Long-term pasireotide therapy in acromegaly: extensive real-life experience of a referral center.

PURPOSE: Pasireotide is a novel therapeutic option for patients with acromegaly resistant to first-generation somatostatin receptor ligands. To date, real-life data are still scant, therefore, the aim of the current study is to evaluate the impact of long-term pasireotide therapy on disease control, pituitary tumor size, gluco-insulinemic and lipid profile in a real-life setting. METHODS: Retrospective study of data prospectively collected, evaluating hormonal, tumoral, and metabolic data of 28 patients with acromegaly administered with pasireotide in a pituitary tertiary referral center. RESULTS: Within the first 12 months of treatment, 70.4% of patients achieved normal IGF-I levels, which was maintained at 36-month evaluation in these responders patients. Patients who started with pasireotide 60 mg monthly exhibited significantly lower IGF-I levels after 36 months (p = 0.05) as compared to patients administered first with pasireotide 20 or 40 mg monthly. The maximal tumoral diameter was significantly decreased after 12 months of pasireotide (p < 0.001) and a further reduction was registered throughout the following months, with 41.2% of patients achieving a significant reduction (> 25% of baseline measurement) after 36 months of treatment. Fasting glucose significantly increased during the first 6 months (p < 0.001) with a gradual rise in diabetes prevalence during the following months, resulting diabetes prevalence after 36 months of pasireotide significantly increased compared to baseline (p = 0.003), although with glycated hemoglobin levels within the normal range. Diabetes was managed using oral glucose-lowering drugs or glucagon-like peptide 1 agonists, with no patient requiring insulin therapy. Pasireotide improved lipid profile, mainly during the first 12 months of treatment, by increasing HDL and decreasing triglycerides levels. CONCLUSION: Pasireotide is effective and safe in the long-term. Hyperglycemia is a common event and is manageable even without insulin treatment.

Pasireotide effects on biochemical control and glycometabolic profile in acromegaly patients switched from combination therapies or unconventional dosages of somatostatin analogs.

PURPOSE: To evaluate the impact of pasireotide (PAS) therapy on hormonal and glycometabolic outcome in patients with acromegaly previously treated with combination medical therapies or unconventional dosages of first-generation somatostatin receptor ligands (fg-SRLs). METHODS: Retrospective study carried out in two referral centers for pituitary diseases. Twenty-one acromegalic patients were switched to PAS (12 had biochemical control, 9 were uncontrolled). Data were collected after 3- and 6-months PAS treatment, and at the last available visit (median 35 months). RESULTS: After switching to PAS therapy, a significant reduction in IGF-1 values was observed [median 39%; 0.79 xULN (IQR 0.5-1.01) vs 1.29 xULN (IQR 1.06-1.83); p = 0.009]. IGF-1 reduction was statistically significant in the 9 patients previously uncontrolled (61%, p = 0.016), and in the 12 controlled subjects (33%, p = 0.037). At last follow-up, the number of patients reaching an acceptable biochemical control (IGF-1 < 1.3 xULN) raised from 57 to 90% (p = 0.032). Mean HbA1c levels increased from 5.7% (5.5-5.9) to 6.0% (5.9-7) (p = 0.002), and the percentage of diabetic patients raised from 14% (3/21) to 67% (14/21) (p = 0.004). At the last evaluation HbA1c was ≥ 7.0% in 5 patients (24%). Antidiabetic drugs were initiated in 9 new patients, and in 7 out of 9 metformin alone was effective. Younger age and male sex were predictors for the maintenance of glucose homeostasis. CONCLUSION: PAS monotherapy can be effective in acromegalic patients previously treated with combination medical therapies or unconventional dosages of fg-SRLs. Glucose imbalance can be managed in the vast majority of cases by use of lifestyle interventions and metformin.

Circulating myomiRNAs as biomarkers in patients with Cushing's syndrome.

