The environment and male reproduction: The effect of cadmium exposure on reproductive function and its implication in fertility.

Cadmium is an environmental pollutant known as endocrine disruptor. Testis is particularly susceptible to cadmium, and testis injury occurs at high but even low levels of exposure. Cadmium reproductive toxicity is mediated by multiple mechanisms, including structural damage to testis vasculature and blood-testis barrier, inflammation, cytotoxicity on Sertoli and Leydig cells, oxidative stress mainly by means of mimicry and interference with essential ions, apoptosis, interference with selected signaling pathways and epigenetic regulation of genes involved in the regulation of reproductive function, and disturbance of the hypothalamus-pituitary-gonadal axis. The current review outlines epidemiological observational findings from environmental and occupational exposure in humans, and reports experimental studies in humans and animals. Lastly, a focus on the pathogenetic mechanisms of cadmium toxicity and on the specific mechanisms of cadmium sensitivity and resistance, particularly assessed in animal models, is included. Despite convincing experimental findings in animals and supporting evidences in humans identifying cadmium as reproductive toxicant, observational findings are controversial, suffering from heterogeneity of study design and pattern of exposure, and from co-exposure to multiple pollutants.

The role of vitamin D in male fertility: A focus on the testis.

In the last decade, vitamin D has emerged as a pleiotropic molecule with a multitude of autocrine, paracrine and endocrine functions, mediated by classical genomic as well as non-classical non-genomic actions, on multiple target organs and systems. The expression of vitamin D receptor and vitamin D metabolizing enzymes in male reproductive system, particularly in the testis, suggests the occurrence of vitamin D synthesis and regulation as well as function in the testis. The role of vitamin D in the modulation of testis functions, including hormone production and spermatogenesis, has been investigated in animals and humans. Experimental studies support a beneficial effect of vitamin D on male fertility, by modulating hormone production through genomic and non-genomic actions, and, particularly, by improving semen quality essentially through non-genomic actions. However, clinical studies in humans are controversial. Indeed, vitamin D seems to contribute to the modulation of the bioavailable rather than total testosterone. Moreover, although an increased prevalence or risk for testosterone deficiency was reported in men with vitamin D deficiency in observational studies, the majority of interventional studies demonstrated the lack of effect of vitamin D supplementation on circulating levels of testosterone. The most consistent effect of vitamin D was reported on semen quality. Indeed, vitamin D was shown to be positively associated to sperm motility, and to exert direct actions on spermatozoa, including non-genomic driven modulation of intracellular calcium homeostasis and activation of molecular pathways involved in sperm motility, capacitation and acrosome reaction. The current review provides a summary of current knowledge on the role of vitamin D in male fertility, by reporting clinical and experimental studies in humans and animals addressing the relationship between vitamin D and testis function.

Complications of acromegaly: cardiovascular, respiratory and metabolic comorbidities.

Acromegaly is associated with an enhanced mortality, with cardiovascular and respiratory complications representing not only the most frequent comorbidities but also two of the main causes of deaths, whereas a minor role is played by metabolic complications, and particularly diabetes mellitus. The most prevalent cardiovascular complications of acromegaly include a cardiomyopathy, characterized by cardiac hypertrophy and diastolic and systolic dysfunction together with arterial hypertension, cardiac rhythm disorders and valve diseases, as well as vascular endothelial dysfunction. Biochemical control of acromegaly significantly improves cardiovascular disease, albeit completely recovering to normal mainly in young patients with short disease duration. Respiratory complications, represented mainly by sleep-breathing disorders, particularly sleep apnea, and respiratory insufficiency, frequently occur at the early stage of the disease and, although their severity decreases with disease control, this improvement does not often change the indication for a specific therapy directed to improve respiratory function. Metabolic complications, including glucose and lipid disorders, are variably reported in acromegaly. Treatments of acromegaly may influence glucose metabolism, and the presence of diabetes mellitus in acromegaly may affect the choice of treatments, so that glucose homeostasis is worth being monitored during the entire course of the disease. Early diagnosis and prompt treatment of acromegaly, aimed at obtaining a strict control of hormone excess, are the best strategy to limit the development or reverse the complications and prevent the premature mortality.

Effects of long-term combined treatment with somatostatin analogues and pegvisomant on cardiac structure and performance in acromegaly.

