Pegvisomant Treatment in Acromegaly.

Neuroendocrinology (DOI:10.1159/000381644)

(Accepted, unedited article not yet assigned to an issue)

© 2015 S. Karger AG, Basel www.karger.com/nen

Advanced Release: March 19, 2015

Received: January 15, 2015 Accepted after revision: March 4, 2015

Pegvisomant treatment in Acromegaly Sebastian J.C.M.M. Neggers1, A. Muhammad, A.J. van der Lely1.

Department of Medicine, section Endocrinology, Erasmus University Medical Centre, Rotterdam, the Netherlands. 1Pituitary center Rotterdam, Erasmus University Medical Centre, Rotterdam, The Netherlands.

SN received research grants and speakers fees from Ipsen and Pfizer. AvdL consultant and received speakers fees from Novartis, Ipsen and Pfizer AM has nothing to disclose. Abstract: 115 words Main text: 2910 words Tables/Figures:0/0 Corresponding author: S.J.C.M.M. Neggers MD, PhD Department Medicine, Endocrinology section Erasmus University Medical Center PO Box 2040 3000 CA Rotterdam, The Netherlands, Phone: +31 10 703 3881 Fax: +31 10 7036801 Email: [email protected] Abstract Historically medical treatment of acromegaly has mainly used as adjuvant after surgery. In the last decades, an increase range of medical therapy options was available. Somatostatin analogues became the cornerstone of medical treatment in acromegaly and are even seen as primary treatment in a selected group of acromegaly subjects. The most recent medical antagonist. To date it is the most effective medical treatment, but it is costly. Pegvisomant is used as monotherapy and combined with somatostatin analogues. In this article we review

Downloaded by: University of Tokyo 157.82.153.40 - 5/29/2015 5:13:39 PM

treatment available for acromegaly patients is pegvisomant, a growth hormone receptor


© 2015 S. Karger AG, Basel

2

clinical studies and cohorts that have documented the efficacy of pegvisomant monotherapy and combined and give a concise view on side effects.

Introduction More than 90% of patients, a benign growth hormone-secreting pituitary adenoma is the cause of acromegaly (1). The increased secreted growth hormone (GH) and insulin-like growth factor 1 (IGF-I) levels cause signs and symptoms of somatic overgrowth. Treatment objectives of active acromegaly are threefold: Management of GH hypersecretion in order to control the hypersecretion of IGF-I, control of tumour size and optimize quality of life (QoL) and this all should be achieved with a minimum of adverse effects. The rationale behind the stringent criteria of biochemical control is the elevated overall standardized mortality rate (SMR) that is approximately two times higher than the general population (2, 3). Elevated GH and IGF-I are associated with this increased SMR (2, 3). When GH is 90%, using the lowest IGF-I levels during treatment. Nevertheless, normalization of IGF-I by PEG-V combined with LA-SRIF analogues showed efficacy rates between 78% and 90% (1.0 ULN and 90% of patients (10). Combined with LA-SRIF analogues, the



4

1288 patients of which 1/3 of the patients received a form of combined treatment showed an efficacy of around 63% with a weekly dose of 126 mg and 140 mg for controlled and uncontrolled, respectively (15). Combined treatment in ACROSTUDY consisted of PEG-V with LA-SRIF in 23%, with dopamine agonist in 6%, and a combination of the 3 agents in 4% of patients included (15). During the lanreotide autogel co-administration study some patients used PEG-V monotherapy before study entry (19). A PEG-V dose reduction of about 50% was observed in these patients (19) when PEG-V was combined with lanreotide. The magnitude of the dose reduction can differ between individuals (23). In 2 patients PEG-V monotherapy was converted from daily PEG-V to a weekly dose combined with LA-SRIF analogues (23). With persistent control of IGF-I, a dose reduction of 80 to 150 mg could be achieved. An attempt to directly compare PEG-V efficacy during monotherapy with combined treatment did not result in significant differences between the 2 modalities (24). The study, however, did not achieve an optimal dose titration due to problems with the IGF-I assay, as IGF-I was used to optimize dosage (24). Finally, the study was designed to assess differences in efficacy and not difference in doses between the combined use with LA-SRIF and PEG-V monotherapy (24). Recently, some reports on different dose requirements in specific groups of patients and during long-term treatment were published. Dose requirements to achieve control of IGF-I seem to be higher in diabetic vs. non-diabetic subjects (25). A Spanish study reported that PEG-V showed an efficacy of > 90%, but patients needed a dose escalation to maintain this high efficacy (13). However, during combined treatment none of these differences in dose requirements could be observed in the Rotterdam cohort (4). In the initial study on the effects of combined treatment, subjects started with 20 mg PEG-V weekly and this dose was increased stepwise with a weekly dose increase of 20 mg (20). PEG-V starting dose was based upon baseline IGF-I levels, during LA-SRIF analogue treatment but never exceeded 80 mg as a single administration (4). Combined or not, PEG-V has a very high efficacy and when combined the necessary dose of PEG-V was lower than during monotherapy. This suggests that in a number of patients the combination therapy is less expensive than treatment with PEG-V alone (4).

