Francesca Rota

Circulating insulin-like growth factor-I levels are correlated with the atherosclerotic profile in healthy subjects independently of age

To investigate the relationships between the GH-IGF-I axis and the atherosclerotic profile, we designed this open, observational, prospective study. Peak GH after GHRH+arginine (ARG) test, serum IGF-I and IGF binding protein-3 (IGFBP-3), lipid profile, homeostasis model assessment (HOMA) index and intima-media thickness (IMT) at common carotid arteries were measured in 174 healthy individuals (92 women, 82 men, aged 18–80 yr). Exclusion criteria for this study were: 1) body mass index (BMI) ≥30 kg/m2; 2) personal history of cardiovascular diseases; 3) previous or current treatments of diabetes or hypertension; 4) previous corticosteroids treatment for longer than 2 weeks or estrogens for longer than 3 months; 5) smoking of more than 15 cigarettes/day and alcohol abuse. Subjects were divided according to age in decade groups from <20 to >70 yr. BMI increased with age, as did systolic and diastolic blood pressures, although they remained in the normal range. The GH peak after GHRH+ARG test was significantly higher in the subjects aged <20 yr than in all the other groups (p<0.01), but was similar in the remaining groups. An inverse correlation was found between the IGF-I z-score and total/HDL-cholesterol ratio (p=0.02) and mean IMT (p=0.0009); IGFBP-3 z-score and mean IMT (p=0.043); IGF: IGFBP-3 molar ratio and total/HDL-cholesterol ratio (p<0.0001) and mean IMT (p<0.0001). Atherosclerotic plaques were found in 7 out of 12 subjects (53.8%) with a z-IGF-I score from ≤−2 to −1, in 4 out of 63 (6.3%) with a z-IGF-I score from −0.99 to 0.1 out of 66 (1.5%) with a z-IGF-I score from 0.1 to 1 and none of the 33 subjects with an IGF-I z-score >1 (p=0.006). At multi-step regression analysis, age was the best predictor of HDL-cholesterol levels and mean IMT, IGF-I level was the best predictor of total cholesterol and total/HDL-cholesterol ratio, the IGF-I/IGFBP-3 molar ratio was the best predictor of triglycerides levels. The z-scores of IGF-I and IGFBP-3 were the second best predictors of mean IMT after age. In conclusion, IGF-I and IGFBP-3 were negatively correlated with common cardiovascular risk factors, studied as total/HDL-cholesterol ratio, and/or early atherosclerosis, studied as IMT at common carotid arteries. The prevalence of atherosclerotic plaques, though not hemodinamically significant, was higher in the subjects having a z-score of IGF-I of ≤−2 to −1. Our results support a role of the IGF/IGFBP-3 axis in the pathogenesis of atherosclerosis.

Growth Hormone Treatment on Atherosclerosis : Results of a 5-Year Open, Prospective, Controlled Study in Male Patients with Severe Growth Hormone Deficiency

BACKGROUND Severe GH deficiency (GHD) is associated with, increased cardiovascular risk and intima-media thickness (IMT) at major arteries. OBJECTIVE The objective of the study was to investigate the 5-yr effects of GH replacement on common carotid IMT and insulin resistance syndrome (IRS) (at least two of the following: triglycerides levels > or = 1.7 mmol/liter, high-density lipoprotein-cholesterol levels < or = 1.0 mmol/liter, blood pressure above 130/85 mm Hg, fasting glucose 6.1-7 or 2 hr after glucose 7.7-11.1 mmol/liter). DESIGN This was an interventional, open, prospective, controlled study. PATIENTS Patients included 35 men with severe GHD and 35 age-matched healthy men as controls. INTERVENTION All patients received standard replacement therapy; GH replacement was added in 22 patients (group A) and refused by 13 others (group B). MEASUREMENTS Five-year changes in IMT and IRS prevalence were measured. RESULTS At baseline, IMT was higher in the patients with (P < 0.001) and without IRS (P = 0.004) than in controls. Eighteen patients (51.4%) and two controls (5.7%; P < 0.0001) had IRS. At study end, use of lipid-lowering drugs (92.3, vs. 13.6 and 34.3%, P < 0.0001), glucose-lowering drugs (69.2 vs. 31.4 and 22.7%; P = 0.016), and antihypertensive drugs (61.5 vs. 20.0 and 4.5%; P < 0.0001) was higher in group B patients than controls and group A patients. IGF-I levels normalized in all group A patients and remained lower than -1 sd score in 77% of group B patients. IMT significantly decreased only in group A and significantly increased in controls and nonsignificantly in group B patients. IRS prevalence significantly reduced only in group A patients. CONCLUSIONS Severely hypopituitary GHD men have more frequently increased IMT at common carotid arteries and IRS than controls. After 5 years, only in GH replaced patients, IMT and prevalence of IRS decreased.

