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Purpose Pegvisomant (PEG) efficaciously controls IGF-I excess in acromegaly and possesses a positive impact on glucose metabolism. Data on very prolonged PEG treatment are still limited, therefore, we investigated the effects of 10-years PEG on disease control, maximal tumour diameter (MTD), and metabolic profile in consecutive patients resistant to somatostatin analogues (SRLs) followed in an European referral centre for acromegaly. Methods Since the 2000s, we collected data on anthropometric, hormonal and metabolic parameters, and MTD of patients receiving PEG. In the current study, we included 45 patients (19 men, 26 women, 46.8 ± 11 years) treated for at least 5 years with PEG mono or combined therapy, analyzing data before, after 5- and 10-years PEG. Results After10 years, 91% of patients showed full disease control and in 37% a significant decrease in MTD was found. Diabetes prevalence was slightly increased, whereas HbA1c remained stable over the decade. Transaminases remained stable and no case of cutaneous lipohypertrophy was recorded. A different metabolic impact between mono- or combined therapy was found. Patients in monotherapy showed significantly lower fasting glucose (p = 0.01), fasting insulin (p = 0.008), HbA1c (p = 0.007), HOMA-IR (p = 0.001), and significantly higher ISI0 (p = 0.002), whereas patients under combined therapy showed significantly lower total (p = 0.03), and LDL cholesterol (p = 0.007). Acromegaly duration before PEG was inversely related to ΔFG (r = − 0.46, p = 0.03) and ΔFI (r = − 0.54, p = 0.05). Conclusions PEG is effective and safe in long term. In patients resistant to SRLs, early beginning of PEG allows a wider gluco-insulinemic improvement.

Purpose Data on the role of prolactin (PRL) in the physiologic range in the female sexual response are scanty. We aimed at investigating the association between PRL and sexual function as assessed by the Female Sexual Function Index (FSFI). We explored the presence of a cut-off level of PRL able to identify Hypoactive Sexual Desire Disorder (HSDD). Methods 277 pre- and post-menopausal women consulting for Female Sexual Dysfunction (FSD) and sexually active were enrolled in an observational, retrospective study. 42 women were used as no-FSD controls. A clinical, biochemical and psychosexual evaluation was performed. The main outcome measures were: FSFI, Female Sexual Distress Scale-Revised, Middlesex Hospital Questionnaire and Sexual excitation/sexual inhibition scale (SIS/SES). Results Normo-PRL FSD women (n = 264) showed lower FSFI Desire score than controls (n = 42), and higher than hyper-PRL FSD women (n = 13). These differences emerged both in pre-menopausal and post-menopausal subjects. In the normo-PRL FSD group, those with PRL in the higher quintile reported higher FSFI Desire scores than those with PRL in the lowest quintile. Women with HSDD presented a lower PRL level than those without (p = 0.032). A ROC curve analysis for PRL showed an accuracy of 0.610 ± 0.044 (p = 0.014) in predicting HSDD. With a threshold of p = 0.006) and lower cortisol levels (p = 0.003) than those with PRL > = 9.83 μg/L. Conclusions Hyper-PRL is associated with low desire; however, among normo-PRL FSD women, those with the lowest levels demonstrated a poorer desire than those with the highest levels. PRL

Prolactinomas are the most common pituitary tumor histotype, with microprolactinomas being prevalent in women and macroprolactinomas in men. Hyperprolactinemia is among the most common causes of hypogonadotropic hypogonadism in both sexes, prompting medical advice for hypogonadism (infertility, oligo-amenorrhea, impotence, osteoporosis/osteopenia) in both sexes, and for signs and symptoms of mass effects (hypopituitarism, visual loss, optic chiasm compression, cranial nerve deficits, headaches) predominantly in men. Diagnostic workup involves a single prolactin measurement and pituitary imaging, but some laboratory artifacts (ie, the “hook effect” and macroprolactin) can complicate or delay the diagnosis. The treatment of choice for prolactinomas is represented by dopamine agonists, mainly cabergoline, which are able to induce disease control, restore fertility in both sexes, and definitively cure one-third of patients, thus permitting treatment discontinuation. Pregnancy and menopause may promote spontaneous prolactin decline and anticipate cabergoline discontinuation in women. Surgery and/or radiotherapy are indicated in case of resistance to cabergoline not overcome by the increase in drug dose up to the maximally tolerated or the patient's personal choice of surgery. The evidence of resistance to cabergoline in invasive and proliferative tumors may indicate biological aggressiveness, thus requiring alternative therapeutic approaches mainly based on temozolomide use as monotherapy or combined with radiotherapy. In uncontrolled patients, new medical approaches (alternative hormonal treatments, cytotoxic drugs, peptide receptor radionuclide therapy, mTOR/Akt inhibitors, tyrosine kinase inhibitors, or immunotherapy) may be offered but the experience collected to date is still very scant. This article reviews different facets of prolactinomas and discusses approaches to the condition in more common clinical situations.

