Annamaria Anita Livia Colao

Guidelines of the Pituitary Society for the diagnosis and management of prolactinomas

In June 2005, an ad hoc Expert Committee formed by the Pituitary Society convened during the 9th International Pituitary Congress in San Diego, California. Members of this committee consisted of invited international experts in the field, and included endocrinologists and neurosurgeons with recognized expertise in the management of prolactinomas. Discussions were held that included all interested participants to the Congress and resulted in formulation of these guidelines, which represent the current recommendations on the diagnosis and management of prolactinomas based upon comprehensive analysis and synthesis of all available data.

Medical treatment of prolactinomas

Prolactinomas, the most prevalent type of neuroendocrine disease, account for approximately 40% of all pituitary adenomas. The most important clinical problems associated with prolactinomas are hypogonadism, infertility and hyposexuality. In patients with macroprolactinomas, mass effects, including visual field defects, headaches and neurological disturbances, can also occur. The objectives of therapy are normalization of prolactin levels, to restore eugonadism, and reduction of tumor mass, both of which can be achieved in the majority of patients by treatment with dopamine agonists. Given their association with minimal morbidity, these drugs currently represent the mainstay of treatment for prolactinomas. Novel data indicate that these agents can be successfully withdrawn in a subset of patients after normalization of prolactin levels and tumor disappearance, which suggests the possibility that medical therapy may not be required throughout life. Nevertheless, multimodal therapy that involves surgery, radiotherapy or both may be necessary in some cases, such as patients who are resistant to the effects of dopamine agonists or for those with atypical prolactinomas. This Review reports on efficacy and safety of pharmacotherapy in patients with prolactinomas.

Treatment of prolactinomas

The objectives of the treatment of hyperprolactinaemia are to suppress excessive hormone secretion and its clinical consequences, to remove tumour mass, to preserve the residual pituitary function and to prevent disease recurrence or progression. Prior to the advent of pharmacotherapy, therapy usually consisted of surgical resection and/or pituitary irradiation. In microprolactinomas, trans-sphenoidal surgical resection normalizes prolactin (PRL) levels, restores normal menses and produces the disappearance of galactorrhoea in a great majority of patients, but normalization of serum PRL levels varies from 35-70%. In macroprolactinomas, trans-sphenoidal surgery is less successful with only 32% of patients appearing to be cured initially. However, the recurrence rate is 19%, and the long-term cure rate is only 26%. In more than 80% of the patients with microprolactinoma, suppression of PRL levels and tumour shrinkage can be achieved with bromocriptine therapy given at doses of 2.5-5 mg per day. In 5-10% of the patients, the appearance of side-effects (nausea, dizziness and postural hypotension) is a limiting factor in continuing the treatment. Dopaminergic compounds cause notable tumour shrinkage in most macroprolactinomas. Treatment with cabergoline, a selective and long-lasting dopamine 2-receptor agonist at weekly doses of 0.5-2 mg has been shown to be effective both in normalizing PRL levels and in inducing tumour shrinkage. Pharmacotherapy with dopamine (DA) agonists is an appropriate first-line treatment for both micro- and macroprolactinomas. Surgery should be recommended for those patients who are severely intolerant of or resistant to DA agonists.

MECHANISMS IN ENDOCRINOLOGY: Vitamin D as a potential contributor in endocrine health and disease

OBJECTIVEnIt has been suggested that vitamin D may play a role in the pathogenesis of several endocrine diseases, such as hyperparathyroidism, type 1 diabetes (T1DM), type 2 diabetes (T2DM), autoimmune thyroid diseases, Addisons disease and polycystic ovary syndrome (PCOS). In this review, we debate the role of vitamin D in the pathogenesis of endocrine diseases.nnnMETHODSnNarrative overview of the literature synthesizing the current evidence retrieved from searches of computerized databases, hand searches and authoritative texts.nnnRESULTSnEvidence from basic science supports a role for vitamin D in many endocrine conditions. In humans, inverse relationships have been reported not only between blood 25-hydroxyvitamin D and parathyroid hormone concentrations but also with risk of T1DM, T2DM, and PCOS. There is less evidence for an association with Addisons disease or autoimmune thyroid disease. Vitamin D supplementation may have a role for prevention of T2DM, but the available evidence is not consistent.nnnCONCLUSIONSnAlthough observational studies support a potential role of vitamin D in endocrine disease, high quality evidence from clinical trials does not exist to establish a place for vitamin D supplementation in optimizing endocrine health. Ongoing randomized controlled trials are expected to provide insights into the efficacy and safety of vitamin D in the management of endocrine disease.

