles indicated a statistically significant 24-h rhythm of both NE and E in N subjects. No evidence of a 24-h rhythm of plasma NE and E and BP was found in A patients. After surgery, a statistically significant 24-h rhythm of NE was detected in the patients with acrophase (13.54 and 13.45 h in C-A and A-A patients, respectively) and mesor (1019.8+/-45.1 and 1017.8+/-54.7 pmol/L in C-A and A-A patients, respectively) similar to those observed in N subjects (acrophase, 13.21 h; mesor, 942.3+/-42.5 pmol/L). After surgery, the plasma concentration of E clearly fluctuated throughout the 24 h in both C-A and A-A patients, even if cosinor analysis failed to reveal a 24-h significant rhythm. A statistically significant 24-h rhythm of BP was restored only in C-A patients. The mean 24-h heart rate was slightly, but significantly (P<0.05), higher in A than in N subjects and decreased after surgery. No significant differences in upright-stimulated NE, E, and plasma aldosterone levels were observed between each group of acromegalics and N subjects. However, basal and upright-stimulated PRA levels were significantly (P<0.001) lower in A patients. In conclusion, our study demonstrates the lack of a clear circadian variation in catecholamine levels and BP in active acromegaly and the return of a significant 24-h rhythm of NE and BP after pituitary surgery, concomitant with the reduction in GH and insulin-like growth factor I serum levels.

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 microg/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 microg/l to nadir values 0.25 +/- 0.1 and 0.2 +/- 0.1 microg/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.

There is evidence that endogenous opioid peptides exert an inhibitory effect on pituitary luteinizing hormone (LH) secretion both in animals and in humans, by interacting with mu-opioid receptors. However, a role for delta-opioid receptors in the regulation of gonadotrophin releasing hormone (GnRH) secretion has recently been suggested. In the present study, we evaluated the effect of the highly selective delta-opioid receptor agonist deltorphin on the LH and follicle stimulating hormone (FSH) responses to naloxone in six healthy fertile women during the luteal phase of the menstrual cycle. Deltorphin infusion alone (7 microg/kg/min for 60 min) did not significantly change the basal serum concentrations of LH in this group of women. The intravenous (i.v.) bolus administration of naloxone (15 mg) induced a significant (P < 0.001) increase in serum LH concentrations (from a mean basal value of 4.24+/-1.10 IU/l to a peak of 13.27+/-1.8 IU/l). The LH response to naloxone was significantly (P < 0.001) blunted by preinfusion of deltorphin (13.27+/- 1.80 IU/l versus 4.80+/-1.18 IU/l). No significant changes in FSH concentrations were observed during deltorphin, naloxone or deltorphin plus naloxone administration. These data indicate that activation of delta-opioid receptors can reduce naloxone-induced LH release, suggesting a possible role of delta receptors in opioidergic modulation of LH secretion in women.

There is evidence that withdrawal of SRIH infusion in man promotes a rebound GH response that allegedly has been proposed to be related to the function of GHRH-producing neurons. In the present study we have evaluated whether a reduction in endogenous GHRH activity contributes to the decreased GH secretion of the elderly. Sixteen young (8 women, aged 23-32 yr, and 8 men, aged 18-27 yr) and 13 elderly (8 women, aged 65-82 yr, and 5 men, aged 65-70 yr) healthy subjects volunteered to participate in this investigation. Each subject was tested on 2 separate occasions: 1) a 90-min iv infusion of SRIH was given in 50 mL 0.9% saline delivered at a rate of 9 micrograms/kg.h; and 2) a 90-min iv infusion of isovolumetric amounts of 0.9% saline was given. Plasma GH levels were determined before and up to 180 min after SRIH or saline infusion, whereas plasma insulin-like growth factor I, estradiol, and testosterone levels were measured in basal samples. In elderly women, the mean maximum (delta) GH peak (2 +/- 0.7 micrograms/L) after withdrawal of SRIH infusion was significantly (P < 0.02) lower than that in young women (7.3 +/- 2 micrograms/L). In elderly men, the mean delta GH peak (2.9 +/- 0.6 micrograms/L) after withdrawal of SRIH infusion was lower than that in young men (6.3 +/- 1.6 micrograms/L), although the difference failed to achieve statistical significance. Baseline insulin-like growth factor I levels were significantly lower in elderly compared to young subjects in both men and in women. In women, both age and basal plasma estradiol and testosterone levels significantly correlated with delta GH peak after SRIH withdrawal (r = -0.61, r = 0.61, and r = 0.66, respectively), whereas in men they did not. These findings are compatible with the view that an age-related decrease in endogenous GHRH function may contribute to the defective GH secretion of the elderly. Alterations in plasma concentrations of sex steroids may have important implications in the observed changes.