Context Fertility represents a major concern in patients with acromegaly. Objective The current retrospective study aimed to investigate gonadal function and fertility rates in acromegalic women. Methods In this referral-center study, 50 acromegalic women with disease onset within reproductive age were evaluated for prevalence of gonadal dysfunction and infertility. Anthropometric, metabolic, hormonal parameters, and gynecological ultrasound were evaluated at diagnosis and after disease control. Data about menstrual disturbances, pregnancy, and polycystic ovarian morphology (PCOM) were investigated at disease onset, at diagnosis, and after disease control. Results At presumed disease onset, menstrual disturbances were reported in 32% of patients. Uterine leiomyoma, ovarian cysts, and PCOM were diagnosed in 18%, 12%, and 8%, respectively; 36.8% of patients were infertile. At diagnosis, menstrual disturbances were found in 58.1% (P = .02), being significantly more prevalent in patients with higher insulin-like growth factor-I quartiles (Q) (P = .03, Q1 vs Q4). Gynecological ultrasound revealed uterine leiomyoma, ovarian cysts, and PCOM in 39.1% (P = .04), 28.2% (P = .09), and 13% (P = .55), respectively. The infertility rate was 100% (P = .02). At disease control, menstrual disturbances were slightly decreased as compared to diagnosis (P = .09). Noteworthy, menstrual disturbances (P = .05) and particularly amenorrhea (P = .03) were significantly more frequent in patients with active disease duration greater than 5 years (median) as compared to those achieving disease control in less than 5 years. Among patients with pregnancy desire, 73.3% conceived at least once, with resulting infertility significantly decreased compared to diagnosis (26.7%; P = .01). At-term deliveries, preterm deliveries, and spontaneous abortions were recorded in 86.7%, 6.6%, and 6.6%, respectively, of the 15 pregnancies reported by the patients. No neonatal malformations and/or abnormalities were recorded. Conclusion Gonadal dysfunction and infertility are common in acromegalic women within reproductive age, being directly influenced by disease status and/or duration.

Purpose The current randomized, double-blind, placebo-controlled clinical trial addressed the effects on penile erectile function of relatively high daily oral doses (6 g/day) of l-ARG for 3 months (N = 51) compared to placebo (N = 47), in patients with vasculogenic ED, with comparison between mild–moderate and severe vasculogenic ED. Methods The outcome measures included IIEF-6 score and cavernous arteries peak systolic flow velocity (PSV) at dynamic penile duplex ultrasonography (PDU). Results l-ARG supplementation for 3 months significantly increased IIEF-6 score in the overall cohort (p p p = 0.007) vasculogenic ED; PSV was significantly increased in the overall cohort (p p Conclusion The results of the current study demonstrated that supplementation with relatively high doses of l-ARG as a single compound for 3 months significantly improved penile erectile function, assessed by both IIEF-6 score and PSV at dynamic PDU in patients with mild–moderate, and improved IIEF-6 score, but not PSV, in patients with severe vasculogenic ED, therefore suggesting that l-ARG might be an alternative treatment in mild–moderate vasculogenic ED patients experiencing adverse effects or with contraindications for chronic treatment with PDE5i compounds.

SommarioLa gestione clinico-terapeutica dei pazienti con prolattinoma è basata sul trattamento con dopamino-agonisti (DA), in particolare la cabergolina, data la loro comprovata efficacia biochimica e antitumorale. Il raggiungimento di normali valori di prolattina associato alla significativa riduzione delle dimensioni tumorali, fino alla sua completa scomparsa, può suggerire l’opportunità di sospendere tale terapia nei pazienti trattati per almeno due anni. Tuttavia, è fortemente raccomandato di evitare la sospensione improvvisa del trattamento con DA e di preferire un protocollo di graduale riduzione del dosaggio di DA fino alla definitiva interruzione del trattamento, al fine di consentire la persistenza di normali valori di prolattina nel tempo. Nei pazienti con evidenza di recidiva di iperprolattinemia dopo un primo tentativo di sospensione dei DA, è possibile effettuare un secondo tentativo di sospensione dopo un ulteriore ciclo di trattamento con DA per due anni.

