scholarly journals Resistance to drug treatment of acromegaly and ways to overcome it

2021 ◽  
Vol 18 (2) ◽  
pp. 150-162
Author(s):  
O. O. Golounina ◽  
L. K. Dzeranova ◽  
E. A. Pigarova ◽  
Zh. E. Belaya
Keyword(s):  
Growth Hormone ◽  
Drug Treatment ◽  
Growth Hormone Receptor ◽  
First Generation ◽  
Treatment Method ◽  
Somatostatin Analogues ◽  
Biochemical Remission ◽  
High Doses ◽  
Personalized Approach ◽  
Selection Of

Acromegaly is a severe disabling neuroendocrine disease caused by hypersecretion of growth hormone (GH) and insulin-like growth factor 1 (IGF-1). The problem of resistance to drug therapy in patients with acromegaly is quite common in clinical practice and requires a personalized approach, considering various predictors of sensitivity to the choice of the treatment method. To date, first-generation somatostatin analogues are first-line drugs in the medical treatment of acromegaly, but up to 50% of patients do not achieve biochemical remission of the disease. The prognosis of sensitivity to somatostatin analogues is of great importance and the selection of patients in whom this therapy will be not successful provides invaluable assistance in choosing the optimal treatment approach. This review summarizes potential predictors of sensitivity and resistance to existing drug treatment of acromegaly, discusses possible ways to overcome the resulting resistance to therapy, suggests options for a personalized approach to choosing a treatment strategy in the absence of disease control against the background of monotherapy with somatostatin analogues, including «off-label» combinations. Timely addition of growth hormone receptor antagonist (pegvisomant) avoids repeated neurosurgical intervention, radiation therapy or prescribing excessively high doses of somatostatin analogues. Optimal use of mono- or combination therapy contributes to the achievement of biochemical remission in most resistant patients.

scholarly journals Role of Receptor Profiling for Personalized Therapy in a Patient with a Growth Hormone-Secreting Macroadenoma Resistant to First-Generation Somatostatin Analogues

2019 ◽  
Vol 9 (4) ◽  
pp. 48 ◽  
Author(s):  
Krystallenia I. Alexandraki ◽  
Eirini Papadimitriou ◽  
Vasiliki Mavroeidi ◽  
Georgios Kyriakopoulos ◽  
Antonios Xydakis ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Pituitary Adenoma ◽  
First Generation ◽  
Residual Disease ◽  
Somatostatin Receptors ◽  
Somatostatin Analogues ◽  
Tumor Control ◽  
High Morbidity ◽  
Number Of Patients ◽  
Surgical Failure

Background: Acromegaly is almost always caused by a pituitary adenoma and is associated with high morbidity and mortality when uncontrolled. Trans-sphenoidal removal of the adenoma is the mainstay of therapy, but fails to control the disease in a significant number of patients who require further treatment. Somatostatin analogues (SSAs) as monotherapy or in combination with growth hormone (GH)-receptor antagonists and/or dopamine agonists are used either alone or in combination following surgical failure to achieve disease control. The use of specific biomarkers may help to individualize the therapeutic plan after surgical failure and direct towards a more personalized approach. Methods: We report a 41-year-old man with acromegaly and residual disease after repeated surgery that was resistant to first-generation SSAs. Results: Biochemical and tumor control were achieved following the administration of a second-generation SSA, pasireotide, combined with pegvisomant, both at maximal doses and along with cabergoline. Histology specimens showed a sparsely-granulated GH-immunostaining pituitary adenoma with intense positivity for somatostatin receptors 2 and 5 and low levels of E-cadherin. Conclusion: Personalized medical therapy guided by currently available biomarkers, such as immunohistochemically-characterized receptor profiling or adhesion molecules, resulted in controlled insulin-like growth factor-1 (IGF-1) and GH levels and symptom alleviation following the combination of three drug-classes.

scholarly journals Identification and overcoming of resistance to somatostatin analogues in real clinical practice

2017 ◽  
Vol 63 (5) ◽  
pp. 338-345
Author(s):  
Irena A. Ilovayskaya
Keyword(s):  
Clinical Practice ◽  
First Generation ◽  
Tumor Response ◽  
Treatment Options ◽  
Combined Treatment ◽  
Somatostatin Analogues ◽  
Response To Treatment ◽  
Ki 67 ◽  
Genetic Predictors ◽  
Personalized Approach

Resistance to somatostatin analogues (SSAs) is defined as the lack of biochemical and tumor response to the treatment for 12 months. An adequate biochemical response means achieving the target criteria of acromegaly treatment or at least a decrease in the GH and/or IGF-1 levels by >50%. A decrease in the somatotropinoma size by ≥ 20% (when using SSAs as the first line treatment) is considered as the tumor response to treatment. On the basis of treatment efficacy, patients may be classified as non-resistant (biochemical control of acromegaly and tumor response), partially resistant (some degree of biochemical and/or tumor response), and fully resistant (neither biochemical nor tumor response) to SSA therapy. Most patients (up to 60—70%) are partially resistant to the first generation of SSAs. Clinical and biochemical predictors for resistance to SSAs include young age, male gender, high GH/IGF-1 levels, and large invasive sparsely granulated somatotropinoma with high Ki-67 and a hyperintense T2-weighted MRI signal. In recent years, various molecular and genetic predictors for resistance to SSAs have been found; they should be introduced in clinical practice to enable the personalized approach to drug therapy. Treatment options for patients resistant to first-generation SSAs include dose escalation, combined treatment with SSAs and cabergoline, and switching to pasireotide or pegvisomant (not available in Russia); non-drug options include tumor debulking followed by SSA therapy and radiosurgery/radiotherapy.