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

OBJECTIVEnCabergoline (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.nnnSUBJECTS AND METHODSnForty 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.nnnRESULTSnAt 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.nnnCONCLUSIONnCAB does not increase the risk of significant cardiac valve regurgitation in prolactinomas after the first 5 years of treatment.

Effects of high-dose octreotide LAR on glucose metabolism in patients with acromegaly inadequately controlled by conventional somatostatin analog therapy

OBJECTIVEnIn this study, the effect of high-dose octreotide LAR on glucose metabolism in patients with acromegaly was investigated.nnnDESIGNnA post-hoc analysis of a clinical trial enrolling 26 patients with acromegaly not controlled by standard maximal somatostatin analog (SSAs) dose and randomized to receive high-dose (60 u200amg/28 days) or high-frequency (30 u200amg/21 days) octreotide i.m. injection (octreotide LAR) for 6 months.nnnMETHODSnGlucose metabolic status was defined as worsened when a progression from normoglycemia to impaired fasting glucose (IFG) or from IFG to diabetes occurred or when an increase of HbAlc by at least 0.5% was demonstrated. An improvement of glucose metabolism was defined in the presence of a regression from IFG to normoglycemia and/or when HbAlc decreased by at least 0.5%.nnnRESULTSnGlucose metabolic status remained unchanged in a majority of patients (16/26 patients, 65.3%), worsened in six patients, and improved in four patients. Pre-existing metabolic status did not predict worsening of glucose metabolism, which, conversely, was significantly related to persistent biochemical activity of the disease. In fact, patients with worsened glucose metabolism exhibited a less frequent decrease in serum GH and IGF1 levels, compared with patients with improved or unchanged glucose metabolism (2/6 vs 18/20; P=0.01).nnnCONCLUSIONnAn increase in octreotide LAR dose or frequency did not impact on glucose metabolism in most patients. Worsening of glucose metabolic status occurred in close relation with persistently uncontrolled acromegaly.

Is diabetes in Cushing's syndrome only a consequence of hypercortisolism?

OBJECTIVEnDiabetes mellitus (DM) is one of the most frequent complications of Cushings syndrome (CS). The aim of this study was to define the changes in insulin sensitivity and/or secretion in relation to glucose tolerance categories in newly diagnosed CS patients.nnnDESIGNnCross-sectional study on 140 patients with CS.nnnMETHODSnA total of 113 women (80 with pituitary disease and 33 with adrenal disease, aged 41.7±15.7 years) and 27 men (19 with pituitary disease and eight with adrenal disease, aged 38.1±20.01 years) at diagnosis were divided according to glucose tolerance into normal glucose tolerance (CS/NGT), impaired fasting glucose and/or impaired glucose tolerance (CS/prediabetes), and diabetes (CS/DM) groups.nnnRESULTSnSeventy-one patients had CS/NGT (49.3%), 26 (18.5%) had CS/prediabetes and 43 (30.8%) had CS/DM. Significant increasing trends in the prevalence of family history of diabetes (P<0.001), metabolic syndrome (P<0.001), age (P<0.001) and waist circumference (P=0.043) and decreasing trends in HOMA-β (P<0.001) and oral disposition index (DIo) (P<0.002) were observed among the groups. No significant trends in fasting insulin levels, area under the curve for insulin (AUCINS), Matsuda index of insulin sensitivity (ISI-Matsuda) and visceral adiposity index were detected.nnnCONCLUSIONSnImpairment of glucose tolerance is characterized by the inability of β-cells to adequately compensate for insulin resistance through increased insulin secretion. Age, genetic predisposition and lifestyle, in combination with the duration and degree of hypercortisolism, strongly contribute to the impairment of glucose tolerance in patients with a natural history of CS. A careful phenotypic evaluation of glucose tolerance defects in patients with CS proves useful for the identification of those at a high risk of metabolic complications.

