American Association of Clinical Endocrinologists and American College of Endocrinology Disease State Clinical Review: Management of Acromegaly Patients: What is the Role of Pre-Operative Medical Therapy?

Objective: Acromegaly is a complex disease characterized by growth hormone (GH) excess originating in most cases from a pituitary tumor. The goals of treatment include removing the tumor or reducing tumor burden, normalizing GH secretion and insulin-like growth factor 1 levels, and preserving normal pituitary function if possible. Surgery by an experienced neurosurgeon is still considered first-line therapy, especially in cases with small tumors. In the last few decades, significant progress in the development of selective pharmacologic agents has greatly facilitated the management of active acromegaly, with agents such as somatostatin-receptor ligands (SRLs), GH-receptor antagonists, and dopamine agonists. In addition to adjuvant treatment, pre-operative medical therapy and primary therapy in de novo patients are increasingly employed.Methods: A United States National Library of Medicine PubMed search (through July 2014) was conducted for the following terms: acromegaly, pre-operative medical therapy, somatostatin-receptor ligands, and somatostatin analogs. Articles not in English and those not in peer-reviewed journals were excluded. In reviewing pertinent articles, focus was placed on biochemical and other postoperative outcomes of medical therapy.Results: An analysis of the full effect of pre-operative use of SRLs on surgical outcomes (remission rates and peri-operative complications) is limited by heterogeneity of methodology, low overall surgical cure rates, and different study designs. The assumption that SRL use prior to surgery reduces peri-operative surgical risk has yet to be proven. A variable degree of tumor shrinkage with preoperative SRLs is observed. Likewise, SRL treatment 3 months before surgery may improve surgical remission rates in the short term; however, positive results do not persist in the long term.Conclusion: We consider that medical therapy before surgery could play a role in carefully selected patients, but treatment should be individualized. Primary medical therapy with a SRL may be considered in patients with macroadenomas without local mass effects on the optic chiasm, as SRLs have been shown to reduce tumor size and control GH hypersecretion. However, the data are insufficient to support general use of a SRL prior to surgery in order to improve post-surgery biochemical outcomes. Theoretically, patients with severe cardiac and respiratory complications due to acromegaly could potentially benefit from pre-operative SRLs in order to reduce peri-operative morbidity. Further investigation and investment in large randomized long-term clinical trials are needed to define the precise role and duration of pre-surgical medical treatment in acromegaly patients.Abbreviations: GH = growth hormone IGF-1 = insulin-like growth factor 1 MRI = magnetic resonance imaging SRL = somatostatin-receptor ligand     

Predicting therapeutic response and degree of pituitary tumour shrinkage during treatment of acromegaly with octreotide LAR

BACKGROUND/AIMS: The efficacy of transsphenoidal surgery in the treatment of patients with acromegaly is largely dependent on tumour size. A reduction in pituitary tumour volume by medical therapy might therefore improve subsequent surgical cure rates. This study prospectively determined the effects of the depot somatostatin analogue octreotide LAR on pituitary tumour size, GH and IGF-I levels and clinical symptoms in a cohort of previously untreated patients with acromegaly. METHODS: Six patients newly diagnosed with acromegaly (mean age 53 years; range 42-76 years) received intramuscular octreotide LAR every 28 days for 6 months. The initial dose of LAR was 20 mg, but increased to 30 mg after the initial 3 injections if mean GH levels were >5 mU/l. Prior to commencing LAR therapy, each patient received 3 injections of subcutaneous octreotide (50, 100 and 200 mug) in a randomized order on separate days, and the serum GH response was measured. Pituitary tumour volume was calculated from MRI or computed tomography scans at baseline, then 3 and 6 months after initiation of treatment, and assessed by a 'blinded' radiologist in random order. At baseline, 4 patients had a macroadenoma and 2 patients had a microadenoma. For the latter, the whole gland volume was measured. RESULTS: Serum GH levels decreased from 29.6 +/- 19.2 mU/l (mean +/- SD) at baseline to 12.1 +/- 10.5 mU/l at 3 months and 10.4 +/- 9.3 mU/l at 6 months. Three patients achieved a mean serum GH level of <5 mU/l. In these patients, the serum GH had declined to <5 mU/l in response to a single 100 mug subcutaneous octreotide injection. Serum IGF-I levels decreased by a mean of 45 +/- 7.4%. Tumour volume decreased in all patients: mean baseline volume 2,175 mm(3) (range 660-6,998) decreasing to 1,567 mm(3) (range 360-4,522) at 3 months (p < 0.05) and 1,293 mm(3) (range 280-4,104) at 6 months (p < 0.002). The mean percentage decrease in size was 29% (range -54 to +4%) at 3 months (p < 0.02) and 47% (range 21-97%) at 6 months (p < 0.002). There was no statistically significant correlation between GH response and tumour shrinkage. CONCLUSIONS: A single test dose of subcutaneous octreotide may be useful in predicting the subsequent efficacy of octreotide LAR. Octreotide LAR results in significant shrinkage of pituitary tumours of newly diagnosed patients with acromegaly. Whether its administration to such patients for 6-12 months can improve the efficacy of subsequent transsphenoidal surgery will require further study.     