The discovery of an asymptomatic adrenal mass (incidentaloma) during the investigation of an unrelated condition is relatively common. In this study, we report the clinical, radiologic, and endocrine evaluation of 38 patients (22 women and 16 men aged 24 to 84 years) with adrenal incidentaloma (size, 1 to 12 cm). The patients underwent basal and dynamic evaluation of the hypothalamic-pituitary-adrenal (HPA) axis, renin-angiotensin-aldosterone system, and adrenomedullary function. Moreover, computed tomograpy (CT) scan and 131I-6beta-iodomethyl-19-norcholest-5(10)-en-3beta-ol(NP-59) and/or 131I-metaiodobenzylguanidine (MIBG) scintigraphy were performed. The endocrine evaluation indicated two cases of pheochromocytoma and four cases of preclinical Cushing's syndrome, three of which underwent surgery with histologic diagnosis of two adrenocortical adenomas and one carcinoma. Low levels of serum dehydroepiandrosterone sulfate (DHEA-S), associated with a markedly increased 17-hydroxyprogesterone (17-OHP) response to a corticotropin (ACTH) test, were found in patients with incidentaloma. On the basis of endocrine and morphologic data, 13 patients underwent surgical treatment: five adrenocortical adenomas (two functioning), two pheochromocytomas, two ganglioneuromas, one cortisol-secreting adrenal carcinoma, one lymphangiomatous cyst, one myelolipoma, and one hemorrhage were found. Careful diagnostic assessment of incidentally discovered adrenal masses must be performed to exclude the presence of malignant and/or functioning lesions and to verify the possibility that patients with incidentaloma have a genetic or acquired deficit of adrenal steroidogenic 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.

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.

To investigate the influence of the sympathoadrenomedullary system on the modulation of the circulating levels of calcitonin gene-related peptide (CGRP), the effects of epinephrine (E) and norepinephrine (NE) were studied in 8 normal subjects (4 females and 4 males). The mean basal levels of CGRP in normal subjects were 10.2 +/- 1 pmol/l. After the infusion of E (20 ng/kg per min for 30 min), a significant rise (P < 0.005) in plasma CGRP levels was observed with the expected increases in systolic blood pressure (BP), heart rate (HR) and plasma renin activity (PRA), and decrease in diastolic BP, whereas plasma aldosterone (PA) levels did not significantly change. The infusion of NE (40 ng/kg per min for 30 min) induced an increase in systolic and diastolic BPs, whereas it failed to modify CGRP, HR, PA and PRA. Our data demonstrate that the sympathoadrenomedullary system may modulate CGRP release in man perhaps via the beta-adrenergic pathway. It is likely that the modifications of plasma CGRP levels may be part of the acute vasal response to E.

Human galanin (hGAL) is a neuropeptide with 30 amino acid residues that has been found in the peripheral and central nervous system, where it often co-exists with catecholamines. In order to clarify the possible role of hGAL in the regulation of sympathoadrenomedullary function, the effect of a 60-min infusion of hGAL (80 pmol.kg-1.min-1) on plasma epinephrine and norepinephrine responses to insulin-induced hypoglycemia in nine healthy subjects was investigated. Human GAL administration significantly reduced both the release of basal norepinephrine and the response to insulin-induced hypoglycemia, whereas it attenuated the epinephrine response by 26%, with the hGAL-induced decrease in epinephrine release failing to achieve statistical significance. Human GAL significantly increased the heart rate in resting conditions and clearly exaggerated the heart rate response to insulin-induced hypoglycemia, whereas it had no effect on the blood pressure. We conclude that GAL receptor stimulation exerts an inhibitory effect on basal and insulin-induced hypoglycemia-stimulated release of norepinephrine. These findings provide further evidence that GAL may modulate sympathetic nerve activity in man but that it does not play an important role in the regulation of adrenal medullary function.

