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Thymic neuroendocrine neoplasms are rare tumours, but their management can often be highly problematic. While previously assumed to be essentially variants of bronchopulmonary (lung) carcinoids, they are generally more aggressive and more difficult to treat. Some 25% are associated with multiple endocrine neoplasia-1, while a higher proportion are associated with the ectopic ACTH syndrome, and occasionally both. We discuss the classification of these tumours, their biology as far as is known, and their clinical, biochemical and imaging features. We also review possible management options and suggest stratagems to optimise their treatment, which even today is far from optimal.

Carcinoid heart disease (CHD) is a rare cardiac manifestation occurring in patients with advanced neuroendocrine tumours and the carcinoid syndrome, usually involving the right-sided heart valves and eventually leading to right heart failure. The pathophysiology of CHD is still obscure and believed to be multifactorial, as a variety of vasoactive substances secreted by the tumour appear to be involved. The management of patients with CHD is complex, as both the systemic malignant disease and the heart involvement have to be addressed. Timely diagnosis and early surgical treatment in appropriately selected patients are of outmost importance, as CHD is associated with increased morbidity and mortality. Valve replacement surgery alleviates right heart failure and may also contribute to improved survival. In the present study we have comprehensively reviewed the existing literature to date, mainly focusing on the pathophysiology of CHD. Other aspects of CHD (such as the clinical presentation, diagnostic tools and therapeutic approach) are addressed in brief.

Medullary thyroid cancer (MTC) arises from neural-crest-derived parafollicular C cells of the thyroid gland and accounts for approximately 4% of all thyroid cancers. Up to 25–30% of MTC cases occur as inherited disorders while the remaining cases represent the sporadic form of the disease. In this review, the structure and signalling properties of the RET proto-oncogene in its wild-type and mutant forms, and its role in hereditary and sporadic MTC, are discussed. A full data search was performed through PubMed over the years 2000–2008 with the key words ‘medullary thyroid cancer, treatment, molecular biology, RET, molecular mechanism’, and all relevant publications have been included, together with selected publications prior to that date. We also review novel therapies for metastatic MTC, especially the tyrosine kinase inhibitors which have activity at multiple receptor subtypes, and summarize the current ongoing trials in this area. While such tyrosine kinase inhibitors, particularly those affecting RET activity such as vandetanib, sorafenib and sunitinib, are promising, the low rate of partial responses and absence of complete responses in all of the various trials of monotherapy emphasize the need for new and more effective single agents or combinations of therapeutic agents with acceptable toxicity.

ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors : Somatostatin Receptor Imaging with In-111-Pentetreotide

Purpose: The sensitivity of computerised tomography (CT) in detecting neuroendocrine liver metastases is variable and three-phase imaging is advocated. However, patients are often young and may require prolonged follow-up, thus a technique that avoids radiation exposure would be desirable. Our purpose was to assess the diagnostic performance of MRI, before and after administration of mangafodipir trisodium (MnDPDP), in the detection of neuroendocrine liver metastases. Methods: Patients who had undergone single-phase or multi-phase contrast-enhanced MD-CT for neuroendocrine liver metastases were invited to have MRI. Two independent observers made quantitative measurements (number and size of lesions). All measurements were made on each available CT phase and all MRI sequences independently, and repeated after an interval to assess reproducibility. The final number of lesions was agreed on by consensus of three observers. A qualitative assessment (contrast and spatial resolution) and preferred modality were agreed on by consensus. Results: 265 lesions were detected by consensus in 11 patients. Non-contrast CT was available in 4/11, arterial phase in 6/11 and portal phase in 10/11 patients. When compared with the consensus number of lesions, MD-CT identified 17% on non-contrast, 44% on arterial and 43% on portal venous imaging. Lesion detection on MRI was 48% on T1W, 52% on T2W and 92% on MnDPDP-MRI. The number of lesions detected on MnDPDP-MRI was closest to the final consensus reading (variance = 0.994, p = 0.0027). The reproducibility of lesion size measurements was best on MnDPDP-MRI (variance = 0.033, p = 0.0021). The preferred modality subjectively was MnDPDP-MRI in 9/11 cases and T2W MRI in 2/11. Conclusion: MRI is a robust technique in the demonstration of neuroendocrine liver metastases. It is highly reproducible in both detecting the number and measuring the size of lesions. We recommend T2W MRI and MnDPDP-MRI in detection and follow-up of neuroendocrine liver metastases.

