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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). Atterm 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. [ABSTRACT FROM AUTHOR]

Introduction: 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. [ABSTRACT FROM AUTHOR]

Objective: Cabergoline (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 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. [ABSTRACT FROM AUTHOR]

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 PEGat initial dose of 10 mg daily and then titrated to 5 mg 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. [ABSTRACT FROM AUTHOR]

In this article, the authors discuss the study of A. F. Casini and colleagues on the aortic root diameter and prevalence of aortic ectasia in 42 patients with acromegaly. They state that the long exposure to growth hormone (GH) and insulin-like growth factor-I (IGF-I) excess affect the cardiovascular system and aortic root. Moreover, they say that the findings suggest performing echocardiography to patients with acromegaly to investigate the possible acromegalic cardiomyopathy characteristics.

Background: Growth hormone (GH)-secreting pituitary adenomas, responsible for the development of acromegaly, are the second most frequent type of secreting pituitary adenomas and are characterized by very variable T2-weighted signal intensity on pituitary magnetic resonance imaging (MRI). Previous data have demonstrated a correlation between T2-weighted tumor signal intensity and response to therapy with conventional somatostatin analogs (SSA) in patients with acromegaly. The aim of the current retrospective study was to investigate the correlation between the T2-weighted tumor signal on pituitary MRI and both biochemical and radiological response to first-line SSA therapy., Methods: Twenty-two naive patients with acromegaly were eligible for the study (14 females and 8 males, mean age ± SD: 58.8±15.74). A biochemical evaluation (GH and IGF-I levels) and an MRI assessment (volume and signal intensity analysis of adenoma) were conducted in each patient at diagnosis and after 12 months of SSA therapy., Results: On diagnostic pituitary MRI, 16 (72.7%) adenomas were T2- hypointense and 6 (27.2%) T2-hyperintense. After 12 months of SSA therapy, IGF-I levels decreased by more than 50% from baseline in 62.5% of patients with T2-hypointense and 33.3% of patients with T2- hyperintense tumor signal, respectively (P=0.03). Moreover, GH levels decreased by more than 80% from baseline in 81.3% and 33.3% of patients with T2-hypointense and T2-hyperintense tumor signal (P=0.02). A significant tumor volume reduction (≥20%) was observed in 75% of the T2-hypointense and 33.3% of the T2-hyperintense adenomas (P=0.001)., Conclusions: In naive patients with acromegaly, first-line SSA therapy is associated with a better biochemical response and greater tumor shrinkage in T2-hypointense compared to T2-hyperintense adenomas. Therefore, T2-weighted sequences of pituitary MRI can help to classify GH-secreting pituitary adenomas into a T2-hypointense and T2-hyperintense type and, therefore, to identify patients who can better respond to first-line SSA therapy., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

