Jean Mockel

Two years of replacement therapy in adults with growth hormone deficiency

Although several studies have shown beneficial short‐term effects of recombinant human growth hormone (rhGH) therapy in adult GH deficient (GHD) patients, few data are available on large groups of patients treated for more than one year. In addition, the optimal dose of rhGH for each patient and the baseline parameters that predict which patients will benefit most from therapy or will have adverse events are not entirely elucidated.

Hypouremia in the Syndrome of Inappropriate Secretion of Antidiuretic Hormone

Excerpt Low blood urea levels are a common finding in the syndrome of inappropriate secretion of antidiuretic hormone (1). Although they usually are attributed to body fluid dilution, some have sug...

Sleep disturbances, daytime sleepiness, and quality of life in adults with growth hormone deficiency.

CONTEXT Low energy and fatigue are frequent complaints in subjects with GH deficiency (GHD). Because interrelations between sleep and GH regulation are well documented, these complaints could partly reflect alterations of sleep quality. OBJECTIVE The objective of the study was to determine objective and subjective sleep quality and daytime sleepiness in adult GHD patients. SUBJECTS Thirty patients, aged 19-74 yr, with untreated GHD (primary pituitary defects confirmed or likely in 26 patients, hypothalamic origin in four patients), and 30 healthy controls individually matched for gender, age, and body mass index participated in the study. Patients with associated pituitary deficiencies (n = 28) were on hormonal replacement therapy. METHODS Polygraphic sleep recordings, assessment of Pittsburgh Sleep Quality Index, and Quality of Life Assessment for GHD in Adults were measured. RESULTS Irrespective of etiology, GHD patients had a Pittsburgh Sleep Quality Index score above the clinical cutoff for poor sleep and lower Quality of Life Assessment for GHD in Adults scores than controls, with tiredness being the most affected domain. Patients with pituitary GHD spent more time in slow-wave sleep (SWS) and had a higher intensity of SWS than their controls. Among these patients, older individuals obtained less total sleep than controls, and their late sleep was more fragmented. Contrasting with pituitary GHD, the four patients with hypothalamic GHD had lower intensity of SWS than their controls. CONCLUSIONS GHD is associated with sleep disorders that may be caused by specific hormonal alterations as well as with poor subjective sleep quality and daytime sleepiness. Disturbed sleep is likely to be partly responsible for increased tiredness, a major component of quality of life in GHD.

Thyrotropin does not activate the phosphatidylinositol bisphosphate hydrolyzing phospholipase C in the dog thyroid

The effects of thyrotropin (TSH) and carbamylcholine (Cchol) on labeling by [3H]inositol of inositol lipids (i.e. total phosphoinositides (PI)) and inositol phosphates (IP) and on diacylglycerol (DAG) generation was studied in dog thyroid slices. Both agents (TSH 1-250 mU/ml, Cchol 10(-6) to 10(-4) M) increased the incorporation of [3H]inositol into PI and IP during 4 h labeling experiments; but the [3H]IP/[3H]PI ratio as compared to the control one was not modified by TSH (10 mU/ml: 1.03 +/- 0.24) while it was increased by Cchol (10(-5) M: 6.14 +/- 1.81). Slices prelabeled in the absence of agonists were then incubated in the presence or absence of 10 mM LiCl +/- 10(-4) M inositol. With LiCl alone, Cchol increased [3H]IP generation, while no such effect of TSH could be detected. However, in the absence of LiCl or in the presence of both LiCl and 10(-4) M inositol, TSH and Cchol both increased [3H]PI and [3H]IP, but IP and PI labeling remained strictly proportional with TSH (10 mU/ml: [3H]IP/[3H]PI ratio = 1.03 +/- 0.06 vs. control), while Cchol increased this ratio (10(-5) M = 2.44 +/- 0.24) with a preferential accumulation of IP. Both agonists stimulated DAG formation with similar kinetics and maximal effects (400% of control at 60 min).(ABSTRACT TRUNCATED AT 250 WORDS)

Ectopic Cushing's syndrome and pulmonary carcinoid tumour identified by [111In-DTPA-D-Phe1]octreotide.