To date, no data are available on the effects of long-term combined treatment with somatostatin analogues (SA) and pegvisomant (PEG) on cardiovascular complications in acromegaly. The current study aimed at investigating the effects of long-term SA + PEG on cardiac structure and performance. Thirty-six patients (14 M, 22 F, aged 52.3 ± 10.2 years) entered this study. Weight, BMI, systolic (SBP) and diastolic (DBP) blood pressure, IGF-I, fasting glucose (FG), fasting insulin (FI), HOMA-IR, HbA1c, and lipids were evaluated at baseline (T0), after long-term (median 36 months) SA (T1), after 12 (T12) and 60 (T60) months of SA + PEG, and at last follow-up (LFU, median 78 months). At each time point, all patients underwent echocardiography. At T1, induced a slight but not significant decrease in IGF-I (p = 0.077), whereas FI (p = 0.004), HOMA-IR (p = 0.013), ejection fraction (EF, p = 0.013), early (E) to late (A) ventricular filling velocities (E/A, p = 0.001), and isovolumetric relaxation time (IVRT, p = 0.000) significantly improved. At T12, IGF-I (p = 0.000) significantly reduced compared to T0, and FI (p = 0.001), HOMA-IR (p = 0.000), LVMI (p = 0.000), and E/A (p = 0.006) further improved compared to T1. At T60, FI (p = 0.027), HOMA-IR (p = 0.049), and E/A (p = 0.005) significantly improved as compared to T1. At LFU IGF-I normalized in 83.3 %, FI (p = 0.000), HOMA-IR (p = 0.000), LVMi (p = 0.000), and E/A (p = 0.005) further improved as compared to T1. PEG dose significantly correlated with LVMi at T12 (r = 0.575, p = 0.000) and T60 (r = 0.403, p = 0.037). Long-term PEG addition to SA improves cardiac structure and performance, particularly diastolic dysfunction, in acromegalic patients resistant to SA.

Prognostic and Predictive Factors in Patients with Advanced Penile Cancer Receiving Salvage (2nd or Later Line) Systemic Treatment: A Retrospective, Multi-Center Study.

Introduction and objectives: Metastatic penile squamous cell carcinoma (PSCC) is associated with dismal outcomes with median overall survival (OS) of 6-12 months in the first-line and <6 months in the salvage setting. Given the rarity of this disease, randomized trials are difficult. Prognostic risk models may assist in rational drug development by comparing observed outcomes in nonrandomized phase II studies and retrospective data vs. predicted outcomes based on baseline prognostic factors in the context of historically used agents. In this retrospective study, we constructed a prognostic model in the salvage setting of PSCC patients receiving second or later line systemic treatment, and also explored differences in outcomes based on type of treatment. Materials and methods: We performed a chart review to identify patients with locally advanced unresectable or metastatic PSCC who received second or later line systemic treatment in centers from North America and Europe. The primary outcome was OS from initiation of treatment, with secondary outcomes being progression-free survival (PFS) and response rate (RR). OS was estimated using the Kaplan-Meier method. Cox proportional hazards regression was used to identify prognostic factors for outcomes using univariable and multivariable models. Results: Sixty-five patients were eligible. Seventeen of 63 evaluable patients had a response (27.0%, 95% confidence interval [CI] = 16.6-39.7%) and median OS and PFS were 20 (95% CI = 20-21) and 12 (95% CI = 12, 16) weeks, respectively. Visceral metastasis (VM) and hemoglobin (Hb) ≤ 10 gm/dl were consistently significant poor prognostic factors for both OS and PFS, and Hb was also prognostic for response. The 28 patients with neither risk factor had a median OS (95% CI) of 24 (20-40) weeks and 1-year (95% CI) OS of 13.7% (4.4-42.7%), while the 37 patients with 1 or 2 risk factors had median OS (95% CI) of 20 (16-20) weeks and 1-year (95% CI) OS of 6.7% (1.8-24.9%). Cetuximab-including regimens were associated with a trend for improved RR compared to other agents (Odds ratio = 5.05, 95% CI = 0.84-30.37, p = 0.077). Taxanes vs. non-taxane, and combination vs. single agent therapy was not associated with improved outcomes. The study is limited by its modest sample size. Conclusion: This is the first prognostic classification proposed for patients receiving salvage systemic therapy for advanced PSCC. The presence of VM and Hb ≤ 10 gm/dl was associated with poor OS and PFS. Cetuximab appeared to be associated with better RR. This prognostic model may assist in salvage therapy drug development for this orphan disease by improving interpretation of outcomes seen in nonrandomized data.

