Acromegaly and Heart Failure.

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.

Complications of acromegaly: cardiovascular, respiratory and metabolic comorbidities.

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.

Clinical outcome and evidence of high rate post-surgical anterior hypopituitarism in a cohort of TSH-secreting adenoma patients: Might somatostatin analogs have a role as first-line therapy?

PURPOSE: Thyrotropin-secreting pituitary adenomas (TSHomas) represent a rare subtype of pituitary tumors. Neurosurgery (NCH) is still considered the first-line therapy. In this study we aimed to investigate the outcome of different treatment modalities, including first line somatostatin analogs (SSA) treatment, with a specific focus on neurosurgery-related complications. METHODS: We retrospectively evaluated thirteen patients diagnosed for TSHomas (9 M; age range 27-61). Ten patients had a magnetic resonance evidence of macroadenoma, three with slight visual field impairment. In the majority of patients, thyroid ultrasonography showed the presence of goiter and/or increased gland vascularization. Median TSH value at diagnosis was 3.29 mU/L (normal ranges 0.2-4.2 mIU/L), with median fT4 2.52 ng/dL (0.9-1.7 ng/dL). RESULTS: Three patients (two microadenoma) were primarily treated with NCH and achieved disease remission, whereas ten patients (nine macroadenomas) were initially treated with SSA. Despite the optimal biochemical response observed during medical treatment in most patients (mean TSH decrease -72%), only two stayed on medical therapy alone, achieving stable biochemical control at the end of the follow-up. The remaining patients (n = 7) underwent NCH later on during their clinical history, followed by radiotherapy or adjuvant SSA treatment in two cases. Noteworthy, five of them developed hypopituitarism. All patients reached a biochemical control, after a multimodal therapeutic approach. CONCLUSIONS: Neurosurgery ultimately led to complete disease remission or to biochemical control in majority of patients, whereas resulting in a considerable percentage of post-operative complications (mainly hypopituitarism, 50%). In the light of the optimal results unanimously reported for medical treatment with SSA, our experience suggests that a careful evaluation of risk/benefit ratio should be taken into consideration when directing the treatment approach in patients with TSHoma.

Pituitary tumors and pregnancy: the interplay between a pathologic condition and a physiologic status.

Pregnancy is becoming a relatively common event in patients with pituitary tumors (PT), due to the increasing availability of medical treatments, which control pituitary diseases associated with the development of PT. However, the presence of PT and its treatment may be a disturbing factor for pregnancy, and pregnancy significantly influences the course and the management of PT. This review summarizes the knowledge about the management of PT during pregnancy and the occurrence of pregnancy in patients with pre-existent PT, focusing on secreting PT characterized by hormonal excess and on clinically non-functioning PT often associated to hormone deficiency, which configure the hypopituitaric syndrome.

Fertility in Acromegaly: A Single-Center Experience of Female Patients During Active Disease and After Disease Remission.

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.

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

BACKGROUND: Acromegaly results from increased growth hormone and its target insulin-like growth factor-1, most commonly due to a pituitary tumour. As it is frequently accompanied by infertility, little is known about the course of this disease in pregnancy. OBJECTIVE: We describe 13 new pregnancies in acromegalic women and compare their outcomes in a systematic review of the literature. METHODS: We collected clinical, biochemical, imaging, and outcomes data during and following pregnancy and performed a systematic review for a total of 47 pregnancies. An extended analysis of 106 pregnancies was also performed. RESULTS: In 13 newly described cases, pregnancy was un-complicated without need for additional surgical intervention. In these pregnancies, adjunctive medical therapy was required in three patients. This was in the form of somatostatin analogs (SA) (3/13) as well as pegvisomant in 1/13 to control symptomatic and biochemical progression. One 37-year-old female succeeded in having two separate pregnancies 2 years apart both without need for any form of medical therapy. Review of an additional 34 published reports allowed for an analysis of outcomes in 47 pregnancies. Adjunctive medical therapy during pregnancy was required in 15 of these cases where 12 received SA and an additional three received dopamine agonists. None of these patients developed endocrine or neurologic complications during pregnancy. In an extended analysis of 106 pregnancies, treatment during pregnancy appears to be associated with good disease control but increased risk of microsomic or macrosomic newborns depending on the medical agent used. CONCLUSIONS: In 13 newly described pregnancies along with systematic review of an additional 34 cases indicate that pregnancy in treated acromegalic women can proceed without significant complications or teratogenicity. Medical treatment during pregnancy with DA or SA appears to be associated with altered neonatal weight. Nevertheless, gestation may have a beneficial impact on acromegaly control both during and following pregnancy.

