Management Of Acromegaly Research Articles

P45 Gamma knife radiosurgery for the primary management of acromegaly

ObjectivesReport outcome and morbidity data for the treatment of acromegaly with primary stereotactic radiosurgery (STRS).DesignRetrospective.Subjects20 patients with acromegaly who underwent primary STRS at the National Centre for Radiosurgery, Sheffield (UK) between 1985 and 2015.MethodsReview of notes, database, laboratory results, patient questionnaire and death certification. Guideline-based control was defined as normal age-sex-adjusted IGF1 levels and either random GH <1 µg/L or GH <0.3 µg/L (OGTT) or mean Growth Hormone Day Curve (GHDC) <1 µg/L.ResultsControl at 20 years was 100% and 75% on and off medication respectively. Median time to control on medication was 3 years and 7.4 years off medication. Median marginal radiation dose was 27.5 Gray and median follow-up was 167 months. Seven patients died, median age 65 years. There were no STRS-related deaths. 53% of patients developed new hypopituitarism at median follow-up of 146 months. First onset of hypopituitarism occurred up to 20 years after treatment. No other complications were noted. Three patients underwent trans-sphenoidal surgery due to poor biochemical control at a mean of 35 months.ConclusionsMorbidity from STRS is low. There is significant latency to biochemical control and new onset hypopituitarism. While primary surgical intervention remains the gold standard in acromegaly, primary STRS results should inform discussions with patients considering non-surgical management.

Molecular determinants of the response to medical treatment of growth hormone secreting pituitary neuroendocrine tumors.

Acromegaly is a chronic systemic disease mainly caused by a growth hormone (GH)-secreting pituitary neuroendocrine tumor (PitNETs), which is associated with many health complications and increased mortality when not adequately treated. Transsphenoidal surgery is considered the treatment of choice in GH-secreting PitNETs, but patients in whom surgery cannot be considered or with persistent disease after surgery require medical therapy. Treatment with available synthetic somatostatin analogues (SSAs) is considered the mainstay in the medical management of acromegaly which exert their beneficial effects through the binding to a family of G-protein coupled receptors encoded by 5 genes (SSTR1-5). However, although it has been demonstrated that the SST1-5 receptors are physically present in tumor cells, SSAs are in many cases ineffective (i.e. approximately 10-30% of patients with GH-secreting PitNET are unresponsive to SSAs), suggesting that other cellular/molecular determinants could be essential for the response to the pharmacological treatment in patients with GH-secreting PitNETs. Therefore, the scrutiny of these determinants might be used for the identification of subgroups of patients in whom an appropriate pharmacological treatment can be successfully employed (responders vs. non-responders). In this review, we will describe some of the existing, classical and novel, genetic and molecular determinants involved in the response of patients with GH-secreting PitNETs to the available therapeutic treatments, as well as new molecular/therapeutic approaches that could be potentially useful for the treatment of GH-secreting PitNETs.

Presentation, Morbidity and Treatment Outcome of Acromegaly Patients at a Single Centre.

Introduction:The management of acromegaly, a rare and potentially curable disease, has undergone a paradigm shift in the past few decades. Many of the treatment modalities recommended for acromegaly are either too expensive or not available in many parts of India. There is a dearth of treatment and outcome data in Indian patients.Aim:Our aim was to study the clinical presentation, hormonal profile, radiology, management, and outcome of the disease at our center.Materials and Methods:Fifty one patients with acromegaly who attended the Department of Endocrinology, SKIMS, Srinagar, between October 2015 and April 2017, were included in the study. Clinical and hormonal profiles, comorbidities, treatment modalities, and outcome were evaluated.Results:The gender distribution was equal with the mean age of 42.3 ± 10.9 years at diagnosis. The majority (41) of the patients had macroadenoma. The most common presenting manifestations were acral enlargement and headache. Hypertension was present in 23, musculoskeletal manifestations in 19, and diabetes mellitus in 11 patients. Surgery was the most common method of treatment. Preoperatively only one patient with micro-adenoma had hypocortisolism, which was persistent in postoperative period, while no patient had preoperative or postoperative hypothyroidism or hypogonadism. As per the present consensus criteria, 23.7% patients achieved disease control (40% with microadenoma and only 19.5% with macroadenoma). The surgical complications occurred in 5 patients–CSF leak in 3 meningitis in 2 patients all except one having macroadenoma.Conclusions:The presentation of disease was generally comparable to that reported in literature. Cure rates were significantly lower than those reported from many large centers.

Toward fully exploiting the therapeutic potential of marketed pharmaceuticals: the use of octreotide and chloroquine in oncology.