Oral Octreotide: A Review of Recent Clinical Trials and Practical Recommendations for Its Use in the Treatment of Patients With Acromegaly

ObjectiveAcromegaly is characterized by chronic growth hormone (GH) and insulin-like growth factor 1 (IGF-1) hypersecretion, often caused by a GH-secreting pituitary adenoma. Even though surgery remains the first line of treatment, medical therapy is essential if surgery is contraindicated, does not achieve remission, or does not prevent recurrence despite apparent surgical remission. Oral octreotide capsules (OOCs) that combine octreotide with a transient permeability enhancer technology are the first oral somatostatin receptor ligands (SRLs) approved in the United States for acromegaly.MethodsWe review the literature and clinical trial data on OOC therapy in patients with acromegaly and discuss the clinical assessment of OOC use, potential drug–drug interactions, drug initiation, dose titration, and monitoring of drug efficacy and tolerability.ResultsIn 4 pivotal clinical trials involving 238 patients with acromegaly treated with OOC, effective suppression of serum GH and IGF-1 levels, maintenance of disease control, decreased breakthrough symptoms and symptomatic improvement with non-inferiority of OOCs to injectable SRLs in maintaining biochemical response was seen. Additionally, the safety profile of OOC therapy is comparable to that of injectable SRLs. Most patients who completed the clinical trials of OOCs have also expressed preference for oral compared with injectable SRL administration.ConclusionOOCs are an effective treatment option for patients with acromegaly who previously responded to injectable SRLs, with the benefits of avoiding injection-related side effects. This article provides a review of the pharmacology, safety, and efficacy and offers practical recommendations on the use of OOCs to treat injectable SRL-responsive patients with acromegaly.     

Pituitary surgery for the management of acromegaly

Active acromegaly is almost always the result of a benign growth hormone (GH)-secreting adenoma of the pituitary gland. Because the same pituitary stem cell can produce both GH and prolactin (PRL), many acromegalic patients also have hyperprolactinemia. The advantages of surgical excision of pituitary adenomas associated with acromegaly include: (1) prompt decrease in GH; (2) reliable and immediate relief of the mass effect from the tumor (decompression of the optic nerves and chiasm), and (3) the opportunity to obtain tumor tissue for characterization and investigative study. Currently, more than 97% of operations for removal of pituitary tumors associated with acromegaly are done using the transsphenoidal approach rather than craniotomy. Technical advances to make the surgery safer continue to evolve, and include endoscopic approaches, computer-guided image-based intraoperative visualization, and intraoperative magnetic resonance imaging. Criteria for satisfactory remission of acromegaly after surgery are the same as those used for medical management. They include normal insulin-like growth factor (IGF)-I and suppression of GH to undetectable levels (<1.0 ng/ml) during an oral glucose tolerance test (OGTT). Data from a recent series of 86 patients operated upon for acromegaly at the University of Virginia and followed for more than 1 year have been reviewed. In patients receiving surgery as the initial procedure, 67% had a normal IGF-I, and 52% suppressed to <1.0 ng/ml in an OGTT. There was one true recurrence of disease diagnosed 81 months after surgery. Results are best in patients with noninvasive microadenomas. Gamma knife radiosurgery has been a valuable adjunct in those patients who fail to achieve postoperative remission. Pathological evaluation of the tumors revealed that 16% expressed GH only, 25% stained for GH and glycoprotein hormones (follicle stimulating hormone, thyroid hormone, thyroid stimulating hormone, alpha-subunit), 21% for GH and PRL, and 33% for GH, PRL and glycoprotein hormones. There was one acidophil stem cell tumor and 10% had the mammosomatotroph subtype. This contemporary series was free of mortality or serious complications. One patient had a transient cerebrospinal fluid leak and 3 developed transient SIADH with hyponatremia. Surgical treatment remains an important aspect of the combined management of patients with acromegaly.     

