More than a decade of real-world experience of pegvisomant for acromegaly: ACROSTUDY

Objective: To report the final long-term safety and efficacy analyses of patients with acromegaly treated with pegvisomant from the ACROSTUDY. Design: Global (15 countries), multicentre, non-interventional study (2004-2017). Methods: The complete ACROSTUDY cohort comprised patients with acromegaly, who were being treated with pegvisomant (PEGV) prior to the study or at enrolment. Main endpoints were long-term safety (comorbidities, adverse events [AEs], pituitary tumour volumes, liver tests) and efficacy (IGF-1 changes). Results: Patients (n = 2221) were treated with PEGV for a median of 9.3 years (range, 0-20.8 years) and followed up for a median of 7.4 years (range, 0-13.9 years). Before PEGV, 96.3% had received other acromegaly treatments (surgery/radiotherapy/medications). Before PEGV treatment, 87.2% of patients reported comorbidities. During ACROSTUDY, 5567 AEs were reported in 56.5% of patients and of these 613 were considered treatment-related (in 16.5% of patients) and led to drug withdrawal in 1.3%. Pituitary imaging showed a tumour size increase in 7.1% of patients; the majority (71.1%) reported no changes. Abnormal AST or ALT liver tests occurred in 3.2% of patients. IGF-1 normalization rate improved over time, increasing from 11.4% at PEGV start to 53.7% at year 1, and reaching 75.4% at year 10 with use of ≥30 mg PEGV/day in an increasing proportion of patients. Conclusion: This comprehensive review of the complete cohort in ACROSTUDY confirmed the overall favourable benefit-to-risk profile and high efficacy of PEGV as mono- and combination therapy in patients with an aggressive course/uncontrolled/active acromegaly requiring long-term medical therapy for control.

GH Receptor Exon 3 Genotype and Echocardiographic Abnormalities in Patients With Active Acromegaly

Background: The GH receptor (GHR) exon 3 polymorphism occurs at a genomic level. Approximately 50-60% of the population is homozygous for the exon-3 containing genotype (+3/+3), 30-40% are heterozygous (+3/-3) and 10-20% are homozygous for the exon-3 lacking genotype (-3/-3). Some studies suggest that children homo- and heterozygous for the GHR exon 3 lacking genotype (-more efficient 3/-3 and +3/-3, respectively) respond better to treatment with exogenous rhGH and there is also in vitro evidence showing a more efficient signal transduction through this exon 3 deleted isoform. Some studies have found that patients with acromegaly harboring the exon 3-deleted genotype may have a higher prevalence of diabetes and hypertension. Hypothesis and Objective: Patients with active acromegaly harboring the exon 3-lacking GHR genotype may have more echocardiographic abnormalities than those who are homozygous for the exon 3 containing genotype. Patients and Methods: This is a cross-sectional study of patients with active acromegaly, defined by an IGF-1 level > 1.3 times the upper limit of normal (x ULN), who underwent transthoracic echocardiography. Exon-3 GHR genotype was determined by PCR using previously described sense and antisense primers. Results: The cohort consisted of 28 patients, 54% female, with a mean age of 51 ± 12 years. Mean disease duration at the time of echocardiographic examination was 4.48 ± 4.7 years; median basal GH and IGF-1 were 12 ± 26 ng/mL and 2.4 ± 1.04 x ULN. The prevalence of hypertension and diabetes were 43% and 36%, respectively. Fifty three percent of the patients were homozygous for the exon 3-containaing genotype (+3/+3), 18% were homozygous for the exon 3-lacking genotype (-3/-3) and 29% were heterozygous (+3/-3). Clinical and biochemical features did not differ between patients with the different GHR genotypes, except for hypertension that was more prevalent in the +3/+3 genotype group (60% vs 23%, p= 0.04). The frequency of the different echocardiographic parameters was similar among groups (left ventricular hypertrophy 33% vs 15%, p= 0.27; diastolic dysfunction 47% vs 31%, p= 0.39; subclinical systolic dysfunction 42% vs 54%, p= 0.54; left ventricular ejection fraction 59±10% vs 60±16%, p= 0.83); aortic valve abnormalities 19% vs 15%, p=0.63; mitral valve abnormalities 46% vs 15%, p=0.07). Conclusions: Echocardiographic abnormalities in patients with active acromegaly do not differ among patients with the different GHR exon 3 genotypes. The clinical spectrum of acromegaly varies considerably. Although such variability is usually related to the severity of the hypersomatotropinemia, in many patients this is not the case.