PURPOSE: Impairment of skeletal muscle mass and strength affects 40-70% of patients with active Cushing's syndrome (CS). Glucocorticoid excess sustains muscle atrophy and weakness, while muscle-specific microRNAs (myomiRs) level changes were associated with muscle organization and function perturbation. The aim of the current study is to explore changes in circulating myomiRs in CS patients compared to healthy controls and their involvement in IGFI/PI3K/Akt/mTOR pathway regulation in skeletal muscle. METHODS: C2C12, mouse myocytes, were exposed to hydrocortisone (HC), and atrophy-related gene expression was investigated by RT-qPCR, WB and IF to assess HC-mediated atrophic signalling. miRNAs were evaluated in HC-treated C2C12 by PCR Arrays. MyomiRs significantly overexpressed in C2C12 were investigated in 37 CS patients and 24 healthy controls serum by RT-qPCR. The anti-anabolic role of circulating miRNAs significantly upregulated in CS patients was explored in C2C12 by investigating the IGFI/PI3K/Akt/mTOR pathway regulation. RESULTS: HC induced higher expression of atrophy-related genes, miR-133a-3p, miR-122-5p and miR-200b-3p in C2C12 compared to untreated cells. Conversely, the anabolic IGFI/PI3K/Akt/mTOR signalling was reduced and this effect was mediated by miR-133a-3p. In CS patients miR-133a-3p and miR-200b-3p revealed higher circulating levels (p < 0.0001, respectively) compared to controls. ROC curves for miR-133a-3p (AUC 0.823, p < 0.0001) and miR-200b-3p (AUC 0.850, p < 0.0001) demonstrated that both myomiRs represent potential biomarkers to discriminate between CS and healthy subjects. Pearson's correlation analysis revealed that circulating levels of miR-133a-3p are directly correlated with 24 h urinary-free cortisol level (r = 0.468, p = 0.004) in CS patients. CONCLUSIONS: HC induces atrophic signals by miR-133a-3p overexpression in mouse myocytes and humans. Circulating miR-133a-3p is promising biomarkers of hypercortisolism.

Control of acromegaly in more than 90% of patients after 10 years of pegvisomant therapy: an European referral centre real-life experience.

PURPOSE: Pegvisomant (PEG) efficaciously controls IGF-I excess in acromegaly and possesses a positive impact on glucose metabolism. Data on very prolonged PEG treatment are still limited, therefore, we investigated the effects of 10-years PEG on disease control, maximal tumour diameter (MTD), and metabolic profile in consecutive patients resistant to somatostatin analogues (SRLs) followed in an European referral centre for acromegaly. METHODS: Since the 2000s, we collected data on anthropometric, hormonal and metabolic parameters, and MTD of patients receiving PEG. In the current study, we included 45 patients (19 men, 26 women, 46.8 ± 11 years) treated for at least 5 years with PEG mono or combined therapy, analyzing data before, after 5- and 10-years PEG. RESULTS: After10 years, 91% of patients showed full disease control and in 37% a significant decrease in MTD was found. Diabetes prevalence was slightly increased, whereas HbA1c remained stable over the decade. Transaminases remained stable and no case of cutaneous lipohypertrophy was recorded. A different metabolic impact between mono- or combined therapy was found. Patients in monotherapy showed significantly lower fasting glucose (p = 0.01), fasting insulin (p = 0.008), HbA1c (p = 0.007), HOMA-IR (p = 0.001), and significantly higher ISI0 (p = 0.002), whereas patients under combined therapy showed significantly lower total (p = 0.03), and LDL cholesterol (p = 0.007). Acromegaly duration before PEG was inversely related to ΔFG (r = - 0.46, p = 0.03) and ΔFI (r = - 0.54, p = 0.05). CONCLUSIONS: PEG is effective and safe in long term. In patients resistant to SRLs, early beginning of PEG allows a wider gluco-insulinemic improvement.

Low prolactin level identifies hypoactive sexual desire disorder women with a reduced inhibition profile.