Recently we demonstrated the inhibitory action on Growth Hormone (GH) secretion of an opioid heptapeptide, deltorphin (DT), that is highly selective in binding delta-opioid receptors. To investigate the possible mechanism leading to the decrease in GH secretion by specific activation of delta-opioidergic pathway in man, we compared, in normal subjects, the effect of DT on GH secretion responses to two different GH secretagogues, namely arginine (ARG) and galanin (GAL). DT completely blunted the GH response to ARG, whereas it attenuated the GH response to GAL, but not at a statistically significant level. We suggest that the specific activation of delta-opioid receptors in man may exert an inhibitory influence on GH secretion principally by modulating endogenous hypothalamic somatostatin (SRIH) release.

The neuropeptide galanin (GAL) is widely distributed in the peripheral and central nervous systems, where it often coexists with catecholamines. To gain insight into the action of human GAL on sympathetic nervous system activity in man, we investigated the effects of a 60-min infusion of human (h) GAL (80 pmol/kg.min) or saline on peripheral norepinephrine (NE) and epinephrine concentrations, heart rate (HR), and systolic and diastolic blood pressure (BP) in the supine position as well as after assumption of the upright posture (UP) in eight healthy male volunteers. hGAL depressed supine plasma NE (0.84 +/- 0.06 vs. 0.33 +/- 0.02 nmol/L) and blunted the NE response to assumption of the UP (1.68 +/- 0.03 vs. 0.44 +/- 0.03 nmol/L), but caused a significant enhancement of the epinephrine response to assumption of the UP (0.22 +/- 0.02 vs. 0.65 +/- 0.06 nmol/L). hGAL significantly increased supine HR (70 +/- 2 vs. 99 +/- 4 beats/min) and potentiated the HR response to assumption of the UP (82 +/- 3 vs. 107 +/- 4 beats/min). hGAL did not alter supine systolic and diastolic BP, but caused a significant decrease in the systolic (121 +/- 3 vs. 98 +/- 2 mm Hg) and diastolic (74 +/- 2 vs. 62 +/- 2 mm Hg) BP responses to assumption of the UP. Our data show that hGAL decreases supine position- and UP-stimulated release of NE, suggesting an inhibitory modulation of hGAL on sympathetic outflow in man. The finding that hGAL induces an increase in HR, both in the supine position and after UP, and an inhibition of the systolic and diastolic BP response to UP provides further support for an involvement of hGAL in regulation of the cardiovascular and autonomic nervous systems in man.

To investigate the influence of the cholinergic system on the modulation of the circulating levels of calcitonin gene-related peptide (CGRP) under basal conditions in normal man, the effects of an acetylcholinesterase inhibitor, pyridostigmine bromide, and a muscarinic receptor blocker, pirenzepine, were studied in 16 normal subjects (8 females and 8 males). Pyridostigmine (120 mg, orally) induced a significant (P < 0.01) rise in basal plasma CGRP, while it reduced systolic and diastolic blood pressure. In all subjects, pirenzepine (0.6 mg/kg, i.v. bolus) was unable to modify the basal CGRP level. In conclusion, a pharmacologically induced enhancement of cholinergic tone resulted in an increase in CGRP, whereas muscarinic receptor blockade had no effect on CGRP levels or blood pressure. Therefore, the cholinergic system seems to be involved in the control of CGRP release in man, acting as a positive modulator. However, the available data do not indicate that there is a tonic cholinergic tone responsible for CGRP secretion under physiological conditions.

To examine the role of delta-opioid receptors in the regulation of the sympathoadrenomedullary system, the effects of the highly selective delta-opioid receptor agonist deltorphin (DT) on plasma catecholamine responses to insulin-induced hypoglycemia (IIH) and cold pressor test (CPT) have been investigated in normal subjects in two separate studies. DT failed to modify basal plasma levels of both norepinephrine (NE) and epinephrine (E). DT completely suppressed the IIH-evoked elevation of NE, whereas it attenuated the E response by 20%, with the DT-induced decrease in E release failing to achieve statistical significance. DT completely blocked the release of both NE and E elicited by CPT. We conclude that specific delta-opioid receptor stimulation exerts an inhibitory effect on NE release induced by both IIH and CPT. These findings provide evidence that delta-opioid receptors may influence the autonomic sympathetic reactivity.

