Somatostatin Analogs In Acromegaly Research Articles

Evaluation of 68Ga-DOTATATE uptake at the pituitary region and the biochemical response to somatostatin analogs in acromegaly

Acromegaly is associated with many comorbidities and increased mortality. The first-line treatment is transsphenoidal surgery. However, many patients also need adjuvant drug treatment after surgery. Somatostatin analog (SSA), which suppresses GH secretion by somatotrophs by binding to the SSTR2 receptor, is the first choice. Nevertheless, 50% of patients are partially or totally resistant to SSA, so predictive factors of response are helpful to individualize drug treatment. 68GaDOTATATE PET/CT has emerged as the gold-standard method in the diagnosis and follow-up of gastroenteropancreatic neuroendocrine tumors, which also express SSTR. Our objective was to evaluate whether 68Ga-DOTATATE uptake (SUV max) at the pituitary region of patients on SSA therapy would be useful as a drug response predictor without the need of tumoral tissue. Fifteen acromegalics patients on SSA treatment for at least 6months were underwent to 68Ga-DOTATATE PET/CT at the nuclear medicine service. There was an SSA complete response group (n = 5), defined as GH < 1µg/L and IFG-1 in the normal range for gender and age, and a group that did not meet these criteria (n = 10). As a result, we did not find out a significantly higher SUV max in the complete response group (p = 0.0576) to SSA. However, we found a significant inverse relationship between postoperative GH values and the SUVmax at the sella turcica (p = 0.0188), probably reflecting tumor SSTR2 expression. Thus, after this initial evaluation, 68GaDOTATATE PET/CT should be better studied to assess its usefulness in the follow-up of acromegalic patients.

To optimize the acute octreotide suppression test in predicting the efficacy of long acting somatostatin analogues in acromegaly

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

Medical Treatment with Somatostatin Analogues in Acromegaly: Position Statement

Acromegaly is a chronic disorder caused by excessive growth hormone (GH) secretion. In most cases, the excess GH originates from GH-producing pituitary adenomas. Surgery is the preferred first-line treatment for patients with acromegaly, but medical man-agement is considered when the disease persists after surgery or in cases where patients refuse surgery or are poor candidates for surgery. Somatostatin analogues are commonly used to treat acromegaly. The Korean Endocrine Society and the Korean Neuroendocrine Study Group have developed a position statement for the use of somatostatin analogues in the medical treatment of acromegaly. This position statement is based on evidence from the current literature and expert opinions. In the case of discrep-ancies among expert opinions, the experts voted to determine the recommended approach. (Korean J Med 2019;94:485-494)

Medical Treatment with Somatostatin Analogues in Acromegaly: Position Statement.

The Korean Endocrine Society (KES) published clinical practice guidelines for the treatment of acromegaly in 2011. Since then, the number of acromegaly cases, publications on studies addressing medical treatment of acromegaly, and demands for improvements in insurance coverage have been dramatically increasing. In 2017, the KES Committee of Health Insurance decided to publish a position statement regarding the use of somatostatin analogues in acromegaly. Accordingly, consensus opinions for the position statement were collected after intensive review of the relevant literature and discussions among experts affiliated with the KES, and the Korean Neuroendocrine Study Group. This position statement includes the characteristics, indications, dose, interval (including extended dose interval in case of lanreotide autogel), switching and preoperative use of somatostatin analogues in medical treatment of acromegaly. The recommended approach is based on the expert opinions in case of insufficient clinical evidence, and where discrepancies among the expert opinions were found, the experts voted to determine the recommended approach.

Predicting response to somatostatin analogues in acromegaly: machine learning-based high-dimensional quantitative texture analysis on T2-weighted MRI.