Aims: This study was designed to determine the sensitivity and specificity of conventional criteria for diagnosis of impaired glucose tolerance (IGT) in a high-risk population of GH-treated GH deficient (GHD) adults. Methods: 33 hypopituitary GHD patients with HbA1c >5.1% and 13 gender- and age-matched control GHD patients were selected. Oral glucose tolerance test (OGTT), fasting plasma glucose (FPG), HbA1c, and homeostatic model assessment (HOMA) parameters were determined in all patients. Receiver operator characteristic curves were used to determined sensitivity and specificity for the detection of glucose intolerance as defined by plasma glucose >7.8 mmol/l at 120 min during OGTT. Results: Sensitivity and specificity for this purpose for HbA1c (>5.1%) were 89 and 17%; for FPG (>5.5 mmol/l): 78 and 67%; for FPG (>6.1 mmol/l): 56 and 89%; for HOMA-derived β-cell function (βCF) (Conclusions: This study shows that FPG (>5.5 mmol/l) and βCF-IS have high sensitivity and relatively high specificity for the detection of IGT and confirms that measurement of FPG or calculation of βCF-IS provides appropriate safety surveillance in hypopituitary patients on GH replacement.

Background/Aims: Growth retardation is a recognised complication of paediatric Cushing’s disease (CD), but there are few published data on skeletal maturation at diagnosis. We assessed factors contributing to skeletal maturation in patients with paediatric CD. Patients/Methods: 17 patients, 12 males, 5 females (median age 12.1 years, range 5.8–17.4) were studied. The bone age (BA) of each child was determined by a single observer using the TW3 RUS method. BA delay, i.e. the difference between chronological age (CA) and BA, was compared with clinical and biochemical variables. Results: BA delay was present in 15/17 patients (mean delay 2.0 years, range –0.5 to 4.1 years) and correlated negatively with height SDS (r = –0.70, p < 0.01) and positively with duration of symptoms (r = 0.48, p = 0.05) and CA (r = 0.48, p = 0.05). No relationships were found with midnight cortisol, ACTH, DHEA-S or cortisol suppression during the low-dose dexamethasone suppression test. Conclusions: BA in most children with CD was delayed and related to length of symptoms and height SDS at diagnosis. Early diagnosis will reduce delay in skeletal maturation and thus contribute to optimal catch-up growth.

Background/Aims: This study was designed to determine whether previous Cushing’s disease (CD) or prolactinoma (PRL) could exert adverse effects additional to those of growth hormone (GH) deficiency as a consequence of variable degrees of prior hypogonadism or hypercatabolism. We report the effects of 5 years GH treatment in 124 GH deficiency adults; 42 patients with non-functioning pituitary adenomas (NFPA), 43 with treated PRL and 39 with treated CD. Methods: Fasting plasma glucose, HbA1c, lipoprotein profile, anthropometry and bone mineral density (BMD) were measured at baseline, 6 months and annually up to 5 years. Results: Mean body mass index remained unchanged in the PRL group and tended to increase in the NFPA group. In contrast, body mass index decreased in the CD group. Decreases in waist and waist/hip ratio were seen in all groups at 6 months. Decreases in total cholesterol and low-density lipoprotein cholesterol were seen in all groups and remained sustained at 5 years. Plasma glucose and HbA1c increased at 6 months. Subsequently, plasma glucose returned to baseline values at 5 years; in contrast, HbA1c remained unchanged at the end of the study. Baseline lumbar spine and hip BMD were lower in the PRL and CD groups than in the NFPA group, decreased over 1 year in all groups and subsequently increased by 2 years in NFPA with a subsequent increase in lumbar spine BMD in PRL and CD groups delayed to 3–5 years. Conclusions: Baseline characteristics and response to GH replacement are qualitatively similar in NFPA, PRL and CD patients. Because improvements in BMD occur later in PRL and CD patients, an extended trial of GH therapy may be indicated in those patients who were commenced on GH therapy as an additional treatment for reduced BMD.

