Rab18 is reduced in pituitary tumors causing acromegaly and its overexpression reverts growth hormone hypersecretion.

CONTEXT: Rab proteins regulate the sequential steps of intracellular membrane transport. Alterations of these GTPases and their associated proteins are emerging as the underlying cause for several human diseases involving dysregulated secretory activities. OBJECTIVE: Herein we investigated the role of Rab18, which negatively regulates hormone secretion by interacting with secretory granules, in relation to the altered functioning of tumoral pituitary somatotropes causing acromegaly. PATIENTS: A total of 18 patients diagnosed with pituitary tumors causing acromegaly (nine patients) or nonfunctioning adenomas (nine patients) underwent endoscopic transsphenoidal surgery. Adenomas were subsequently processed to evaluate Rab18 production in relation to GH secretion. RESULTS: We found that somatotropinoma cells are characterized by a high secretory activity concomitantly with a remarkably reduced Rab18 expression (15%) and protein content levels (30%), as compared with cells from nonfunctioning pituitary adenomas derived from patients with normal or reduced GH plasma levels (100%). Furthermore, immunoelectron microscopy revealed that Rab18 association with the surface of GH-containing secretory granules was significantly lower in somatotropes from acromegalies than nonfunctioning pituitary adenomas. Finally, we provide evidence that modulation of Rab18 gene expression can revert substantially the hypersecretory activity of cells because Rab18 overexpression reduced by 40% the capacity of cells from acromegalies to respond to GHRH stimulation. CONCLUSION: These results suggest that molecular alterations affecting individual components of the secretory granule traffic machinery can contribute to maintain a high level of GH in plasma. Accordingly, Rab18 constitutes a valuable target as a diagnostic, prognostic, and/or therapeutic tool for human acromegaly.

Persistent body fat mass and inflammatory marker increases after long-term cure of Cushing's syndrome.

OBJECTIVE: Although increased central fat mass is characteristic of active Cushing's syndrome (CS), little is known about body composition and secretion of adipokines after long-term recovery of CS. The aim of this study was to evaluate central fat mass and its correlation with adipokines and cardiovascular risk factors in patients after long-term remission of CS. METHODS: Thirty-seven women with CS in remission (27 of pituitary and 10 of adrenal origin; mean age, 50 +/- 14 yr; mean time of hormonal cure, 11 +/- 6 yr) were enrolled and compared to 14 women with active CS and 85 gender-, age-, and body mass index-matched healthy controls. Total and trunk fat mass were measured by dual-energy x-ray absorptiometry scanning. Laboratory parameters and adipokine levels [including adiponectin, visfatin, soluble TNFalpha-receptor 1 (sTNF-R1), sTNF-R2, and IL-6] were measured. RESULTS: Cured CS patients had more total and trunk fat mass than controls. Cured and active CS had higher levels of sTNF-R1 and IL-6 and lower adiponectin levels than controls. Higher insulin levels and blood pressure in both groups of CS patients and higher apolipoprotein B in cured CS were observed compared to controls. sTNF-R1 correlated positively with percentage of trunk fat mass and remained significant after adjusting for anthropometric parameters. CONCLUSION: Despite long-term cure, patients who have suffered CS exhibit persistent accumulation of central fat, as in active hypercortisolemia, with the consequent unfavorable adipokine profile, leading to a state of low-grade inflammation. This situation determines a persistent and increased cardiovascular risk in these patients.

Deleterious effects of glucocorticoid replacement on bone in women after long-term remission of Cushing's syndrome.

Endogenous hypercortisolism and high-dose and long-term glucocorticoid (GC) therapy reduce bone mass. Patients in remission after successful treatment of Cushing's syndrome (CS) often present hypoadrenalism and require long-term GC replacement. The aim of our study was to evaluate whether this GC "replacement" had any further effect on bone in women after long-term remission of CS. Thirty-seven women (mean age: 50 +/- 14 yr; 27 of pituitary and 10 of adrenal origin) with cured CS (mean time of cure: 11 +/- 6 yr), 14 with active CS, and 85 sex-, body mass index (BMI)-, and age-matched controls were enrolled. BMD and BMC were measured by DXA scanning. Bone biochemical markers were also measured. Duration and dose of GC replacement and duration of endogenous hypercortisolism were calculated. Cured and active CS patients had less BMC, BMD, and osteocalcin than controls (p < 0.01). These differences were observed in estrogen-sufficient women but not in those with estrogen deficiency. Duration of GC treatment (mean: 42 mo; range, 2-420 mo) and endogenous hypercortisolism (mean: 70 mo; range, 13-241 mo) negatively correlated with BMC and lumbar spine BMD. After regression analysis, the main predictor of abnormal BMC and BMD was the duration of GC replacement (p < 0.01). Patients treated for CS persistently have less bone mass despite long-term cure. Both duration of endogenous hypercortisolism and mainly exogenous "replacement" therapy with GC negatively affect bone mass. Thus, the additional deleterious effect of GC for the treatment of adrenal axis suppression should be considered.