The coronavirus disease 2019 (COVID-19) outbreak, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global public health issue which has profound effects on most aspects of societal well-being, including physical and mental health. A plethora of studies globally have suggested the existence of a sex disparity in the severity and outcome of COVID-19 patients, mainly due to mechanisms of virus infection, immune response to the virus, development of systemic inflammation, and consequent systemic complications, particularly thromboembolism. Epidemiological data report a sex difference in the severity of COVID-19, with a more favorable course of the disease in women compared to men regardless of age, although the rate of SARS-CoV-2 infection seems to be similar in both sexes. Sex hormones, including androgens and estrogens, may not only impact virus entry and load, but also shape the clinical manifestations, complications, and ultimately the outcome of the disease. The current review comprehensively summarizes the current literature on sex disparities in susceptibility and outcome of COVID-19 as well as the literature underpinning the pathophysiological and molecular mechanisms, which may provide a rationale to a sex disparity. These mechanisms include sex hormone influence on factors that facilitate virus entry and priming, immune and inflammatory response, as well as coagulation and thrombosis diathesis. Based on present evidence, women appear to be relatively protected from COVID-19 because of a more effective immune response and a less pronounced systemic inflammation, with consequent moderate clinical manifestations of the disease, together with a lesser predisposition to thromboembolism. Conversely, men appear to be particularly susceptible to COVID-19 because of a less effective immune response with consequent severe clinical manifestations of the disease, together with a greater predisposition to thromboembolism. In the elderly, generally characterized by the phenomenon of inflammaging, sex disparities in overall mortality following SARS-CoV-2 infection are even more palpable as elderly men appear to be more prone to severe COVID-19 because of a greater predisposition to infections, a weaker immune defense, and an enhanced thrombotic state compared to women. The information revealed from the review highlights potential novel therapeutic approaches employing the administration of hormonal or antihormonal therapy in combination with antiviral drugs in COVID-19 patients.

Objective: Sensory deficits are important risk factors for delirium but have been investigated in single-center studies and single clinical settings. This multicenter study aims to evaluate the association between hearing and visual impairment or bi-sensory impairment (visual and hearing impairment) and delirium. Design: Cross-sectional study nested in the 2017 "Delirium Day" project. Setting and participants: Patients 65 years and older admitted to acute hospital medical wards, emergency departments, rehabilitation wards, nursing homes, and hospices in Italy. Methods: Delirium was assessed with the 4AT (a short tool for delirium assessment) and sensory deficits with a clinical evaluation. We assessed the association between delirium, hearing and visual impairment in multivariable logistic regression models, adjusting for: Model 1, we included predisposing factors for delirium (ie, dementia, weight loss and autonomy in the activities of daily living); Model 2, we added to Model 1 variables, which could be considered precipitating factors for delirium (ie, psychoactive drugs and urinary catheters). Results: A total of 3038 patients were included; delirium prevalence was 25%. Patients with delirium had a higher prevalence of hearing impairment (30.5% vs 18%; P < .001), visual impairment (24.2% vs 15.7%; P < .01) and bi-sensory impairment (16.2% vs 7.5%) compared with those without delirium. In the multivariable logistic regression analysis, the presence of bi-sensory impairment was associated with delirium in Model 1 [odds ratio (OR) 1.5, confidence interval (CI) 1.2-2.1; P = .00] and in Model 2 (OR 1.4; CI 1.1-1.9; P = .02), whereas the presence of visual and hearing impairment alone was not associated with delirium either in Model 1 (OR 0.8; CI 0.6-1.2, P = .36; OR 1.1; CI 0.8-1.4; P = .42) or in Model 2 (OR 0.8, CI 0.6-1.2, P = .27; OR 1.1, CI 0.8-1.4, P = .63). Conclusions and implications: Our findings support the importance of routine screening and specific interventions by a multidisciplinary team to implement optimal management of sensory impairments and hence prevention and the management of the patients with delirium.

