Medical Therapy For Acromegaly Research Articles

8008 Insulin-like Growth Factor-1 (IGF-1) Level Fluctuations and Patient Reported Outcomes (PROMS) During Treatment with Long-acting Somatostatin Receptor Ligands (SRLs) for Acromegaly: a Prospective Study

Abstract Disclosure: I. Remba-Shapiro: None. J.R. Schweizer: None. K.J. Liebert: Consulting Fee; Self; Crinetics, Recordati Rare Diseases, Novo Nordisk. K. Schilbach: None. M. Adams: Consulting Fee; Self; Chiesi. N.A. Tritos: None. M. Bidlingmaier: Consulting Fee; Self; Ipsen, Ionis Pharmaceuticals Inc., Novartis Pharmaceuticals, Novo Nordisk, Pfizer, Inc., Roche Pharmaceuticals. L.B. Nachtigall: Consulting Fee; Self; Crinetics. Grant Recipient; Self; Amryt, Recordati Rare Diseases. Background: SRLs are the most used medical therapy for acromegaly. Some patients report symptoms of acromegaly towards the end of the injection cycle even when IGF-1 levels are controlled. IGF-1 fluctuations within an injection cycle have been observed. In this study we investigated the variability of biochemical markers and PROMS in patients receiving long-acting SRLs. Methods: Subjects with acromegaly controlled with monthly lanreotide depot or octreotide LAR were recruited. Blood samples at 1 and 4 weeks after SLR injection were collected in 2 consecutive cycles. Clinical characteristics were evaluated. Quality of life (QoL) surveys included: Acromegaly Quality of Life Questionnaire (AcroQoL) (higher scores = better QoL) and Patient Assessed Acromegaly Symptom Questionnaire (PASQ) (higher scores = worse QoL). Week 1 vs. week 4 values were compared. Quest Diagnostics LC-MS assay was used to measure IGF-1. Coefficient of variation (CV = (IGF-1 SD)/(IGF-1 mean)%) of IGF-1 was calculated. Values ≤5% were interpreted as being a consequence of assay variability. Variables are presented as mean (SD) and compared using t-test; p <0.05 was considered significant. Results: Patients (6 women, 4 men) had a mean age of 56.1 (15.4) years. Eight underwent TSS. One had diabetes mellitus, 3 had hypertension. Mean IGF-1 index (IGF-1 x upper limit of normal) at screening was 0.63 (0.23). BMI was 27.7 (5.8) kg/m2. IGF-1 index at week 1 was 0.57 [0.16] vs. 0.61 [0.23] at week 4, p=0.271. Insulin levels were lower in week 1 vs. week 4 (7.3 [4.4] vs. 9.7 [6.0]mIU/mL p=0.041). There were no significant differences in GH, glucose, weight, blood pressure and ring size in week 1 vs. week 4. PASQ varied significantly within the injection cycle with higher scores in week 4 (18.1 [10.8]) compared to week 2 (16.1 [10.4] p=0.032) and week 3 (14.2 [8.8] p= 0.002). ACROQoL scores did not differ by injection phase. IGF-1 increased more than assay CV from week 1 to week 4 in 8/20 (40%) determinations. An ROC curve identified an IGF-1 index cutoff of 0.57 at week 4 (AUC: 0.812, p=0.021) as a predictor of IGF-1 index increase within the injection cycle (CV > 5%): sensitivity 88%, specificity 75%. Five patients had IGF-1 index > 0.57 at week 4 during both cycles (range 0.60-1.2). In this group, mean IGF-1 index was higher at week 4 vs. week 1 (0.77 [0.21] vs. 0.66 [0.14] p=0.026). The 5 patients with IGF-1 index < 0.57 at week 4 had no difference in IGF-1 index between week 4 and week 1 (0.48 [0.14] vs. 0.44 [0.09] p=0.144). Conclusions: This prospective study of patients with acromegaly controlled with long-acting SRLs demonstrates injection phase variability in self-reported symptoms by PASQ. An IGF-1 index > 0.57 at the end of the cycle may warrant injection phase-dependent monitoring. Larger studies to confirm the IGF-1 cutoff above which patients should be monitored in a cycle-dependent manner will allow an individualized approach to optimize management. Presentation: 6/2/2024

Clinical Management of Acromegaly: Therapeutic Frontiers and New Perspectives for Somatostatin Receptor Ligands (SRLs).