Calcitonin gene-related peptide (CGRP) has positive chronotropic and inotropic effects in animals and humans, and produces the most potent vasodilation known for an endogenous peptide. Yet, a physiological role for CGRP in the regulation of vascular tone and blood pressure has not been demonstrated. We studied the effects of 1) assumption of the upright position and 2) iv infusion of angiotensin-II (sequential doses of 8, 16, and 32 ng/kg.min, each dose for 20 min) in eight normal subjects (four men). Serial venous blood samples were taken to determine the plasma CGRP, epinephrine, norepinephrine, and aldosterone levels and PRA. Blood pressure and heart rate were continuously monitored at the finger with a Finapres 2300 instrument. After assumption of the upright posture, a quick rise in plasma CGRP levels was observed together with the expected increases in plasma norepinephrine and aldosterone and PRA. A transient increment was also observed for diastolic blood pressure and heart rate. Angiotensin-II infusion caused dose-dependent increases in plasma CGRP and aldosterone concentrations, already significant at the lowest infusion rate and parallel with the blood pressure rise. Plasma catecholamines significantly increased only at higher infusion rates. Our data demonstrate that modifications of plasma CGRP concentrations are part of the normal response to postural and vasomotor changes. These findings suggest a physiological role for CGRP in regulation of the peripheral vascular tone and possibly blood pressure in man.

To investigate the role of delta-opioid receptors in the modulation of growth hormone (GH) secretion, we compared in normal subjects the effect of the highly selective delta-opioid receptor agonist Deltorphin (DT) on the GH secretion responses to pituitary (GH-releasing hormone, GHRH)- and hypothalamic (insulin-induced hypoglycemia, IIH)-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 delta-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.

Objective: To assess the existence of an altered circulating pattern of calcitonin gene-related peptide (CGRP) in hypertension., Design: The 24 h variation in plasma CGRP was measured and compared in 10 patients affected by uncomplicated essential hypertension and in nine age- and sex-matched healthy volunteers. The diurnal variations in blood pressure, atrial natriuretic peptide (ANP), plasma renin activity (PRA), plasma aldosterone and plasma cortisol were also assessed., Methods: Recumbency studies were performed under standardized, drug-free conditions beginning at 0800 h. Venous samples were drawn every 4 h for 24 h and hormone levels were assessed with specific radioimmunoassays. The blood pressure was measured every 15 min with a SpaceLabs 90207 monitor., Results: The mean 24-h plasma CGRP concentrations were significantly lower in the hypertensive group than in the control group. In both groups a circadian rhythm was present with the same pattern, but at a lower level in hypertension. A temporal sequence starting with the nocturnal rise in plasma CGRP concentrations and progressing with the elevations of ANP, PRA, and plasma aldosterone and cortisol was apparent in both groups. The nocturnal rise in the CGRP and ANP concentrations coincided with the blood pressure and the heart rate falls., Conclusions: Our data show that CGRP is lower than normal but maintains its circadian variability and its relationship with the diurnal variations in blood pressure and other hormones known to be active on the cardiovascular system.

To determine the role of delta-opioid receptors in the modulation of hypothalamic-pituitary-adrenal activity, we studied in normal subjects the effect of the highly selective delta-opioid receptor agonist deltorphin (DT) on the secretion of ACTH, cortisol, and arginine vasopressin in response to insulin-induced hypoglycemia. In an attempt to clarify the site of opiate modulation of ACTH secretion, we also studied in normal subjects the effect of DT on the ACTH response to ovine CRH-41. DT blunted the ACTH, cortisol, and arginine vasopressin responses to insulin-induced hypoglycemia, whereas it had no effect on the ACTH and cortisol responses to CRH. We conclude that DT-induced activation of delta-opioid receptors exerts an inhibitory influence on hypoglycemia-stimulated ACTH secretion. Based on the lack of an effect of DT on the ACTH response to CRH, we postulate that DT may modulate the secretion of ACTH through suprapituitary mechanisms.

We report 4 cases of abnormal results using iodine-123 metaiodobenzylguanidine (123I-mIBG) or technetium-99m (V) dimercaptosuccinic acid (99mTc(V)-DMSA) scintigraphy in the diagnosis and follow-up of presumed neuroendocrine tumours. The present series consisted of 2 false-positive cases (1 adenomatous polyp of the caecum with mIBG and 1 follicular adenoma of the thyroid with DMSA) and 2 cases of anomalous uptake of (V)-DMSA in a non-neuroendocrine tissue.