Erectile Dysfunction is Common among Men with Acromegaly and is Associated with Morbidities Related to the Disease.

INTRODUCTION: The prevalence of erectile dysfunction (ED) and its correlates in men with acromegaly has never been investigated. AIM: The aim of this study was to evaluate sexual function in men with acromegaly. METHODS: Multicenter-based, retrospective analysis of a nonselected series of 57 acromegalic subjects (mean age: 52.7 ± 14.2 years) was performed. Acromegalic subjects reporting ED (n = 24) were compared with matched ED patients without acromegaly or pituitary disease (controls), selected from a cohort of more than 4,000 subjects enrolled in the Florence Sexual Medicine and Andrology Unit. MAIN OUTCOME MEASURES: Patients were interviewed using Structured Interview on Erectile Dysfunction (SIEDY) structured interview, a 13-item tool for the assessment of ED-related morbidities. Several clinical and biochemical parameters were taken. Penile color Doppler ultrasound (PCDU) was performed in a subgroup of 37 acromegalic subjects. RESULTS: ED was reported by 42.1% of acromegalic subjects. After adjusting for age and testosterone, acromegalic subjects with ED had a higher prevalence of hypertension and more often reported an impairment of sleep-related erections and a longer smoking habit. Accordingly, acromegaly-associated ED was characterized by a higher organic component and worse PCDU parameters. No relationship between ED and testosterone levels or other acromegaly-related parameters was found. However, acromegalic subjects with severe ED reported a longer disease duration. In a case-control analysis, comparing acromegalic subjects with ED-matched controls free from acromegaly (1:5 ratio), acromegalic men had a worse ED problem and a higher organic component of ED, as derived from SIEDY score. In line with these data, acromegalic patients with ED had a higher prevalence of major adverse cardiovascular events history at enrollment and lower PCDU parameters. CONCLUSIONS: Subjects with complicated acromegaly are at an increased risk of developing ED, especially those with cardiovascular morbidities. Our data suggest including a sexual function evaluation in routine acromegaly follow-up.

Effect of chronic cabergoline treatment and testosterone replacement on metabolism in male patients with prolactinomas.

INTRODUCTION: Hyperprolactinemia and hypogonadism are reportedly associated with an impaired metabolic profile. The current study aimed at investigating the effects of testosterone replacement and cabergoline (CAB) treatment on the metabolic profile in male hyperprolactinemic patients. PATIENTS AND METHODS: Thirty-two men with prolactinomas, including 22 with total testosterone (TT) <8 nmol/l (HG, 69%) and 10 with TT >8 nmol/l (non-HG, 31%), were entered in the study. In all patients, metabolic parameters were assessed at diagnosis and after 12- and 24-month treatment. RESULTS: Compared to non-HG patients, at baseline the HG patients had higher waist circumference (WC). TT significantly correlated with body mass index (BMI). Twelve-month CAB induced PRL normalization in 84%. HG prevalence significantly decreased (28%) and non-HG prevalence significantly increased (72%). Anthropometric and lipid parameters, fasting insulin (FI), insulin sensitivity index (ISI0), homeostatic model assessment of insulin secretion (HOMA-ß) and homeostatic model assessment of insulin resistance (HOMA-IR) significantly improved compared to baseline. TT was the best predictor for FI. Percent change (Δ) of TT significantly correlated with ΔCholesterol, ΔWeight and ΔBMI. Compared to non-HG patients, the HG patients had a higher weight, BMI, WC and HOMA-ß. In HG, testosterone replacement was started. After 24 months, PRL normalized in 97%. HG prevalence significantly decreased (6%) and non-HG prevalence significantly increased (94%). Anthropometric and lipid parameters, FI, ISI0, HOMA-ß and HOMA-IR significantly improved compared to baseline, with FI, ISI0, HOMA-ß and HOMA-IR further ameliorating compared to the 12-month evaluation. Compared to non-HG patients, the HG patients still had a higher weight, BMI and WC. CONCLUSIONS: In hyperprolactinemic hypogonal men, proper testosterone replacement induces a significant improvement in the metabolic profile, even though the amelioration in the lipid profile might reflect the direct action of CAB.