Limitations of Current Approaches For The Treatment of Acromegaly

Objective: Acromegaly is a rare disease characterized by hypersecretion of growth hormone (GH), typically from a benign pituitary somatotroph adenoma, that leads to subsequent hypersecretion of insulin-like growth factor 1 (IGF-1). Patients with acromegaly have an increased risk of mortality and progressive worsening of comorbidities. Surgery, medical therapy, and radiotherapy are currently available treatment approaches for patients with acromegaly, with overall therapeutic goals of lowering GH levels and achieving normal IGF-1 levels, reducing tumor size, improving comorbidities, and minimizing mortality risk. Although surgery can lead to biochemical remission in some patients with acromegaly, many patients will continue to have uncontrolled disease and require additional treatment.Methods: We reviewed recently published reports and present a summary of the safety and efficacy of current treatment modalities for patients with acromegaly.Results: A substantial proportion of patients who receive medical therapy or radiotherapy will have persistently elevated GH and/or IGF-1. Because of the serious health consequences of continued elevation of GH and IGF-1, there is a need to improve therapeutic approaches to optimize biochemical control, particularly in high-need patient populations for whom current treatment options provide limited benefit.Conclusion: This review discusses current treatment options for patients with acromegaly, limitations associated with each treatment approach, and areas within the current treatment algorithm, as well as patient populations for which improved therapeutic options are needed. Novel agents in development were also highlighted, which have the potential to improve management of patients with uncontrolled or persistent acromegaly.Abbreviations:AACE = American Association of Clinical EndocrinologistsAE = adverse eventATG = AutogelCFRT = conventional fractionated radiotherapyDA = dopamine agonistENDO = Endocrine SocietyGH = growth hormoneGHRA = growth hormone receptor antagonistIGF-1 = insulin-like growth factor 1LAR = long-acting releaseLFT = liver function testSC = subcutaneousSRS = stereotactic radiosurgerySSA = somatostatin analoguesst = somatostatin receptorsst₂ = somatostatin receptor subtype 2sst₅ = somatostatin receptor subtype 5TSS = transsphenoidal surgery     

Circulating growth hormone releasing factor concentrations in normal subjects and patients with acromegaly.

A highly specific and sensitive radioimmunoassay was developed for measuring circulating growth hormone releasing factor (GRF) in human plasma. Before measuring immunoreactive GRF plasma samples were extracted on to Vycor glass. Immunoreactive GRF concentrations in plasma samples from 37 fasting normal subjects ranged from less than 10 to 60 ng/l (mean 21 ng/l). Fasting concentrations in 76 out of 80 acromegalic subjects were within the normal range, but the remaining four patients had values of 92 to 25 000 ng/l. Of these, only the patient with the highest concentration had evidence of ectopic GRF secretion from a disseminated carcinoid tumour. Two of the others had longstanding pituitary tumours, and the fourth patient had a pituitary growth hormone (GH) secreting tumour proved by its removal and subsequent remission of acromegaly. There was no correlation between serum GH and plasma immunoreactive GRF concentrations, irrespective of whether the patients were untreated or had been given radiotherapy or dopamine agonists. The assay should help elucidate the physiological role(s) of GRF and may also prove useful in differentiating between pituitary and hypothalamic defects in patients with acromegaly.     

Acromegaly with 'normal' serum growth hormone levels. Clinical features, diagnosis and results of transsphenoidal microsurgery.

Among 216 consecutive patients with growth hormone secreting pituitary adenomas who underwent primary neurosurgical treatment at the University of Erlangen-Nürnberg, 8 cases of acromegaly with 'normal' basal growth hormone levels (less than or equal to 5 ng/ml) were seen. They all had the typical clinical features of acromegaly, exhibited an abnormal growth hormone secretion following an oral glucose load, and had markedly elevated somatomedin C levels. The GRH- and TRH/GnRH-tests were not found helpful in establishing the diagnosis. Neuroradiology could demonstrate a pituitary adenoma in all of the patients. Following transsphenoidal microsurgical resection of the tumours, growth hormone secretion during oral glucose tolerance testing was normalised in 7 of the 8 patients. Immunohistology and explant culture studies documented growth hormone secreting pituitary adenomas in all cases. The authors conclude that even the finding of repetitive 'normal' (less than or equal to 5 ng/ml) serum GH levels does not exclude active acromegaly and when the clinical diagnosis of acromegaly is suspected, dynamic endocrine testing may reveal abnormal secretion patterns of GH in these cases. Transsphenoidal microsurgical resection of a pituitary adenoma offers a good chance of clinical and endocrinological remission in these cases.     