Most prolactinomas are diagnosed in women of reproductive age and are generally microadenomas. Prolactinomas diagnosed in postmenopausal women are less common and are not usually associated with the typical syndrome induced by prolactin excess, including infertility and oligo-amenorrhea. This implies that the diagnosis of prolactinomas after menopause may be delayed and require greater clinical effort. Limited data are available on the management and prognosis of prolactinomas in postmenopausal women. However, the physiologic decline of prolactin levels during menopause and the lack of fertility concerns, which represent specific indications for medical treatment with dopamine agonists, might require a careful reassessment of therapeutic management in such patients. Postmenopausal women with microprolactinoma may be successfully withdrawn from medical therapy with dopamine agonists, whereas in those with macroprolactinomas greater caution is advisable before dopamine agonists are discontinued, considering the potential, although rare, tumor enlargement. This review focuses on the diagnostic challenges and therapeutic management of prolactinomas in postmenopausal women.

The discovery of dopamine inhibitory effects on prolactin secretion has led to an era of successful dopaminergic therapy for prolactinomas. Herein we provide an overview of the evolution of dopamine agonists and their use in patients with PRL-secreting pituitary tumors, starting from the 1970s up to today, highlighting that normalization of PRL levels, restoration of eugonadism, and reduction of tumor mass can be achieved in the majority of patients by treatment with dopamine agonists.

Purpose COVID-19 pandemics and cardiometabolic health are mutually interconnected. Chronic metabolic diseases are known risk factors for increased mortality after SARS-CoV-2 infection. In turn, COVID pandemics imposed sudden changes in lifestyle and social isolation with consequent potential cardiometabolic sequelae. The present study aimed at investigating the impact of changes in lifestyle and social life on metabolic profile in hyperprolactinemic or osteoporotic patients without pre-existing cardiometabolic diseases at the time of COVID-19. Methods The primary study outcome measurement was the prevalence of obesity, arterial hypertension, impaired glucose tolerance (IGT) or diabetes mellitus (DM), dyslipidemia and metabolic syndrome after COVID-19 outbreak. Seventy-four patients (21 men and 53 women, aged 51.8 ± 17.8 years) were admitted to the outpatient clinic of the Neuroendocrine Disease Unit at University “Federico II” of Naples, Italy, as per their routine clinical practice because of tumoral and non-tumoral hyperprolactinemia in 52 patients (70.3%), and osteoporosis/osteopenia in 22 (29.7%). Among female patients, 25 (47.2%) were at menopausal age. Results At the end of lockdown, prevalence of obesity (from 37.8% to 51.3%, p p = 0.003) and metabolic syndrome (from 14.9 to 27%, p Conclusion SARS-CoV-2 outbreak has led to a rapid increase in the prevalence of metabolic syndrome, potentially contributing to the increased COVID-19 related mortality.

PI3K/Akt/mTOR pathway activation is common in GH-secreting pituitary tumours, and a target for treatment with mTOR inhibitors, including everolimus (EVE). The current study aimed to evaluate the efficacy of two PI3K inhibitors (PI3Ki), NVP-BKM120 and NVP-BYL719, alone and in combination with EVE in rat GH-secreting pituitary tumour cell line (GH3) and human GH-secreting pituitary tumour cell cultures. In GH3 cell line and in six GH-secreting tumour cell cultures, the effects of PI3Ki and EVE, as single agents and in combination, were tested on cell viability and colony survival, by MTT and clonogenic assay, respectively, whereas western blot was performed to evaluate the underlying intracellular signalling pathways. PI3Ki and EVE showed a dose-dependent inhibition of cell viability in GH3 cell line, with PI3Ki displaying a synergistic effect when combined with EVE. PI3Ki and EVE inhibited colony survival in GH3 cell line with no further improvement in combination. In GH-secreting pituitary tumour cell cultures PI3Ki are effective in inhibiting cell viability increasing the slight and non significant inhibition induced by EVE as single agent, generally showing a synergistic effect. Despite in both GH3 cell line and GH-secreting pituitary tumour cell cultures combination of PI3Ki enhanced EVE effect, the study of intracellular signalling pathways revealed a different regulation of PI3K/Akt/mTOR and MAPK between the two models. The results of the current study demonstrated that PI3Ki, especially in combination with EVE, are effective in inhibiting cell proliferation, therefore representing a promising therapeutic tool for the treatment of aggressive GH-secreting pituitary tumours, not responsive to standard medical therapies.

Gli adenomi ipofisari insorgono nel 5–6% dei casi in un contesto familiare, nell’ambito di sindromi come le Neoplasia Endocrine Multiple (MEN1, MEN4) o in forma isolata (Familial Isolated Pituitary Adenomas, FIPA). Negli ultimi anni sono state riconosciute nuove entita e nuovi geni di predisposizione tra cui, in particolare, il gene Aryl hydrocarbon receptor Interacting Protein (AIP). Il riconoscere una predisposizione genetica, anche in forme apparentemente sporadiche, e essenziale non solo per il caso indice ma anche per la sua famiglia.