Evaluation of Acromegaly patients with sleep disturbance related symptoms

Background and Objectives: It is known that the prevalence of obstructive sleep apnea (OSA) is increased in acromegaly. Craniofacial anomalies, macroglossia, and thickening of the laryngeal wall caused by the increase in soft tissue in these patients lead to OSA. Also, the increase in growth hormone can trigger central apnea by causing a decrease in respiratory drive. Determining the polysomnographic characteristics of acromegaly patients is important to reveal the effect of these mechanisms. Methods: The demographic and polysomnographic characteristics of 33 acromegaly patients who underwent polysomnography (PSG) with suspicion of sleep disorders between 2011 and 2018 in the sleep laboratory of our hospital were retrospectively analyzed. One of the patients was excluded from the analysis because PSG was performed in the postoperative period. The remaining 32 patients with active acromegaly were grouped according to their gender and the presence of OSA and compared with statistical methods in terms of polysomnographic and clinical features. Results: OSA (AHI>5) was detected in 78.1% of 32 active acromegaly patients (18 females, 14 males) who underwent PSG with suspicion of sleep-disordered breathing. Moderate-severe OSA (62.5%) was found in most patients, and there was no difference between the sexes in terms of OSA detection rate and OSA severity. Respiratory events appear to be predominantly obstructive hypopneas. Also, the polysomnographic features of female and male acromegaly patients with OSA were found to be similar. It is seen that the OSA group is similar to the group with simple snoring in terms of body mass index (BMI), but is statistically significantly older (p=0,007). A positive correlation was found between age and AHI in pairwise correlation analysis (r:0,426 p:0,015, respectively). Conclusion: Considering that the prevalence of OSA in the population is approximately 5%, our results show that the risk of OSA in acromegaly increases, and obstructive pathways are effective in this increase. The probability of OSA occurrence and polysomnographic features between the genders are similar. Although the median BMI of the patients with and without OSA was similar, the median age was higher in the group with OSA, middle-aged acromegaly patients should be evaluated in terms of OSA even if there is no obvious obesity. doi: https://doi.org/10.12669/pjms.37.4.4229 How to cite this:Celik D, Duyar SS, Aksu F, Firat S, Ciftci B. Evaluation of Acromegaly patients with sleep disturbance related symptoms. Pak J Med Sci. 2021;37(4):---------. doi: https://doi.org/10.12669/pjms.37.4.4229 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Body Composition Changes with Long-term Pegvisomant Therapy of Acromegaly

Context In active acromegaly, the lipolytic and insulin antagonistic effects of growth hormone (GH) excess alter adipose tissue (AT) deposition, reduce body fat, and increase insulin resistance. This pattern reverses with surgical therapy. Pegvisomant treats acromegaly by blocking GH receptor (GHR) signal transduction and lowering insulin-like growth factor 1 (IGF-1) levels. The long-term effects of GHR antagonist treatment of acromegaly on body composition have not been studied. Methods We prospectively studied 21 patients with active acromegaly who were starting pegvisomant. Body composition was examined by whole body magnetic resonance imaging, proton magnetic resonance spectroscopy of liver and muscle and dual-energy x-ray absorptiometry, and endocrine and metabolic markers were measured before and serially during 1.0 to 13.4 years of pegvisomant therapy. The data of patients with acromegaly were compared with predicted and to matched controls. Results Mass of visceral AT (VAT) increased to a peak of 187% (1.56-229%) (P < .001) and subcutaneous AT (SAT) to 109% (–17% to 57%) (P = .04) of baseline. These remained persistently and stably increased, but did not differ from predicted during long-term pegvisomant therapy. Intrahepatic lipid rose from 1.75% to 3.04 % (P = .04). Although lean tissue mass decreased significantly, skeletal muscle (SM) did not change. IGF-1 levels normalized, and homeostasis model assessment insulin resistance and HbA1C were lowered. Conclusion Long-term pegvisomant therapy is accompanied by increases in VAT and SAT mass that do not differ from predicted, stable SM mass and improvements in glucose metabolism. Long-term pegvisomant therapy does not produce a GH deficiency-like pattern of body composition change.

Two successful pregnancies in a woman with active acromegaly

Acromegaly is a rare systemic disease, predominantly caused by growth hormone (GH)-secreting pituitary adenoma, leading to insulin-like growth factor-1 (IGF-1) overproduction. Pituitary adenoma extension and/or its treatment can cause infertility or subfertility in both sexes in different mechanisms. Pregnancies in women with active acromegaly are rarely observed but considered generally safe. Growth hormone and IGF-1 concentrations are usually stable during pregnancy and in most cases no significant tumour expansion emerges despite pharmacological therapy withdrawal. A 28 year-old woman with symptoms of acromegaly and amenorrhoea was admitted to the Department of Endocrinology. Diagnosis of acromegaly was made and treatment with somatostatin analogues (SSA) was initiated with subsequent surgical intervention. However, persistent acromegaly was diagnosed post-operatively due to residual tumour and the medical treatment was restarted. During follow-up the patient became pregnant twice and then treatment with somatostatin analogues was ceased. Both pregnancies were complicated by gestational diabetes and in the course of the second pregnancy treatment with dopamine agonist (DA) was commenced to alleviate persistent headaches and it was followed by clinical and biochemical improvement. The patient successfully delivered two healthy babies. After second labour treatment with SSA was resumed and the patient has achieved adequate disease control. The risk of pregnancy complications in women with acromegaly is slightly higher than in general population, especially if uncontrolled disease was present before conception or acromegaly was diagnosed during pregnancy. In rare cases pituitary tumour expansion during pregnancy occurs and then pharmacological or surgical interventions should be considered.