Somatostatin receptor ligands (SRLs) represent a true milestone in the medical therapy for acromegaly. The first-generation SRLs (FG-SRLs), octreotide and lanreotide, have demonstrated good efficacy in disease control and tumor shrinkage, and are still considered first-line medical therapies. The development of long-acting release (LAR) formulations has certainly improved the therapeutic tolerability of these drugs, although many patients still experience therapy-related burden. As such, new formulations have recently been developed to improve adherence and therapeutic efficacy and more solutions are on the way. In the case of FG-SRL-resistant disease, pasireotide, the only second generation SRL currently available, demonstrated superiority in disease control and tumor shrinkage compared to FG-SRLs. However, its use in clinical practice is still limited due to concern for impairment in glucose homeostasis. In this review, we discuss the news about the present and future role of SRLs in acromegaly, exploring the therapeutical frontiers of this drug class. Moreover, we provide practical guidance on the use of pasireotide, based on the data in the literature and our clinical experience.

Octreotide and Pasireotide Combination Treatment in Somatotroph Tumor Cells: Predominant Role of SST2 in Mediating Ligand Effects.

Simple SummaryFirst-generation somatostatin receptor ligands, such as octreotide, are the first-line medical therapy in acromegaly. Octreotide shows preferential binding for somatostatin receptor subtype 2 (SST2), while the second-generation ligand, pasireotide, has high affinity for multiple SSTs. We aimed to elucidate whether pasireotide acts via other receptors than SST2 in somatotroph tumors, and to investigate the potential role of the combination therapy octreotide plus pasireotide. We found that octreotide and pasireotide are superimposable in reducing GH secretion in cultured somatotroph tumor cells, as well as in inhibiting cell proliferation and intracellular pathway activity in rat GH4C1 cells (a model of somatotroph tumors). We did not find any additive/synergistic effect for the combination treatment. Furthermore, we observed that co-incubation with a SST2-selective antagonist reversed the inhibitory effect of both compounds. Therefore, the two drugs act mainly via SST2 in somatotroph tumor cells, and their combination is not superior to single agent treatment.First-generation somatostatin receptor ligands (fg-SRLs), such as octreotide (OCT), represent the first-line medical therapy in acromegaly. Fg-SRLs show a preferential binding affinity for somatostatin receptor subtype-2 (SST2), while the second-generation ligand, pasireotide (PAS), has high affinity for multiple SSTs (SST5 > SST2 > SST3 > SST1). Whether PAS acts via SST2 in somatotroph tumors, or through other SSTs (e.g., SST5), is a matter of debate. In this light, the combined treatment OCT+PAS could result in additive/synergistic effects. We evaluated the efficacy of OCT and PAS (alone and in combination) on growth hormone (GH) secretion in primary cultures from human somatotroph tumors, as well as on cell proliferation, intracellular signaling and receptor trafficking in the rat GH4C1 cell line. The results confirmed the superimposable efficacy of OCT and PAS in reducing GH secretion (primary cultures), cell proliferation, cAMP accumulation and intracellular [Ca2+] increase (GH4C1 cells), without any additive effect observed for OCT+PAS. In GH4C1 cells, co-incubation with a SST2-selective antagonist reversed the inhibitory effect of OCT and PAS on cell proliferation and cAMP accumulation, while both compounds resulted in a robust internalization of SST2 (but not SST5). In conclusion, OCT and PAS seem to act mainly through SST2 in somatotroph tumor cells in vitro, without inducing any additive/synergistic effect when tested in combination.

Medical Therapy of Acromegaly in Germany 2019 - Data from the German Acromegaly Registry.

Acromegaly is a rare disease caused by excessive growth hormone (GH) secretion from pituitary adenomas in most cases. If neurosurgical therapy is contraindicated or not sufficient, medical therapy is the second line therapy. To describe current medical therapy in acromegaly. Retrospective data analysis from 2732 patients treated in 69 centers of the German Acromegaly Registry. 749 patients were seen within the recent 18 months, of which 420 were on medical therapy (56.1%). 73% of medically treated acromegalic patients had normal/low IGF-1 levels. 57% of patients with non-normalized IGF-1 levels had an IGF-1 value between 1- and 1.25-fold above the upper limit of normal. Most patients (55%) received somatostatin analogs as monotherapy, 12% GH receptor monotherapy, and 9% dopamine agonist therapy. Doses of each medical therapy varied widely, with 120 mg lanreotide LAR every 4 weeks, 30 mg octreotide LAR every 4 weeks, 140 mg pegvisomant per week and 1mg cabergoline per week being the most frequent used regimens. A combination of different medical regimens was used in almost 25% of the patients. The majority of German acromegalic patients receiving medical therapy are controlled according to normal IGF-1 levels.