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.

Primary or acquired resistant mechanisms prevent the employment of individualized therapy with target drugs like the mTOR inhibitor everolimus (EVE) in hepatocellular carcinoma (HCC). The current study evaluated the effect of 1,25(OH)2Vitamin D (VitD) treatment on EVE sensitivity in established models of HCC cell lines resistant to everolimus (EveR). DNA content and colony formation assays, which measure the proliferative index, revealed that VitD pre-treatment re-sensitizes EveR cells to EVE treatment. The evaluation of epithelial and mesenchymal markers by western blot and immunofluorescence showed that VitD restored an epithelial phenotype in EveR cells, in which prolonged EVE treatment induced transition to mesenchymal phenotype. Moreover, VitD treatment prompted hepatic miRNAs regulation, evaluated by liver miRNA finder qPCR array. In particular, miR-375 expression was up-regulated by VitD in EveR cells, in which miR-375 was down-regulated compared to parental cells, with consequent inhibition of oncogenes involved in drug resistance and epithelial-mesenchymal transition (EMT) such as MTDH, YAP-1 and c-MYC. In conclusion, the results of the current study demonstrated that VitD can re-sensitize HCC cells resistant to EVE treatment triggering miR-375 up-regulation and consequently down-regulating several oncogenes responsible of EMT and drug resistance.

Background/Introduction: The European Registry for Rare Bone and Mineral Conditions (EuRR-Bone) was founded in April 2020 and is the affiliated registry of the European Reference Network for Rare Bone Diseases (ERN BOND). Purpose: As bone and mineral conditions are seen by a variety of specialists there is a close connection with the European Registries for Rare Endocrine Conditions (EuRRECa) and its affiliated ERN Rare Endocrine Diseases (Endo-ERN). EuRR-Bone is open not only to centres within these ERNs but also to others and consists of a core registry for all cases and an e-reporting registry for new cases. Methods: The latter is accomplished via an electronic reporting platform, e-REC (e-Reporting of Rare Conditions), a light touch approach that does not collect personally identifiable information. Unique IDs for reported cases are generated instantaneously and emailed to users to be stored locally at reporting centres. Data are available to all collaborators following approval by the joint Data Access Committee of EuRRECa and EuRR-Bone. Results: Until July 2020, 12 centres from 9 different countries joined, of which 5 are ERN BOND members and 10 are Endo-ERN members. A total of 23 adults and 20 children were newly diagnosed with a Bone and Mineral condition. Amongst adults, the most frequently reported conditions were fibrous dysplasia and PTH independent hypercalcemia, while in children pseudohypoparathyroidism and osteogenesis imperfecta were the most reported. Since April 2020, the e-REC platform is also being used to capture the occurrence of a new COVID19 infection in a patient with an existing bone or mineral condition. Conclusion(s): e-REC is a promising tool enabling clinical networks to objectively map conditions and related activity, providing a better understanding of the occurrence of the rare bone and mineral conditions.

Therapies for acromegaly aim at normalizing hormonal excess and controlling tumor growth . Therapeutic approaches are surgery, pharmacotherapy and radiotherapy. Area covered: This review focuses on the role of medical therapy of acromegaly, comparing the efficacy of somatostatin analogues (SSA), dopamine-agonists (DA) and pegvisomant (PEG), the three available drug classes for treating acromegaly. To clarify the difference in response rates reported in the literature for these therapies, we performed a search for original articles published in PubMed. SSA represent the first-line approach to medical treatment. This therapy is effective in controlling acromegaly in about 40% of patients, however there are great differences in the reported hormonal efficacy of SSA in the different series. In patients partially resistant to SSA, cabergoline can be added when hormonal levels are close to normalization, resulting effective in control IGF-I levels in 43% of patients. In patients with higher hormonal levels PEG is indicated, normalizing IGF-I levels in 79.8% and 80.6% of cases when used in monotherapy or in combination with SSA. Pasireotide, the newly developed SSA multi-ligand receptor, represents a new option in SSA resistant patients. Expert commentary: Medical therapy represents an important therapeutic option resulting safe and effective in controlling acromegaly in a high percentage of patients. The best treatment should be individually tailored for each patient, taking into account sex, age, comorbidities, tumor characteristics and hormonal levels.