Pituitary tumours are characterized by a series of phenotypic abnormalities, but the molecular nature of the underlying defects has proved peculiarly intractable. Oncogenes and tumour suppressor genes involved in other tumours do not appear to play a major role in the pathogenesis of pituitary tumours. In addition, germline genetic disorders in which pituitary tumours are a common feature have not shed much light on the more common sporadic tumour. A number of defects in specific feedback regulation in the secretory tumours have been identified, but it is presently unclear as to what extent these are a consequence of the tumour, possibly enhancing its growth or survival, rather than the cause. However, recent studies on the cell cycle have demonstrated significant abnormalities that have been traced to a cytoplasmic kinase which appears to be abnormally expressed in the majority of pituitary adenomas, and we are beginning to see a possible unifying abnormality.

Cushing’s syndrome is defined as the symptoms and signs of glucocorticoid excess, but the precise diagnosis may be difficult to establish and harder to localise. The clinicial, biochemical and imaging features of the syndrome are discussed in the light of our own extensive experience and the published literature. We describe the optimal diagnostic routines currently recommended in major centres, and analyse the sensitivities and specialities of the various tests employed. Only by means of establishing a precise diagnosis can the disorder be successfully treated.

Continuous 24-hour infusions of a maximally stimulating dose (1 microgram/kg/h) of corticotropin-releasing hormone (CRH) have been shown to cause elevations of plasma cortisol and ACTH, but the pattern of results were confounded by serum cortisol causing feedback changes. We have looked at ACTH responses to saline or CRH infusions over 24 h in 6 normal subjects who, in addition, received either placebo or metyrapone, an 11 beta-hydroxylase inhibitor which blocks the formation of cortisol and thus abolishes glucocorticoid feedback. Cortisol and ACTH levels were measured by radioimmunoassay. Before metyrapone, CRH infusion resulted in exaggerated ACTH peaks throughout the day, as compared with normal saline: there was no influence on the noctural rise in ACTH. Following metyrapone alone, absolute cortisol levels were lower but circadian rhythmicity was preserved. Circadian rhythm of ACTH was maintained, with a fall in the evening to 14.5 +/- 4 pg/ml (mean +/- SE) at midnight and an exaggerated rise overnight, reaching a peak level of 90 +/- 33 pg/ml at 07:00 h. Subjects receiving CRH with metyrapone showed a similar pattern of responses, but with further enhanced ACTH levels. The evening fall reached a nadir of 30 +/- 6 pg/ml at 01:00 h. With diminished glucocorticoid feedback the nocturnal rise in ACTH was augmented by CRH infusion, with a morning peak of 193 +/- 21 pg/ml at 07:00 h. Thus, continuous infusion of CRH in the absence of steroid feedback leads to a retention of the circadian rhythmicity in ACTH secretion, reset at a higher absolute level.(ABSTRACT TRUNCATED AT 250 WORDS)

It has previously been shown that interleukin (IL)-1-like bioactivity is released from rat hypothalamic explants in short-term incubations. Experiments conducted with antiserum against IL-1 alpha or IL-1 beta showed that IL-1 alpha is released more abundantly under basal conditions. For the present study, we developed a specific radioimmunoassay to investigate the release of immunoreactive (ir) IL-1 alpha from the rat hypothalamus in short-term experiments, and observed that release of irIL-1 alpha increased with time and was significantly increased by high KCL concentrations. The stimulatory effect of 28 mM KCL was significantly inhibited by verapamil. Subsequent investigation of the effects of putative modulators of IL-1 alpha secretion, bacterial lipopolysaccharide (LPS) and the prostaglandins E2 (PGE2) and F2 alpha (PGF2 alpha), showed that irIL-1 alpha release was stimulated by 100 ng/ml LPS, but not by higher concentrations, PGE2 had no effect and PGF2 alpha caused dose-dependent inhibition. However, the latter did not seem to exert a tonic inhibitory influence on irIL-1 alpha release, since blockade of cyclo-oxygenase activity by indomethacin had no effect on cytokine release under basal conditions. We conclude that LPS stimulates and PGF2 alpha inhibits basal release of hypothalamic IL-1 alpha, the characteristics of the secretion of which suggest that it may be, at least in part, of neuronal origin.