PURPOSE: Data on the role of prolactin (PRL) in the physiologic range in the female sexual response are scanty. We aimed at investigating the association between PRL and sexual function as assessed by the Female Sexual Function Index (FSFI). We explored the presence of a cut-off level of PRL able to identify Hypoactive Sexual Desire Disorder (HSDD). METHODS: 277 pre- and post-menopausal women consulting for Female Sexual Dysfunction (FSD) and sexually active were enrolled in an observational, retrospective study. 42 women were used as no-FSD controls. A clinical, biochemical and psychosexual evaluation was performed. The main outcome measures were: FSFI, Female Sexual Distress Scale-Revised, Middlesex Hospital Questionnaire and Sexual excitation/sexual inhibition scale (SIS/SES). RESULTS: Normo-PRL FSD women (n = 264) showed lower FSFI Desire score than controls (n = 42), and higher than hyper-PRL FSD women (n = 13). These differences emerged both in pre-menopausal and post-menopausal subjects. In the normo-PRL FSD group, those with PRL in the higher quintile reported higher FSFI Desire scores than those with PRL in the lowest quintile. Women with HSDD presented a lower PRL level than those without (p = 0.032). A ROC curve analysis for PRL showed an accuracy of 0.610 ± 0.044 (p = 0.014) in predicting HSDD. With a threshold of < 9.83 µg/L, sensitivity and specificity for HSDD were 63% and 56%, respectively. Subjects with PRL < 9.83 µg/L also reported lower sexual inhibition (p = 0.006) and lower cortisol levels (p = 0.003) than those with PRL > = 9.83 µg/L. CONCLUSIONS: Hyper-PRL is associated with low desire; however, among normo-PRL FSD women, those with the lowest levels demonstrated a poorer desire than those with the highest levels. PRL < 9.83 µg/L predicted HSDD and a lower sexual inhibitory trait.

Long-term high-dose L-arginine supplementation in patients with vasculogenic erectile dysfunction: a multicentre, double-blind, randomized, placebo-controlled clinical trial.

PURPOSE: The current randomized, double-blind, placebo-controlled clinical trial addressed the effects on penile erectile function of relatively high daily oral doses (6 g/day) of L-ARG for 3 months (N = 51) compared to placebo (N = 47), in patients with vasculogenic ED, with comparison between mild-moderate and severe vasculogenic ED. METHODS: The outcome measures included IIEF-6 score and cavernous arteries peak systolic flow velocity (PSV) at dynamic penile duplex ultrasonography (PDU). RESULTS: L-ARG supplementation for 3 months significantly increased IIEF-6 score in the overall cohort (p < 0.0001) and in subgroups of patients with mild-moderate (p < 0.0001) and severe (p = 0.007) vasculogenic ED; PSV was significantly increased in the overall cohort (p < 0.0001) and in patients with mild-moderate (p < 0.0001), but not severe vasculogenic ED. At study completion, 74% of patients improved ED degree category, although only 24% of patients, mainly belonging to the baseline category of mild ED, reached IIEF-6 scores compatible with absence of ED; moreover, 20% of patients, exclusively belonging to the baseline category of mild-moderate vasculogenic ED, reached PSV values compatible with absence of ED. CONCLUSION: The results of the current study demonstrated that supplementation with relatively high doses of L-ARG as a single compound for 3 months significantly improved penile erectile function, assessed by both IIEF-6 score and PSV at dynamic PDU in patients with mild-moderate, and improved IIEF-6 score, but not PSV, in patients with severe vasculogenic ED, therefore suggesting that L-ARG might be an alternative treatment in mild-moderate vasculogenic ED patients experiencing adverse effects or with contraindications for chronic treatment with PDE5i compounds.

Metabolic syndrome in the era of COVID-19 outbreak: impact of lockdown on cardiometabolic health.

PURPOSE: COVID-19 pandemics and cardiometabolic health are mutually interconnected. Chronic metabolic diseases are known risk factors for increased mortality after SARS-CoV-2 infection. In turn, COVID pandemics imposed sudden changes in lifestyle and social isolation with consequent potential cardiometabolic sequelae. The present study aimed at investigating the impact of changes in lifestyle and social life on metabolic profile in hyperprolactinemic or osteoporotic patients without pre-existing cardiometabolic diseases at the time of COVID-19. METHODS: The primary study outcome measurement was the prevalence of obesity, arterial hypertension, impaired glucose tolerance (IGT) or diabetes mellitus (DM), dyslipidemia and metabolic syndrome after COVID-19 outbreak. Seventy-four patients (21 men and 53 women, aged 51.8 ± 17.8 years) were admitted to the outpatient clinic of the Neuroendocrine Disease Unit at University "Federico II" of Naples, Italy, as per their routine clinical practice because of tumoral and non-tumoral hyperprolactinemia in 52 patients (70.3%), and osteoporosis/osteopenia in 22 (29.7%). Among female patients, 25 (47.2%) were at menopausal age. RESULTS: At the end of lockdown, prevalence of obesity (from 37.8% to 51.3%, p < 0.0001), dyslipidemia (from 28.4 to 48.6%, p = 0.003) and metabolic syndrome (from 14.9 to 27%, p < 0.0001) significantly increased compared to pre-COVID evaluation. No significant change was found in the prevalence of arterial hypertension and IGT/DM. CONCLUSION: SARS-CoV-2 outbreak has led to a rapid increase in the prevalence of metabolic syndrome, potentially contributing to the increased COVID-19 related mortality.

