Therapeutic options in the management of acromegaly: focus on lanreotide Autogel®

In acromegaly, expert surgery is curative in only about 60% of patients. Postoperative radiation therapy is associated with a high incidence of hypopituitarism and its effect on growth hormone (GH) production is slow, so that adjuvant medical treatment becomes of importance in the management of many patients. To delineate the role of lanreotide in the treatment of acromegaly. Search of Medline, Embase, and Web of Science databases for clinical studies of lanreotide in acromegaly. Treatment with lanreotide slow release and lanreotide Autogel((R)) normalized GH and insulin-like growth factor-I (IGF-I) concentrations in about 50% of patients. The efficacy of 120 mg lanreotide Autogel((R)) on GH and IGF-I levels was comparable with that of 20 mg octreotide LAR. There were no differences in improvement of cardiac function, decrease in pancreatic beta-cell function, or occurrence of side effects, including cholelithiasis, between octreotide LAR and lanreotide Autogel(R). When postoperative treatment with somatostatin analogs does not result in normalization of serum IGF-I and GH levels after noncurative surgery, pegvisomant alone or in combination with somatostatin analogs can control these levels in a substantial number of patient

Response to Letter to the Editor from Richard Dorin:Dynamic pituitary-adrenal interactions in the critically ill after cardiac surgery

Diabetes mellitus: pathophysiological changes and therap

Dynamic pituitary-adrenal interactions in the critically ill after cardiac surgery

Context: Patients with critical illness are thought to be at risk of adrenal insufficiency. There are no models of dynamic hypothalamic-pituitary-adrenal (HPA) axis function in this group of patients and thus current methods of diagnosis are based on aggregated, static models.Objective: To characterize the secretory dynamics of the HPA axis in the critically ill (CI) after cardiac surgery.Design: Mathematical modeling of cohorts.Setting: Cardiac critical care unit.Patients: 20 male patients CI at least 48 hours after cardiac surgery and 19 healthy (H) male volunteers. Interventions: None.Main Outcome Measures: Measures of hormone secretory dynamics were generated from serum adrenocorticotrophic hormone (ACTH) sampled every hour and total cortisol every 10 min for 24 h.Results: All CI patients had pulsatile ACTH and cortisol profiles. CI patients had similar ACTH secretion (1036.4 [737.6] pg/mL/24 h) compared to the H volunteers (1502.3 [1152.2] pg/mL/24 h; P=.20), but increased cortisol secretion (CI: 14 447.0 [5709.3] vs H: 5915.5 [1686.7)] nmol/L/24 h; P<.0001). This increase in cortisol was due to nonpulsatile (CI: 9253.4 [3348.8] vs H: 960 [589.0] nmol/L/24 h, P<.0001), rather than pulsatile cortisol secretion (CI: 5193.1 [3018.5] vs H: 4955.1 [1753.6] nmol/L/24 h; P=.43). Seven (35%) of the 20 CI patients had cortisol pulse nadirs below the current international guideline threshold for critical illness-related corticosteroid insufficiency, but an overall secretion that would not be considered deficient.Conclusions: This study supports the premise that current tests of HPA axis function are unhelpful in the diagnosis of adrenal insufficiency in the CI. The reduced ACTH and increase in nonpulsatile cortisol secretion imply that the secretion of cortisol is driven by factors outside the HPA axis in critical illness.Diabetes mellitus: pathophysiological changes and therap

Ghrelin Gene Deletion Alters Pulsatile Growth Hormone Secretion in Adult Female Mice