Insulin‐like growth factor‐1 deficiency determines increased intima–media thickness at common carotid arteries in adult patients with growth hormone deficiency

objective  To investigate the role of IGF‐1 on intima–media thickness (IMT) at common carotid arteries by Doppler ultrasonography.

Somatostatin analogs in treatment of non-growth hormone-secreting pituitary adenomas.

Besides well-known effects in GH-secreting adenomas, somatostatin analogs such as octreotide and lanreotide have been used in TSH-secreting adenomas and in the so-called clinically nonfunctioning adenomas. The rationale for their use is based on the evidence that both these tumor types express large amounts of somatostatin receptor subtypes 2 and 5, which are preferentially bound by octreotide and lanreotide. However, whether in TSH-secreting adenomas the results are excellent in the nonfunctioning type, the results are controversial. Some preliminary results showing a very rapid recovery of the visual field have not been confirmed subsequently. No evident effect of tumor shrinkage has been reported. At present, the use of somatostatin analogs in clinically nonfunctioning adenomas is questioned.

GH and IGF‐I deficiency are associated with reduced loss of fat mass after laparoscopic‐adjustable silicone gastric banding

Context  GH secretion is reduced in obese subjects and increases after body weight loss. It is still unclear if changes in the GH/IGF‐I axis after laparoscopic‐adjustable silicone gastric banding (LASGB) are associated with changes of body composition.

Bone density and turnover in young adult patients with growth hormone deficiency after 2-year growth hormone replacement according with gender

GH deficiency (GHD) in adults is accompanied by reduced bone mass that may revert only after 2 yr of GH replacement. However, it is unclear whether the gender may modify bone responsiveness to GH replacement in adults. In this study we have evaluated whether bone mineral density (BMD) and turnover improve after GH replacement according to patients’ gender. BMD at lumbar spine (LS) and femoral neck (FN), serum osteocalcin (OC), and urinary cross-linked N-telopeptides of type I collagen (Ntx) were assessed in 64 hypopituitaric patients (35 men, 30–50 yr) before and 2 yr after the beginning of GH replacement. Values of IGF-I and BMD at LS and at FN were expressed as Z-scores. At study entry, IGF-I and BMD resulted similar among men and women with GHD. During GH replacement, IGF-I levels increased in both men and women without any difference in the percentage of IGF-I increase between the genders (p=0.47). In women receiving estrogen replacement, however, the percentage of IGF-I increase (p<0.05), and the Z IGF-I score (p<0.001) were significant lower than estrogen untreated women, although IGF-I levels were similar in the 2 groups (p=0.53). The GH dose adjusted for body weight required to restore normal age- and sex-matched IGF-I levels was lower in men than in women (p<0.001), and was higher in women receiving than in those not receiving estrogen replacement (p<0.05). In contrast, hypogonadal men treated with testosterone and eugonadal men received a similar GH dose (p=0.97). Also OC, Ntx levels, lumbar and femoral BMD improved (p<0.001) in all patients. Nevertheless, a greater increase in lumbar BMD increase was observed in men than in women (8.0±2.1 vs 2.6±0.4%; p<0.05). No significant difference was revealed in bone parameters in women treated or untreated with estrogen replacement and in men treated or not with testosterone replacement for concomitant hypogonadism. At the multiple correlation analysis, gender was a stronger predictor for the required GH dose than the age (p<0.001 and p=0.02, respectively). In conclusion, a 2-yr GH replacement normalizes IGF-I levels, increases bone mass and improves bone turnover both in men and in women with GHD without any difference between the 2 groups, provided that the dose of GH was modulated on the basis of IGF-I levels. Women receiving oral estrogens should receive a GH dose approximately doubled, as compared to men and women not receiving oral estrogens, to achieve similar effects on bone density and turnover. In particular, GH replacement dose, to be successful on bone mass and turnover, depends on gender in hypopituitary patients aged below 50 yr.

When can we stop cabergoline treatment in prolactinomas

Prolactinoma is the most common hormone-secreting pituitary adenoma. The approach to prolactinomas has changed in the past 25 years, thanks to treatment with dopamine agonists, which is characterized by a potent prolactin inhibitory effect, a tumor-shrinking effect, and a good tolerability. Cabergoline is a new dopamine agonist with a natural long duration of action and selectivity for the D2 receptor. The authors discuss the criteria for stopping treatment with cabergoline in prolactinomas. According to their experience, they withdraw cabergoline treatment in prolactinomas after normalization of serum prolactin levels and tumor disappearance or no further reduction of tumor size on MRI during the last 12 months of follow-up.