Increased risk of osteoporosis in postmenopausal women with type 2 diabetes mellitus: a three-year longitudinal study with phalangeal QUS measurements.

Type 2 diabetes mellitus (T2DM) is associated with a higher risk of fractures even in presence of normal or increased bone mineral density. The purpose of this three-year longitudinal study was to evaluate the risk of osteoporotic fractures by assessing the changes of Quantitative Ultrasound (QUS) parameters in a group of postmenopausal women with type 2 diabetes mellitus (T2DM) compared with non-diabetic controls. The measurements were taken on a group of 18 postmenopausal women affected by T2DM and 18 healthy age-matched controls, aged 55-70 years, referring to the Osteolab laboratory at the ISBEM Research Institute (Brindisi, Italy) between 2009 and 2013. Subjects had baseline and 3-year follow-up measurements with phalangeal QUS carried out by a DBM Sonic Bone Profiler 1200 (Igea®); medical history, current drug therapies and risk factors for fractures were recorded for each patient. The analyzed phalangeal QUS parameters were Amplitude-Dependent Speed of Sound (AD-SoS), Bone Transmission Time (BTT), Fast Wave Amplitude (FWA) and Signal Dynamic (SDy). At the baseline visit we found no statistically significant difference between T2DM and non-diabetic patients when looking at phalangeal QUS parameters. At the three-year follow-up visit, a significantly higher decrease of both BTT (P<0.001) and AD-SoS (P<0.001) parameters was found in the T2DM group. On the contrary, the decrease of FWA was significantly higher in non-diabetic controls (P<0.001). Our data confirm the ability of phalangeal QUS to detect differences in the risk of osteoporotic fractures in T2DM postmenopausal women compared to non-diabetic controls. The study suggests that T2DM women present a higher cortical porosity and increased trabecular bone density compared to non-diabetic controls, respectively shown by the higher decrease of both AD-SoS and BTT and the lower decrease of FWA.

Glycometabolic control in acromegalic patients with diabetes: a study of the effects of different treatments for growth hormone excess and for hyperglycemia.

BACKGROUND: Diabetes mellitus is frequently observed in patients with acromegaly. Current therapies for acromegaly may impact glucose regulation, influencing insulin sensitivity and secretion. The question whether these therapies modify control and progression of diabetes once present is still open. AIM: Aim of our study is to analyze glucose control in acromegalic patients with diabetes, evaluating the relation with treatments for GH excess and for diabetes. METHODS: Seventy patients with acromegaly and diabetes were studied. Duration and treatments of acromegaly and diabetes were recorded, together with clinical and metabolic parameters. RESULTS: Most patients (92.8%) were treated with somatostatin analogs (SSA), either alone or in combination with dopamine-agonists (20%) or pegvisomant (15.7%); 7.1% of patients had been treated by surgery alone. Metformin (65.7%), alone or in combination with other hypoglycemic drugs, was the most frequent treatment for diabetes, followed by insulin (21.5%). Only 15.7% were treated with diet alone. The whole cohort showed a very good control of diabetes and acromegaly. Median glycated hemoglobin was 6.4% (5.9-7). IGF-I was within normal range for age in most patients. No relation was observed between duration of acromegaly or diabetes and metabolic control. SSA had a negative effect on insulin secretion, but these effects did not influence glucose control. Finally, we observed a low prevalence of nephropathy (6%) and retinopathy (20%). CONCLUSIONS: Our study shows that a good control of hyperglycemia can be obtained with success in the majority of acromegalic patients with diabetes, independently of the type of treatment for GH excess.

The treatment with growth hormone receptor antagonist in acromegaly: effect on vascular structure and function in patients resistant to somatostatin analogues.

