S. Tsagarakis

The European Registry on Cushing's syndrome: 2-year experience. Baseline demographic and clinical characteristics

OBJECTIVE The European Registry on Cushings syndrome (ERCUSYN) is designed to collect prospective and follow-up data at EU level on Cushings syndrome (CS). DESIGN AND METHODS Baseline data on 481 CS patients (390 females, 91 males; mean age (±s.d.): 44±14 years) collected from 36 centres in 23 countries, including new patients from 2008 and retrospective cases since 2000. Patients were divided into four major aetiologic groups: pituitary-dependent CS (PIT-CS) (66%), adrenal-dependent CS (ADR-CS) (27%), CS from an ectopic source (ECT-CS) (5%) and CS from other aetiologies (2%). RESULTS Proportion of men in the ECT-CS group was higher than in the other groups (P<0.05). The ADR-CS group was older than the PIT-CS (P<0.05). Prevalence of hirsutism (92%) and diabetes (74%) in ECT-CS was higher than in the other groups (P<0.05 and P<0.01 respectively). PIT-CS had more skin alterations, menstrual irregularities and hirsutism than ADR-CS (P<0.01). Reduced libido was more prevalent in men than women (P<0.01). Prevalence of spine osteoporosis was higher in men than women (P<0.05), and males had more vertebral and rib fractures than females (52 vs 18% for vertebrae; P<0.001 and 34 vs 23% for ribs; P<0.05). ECT-CS consulted a diabetologist more frequently than ADR-CS (P<0.05), while a gynaecologist was consulted more often by women with PIT-CS or ADR-CS than with ECT-CS (P<0.05). Overall, weight gain was more common in women than men (P<0.01). CushingQoL and EuroQoL visual analogue scale scores did not differ between the groups. CONCLUSIONS The ERCUSYN project demonstrates a heterogeneous clinical presentation of CS at a European level, depending on gender and aetiology.

GH FEEDBACK OCCURS THROUGH MODULATION OF HYPOTHALAMIC SOMATOSTATIN UNDER CHOLINERGIC CONTROL: STUDIES WITH PYRIDOSTIGMINE AND GHRH

We have studied the effect of increased cholinergic tone on the GH response to growth hormone‐releasing hormone (GHRH) and on GH feedback, using pyridostigmine, an acetylcholinesterase inhibitor. In six healthy male adult volunteers 120 mg oral pyridostigmine increased basal GH secretion compared to placebo and augmented the GH response to 100 μg i.v. GHRH (1‐29) NH2; the effect was more than the additive effect of pyridostigmine and GHRH when each was given alone. Pretreatment with 2 IU methionyl‐hGH given i.v. abolished the serum GH response to GHRH given 3 h later, demonstrating a negative feedback loop of GH on the response to GHRH; this inhibited response to GHRH was restored in subjects given pyridostigmine as well as methionyl‐hGH. The data demonstrate that enhanced cholinergic tone releases GH, augments the serum GH response to GHRH and unblocks the negative feedback effect of methionyl‐hGH pretreatment on the GH response to GHRH. These results suggest that GH negative feedback effects on its own secretion occur predominantly through increased hypothalamic somatostatin secretion; this somatostatin secretion is under inhibitory cholinergic control.

Megavoltage pituitary irradiation in the management of prolactinomas : long-term follow-up

objective To determine the long‐term effects of external beam megavoltage radiotherapy (RT: 4500 cGy via three portals at 180 cGy or less total daily dose) on endocrine function in prolactinomas.

Neuropeptide-Y stimulates CRF-41 release from rat hypothalami in vitro.

There is increasing evidence that neuropeptide-Y (NPY) exerts a stimulatory effect on the hypothalamo-pituitary-adrenal axis. Although it has been suggested that this stimulatory effect may be mediated via an action on hypothalamic CRF-41 release, direct measurements have not previously been made. In this study, the direct effect of NPY on hypothalamic CRF-41 secretion has been investigated in vitro using acute hypothalamic explants and previously described incubation techniques. NPY in the concentration range 10(-8)-10(-5) M produced a dose-dependent stimulation of CRF-41 release which was maximum at a concentration of 10(-6) M. The possibility that this stimulatory effect might reflect an interaction with noradrenergic inputs to CRF-41 neurons was excluded by incubating the hypothalami in the presence of NPY in combination with either the beta-adrenoceptor antagonist, propranolol (10(-5) M), or the alpha 1-adrenoceptor antagonist, prazosin (10(-5) M); neither inhibited NPY-stimulated CRF-41 release, suggesting that this effect is unrelated to noradrenergic pathways and is exerted through distinct receptor mechanisms. Furthermore, norepinephrine-stimulated (10(-8)-10(-6) M) CRF-41 release was not potentiated in the presence of NPY (10(-6) M). In summary, these data provide evidence for a direct stimulatory effect of NPY on CRF-41 secretion from the rat hypothalamus in vitro. This effect is independent of catecholaminergic interactions, suggesting that it is mediated either directly on CRF-41 neurons or through non-catecholaminergic neuronal systems.