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.

Introduction: Hyperprolactinaemia has been implicated in the pathogenesis of obesity and glucose intolerance and is reportedly associated with impaired metabolic profile and metabolic syndrome in approximately one third of patients.Area covered: Suppression of dopaminergic tone has been proposed as a potential mechanism responsible for weight gain and metabolic abnormalities in such patients. Dopamine receptor type 2 (D2R) is abundantly expressed on human pancreatic β-cell and adipocytes, suggesting a regulatory role for peripheral dopamine in insulin and adipose functions. Medical treatment with the dopamine-agonists bromocriptine and cabergoline has been shown to significantly improve gluco-insulinemic and lipid profile, also reducing the prevalence of metabolic syndrome. In patients with concomitant hypogonadism, simultaneous correction of both PRL excess and testosterone deficiency is mandatory to improve insulin resistance and metabolic abnormalities.Expert commentary: Hyperprolactinemia prom...

Objective: Cognitive deficits are common in Parkinson’s disease (PD) since the early stages and many patients eventually develop dementia. Yet, occurrence of dementia in PD is unpredictable. Evidence supports the hypothesis that insulin-like growth factor-1 (IGF-1) is involved in cognitive deficits. Our aim was to evaluate the relationship between serum IGF-1 levels and neuropsychological scores in a large cohort of drug-naïve PD patients during the earliest stages of the disease. Methods: Serum IGF-1 levels were determined in 405 early, drug-naïve PD patients and 191 healthy controls (HC) enrolled in the Parkinson’s Progression Markers Initiative (PPMI). The association between serum IGF-1 levels and neuropsychological scores was evaluated with linear regression analysis. Results: IGF-1 levels were similar in PD and HC. In PD patients the lowest IGF-1 quartile was a predictor of lower performances at the Semantic Fluency task (β = -3.46, 95%CI: -5.87 to -1.01, p = 0.005), the Symbol Digit Modalities Score (β = -2.09, 95%CI: -4.02 to -0.15, p = 0.034), and Hopkins Verbal Learning Test Retention (β = -0.05, 95%CI: -0.09 to -0.009, p = 0.019). Conclusions: Lower serum IGF-1 levels are associated to poor performances in cognitive tasks assessing executive function, attention and verbal memory in a large cohort of early PD patients. Follow-up studies are warranted to assess if IGF-1 is related to the development of dementia in PD.

Since the 1990's cabergoline has been the treatment of choice in prolactinoma, as it permits rapid and effective hormonal and tumor control in most cases. Evidence of cardiac valvulopathy was demonstrated in Parkinson's disease patients treated with dopamine agonists. Retrospective studies in prolactinoma patients treated with cabergoline at lower doses did not show such an effect. However, few prospective data with long-term follow-up are available. The aim of this study was to assess the safety of cabergoline regarding cardiac valvular status during prospective follow-up in patients treated for prolactinoma or idiopathic hyperprolactinemia. We report here a series of 100 patients (71F; median age at diagnosis: 41.5 years) treated with cabergoline for endocrine diseases (prolactinoma n = 89, idiopathic hyperprolactinemia n = 11). All patients underwent complete transthoracic echocardiographic studies at baseline and during long-term prospective surveillance using the same equipment and performed by the same technicians. The median interval between baseline and last follow-up echocardiographic studies while on cabergoline was 62.5 months (interquartile range: 34.75-77.0). The median total duration of cabergoline treatment was 124.5 months (interquartile range: 80.75-188.75) and the median cumulative total dose of cabergoline was 277.8 mg (interquartile range : 121.4-437.8 mg) at last follow-up. We found no clinically relevant alterations in cardiac valve function or valvular calcifications with cabergoline treatment. Our data suggest that findings from retrospective analyses are correct and that cabergoline is a safe chronic treatment at the doses used typically in endocrinology.

Heterozygous de novo mutations in SOX2 have been reported in approximately 10-20% of patients with unilateral or bilateral anophthalmia or microphthalmia. An additional phenotype of hypopituitarism, with anterior pituitary hypoplasia and hypogonadotropic hypogonadism, has been reported in patients carrying SOX2 alterations. We report a novel heterozygous mutation in the SOX2 gene in a male affected with congenital bilateral anophthalmia, hypogonadotrophic hypogonadism and growth hormone deficiency. The mutation we describe is a cytosine deletion in position 905 (c905delC) which causes frameshift and an aberrant C-terminal domain. Our report highlights the fact that subjects affected with eye anomalies and harboring SOX2 mutations are at high risk for gonadotropin deficiency, which has important implications for their clinical management.