BACKGROUND: Acromegaly is known to be associated to vascular damage characterized by an increase of vascular wall thickness and an impairment of vascular function. AIM: The aim of this study was to evaluate the effect of medical treatment with the GH receptor antagonist pegvisomant on vascular structure and function in acromegalic patients resistant to somatostatin analogues. PATIENTS: Ten patients (4 males and 6 females, 28-58 yr) and 20 sex-, age-, and body mass index-matched healthy controls entered the study. All patients were treated for 18 months with pegvisomant at doses ranging from 10 to 40 mg/day. OUTCOME MEASURES: Primary outcome measures were measurement of carotid arteries intima-media thickness (IMT), and brachial arteries flow mediated dilation (FMD); secondary outcome measures were blood pressure, blood glucose and lipids levels. RESULTS: Carotid arteries maximal IMT was significantly higher in patients than in controls at baseline (1.18±0.59 vs 0.69±0.13, p=0.001) and slightly, but not significantly, decreased after treatment (0.97±0.17). Brachial arteries FMD was significantly lower in patients than controls at baseline (7.5±2.5 vs 13.1±1.4, p<0.001) and significantly increased after treatment (8.8±3.7, p=0.016). Systolic (SBP) and diastolic (DBP) blood pressure values, serum glucose and insulin levels and homeostasis model assessment (HOMA) index were higher, whereas HDL-cholesterol levels were lower in patients than controls at baseline. After treatment, SBP and DBP, as well as serum glucose and insulin levels and HOMA index significantly decreased whereas no significant change was found in serum lipid profile. CONCLUSIONS: The results of the current study suggested that long-term treatment with pegvisomant induced a slight reduction of carotid arteries wall thickness and a significant improvement of brachial arteries vascular function in patients with acromegaly resistant to somatostatin analogues.

Octreotide-LAR vs lanreotide-SR as first-line therapy for acromegaly: a retrospective, comparative, head-to-head study.

No head-to-head comparisons are available to analyze the efficacy of octreotide (LAR) and lanreotide (LAN) as first-line treatment of acromegaly.We compared the efficacy of these two drugs in 54 newly diagnosed patients (21 women, 33 men), 27 treated with LAR (10-30 mg every 28 days) and 27 with LAN (60-90 mg/28 days), for 12 months. Each LAR-treated patient was matched with one LAN-treated patient as for GH levels, sex, and age (+/-5 yr). Outcome measures were GH and IGF-I levels and tumor shrinkage and secondarily classical cardiovascular risk factors (total/HDL-cholesterol ratio, glucose tolerance), blood pressure and drug tolerability. In LAR- and in LAN-treated patients, respectively: GH and IGF-I were controlled in 21 (77.7%) and in 16 patients (59.3%; p=0.26); tumor shrinkage was absent (<25%) in 4 and 5 patients (p=1), mild (25.1-50%) in 9 and 12 (p=0.57), moderate (50.1-75%) in 10 and 6 (p=0.37) and notable (>75%) in 4 and 4 patients (p=1). The total/HDL-cholesterol ratio and insulin levels significantly decreased while glucose levels significantly increased in both groups. None of the patients with normal glucose tolerance at diagnosis developed diabetes mellitus. Side effects were mostly at the gastrointestinal level and were similar with both drugs. In conclusion, newly diagnosed patients with acromegaly treated with LAR and LAN have no significantly different prevalence of disease control, tumor shrinkage, improvement of cardiovascular risk markers and side effects. Therefore, both drugs can be safely employed as first-line therapy of acromegaly.

A retrospective analysis on biochemical parameters, cardiovascular risk and cardiomyopathy in elderly acromegalic patients.

This analytical, observational, retrospective, case-control study was designed to describe clinical presentation, biochemical disease severity, presence, and severity of metabolic and cardiovascular complications in patients diagnosed as having acromegaly at 60 yr or older (no.=57) as compared to sex- and age-matched healthy controls. Patients and controls underwent a complete endocrine, metabolic, and cardiovascular check-up. The age at diagnosis was equally distributed between 60 to 75 yr while only a minority of the patients (5.3%) was diagnosed after 75 yr. Median GH and IGF-I levels were 15 microg/l and 557 microg/l. The prevalence of microadenomas, enclosed macroadenomas, and extrasellar/invasive macroadenomas was 30%, 49%, and 21%, respectively. All patients had joint complaints and goiter (euthyroid in 65% and pre-toxic/toxic in 35%), 82% had hypertension, 58% diabetes and 54% had both. As compared to controls, a higher number of patients were receiving treatment with anti-arrhythmiacs (p=0.033), anti-aggregants (p=0.013), levothyroxine (p=0.015), and metformin (p=0.022). Nevertheless, the patients had higher systolic and diastolic blood pressure, heart rate, left ventricular mass index, lipids, glucose and insulin levels as well as percent function of beta cells than controls. In conclusion, the high prevalence of systemic complications makes elderly acromegalics more susceptible than controls to cardiovascular events. We suggest that an accurate clinical check-up and, possibly, a more aggressive treatment of hypertension and diabetes are required in elderly acromegalics.