Cushing, acromegaly, GH deficiency and tendons.

Cushing's syndrome, induced by an endogenous or exogenous cortisol excess, and acromegaly, the clinical syndrome caused by growth hormone (GH) excess in adulthood, as well as the disease induced by GH deficiency (GHD), represent perfect models for the evaluation of the effects induced by chronic exposure in vivo, respectively, to cortisol and GH/IGF-1 excess or deficiency on the complex structure of the tendons as well as on the related post-traumatic repair mechanism. Although the literature is still scant, here in main scientific evidence on this topic is summarized in order to provide suggestions about the management of the above mentioned illnesses, to translate such information in the field of sports medicine and/or traumatology, and to increase and to disseminate knowledge on this misunderstood theme.

Effect of cabergoline on metabolism in prolactinomas.

INTRODUCTION: Hyperprolactinemia has been implicated in the pathogenesis of obesity and glucose intolerance and is reportedly associated with an impaired metabolic profile. The current study aimed at investigating the effects of 12- and 60-month treatment with cabergoline (CAB) on metabolic syndrome (MetS) in patients with prolactinomas. PATIENTS AND METHODS: 61 patients with prolactinomas (13 men, 48 women, 41 with microadenoma, 20 with macroadenoma), aged 34.4 ± 10.3 years, entered the study. In all patients, prolactin (PRL) and metabolic parameters were assessed at diagnosis and after 12 and 60 months of continuous CAB treatment. MetS was diagnosed according to NCEP-ATP III criteria. RESULTS: Compared to baseline, CAB induced a significant decrease in PRL with complete normalization in 93% of patients after the 60-month treatment. At baseline, MetS prevalence was significantly higher in patients with PRL above (34.5%) than in those with PRL lower (12.5%) than the median (129 µg/l, p = 0.03). MetS prevalence significantly decreased after 12 (11.5%, p = 0.039) and 60 (5.0%, p = 0.001) months compared to baseline (28.0%). At both evaluations the lipid profile significantly improved compared to baseline. Fasting insulin and homeostatic model assessment of insulin resistance significantly decreased after 1 year of CAB (p = 0.012 and p = 0.002, respectively) and further improved after 60 months (p = 0.000). The visceral adiposity index significantly decreased after the 60-month treatment (p = 0.000) compared to baseline. At the 5-year evaluation CAB dose was the best predictor of percent decrease in fasting insulin (t = 2.35, p = 0.022). CONCLUSIONS: CAB significantly reduces MetS prevalence and improves the adipose tissue dysfunction index. The improvement in PRL, insulin sensitivity and other metabolic parameters might reflect the direct effect of CAB.

Treatment with GH receptor antagonist in acromegaly: effect on cardiac arrhythmias.

OBJECTIVE: To evaluate the effects of short- and long-term treatment with pegvisomant (PEG) on arrhythmias in acromegalic patients resistant to long-term, high-dose therapy with somatostatin analogs (SA). MATERIALS AND METHODS: Thirteen patients entered the study. all patients started peg at initial dose of 10MG daily and then titrated to 5MG every 6 weeks on the basis of IGF1. A standard 24-H electrocardiography registration was performed in all patients at baseline and after 6 AND 18 months of PEG to evaluate: mean (HR), maximum (MHR), and minimum (mHR) heart rate; pauses number (P) and duration (PD); supraventricular episodes (SEs) number and duration (SED); and ventricular ectopic beats (EB) number and duration (EBD). Left ventricular mass (LVM) was also evaluated by standard echocardiography. RESULTS: A slight but not significant decrease in HR, MHR, and mHR was observed after 6-month PEG, whereas a significant decrease in HR (P=0.03), MHR (P=0.05), and mHR (P=0.05) was found after 18-month PEG compared with baseline. LVM significantly (P=0.05) correlated with MRH (r=-0.50) after short-term treatment, and with HR (r=-0.54) and mHR (r=-0.55) after long-term treatment. Long-term PEG induced the complete recovery of arrhythmias recorded at baseline in one patient and the improvement of rhythm disorders developed after 6-month therapy in another patient. The prevalence of conduction disturbances passed from 15 to 7.7% after long-term PEG. CONCLUSIONS: Long-term treatment with PEG reduces HR, MHR, and mHR and improves rhythm abnormalities in acromegaly.