Clinical and metabolic effects of first-line treatment with somatostatin analogues or surgery in acromegaly: a retrospective and comparative study.

To evaluate the metabolic effects of first-line somatostatin analogues or surgery in acromegaly. Retrospective, comparative, 12-month follow-up. Two hundred and thirty one patients (123 men, age 47.32 ± 14.63 years) with active acromegaly, first line treatments were somatostatin analogues in 151 (65.4%) and surgery in 80 (34.6%). Metabolic syndrome (MS) parameters, glucose, insulin and GH during oral glucose tolerance test, stimulated insulin sensitivity by insulin sensitivity index (ISI Matsuda), early and total insulin-secretion rate by insulinogenic index and AUC(INS), visceral adiposity function, expressed by visceral adipose index (VAI). Somatostatin analogues treatment improved all MS parameters and significantly reduced fasting glucose (P < 0.001), HbA1c (P = 0.014) and the prevalence of DM (P = 0.003) when disease control was achieved. Both somatostatin analogues and surgery improved ISI Matsuda (P < 0.001) and reduced AUC(INS) (P < 0.001) and VAI (P < 0.001 and P = 0.003, respectively). Only in controlled somatostatin analogues-treated patients a significant reduction in insulinogenic index (P = 0.010) was observed. ISI Matsuda showed a significant independent correlation with IGF-1 levels (ß = -0.258; P = 0.001) and VAI score (ß = -0.430; P < 0.001). VAI was independently correlated with IGF-1 (ß = 0.183; P = 0.004). Both somatostatin analogues and surgery can safely be used as first-line therapy in acromegaly, without any untoward effects on glucose tolerance. The control of acromegaly is the main determinant of beneficial effects on general features of insulin sensitivity. VAI could represent an additional link between disease control and insulin sensitivity.

Growth hormone nadir during oral glucose load depends on waist circumference, gender and age: normative data in 231 healthy subjects.

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 15-80years) 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.

Treatment of Acromegalic Osteopathy in Real-life Clinical Practice: The BAAC (Bone Active Drugs in Acromegaly) Study.

BACKGROUND: Vertebral fractures (VFs) are a frequent complication of acromegaly, but no studies have been so far published on effectiveness of antiosteoporotic drugs in this clinical setting. OBJECTIVE: To evaluate whether in real-life clinical practice bone active drugs may reduce the risk of VFs in patients with active or controlled acromegaly. STUDY DESIGN: Retrospective, longitudinal study including 9 tertiary care endocrine units. PATIENTS AND METHODS: Two hundred and forty-eight patients with acromegaly (104 males; mean age 56.00 ±â€…13.60 years) were evaluated for prevalent and incident VFs by quantitative morphometric approach. Bone active agents were used in 52 patients (20.97%) and the median period of follow-up was 48 months (range 12-132). RESULTS: During the follow-up, 65 patients (26.21%) developed incident VFs in relationship with pre-existing VFs (odds ratio [OR] 3.75; P < .001), duration of active acromegaly (OR 1.01; P = .04), active acromegaly at the study entry (OR 2.48; P = .007), and treated hypoadrenalism (OR 2.50; P = .005). In the entire population, treatment with bone active drugs did not have a significant effect on incident VFs (P = .82). However, in a sensitive analysis restricted to patients with active acromegaly at study entry (111 cases), treatment with bone active drugs was associated with a lower risk of incident VFs (OR 0.11; P = .004), independently of prevalent VFs (OR 7.65; P < .001) and treated hypoadrenalism (OR 3.86; P = .007). CONCLUSIONS: Bone active drugs may prevent VFs in patients with active acromegaly.