Medical Therapy for Acromegaly: Towards The Practice of A Personalized Medicine Approach

Medical Therapy for Acromegaly: Towards The Practice of A Personalized Medicine Approach

Diabetes in Patients With Acromegaly.

Acromegaly is a clinical syndrome which results from growth hormone excess. Uncontrolled acromegaly is associated with cardiovascular mortality, due to an excess of risk factors including diabetes mellitus, hypertension and cardiomegaly. Diabetes mellitus is a frequent complication of acromegaly with a prevalence of 12-37%. This review will provide an overview of a number of aspects of diabetes mellitus and glucose intolerance in acromegaly including the following: 1. Epidemiology and pathophysiology of abnormalities of glucose homeostasis 2. The impact of different management options for acromegaly on glucose homeostasis 3. The management options for diabetes mellitus in patients with acromegaly RECENT FINDINGS: Growth hormone and IGF-1 have complex effects on glucose metabolism. Insulin resistance, hyperinsulinaemia and increased gluconeogenesis combine to produce a metabolic milieu which leads to the development of diabetes in acromegaly. Treatment of acromegaly should ameliorate abnormalities of glucose metabolism, due to reversal of insulin resistance and a reduction in gluconeogenesis. Recent advances in medical therapy of acromegaly have varying impacts on glucose homeostasis. These adverse effects influence management choices in patients with acromegaly who also have diabetes mellitus or glucose intolerance. The underlying mechanisms of disorders of glucose metabolism in patients with acromegaly are complex. The aim of treatment of acromegaly is normalisation of GH/IGF-1 with reduction of co-morbidities. The choice of therapy for acromegaly should consider the impact of therapy on several factors including glucose metabolism.

The role of combination medical therapy in the treatment of acromegaly.

Uncontrolled acromegaly results in approximately 2-fold excess mortality. Pituitary surgery is first-line therapy, and medical treatment is indicated for persistent disease. While cabergoline and pegvisomant are used in select patients, somatostatin receptor ligands (SRLs) remain the cornerstone of medical treatment. Management of patients poorly responsive to SRLs is therefore, challenging. The purpose of this review is to highlight the options for combination medical therapy in the treatment of acromegaly, with an emphasis on efficacy and safety. All original articles/abstracts detailing combination medical therapy in acromegaly were identified from a PubMed search. Studies reviewed included retrospective and open-label prospective studies. While the combination of SRL and cabergoline was generally well tolerated, a lower baseline insulin-like growth factor-1 (IGF-1) level was the best predictor of efficacy; this combination may be most effective in patients with mildly elevated IGF-1. SRL-pegvisomant combination normalized IGF-1 in the majority of patients; continued efficacy despite individual drug dosing reduction was also reported. The risk of significant liver enzyme elevation was, however, higher than that reported with SRL monotherapy; close monitoring is recommended. Data on pegvisomant-cabergoline combination is limited, but this may be an option in the setting of SRL intolerance. Reports on temozolomide used in combination with other medical therapies in patients with aggressive GH-secreting tumors are also summarized. While more prospective, randomized controlled trials on long-term efficacy and safety are needed, combination medical therapy remains a treatment strategy that should be considered for acromegaly patients poorly responsive to SRLs.

OR1-6: Combination medical therapy for acromegaly: the ACROSTUDY experience

OR1-6: Combination medical therapy for acromegaly: the ACROSTUDY experience

Use of Pegvisomant in acromegaly. An Italian Society of Endocrinology guideline.