E‐cadherin expression is associated with somatostatin analogue response in acromegaly

Acromegaly is a rare disease resulting from hypersecretion of growth hormone (GH) and insulin‐like growth factor 1 (IGF1) typically caused by pituitary adenomas, which is associated with increased mortality and morbidity. Somatostatin analogues (SSAs) represent the primary medical therapy for acromegaly and are currently used as first‐line treatment or as second‐line therapy after unsuccessful pituitary surgery. However, a considerable proportion of patients do not adequately respond to SSAs treatment, and therefore, there is an urgent need to identify biomarkers predictors of response to SSAs. The aim of this study was to examine E‐cadherin expression by immunohistochemistry in fifty‐five GH‐producing pituitary tumours and determine the potential association with response to SSAs as well as other clinical and histopathological features. Acromegaly patients with tumours expressing low E‐cadherin levels exhibit a worse response to SSAs. E‐cadherin levels are associated with GH‐producing tumour histological subtypes. Our results indicate that the immunohistochemical detection of E‐cadherin might be useful in categorizing acromegaly patients based on the response to SSAs.     

Homocysteine levels in acromegaly patients

Acromegaly is associated with a two to three-fold increase in mortality related predominantly to cardiovascular disease. The excess mortality is associated most closely with higher levels of growth hormone (GH). Survival in acromegaly may be normalized to a control age-matched rate by controlling GH levels; in particular, GH levels less than 2.5 ng/mL are associated with survival rates equal to those of the general population. Hyperhomocysteinemia has also been recognized as a risk factor for cardiovascular disease, yet there are limited data on the prevalence of hyperhomocysteinemia in patients with acromegaly. Eighteen acromegaly patients (7 male, 11 female, mean age 42.8 +/- 11.0 years) in our endocrine clinic consented to having the following tests performed: complete blood count (CBC), thyroid hormones, folic acid, vitamin B12, plasma homocysteine levels, uric acid, fibrinogen, CRP, fasting glucose, insulin, C-peptide, total serum cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, GH, insulin-like growth factor-1 (IGF-1) and GH levels after an oral glucose tolerance test (OGTT). By history, fourteen had macroadenomas and four had microadenomas; eight had hypertension; two had glucose intolerance, and four had diabetes. Fifteen had had transsphenoidal or transfrontal surgery: two had been cured, but 13 others were taking long-acting octreotide. Five patients had undergone radiotherapy and the acromegaly in two was treated primarily with long-acting octreotide. CBC, thyroid hormone, folic acid, and vit B12 levels were normal in all patients. We divided the patients into two groups according to mean GH levels after an OGTT: Group 1 (GH<2.5 ng/mL, n=10), and Group 2 (GH<2.5 ng/mL, n=8). Comparison of the two groups using Mann-Whitney U testing revealed statistically significant lower levels in Group 1 of the following parameters: GH (1.91 +/- 0.90 vs. 8.58 +/- 5.55 ng/mL, p=0.002), IGF-1 (338.30 +/- 217.90 vs. 509.60 +/- 293.58 ng/dL, p=0.06), GH after an OGTT (1.42 +/- 0.81 vs. 9.01 +/- 4.53 ng/mL, p=0.001), plasma homocysteine (12.85 +/- 4.47 vs. 18.20 +/- 4.99 micromol/L, p=0.05), total cholesterol (164.0 +/- 20.81 vs. 188.0 +/- 22.26 mg/dL, p=0.05) and LDL cholesterol (81.0 +/- 9.64 vs. 116.70 +/- 13.03 mg/dl, p=0.01). Differences between the other parameters were not significantly different. Acromegaly patients with high GH levels after an OGTT have much higher levels of homocysteine than patients with lower GH levels. The role of elevated homocysteine levels as an independent cardiovascular risk factor in the mortality of acromegaly patients should be determined in future studies.     

