View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Archivio istituzionale della ricerca - Università di Palermo Clinical Endocrinology (2013) doi: 10.1111/cen.12204 ORIGINAL ARTICLE Higher doses of cabergoline further improve metabolic parameters in patients with prolactinoma regardless of the degree of reduction in prolactin levels Alessandro Ciresi, Marco Calogero Amato, Valentina Guarnotta, Flavia Lo Castro and Carla Giordano Section of Endocrinology, Dipartimento Biomedico di Medicina Interna e Specialistica (Di.Bi.Mi.S), University of Palermo, Palermo, Italy treatment, especially when higher doses were used, highlighting Summary the importance of considering the metabolic profile in these patients and the role of active treatment with high CAB doses. Objective Currently available studies that fully analyse the met- abolic parameters in patients with prolactinoma are scarce and (Received 14 January 2013; returned for revision 30 January 2013; discordant. The aim of this study was to evaluate the metabolic finally revised 27 February 2013; accepted 14 March 2013) effects of cabergoline (CAB) treatment in patients with newly diagnosed prolactinoma in relation to disease control and CAB dosage. Design This is a retrospective clinical-based therapy analysis. Introduction Patients Forty-three patients with prolactinoma (eight men, 35 Prolactinoma is the most frequent secreting pituitary tumour Á Æ Á women), aged 33 65 11 23 years, were evaluated metabolically and mainly affects the female gender.1 Besides the well-known at baseline and after 12 months of CAB treatment. consequences on the reproductive axis both in men and women, Measurements Body mass index (BMI), systolic and diastolic hyperprolactinaemia can be associated with alterations in body blood pressure, waist circumference (WC), lipid profile, haemo- composition and obesity,2 although the evidence is discordant. globinA1c (HbA1c), glucose and insulin levels (and their areas Reduced bone density 3,4 and total body fat 5,6 have been posi- under the curve, AUC) after an oral glucose tolerance test, tively associated with high prolactin (PRL) levels in patients with homoeostasis model assessment of insulin resistance (Homa-IR) prolactinoma. Schmid et al.7 demonstrated significantly higher index, insulin sensitivity index (ISI) Matsuda, oral disposition body mass index (BMI) in patients with macroprolactinoma index (DIo) and visceral adiposity index (VAI) were measured than both patients with inactive adenomas and the general pop- at baseline and after 12 months of treatment. ulation. Conversely, Naliato et al. showed similar body fat in < Á Results Twelve months of CAB reduced WC (P 0 001), total women with prolactinoma and controls.5 = Á < Á (P 0 001) and low-density lipoprotein \terol (P 0 001), Dopamine agonists (DA) are recognized as the recommended = Á < Á triglycerides (P 0 024), fasting insulin (P 0 001), AUCINSULIN therapy to lower PRL levels and decrease tumour size for < Á = Á < Á (P 0 001), HbA1c (P 0 022), Homa-IR (P 0 001) and VAI patients with prolactinoma, and the use of cabergoline (CAB) is < Á (P 0 001), with a concomitant increase in high-density lipo- suggested in preference to other DA because of its higher effi- < Á < Á protein cholesterol (P 0 001) and in ISI Matsuda (P 0 001), cacy.8 Several studies have analysed the effects of DA treatment regardless of the degree of reduction in prolactin levels. The on body fat and metabolism, but most of them used mainly > Á patients receiving higher doses ( 0 50 mg/week) of CAB showed bromocriptine.9 In this setting, reduced body fat content and a = Á = Á lower BMI (P 0 009), fasting insulin (P 0 001), Homa-IR lower risk of metabolic syndrome have been associated with the < Á = Á (P 0 001) and VAI (P 0 018) and higher ISI Matsuda normalization of PRL during DA treatment.5 Decreased BMI = Á = Á (P 0 002) and DIo (P 0 011), compared with those on lower and waist circumference (WC) have been reported during DA doses. therapy in some studies,10 but not in others.11 However, Conclusions A significant metabolic improvement was currently available studies that fully analyse the metabolic observed in patients with prolactinoma after 12 months of CAB parameters in patients with prolactinoma at diagnosis and during treatment with CAB are scarce, and discordant data have been reported. Based on the data that link the body composition Correspondence: Carla Giordano, Section of Endocrinology, Dipartimen- parameters with PRL levels and DA administration, the aim of to Biomedico di Medicina Interna e Specialistica (Di.Bi.Mi.S), University of Palermo, Piazza delle Cliniche 2, Palermo 90127, Italy. Tel.: +39 091 the current study was to fully evaluate the effects of 12 months 6552109; Fax: +39 091 6552123; E-mail: [email protected] of CAB treatment on the metabolic syndrome (MS), insulin © 2013 John Wiley & Sons Ltd 1 2 A. Ciresi et al. sensitivity and visceral adiposity index (VAI),12 a surrogate women, 81%) aged 33Á65 Æ 11Á23 years (range: 16–63), with parameter indicating adipose tissue