To investigate the value of machine learning (ML)-based high-dimensional quantitative texture analysis (qTA) on T2-weighted magnetic resonance imaging (MRI) in predicting response to somatostatin analogues (SA) in acromegaly patients with growth hormone (GH)-secreting pituitary macroadenoma, and to compare the qTA with quantitative and qualitative T2-weighted relative signal intensity (rSI) and immunohistochemical evaluation. Forty-seven patients (24 responsive; 23 resistant patients to SA) were eligible for this retrospective study. Coronal T2-weighted images were used for qTA and rSI evaluation. The immunohistochemical evaluation was based on the granulation pattern of the adenomas. Dimension reduction was carried out by reproducibility analysis and wrapper-based algorithm. ML classifiers were k-nearest neighbours (k-NN) and C4.5 algorithm. The reference standard was the biochemical response status. Predictive performance of qTA was compared with those of the quantitative and qualitative rSI and immunohistochemical evaluation. Five hundred thirty-five out of 828 texture features had excellent reproducibility. For the qTA, k-NN correctly classified 85.1% of the macroadenomas regarding response to SAs with an area under the receiver operating characteristic curve (AUC-ROC) of 0.847. The accuracy and AUC-ROC ranges of the other methods were 57.4-70.2% and 0.575-0.704, respectively. Differences in predictive performance between qTA-based classification and the other methods were significant (p < 0.05). The ML-based qTA of T2-weighted MRI is a potential non-invasive tool in predicting response to SAs in patients with acromegaly and GH-secreting pituitary macroadenoma. The method performed better than the qualitative and quantitative rSI and immunohistochemical evaluation. • Machine learning-based texture analysis of T2-weighted MRI can correctly classify response to somatostatin analogues in more than four fifths of the patients. • Machine learning-based texture analysis performs better than qualitative and quantitative evaluation of relative T2 signal intensity and immunohistochemical evaluation. • About one third of the texture features may not be excellently reproducible, indicating that a reliability analysis is necessary before model development.

Pre-surgical medical treatment, a major prognostic factor for long-term remission in acromegaly.

To determine whether pre-surgical medical treatment (PSMT) using long-acting Somatostatin analogues in acromegaly may improve long-term surgical outcome and to determine decision making criteria. This retrospective study included 110 consecutive patients newly diagnosed with acromegaly, who underwent surgery in a reference center (Marseille, France). The mean long-term follow-up period was 51.4 ± 36.5 (median 39.4) months. Sixty-four patients received PSMT during 3-18 (median 5) months before pituitary surgery. Remission was defined at early (3 months) evaluation and at last follow-up by GH nadir after oral glucose tolerance test < 0.4µg/L and normal IGF-1. Pretreated and non-pretreated groups were comparable for the main confounding factors except for higher IGF-1at diagnosis in PSMT patients. Remission rates were significantly different in pretreated or not pretreated groups (61.1% vs. 36.6%, respectively at long-term evaluation). In multivariate analysis, PSMT was significantly linked to 3 months (p < 0.01) and long-term remission (p < 0.01). Duration of PSMT was not significantly different in cured or non-cured patients, at both evaluation times. PSMT appeared to be more beneficial for patients with an invasive tumor. No patient with a tumor greater than 18mm or mean GH level exceeding 35ng/mL at diagnosis was cured by surgery alone (vs. 8 and 9 patients in the pretreated group, respectively). Patients with PSMT showed more transient mild hyponatremia after surgery. PSMT significantly improved short and long-term remission in patients with acromegaly, independent of its duration, especially in invasive adenomas.

Association between dopamine and somatostatin receptor expression and pharmacological response to somatostatin analogues in acromegaly.

Acromegaly is a hormonal disorder resulting from excessive growth hormone (GH) secretion frequently produced by pituitary adenomas and consequent increase in insulin‐like growth factor 1 (IGF‐I). Elevated GH and IGF‐I levels result in a wide range of somatic, cardiovascular, endocrine, metabolic and gastrointestinal morbidities. Somatostatin analogues (SSAs) form the basis of medical therapy for acromegaly and are currently used as first‐line treatment or as second‐line therapy in patients undergoing unsuccessful surgery. However, a considerable percentage of patients do not respond to SSAs treatment. Somatostatin receptors (SSTR1‐5) and dopamine receptors (DRD1‐5) subtypes play critical roles in the regulation of hormone secretion. These receptors are considered important pharmacological targets to inhibit hormone oversecretion. It has been proposed that decreased expression of SSTRs may be associated with poor response to SSAs. Here, we systematically examine SSTRs and DRDs expression in human somatotroph adenomas by quantitative PCR. We observed an association between the response to SSAs treatment and DRD4, DRD5, SSTR1 and SSTR2 expression. We also examined SSTR expression by immunohistochemistry and found that the immunohistochemical detection of SSTR2 in particular might be a good predictor of response to SSAs.