Determinants of cardiac disease in newly diagnosed patients with acromegaly: results of a 10 year survey study.

CONTEXT: The most frequent cause of death in acromegaly is cardiomyopathy. OBJECTIVE: To evaluate determinants of acromegalic cardiomyopathy. DESIGN: Observational, open, controlled, retrospective study. SUBJECTS: Two hundred and five patients with newly diagnosed active acromegaly (108 women and 97 men; median age 44 years) and 410 non-acromegalic subjects sex- and age-matched with the patients. MAIN OUTCOME MEASURES: Left ventricular (LV) mass index (LVMi), transmitral inflow early-to-atrial (E/A) peak velocity ratio, and LV ejection fraction (LVEF) were measured by Doppler echocardiography to determine the prevalence of LV hypertrophy (LVH), diastolic and systolic dysfunction. The role of age, estimated disease duration, body mass index, GH and IGF1 levels, systolic and diastolic blood pressure, lipid profile and glucose tolerance in determining different features of the acromegalic cardiomyopathy was investigated. RESULTS: Compared with controls, the patients had lower E/A, LVEF, high-density lipoprotein (HDL)-cholesterol levels and higher LVMi, total- and low-density lipoprotein (LDL)-cholesterol, triglycerides, glucose and insulin levels, homeostatic model assessment of insulin resistance (HOMA-R) and HOMA-ß. The relative risk to develop mild (odds ratio (OR)=1.67 (1.05-2.66); P=0.027) or severe hypertension (OR=1.58 (1.04-2.32); P=0.027), arrhythmias (OR=4.93 (1.74-15.9); P=0.001), impaired fasting glucose/impaired glucose tolerance (OR=2.65 (1.70-4.13); P<0.0001), diabetes (OR=2.14 (1.34-3.40); P=0.0009), LVH (OR=11.9 (7.4-19.5); P<0.0001), diastolic (OR=3.32 (2.09-5.31); P<0.0001) and systolic dysfunction (OR=14.2 (6.95-32.2); P<0.0001), was higher in acromegaly. The most important predictor of LVH (t=2.4, P=0.02) and systolic dysfunction (t=-2.77, P=0.006) was disease duration and that of diastolic dysfunction was patient's age (t=-3.3, P=0.001). Patients with an estimated disease duration of >10 years had a relative risk to present cardiac complications three times higher than patients with estimated disease duration ≤5 years. CONCLUSIONS: The prevalence of different features of cardiomyopathy is 3.3-14.2 times higher in the acromegalic than in the non-acromegalic population. The major determinant of cardiomyopathy is disease duration.

Growth hormone nadir during oral glucose load depends on waist circumference, gender and age: normative data in 231 healthy subjects.

OBJECTIVE: (i) To analyse the predictors of GH suppression after standard glucose load (oGTT) in the healthy population and (ii) to establish the 97th percentile of GH nadir post-oGTT according to these variables. Design Analytical, retrospective. MEASUREMENTS: GH nadir after oGTT. SUBJECTS: Two hundred and thirty-one healthy subjects (113 women, 118 men 15-80years) were studied. RESULTS: The GH nadir after glucose load ranged from 0·01 (88 cm in women and 102 cm in men (97th percentile 0·16 µg/l). CONCLUSIONS The results of this study show that GH nadir after oGTT should be analysed according to gender, menopausal status and waist circumference. The GH cut-off should be limited to the assay used.

The kidney in acromegaly: renal structure and function in patients with acromegaly during active disease and 1 year after disease remission.

BACKGROUND: The GH/insulin-like growth factor 1 axis is physiologically involved in the regulation of electrolytes and water homeostasis by kidneys, and influences glomerular filtration and tubular re-absorption processes. The aim of the study was to investigate renal structure and function in acromegalic patients during active disease and disease remission. PATIENTS: Thirty acromegalic patients (15 males and 15 females), aged 32-70 years, were enrolled for the study. Ten de novo patients had active disease, whereas 20 patients showed disease remission 1 year after medical treatment with somatostatin analogs (SA) (ten patients) or surgery (ten patients). Thirty healthy subjects matched for age, gender, and body surface area were enrolled as controls. RESULTS: In both active (A) and controlled (C) patients, creatinine clearance (P<0.001) and citrate (P<0.05) and oxalate levels (P<0.001) were higher, whereas filtered Na (P<0.001) and K (P<0.001) fractional excretions were lower than those in the controls. Urinary Ca (P<0.001) and Ph (P<0.05) levels were significantly increased compared with the controls, and in patients with disease control, urinary Ca (P<0.001) levels were significantly reduced compared with active patients. Microalbuminuria was significantly increased in active patients (P<0.05) compared with controlled patients and healthy control subjects. The longitudinal (P<0.05) and transverse (P<0.05) diameters of kidneys were significantly higher than those in the controls. In all patients, the prevalence of micronephrolithiasis was higher than that in the controls (P<0.001), and was significantly correlated to disease duration (r=0.871, P<0.001) and hydroxyproline values (r=0.639, P<0.001). CONCLUSIONS: The results of the current study demonstrated that acromegaly affects both renal structure and function. The observed changes are not completely reversible after disease remission.

