Nuria Sucunza

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 Cushings 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.

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.

Gender dimorphism in body composition abnormalities in acromegaly: males are more affected than females

BACKGROUND Acromegaly changes body composition (BC), but long-term gender differences have not been reported. OBJECTIVE To evaluate BC in active and controlled acromegalic patients. DESIGN AND METHODS Clinical and biochemical variables and BC (by dual-energy X-ray absorptiometry) were evaluated in 60 acromegalic patients (19 active, 41 controlled) and 105 controls, matched for age and gender. RESULTS Acromegalic males (n=24) had more total mass (89+/-13 vs 76.5+/-15.3 kg, P<0.001), lean body mass (LBM; 64.6+/-8.7 vs 56.4+/-5.8 kg, P<0.001), and bone mineral content (BMC; 2.9+/-0.5 vs 2.6+/-0.3 kg, P<0.05) than controls (n=33). Controlled male patients (n=14) had more total mass (89+/-14.7 vs 76.5+/-15.3 kg, P<0.05) and a trend to have more LBM (61.8+/-9.4 vs 56.4+/-5.8 kg, P=0.065) than controls. Only in active disease was a decrease in fat mass (FM) observed, compared with controlled patients and controls (males: 19.5+/-5.3 vs 27+/-6.2 and 25.9+/-4%, P<0.001; females: 30.3+/-6.7 vs 37.1+/-5.8 and 36.5+/-6.6%, P<0.01). In females, no further differences were observed. No differences in BMC were found between eugonadal and hypogonadal acromegalic patients, but in hypogonadal females, acromegaly appeared to prevent the BMC loss seen in hypogonadal postmenopausal controls. GH and IGF1 levels were negatively correlated with FM (males, P<0.05; females, P<0.001), but in the regression analysis GH was a predictor of FM only in women. CONCLUSIONS Control of acromegaly reverts decreased FM in both genders; only in males more total mass and a trend for more LBM persist. The anabolic effect of GH on bone reverted in cured males, but persisted in females and appeared to override the bone loss of menopause.