Management of pituitary tumours: strategy for investigation and follow-up

Investigation of a patient presenting with evidence of a pituitary tumour has three main objectives: investigation of any hormonal hypersecretion; assessment of residual pituitary function, and examination of any mass effect of the tumour. A prolactin-secreting adenoma is often easily diagnosed by performance of a basal prolactin level. Biochemical assessment to exclude acromegaly or Cushing's disease should only be performed if clinically indicated. The standard investigations for acromegaly consist of establishing the degree of growth hormone (GH) suppression following a glucose load and estimating the basal insulin-like growth factor-I level. Before detailed investigation for Cushing's disease is initiated, the presence of Cushing's syndrome must be established. The second requirement is to determine the presence of any pituitary hyposecretion. Whilst the remainder of pituitary function can be assessed by baseline hormonal estimations, the evaluation of ACTH and GH secretion necessitates dynamic function testing. Lastly, the impact of the mass itself requires careful examination. Both neuroradiology, preferably magnetic resonance imaging at a centre specialized in examination of the pituitary fossa, and careful detailed clinical examination of the visual fields should be performed. The follow-up requirements in an individual patient are affected by a number of factors including the size and nature of the underlying tumour and any treatment administered. In patients with a hormone-secreting tumour, the hormone levels themselves provide a 'tumour marker' to aid follow-up. An important caveat, however, is that on some occasions tumour size and hormone levels do not change in parallel. Patients who have undergone pituitary surgery should have dynamic assessment of pituitary function performed approximately 6 weeks after surgery. There is no reason to suspect any further impairment of pituitary function after this date. In direct contrast, pituitary hormone deficiencies after radiotherapy are unlikely less than 6 months after treatment. Patients should undergo testing of pituitary reserve at 6 months, and then at yearly intervals for at least 10 years after radiotherapy, if they have not already developed panhypopituitarism. Even after this period, if patients develop new symptoms the possibility of further pituitary hormone deficits should be considered. Neuroradiology should be performed approximately 6 weeks to 3 months after surgery. If radiotherapy is not administered, neuroradiology should be performed yearly for at least 10 years. If the patient has received radiotherapy, tumour recurrence is much less likely and therefore in these individuals neuroradiology does not need to be performed with such regularity. In conclusion, when planning the investigation and follow-up of an individual patient, one should take into account the size and characteristics of the tumour, as well as the treatment modalities.     

Radiotherapy Versus Radiosurgery in Treating Patients with Acromegaly: A Systematic Review and Meta-Analysis

Objective: When patients with acromegaly have residual disease following surgery, adjuvant radiation therapy is considered. Both stereotactic radiosurgery (SRS) and conventional fractionated radiotherapy (RT) are utilized. We conducted a systematic review and meta-analysis to synthesize the existing evidence and compare outcomes for SRS and RT in patients with acromegaly.Methods: We searched Medline In-Process & Other Non-Indexed Citations, MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Scopus through April 2014 for studies in which SRS or RT were used in patients with acromegaly. Outcomes evaluated were serum insulin-like growth factor-I (IGF-I) and growth hormone (GH) levels, biochemical remission, all-cause mortality, hypopituitarism, headaches, and secondary malignancies. We pooled outcomes using a random-effects model.Results: The final search yielded 30 eligible studies assessing 2,464 patients. Compared to RT, SRS was associated with a nonsignificant increase in remission rate at the latest follow-up period (52% vs. 36%; P = .14) and a significantly lower follow-up IGF-I level (-409.72 μg/L vs. -102 μg/L, P = .002). SRS had a lower incidence of hypopituitarism than RT; however, the difference was not statistically significant (32% vs. 51%, respectively; P = .05).Conclusion: SRS may be associated with better biochemical remission, and it had a lower risk of hypopituitarism with at least 1 deficient axis when compared with RT; however, the confidence in such evidence is very low due to the noncomparative nature of the studies, high heterogeneity, and imprecision.Abbreviations: GH = growth hormone GKRS = gamma-knife radio-surgery IGF-I = insulin-like growth factor-I LINAC = linear accelerator RT = conventional radiotherapy SRS = stereotactic radiosurgery     

The importance of presurgical somatostatin analogue therapy in acromegaly

Different types of treatment, including surgery, medical therapy and radiotherapy, are possible in achieving control of acromegaly. Of the medical therapies available, somatostatin analogues are effective in the majority of patients and can induce pituitary tumour shrinkage. The rationale and outcome of somatostatin analogue treatment before surgery in patients with acromegaly is briefly presented. In summary, the benefits of somatostatin analogues given preoperatively should be considered carefully as optimisation of cardiovascular, respiratory and metabolic functions is clinically relevant for perioperative morbidity. Somatostatin analogues also induce significant shrinkage of GH-secreting pituitary tumours, although this does not seem to be helpful in terms of improved surgical outcome.     