Hormone and tumor responses to primary or pre-operative therapy with somatostatin analogs in acromegaly and the relation with T2-weighted MRI signal

Hormone and tumor responses to primary or pre-operative therapy with somatostatin analogs in acromegaly and the relation with T2-weighted MRI signal

T2-weighted MRI signal and response to somatostatin analogs in acromegaly

T2-weighted MRI signal and response to somatostatin analogs in acromegaly

Somatostatin analogues in acromegaly and gastroenteropancreatic neuroendocrine tumours: past, present and future.

Acromegaly is a hormonal disorder that arises when the pituitary gland secretes excess growth hormone (GH), which in turn stimulates a concomitant increase in serum insulin-like growth factor 1 (IGF-1) levels. Gastroenteropancreatic neuroendocrine tumours (GEP-NET) constitute a heterogeneous group of tumours that can secrete serotonin and a variety of peptide hormones that may cause characteristic symptoms known as carcinoid syndrome or other symptoms and hormonal hypersecretion syndromes depending on the tumour's site of origin. Current medical therapy for the treatment of acromegaly and GEP-NET involves the administration of somatostatin analogues that effectively suppress excess hormone secretion. After its discovery in 1979, octreotide became the first synthetic biologically stable somatostatin analogue with a short-acting formulation of octreotide introduced into clinical practice in the late 1980s. Lanreotide, another somatostatin analogue, became available in the mid-1990s initially as a prolonged-release formulation administered every 10 or 14 days. Long-acting release formulations of both octreotide (Sandostatin LAR and Novartis) and lanreotide (Somatuline Autogel, Ipsen), based on microparticle and nanoparticle drug-delivery technologies, respectively, were later developed, which allowed for once-monthly administration and improved convenience. First-generation somatostatin analogues remain one of the cornerstones of medical therapy in the management of pituitary and GEP-NET hormone hypersecretion, with octreotide having the longest established efficacy and safety profile of the somatostatin analogue class. More recently, pasireotide (Signifor), a next-generation multireceptor-targeted somatostatin analogue, has emerged as an alternative therapeutic option for the treatment of acromegaly. This review summarizes the development and clinical success of somatostatin analogues.

Predictive value of T2 relative signal intensity for response to somatostatin analogs in newly diagnosed acromegaly.

The difficulty of predicting the efficacy of somatostatin analogs (SSA) is not fully resolved. Here, we quantitatively evaluated the predictive value of relative signal intensity (rSI) on T1- and T2-weighted magnetic resonance imaging (MRI) for the short-term efficacy (3months) of SSA therapy in patients with active acromegaly and assessed the correlation between MRI rSI and expression of somatostatin receptors (SSTR). This was a retrospective review of prospectively recorded data. Ninety-two newly diagnosed patients (37 males and 55 females) with active acromegaly were recruited. All patients were treated with pre-surgical SSA, followed by reassessment and transspenoidal surgery. rSI values were generated by calculating the ratio of SI in the tumor to the SI of normal frontal white matter. The Youden indices were calculated to determine the optimal cutoff of rSI to determine the efficacy of SSA. The correlation between rSI and expression of SSTR2/5 was analyzed by the Spearman rank correlation coefficient. T2 rSI was strongly correlated with biochemical sensitivity to SSA. The cutoff value of T2 rSI to distinguish biochemical sensitivity was 1.205, with a positive predictive value (PPV) of 81.5% and a negative predictive value (NPV) of 77.3%. No correlation was found between MRI and tumor size sensitivity. Moreover, T2 rSI was negatively correlated with the expression of SSTR5. T2 rSI correlates with the expression of SSTR5 and quantitatively predicts the biochemical efficacy of SSA in acromegaly.

Pros and cons in endocrine practice: pre-surgical treatment with somatostatin analogues in acromegaly.