Pleiotropy in biological systems and their targeting allows many pharmaceuticals to be used for multiple therapeutic purposes. Fully exploiting the therapeutic properties of drugs that are already marketed would be highly advantageous. This is especially the case in the field of oncology, where the ineffectiveness of typical anticancer agents is a common issue, while the development of novel anticancer agents is a costly and particularly time-consuming process. Octreotide and chloroquine are two pharmaceuticals that exhibit profound antitumorigenic activities. However, the current therapeutic use of octreotide is restricted primarily to the management of acromegaly and neuroendocrine tumors, both of which are rare medical conditions. Similarly, chloroquine is used mainly for the treatment of malaria, which is designated as a rare disease in Western countries. This limited exploitation contradicts the experimental findings of numerous studies outlining the possible expansion of the use of octreotide to include the treatment of common human malignancies and the repositioning of chloroquine in oncology. Herein, we review the current knowledge on the antitumor function of these two agents stemming from preclinical or clinical experimentation. In addition, we present in silico evidence on octreotide potentially binding to multiple Wnt-pathway components. This will hopefully aid in the design of new efficacious anticancer therapeutic regimens with minimal toxicity, which represents an enormous unmet demand in oncology.

Gamma knife radiosurgery for the primary management of acromegaly

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

Expert document on management of acromegaly

ObjectivesTo seek a consensus on issues that may generate doubts in management of acromegaly in Spain. MethodNominal groups and Delphi. Four experts defined relevant issues in management of acromegaly and generated different assertions and recommendations. Subsequently, a group of 30 additional experts was selected to test agreement with the assertions through two Delphi rounds. The following response categories were established: (1) Totally disagree; (2) Basically disagree; (3) Basically agree; (4) Totally agree. Agreement was defined as ≥70% of answers in categories 1 and 2 (consensus with the disagreement) or 3 and 4 (consensus with the agreement) in the second Delphi round. ResultsAssertions covers various aspects of clinical practice, including: (1) Useful instruments in individualization of treatment (response predictive markers, imaging techniques, etc.); (2) Clinical profiles and relevant comorbidities in treatment individualization; (3) Role of patient in treatment decision-making; (4) Access to treatments (accessibility and equity). The first Delphi round included 35 assertions. Consensus was reached on six of these assertions, two were eliminated, and two were reformulated. Of the 27 assertions included in the second round, consensus was reached on 24 (22 in the agreement, two in the disagreement) and three were eliminated. ConclusionsThis document is intended to solve some common clinical questions and to facilitate decision making in the management of patients with acromegaly.

Documento de expertos sobre el manejo de la acromegalia

ObjectivesTo seek a consensus on issues that may generate doubts in management of acromegaly in Spain. MethodNominal groups and Delphi. Four experts defined relevant issues in management of acromegaly and generated different assertions and recommendations. Subsequently, a group of 30 additional experts was selected to test agreement with the assertions through two Delphi rounds. The following response categories were established: 1) Totally disagree; 2) Basically disagree; 3) Basically agree; 4) Totally agree. Agreement was defined as ≥70% of answers in categories 1 and 2 (consensus with the disagreement) or 3 and 4 (consensus with the agreement) in the second Delphi round. ResultsAssertions covers various aspects of clinical practice, including: 1) Useful instruments in individualization of treatment (response predictive markers, imaging techniques, etc.); 2) Clinical profiles and relevant comorbidities in treatment individualization; 3) Role of patient in treatment decision-making; 4) Access to treatments (accessibility and equity). The first Delphi round included 35 assertions. Consensus was reached on six of these assertions, two were eliminated, and two were reformulated. Of the 27 assertions included in the second round, consensus was reached on 24 (22 in the agreement, two in the disagreement) and three were eliminated. ConclusionsThis document is intended to solve some common clinical questions and to facilitate decision making in the management of patients with acromegaly.

Management of acromegaly: an exploratory survey of physicians from the Middle East and North Africa.