The endothelins consist of a family of vasoconstrictor peptides originally isolated from endothelial tissue which are now known to be involved in neuroendocrine regulation. However, while there are data indicating the involvement of endothelins in the modulation of the hypothalamo-pituitary-adrenal (HPA) axis, the precise mechanisms involved have been unclear. We have therefore used a previously validated rat hypothalamic explant system in order to investigate the possible modulation of the neurohypophyseal hormones vasopressin and oxytocin, and corticotropin-releasing hormone (CRH), by endothelin-1 (ET-1) and endothelin-3 (ET-3). Following a period of stabilisation, the release of vasopressin, oxytocin and CRH remained approximately constant in successive 20-min incubations. Addition of ET-1 stimulated the release of vasopressin at a dose of 0.1 nmol/l (p A receptor subtype antagonist cyclo (D-Trp-D-Asp-Pro-D-Val-Leu) (BQ-123). ET-1 had no effect on CRH release in the dose range of 0.1-1,000 nmol/l. In case any possible stimulation of CRH might be masked by simultaneous generation of nitric oxide (NO), an inhibitor of CRH secretion, addition of ET-1 was also carried out in the presence of the NO synthase inhibitor, L-NO-Arg: ET-1 was again without effect in this dose range. ET-3 had no effect on any hormone at any concentration. It is concluded that ET-1 may be involved in the control of both vasopressin and oxytocin secretion, most probably at receptors relatively unresponsive to ET-3, the ETA recpetor. Any direct effect of the endothelins on the HPA axis is likely to be exerted via hypothalamic vasopressin rather than CRH.

While interleukin-1 (IL-1) is intimately involved in locally modulating the acute inflammatory response, it is also able to influence processes at remote sites, i.e., in an endocrine manner. While the

Severe exercise in young females is a potent cause of menstrual irregularity, although the exact pathogenesis is currently unknown. We performed a cross-sectional endocrine and metabolic analysis of a group of elite athletes and dancers in order to establish which variable, if any, was specifically associated with changes in menstruation. By using a step-wise discriminant analysis, two independent predictors, elevated serum cortisol and insulin-like growth factor binding protein 1 (IGFBP-1) levels, were found to account for the majority (67%) of the variance. IGFBP-1 is a hepatic protein which is acutely and inversely regulated by insulin, and is thought to modulate the peripheral actions of IGF-1. While the change in serum cortisol may reflect activation of central stress pathways, these findings suggest for the first time that there is a second peripheral signal, IGFBP-1, which may relate the availability of metabolic fuels to the control of reproduction.

It has previously been shown that the cytokines interleukin-1 beta and interleukin-6 (IL-1 beta and IL-6) stimulate directly the release of corticotrophin-releasing-hormone-41 from the rat hypothalamus in vitro, while IL-1 beta can also stimulate the release of somatostatin. These effects can be antagonized by drugs which block prostaglandin (PG) synthesis. PGs are also involved in the control of hypothalamic neuropeptides by other neurotransmitters. In the present study, we have characterized the production of PGs from the rat hypothalamus in vitro, and investigated the effects of IL-1 beta and IL-6, as well as the neurotransmitters norepinephrine, acetylcholine and 5-hydroxytryptamine, on the acute release of PGs, using a well-validated acute hypothalamic incubation system. The rate of release of PGs [PGE2, PGF2 alpha, 6-keto-PGF1 alpha (6KPGF1 alpha) and thromboxane B2 (TXB2) in the medium was found to stabilize after 60 min of preincubation and thereafter remain constant, with TXB2 being the predominant species. Twenty-minute incubation in the presence of human recombinant IL-1 beta or IL-6, in the dose range 1-100 U/ml, had no effect on the release of PGF2 alpha, 6KPGF1 alpha or TXB2; however, the release of PGE2 was significantly increased by both IL-1 beta and IL-6. The effect of IL-1 beta was antagonized by both indomethacin and dexamethasone. None of the other neurotransmitters tested had any effect on the release of any of the PGs.(ABSTRACT TRUNCATED AT 250 WORDS)

It has been suggested that the well-documented hypercortisolaemia found in a proportion of patients with severe depression occurs either in response to excessive secretion of corticotrophin-releasing hormone-41 (CRH-41) from the hypothalamus, or as a consequence of up-regulation of pituitary CRH-41 receptors. The attenuation of the normal ACTH response to CRH-41 in these subjects is thought to result from inhibition of corticotrophin secretion by elevated cortisol levels. We tested these hypotheses by examining ACTH responses to metyrapone, an 11 beta-hydroxylase inhibitor which blocks the formation of cortisol, followed by CRH-41 in 15 severely depressed in-patients diagnosed according to DSM-IIIR criteria. Patients were assigned to two groups according to their response to overnight administration of 1 mg dexamethasone: suppressors (8) and nonsuppressors (7). A third group consisted of 6 healthy matched controls. Metyrapone 750 mg was given 4-hourly for 24 h and samples were taken for cortisol and ACTH. Six of the original 15 patients (3 from each group) were given a bolus dose of 100 micrograms human CRH-41 intravenously after 24 h of metyrapone, and ACTH levels were measured over 2 h. Falls in circulating cortisol in response to metyrapone were similar in all three groups. However, we found exaggerated rises in ACTH amongst the nonsuppressors, as compared to the suppressors and the control group, after metyrapone.(ABSTRACT TRUNCATED AT 250 WORDS)