Inhibition of CRH-41 release by substance P, but not substance K, from the rat hypothalamus in vitro

Substance P is one of a series of tachykinins which is present throughout the central nervous system, and has potent effects on neuroendocrine function. Recent studies have suggested that it inhibits pituitary-adrenal activity at a site above the level of the pituitary. We have therefore used a well-validated rat hypothalamic incubation system to investigate the effects of substance P on the release of the principal corticotrophin-releasing hormone, CRH-41. Substance P caused a dose-dependent inhibition of the 28-mM KCl-stimulated release of CRH-41, with a maximum effect at 100 nM (P less than 0.01). This effect was attenuated by 10 microM of the substance P antagonist (D-Pro2,-D-Trp7,9)-substance P. No statistically significant effect of substance K was seen at 1 or 100 nM. Substance P, at a dose of 100 nM, did not alter the 28-mM KCl-stimulated release of CRH-41 from isolated median eminences in vitro. It is concluded that substance P is a potent inhibitor of the stimulated release of CRH-41, probably acting at a site within the hypothalamic paraventricular nucleus.

Interleukin-6, a growth promoting cytokine, is present in human pituitary adenomas: an immunocytochemical study.

OBJECTIVE The aim of this study was to investigate the presence of interleukin‐6 (IL‐6) in human pituitary adenomas.

Gamma-Aminobutyric Acid Modulation of Corticotrophin-Releasing Factor-41 Secretion from the Rat Hypothalamus in vitro.

There is increasing evidence for a centrally mediated inhibitory effect of the amino‐acid neurotransmitter y‐aminobutyric acid (GABA) on the hypothalamo‐pituitary‐adrenal axis. In the present study, the direct effect of GABA in modulating the release of the 41‐residue corticotrophin‐releasing factor (CRF‐41), the major CRF identified so far, was investigated in acute hypothalamic explants by utilizing previously validated incubation and assay techniques. While GABA (10‐7’to 10‐5 M) had no effect on basal CRF‐41 release (P > 0.05), it significantly suppressed K ‐ (28 mM)‐stimulated release in a dose‐dependent manner (P < 0.01). A similar inhibitory effect was observed with the GABA agonist muscimol (10‐7 to 10‐5 M). Noradrenaline (10‐6 M) ‐induced CRF‐41 release was also significantly inhibited by GABA 10‐6 M. The inhibitory effect of GABA on K+‐stimulated CRF‐41 secretion was completely. reversed by the GABA antagonists bicuculline and picrotoxin (10‐6 to 10‐5 M) in a dose‐dependent fashion. Both bicuculline and picrotoxin stimulated basal and K+ (28 mM)‐stimulated CRF‐41 release, indicating the presence of tonic inhibition by endogenous GABA in the basal state. Finally, GABA 10‐5 M was able to significantly inhibit the stimulated release of CRF‐41 from the isolated median eminence.

Diagnostic tests for Cushing's syndrome differ from published guidelines: data from ERCUSYN.

OBJECTIVE To evaluate which tests are performed to diagnose hypercortisolism in patients included in the European Registry on Cushings syndrome (ERCUSYN), and to examine if their use differs from the current guidelines. PATIENTS AND METHODS We analyzed data on the diagnostic tests performed in 1341 patients with Cushings syndrome (CS) who have been entered into the ERCUSYN database between January 1, 2000 and January 31, 2016 from 57 centers in 26 European countries. Sixty-seven percent had pituitary-dependent CS (PIT-CS), 24% had adrenal-dependent CS (ADR-CS), 6% had CS from an ectopic source (ECT-CS) and 3% were classified as having CS from other causes (OTH-CS). RESULTS Of the first-line tests, urinary free cortisol (UFC) test was performed in 78% of patients, overnight 1 mg dexamethasone suppression test (DST) in 60% and late-night salivary cortisol (LSaC) in 25%. Use of LSaC increased in the last five years as compared with previous years (P < 0.01). Use of HDDST was slightly more frequent in the last 5 years as compared with previous years (P < 0.05). Of the additional tests, late-night serum cortisol (LSeC) was measured in 62% and 48-h 2 mg/day low-dose dexamethasone suppression test (LDDST) in 33% of cases. ACTH was performed in 78% of patients. LSeC and overnight 1 mg DST supported the diagnosis of both PIT-CS and ADR-CS more frequently than UFC (P < 0.05). CONCLUSIONS Use of diagnostic tests for CS varies across Europe and partly differs from the currently available guidelines. It would seem pertinent that a European consensus be established to determine the best diagnostic approach to CS, taking into account specific inter-country differences with regard to the availability of diagnostic tools.

Similar high molecular weight forms of growth hormone-releasing hormone are found in rat brain and testis

We have utilized a new radioimmunoassay for rat growth hormone-releasing hormone (GHRH) to investigate the presence of GHRH in different organ systems of adult rat, and specifically the rat central nervous system (CNS). The highest concentration of GHRH was found, as expected, in the hypothalamus, but significant amounts were also located in the brain cortex, predominantly the frontal cortex, as well as in the testis. Smaller amounts were identified in the cerebellum and brain stem. Sephadex and reversed phase high performance liquid chromatography demonstrated that while hypothalamic GHRH exclusively eluted at the position of rat GHRH (1-43), in testis and brain the major form was predominantly (testis) or wholly (brain) of a higher molecular weight. While this molecular species has yet to be further characterized, the data suggest the similar GHRH-like species exist in the CNS as well as the testis.

Isolated ACTH deficiency with absent response to corticotrophin-releasing factor--41. Evidence for a primary pituitary defect.

ABSTRACT. An 8‐year‐old girl presenting in hypoglycaemic coma was shown to have isolated deficiency of adrenocorticotrophic hormone (ACTH) secretion. Failure to secrete ACTH in response to intravenous administration of synthetic ovine corticotrophin‐releasing factor (CRF‐41) suggests that this disorder was due to a primary pituitary defect, rather than of hypothalamic origin.