Impact of somatostatin analogs versus surgery on glucose metabolism in acromegaly: results of a 5-year observational, open, prospective study.

OBJECTIVE: The aim of the study was to investigate the 5-yr impact of surgery and somatostatin analogs (SSA) on glucose metabolism in acromegaly. DESIGN: We conducted an observational, prospective, comparative, nonrandomized study. PATIENTS: The 100 patients (48 women, 52 men; median age, 49 yr) in the study were grouped as follows for treatment: SSA only (group A; n = 34); SSA followed by surgery (group B; n = 20); surgery only (group C; n = 30); and surgery followed by SSA (group D; n = 16). RESULTS: At diagnosis, 28% had impaired glucose tolerance, and 22% had diabetes mellitus; fasting glucose levels (4.13-10.60 mmol/liter) were best predicted by age (t = 2.88; P = 0.0049) and disease duration (t = 1.99; P = 0.049). After 60 months, fasting glucose levels reduced (-4.9 +/- 19.7%) in group A only, whereas they did not change in the other groups. In the 68 nondiabetic patients at baseline, fasting glucose levels increased by 0.7 +/- 11.2%, 7.5 +/- 10.3%, 4.3 +/- 10.4%, and 4.3 +/- 14.8% (P = 0.28), from groups A to D, respectively. Percentage change of fasting glucose in all patients receiving SSA was 1.9 +/- 12.3%, and in those not receiving SSA it was 6.4 +/- 10.8% (P = 0.13). Overall, prevalence of new onset of diabetes during SSA treatment was nine of 55 (16.4%) vs. three of 23 after surgery (13.0%, P = 0.98). Deterioration of glucose tolerance was correlated with increased body mass index (r = 0.49, P < 0.0001) and not with use of SSA or surgery (r = 0.06; P = 0.53), control or not of GH (r = -0.10, P = 0.31) and IGF-I (r = -0.12; P = 0.22). CONCLUSIONS: The results of this study demonstrate a similar deterioration of glucose tolerance after 60 months in patients receiving SSA or cured with surgery. Increase in body mass index was the major predictor of deterioration of glucose tolerance.

Medical therapy of pituitary adenomas: effects on tumor shrinkage.

The efficacy of dopamine-agonists (DA) in patients with prolactinomas and that of somatostatin analogues (SSA) in those with GH- and TSH-secreting adenomas is well established. More recently, data are accumulating suggesting a potential therapeutic role of DA also in patients with ACTH-secreting and clinically non-functioning (NFA) pituitary adenomas. This review aims at summarizing published results of DA and SSA on tumor shrinkage in patients with different histotypes of pituitary adenomas. Results of tumor shrinkage are of clinical relevance as tumor size is the one of the most important determinant of surgical outcome. While reduction of tumor size more than 50% of baseline size in macroprolactinomas treated with DA is a frequent finding in patients with GH-secreting adenomas treated with SSA tumor shrinkage only recently is becoming frequent thanks to the availability of depot formulations. Data on tumor shrinkage in patients with TSH-secreting adenomas treated with SSA are limited because of the rarity of these tumors. Very recently, DA have been reported of some efficacy also in patients with ACTH-secreting adenomas but data are still very limited. NFA respond very scantly to both DA and SSA even if receptors targeting these drugs are present. Whether this is due to limited receptor number or alterations of post-receptor pathway is still unknown.

Acromegaly.