In patients with acromegaly, chronic GH and IGF-I excess commonly causes a specific cardiomyopathy characterized by a concentric cardiac hypertrophy associated with diastolic dysfunction and, in later stages, with systolic dysfunction ending in heart failure in untreated and uncontrolled patients. Additional relevant cardiovascular complications are represented by arterial hypertension, valvulopathies, arrhythmias, and vascular endothelial dysfunction, which, together with the respiratory and metabolic complications, contribute to the development of cardiac disease and the increase cardiovascular risk in acromegaly. Disease duration plays a pivotal role in the determination of acromegalic cardiomyopathy. The main functional disturbance in acromegalic cardiomyopathy is the diastolic dysfunction, observed in 11% to 58% of patients, it is usually mild, without clinical consequence, and the progression to systolic dysfunction is generally uncommon, not seen or observed in less than 3% of the patients. Consequently, the presence of overt CHF is rare in acromegaly, ranging between 1 and 4%, in patients with untreated and uncontrolled disease. Control of acromegaly, induced by either pituitary surgery or medical therapy improves cardiac structure and performance, limiting the progression of acromegaly cardiomyopathy to CHF. However, when CHF is associated with dilative cardiomyopathy, it is generally not reversible, despite the treatment of the acromegaly., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Introduction: In patients with acromegaly, somatostatin analogs (SSA) represent the first choice medical treatment. The long-acting SSA have been found to be effective in controlling growth hormone and IGF-I levels in a high percentage of patients, resulting in an improvement in the quality of life; moreover, these peptide analogs have a proven safety record and are generally well tolerated., Areas Covered: The most commonly reported adverse events include injection-site discomfort and erythema, gastrointestinal (GI) disturbances such as diarrhea, abdominal pain, nausea and vomiting, biliary sludge or gallstones, and abnormal glucose metabolism. Most SSA-related adverse events are transient and of mild-to-moderate intensity, and the prevalence of such effects markedly and progressively decreases during treatment, so that treatment discontinuations due to adverse events are rare and commonly related to GI disturbances. Cholelithiasis represents the most serious complication of SSA, but is generally asymptomatic, and has been reported in 3 - 56% of patients. Whereas the effect of SSA on glucose metabolism is still controversial, several pieces of evidence have confirmed a modest and transient negative impact on glucose homeostasis. Also the novel SSA pasireotide has shown a safety profile as expected for a SSA, except for the degree of hyperglycemia., Expert Opinion: On the basis of these findings, a close and careful monitoring of gallbladder ultrasound and glucose levels is recommended in patients receiving SSA for medical treatment of acromegaly.

Introduction: The treatment of acromegaly aims at normalizing growth hormone (GH) and insulin-like growth factor (IGF-I) levels and controlling tumor growth. The approaches to therapy are essentially three: surgery and pharmacotherapy, alone or in combination, and radiotherapy, generally used in more aggressive tumors., Areas Covered: This review focuses on the novel drug formulations being developed for medical therapy of acromegaly. Even though many efficient treatments have been made available to manage acromegaly in the last two decades, a significant number of patients remain still uncontrolled. Medical therapy represents an important therapeutic option and can be used as the first-line treatment in many patients. However, roughly 25% of patients might be considered as poor responsive or resistant to conventional long-acting somatostatin analogs (SSA) treatment. Therefore, new longer-acting SSA, oral SSA formulations, new combined therapies with weekly doses of pegvisomant, combination therapy with pegvisomant (PEG) and cabergoline (CAB) or SSA and new approaches have been proposed. New molecules are currently under investigation in clinical trials, such as the SSA multi-receptor ligand, pasireotide, which represents a promising option therapy, especially in patients not adequately controlled with currently available SSA. Further, temozolomide has been suggested as an efficient drug for treating GH-aggressive pituitary tumors resistant to conventional therapy., Expert Opinion: All these novel SSA formulations and new molecules implement the available options in therapies of acromegaly to improve disease control. However, further studies are needed to define the exact role of these newer agents. The predicting factors for response to these new therapies should also be determined.

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.

Purpose of Review: To discuss the role of medical therapy of acromegaly as a first-line treatment, focusing on recent data on the use of somatostatin analogs (SSAs), the first-choice pharmacotherapy for treating acromegaly., Recent Findings: Despite pituitary surgery and radiotherapy, a significant number of patients with acromegaly needed adjuvant medical therapy, and primary medical therapy nowadays is increasingly considered. According to a recent consensus statement on the management of acromegaly, primary pharmacological therapy with SSAs may be indicated in patients who are otherwise poor surgical candidates or refuse surgery, and in those in whom there is a low probability of a surgical cure. The long-acting SSAs have been found to be effective in improving symptoms and signs of acromegaly in a high percentage of patients and induce normalization of growth hormone and insulin-like growth factor-I levels approximately in 60-80% of patients, respectively. Evidence has suggested that SSAs induce a clinically significant tumor shrinkage when given as first-line, when this reduction of tumor volume could be helpful in improving the outcome of subsequent surgery or improving the clinical syndrome in patients with unacceptable surgical risk, whereas the tumor shrinkage was seen less frequently when the drug was used after surgical resection and/or radiotherapy., Summary: Pharmacological management plays a pivotal role in the treatment of acromegaly, and first-line medical therapy with SSAs is being widely used in clinical practice, either prior to surgery or in patients who are otherwise poor surgical candidates and in those in whom there is a low probability of a surgical cure.