Evaluation of the retinal nerve fibre layer and ganglion cell complex thickness in pituitary macroadenomas without optic chiasmal compression.

PURPOSE: The aim of this prospective study was to measure the thickness of the circumpapillary retinal nerve fibre layer (cpRNFL) and the ganglion cell complex (GCC) using spectral domain optical coherence tomography (SD-OCT) in a cohort of consecutive de novo patients with pituitary macroadenomas without chiasmal compression. PATIENTS AND METHODS: Twenty-two consecutive patients with pituitary macroadenoma without chiasmal compression (16 men, 6 women, aged 45.2±14.6 years, 43 eyes) entered the study between September 2011 and June 2013. Among them, 31.8% harboured a growth hormone-secreting pituitary adenoma, 27.3% a prolactin-secreting pituitary adenoma, 27.3% a corticotrophin-secreting pituitary adenoma, and 13.6% a non-secreting pituitary tumour. Eighteen subjects (nine females, nine males, mean age 36.47±6.37 years; 33 eyes) without pituitary adenoma, with normal ophthalmic examination, served as controls. In both patients and controls, cpRNFL and GCC thicknesses were measured by SD-OCT. RESULTS: Patients were significantly older (P=0.02) than controls. Best corrected visual acuity, intraocular pressure, colour fundus photography, and automatic perimetry test were within the normal range in patients and controls. Conversely, cpRNFL (P=0.009) and GCC (P<0.0001) were significantly thinner in patients than in controls. The average GCC (r=0.306, P=0.046) significantly correlated with the presence of arterial hypertension. OCT parameters did not differ significantly between patients with a tumour volume above the median and those with a tumour volume below the median. CONCLUSION: Pituitary macroadenomas, even in the absence of chiasmal compression, may induce GCC and retinal nerve fibre layer thinning. SD-OCT may have a role in the early diagnosis and management of patients with pituitary tumours.

The role of somatostatin receptors in the medical treatment of acromegaly.

Somatostatin is a hypothalamic inhibitor of pituitary growth hormone secretion and cell proliferation, binding to five distinct receptor subtypes (sstr1-5). Since native somatostatin has a short half-life, somatostatin analogues with a longer half-life have been developed for therapeutic purposes. Octreotide and lanreotide are currently available for treatment of acromegaly, binding with high-affinity sstr2 and sstr5. Octreotide, the first somatostatin analogue used in the medical therapy of acromegaly, was initially given subcutaneously at doses of 100-500 microg three times daily. The introduction of new depot formulations, such as octreotide long-acting release, slow-release lanreotide and lanreotide-autogel, improved patients compliance of long-term therapy, overcoming the inconvenience of multiple daily administration. The treatment with somatostatin analogues induces biochemical control and tumour shrinkage in about 50-70% and 30-60% of patients with acromegaly, respectively. However, the efficacy of this therapy lies on an adequate expression of sstr2 and sstr5 on tumor cells. In the past, somatostatin receptor expression was tested in vivo by (111)In-diethylenetriaminepentaacetate-D-Phe-octreotide scintigraphy: this method has been abandoned since normal pituitary tissue can be visualised by (111)In-diethylenetriaminepentaacetate-D-Phe-octreotide scintigraphy. Currently, the somatostatin receptorial profile can be characterised by autoradiography, molecular biology techniques and immunohistochemistry on surgically removed tumor tissue. These methods may offer an individualised approach sparing patients from unnecessary treatment.

[Somatostatin analogs in the clinical management of pituitary neoplasms]. / Gli analoghi della somatostatina nell'inquadramento clinico della patologia ipofisaria.