According to Pituitary and Endocrine Society recommendations, cabergoline (CAB) therapy can be discontinued after 2 years in hyperprolactinemic patients who fit certain criteria. Previous studies found recurrence rates ranging between 26 and 69 %. Whether CAB therapy can be successfully discontinued after one unsuccessful withdrawal is unknown.We conducted a pilot prospective two-center study on a second attempt of CAB withdrawal. Inclusion criteria were: (1) recurrence of hyperprolactinemia after first withdrawal; (2) additional CAB therapy for at least 2 years; (3) normal serum prolactin; (4) CAB dose ≤ 1 mg/week. Prolactin level was monitored after discontinuing therapy. Median follow up for patients who are still in remission was 42 months (range = 24-60).A total of 17 patients were recruited. Mean age was 41.0 ± 17.3 years. 65 % were female. Initial tumors were microadenoma in 64.7 %, and macroadenoma in 35.3 %. The average weekly CAB dose at second withdrawal was 0.38 ± 0.20 mg (median = 0.25, range = 0.175-1). Eleven of 17 patients (64.7 %) recurred. Median time to recurrence was 6 months. The incidence of recurrence was 44 events per 100 person-years. The estimated cumulative hazard of recurrence was 40 and 82 % at 6 and 12 months respectively. The probability to be recurrence-free at 6 and 12 months was 65 and 41 %, respectively.Second attempt of CAB withdrawal after 2 additional years of therapy may be successful in some patients. A second withdrawal can be attempted with close monitoring of prolactin level. In this study, we could not identify any predictor of recurrence. Most of the recurrences occurred within the first 12 months after withdrawal.

ObjectiveCabergoline (CAB) has been found to be associated with increased risk of cardiac valve regurgitation in Parkinson's 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 methodsForty 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.ResultsAt 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.ConclusionCAB does not increase the risk of significant cardiac valve regurgitation in prolactinomas after the first 5 years of treatment.

ObjectiveAcromegalic patients have an increased risk of mortality. The objective of this study was to compare the effect of different therapies for acromegaly on mortality.Design and methodsThe mortality rate of 438 consecutive acromegalic patients was compared with that of the general population using the standardized mortality ratio (SMR); the effect of different therapies on survival was evaluated using Cox regression analysis.ResultsTwenty patients (4.5%) died between 1999 and 2009. Age- and sex-adjusted SMR was 0.70 (95% CI 0.43–1.08). The Cox regression analysis revealed that, in the whole population, both general risk factors (age and physical status) and specific factors for acromegaly (macroadenoma, hypopituitarism and uncontrolled disease) were associated with death. The most compromised patients at diagnosis had a higher mortality rate (P=0.001), which also occurred in patients with controlled acromegaly. Death occurred in 2.4% (adenomectomy), 2.6% (adenomectomy followed by somatostatin analogue (SSA) therapy) and 11.4% (SSA therapy as the primary therapy) of the patients. The risk of death was higher in patients receiving SSA therapy as the primary therapy (hazard ratio (HR) 5.52, 95% CI 1.06–28.77,P=0.043) than in all patients submitted to adenomectomy; however, a higher risk of death occurred only in diabetic patients treated with SSAs alone (HR 21.94, 95% CI 1.56–309.04,P=0.022). Radiotherapy was associated with an increased risk of mortality, which occurred in patients with the more locally advanced disease.ConclusionsTherapies for acromegaly and comorbidities have lowered the risk of mortality to the level of the general population; the effect of SSA therapy alone or that following pituitary adenomectomy was comparable to that of curative neurosurgery on survival in non-diabetic patients; on the contrary, SSA therapy as the primary therapy may be less effective than adenomectomy in reducing mortality rate in diabetic patients.