Introduction: Aggressive tumors of the pituitary gland are classically defined as pituitary tumors with a massive invasion of the surrounding anatomical structures and rapid growth. They are notoriously difficult to manage and are associated with poor prognosis because the therapeutic options are limited and the tumors are generally unresponsive to therapy., Areas Covered: This review focuses on treatment options for aggressive pituitary tumors, including surgery, radiotherapy and medical treatment, as well as focusing on the promising therapeutic options for aggressive pituitary tumors, evaluating the literature of the last 15 years. With the exception of prolactinomas, surgery is the first-line option, but most aggressive pituitary tumors often require repeated surgery. Pharmacotherapies are useful when surgery is unlikely to improve symptoms, or as an adjunct therapy to surgery. In prolactinomas, dopamine agonists are the first-line treatment and normalize prolactin levels in most patients, even those with macroprolactinomas. Somatostatin analogs are effective agents for primary therapy, pre-operatively or post-operatively to control tumor re-expansion of pituitary adenomas. However, dopamine agonists and somatostatin analogs are not as effective as they are for the treatment of non-aggressive adenomas. When surgery and pharmacotherapy fail, radiotherapy is a useful third-line strategy. Conventional chemotherapy is poorly effective but recent case reports with the temozolomide, an alkylating agent, have provided better results in the short term., Expert Opinion: Aggressive pituitary tumors are associated with poor prognosis as therapeutic options are limited. Moreover, they tend to recur quickly after initial treatment, are generally unresponsive to therapy, and are difficult to manage. To improve the overall response rate, the early application of current therapeutic approaches with the incorporation of new therapeutic developments is mandatory., (© 2011 Informa UK, Ltd.)

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.

Background: Somatostatin 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 Report: A 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., Conclusions: This 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.

Background: In the general population, low IGF1 has been associated with higher prevalence of cardiovascular disease and mortality., Objective: To investigate the relationships between IGF1 levels, blood pressure (BP), and glucose tolerance (GT)., Subjects: Four-hundred and four subjects (200 men aged 18-80 years)., Exclusion Criteria: personal history of pituitary or cardiovascular diseases; previous or current treatments with drugs interfering with BP, GT, or lipids, corticosteroids (>2 weeks), estrogens, or testosterone (>12 weeks); smoking of >15 cigarettes/day and alcohol abuse (>3 glasses of wine/day)., Results: Two hundred and ninety-six had normal BP (73.3%), 86 had mild (21.3%), and 22 had severe (5.4%) hypertension; 322 had normal GT (NGT (79.7%)), 53 had impaired glucose tolerance (IGT (13.1%)), 29 had diabetes mellitus (7.2%). Normotensive subjects had significantly higher IGF1 levels (0.11+/-0.94 SDS) than those with mild (-0.62+/-1.16 SDS, P<0.0001) or severe (-1.01+/-1.07 SDS, P<0.0001) hypertension. IGF1 SDS (t=-3.41, P=0.001) independently predicted systolic and diastolic BP (t=-2.77, P=0.006) values. NGT subjects had significantly higher IGF1 levels (0.13+/-0.90 SDS) than those with IGT (-0.86+/-1.14 SDS, P<0.0001) or diabetes mellitus (-1.31+/-1.13 SDS, P<0.0001). IGF1 SDS independently predicted fasting glucose (t=-3.49, P=0.0005) and homeostatic model assessment (HOMA)-R (t=-2.15, P=0.033) but not insulin (t=-1.92, P=0.055) and HOMA-beta (t=-0.19, P=0.85)., Conclusion: IGF1 levels in the low normal range are associated with hypertension and diabetes in subjects without pituitary and cardiovascular diseases.