The aim of this commentary is to balance the pros and cons for pre-surgical SSA treatment in a modern perspective ending up with a pragmatic recommendation for treatment based on the current evidence and expertise of the authors. Even though prospective and randomized studies in this particular area are hampered by obvious limitations, the interpretation of the four published trials has in general been in favor of pre-treatment with SSA, showing a better outcome following surgery. However, major drawbacks of these studies, such as non-optimal diagnostic criteria for cure, potential selection bias, and timing of the postoperative evaluation in SSA pre-treated patients, limit their overall interpretation. Three matched-controlled studies showed remarkably similar results with no apparent beneficial effect of SSA pre-treatment on surgical outcome. Both prospective, randomized studies and retrospective studies did not find any significant difference in the rate of endocrine and non-endocrine complications related to surgery, despite the beneficial clinical effects of SSA treatment in most acromegalic patients. The newly diagnosed patient with acromegaly should be carefully evaluated in the trans-disciplinary neuroendocrine team and treatment individualized accordingly. The issue of SSA pre-treatment to improve surgical outcome is yet to be settled and further methodologically sound studies are probably necessary to clarify this point.

Interpreting biochemical control response rates with first-generation somatostatin analogues in acromegaly.

ContextThe somatostatin analogues octreotide LAR and lanreotide Autogel have been evaluated for the treatment of acromegaly in numerous clinical trials, with considerable heterogeneity in reported biochemical response rates. This review examines and attempts to account for these differences in response rates reported in the literature.Evidence acquisitionPubMed was searched for English-language studies of a minimum duration of 24 weeks that evaluated ≥10 patients with acromegaly treated with octreotide LAR or lanreotide Autogel from 1990 to March 2015 and reported GH and/or IGF-1 data as the primary objective of the study.Evidence synthesisOf the 190 clinical trials found, 18 octreotide LAR and 15 lanreotide Autogel studies fulfilled the criteria for analysis. It is evident from the protocols of these studies that multiple factors are capable of impacting on reported response rates. Prospective studies reporting an intention-to-treat analysis that evaluated medically naïve patients and used the composite endpoint of both GH and IGF-1 control were associated with lower response rates. The use of non-composite biochemical control endpoints, heterogeneous patient populations, analyses that exclude treatment non-responders, assay variability and prior responsiveness to medical therapy are just a few of the factors identified that likely contribute to higher success rates.ConclusionsThe wide range of reported response rates with somatostatin analogues may be confusing and could lead to misinterpretation by both the patient and the physician in certain situations. Understanding the factors that potentially drive the variation in response rates should allow clinicians to better gauge treatment expectations in specific patients.

Pegvisomant in combination with long-acting somatostatin analogues in acromegaly: the role of the GH receptor deletion of exon 3.

Doses of the GH receptor (GHR) antagonist pegvisomant (PEGV) that normalize insulin-like growth factor 1 (IGF1) levels vary widely among acromegaly patients. Predictors for PEGV response are baseline IGF1 levels, sex, body weight and previous radiotherapy. A GHR polymorphism lacking exon 3 (d3-GHR) is frequent in the general population. The influence of d3-GHR on PEGV responsiveness in acromegaly is unclear. To assess the influence of d3-GHR on IGF1 levels and PEGV responsiveness in acromegaly patients using combined PEGV and long-acting somatostatin receptor ligand (LA-SRIF) treatment. Data were collected at the Rotterdam Pituitary Centre between 2004 and 2013. Patients with elevated IGF1 levels (>1.2 upper limit of normal; n=112) and over 6 months of high-dose LA-SRIF treatment were co-treated with PEGV. GHR genotype was assessed using genomic DNA in 104 patients. D3-GHR was observed in 51 (49.0%) of the patients (7.7% homozygous, 41.3% heterozygous) and was in Hardy-Weinberg equilibrium (P=0.859). Baseline characteristics were similar in d3-GHR and full-length (fl)-GHR genotypes. During PEGV/LA-SRIF treatment IGF1 levels were not different between d3-carriers and non-carriers. Similarly, no difference in PEGV dose required to normalize IGF1 (P=0.337) or PEGV serum levels (P=0.433) was observed between the two groups. However, adenoma size decreased significantly (>20% of largest diameter) in 25.6% of the fl-GHR genotype but only in 7.5% of d3-carriers (P=0.034, OR: 4.6 (CI: 1.1-18.9)). GHR genotype does not predict the IGF1 normalizing dose of PEGV in acromegaly patients using combination PEGV/LA-SRIF treatment. However, fewer d3-carriers showed significant reductions in adenoma size.