Prolactinomas are the most common hormone-secreting pituitary tumors, accounting for approximately 40% of all pituitary tumors. Infertility, gonadal and sexual dysfunction are usually the most relevant clinical features in both sexes.This review focuses on safety and tolerability of therapeutic approaches for prolactinomas. Complications from trans-sphenoidal surgery vary depending on tumor size, and mortality rate ranges 0.6%-31% for patients with microprolactinomas and macroprolactinoms, respectively. More than 50% of patients receiving pituitary radiotherapy will develop at least one hormone deficiency within the following decade, whereas cerebrovascular accidents, second brain tumors and optic neuropathy rarely occur. Nowadays, treatment of prolactinomas is based on dopamine-agonists (DA), mainly cabergoline (CAB). Whether CAB is associated with an increased risk of clinically relevant cardiac valvulopathy in patients with prolactinomas as in those with Parkinson's disease (PD), is still debated. In most studies, CAB has been found not to be associated with an increased risk of significant valvulopathy in prolactinomas, and no correlation has been shown between valvular abnormalities and CAB duration or cumulative dose.DA are safe and well tolerated, and the main safety concerns are related to the potential risk of clinically relevant valvulopathy following treatment with CAB, rarely occurring in patients with prolactinomas.

Idopamino-agonisti (DA), specialmente cabergolina (CAB) e bromocriptina (BRC), rappresentano la terapia di prima linea dei prolattinomi. In particolare, CAB e in grado di normalizzare i valori di prolattina e di indurre riduzione del volume tumorale nella grande maggioranza dei pazienti. Evidenze riportate in letteratura hanno sottolineato l’esistenza di una possibile associazione tra l’uso dei DA e lo sviluppo di fibrosi valvolare cardiaca nei pazienti affetti da malattia di Parkinson, mentre nei pazienti affetti da prolattinoma non esistono sufficienti evidenze di una chiara associazione tra prevalenza e/o gravita di valvulopatia e terapia con CAB. E, comunque, raccomandabile un adeguato follow-up cardiologico dei pazienti con prolattinoma che assumono CAB mediante valutazione ecocardiografica annuale.

Context The somatostatin analogues octreotide LAR and lanreotide Autogel have been evaluated for the treatment of acromegaly in numerous clinical trials, with considerable heterogeneity in reported biochemical response rates. This review examines and attempts to account for these differences in response rates reported in the literature. Evidence acquisition PubMed was searched for English-language studies of a minimum duration of 24 weeks that evaluated ≥10 patients with acromegaly treated with octreotide LAR or lanreotide Autogel from 1990 to March 2015 and reported GH and/or IGF-1 data as the primary objective of the study. Evidence synthesis Of the 190 clinical trials found, 18 octreotide LAR and 15 lanreotide Autogel studies fulfilled the criteria for analysis. It is evident from the protocols of these studies that multiple factors are capable of impacting on reported response rates. Prospective studies reporting an intention-to-treat analysis that evaluated medically naïve patients and used the composite endpoint of both GH and IGF-1 control were associated with lower response rates. The use of non-composite biochemical control endpoints, heterogeneous patient populations, analyses that exclude treatment non-responders, assay variability and prior responsiveness to medical therapy are just a few of the factors identified that likely contribute to higher success rates. Conclusions The wide range of reported response rates with somatostatin analogues may be confusing and could lead to misinterpretation by both the patient and the physician in certain situations. Understanding the factors that potentially drive the variation in response rates should allow clinicians to better gauge treatment expectations in specific patients.

Summary 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 15–80 years) 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.

BACKGROUND: Acromegaly is known to be associated to vascular damage characterized by an increase of vascular wall thickness and an impairment of vascular function. AIM: The aim of this study was to evaluate the effect of medical treatment with the GH receptor antagonist pegvisomant on vascular structure and function in acromegalic patients resistant to somatostatin analogues. PATIENTS: Ten patients (4 males and 6 females, 28-58 yr) and 20 sex-, age-, and body mass index-matched healthy controls entered the study. All patients were treated for 18 months with pegvisomant at doses ranging from 10 to 40 mg/day. OUTCOME MEASURES: Primary outcome measures were measurement of carotid arteries intima-media thickness (IMT), and brachial arteries flow mediated dilation (FMD); secondary outcome measures were blood pressure, blood glucose and lipids levels. RESULTS: Carotid arteries maximal IMT was significantly higher in patients than in controls at baseline (1.18±0.59 vs 0.69±0.13, p=0.001) and slightly, but not significantly, decreased after treatment (0.97±0.17). Brachial arteries FMD was significantly lower in patients than controls at baseline (7.5±2.5 vs 13.1±1.4, p

BackgroundSomatostatin 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 reportA 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.ConclusionsThis 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.

The objective of the study was to investigate the impact of first-line somatostatin analogs (SSAs) on glucose tolerance (GT) in acromegaly.The design was open and prospective.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.Fasting glucose and glycosylated hemoglobin levels were measured.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 (P0.0001). The major predictors of GT changing were disease control (t = -4.99; P0.0001), 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).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.