Everolimus as first line therapy for pancreatic neuroendocrine tumours: current knowledge and future perspectives

PurposeEverolimus has been shown to be effective for advanced pancreatic neuroendocrine tumours (pNETs), but its positioning in the therapeutic algorithm for pNETs is matter of debate.MethodsWith the aim to shed light on this point, we performed an up-to-date critical review taking into account the results of both retrospective and prospective published studies, and the recommendations of international guidelines. In addition, we performed an extensive search on the Clinical Trial Registries databases worldwide, to gather information on the ongoing clinical trials related to this specific topic.ResultsWe identified eight retrospective published studies, two prospective published studies, and five registered clinical trials. Moreover, we analyzed the content of four widespread international guidelines.ConclusionsOur critical review confirms the lack of high-quality data to recommend everolimus as the first line therapy for pNETs. The ongoing clinical trials reported in this review will hopefully help clinicians, in the near future, to better evaluate the role of everolimus as the first line therapy for pNETs. However, at the moment, there is already enough evidence to recommend everolimus as the first line therapy for patients with symptomatic malignant unresectable insulin-secreting pNETs, to control the endocrine syndrome regardless of tumour growth.

Nuove strategie terapeutiche per il trattamento dei NET

SommarioLa strategia terapeutica dei tumori neuroendocrini (NET) comprende la chirurgia per le forme localizzate e le terapie sistemiche per quelle metastatiche o inoperabili. La peculiarità biologica dei NET vede utilizzati in prima linea gli analoghi della somatostatina, anche ad alto dosaggio o in combinazione con gli altri farmaci, gli inibitori delle tirosinochinasi e di mTOR e la terapia radiorecettoriale. Chemioterapia e immunoterapia sono riservate ai NET più aggressivi. Nuovi studi clinici valuteranno, insieme a efficacia e sicurezza, le migliori sequenze terapeutiche.

Gli analoghi della somatostatina nel trattamento degli adenomi ipofisari non GH-secernenti

RiassuntoIl trattamento dei tumori ipofisari non GH-secernenti ha lo scopo di prevenire o limitare la compromissione della funzione ipofisaria, nonché le conseguenze dell’estensione a livello del chiasma ottico, dell’ipotalamo e dei seni cavernosi. La principale linea di trattamento di questi tumori dell’ipofisi è rappresentata dalla chirurgia, che è quasi sempre praticabile con approccio transfenoidale, con eccezione dei tumori molto voluminosi. Sebbene la resezione chirurgica determini una rapida decompressione del chiasma e dei nervi ottici e possa prevenire l’insorgenza o il peggioramento dell’ipopituitarismo, tuttavia, difficilmente permette una completa escissione del tumore, soprattutto in caso di estensione extrasellare. Residui tumorali si riscontrano nel 30–50% dei pazienti operati. La radioterapia viene considerata una terapia adiuvante nei pazienti con resezione chirurgica incompleta, allo scopo di prevenire la ricrescita del tumore e di ridurne i residui. Tale approccio terapeutico è, peraltro, gravato da alcuni aspetti negativi, come il lungo tempo richiesto per determinare un effetto completo, l’insorgenza di effetti collaterali acuti, come la neurite ottica e la necrosi cerebrale, e cronici, come l’induzione di ipopituitarismo. Inoltre, la ricrescita del tumore e la ricomparsa delle manifestazioni cliniche si verificano nel 20% dei casi trattati con radioterapia. Attualmente la terapia medica ha un suo razionale dopo l’intervento chirurgico e/o contemporaneamente alla radioterapia in attesa dei risultati di questa, nonché nei pazienti giovani al posto della radioterapia, allo scopo di preservare la fertilità, o negli anziani che non possono essere sottoposti ad intervento chirurgico. L’utilizzo degli analoghi della somatostatina nel trattamento di questi tumori è stato proposto sulla base dell’evidenza dell’espressione in vivo e in vitro dei recettori della somatostatina. Tuttavia, un’effettiva riduzione tumorale è stata dimostrata solo nel 13% di pazienti con adenomi clinicamente definiti non funzionanti (NFA) trattati con analoghi della somatostatina, indicando una scarsa correlazione tra espressione dei recettori per la somatostatina ed efficacia del trattamento con analoghi. Un discorso a parte merita il ruolo degli analoghi della somatostatina sulla cefalea e le alterazioni della funzione visiva. Un miglioramento di questi disturbi segue rapidamente l’inizio della terapia. Poiché non si assiste a nessuna contemporanea riduzione della massa tumorale, questo effetto sembra essere legato ad un’azione diretta degli analoghi sulla retina, sul nervo ottico e sulle strutture vascolari e cerebrali piuttosto che ad un’azione mediata dai recettori della somatostatina espressi dalle cellule tumorali. In conclusione, il trattamento con analoghi della somatostatina può essere considerato come alternativa temporanea alla chirurgia o nell’intento di ottenere un miglioramento della cefalea e dei disturbi visivi. Recentemente è stato anche proposto il trattamento combinato con analoghi della somatostatina e dopamino-agonisti, sulla base di un possibile sinergismo di azione.