Using preproghrelin-deficient mice (Ghrl-/-), we previously observed that preproghrelin modulates pulsatile growth hormone (GH) secretion in post-pubertal male mice. However, the role of ghrelin and its derived peptides in the regulation of growth parameters or feeding in females is unknown. We measured pulsatile GH secretion, growth, metabolic parameters and feeding behavior in adult Ghrl-/- and Ghrl+/+ male and female mice. We also assessed GH release from pituitary explants and hypothalamic growth hormonereleasing hormone (GHRH) expression and immunoreactivity. Body weight and body fat mass, linear growth, spontaneous food intake and food intake following a 48-h fast, GH pituitary contents and GH release from pituitary explants ex vivo, fasting glucose and glucose tolerance were not different among adult Ghrl-/- and Ghrl+/+ male or female mice. In vivo, pulsatile GH secretion was decreased, while approximate entropy, that quantified orderliness of secretion, was increased in adult Ghrl-/- females only, defining more irregular GH pattern. The number of neurons immunoreactive for GHRH visualized in the hypothalamic arcuate nucleus was increased in adult Ghrl-/- females, as compared to Ghrl+/+ females, whereas the expression of GHRH was not different amongst groups. Thus, these results point to sex-specific effects of preproghrelin gene deletion on pulsatile GH secretion, but not feeding, growth or metabolic parameters, in adult mice.Fil: Hassouna, Rim. Université Paris Cité; Francia. Universite de Bordeaux; Francia. Inserm; FranciaFil: Fernandez, Gimena. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Multidisciplinario de Biología Celular. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Multidisciplinario de Biología Celular. Universidad Nacional de La Plata. Instituto Multidisciplinario de Biología Celular; ArgentinaFil: Lebrun, Nicolas. Université Paris Cité; FranciaFil: Fiquet, Oriane. Universite de Bordeaux; Francia. Université Paris Cité; Francia. Inserm; FranciaFil: Roelfsema, Ferdinand. Leiden University Medical Center; Países BajosFil: Labarthe, Alexandra. Université Paris Cité; Francia. Universite de Bordeaux; Francia. Inserm; FranciaFil: Zizzari, Philippe. Universite de Bordeaux; Francia. Université Paris Cité; Francia. Inserm; FranciaFil: Tomasetto, Catherine. Universite de Bordeaux; Francia. Université Paris Cité; Francia. Inserm; FranciaFil: Epelbaum, Jacques. Universite de Bordeaux; Francia. Université Paris Cité; Francia. Inserm; FranciaFil: Viltart, Odile. Universite de Bordeaux; Francia. Université Paris Cité; Francia. Inserm; FranciaFil: Chauveau, Christophe. Université Du Littoral Côte D‘opale; FranciaFil: Perello, Mario. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Multidisciplinario de Biología Celular. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Multidisciplinario de Biología Celular. Universidad Nacional de La Plata. Instituto Multidisciplinario de Biología Celular; ArgentinaFil: Tolle, Virginie. Université Paris Cité; Franci

Interrelationships Between Pituitary Hormones as Assessed From 24-hour Serum Concentrations in Healthy Older Subjects

Context: Hormones of the hypothalamic-pituitary-target gland axes are mostly investigated separately, whereas the interplay between hormones might be as important as each separate hormonal axis.Objective: Our aim is to determine the interrelationships between GH, TSH, ACTH, and cortisol in healthy older individuals.Design: We made use of 24-hour hormone serum concentrations assessed with intervals of 10 minutes from 38 healthy older individuals with a mean age (SD) of 65.1 (5.1) years from the Leiden Longevity Study. Cross-correlation analyses were performed to assess the relative strength between 2 24-hour hormone serum concentration series for all possible time shifts. Cross-approximate entropy was used to assess pattern synchronicity between 2 24-hour hormone serum concentration series.Results: Within an interlinked hormonal axis, ACTH and cortisol were positively correlated with a mean (95% confidence interval) correlation coefficient of 0.78 (0.74-0.81) with cortisol following ACTH concentrations with a delay of 10 minutes. Between different hormonal axes, we observed a negative correlation coefficient between cortisol and TSH of -0.30 (-0.36 to -0.25) with TSH following cortisol concentrations with a delay of 170 minutes. Furthermore, a positive mean (95% confidence interval) correlation coefficient of 0.29 (0.22-0.37) was found between TSH and GH concentrations without any delay. Moreover, cross-approximate entropy analyses showed that GH and cortisol exhibit synchronous serum concentration patterns.Conclusions: This study demonstrates that interrelations between hormones from interlinked as well as different hypothalamic-pituitary-target gland axes are observed in healthy older individuals. More research is needed to determine the biological meaning and clinical consequences of these observations.Pathophysiology, epidemiology and therapy of agein