scholarly journals Pegvisomant and current approaches to the medical treatment of acromegaly (literature review and case report)

2020 ◽  
Vol 16 (4) ◽  
pp. 73-79
Author(s):  
Larisa K. Dzeranova ◽  
Alexandra A. Povaliaeva ◽  
Anastasia A. Romanova ◽  
Elena G. Przhiyalkovskaya ◽  
Ekaterina A. Pigarova ◽  
...  
Keyword(s):  
Adverse Events ◽  
Growth Hormone Receptor ◽  
Clinical Observation ◽  
Practical Experience ◽  
Somatostatin Analogues ◽  
Minimal Amount ◽  
Good Prospect ◽  
The Russian Federation ◽  
Biochemical Remission

This review provides the main results of clinical trials and the literature on the experience of using pegvisomant, the first drug from the class of growth hormone receptor antagonists. The mechanism of action of the drug, its effectiveness with respect to disease control and its effect on complications, information on adverse events, and brief information on the experience of use during pregnancy are discussed in detail. In conclusion, a clinical observation of successful use of pegvisomant in resistant to standart treatment acromegaly is given. A discussion of the available literature data, the results of clinical studies and practical experience allows us to conclude that the drug is highly effective in terms of achieving biochemical remission of acromegaly, and also has a number of additional valuable properties: it is capable of improvement of patients glucose metabolism and quality of life and has a minimal amount of adverse events. Pegvisomant is currently registered in the Russian Federation only for use in monotherapy; the possibility of combination therapy with somatostatin analogues will additionally allow to reliably control the growth of the pituitary adenoma and significantly cut treatment costs by reducing the dose of pegvisomant. These features of the drug make it very relevant when discussing issues related to drug therapy of acromegaly, and suggest a good prospect for use in clinical practice.

scholarly journals A multivariable prediction model for pegvisomant dosing: monotherapy and in combination with long-acting somatostatin analogues

2017 ◽  
Vol 176 (4) ◽  
pp. 421-431 ◽  
Author(s):  
S E Franck ◽  
T I M Korevaar ◽  
P Petrossians ◽  
A F Daly ◽  
P Chanson ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Regression Models ◽  
Growth Hormone Receptor ◽  
Somatostatin Analogues ◽  
Dose Titration ◽  
Factor I ◽  
Igf I ◽  
Multivariable Regression ◽  
Long Acting ◽  
Multivariable Regression Models

Background Effective treatment of acromegaly with pegvisomant (PEGV), a growth hormone receptor antagonist, requires an appropriate dose titration. PEGV doses vary widely among individual patients, and various covariates may affect its dosing and pharmacokinetics. Objective To identify predictors of the PEGV dose required to normalize insulin-like growth factor I (IGF-I) levels during PEGV monotherapy and in combination with long-acting somatostatin analogues (LA-SSAs). Design Two retrospective cohorts (Rotterdam + Liège Acromegaly Survey (LAS), total n = 188) were meta-analyzed as a form of external replication to study the predictors of PEGV dosing in addition to LA-SSA, the LAS (n = 83) was used to study the predictors of PEGV monotherapy dosing. Multivariable regression models were used to identify predictors of the PEGV dose required to normalize IGF-I levels. Results For PEGV dosing in combination with LA-SSA, IGF-I levels, weight, height and age, were associated with the PEGV normalization dosage (P ≤ 0.001, P ≤ 0.001, P = 0.028 and P = 0.047 respectively). Taken together, these characteristics predicted the PEGV normalization dose correctly in 63.3% of all patients within a range of ±60 mg/week (21.3% within a range of ±20 mg/week). For monotherapy, only weight was associated with the PEGV normalization dose (P ≤ 0.001) and predicted this dosage correctly in 77.1% of all patients within a range of ±60 mg/week (31.3% within a range of ±20 mg/week). Conclusion In this study, we show that IGF-I levels, weight, height and age can contribute to define the optimal PEGV dose to normalize IGF-I levels in addition to LA-SSA. For PEGV monotherapy, only the patient’s weight was associated with the IGF-I normalization PEGV dosage.