Acromegaly is characterized by increased release of growth hormone and, consequently, insulin-like growth factor I (IGF1), most often by a pituitary adenoma. Prolonged exposure to excess hormone leads to progressive somatic disfigurement and a wide range of systemic manifestations that are associated with increased mortality. Although considered a rare disease, recent studies have reported an increased incidence of acromegaly owing to better disease awareness, improved diagnostic tools and perhaps a real increase in prevalence. Acromegaly treatment approaches, which include surgery, radiotherapy and medical therapy, have changed considerably over time owing to improved surgical procedures, development of new radiotherapy techniques and availability of new medical therapies. The optimal use of these treatments will reduce mortality in patients with acromegaly to levels in the general population. Medical therapy is currently an important treatment option and can even be the first-line treatment in patients with acromegaly who will not benefit from or are not suitable for first-line neurosurgical treatment. Pharmacological treatments include somatostatin receptor ligands (such as octreotide, lanreotide and pasireotide), dopamine agonists and the growth hormone receptor antagonist pegvisomant. In this Primer, we review the main aspects of acromegaly, including scientific advances that underlie expanding knowledge of disease pathogenesis, improvements in disease management and new medical therapies that are available and in development to improve disease control.

Pituitary magnetic resonance imaging predictive role in the therapeutic response of growth hormone-secreting pituitary adenomas.

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.

Author Correction: Acromegaly.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Growth hormone-secreting tumor shrinkage after 3 months of octreotide-long-acting release therapy predicts the response at 12 months.

OBJECTIVE: The objective of the study was to evaluate whether tumor shrinkage or GH and IGF-I levels achieved after 3 months predicted tumor shrinkage after 12 months of octreotide-long-acting release (LAR) treatment. PATIENTS: Patients included 67 patients with de novo acromegaly (33 women, 34 men; aged 20-82 yr) receiving LAR at a dose of 20 mg every 28 d for 3 months. Final LAR dose was 10 mg every 28 d in 4, 30 mg every 28 d in 39, 20 mg every 28 d in 24 patients. DESIGN: The design of the study was analytical, observational, open, and retrospective. OUTCOME MEASURES: Percent change in GH and IGF-I levels and tumor volume after 3 and 12 months of therapy was measured. Stepwise regression and receiving-operator characteristics analysis were used to calculate the optimal cutoff to predict 12 months tumor shrinkage at 12 months. RESULTS: The percent tumor shrinkage after 12 months was significantly correlated with GH, IGF-I, and tumor volume at 3 months and with the dose of LAR administered between 3 and 12 months. There was no correlation with gender, age, baseline GH levels and tumor volume. In a stepwise regression analysis, percent tumor shrinkage after 3 months was the best predictor of tumor shrinkage after 12 months (t = 5.92; P < 0.0001), followed by GH levels after 3 months (t = 2.86; P = 0.0056). To predict 50% or greater tumor shrinkage after 12 months, the best cutoff point of tumor shrinkage at 3 months was 22.1% [sensitivity (95% confidence interval) = 85.5% (71.2-95.4); specificity = 83.3% (65.3-94.3)], whereas that of GH levels after 3 months was 7.8 microg/liter [sensitivity = 70.3% (53.0-84.1); specificity = 93.3% (79.0-99.0)]. CONCLUSION: Tumor shrinkage achieved after 3 months of LAR treatment at 20 mg/28 d predicted tumor shrinkage at 12 months, provided that dosages were changed according to individual patients requirement.

Effect of combined treatment with a pan-PI3K inhibitor or an isoform-specific PI3K inhibitor and everolimus on cell proliferation in GH-secreting pituitary tumour in an experimental setting.

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Somatostatin analogs, cabergoline and pegvisomant: comparing the efficacy of medical treatment for acromegaly.

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.

Effects of long-term combined treatment with somatostatin analogues and pegvisomant on cardiac structure and performance in acromegaly.

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.

The safety of treatments for prolactinomas.

INTRODUCTION: 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. AREA COVERED: 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. EXPERT OPINION: 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.