Topoisomerase IIα as a prognostic factor in pituitary tumors.

There is an ongoing search for markers of pituitary tumor proliferation and progression that could facilitate further treatment and patient monitoring. We studied topoisomerase IIα (topo IIα) expression in different types of pituitary adenomas to evaluate its prognostic value. In a retrospective study of 60 patients (mean age, 46.7 ±17.6 y) who underwent pituitary tumor surgery, expression of topo IIα was assessed by immunohistochemistry and compared with histopathological tumor features, clinical symptoms, magnetic resonance imaging, and postoperative tumor recurrence or progression. Expression of topo IIα was observed in 44 of 60 pituitary adenomas (73%). The highest topo IIα index was observed in adrenocorticotropic hormone (ACTH)-secreting tumors (median, 1.13% [0.37-1.21]), followed by silent-ACTH tumors (0.94% [0.89-1.0]), and hormone immunonegative adenomas (0.8% [0.65-1.55]). There were no differences in topo IIα expression with respect to age or sex. Significant correlations were observed between the topo IIα index and tumor size, its invasiveness, abnormal ocular test results, and postoperative tumor recurrence. In patients with a topo IIα index exceeding 1%, we observed a 3.5-fold higher relative risk of tumor recurrence as compared with patients with a topo IIα index lower than 1% (95% confidence interval: 1.8-6.9; P <0.001). Patients with acromegaly who received somatostatin analogues before the surgery had a lower median topo IIα index compared with untreated patients (0%[0-0.22] vs. 0.71% [0.17-1.0]; P <0.05). In our study group, a topo IIα index exceeding 1% was a prognostic factor for tumor recurrence or progression, especially in patients with hormonally inactive adenomas, which facilitates patient selection for intensive postoperative treatment. Use of somatostatin analogues in acromegaly inhibits topo IIα expression, providing molecular evidence for the effectiveness of these analogues.

Short-term (3 months) compared to long-term response to somatostatin analogues in acromegaly

METHOD: A retrospective review of 71 patients with acromegaly admitted in the Department of Neuroendocrinology, “C.I. Parhon” Institute, Bucharest (2006 – 2012) and treated for at least 6 months with SSA according to the Protocol of the Romanian National House of Health Insurance for patients with acromegaly. In 40 of them data on random serum GH and IGF-1 were available at baseline, after 3 months and at the last evaluation on the same SSA dose. Two patients have been evaluated on 2 different doses of SSA. In the other 31 patients not included in this study, the dosage has been either increased after 3 months – in 21 patients, or evaluated after > 3 months – in 10 patients).

Immunoreactivity Score Using an Anti-sst2A Receptor Monoclonal Antibody Strongly Predicts the Biochemical Response to Adjuvant Treatment with Somatostatin Analogs in Acromegaly

Somatostatin receptor subtype 2 (sst2A) protein expression has been demonstrated to positively correlate with somatostatin analog treatment outcome in GH-secreting adenomas. Recently, a new rabbit monoclonal anti-sst2A antibody (clone UMB-1) has been validated as a reliable method to selectively detect sst2A protein levels in formalin-fixed tissues. The aim of the study was to establish whether the evaluation of sst2A protein levels, assessed with a routine reproducible immunohistochemistry protocol using UMB-1 antibody, may predict the successful adjuvant therapy with somatostatin analogs in acromegalic patients. Thirty-six acromegalic patients from our referral hospital were evaluated retrospectively. Sst2A expression analysis was performed by immunohistochemistry in 25 patients and by quantitative RT-PCR in 26 patients. Sst2A immunoreactivity was evaluated using an immunoreactivity score (IRS), which takes into account both the percentage of positive cells and staining intensity. Patients with persistent disease after surgery (n = 26) were treated with somatostatin analogs for a median duration of 6 months. GH and IGF-I levels were measured before and after postoperative treatment. Sst2A IRS showed a significant positive correlation with both GH (P = 0.039) and IGF-I (P = 0.001) suppression by octreotide. Sst2A IRS was negatively associated with IGF-I levels reached after treatment (P = 0.001), and patients that achieved IGF-I normalization showed significantly higher sst2A IRS compared to the group that was not normalized (P = 0.002). A sst2A IRS of at least 5 showed a sensitivity of 86% and a specificity of 91% in predicting IGF-I normalization during adjuvant octreotide treatment. Sst2A IRS with the anti-sst2A antibody UMB-1 represents a valid tool in the clinical practice to identify acromegalic patients likely to be responders to adjuvant therapy with the currently available somatostatin analogs.