The differential diagnosis and management of Cushings syndrome remain difficult, particularly for ectopic adrenocorticotropin (ACTH) syndromes resulting from small bronchial carcinoids. We report the case of a 41-year-old man with ectopic ACTH-dependent Cushings syndrome. Two computed tomography scans of the thorax were normal and magnetic resonance imaging of the chest showed a 6-mm hyperintense T1-weighted area close to the left pulmonary hilus, interpreted as probably vascular by the radiologists. An [111In-DTPA-D-Phe1]octreotide scintigraphy scan demonstrated a positive image for somatostatin receptors in exactly the same location and surgery confirmed the presence of a small ACTH-secreting carcinoid tumour in the upper left lung lobe which was resected. Surgery cured the hypercorticism of the patient. The differential diagnosis of Cushings syndrome and the procedure for localisation of an ACTH source are discussed.

Chronic Alcoholism: a Predisposing Factor for Hypocalcemia in Acute Pancreatitis

The serum levels of calcium, corrected for serum albumin, were investigated in 65 consecutive patients with acute pancreatitis. Hypocalcemia was present in 55% of 38 patients in whom chronic alcoholism was the associated etiology, and in 26% of 27 other patients (p less than 0.02). In the alcoholic patients, the mean duration of hypocalcemia was significantly longer than in the non-alcoholic patients (5 vs. 1--2 days; p less than 0.001). The severity of pancreatitis seemed to be comparable in both groups of patients. This suggests that chronic alcoholism may be a predisposing factor for hypocalcemia in acute pancreatitis.

Effetti della terapia sostitutiva con GH sul sonno nei pazienti adulti con deficit di GH di origine ipofisaria

L.L. Morselli, A. Nedeltcheva, R. Leproult, K. Spiegel, E. Martino, J.J. Legros, R.E. Weiss, J. Mockel, E. Van Cauter, G. Copinschi Eur J Endocrinol 2013; 168: 763-770 La secrezione ipofisaria di GHRH non solo regola la produzione di GH da parte delle cellule somatotrope dell’ipofisi, ma influenza anche il sonno. In modo particolare, l’attività di GHRH è legata all’induzione degli stadi più profondi del sonno, caratterizzati dalla presenza all’elettroencefalogramma delle tipiche onde delta di ampio voltaggio e bassa frequenza (0,75-4 Hz). L’assenza di feedback negativo sulla regolazione dell’attività dei neuroni ipotalamici che rilasciano GHRH, come avviene nel deficit di GH (GHD) di origine ipofisaria, potrebbe quindi tradursi in una marcata stimolazione del sonno non REM profondo o sonno a “onde lente”. I pazienti con GHD non trattati riferiscono spesso sonnolenza diurna e una generale perdita delle proprietà rigeneranti del sonno, con conseguenti ripercussioni negative sulla qualità di vita. Recenti studi dimostrano infatti che il sonno in pazienti con GHD legato a cause ipofisarie si presenta frammentato, costituito da una attività delta o slowwave activity (SWA) preponderante rispetto ai soggetti sani. Lo scopo di questo studio è stato quello di valutare se la somministrazione di rhGH per 4 mesi fosse in grado di modificare l’eccessiva presenza di sonno ad onde lente nei pazienti adulti con GHD ipofisario. Lo studio ha coinvolto 13 pazienti adulti (età 22-77 anni) con diagnosi certa o presunta di GHD di origine ipofisaria formulata in base al riscontro di valori di GH <3 μg/l in risposta all’insulin tolerance test (ITT). I pazienti venivano suddivisi in maniera randomizzata in un gruppo che riceveva placebo e in uno a cui veniva somministrato rhGH. Al termine di 4 mesi di trattamento venivano acquisite informazioni sulla durata e sulla struttura del sonno nei due gruppi mediante registrazione polisonnografica e attraverso un sensore di movimento applicato al polso (wrist actigraphy). La somministrazione di rhGH ha determinato una riduzione della durata totale di sonno rispetto al placebo (479±11 vs 431±19 minuti; p=0,005). Questo dato riflette principalmente la tendenza al risveglio anticipato nei pazienti trattati con GH rispetto al placebo. Il trattamento ha provocato una riduzione del 27% dell’attività ad onde lente (stadio III e IV NREM) statisticamente non significativa. Tuttavia l’attività delta registrata durante le prime 6 ore di sonno è diminuita del 30% al termine del trattamento con rhGH rispetto al placebo (p=0,048). I dati polisonnografici registrati concordavano con le sensazioni riportate dai pazienti al termine del periodo di trattamento, con una riduzione del sonno (differenza di 24 minuti; p=0,002) e un risveglio anticipato (differenza di 46 minuti; p=0,007) rispetto al placebo. Questo studio, sebbene sia stato condotto in un campione esiguo di soggetti e per la maggior parte di età superiore ai 40 anni (l’attività delta tende a ridursi fisiologicamente con l’avanzare dell’età), dimostra che il trattamento con rhGH per 4 mesi può invertire alcuni dei disturbi del sonno osservati nei pazienti adulti con GHD. Questi risultati, inoltre, aggiungono una serie di prove del ruolo centrale svolto dal GHRH nel modulare la qualità del sonno nell’uomo.