Acromegaly management is a significant challenge for endocrinologists. The Acromegaly Consensus Group developed several statements on the management of acromegaly and specifically on its medical treatment [1–3]. Acromegaly is a quite rare condition generally caused by a growth hormone (GH)-secreting pituitary adenoma [4]. Delayed diagnosis leads to prevalent presentation of the disease at the stage of macroadenoma (two-thirds of patients) and frequent persistence of active disease after surgery which remains in many patients the primary treatment option [5]. However, active acromegaly is potentially a life threatening condition due its severe systemic complications [6, 7] Therefore, elevated GH and insulin-like growth factor (IGF)-1 levels need to be strictly controlled after failure of surgery with medical or radiation treatments [8]. Furthermore, criteria for disease control may not be fulfilled in a considerable proportion of patients undergoing medical treatment with somatostatin receptor ligands (SRLs) after unsuccessful surgery [9, 10]. Accordingly, some acromegaly patients require the administration of GH antagonist Pegvisomant [11]. Pegvisomant has been introduced in clinical practice more than a decade ago as a medical therapy of acromegaly. However, specific guidelines for Pegvisomant use in acromegaly are lacking. Therefore, the Italian Society of Endocrinology constituted a task force with the objective of assessing the published literature and the clinical experience with Pegvisomant. This group involved endocrinologists recognized experts in the field of acromegaly management and their understanding of the data reported so far worldwide as well as their recommendations for Pegvisomant use in clinical practice are presented here. Biochemical and clinical results of Pegvisomant, indications, treatment modalities, combination therapies, safety and regulatory and cost/efficacy issues were evaluated. Evidences were graded with GRADE system [1–3, 12, 13] based on the quality of evidence as very low quality (VLQ; expert opinion with one or a small number of small uncontrolled studies in support), low quality (LQ; large series of small uncontrolled studies), moderate quality (MQ; one or a small number of large uncontrolled studies or meta-analyses), or high quality (HQ; controlled studies or large series of large uncontrolled studies with sufficiently long follow-up). Recommendations were defined discretionary (DR) if based on VLQ-LQ evidence, or strong (SR) if supported by MQ-HQ evidence.

The role of combination medical therapy in acromegaly

This review focuses on combination drug treatment for acromegaly patients, including novel concepts and experimental therapies, with an emphasis on the author's personal experience. A review of published clinical studies demonstrates that combination therapy; somatostatin receptor ligands and dopamine agonists, somatostatin receptor ligands and pegvisomant, or cabergoline and pegvisomant could provide significant additive biochemical control of acromegaly in patients inadequately controlled with conventional somatostatin receptor ligand therapy. Advances in combination medical therapy have opened up new perspectives for acromegaly patients who are poorly, or nonresponsive to, presently available single drug therapies.

Medical therapy of acromegaly

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Desensitization treatment for hypersensitivity reaction to octreotide in an acromegalic patient

Octreotide is widely used as medical therapy for acromegaly. It is known to markedly reduce growth hormone levels, improve symptoms and reduce tumor size. Common side effects include gastrointestinal symptoms, hepatobiliary disorders, dizziness, headaches, bradycardia, hyperglycemia or hypoglycemia and thyroid dysfunction. Although urticaria, allergy/hypersensitivity reactions and anaphylaxis have been noted as possible adverse reactions, there is a lack of data showing a causal relationship between octreotide and hypersensitivity reactions and there is no information on management when continued use of this medication is essential. We now report a case of a 60 year old male with acromegaly who had presented with a cutaneous hypersensitivity reaction to octreotide. In addition he failed treatment with surgery, radiation, and dopamine agonist and could no longer afford to continue treatment with pegvisomant. The patient underwent desensitization treatment for his octreotide allergy and was able to resume treatment without any further side effects. We believe this case represents the first report of successful desensitization treatment for octreotide allergy in an acromegalic patient.

Medical Therapy of Acromegaly

This paper outlines the present status of medical therapy of acromegaly. Indications for permanent postoperative treatment, postirradiation treamtent to bridge the interval until remission as well as primary medical therapy are elaborated. Therapeutic efficacy of the different available drugs—somatostatin receptor ligands (SRLs), dopamine agonists, and the GH antagonist Pegvisomant—is discussed, as are the indications for and efficacy of their respective combinations. Information on their mechanism of action, and some pharmakokinetic data are included. Special emphasis is given to the difficulties to define remission criteria of acromegaly due to technical assay problems. An algorithm for medical therapy in acromegaly is provided.