Medical treatment of acromegaly

2013 ◽  
Vol 154 (39) ◽  
pp. 1527-1534 ◽  
Author(s):  
Miklós Góth
Keyword(s):  
Growth Hormone ◽  
Growth Factor ◽  
Medical Treatment ◽  
Dopamine Agonists ◽  
Tumour Growth ◽  
Growth Hormone Receptor ◽  
Somatostatin Analogues ◽  
Diagnostic Tools ◽  
Insulin Like Growth Factor ◽  
Team Management

Prolonged overproduction of growth hormone, like insulin-like growth factor-1 hypersecretion leads to acromegaly in adults. This is associated with several co-morbidities and increased mortality. Despite typical clinical features and modern diagnostic tools, it often takes years to diagnose from the onset of the disease. The aims of the treatment are to reduce or control tumour growth, inhibit growth hormone hypersecretion, normalize insulin-like growth factor-1 levels, treat co-morbidities and, therefore, reduce mortality. There are three approaches for therapy: surgery, medical management (dopamine agonists, somatostatin analogues and growth hormone receptor antagonist), and radiotherapy. Efficient therapy of the disease is based on the appropriate multidisciplinary team management. The review provides a summary of medical treatment for acromegaly. Orv. Hetil., 2013, 154, 1527–1534.

scholarly journals New opportunities for secondary drug therapy of acromegaly

2020 ◽  
pp. 137-144
Author(s):  
V. S. Pronin ◽  
E. V. Pronin
Keyword(s):  
Growth Hormone ◽  
Clinical Practice ◽  
Drug Therapy ◽  
Life Expectancy ◽  
Dopamine Agonists ◽  
Growth Hormone Receptor ◽  
Tumor Tissue ◽  
Somatostatin Analogues ◽  
Primary Therapy ◽  
Combined Use

Introduction. Acromegaly is a severe multi-organ disease that negatively affects the quality and life expectancy of patients. The continuing complexity of acromegaly curation is due to the multiplicity of pathomorphological variants growth hormone-secreting adenomas and the lack of differentiated approach in choosing a therapeutic strategy. The high percentage of non-radical adenomectomy, due to the large size and invasive growth of somatotropin, involves the operative connection of adequate secondary drug therapy.Purpose. The aim of the study is to compare the effectiveness of different classes of drugs, as well as algorithms of their combined use in the treatment of acromegaly.Methods of treatment. The review uses information on factors affecting the results of clinical use of modern pharmacological preparations (somatostatin analogues, dopamine agonists, growth hormone receptor antagonists) used in secondary drug therapy of acromegaly. The indications for the administration of a drug are discussed taking into account the features of the pathomorphological structure of the tumor tissue, as well as the tactics of the therapeutic allowance in absolute or relative resistance to somatostatin analogues of the 1st generation (octreotide and lanreotide) and dopamine agonists (cabergoline). Data on efficiency of the new drug – pegvisomant providing stable control of acromegaly irrespective of secretory activity and receptor phenotype of tumor tissue are summed up.Results. Interim reports of the ACROSTUDY observational project and other clinical studies regarding the therapeutic efficacy and safety of pegvisomant are presented. A relatively low risk of continued growth of tumor tissue and other adverse reactions against the background of treatment with this drug is shown. Prognostic factors of insufficient efficiency of pegvisomant include young age, increased BMI, high initial level of ИРФ-1, presence of diabetes mellitus. There is an advantage of combined use of pegvisomant and somatostatin analogues to maintain acromegaly control and prevent tumor growth. The topic of primary therapy of pegvisomant is touched upon. Based on the results of real clinical practice, modern international recommendations are presented, which indicate the place of pegvisomant in the algorithm of secondary drug therapy.Conclusions. Due to the introduction into clinical practice of various therapeutic agents, which allow, regardless of the activity of the disease, the specificity of the pathomorphological structure of tumor tissue and somatic status, to achieve stable maintenance of biochemical remission, patients have real opportunities for improving the quality and life expectancy.

Laron syndrome – A case Report

JMS SKIMS ◽  
2017 ◽  
Vol 20 (2) ◽  
pp. 104-106
Author(s):  
Javaid Ahmad Bhat ◽  
Moomin Hussain Bhat ◽  
Hilal Bhat ◽  
Mona Sood ◽  
Shariq Rashid Masoodi
Keyword(s):  
Growth Hormone ◽  
Case Report ◽  
Hormone Receptor ◽  
Growth Hormone Receptor ◽  
Genetic Disorder ◽  
Female Child ◽  
Receptor Signaling ◽  
Laron Syndrome ◽  
Rare Genetic Disorder ◽  
Igf I

Background : Laron & colleagues (1966) reported a rare genetic disorder in Israliei Jewish sublings which was characterized by insensitivity to growth hormone due to abnormality in growth hormone receptor or post receptor signaling pathway.Case Report: We hereby report a case of a 5 year old female child who presented to us with features similar to Laron syndrome. The diagnosis was made & confirmed by various Lab. investigations like low IGF-I levels and managed accordingly. JMS 2017; 20 (2):104-106  

Three novel Growth Hormone Receptor (GHR) splicing mutations causing a spectrum of Growth Hormone Insensitivity

2019 ◽  
Author(s):  
Emily Cottrell ◽  
Avinaash Maharaj ◽  
Tasneem Ladha ◽  
Sumana Chatterjee ◽  
Anna Grandone ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Hormone Receptor ◽  
Growth Hormone Receptor ◽  
Splicing Mutations ◽  
Growth Hormone Insensitivity
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