The medical approach to patients with secreting or clinically non-functioning pituitary adenoma as made considerable progress thanks to the use of new somatostatin analogs. They were first used to treat acromegaly in the mid 1980s and numerous studies have shown a reduction in GH concentration in over 90% of acromegalic patients. Good results were obtained using slow-release analog treatment also in TSH-secreting adenomas, whereas the therapeutic efficacy of these peptides in clinically non-functioning adenomas is still controversial. Treatment with somatostatin analogs improves symptoms, normalises hormone secretion and in some cases may induce a reduction in the volume of pituitary adenomas. Scintigraphy with octreotide may help to select patients who respond to this form of treatment.

New perspectives in the medical treatment of acromegaly.

Currently available medical treatment of acromegaly includes dopamine agonists, slow release formulation of somatostatin analogues and pegvisomant, a GH-receptor antagonist. Dopamine agonists are well tolerated, not expensive but poorly effective. Somatostatin analogues are highly effective in 60-70% of patients based on the receptor profile of individual tumors. Pegvisomant is reported to normalize IGF-I levels in nearly the totality of the patients, but is devoted of tumor shrinking effect. In a preliminary study in patients with acromegaly, a new somatostatin analogue with affinity to four of the five somatostatin receptors (SOM230) was shown to be similarly effective as octreotide in some patients and more effective than octreotide in other patients. Moreover, new molecules with selective activity on the somatostatin receptor type 2, or 5, or 1 have been reported in vitro to strongly suppress GH secretion. Other new promising alternatives are the chimeric compounds with both somatostatin receptor and dopamine receptor binding. These drugs have been also shown to possess strong GH-inhibitory activity in primary cultures from GH-secreting adenomas. These drugs are the future perspectives in the treatment of patients with GH-secreting or GH/PRL-secreting tumors.

Severe systemic complications of acromegaly.

It is well accepted that mortality in acromegaly is increased because of cardiovascular and respiratory diseases while neoplastic complications account less to mortality. Amongst different cardiovascular complications the most frequent is biventricular hypertrophy, which occurs independently of hypertension and metabolic complications that, in turn, aggravate the cardiomyopathy. Diastolic and systolic dysfunction develops in a variable number of patients, depending on age and disease duration. Other cardiac disorders, such as arrhythmias, valve disease, hypertension, atherosclerosis and endothelial dysfunction have been less characterized but all appear to be present in acromegaly, depicting the so called "acromegalic cardiomyopathy". The best characterized respiratory disease is the sleep apnea. Ventilatory dysfunction recognizes bony changes of thoracic cage and lung overgrowth as relevant pathogenetic factors. Earlier evidences that patients with acromegaly have an increased risk of developing malignancies have become more realistic in recent years. Most studies have reported an increased risk of colonic polyps, which more frequently recur in patients not controlled after treatment. Malignancies in other organs have also been described, but less convincingly than at the gastrointestinal level and are not a main cause of mortality. Bone changes are also feature of the disease. They involve theoretically all bones and, particularly, the appendicular and the axial skeleton. Patients with long-standing disease are more prone to develop degenerative changes. Control of acromegaly by surgery or pharmacotherapy, especially by somatostatin analogs, improves cardiovascular morbidity and sleep apnea. There is still no demonstration that improvement of different complications corresponds a reduction in mortality.

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) > or = 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 < or = -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 < or = -2 to -1. Our results support a role of the IGF/IGFBP-3 axis in the pathogenesis of atherosclerosis.

The use of a GH receptor antagonist in patients with acromegaly resistant to somatostatin analogs.

Pegvisomant, a GH receptor antagonist, is a new pharmaceutical approach to acromegaly. It enables IGF-I levels to return in the age- and sex-reference range in approximately 90% of patients. This new approach is particularly beneficial in those patients who do not experience control of hormone hypersecretion after surgery and/or medical treatment with somatostatin analogs. In our preliminary experience, out of 16 patients unsuccessfully operated on by transsphenoidal surgery and resistant to 40-mg octreotide-LAR or 120-mg lanreotide for at least 6 months, 13 normalized their IGF-I levels within 6 months from treatment beginning. Normalization of IGF-I levels was accompanied by a significant decrease of ring size. We did not observe any increase of tumor remnant in this short period of treatment. In two cases we observed a significant increase of liver transaminases levels. In conclusion, more than 80% of patients with acromegaly unsuccessfully treated by surgery or currently available somatostatin analogs can achieve normal IGF-I levels after short-term treatment with pegvisomant.