Necessity of Multimodal Treatment of Acromegaly and Outcomes

Objective: Uncontrolled acromegaly is associated with increased morbidity and mortality. Despite multimodal therapeutic options, adequate control can be challenging and lead to prolonged exposure to growth hormone excess. The aim of this study was to assess treatment patterns and outcomes in patients with acromegaly following surgery at a single institution.Methods: A retrospective analysis of response to treatment modalities for patients with a new diagnosis of acromegaly at the Mayo Clinic in Rochester, Minnesota, from 1995–2015.Results: A total of 245 patients with newly diagnosed acromegaly (mean age at diagnosis, 47 ± 14 years; mean follow-up, 5.5 ± 5 years) were evaluated. Primary surgical intervention was performed in 236 patients; 117 (54%) did not achieve remission. Among those with ≥3 months follow-up, 76/217 (35%) patients required three or more forms of treatment. Mean tumor size at diagnosis was 1.6 ± 0.8 cm (80% macroadenomas), and 35% (75/217) had cavernous sinus invasion on pre-operative imaging. The most common second-line treatment was radiation treatment (RT) (50%, 59/117). Among those with persistent disease following surgery, a normal insulin-like growth factor 1 (IGF-1) was achieved in 52% (61/117), with a median time to acromegaly control of 4.5 years. The rate of IGF-1 normalization was 2.1-fold higher in those who received RT compared to those who did not.Conclusion: In patients with persistent acromegaly following surgery, multiple treatment modalities, including RT, may be required to achieve remission. Treatment outcome uncertainty and the need for multiple interventions add to the disease burden associated with persistent acromegaly.Abbreviations: CI = confidence interval; GH = growth hormone; IGF-1 = insulin like growth factor-1; KM = Kaplan-Meier; RT = radiation treatment     

Recurrence following transsphenoidal surgery for acromegaly.

The long-term results of transsphenoidal adenomectomy and the incidence of possible recurrences were studied in 61 patients who had normal basal serum growth hormone (GH) levels 1 week after surgery. The patients were followed up for an average of 6.0 years (range: 1.5-14.0 years) by repeated measurements of GH, oral glucose tolerance testing (OGTT) and at the last follow-up visit also by assaying somatomedin C levels. In 4 of the patients, the basal GH levels had increased to values above 5 ng/ml. In 43 patients, a normal suppression of GH during an oral glucose load was observed shortly after surgery. In only 2 of these cases did a transiently inadequate suppression develop during the follow-up period, although clinical acromegaly did not recur and the somatomedin C levels remained normal. It is concluded that recurrence of active acromegaly is unlikely to occur in patients who achieve a normal glucose-induced suppression of GH levels shortly after adenomectomy. As such, an OGTT provides better prognostic information than basal human GH level measurements and may give a clearer and earlier indication of surgical success.     

Growth-hormone-binding protein in patients with acromegaly.

The present study was undertaken to investigate the possible regulatory effect of chronic exposure to human growth hormone (hGH), in patients with acromegaly, on growth-hormone-binding protein (GH-BP). Nineteen patients with active acromegaly, before, during or after treatment, comprised the subjects of this study. Serum GH was measured by radioimmunoassay and GH-BP by a binding assay with dextran-coated charcoal separation. The specific binding of [125I]hGH (1 ng) obtained with 50 microliters serum was expressed as a percentage of total cpm. To evaluate the impact of the lower GH-BP on GH activity, we studied the effect of acromegalic serum on hGH displacement of [125I]hGH binding to GH receptors in rabbit liver membranes. Compared to normal controls (11.43 +/- 0.37%), the acromegalic patients had low serum levels of GH-BP (5.45 +/- 0.40%; p < 0.001), which correlated negatively with serum GH levels (p < 0.01). In 7 patients, GH-BP normalized within 2-3 months of successful therapy. The lower GH-BP was due to a reduction in binding capacity, whereas binding affinity remained unchanged. Acromegalic serum, with its low GH-BP, resulted in a shift to the left of the GH displacement curve when compared with normal human sera: IC50 values were 7.47 +/- 0.29 and 11.19 +/- 0.84 ng (p < 0.02) for acromegalic and normal human sera, respectively. We conclude that acromegaly is characterized by low levels of GH-BP due to a decrease in serum-binding capacity. The decrease in GH-BP may render the acromegalic serum GH relatively more active in the GH receptor assay.     