Why is the necessary dose of pegvisomant lower when combined with somatostatin

One of the explanations for the decrease in PEG-V dose is the 20% increase in PEG-V serum levels during combination treatment with LA-SRIF compared to identical dosing during


analogues?



5

monotherapy (26, 27). The efficacy of PEG-V, a competitive blocker of the growth hormone receptor (GHR), is affected by GH serum concentrations. During PEG-V monotherapy GH levels increase (10). However, the addition of LA-SRIF analogues results in lower GH serum levels which might reduce the necessary PEG-V dose due to reduced competition for the GHR (26, 27). Moreover, SRIF analogues decrease the number of GHRs expressed in the liver as a result of decreased portal insulin concentrations (28-30). Finally, SRIFs have direct inhibitory effects on IGF-I secretion that are GH independent (REF). These effects of SRIFs, therefore, might make clinicians to overestimate the efficacy of this class of drugs, as their selective effect on IGF-I might still leave patients with symptomatic elevated GH levels (REF), In summary, during combined treatment with LA-SRIF analogues, the competitive blocker PEG-V has lower serum GH levels to compete with, a lower number of GHRs to block and is present in higher serum concentrations. Finally, LA-SRIF analogues seem to inhibit IGF-I production by hepatocytes directly (31). Together, these actions are the explanations for the possible dose reduction that can be obtained during combined treatment of LA-SRIF analogues and PEG-V (4, 5, 19-23, 32).

Quality of life For clinicians, the main treatment goals are normalization of both GH and IGF-I because this coincides with a normalization of long-term mortality rates (3, 33-36). Quality of life (QoL) may be the most important disease control parameter from a patient’s perspective (37, 38). However, normalized biochemical parameters like GH and IGF-I do not guarantee a complete relief of acromegaly symptoms (37, 39). Residual symptoms result in a measurable impaired QoL in patients with acromegaly (40-42). QoL is quantifiable by questionnaires such as a disease specific one like the Acromegaly Quality of Life Questionnaire (AcroQoL™) (43) and symptoms can be scored by a disease specific questionnaire such as the Patientassessed Acromegaly Symptom Questionnaire (PASQ™) (10). In a prospective double blind, placebo controlled crossover trial, 20 acromegaly patients with an IGF-I level within the age-adjusted normal limits and GH levels < 2.5 μg/l had an impaired QoL during long-term LA-SRIF analogue treatment (37). In this study, symptoms were assessed by PASQ and QoL by AcroQoL. When the “controlled” patients added 40 mg PEGV on top of the LA-SRIF analogues during a period of 16 weeks, patients’ QoL and symptoms improved without a significant decrease in IGF-I levels. Improvement in AcroQoL total score was mainly explained by the physical dimension of the AcroQoL. The the single PASQ questions like perspiration and soft tissue swelling. Improvements in AcroQoL physical were associated with a reduction in body weight (37). However, in a recent


imporvement of symptoms were observed in total PASQ score, overall health, and in some of



6

report, the addition of PEG-V did not improve QoL in acromegaly patients (44).The study design was different compared to the Dutch study, as the dose of LA-SRIF analogues was reduced during the addition of PEG-V (44), whereas in the Dutch study the LA-SRIF dose was not changed (37). To assess QoL, Neggers et al. used a disease specific questionnaire the AcroQoL (37), whereas Madsen et al. used a non-disease specific questionnaire (44). Finally, the Danish did not use a crossover design. These differences between the two studies might be responsible for the observed different results (37, 44).

