Mariano Galdiero

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 No patient was withdrawn from treatment because of side effects, and glucose tolerance was stable.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 patients indications and preferences.

Beneficial effect of dose escalation of Octreotide-LAR as first-line therapy in patients with acromegaly

OBJECTIVE To evaluate the efficacy of dose escalation of Octreotide-long-acting repeatable (LAR) up to 40 mg/month we studied 56 newly diagnosed patients with acromegaly (24 women, 32 men; age 20-82 years). DESIGN Analytical, observational, open and prospective. METHODS Three months after LAR treatment beginning with a dose of 20 mg /q28d (every 28 days), 24 patients maintained the same dose (Group A), while 32 required a dose of 30 mg/q28d (Group B). The dose was further increased to 40 mg/q28d in 17 out of the 32 patients of Group B for another 12 months (Group C). RESULTS After 24 months, serum GH and IGF-I levels decreased by 93.1 +/- 8.6% (95% confidence limit (CL) 90.8-95.4%) and 62.7 +/- 13.4% (95% CL 59.1-66.3%) respectively. Control of GH and IGF-I levels was achieved in 45 patients (80.3%). Tumor shrinkage after 12 months was 49.8 +/- 23%; the relative tumor shrinkage during the second 12 months of treatment was 35.3 +/- 13.1% and overall tumor volume was 68.1 +/- 16.5% (95% CL 63.7-72.5%). Glucose tolerance impaired in eight patients (14.3%): four in Group A and four in Group C (16.7% vs 36.4%, P=0.39). The final dose was predicted by the patients age at diagnosis (t=-2.2; P=0.032) and baseline tumor volume (t=2.1; P=0.043). CONCLUSION An increase of the LAR dose up to 40 mg/q28d in patients resistant to 30 mg/q28d is followed by greater suppression of GH and IGF-I levels and tumor shrinkage without further significant impairment of glucose tolerance when compared with lower doses. These results suggest that a new dosage schedule of 40 mg every 28 days is applied in patients with acromegaly mostly of young age and with bigger tumors who are likely to be poorly responsive to standard doses of Octreotide-LAR.

Acromegaly and the Cardiovascular System

Acromegaly is characterized by an increased cardiovascular morbidity and mortality. In fact, growth hormone and insulin-like growth factor-I excess induces a specific cardiomyopathy. The heart is involved from the very early stages of the disease in which the hyperkinetic syndrome (high heart rate and increased systolic output) takes place. Frequently, if the disease is untreated for many years or unsuccessfully treated, concentric biventricular hypertrophy and diastolic dysfunction can develop and, at least, lead to diastolic congestive heart failure. Rhythm disturbances and valve dysfunction are also frequently described in acromegaly. The coexistence of other complications, such as diabetes and arterial hypertension, can induce the worsening of acromegalic cardiomyopathy. Control of acromegaly by surgery or pharmacotherapy could improve cardiovascular morbidity thanks to decreasing left ventricular mass and reducing cardiac dysfunction. In conclusion, an early diagnosis and a careful evaluation of cardiac function, morphology and activity seem to be mandatory in acromegaly.

Significant tumour shrinkage after 12 months of lanreotide Autogel-120 mg treatment given first-line in acromegaly

Objective  To evaluate GH and IGF‐I control and tumour shrinkage in newly diagnosed patients with acromegaly treated first‐line with lanreotide‐Autogel (ATG) 120 mg.

Impact of Treating Acromegaly First with Surgery or Somatostatin Analogs on Cardiomyopathy

OBJECTIVE The objective of the study was to investigate whether first-line surgery or somatostatin analogs (SSA) have a different outcome on cardiomyopathy after 12 months. DESIGN This was a retrospective, comparative, nonrandomized study. PATIENTS Fifty-six patients treated with SSA and 33 operated on by transsphenoidal approach participated in the study. For the purposes of this study, only controlled patients were included. MEASUREMENTS Primary outcome measures were changes in left ventricular mass index, diastolic (early to atrial mitral flow velocity), and systolic performance (left ventricular ejection fraction). Secondary outcome measures were reduction of total to high-density lipoprotein-cholesterol ratio as a cardiovascular risk parameter, and improvement of glucose profile and pituitary function as indirect causes of cardiovascular improvement. RESULTS SSA and surgery groups were similar for gender, age, estimated disease duration, GH and IGF-I levels, and severity of cardiomyopathy lipid and glucose profile. Twelve months after treatment in both groups, left ventricular mass index, early to atrial mitral flow velocity, diastolic blood pressure, and heart rate decreased significantly, whereas only in SSA-treated patients, left ventricular ejection fraction increased significantly. The total to high-density lipoprotein-cholesterol ratio significantly reduced only in SSA-treated patients, whereas fasting glucose levels significantly decreased only in surgery-treated patients. A normal pituitary function was found in 46.4% of SSA- and 36.4% of surgery-treated patients, with results unchanged in the former and slightly reduced in the latter. CONCLUSIONS Twelve months after first-line treatment with SSA or surgery, we found a similar improvement in left ventricular hypertrophy and diastolic filling. In contrast, systolic function improved more evidently in SSA-treated patients. Both a direct effect of SSA and a more preserved pituitary function might explain these results.