Epidemiología de la acromegalia en España

Epidemiology of acromegaly in Spain does not differ from that reported in other published series. Prevalence rate is approximately 60 cases per million, peak incidence occurs in middle age, more women are affected (61%), and there is a substantial delay between occurrence of the first symptoms and diagnosis. Studies REA (Spanish Acromegaly Registry) and OASIS analyzed the epidemiology, clinical characteristics, and management of the disease in Spain. Surgery, performed in more than 80% of patients, has been (and continues to be) the main treatment for the past four decades. In the past decade, however, more patients have received somatostatin analogs (SSAs) as first-line treatment. Use of radiation therapy has significantly decreased in recent decades. Somatostatin analogs (SSAs) are the most commonly used drugs, administered to 85% of patients; however, only 12%-15% continue on drug treatment alone. The surgical remission rate was 38.4% in the last decade, with a significant improvement over decades. Preoperative treatment with SSAs has no influence on surgical cure rates. Second-line therapies used after surgical failure in the past decade included SSAs in 49% of patients, repeat surgery in 27%, radiotherapy in 11%, pegvisomant in 15%, and dopamine agonists in 5%. Mean cost of acromegaly treatment was 9.668€ (data estimated in 2009 and adjusted in 2010), of which 71% was due to the cost of SSAs. Patients treated with pegvisomant have a more aggressive form of the disease and higher comorbidity rates.     

Surgical Reintervention in Acromegaly: is it Still worth trying?

Background and ObjectiveThere has not been a formal evaluation of how frequently and to what extent surgical reintervention in patients with persistently active acromegaly may achieve significant, albeit incomplete, reductions in growth hormone (GH) and insulinlike growth factor-I (IGF-I) levels. Of importance, recent studies suggest that the response to radiotherapy and pharmacotherapy is better with lower degrees of hypersomatotropism. The objective of this study was to evaluate the outcome of surgical reintervention in patients with active acromegaly at our institution between 1995 and 2005.MethodsWe retrospectively evaluated the outcome in 53 patients with active acromegaly (49 with macroadenomas) who underwent a second operation a mean of 24.1 ± 25.2 months after the first intervention. Basal and postglucose GH as well as IGF-I levels were analyzed at diagnosis and after the first and second pituitary procedures.ResultsBasal GH decreased in 38 patients (72%): to < 10 ng/mL in 17 and to < 2.5 ng/mL in 11. The mean IGF- I index and basal GH decreased significantly after surgical reintervention: 1.7 ± 0.4 to 1.4 ± 0.4 (P = .0001) and 13.0 ± 12.8 to 8.3 ± 11.3 ng/mL (P = .0001), respectively. Some decrement in IGF-I was observed after surgical reintervention in 30 patients (57%), being greater than 30% in 9 (17%). Only 5 patients (9%) achieved complete biochemical cure (normal IGF-I and a postglucose GH level of < 1 ng/mL). Reoperation achieved a significant decline in basal and postglucose GH levels as well as in IGF-I index only in patients with noninvasive macroadenomas.ConclusionPituitary surgical reintervention in patients with acromegaly results in a low percentage of biochemical cure. If a remnant of a noninvasive macroadenoma is visible and accessible, however, such a procedure may significantly reduce GH and IGF-I levels. (Endocr Pract. 2009;15:431-437)     