Acromegaly

British Journal of Hospital MedicineVol. 73, No. Sup8 What you Need to Know AboutAcromegalyAhmed Yousseif, Efthimia Karra, Stephanie E BaldewegAhmed YousseifSearch for more papers by this author, Efthimia KarraSearch for more papers by this author, Stephanie E BaldewegSearch for more papers by this authorAhmed Yousseif; Efthimia Karra; Stephanie E BaldewegPublished Online:16 Aug 2013https://doi.org/10.12968/hmed.2012.73.Sup8.C119AboutSectionsView articleView Full TextPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareShare onFacebookTwitterLinked InEmail View article References Ahmed S, Elsheikh M, Stratton IM, Page RC, Adams CB, Wass JA (1999) Outcome of transphenoidal surgery for acromegaly and its relationship to surgical experience. Clin Endocrinol (Oxf) 50: 561–7 Crossref, Medline, Google Scholar Biermasz NR, Pereira AM, Smit JW, Romijn JA, Roelfsema F (2005) Morbidity after long-term remission for acromegaly: persisting joint-related complaints cause reduced quality of life. J Clin Endocrinol Metab 90: 2731–9 Crossref, Medline, Google Scholar Colao A, Pivonello R, Auriemma RS et al. (2006) Predictors of tumor shrinkage after primary therapy with somatostatin analogs in acromegaly: a prospective study in 99 patients. J Clin Endocrinol Metab 91: 2112–18 Crossref, Medline, Google Scholar Drange MR, Fram NR, Herman-Bonert V, Melmed S (2000) Pituitary tumor registry: a novel clinical resource. J Clin Endocrinol Metab 85: 168–74 Medline, Google Scholar Giustina A, Barkan A, Casanueva FF et al. (2000) Criteria for cure of acromegaly: a consensus statement. J Clin Endocrinol Metab 85: 526–9 Medline, Google Scholar Holdaway IM, Rajasoorya C (1999) Epidemiology of acromegaly. Pituitary 2: 29–41 Crossref, Medline, Google Scholar Holdaway IM, Rajasoorya RC, Gamble GD (2004) Factors influencing mortality in acromegaly. J Clin Endocrinol Metab 89: 667–74 Crossref, Medline, Google Scholar Iranmanesh A, Grisso B, Veldhuis JD (1994) Low basal and persistent pulsatile growth hormone secretion are revealed in normal and hyposomatotropic men studied with a new ultrasensitive chemiluminescence assay. J Clin Endocrinol Metab 78: 526–35 Medline, Google Scholar Jenkins PJ, Bates P, Carson MN, Stewart PM, Wass JA (2006) Conventional pituitary irradiation is effective in lowering serum growth hormone and insulin-like growth factor-I in patients with acromegaly. J Clin Endocrinol Metab 91: 1239–45 Crossref, Medline, Google Scholar Lieberman SA, Bjorkengren AG, Hoffman AR (1992) Rheumatologic and skeletal changes in acromegaly. Endocrinol Metab Clin North Am 21: 615–31 Medline, Google Scholar Manjila S, Wu OC, Khan FR, Khan MM, Arafah BM, Selman WR (2010) Pharmacological management of acromegaly: a current perspective. Neurosurg Focus 29: E14 Crossref, Medline, Google Scholar Melmed S (2006) Medical progress: acromegaly. N Engl J Med 355: 2558–73 Crossref, Medline, Google Scholar Minniti G, Traish D, Ashley S, Gonsalves A, Brada M (2005) Risk of second brain tumor after conservative surgery and radiotherapy for pituitary adenoma: update after an additional 10 years. J Clin Endocrinol Metab 90: 800–4 Crossref, Medline, Google Scholar Murray RD, Melmed S (2008) A critical analysis of clinically available somatostatin analog formulations for therapy of acromegaly. J Clin Endocrinol Metab 93: 2957–68 Crossref, Medline, Google Scholar Rajasoorya C, Holdaway IM, Wrightson P, Scott DJ, Ibbertson HK (1994) Determinants of clinical outcome and survival in acromegaly. Clin Endocrinol (Oxf) 41: 95–102 Crossref, Medline, Google Scholar Reddy R, Hope S, Wass J (2010) Acromegaly. BMJ 341: C4189 Crossref, Medline, Google Scholar Renehan AG, Shalet SM (2002) Acromegaly and colorectal cancer: risk assessment should be based on population-based studies. J Clin Endocrinol Metab 87: 1909 Medline, Google Scholar Rosenow F, Reuter S, Deuss U, Szelies B, Hilgers RD, Winkelmann W, Heiss WD (1996) Sleep apnoea in treated acromegaly: relative frequency and predisposing factors. Clin Endocrinol (Oxf) 45: 563–9 Crossref, Medline, Google Scholar FiguresReferencesRelatedDetails 1 August 2012Volume 73Issue Sup8ISSN (print): 1750-8460ISSN (online): 1759-7390 Metrics History Published online 16 August 2013 Published in print 1 August 2012 Information© MA Healthcare LimitedPDF download

