Ludovica F. S. Grasso

Results of a Single-Center Observational 10-Year Survey Study on Recurrence of Hyperprolactinemia after Pregnancy and Lactation

CONTEXT The current survey study investigated the recurrence rate of hyperprolactinemia after cabergoline (CAB)-induced pregnancy and after lactation as well as safety of CAB exposure during early gestation. PATIENTS AND METHODS From 1997-2008, 143 pregnancies were recorded in 91 patients with hyperprolactinemia (age 30.4 ± 4.7 yr, 76 microadenomas, 10 macroadenomas, and five nontumoral hyperprolactinemia). CAB therapy was discontinued within wk 6 of gestation in all. Pregnancies were monitored until delivery or termination, during and after lactation, twice yearly up to 60 months. The incidence of abortions, premature delivery, and fetal malformations was also analyzed. RESULTS Pregnancies resulted in 13 (9.1%) spontaneous abortions and 126 (88.1%) live births. No neonatal malformations and/or abnormalities were recorded. In 29 of 91 patients (three with macroadenomas), treatment with CAB had to be restarted within 6 months after lactation because of hyperprolactinemia recurrence, whereas in 68% of cases, no additional therapy was required up to 60 months. No tumor mass enlargement was observed. All patients but three were breastfeeding, 35 (38.5%) for less than 2 months and 56 (61.5%) for 2-6 months. Three months after cessation of lactation and 60 months after pregnancy, no difference in prolactin levels was found between patients nursing for less than 2 months and 2-6 months. CONCLUSIONS Fetal exposure to CAB at conception does not induce any increased risk of miscarriage or malformations. Pregnancy is associated with normalization of prolactin levels in 68% of patients. Breastfeeding does not increase the recurrence rate of hyperprolactinemia.

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.

Pregnancy in acromegaly: experience from two referral centers and systematic review of the literature.

Background  Acromegaly results from increased growth hormone and its target insulin‐like growth factor‐1, most commonly due to a pituitary tumour. As it is frequently accompanied by infertility, little is known about the course of this disease in pregnancy.

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.

The Circulating Level of FABP3 Is an Indirect Biomarker of MicroRNA-1

OBJECTIVES This study sought to identify proteins from the cardiomyocyte (CM) secretome that are directly targeted by the muscle-specific microRNA-1 (miR-1), and thus reflect the pathophysiological state of the CM. BACKGROUND MicroRNAs play critical regulatory roles during myocardial remodeling and progression to heart failure. However, it remains unknown whether secreted microRNA-targeted proteins can be used as indicators of myocardial microRNA expression and function. METHODS A proteomic analysis based on multidimensional protein identification technology was performed on supernatants from cultured CMs overexpressing miR-1. Biochemical assays and an inducible cardiac-specific transgenic mouse model overexpressing miR-1 were used to demonstrate that heart-type fatty acid-binding protein-3 (FABP3) is a target of miR-1. Levels of miR-1 and FABP3 in cardiac tissue and plasma samples from mouse models as well as human patients were quantified by quantitative reverse-transcription polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. The study included wild-type mice subjected to ventricular pressure overload or fasting, as well as patients diagnosed with ventricular hypertrophy due to valvular aortic stenosis, acromegaly, or growth hormone deficiency, conditions associated with altered miR-1 expression. RESULTS An inverse relationship between myocardial expression of miR-1 and circulating levels of FABP3 was found both in vitro and in vivo under various pathological conditions. CONCLUSIONS Assessment of FABP3 plasma levels in human patients might be used for indirectly measuring cardiac miR-1 activity.

Safety of long-term treatment with cabergoline on cardiac valve disease in patients with prolactinomas

OBJECTIVE Cabergoline (CAB) has been found to be associated with increased risk of cardiac valve regurgitation in Parkinsons disease, whereas several retrospective analyses failed to detect a similar relation in hyperprolactinemic patients. The current study aimed at investigating cardiac valve disease before and after 24 and 60 months of continuous treatment with CAB only in patients with hyperprolactinemia. SUBJECTS AND METHODS Forty patients (11 men and 29 women, aged 38.7 ± 12.5 years) newly diagnosed with hyperprolactinemia entered the study. Cumulative CAB dose ranged from 12 to 588 mg (median 48 mg) at 24 months and 48-1260 mg (median 149 mg) at 60 months. All patients underwent a complete trans-thoracic echocardiographic examination. Valve regurgitation was assessed according to the American Society of Echocardiography. RESULTS At baseline, the prevalence of trace mitral, aortic, pulmonic, and tricuspid regurgitations was 20, 2.5, 10, and 40% respectively, with no patient showing clinically relevant valvulopathy. After 24 months, no change in the prevalence of trace mitral (P=0.78) and pulmonic (P=0.89) regurgitations and of mild aortic (P=0.89) and tricuspid (P=0.89) regurgitations was found when compared with baseline. After 60 months, the prevalence of trace tricuspid regurgitation was only slightly increased when compared with that after 24 months (37.5%; P=0.82), but none of the patients developed significant valvulopathy. No correlation was found between cumulative dose and prevalence or grade of valve regurgitation at both evaluations. Prolactin levels normalized in all patients but one. CONCLUSION CAB does not increase the risk of significant cardiac valve regurgitation in prolactinomas after the first 5 years of treatment.

The Metabolic Profile in Active Acromegaly is Gender-Specific

CONTEXT The sexual dimorphism of the somatotroph axis has been documented, but whether the acromegaly-related metabolic alterations are gender-dependent has never been investigated. OBJECTIVE The aim of the study was to evaluate the impact of gender on the metabolic parameters in acromegaly. DESIGN We conducted a retrospective, comparative, multicenter study. PATIENTS The 307 newly diagnosed acromegalic patients included in the study were grouped by gender: 157 men (aged 48.01 ± 14.28 yr), and 150 women (aged 48.67 ± 14.95 yr; of which 77 were premenopausal and 73 postmenopausal). OUTCOME MEASUREMENTS We measured each component of the metabolic syndrome (MS), hemoglobin A1c, the areas under the curve (AUCs) of glucose and insulin during 2-h oral glucose tolerance test, basal insulin resistance using the homeostasis model assessment of the insulin resistance index, stimulated insulin sensitivity using the insulin sensitivity index, early insulin-secretion rate using the insulinogenic index, β-cell function relative to insulin sensitivity using the oral disposition index and the visceral adiposity index (VAI) as the surrogate of visceral fat function. RESULTS Women showed a higher prevalence of MS (P < 0.001), higher fasting insulin levels (P < 0.001), AUC for insulin (P = 0.002), homeostasis model assessment of the insulin resistance index (P < 0.001), and VAI (P < 0.001) and a lower insulin sensitivity index (P = 0.002) than men, whereas no difference was found in fasting glucose, AUC for glucose, hemoglobin A1c, insulinogenic index, and oral disposition index. In women, fasting glucose and fasting insulin showed a significant trend toward increase (P < 0.001) and decrease (P = 0.004), respectively, from the first to the fourth quartiles of age, whereas VAI showed a trend toward increase in both groups (P < 0.001). A significantly higher prevalence of MS (P < 0.001), increased waist circumference (P < 0.001), low high-density lipoprotein cholesterol (P < 0.001), and overt diabetes mellitus (P < 0.001) was found in postmenopausal women compared with premenopausal women, as well as with men. CONCLUSIONS The majority of metabolic features in acromegaly are gender-specific. Active acromegaly in women is strongly associated with higher visceral adiposity dysfunction, insulin resistance, and the features of MS. We suggest more accurate metabolic management in acromegalic women, especially in the postmenopausal years.

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.

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.

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.