Worldwide variations exist in the diagnosis and management of patients with acromegaly. For such a rare condition, the knowledge and perception of physicians would most likely direct the care of patients. However, the adherence of physicians in non-Western regions to guidelines for the diagnosis and management of acromegaly has not been previously ascertained. An online survey was conducted to assess the perceptions and practice of physicians regarding acromegaly diagnosis and management as per international guidelines. An electronic questionnaire containing key questions was mailed, initially to physicians in Saudi Arabia (KSA) and later to other countries in the Middle East and North Africa (MENA) region. Additional questions were included to ensure the relevance of the respondents' replies. The responses were captured and summarized anonymously. Descriptive comparisons were made with two similar international and national surveys from other regions. Two hundred forty-seven doctors responded to the survey. Of these, 155 (64.5%) fulfilled the inclusion criteria and, in particular, confirmed having treated acromegaly patients in the previous 12months, and they constituted the basis of this study. The three most common referring specialties for patients were internists (44; 28.4%), neurosurgeons (46; 29.6%), and family medicine physicians (42; 27.1%), respectively. The combination of growth hormone (GH) nadir during the oral glucose tolerance test (OGTT) and elevated insulin-like growth factor-1 (IGF-1) levels was used by 99 physicians (63.9%) to diagnose acromegaly. The main determinant for treatment choice was tumor mass characteristics confirmed by 117 respondents (75.5%) with neurosurgery as first treatment choice confirmed by 124 respondents (80%). Combined measurement of IGF-1 and GH levels after OGTT at 3months after surgery was the most widely used criterion for assessment of surgical outcomes, confirmed by 82 physicians (52.9%). The biggest barriers to optimal management of acromegaly as perceived by 38.1% and 35.5% of the respondents were high cost of medications and lack of physicians' awareness, respectively. The majority of the surveyed physicians reported variable adherence to the international acromegaly guidelines. Clearly, higher awareness is needed among physicians for early diagnosis and timely referral for specialist management.

Successful Treatment of Acromegaly and Associated Hypogonadism with First-Line Clomiphene Therapy

Clomiphene citrate (CC) has been reported as an effective add-on therapy to somatostatin analogs and dopamine agonists in patients with acromegaly accompanied by hypogonadism; its use as a single agent to treat acromegaly and associated hypogonadism following incomplete surgery has not been previously reported. We report the first case in which clomiphene was utilized as a single agent for the dual management of acromegaly and hypogonadism, not controlled by pituitary surgery alone. The treatment was well tolerated and proved to be effective after a process of treatment withdrawal and reintroduction. We propose that clomiphene may be considered as a cost-effective oral treatment option in select cases of hypogonadal acromegaly.

Consensus on the management of acromegaly in Spain

Consensus on the management of acromegaly in Spain

The complexity of management of persistent acromegaly from repeated surgical interventions and multiple medical therapies

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

Management of acromegaly in pregnancy and post-partum

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

Novel Somatostatin Receptor Ligands Therapies for Acromegaly.

Surgery is considered the treatment of choice in acromegaly, but patients with persistent disease after surgery or in whom surgery cannot be considered require medical therapy. Somatostatin receptor ligands (SRLs) octreotide (OCT), lanreotide, and the more recently approved pasireotide, characterized by a broader receptor ligand binding profile, are considered the mainstay in the medical management of acromegaly. However, in the attempt to offer a more efficacious and better tolerated medical approach, recent research has been aimed to override some limitations related to the use of currently approved drugs and novel SRLs therapies, with potential attractive features, have been proposed. These include both new formulation of older molecules and new molecules. Novel OCT formulations are aimed in particular to improve patients’ compliance and to reduce injection discomfort. They include an investigational ready-to-use subcutaneous depot OCT formulation (CAM2029), delivered via prefilled syringes and oral OCT that uses a “transient permeability enhancer” technology, which allows for OCT oral absorption. Another new delivery system is a long-lasting OCT implant (VP-003), which provide stable doses of OCT throughout a period of several months. Finally, a new SRL DG3173 (somatoprim) seems to be more selective for GH secretion, suggesting possible advantages in the presence of hyperglycemia or diabetes. How much these innovations will actually be beneficial to acromegaly patients in real clinical practice remains to be seen.

Effects of growth hormone on thyroid function are mediated by type 2 iodothyronine deiodinase in humans.

Growth hormone (GH) therapy in adults alters thyroid function, and acromegaly often involves thyroid disease. The present study aimed to elucidate roles and mechanisms of GH in regulating thyroid function. We performed two retrospective observational studies, which focused on consecutive patients with severe adult GH deficiency who received recombinant human GH (rhGH) therapy (n = 20) and consecutive patients with acromegaly who underwent transsphenoidal surgery (TSS) (n = 25). In both studies, serum free triiodothyronine (fT3), free thyroxine (fT4), and fT3/fT4 ratio were examined before and after the interventions. We subsequently administered GH to four human cell lines (HepG2, TSA201, MCF7, and HTC/C3) in vitro, and examined changes in mRNA levels of iodothyronine deiodinases (D1, D2, and D3). Median serum fT3 level significantly increased after rhGH therapy from 2.38 to 2.78 pg/mL (p < 0.001), and fT4 decreased from 1.115 to 1.065 ng/dL (p = 0.081). TSS significantly decreased median serum fT3 from 3.03 to 2.53 pg/mL (p < 0.001), and increased fT4 from 1.230 to 1.370 ng/dL (p < 0.001). In vitro, GH significantly increased D2 expression at the mRNA level in HTC/C3 cells (p < 0.01), as well as D2 protein and its activity. GH increased serum fT3 level and decreased serum fT4 level in humans. Our results suggest that its mechanism involves D2 upregulation. Considering this GH effect on thyroid hormone metabolism, data on thyroid function could be useful in the management of GH deficiency and acromegaly.