Calcitonin gene-related peptide (CGRP) is known to exert potent cardiovascular effects and is presumed to participate in the neural control of circulation and blood flow. It has been assayed in many physiological and disease conditions, yet virtually nothing is known of the normal fluctuations in its circulating levels. We have studied the variability throughout a 24-h period of plasma concentrations of CGRP in eight recumbent healthy volunteers (four men and four women, 25-37 yr old), after careful standardization of their daily diet and routine schedules. A correlation with the circadian rhythms of blood pressure (BP), heart rate (HR), and plasma aldosterone (PA), PRA, plasma cortisol (PC), and atrial natriuretic peptide (ANP) was also made. Plasma CGRP concentrations ranged from a mean peak value of 18.1 +/- 1.5 pmol/L to a mean lowest value of 11.7 +/- 0.4 pmol/L (P less than 0.05). The mean circadian acrophase of CGRP (calculated by cosinor analysis to occur at 2314 h) anticipated the corresponding acrophases of the other hormones (0122, 0528, 0809, and 0840 h for ANP, PRA, PA, and PC, respectively). Instead, BP and HR rhythms seemed to be antiphasic with the ANP rhythm (calculated acrophases occurred at 1356, 1339, and 1314 h for systolic BP, diastolic BP, and HR, respectively). Our data demonstrate that, like many other hormones, CGRP circulates in plasma with a circadian rhythm. There seems to be a temporal sequence starting with the nocturnal rise in plasma CGRP concentrations and progressing with the ensuing elevations of ANP, PRA, PA, and PC, whereas BP and HR are kept to their lowest values. These findings are in favor of a physiological role of CGRP in the complex regulation of BP homeostasis.

In this study we investigated the effect of intravenous infusion of angiotensin II (AII) on plasma luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels in fertile healthy women examined both in the middle follicular phase (MFP) and in the middle luteal phase (MLP). As expected, AII induced a significant increase in blood pressure and plasma aldosterone concentration. In MFP, plasma FSH and LH levels did not show any significant change after AII infusion, if compared to both saline and preinfusion basal values. In MLP, AII significantly increased plasma LH (p less than 0.02 vs. baseline values and p less than 0.01 vs. placebo values), but not plasma FSH. The area under the curve during AII infusion resulted significantly higher than during placebo infusion (p less than 0.001). Therefore, these data demonstrate that peripherally injected AII at pressive dose produces an increase in plasma LH levels in normal women on luteal phase when the circulating concentrations of both estradiol and progesterone are high. The study suggests that AII may have a stimulatory role in the regulation of LH secretion, but this role is closely related to the gonadal steroid plasma levels.

The intravenous (IV) infusion of angiotensin II (AII) was administered to seven healthy male volunteers in a randomized placebo-controlled study. As expected, AII induced a significant increase in blood pressure and plasma aldosterone concentrations. AII caused a significant increase in corticotropin (ACTH) and growth hormone (GH) release, but had no effect on the release of thyrotropin (TSH) and prolactin (PRL). These findings suggest that peripherally circulating AII might influence ACTH and GH secretion in humans.

Empty sella syndrome is an anatomical entity in which the pituitary fossa is enlarged and partially filled with cerebrospinal fluid owing to the arachnoid herniation, while the pituitary gland is compressed against the posterior rim of the fossa. This condition can be due to an inherent weakness of the diaphragm sella and/or to an increase in intracranial pressure which promote the herniation of the arachnoid membrane into the pituitary fossa (primary empty sella) or it can results following surgery, radiation or vascular and tumorous pituitary diseases (secondary empty sella). Empty sella can be associated with neuroradiological and endocrine symptoms. This study reports the clinical, endocrine, and roentgenographic features in 20 patients with primary empty sella syndrome. Disturbances of hypothalamic-pituitary function were detected in 6 patients (hyperprolactinemia, hypopituitarism, central diabetes insipidus, hypothalamic hypothyroidism). Three patients exhibited hypergonadotropic hypogonadism. This report supports the following conclusions: a) there is no correlation between size of pituitary fossa, type an extension of arachnoid herniation and the degree of hypothalamic-pituitary dysfunction; b) endocrine alterations are frequent in the empty sella syndrome; c) the association of empty sella and primary diabetes insipidus is not a very rare event.