Detecting Regulatory Mechanisms in Endocrine Time Series Measurements

The regulatory mechanisms underlying pulsatile secretion are complex, especially as it is partly controlled by other hormones and the combined action of multiple agents. Regulatory relations between hormones are not directly observable but may be deduced from time series measurements of plasma hormone concentrations. Variation in plasma hormone levels are the resultant of secretion and clearance from the circulation. A strategy is proposed to extract inhibition, activation, thresholds and circadian synchronicity from concentration data, using particular association methods. Time delayed associations between hormone concentrations and/or extracted secretion pulse profiles reveal the information on regulatory mechanisms. The above mentioned regulatory mechanisms are illustrated with simulated data. Additionally, data from a lean cohort of healthy control subjects is used to illustrate activation (ACTH and cortisol) and circadian synchronicity (ACTH and TSH) in real data. The simulation and the real data both consist of 145 equidistant samples per individual, matching a 24-hr time span with 10 minute intervals. The results of the simulation and the real data are in concordance

Limited effects of growth hormone replacement in patients with GH deficiency during long-term cure of acromegaly

The aim of this study was to assess the effects of replacement with recombinant human growth hormone (rhGH) in patients with GH deficiency (GHD) after treatment of acromegaly. Intervention study. Sixteen patients (8 men, age 56 years), treated for acromegaly by surgery and radiotherapy, with an insufficient GH response to insulin-induced hypoglycaemia, were treated with 1 year of rhGH replacement. Study parameters were assessed at baseline and after 1 year of rhGH replacement. Study parameters were cardiac function, body composition, bone mineral density (BMD), fasting lipids, glucose, bone turnover markers, and Quality of Life (QoL). During rhGH replacement IGF-I concentrations increased from −0.4 ± 0.7 to 1.0 ± 1.5 SD (P = 0.001), with a mean daily dose of 0.2 ± 0.1 mg in men and 0.3 ± 0.2 mg in women. Nonetheless, rhGH replacement did not alter cardiac function, lipid and glucose concentrations, body composition or QoL. Bone turnover markers (PINP and β crosslaps) levels increased (P = 0.005 and P = 0.021, respectively), paralleled by a small, but significant decrease in BMD of the hip. The beneficial effects of rhGH replacement in patients with GHD during cure from acromegaly are limited in this study

Acromegaly caused by growth hormone-releasing hormone-producing tumors: long-term observational studies in three patients

We report on three newly diagnosed patients with extracranial ectopic GHRH-associated acromegaly with long-term follow-up after surgery of the primary tumor. One patient with a pancreatic tumor and two parathyroid adenomas was the index case of a large kindred of MEN-I syndrome. The other two patients had a large bronchial carcinoid. The first patient is still in remission now almost 22 years after surgery. In the two other patients GHRH did not normalize completely after surgery and they are now treated with slow-release octreotide. IGF-I normalized in all patients. During medical treatment basal GH secretion remained (slightly) elevated and secretory regularity was decreased in 24 h blood sampling studies. We did not observe development of tachyphylaxis towards the drug or radiological evidence of (growing) metastases. We propose life-long suppressive therapy with somatostatin analogs in cases with persisting elevated serum GHRH concentrations after removal of the primary tumor. Independent parameters of residual disease are elevated basal (nonpulsatile) GH secretion and decreased GH secretory regularity

Mutations in IRS4 are associated with central hypothyroidism

Background: Four genetic causes of isolated congenital central hypothyroidism (CeH) have been identified, but many cases remain unexplained. We hypothesised the existence of other genetic causes of CeH with a Mendelian inheritance pattern. Methods: We performed exome sequencing in two families with unexplained isolated CeH and subsequently Sanger sequenced unrelated idiopathic CeH cases. We performed clinical and biochemical characterisation of the probands and carriers identified by family screening. We investigated IRS4 mRNA expression in human hypothalamus and pituitary tissue, and measured serum thyroid hormones and Trh and Tshb mRNA expression in hypothalamus and pituitary tissue of Irs4 knockout mice. Results: We found mutations in the insulin receptor substrate 4 (IRS4) gene in two pairs of brothers with CeH (one nonsense, one frameshift). Sequencing of IRS4 in 12 unrelated CeH cases negative for variants in known genes yielded three frameshift mutatio