A link between bone mineral density and serum adiponectin and visfatin levels in acromegaly.

CONTEXT: Two adipokines highly expressed in fat mass, adiponectin with antiinflammatory and antiatherogenic properties and visfatin with an insulin-mimetic effect, are potential contributors to bone metabolism. In acromegaly, data on adiponectin are contradictory, and there are no data on visfatin. OBJECTIVES: The aim of the study was to evaluate adiponectin and visfatin in acromegaly, compared to control subjects, and to analyze their relationship with body composition and bone markers. METHODS: Bone markers [osteocalcin, total amino-terminal propeptide of type 1 procollagen (total P1NP), carboxy-terminal telopeptide (beta-Crosslaps)], body composition (by dual-energy x-ray absorptiometry), adiponectin (by ELISA), and visfatin (by immunoanalysis)] were evaluated in 60 acromegalic patients (24 males and 36 females) and in 105 age- and gender-matched healthy controls (33 males and 72 females). Acromegalic patients were classified as controlled, with normal IGF-I and nadir GH no greater than 1 microg/liter (n = 41), or active (n = 19). RESULTS: Acromegalic patients had lower adiponectin (P < 0.01), more lean body mass (P < 0.01), more total body mass (P < 0.01), higher bone formation markers (osteocalcin and total P1NP, P < 0.05 and P < 0.01, respectively), but less bone resorption markers (beta-Crosslaps, P < 0.001) than controls. No differences in visfatin and BMD were found between patients and controls. Adiponectin correlated negatively with BMD (r = -0.374; P < 0.05) and lean mass (r = -0.301; P < 0.05) and positively with age (r = 0.341; P < 0.001) in acromegaly. Visfatin correlated negatively with BMD (r = -0.359; P < 0.05). BMD was the predictor for adiponectin and visfatin. CONCLUSIONS: Acromegalic patients present hypoadiponectinemia and a favorable bone marker profile. Adiponectin and visfatin could be a link between fat mass and bone in acromegaly.

Period of gestational diabetes mellitus diagnosis and maternal and fetal morbidity.

BACKGROUND: The aim of the study was to analyze the association between the period of diagnosis of gestational diabetes mellitus (GDM) and maternal and neonatal outcome. METHODS: In this retrospective study, 1708 offspring (1571 singleton, 119 twins, and 18 triplets) born to women with GDM who attended the Diabetic and Pregnancy Clinic were included. Pregnancies were divided into three groups according to the gestational age at GDM diagnosis. The association of the period of diagnosis with maternal and fetal outcome was assessed adjusting for potentially confounding variables (logistic regression analysis). RESULTS: The period of diagnosis was a predictor in two out of three maternal outcomes (pregnancy-induced hypertension and insulin treatment) and in four out of 12 fetal outcomes (preterm birth, 5-min Apgar <7, perinatal mortality, and hyperbilirubinemia). Whereas pregnancy-induced hypertension was higher in women diagnosed with GDM in the second period, the other outcomes displayed higher occurrences with earlier diagnosis. CONCLUSIONS: Diagnosis of GDM earlier in pregnancy is a predictor of adverse maternal and neonatal outcome.

Hypothyroidism as a cause of rhabdomyolysis.

We describe a patient presenting with muscular symptoms and rhabdomyolysis without any other precipitating factor, except primary hypothyroidism. After thyroxine replacement, musculoskeletal symptoms disappeared and creatine kinase concentrations decreased. Hypothyroidism is a rare cause of rhabdomyolysis, but should always be considered in a patient with an unexplained increase in creatine kinase concentrations.