One-Center Analysis of Cost Associated With Acromegaly Management In Poland

One-Center Analysis of Cost Associated With Acromegaly Management In Poland

MECHANISMS IN ENDOCRINOLOGY: Clinical and pharmacogenetic aspects of the growth hormone receptor polymorphism.

Pharmacogenetics aims to maximize the beneficial effects of a medical therapy by identifying genetic finger prints from responders and non-responders and, thereby improving safety and efficacy profile of the drug. Most subjects who are deficient in growth hormone (GHD) are candidates for recombinant human GH (rhGH) therapy. To date, it is well established that even after adjustments for several clinical variables, such as age, gender, body composition and the age at onset of the GHD, response to rhGH treatment is highly variable among individuals, part of which is believed to be due to genetic factors within the GH system. As the first genetic variant to potentially influence the individual response to rhGH therapy in children with growth disorders, polymorphism in the GH receptor (GHR) has attracted a great interest as a target for pharmacogenetics. Studies have been conducted to compare the functional and molecular effects of the full-length GHR (fl-GHR) isoform with the exon 3 deleted (d3-GHR) isoform in children and adults treated with rhGH therapy. Additionally, the impact of the GHR polymorphism has been investigated in relation to the clinical status and response to medical treatment in acromegaly, especially to the GHR antagonist drug pegvisomant. We have performed a narrative review of the studies performed to date on the association of GHR polymorphism with rhGH response in children and adults, and its potential influence in the medical management of acromegaly. In addition, data from studies on the general population and in other chronic diseases examining a role of this genetic variant in the regulation of growth and metabolism are summarized.

Changes in the management and comorbidities of acromegaly over three decades: the French Acromegaly Registry.

Acromegaly is a rare disease associated with chronic multisystem complications. National registries have been created in several countries. The French Registry contains data on acromegaly epidemiology, management and comorbidities recorded over more than three decades, retrospectively until 1999 and prospectively from 1999 to 2012. Data could be analyzed for 999 of the 1034 patients included in the registry (46% males). Disease control, defined as IGF-I normalization (adjusted for age and sex), was achieved in 75% of patients at the last follow-up visit. Half the patients with uncontrolled disease had IGF-I levels below 1.5 times the upper limit of normal (ULN). The proportion of patients with surgically cured disease did not change markedly over time, whereas the proportion of patients with uncontrolled disease fell and the proportion of patients with medically controlled disease rose. Cardiovascular, metabolic, respiratory and rheumatologic comorbidities and their outcomes were recorded for most patients, and no noteworthy overall deterioration was noted over time. Cancer occurred in 10% of patients, for a standardized incidence ratio of 1.34 (95% CI: 0.94-1.87) in men and 1.24 (0.77-1.73) in women. Forty-one patients died during follow-up, for a standardized mortality ratio of 1.05 (0.70-1.42). Most deaths were due to cancer. The majority of patients with acromegaly now have successful disease control thanks to the multistep management. The incidence of comorbidities following diagnosis of acromegaly is very low. Life expectancy is now close to that of the general population, probably owing to better management of the GH/IGF-I excess and comorbidities.

Quality of Life in Acromegaly and the Association with the Clinical Parameters of the Disease