Complete disappearance of a GH-secreting pituitary macroadenoma in a patient with acromegaly: effect of treatment with lanreotide Autogel and consequence of treatment withdrawal.

BACKGROUND: Somatostatin analogs (SA) are the cornerstone in the medical treatment of acromegaly, used as either primary or adjunctive therapy. In particular, SA are effective in inducing the biochemical remission of the disease and tumor shrinkage, although only few cases of complete disappearance of the pituitary tumor in patients treated with SA as long-acting formulations have been reported. SA withdrawal has been demonstrated to keep safe levels of GH and IGF1 at least in a small subset of patients well responsive to SA, although it is generally followed by disease recurrence after several months. CASE REPORT: A 61-year-old female patient bearing a very large GH-secreting pituitary macroadenoma was treated with 12-month lanreotide Autogel (ATG), at the initial dose of 120 mg/28 days. After 3 months, GH and IGF1 levels were fully normalized, to prolong the administration interval from 28 to 56 days. After 6 months of treatment, a significant tumor shrinkage (90% of baseline size) was observed, whereas GH and IGF1 excess was still well controlled. After 12-month therapy, a complete disappearance of the pituitary tumor was observed, and the hormonal evaluation confirmed the complete biochemical remission of acromegaly. Lanreotide ATG treatment was withdrawn. The clinical, biochemical, and radiological remission of acromegaly was maintained 24 months after lanreotide ATG treatment discontinuation, without evidence of disease recurrence. CONCLUSIONS: This report represents an exemplary case of the potentiality of treatment with lanreotide ATG in inducing a complete remission of acromegalic disease, persistent after a long period of time from treatment withdrawal.

Effects of initial therapy for five years with somatostatin analogs for acromegaly on growth hormone and insulin-like growth factor-I levels, tumor shrinkage, and cardiovascular disease: a prospective study.

OBJECTIVE: The objective of the study was to evaluate the efficacy of 5 yr of depot somatostatin analogs (SSAs) as first-line therapy in acromegaly. OUTCOME MEASURES: Primary measures were fasting GH 2.5 microg/liter or less and IGF-I normalized for age and tumor shrinkage. Secondary measures were control of hypertension, arrhythmias, left ventricular hypertrophy, diastolic and systolic dysfunction, and change in lipid and glucose profile. PATIENTS: Patients included 45 de novo patients (18 women and 27 men, aged 20-82 yr); 28 were treated with octreotide-long-acting release and 17 with lanreotide. RESULTS: GH was controlled in 100% and IGF-I levels in 97.8%, tumor shrinkage was 74.9 +/- 22.1 and 78.2+/-14.5%, in the octreotide-long-acting release and lanreotide groups, respectively. There was a significant improvement in the prevalence of hypertension (from 46.7 to 22.2%, P = 0.027), arrhythmias (from 17.8% to zero, P = 0.01), left ventricular hypertrophy (from 82.2 to 42.2%, P < 0.0001), diastolic dysfunction (from 60.0 to 15.6%, P < 0.0001), systolic dysfunction (from 40.0 to 4.4%, P < 0.0001), and hypertriglyceridemia (from 40.0 to 4.4%, P < 0.0001). The prevalence of impaired glucose tolerance (IGT; from 28.9 to 20.0%. P = 0.46) and diabetes mellitus (from 22.4 to 31.1%, P = 0.64) did not change. CONCLUSIONS: In patients with severe comorbidities and those who refuse surgery, 5 yr of exclusive SSA therapy induce successful control of GH and IGF-I; tumor shrinkage (by median 80%), and improvement of hypertension, cardiac performance; and dyslipidemia. No patient was withdrawn from treatment because of side effects, and glucose tolerance was stable. We suggest that first-line SSA treatment may be safely continued in patients with acromegaly, according to an individual patient's indications and preferences.