dysfunction associated with newly diagnosed prolactinoma. The diagnosis was based on signs cardiometabolic risk, in a group of patients with newly diagnosed and symptoms of hyperprolactinaemia, high-serum PRL levels prolactinoma in relation to disease control and CAB dosage. and magnetic resonance imaging (MRI) demonstrating a pitui- tary tumour.8 This study was conducted in compliance with the ‘Ethical principles for medical research involving human Patients and methods subjects’ of the Helsinki Declaration. At the time of hospitalization, We conducted a retrospective chart review of patients affected all patients signed a consent form for the scientific use of their by hyperprolactinaemia seen at the Unit of Endocrinology of the data and the identity of the participants remained anonymous University of Palermo from 1 January 2011 to 30 October 2012. during the analysis. We analysed data from a total of 89 patients. The flow chart of patient distribution and inclusion in the study according to the Study design criteria adopted is shown in Fig. 1. Patients with hyperprolactinaemia secondary to drugs (includ- All patients, at baseline and after 12 months of CAB treatment, ing neuroleptics, antidepressants, opiates and gastrointestinal underwent a complete clinical and metabolic evaluation. Prolac- prokinetics) or mixed-secreting tumours, those already receiving tin levels were considered as the mean value of measurements in dopamine agonists at the baseline visit and those with a follow- at least three blood samples collected at 20-min intervals for up of less than 12 months were excluded from this analysis. In 1 h, obtained through venous cannulation, without repeated addition, we excluded patients with multiple pituitary hormone venepuncture stress. Women who presented with menstrual deficiencies and/or the presence of other concomitant causes of cycles, even if irregular, were studied in the early follicular phase overt hypogonadism to avoid the potential impact of hormonal (1–7 days from bleeding). In all patients, MRI revealed the deficit or gonadal replacement therapy on metabolic parameters. presence of a pituitary tumour. Tumour volume was calculated No women receiving oestrogens and/or progesterone as contra- in line with the Di Chiro and Nelson formula (vol- ceptives or postmenopausal hormone replacement therapy were ume = height 9 length 9 width 9 p/6) and was expressed as included. All patients with already known glucose abnormalities mm3. BMI and systolic (SBP) and diastolic (DBP) blood pres- were treated with diet alone. Patients already receiving hypogly- sure were measured in all patients. WC was measured at the caemic agents were excluded from this study. For the purpose of midpoint between the lower rib and the iliac crest. After an this study, we enrolled 43 consecutive patients (8 men, 19%; 35 overnight fast, total, high-density lipoprotein (HDL) and Fig. 1 Flow chart of patient distribution and inclusion in the study according to criteria adopted and dosage of cabergoline used. Dopamine agonists: dopamine agonists; EP: oestro/ progesterone; HA: hypoglycaemic agents; CAB: cabergoline; PRL: prolactin. © 2013 John Wiley & Sons Ltd Clinical Endocrinology (2013), 0, 1–8 Metabolic effects of cabergoline in patients with prolactinoma patients 3 low-density lipoprotein (LDL) cholesterol, triglycerides and hae- were presented as mean Æ Standard Deviation (SD) for continu- moglobinA1c (HbA1c) were measured. In addition, an oral glu- ous variables; rates and proportions were calculated for categori- cose tolerance test (OGTT) was performed by measuring plasma cal data. Differences between groups in univariate analysis were blood glucose and insulin levels every 30 min for 2 h after a detected by the unpaired Student’s t-test for continuous vari- 75-g oral glucose load. The areas under the curve of glucose ables and by the chi-square test and Fisher’s exact test (when (AUCGLU) and insulin (AUCINS) during the 2-h OGTT were appropriate) for categorical variables. The differences between also calculated. The diagnosis of diabetes or glucose tolerance paired continuous variables (before and after 12 months of ther- abnormalities was made according to the American Association apy) were analysed by the paired Student’s t-test for continuous of Clinical Endocrinologists medical guidelines.13 Basal insulin variables and by the McNemar test for categorical variables. A P resistance (IR) was assessed using homoeostasis model assess- value of <0Á05 was considered statistically significant. ment of the insulin resistance (Homa-IR) index.14 Stimulated insulin sensitivity was measured using the insulin sensitivity Results index (ISI), a composite index derived from the OGTT and vali- dated by Matsuda et al.15 Total insulin secretion was assessed by Baseline AUCINS, while b-cell function relative to insulin sensitivity was assessed by oral disposition index (DIo).16 The hormonal and metabolic parameters of patients at diagnosis VAI was calculated as described,12 using the following formula are shown in Table 1.