Background: Quality of life is currently considered a major factor in the assessment of disease outcome. Most patients with acromegaly present with skin, bone and soft tissue alterations, as well as hypertension, diabetes mellitus and other cardiovascular symptoms and all these affect patient’s mood, personality, interpersonal relationships and social behavior. The aim of this study was to assess quality of life in acromegaly and the association with the clinical characteristics of the disease. Methods: This cross-sectional study included a total of 101 (45 male, 56 female) patients with acromegaly, mean age 59.51 ± 1.35 years (mean ± SEM), with a disease duration of 12.88 ± 0.96 years. All subjects completed the Acromegaly Quality of Life Questionnaire (AcroQoL). Results: Total (mean ± SEM) score was 86.15±1.37 (min22-max110), psychological parameters score was 54.98±0,95 (min 14-max 70), appearance score was 25.95±0.54 (min 7-max 35), personal relationship score was 29.37±0.52 (min7-max 35) and finally physical parameters score was 30.93±0.58 (min8- max 40). Women and older patients showed slightly worse scores. Patients with macroadenomas, those who received radiotherapy, and those with comorbidities appeared with less mean total QoL scores. Conclusion: The assessment of quality of life is a critical end point in the management of acromegaly and improvement of quality of life is a major aim in the therapeutic management of acromegaly. Background: Quality of life is currently considered a major factor in the assessment of disease outcome. Most patients with acromegaly present with skin, bone and soft tissue alterations, as well as hypertension, diabetes mellitus and other cardiovascular symptoms and all these affect patient’s mood, personality, interpersonal relationships and social behavior. The aim of this study was to assess quality of life in acromegaly and the association with the clinical characteristics of the disease. Methods: This cross-sectional study included a total of 101 (45 male, 56 female) patients with acromegaly, mean age 59.51 ± 1.35 years (mean ± SEM), with a disease duration of 12.88 ± 0.96 years. All subjects completed the Acromegaly Quality of Life Questionnaire (AcroQoL). Results: Total (mean ± SEM) score was 86.15±1.37 (min22-max110), psychological parameters score was 54.98±0,95 (min 14-max 70), appearance score was 25.95±0.54 (min 7-max 35), personal relationship score was 29.37±0.52 (min7-max 35) and finally physical parameters score was 30.93±0.58 (min8- max 40). Women and older patients showed slightly worse scores. Patients with macroadenomas, those who received radiotherapy, and those with comorbidities appeared with less mean total QoL scores. Conclusion: The assessment of quality of life is a critical end point in the management of acromegaly and improvement of quality of life is a major aim in the therapeutic management of acromegaly.

Biochemical investigations in diagnosis and follow up of acromegaly.

Measurements of human growth hormone (GH) and insulin-like growth-factor I (IGF-I) are cornerstones in the diagnosis of acromegaly. Both hormones are also used as biochemical markers in the evaluation of disease activity during treatment. Management of acromegaly is particularly challenging in cases where discordant information is obtained from measurement of GH concentrations following oral glucose load and from measurement of IGF-I. While in some patients biological factors can explain the discrepancy, in many cases issues with the analytical methods seem to be responsible. Assays used by endocrine laboratories to determine concentrations of GH and IGF-I underwent significant changes during the last decades. While generally leading to more sensitive and reproducible methods, these changes also had considerable impact on absolute concentrations measured. This must be reflected by updated decision limits, cut-offs and reference intervals. Since different commercially available assays do not agree very well, method specific interpretation of GH and IGF-I concentrations is required. This complexity in the interpretation of hormone concentrations is not always appropriately reflected in laboratory reports, but also not in clinical guidelines reporting decision limits not related to a specific analytical method. The present review provides an overview about methodological and biological variables affecting the biochemical assessment of acromegaly in diagnosis and follow up.

Patient satisfaction and preferences of lanreotide Autogel treatment in acromegaly.

Despite the known importance of somatostatin analogues (SSAs) in the treatment of acromegaly, patient satisfaction leading to preferences for specific SSAs have received little attention so far. This open, prospective, observational, multicentre patient-reported outcome study included adult patients with acromegaly, who switched from another SSA to lanreotide Autogel (new and previous devices) at least two months prior to enrolment. The observation period was around 12 months. The primary outcome assessed was overall treatment satisfaction, measured using the five-point Likert scale. The secondary outcomes were: 1) treatment effectiveness, in terms of symptom control; 2) technical problems related to treatment administration, measured by the Visual Analog Scale (VAS); and 3) ease and safety of lanreotide Autogel delivery (new device vs. previous device). Of the 102 patients who completed the study, 97 (95.1%) were "completely or rather satisfied" with lanreotide Autogel therapy, four (3.9%) were "neither satisfied nor dissatisfied", and one (1%) was "rather dissatisfied". Symptom control was reported as "excellent" or "good" by 88-89% of patients throughout the study. Patients reported fewer technical problems related to administration of lanreotide Autogel (final mean VAS: 5.3) compared to previous SSAs (mean VAS: 37.6). Of the 31 patients treated with lanreotide Autogel using the previous device followed by the new device, 64.5% reported the new device as improved. Lanreotide Autogel therapy resulted in greater patient satisfaction with overall acromegaly management, when compared to previous SSAs. The new lanreotide Autogel device was found to be easier to use than the previous one. (Endokrynol Pol 2016; 67 (6): 572-579).