Glucose tolerance and somatostatin analog treatment in acromegaly: a 12-month study.

OBJECTIVE: The objective of the study was to investigate the impact of first-line somatostatin analogs (SSAs) on glucose tolerance (GT) in acromegaly. DESIGN: The design was open and prospective. PATIENTS: One hundred twelve patients [63 with normal GT (56.2%), 24 with impaired GT (21.4%), and 25 with diabetes (22.3%)] were treated with depot SSAs for 12 months: 54 patients (48.2%) achieved mean fasting GH levels less than 2.5 microg/liter in presence of normal IGF-I levels (controlled) during SSA. PRIMARY OUTCOME MEASURES: Fasting glucose and glycosylated hemoglobin levels were measured. RESULTS: At study end, 57 patients had normal GT (50.1% vs. baseline; P = 0.55), 30 had impaired fasting glucose or impaired GT (26.8%, P =0.43) and 25 had diabetes (22.3%; P = 1.0). Twenty-eight patients (25.0%), modified their GT [11 improved (9.8%), 17 worsened (15.2%)]: 90% of the patients with GT improvement achieved control of acromegaly and 89% of those having GT worsening did not (P < 0.0001). The major predictors of GT changing were disease control (t = -4.99; P < 0.0001), baseline GT (t = -2.84; P = 0.0054), and GH levels (t = 2.70; P = 0.008). Fasting glucose levels were predicted by patients' age (t = 2.74; P = 0.0071) and IGF-I levels (t = 2.14; P = 0.035). Glycosylated hemoglobin levels were predicted by disease duration (t = 3.53; P = 0.0006), GH levels (t = 2.70; P = 0.0071), and IGF-I levels (t = 2.11; P = 0.037). CONCLUSIONS: This study showed a similar prevalence of deterioration and improvement of GT 12 months after first-line SSA treatment. Uncontrolled acromegaly during SSA treatment and abnormal GT at baseline were associated with GT worsening.

Impact of somatostatin analogs versus surgery on glucose metabolism in acromegaly: results of a 5-year observational, open, prospective study.

OBJECTIVE: The aim of the study was to investigate the 5-yr impact of surgery and somatostatin analogs (SSA) on glucose metabolism in acromegaly. DESIGN: We conducted an observational, prospective, comparative, nonrandomized study. PATIENTS: The 100 patients (48 women, 52 men; median age, 49 yr) in the study were grouped as follows for treatment: SSA only (group A; n = 34); SSA followed by surgery (group B; n = 20); surgery only (group C; n = 30); and surgery followed by SSA (group D; n = 16). RESULTS: At diagnosis, 28% had impaired glucose tolerance, and 22% had diabetes mellitus; fasting glucose levels (4.13-10.60 mmol/liter) were best predicted by age (t = 2.88; P = 0.0049) and disease duration (t = 1.99; P = 0.049). After 60 months, fasting glucose levels reduced (-4.9 +/- 19.7%) in group A only, whereas they did not change in the other groups. In the 68 nondiabetic patients at baseline, fasting glucose levels increased by 0.7 +/- 11.2%, 7.5 +/- 10.3%, 4.3 +/- 10.4%, and 4.3 +/- 14.8% (P = 0.28), from groups A to D, respectively. Percentage change of fasting glucose in all patients receiving SSA was 1.9 +/- 12.3%, and in those not receiving SSA it was 6.4 +/- 10.8% (P = 0.13). Overall, prevalence of new onset of diabetes during SSA treatment was nine of 55 (16.4%) vs. three of 23 after surgery (13.0%, P = 0.98). Deterioration of glucose tolerance was correlated with increased body mass index (r = 0.49, P < 0.0001) and not with use of SSA or surgery (r = 0.06; P = 0.53), control or not of GH (r = -0.10, P = 0.31) and IGF-I (r = -0.12; P = 0.22). CONCLUSIONS: The results of this study demonstrate a similar deterioration of glucose tolerance after 60 months in patients receiving SSA or cured with surgery. Increase in body mass index was the major predictor of deterioration of glucose tolerance.