Pegvisomant--growth hormone receptor antagonist in the treatment of acromegaly

INTRODUCTION: Pegvisomant, growth hormone (GH) antagonist is a new perspective in the treatment of acromegaly. Pegvisomant interferes with GH action by competitive binding to receptor and blocking signal transduction. We present first experiences with treatment acromegaly with pegvisomant in Poland. Aim of the study was to assess pegvisomant efficacy in treatment patients with persistent acromegaly after transspheno-ideal surgery and unsatisfactory disease control with somatostatin analogue octreotide (OCTR). MATERIAL AND METHODS: Material consisted of 10 patients (6 M, 4 F) aged 24-48 with active acromegaly, after neurosurgery, in which OCTR was ineffective in disease control. Patients with glucose metabolism disturbances were assigned to group receiving PEG. Controls were matched for age, sex, disease history, GH and IGF-1 levels. Patients received pegvisomant throughout 12 weeks, then combined therapy with PEG and OCTR-LAR was started for 8 weeks and then OCTR-LAR alone was given for next 8 weeks. Controls were medicated with OCTR-LAR 30 mg each 4 weeks during study. Clinical symptoms and IGF-1 level, fasting glucose and HbA(1c) was measured to assess treatment efficacy. RESULTS: Pegvisomant reduced IGF-1 after first week of therapy from 1270+/-229 to 759+/-223 (40%, p<0.04). Prolonged therapy led to further IGF-1 decrease. After 12 weeks of treatment IGF-1 was significantly lower in comparison to initial as well as to controls (604 mg/l vs. 1270 and 1330, respectively, p<0.02). Combined therapy with PEG and OCTR-LAR was not superior to PEG alone. During treatment with pegvisomant improvement of glucose metabolism was seen, as well as decrease in insulin doses required. No adverse events was recorded. CONCLUSIONS: Pegvisomant--GH receptor antagonist--effectively lowers IGF-1 concentration and improves disease control in patients with acromegaly after unsuccessful surgery and with octreotide unresponsiveness. Significantly improves glucose metabolism. Pegvisomant is indicated in patients with active acromegaly after standard treatment failure, especially in cases of coexistent diabetes mellitus.     

Diagnostic value of serum IGF-I and IGFBP-3 in growth hormone disorders in adults

OBJECTIVE: To investigate the diagnostic value of serum insulin-like growth factor-I (IGF-I) and insulin-like growth factor-binding protein-3 (IGFBP-3) measurements in adult patients with acromegaly and GH deficiency (GHD). METHODS: Serum IGF-I and IGFBP-3 levels were measured in 39 active acromegalic patients, 34 adult patients with GHD and 150 healthy adults. Disease activity in patients with acromegaly was confirmed by nadir GH levels during an oral glucose tolerance test (OGTT). Among patients with acromegaly, 15 had not been treated previously and 24 had been treated but not cured. GHD in adults was diagnosed by an insulin tolerance test (ITT). Among patients with GHD, 15 were aged 20-40 years (9 men and 6 women) and 19 were aged over 40 years (9 men and 10 women). One hundred and fifty healthy subjects were recruited as a control group. To compare the individual serum IGF-I and IGFBP-3 levels of patients with the results of the gold standard, we calculated age- and sex-corrected standard deviation scores (SDS) for individual IGF-I and IGFBP-3 levels. The sensitivities of serum IGF-I and IGFBP-3 measurements for the disease diagnosis were analyzed using the mean +/- 2 SD of the values of healthy control subjects as a diagnostic cutoff, defining 95% specificity. RESULTS: The mean IGF-I and IGFBP-3 SDS levels were significantly higher in active acromegalic patients, both untreated and treated but not cured, than in the control subjects (p < 0.05). The sensitivities of serum IGF-I and IGFBP-3 measurements for the diagnosis of acromegaly were 97.4 and 81.8%, respectively. In untreated patients with acromegaly, the sensitivities of serum IGF-I and IGFBP-3 measurements for the diagnosis of disease were 100 and 100%, while these were 95.8 and 72.7% in treated patients with acromegaly. In adult patients with GHD, the mean IGF-I and IGFBP-3 SDS were significantly lower than those of the control subjects (IGF-I, -2.2 +/- 0.8 vs. 0.0 +/- 1.0 SDS, p < 0.0001); IGFBP-3, -1.7 +/- 1.2 vs. 0.0 +/- 1.0 SDS, p < 0.0001), but there was a considerable overlap between GHD in adults and the controls. In all patients with GHD, the sensitivities of serum IGF-I and IGFBP-3 measurements were 64.7 and 52.9%, respectively. In the group of women aged 20-40 years, the sensitivity of IGF-I measurement for the diagnosis of GHD was 100%, although the number of patients was only 6. CONCLUSION: Both serum IGF-I and IGFBP-3 measurements are comparable to an oral glucose tolerance test in patients with untreated acromegaly, but in acromegalic patients that have undergone surgery and/or radiotherapy, serum IGF-I is more valuable for determining disease activity than serum IGFBP-3. Serum IGF-I and IGFBP-3 measurements are not valuable for the diagnosis of GHD in adults, but in women aged 20-40 years serum IGF-I measurement appears to be useful in the diagnosis of GHD.