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.

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-β. 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 patients 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.

Epidemiology, diagnosis, and treatment of male hypogonadotropic hypogonadism

Hypogonadotropic hypogonadism (HH), or secondary hypogonadism, is a clinical condition due to an impairment of the pituitary function, characterized by low testosterone plasma levels associated with normal or low FSH and LH plasma levels. An impairment of gonadotropin secretion and, therefore, a reduced efficiency of spermatogenesis was reported to be frequently associated to conditions different from the classical causes of secondary hypogonadism. These conditions (metabolic, endocrine and eating disorders, physical exercise etc.) have been associated with a non-classical form of HH that could be called “functional” HH (FHH). FHH differs from the classical one by the evidence that gonadotropin levels are in the low-normal range, but are inadequate for the testosterone levels, that often are also in the low-normal range. This commentary aims at reviewing knowledge on the forms of male HH in order to indicate and discuss clinical context, diagnostic and therapeutic approach in the less known non-classical form, i.e. FHH.

Growth Hormone-Secreting Tumor Shrinkage after 3 Months of Octreotide-Long-Acting Release Therapy Predicts the Response at 12 Months

OBJECTIVE The objective of the study was to evaluate whether tumor shrinkage or GH and IGF-I levels achieved after 3 months predicted tumor shrinkage after 12 months of octreotide-long-acting release (LAR) treatment. PATIENTS Patients included 67 patients with de novo acromegaly (33 women, 34 men; aged 20-82 yr) receiving LAR at a dose of 20 mg every 28 d for 3 months. Final LAR dose was 10 mg every 28 d in 4, 30 mg every 28 d in 39, 20 mg every 28 d in 24 patients. DESIGN The design of the study was analytical, observational, open, and retrospective. OUTCOME MEASURES Percent change in GH and IGF-I levels and tumor volume after 3 and 12 months of therapy was measured. Stepwise regression and receiving-operator characteristics analysis were used to calculate the optimal cutoff to predict 12 months tumor shrinkage at 12 months. RESULTS The percent tumor shrinkage after 12 months was significantly correlated with GH, IGF-I, and tumor volume at 3 months and with the dose of LAR administered between 3 and 12 months. There was no correlation with gender, age, baseline GH levels and tumor volume. In a stepwise regression analysis, percent tumor shrinkage after 3 months was the best predictor of tumor shrinkage after 12 months (t = 5.92; P < 0.0001), followed by GH levels after 3 months (t = 2.86; P = 0.0056). To predict 50% or greater tumor shrinkage after 12 months, the best cutoff point of tumor shrinkage at 3 months was 22.1% [sensitivity (95% confidence interval) = 85.5% (71.2-95.4); specificity = 83.3% (65.3-94.3)], whereas that of GH levels after 3 months was 7.8 microg/liter [sensitivity = 70.3% (53.0-84.1); specificity = 93.3% (79.0-99.0)]. CONCLUSION Tumor shrinkage achieved after 3 months of LAR treatment at 20 mg/28 d predicted tumor shrinkage at 12 months, provided that dosages were changed according to individual patients requirement.

Medical consequences of acromegaly: what are the effects of biochemical control?

This chapter discusses the effects of biochemical control of acromegaly on cardiovascular diseases, metabolic complications, respiratory abnormalities, malignancies and bone alterations. Acromegaly is associated with increased morbidity and mortality for cardiovascular and respiratory complications, whereas neoplasms seem to be a minor cause of increased risk of death. Other associated diseases are osteoarthritis, carpal tunnel syndrome, fatigue, visual abnormalities and reproductive disorders. Acromegaly results in premature death because of prolonged elevation of GH an IGF-I levels, and a strong biochemical control improves well-being and restores life expectancy to normal. The main goals of medical treatment of acromegaly include normalization of biochemical markers of disease activity, improvement in signs and symptoms of the disease, removal or reduction of tumor mass and preservation of pituitary function.