Role of UGT1A1 and ADH gene polymorphisms in pegvisomant-induced liver toxicity in acromegalic patients.

CONTEXTnHepatotoxicity is one of the most serious adverse effects in acromegalic patients treated with pegvisomant (PEG-V). Recent studies have found an association between this adverse event and the UGT1A1 allele 28 polymorphism associated with Gilberts syndrome.nnnOBJECTIVEnTo determine whether UGT1A1*28 and alcohol dehydrogenase (ADH) polymorphisms influence liver toxicity during PEG-V treatment.nnnDESIGN AND SETTINGnMulticenter observational retrospective study conducted in 13 tertiary care endocrinology units in Italy.nnnPATIENTSnA total of 112 patients with active disease resistant to somatostatin analogs (SSTa) and 108 controls were enrolled.nnnINTERVENTIONSnClinical and biochemical data were recorded by electronic clinical reporting forms. Blood or DNA samples were sent to the coordinating center for genotyping.nnnRESULTSnNo differences in genotypes between patients and controls were found. During PEG-V therapy liver function tests (LFT), abnormalities and overt hepatotoxicity developed in 17 and 4.5% of patients respectively. Logistic and linear regression analyses showed an association between LFT abnormalities during the follow-up visit and prior events of LFT abnormalities in medical history (odds ratio=1.25; P=0.04) and the number of concomitant medications, other than SSTa (B=3.9; P=0.03). No correlation between LFT alterations and UGT1A1 allele 28 as well as ADH1C and B polymorphisms was found.nnnCONCLUSIONSnUGT1A1 allele 28 and ADH1C and B polymorphisms do not predict increased risk of hepatotoxicity during PEG-V therapy. Conversely, patients with multi-therapies and with previous episodes of liver disease should be carefully managed, due to the observed association between these conditions and LFT abnormalities during PEG-V therapy.

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

OBJECTIVEnTo 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).nnnMATERIALS AND METHODSnThirteen 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.nnnRESULTSnA 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.nnnCONCLUSIONSnLong-term treatment with PEG reduces HR, MHR, and mHR and improves rhythm abnormalities in acromegaly.

A multivariable prediction model for pegvisomant dosing: monotherapy and in combination with long-acting somatostatin analogues

BACKGROUNDnEffective treatment of acromegaly with pegvisomant (PEGV), a growth hormone receptor antagonist, requires an appropriate dose titration. PEGV doses vary widely among individual patients, and various covariates may affect its dosing and pharmacokinetics.nnnOBJECTIVEnTo identify predictors of the PEGV dose required to normalize insulin-like growth factor I (IGF-I) levels during PEGV monotherapy and in combination with long-acting somatostatin analogues (LA-SSAs).nnnDESIGNnTwo retrospective cohorts (Rotterdamu2009+u2009Liège Acromegaly Survey (LAS), total nu2009=u2009188) were meta-analyzed as a form of external replication to study the predictors of PEGV dosing in addition to LA-SSA, the LAS (nu2009=u200983) was used to study the predictors of PEGV monotherapy dosing. Multivariable regression models were used to identify predictors of the PEGV dose required to normalize IGF-I levels.nnnRESULTSnFor PEGV dosing in combination with LA-SSA, IGF-I levels, weight, height and age, were associated with the PEGV normalization dosage (Pu2009≤u20090.001, Pu2009≤u20090.001, Pu2009=u20090.028 and Pu2009=u20090.047 respectively). Taken together, these characteristics predicted the PEGV normalization dose correctly in 63.3% of all patients within a range of ±60u2009mg/week (21.3% within a range of ±20u2009mg/week). For monotherapy, only weight was associated with the PEGV normalization dose (Pu2009≤u20090.001) and predicted this dosage correctly in 77.1% of all patients within a range of ±60u2009mg/week (31.3% within a range of ±20u2009mg/week).nnnCONCLUSIONnIn this study, we show that IGF-I levels, weight, height and age can contribute to define the optimal PEGV dose to normalize IGF-I levels in addition to LA-SSA. For PEGV monotherapy, only the patients weight was associated with the IGF-I normalization PEGV dosage.