Lanreotide slow release in the treatment of acromegaly: a study in 66 patients

OBJECTIVE Slow-release (SR) lanreotide is a long-acting somatostatin analog that has been developed in order to overcome the inconvenience of multiple daily subcutaneous injections of octreotide, required for metabolic control in acromegaly. Lanreotide SR has been found to be well tolerated and effective in reducing GH and IGF-I levels but clinical data are still limited compared with those with subcutaneous octreotide treatment. DESIGN Sixty-six unselected patients with active acromegaly were therefore evaluated in a multi-center, prospective, open label study. Lanreotide SR was given at a dose of 30mg intramuscular every 7-14 days. METHODS At baseline and after 2, 4, 8, 12, 24, 36 and 48 weeks patients underwent a clinical examination with assessment of acromegaly related symptoms, and blood was sampled for serum GH, IGF-I, prolactin, glycosylated hemoglobin, fasting glucose, hematology, kidney function and liver function tests. Biliary ultrasonography and pituitary magnetic resonance imaging were performed at baseline and after one year. RESULTS Treatment resulted in a significant improvement in the symptom score from 2.69+/-0.27 to 1.06+/-0.17 (P<0.0001). Serum IGF-I levels fell from 699+/-38microg/l at baseline to 399+/-26microg/l (P<0.0001, n=60) after one month, after which levels remained stable: 480+/-37microg/l after 6 months (n=54) and 363+/-32microg/l after one year (n=46). GH levels dropped from 13.8+/-3.2microg/l to 4.3+/-0.7microg/l after one month (P<0.0001, n=60) and remained stable thereafter: 3.9+/-0.4microg/l (n=54) after 6 months and 3.5+/-1.1microg/l after one year (n=46). Twenty-nine out of 66 patients (44%) attained a normal age-corrected IGF-I level and 30 patients (45%) attained a GH level below 2.5microg/l. Pituitary adenoma shrinkage of at least 25% was found in 5 of 14 patients (36%) after one year. Side effects were mainly transient gastrointestinal symptoms and pain at the injection site, resulting in drug discontinuation in only 6 patients (9%). Two patients developed new gall stones. No difference was found between subcutaneous octreotide and lanreotide SR in efficacy and almost all patients preferred the easier dose administration of lanreotide SR. CONCLUSIONS Long-term treatment of acromegaly with SR-lanreotide is effective in controlling GH and IGF-I levels and symptoms and is well tolerated in the majority of patients. Compared with subcutaneous octreotide, lanreotide SR considerably improves patients acceptance of therapy while having the same overall efficacy.

Retroinhibition of the calcium-phosphatidylinositol cascade by diacylglycerol in thyroid

A few years ago, cell control was still often described by 2 or 3 simple regulatory pathways (involving cyclic AMP, calcium and cyclic GMP), the relative importance of which was much contested by their various proponents. We predicted that interconnections between these pathways and between various steps of each pathway would be progressively demonstrated, so that at some time, any possible regulatory link between the steps of the different pathways would eventually been shown to exist in at least one system (1). Thus the concept of a specific regulatory network for each type of cell would at some time prevail over simplistic theories. The present symposium clearly supports these ideas. In this communication, we wish to report evidence in favor of the operation in the dog thyroid follicular cell of a negative feedback of one of the intracellular signals generated by the phosphatidy1inositol cascade on the first step of this cascade.