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.

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.

Author Correction: Acromegaly.

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

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.

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.

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.

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.

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.

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.

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.

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.

Adverse events associated with somatostatin analogs in acromegaly.

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.

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.

Could different treatment approaches in acromegaly influence life expectancy? A comparative study between Bulgaria and Campania (Italy).

BACKGROUND: Mortality in acromegaly strictly depends on optimal control of GH and IGF1 levels. Modern medical therapy with somatostatin analogs (SSAs) and GH receptor antagonists (GHRAs) is not available in many countries due to funding restrictions. This retrospective, comparative, cohort study investigated the impact of different treatment modalities on disease control (GH and IGF1) and mortality in acromegaly patients. METHODS: Two cohorts of patients with acromegaly from Bulgaria (n=407) and Campania, Italy (n=220), were compared, and mortality rates were evaluated during a 10-year period (1999-2008). RESULTS: The major difference in treatment approach between cohorts was the higher utilization of SSAs and GHRAs in Italy, leading to a decreased requirement for radiotherapy. Significantly more Italian than Bulgarian patients had achieved disease control (50.1 vs 39.1%, P=0.005) at the last follow-up. Compared with the general population, the Bulgarian cohort had a decreased life expectancy with a standardized mortality ratio (SMR) of 2.0 (95% CI 1.54-2.47) that was restored to normal in patients with disease control - SMR 1.25 (95% CI 0.68-1.81). Irradiated patients had a higher cerebrovascular mortality - SMR 7.15 (95% CI 2.92-11.37). Internal analysis revealed an independent role of age at diagnosis and last GH value on all-cause mortality and radiotherapy on cerebrovascular mortality. Normal survival rates were observed in the Italian cohort: SMR 0.66 (95% CI 0.27-1.36). CONCLUSIONS: Suboptimal biochemical control was associated with a higher mortality in the Bulgarian cohort. Modern treatment options that induce a strict biochemical control and reduce the necessity of radiotherapy might influence the life expectancy. Other factors, possibly management of comorbidities, could contribute to survival rates.

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.

Comparison of the effects of primary somatostatin analogue therapy and pituitary adenomectomy on survival in patients with acromegaly: a retrospective cohort study.

OBJECTIVE: Acromegalic 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 METHODS: The 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. RESULTS: Twenty 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. CONCLUSIONS: Therapies 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.

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

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.

Investigational therapies for 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.

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

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.