Role of somatostatin receptor ligands in the treatment of acromegaly – review of literature

Acromegaly is a rare disease with typical clinical manifestations. Untreated acromegaly carries a 2-4-fold increase in mortality in long-term outcome. The goal of treatment is double, including biochemical control of the disease (normalization of serum IGF1 levels compared to age and gender matched controls, GH levels below 1 ng/ml after oral glucose load, or random GH below 2.5 ng/ml) and control of the tumor mass. The therapeutic modalities currently available for the treatment of acromegaly are: surgery, medical therapy, radiation therapy and their combinations. The cornerstones of medical therapy in acromegaly are the somatostatin receptor ligands due to their effectiveness in controlling GH excess in 60-70 % of patients and their beneficial effects on tumor volume. Somatostatin analogues have an established role as adjuvant therapy after non-curative surgery, and evidence suggests their use as primary treatment for selected patients. The long-term use of somatostatin receptor ligands is safe and they are well tolerated. Future medical therapy consists of pasireotide, a novel, universal somatostatin receptor agonist, and a new class of drugs named dopastatins. The latter so-called chimeric molecules have strong affinity for somatostatin receptors and dopamine-2 receptors, resulting in a more effective blocking of GH secretion, according to preliminary data. The authors of this paper review the current medical therapy of acromegaly, focusing on the role of somatostatin receptor ligands. Orv. Hetil., 2011, 152, 715–721.

Medical therapy in acromegaly

Acromegaly is a rare disease characterized by excess secretion of growth hormone (GH) and increased circulating insulin-like growth factor 1 (IGF-1) concentrations. The disease is associated with increased morbidity and premature mortality, but these effects can be reduced if GH levels are decreased to <2.5 μg/l and IGF-1 levels are normalized. Therapy for acromegaly is targeted at decreasing GH and IGF-1 levels, ameliorating patients' symptoms and decreasing any local compressive effects of the pituitary adenoma. The therapeutic options for acromegaly include surgery, radiotherapy and medical therapies, such as dopamine agonists, somatostatin receptor ligands and the GH receptor antagonist pegvisomant. Medical therapy is currently most widely used as secondary treatment for persistent or recurrent acromegaly following noncurative surgery, although it is increasingly used as primary therapy. This Review provides an overview of current and future pharmacological therapies for patients with acromegaly.

Medical therapy of acromegaly in Turkey

Acromegaly is associated with multiple co-morbidities and risk of premature mortality. Mortality rate of acromegalic patients is similar to that of the general population when normal GH levels are achieved. Surgery is the mainstay of acromegaly but when surgery fails to achieve disease control, or when surgery is impossible or contraindicated, patients are offered medical therapy and/or radiotherapy. Current medical therapy modalities were revised in this short review.

Medical therapy for acromegaly: can we predict response?

Response to medical therapy for acromegaly is highly variable, with few predictive factors available to help clinicians make informed treatment choices. Researchers in the UK now suggest that prior radiotherapy might influence an individual's response to secondary therapy with dopamine agonists or somatostatin analogs.

Clinical and biochemical improvement in acromegaly during pregnancy

Numerous case reports of pregnancy in acromegaly exist, however detailed descriptions of changes in placental and pituitary GH and IGF-I throughout gestation are rare. A 19-yr-old female presented to this institution with signs and symptoms of a GH-secreting pituitary adenoma. Following transphenoidal hypophysectomy, she had 3 unplanned pregnancies, despite ongoing active disease. No pregnancy was complicated by glucose intolerance or hypertension and 3 healthy newborns were delivered near or at term. Clinical improvement was observed during each pregnancy, accompanied by IGF-I levels lower than in the non-pregnant state, the majority lying within the normal range. This was despite increasing placental GH levels, and was not consistent with previous reports in the literature. Further surgical and medical therapies for acromegaly failed to normalize nonpregnant GH or IGF-I levels in this woman. Estrogen is known to alter GH signaling via its interaction with Janus kinase/signal transducers and activators of transcription (JAK-STAT) pathways. We hypothesize that increasing concentrations of estrogen or other pregnancy-related hormones resulted in her clinical and biochemical improvement during pregnancy. This may be used for future therapeutic benefit.

先端巨人症の内科的治療 : 最近の進歩(GH産生下垂体腺腫のupdate)

先端巨人症の内科的治療 : 最近の進歩(<特集>GH産生下垂体腺腫のupdate)

Recent advances in medical therapy for acromegaly

For a considerable time, somatostatin analogues (SA) have been the medical therapy of choice for the treatment of acromegaly. In addition to their well-established use as an adjunctive therapy, primary therapy with SA has been investigated in recent years, demonstrating biochemical and proliferative control in a relevant percentage of patients.