Effects of chronic slow release-lanreotide treatment on insulin-like growth factor system and metabolic parameters in acromegalic patients.

Insulin and IGF binding protein (IGFBP)-1 are linked by negative association. Somatostatin (SS) reduces insulin secretion by acting on pancreatic β-cell and also by decreasing GH secretion. SS analogues in acromegaly reduce total IGF-I levels inhibiting GH hypersecretion, but they also reduce free IGF-I bioactivity increasing IGFBP-1 levels by inducing insulin decrease. In 13 acromegalic patients we studied GH, IGF system, insulin, and glucagon levels at baseline and at 7 days, 1 and 6 months under treatment with slow release (SR)-lanreotide (LAN) (60 mg im monthly). The hormonal and metabolic response to arginine (ARG) (0.5 g/kg iv in 30 min) was also studied at each time point. LAN decreased GH, total IGF-I, and IGFBP-3 levels at each time point. Insulin and glucagon levels were reduced, while IGFBP-1 and free IGF-I levels were increased by LAN at day 7 and after 1 month only. LAN did not modify the GH, insulin, glucagon, glucose, and IGFBP-1 responses to ARG. At each time point ARG-induced insulin increase was coupled to increase in glucagon and IGFBP-1 levels. This study shows that acromegalic patients under chronic treatment with LAN display: a) inhibition of GH and total IGF-I levels, not coupled to persistent decrease in free IGF-I levels; b) persistent decrease in IGFBP- 3 but transient decrease and increase in insulin and IGFBP- 1, respectively; c) unchanged hormonal and metabolic response to ARG. Our findings also show that ARG stimulates IGFBP-1 despite marked increase in insulin secretion; this escape from the negative relationship linking insulin and IGFBP- 1 would likely reflect the ARG-induced glucagon increase.

Resistance to Somatostatin Analogs in Acromegaly

Somatostatin analogs (SA) are widely used in acromegaly, either as first-line or adjuvant treatment after surgery. First-line treatment with these drugs is generally used in the patients with macroadenomas or in those with clinical conditions so severe as to prevent unsafe reactions during anesthesia. Generally, the response to SA takes into account both control of GH and IGF-I excess, with consequent improvement of clinical symptoms directly related to GH and IGF-I excess, and tumor shrinkage. This latter effect is more prominent in the patients treated first-line and bearing large macroadenomas, but it is also observed in patients with microadenomas, even with little clinical implication. Predictors of response are patients' gender, age, initial GH and IGF-I levels, and tumor mass, as well as adequate expression of somatostatin receptor types 2 and 5, those with the highest affinity for octreotide and lanreotide. Only sporadic cases of somatostatin receptor gene mutation or impaired signaling pathways have been described in GH-secreting tumors so far. The response to SA also depends on treatment duration and dosage of the drug used, so that a definition of resistance based on short-term treatments using low doses of long-acting SA is limited. Current data suggest that response to these drugs is better analyzed taking together biochemical and tumoral effects because only the absence of both responses might be considered as a poor response or resistance. This latter evidence seems to occur in 25% of treated patients after 12 months of currently available long-acting SA.