Ten normal male subjects were administered clonidine (0.1 and 0.2 mg) or a highly-selective alpha2-adrenoceptor agonist S 3341 (1 and 2 mg) on separate occasions in a double-blind randomise

The established technique of dynamic perfusion of dispersed rat anterior pituitary cells was used to investigate the role of dopamine in the release of thyroid-stimulating hormone (TSH). The basal release of TSH was 124 +/- 22 ng/ml (mean +/- SEM) and this remained unchanged in the presence of dopamine (5 X 10(-6) M), while basal prolactin release was suppressed to 50% of control values. Perfusion with thyrotrophin-releasing hormone (TRH) in doses between 1.4 X 10(-10) and 22.4 X 10(-10) M produced a consistent and reproducible dose-response curve for TSH (n = 14) which was not significantly altered by the presence of dopamine (n = 5). Perfusion with bromocriptine (10(-6) M), a dopamine agonist, did not alter the basal or stimulated TSH release. No stimulation of TSH release was observed when the cells were challenged with 2-min pulses of domperidone, a dopamine antagonist (2 X 10(-9) to 2 X 10(-5) M). The inclusion of somatostatin-14 (3 X 10(-9) M) in the perfusate inhibited TRH-stimulated TSH release. Our results suggest that, in the rat, dopaminergic inhibition of TSH release does not occur at the level of the pituitary.

It is well established that compounds that modify dopaminergic and cholinergic activity in man may induce changes in circulating growth hormone (GH). We have, therefore, investigated the effect of a dopamine agonist, bromocriptine, and a dopamine antagonist, domperidone, as well as a muscarinic cholinergic antagonist, pirenzepine, on the GH response to an analogue of GH-releasing hormone (GHRH) in normal male subjects. GHRH(1-29)NH2 induced a rise in serum GH that was augmented by bromocriptine, antagonized by pirenzepine, but was unaltered by domperidone. As this dose of GHRH(1-29) NH2 has been shown to be maximally stimulatory to GH release, it is suggested that there are dopamine stimulatory and cholinergic inhibitory receptors to GH release independent of GHRH in man.

Both the pituitary-adrenal axis and the pituitary-gonadal axis are under the tonic inhibitory control of endogenous opioid peptides in man. However, the precise opioid receptor involved in the modulation of these hormones remains unknown. The effect of a dose of intravenous naloxone on serum levels of luteinising hormone (LH), follicle-stimulating hormone (FSH) and plasma cortisol was therefore investigated in ten normal subjects. In the male subjects, naloxone at a dose of 25 micrograms/kg caused a significant increase in serum LH and FSH; no increase in response was seen at the two higher doses (100 micrograms/kg and 250 micrograms/kg). The lowest dose (6 micrograms/kg) caused no change in serum LH and FSH. In the female subjects, tested in the early follicular phase of their cycles, no dose of naloxone significantly increased circulating gonadotrophins. In both male and female subjects, naloxone only stimulated a rise in serum cortisol at the highest dose (250 micrograms/kg). A second study in six normal subjects demonstrated that the rise in cortisol with the highest dose of naloxone was secondary to a rise in plasma ACTH. It is concluded that the opioid receptor(s) controlling gonadotrophin release in man are naloxone-sensitive, and are probably epsilon-receptors; the naloxone insensitivity of the pituitary-adrenal axis suggests that these responses are modulated by kappa- or delta-receptors.

We report the chromatographic characterization of the ACTH- and LPH-related peptides released from isolated cells prepared from human ACTH-secreting pituitary tumours obtained at surgery (trans-sphenoidal hypophysectomy) from 2 patients with pituitary-dependent Cushing's disease and 2 patients with Nelson's syndrome. The dynamic release of these peptides in response to various stimuli, including rat stalk-median eminence extract (SME) and synthetic arginine vasopressin (AVP) was studied.