Side effects of Pegvisomant treatment The most frequent occurring side effects of PEG-V are usually mild, transient or self-limiting. One of them with a low prevalence is lipohypertrophy, reported during both PEG-V monotherapy and when combined with LA-SRIF (4, 15, 21, 45, 46). Frequent rotation of injection sites seems to reverse local lipohypertrophy or prevent it (4, 21). However, in some cases it takes up to 8 months to disappear and PEG-V therapy sometimes needs to be discontinued while in exceptional cases additional medical treatment was required (4). The possible pathophysiology behind lipohypertrophy is that at the injection site PEG-V induced a significant state of tissue GH deficiency in the presence of insulin (5, 32). Transient and self-limiting hepatocellular liver enzyme disturbances are probably the most common side effect (4-6, 15). Transient elevated transaminases (TETs) levels appear to be present both during PEG-V in combination with LA-SRIF analogues and during monotherapy. However the incidence of TET is reported to be higher during combination therapy compared to PEGV alone. During combination treatment TET incidences range from 11-15% when ALT cut-off levels between 2-3 times the upper limit of normality (ULN) are used (4, 19). In 5.2% of the patients, TETs ≥3 ULN were observed during PEG-V monotherapy (16). In a recent report of ACROSTUDY outcome data, only 2.5% of subjects (n=30) had an ALT or AST > 3x ULN (15). As mentioned previously, 1/3 of the 1288 subjects received a form of combined treatment (15). Again, TETs occurred more frequent in combination treated patients (15). It is questionable if the ACROSTUDY reported the real frequency of PEGV-related TET. When patients are not seen at an outpatient clinic in a systematic and repetitive way, TETs will go unnoticed. The differences in the reported incidences of TET between the various studies, like 15% vs. 2.5% vs. 5.2%, may at least be explained partly be differences in frequencies of the assessments. (4, 15, 16). Different risk factors for developing TET have been suggested. Diabetes Mellitus type 2 was was lost in a large cohort study (4, 21). A Spanish group (47) found additional risk factors such as a common polymorphism (UGT1A1) of Gilbert’s syndrome and male sex. Neither the


one the associated risk factors during combined treatment (22). However the association



7

heterozygote nor the homozygote carriers of this polymorphism of Gilbert’s syndrome had an increased risk for TET in another large single centre study that addressed a large cohort of patients on combined treatment (4). Also, carriers of this polymorphism of Gilbert’s syndrome polymorphism were as common as in the general population (54.2%) (4). In the Rotterdam cohort, no other association for TET was observed, expect for the re-exposure to PEG-V after having developed TET before (4). To date, the mechanism behind TET development during PEG-V treatment has not yet been elucidated, except for the hypothesis that combined treatment of SRIF and PEG-V increases the intrahepatic lipid content when assessed by MR (48). The higher lipid content in the liver may lead to the higher frequency in TET (48).

Pituitary tumour volume In the past safety concerns have been raised about the potential risk of tumour size increase PEG-V which might induce growth of the pituitary tumour. Despite the fact that there are a few reports increase in tumour size during the use of PEG-V, there is no clear evidence that PEG-V directly promotes tumour growth (12, 19, 38). Therefore, currentlyit is safe to conclude that PEG-V does not influence the natural course of the growth of the tumour. Since patients are mainly treated with PEG-V when LA-SRIF analogues are unable to control biochemical parameters, the patient population on PEG-V is more difficult than the average LA-SRIF analogue population. During LA-SRIF analogue treatment, tumour growth only occurs when the tumour does not express somatostatin receptors. These patients are usually switched to PEG-V treatment. In general, about 2.6% of the treated patients with long-term LA-SRIF analogues show a clinically significant growth of their pituitary adenoma (49, 50). A comprehensive systematic review of changes in pituitary tumour volumes in more than 300 patients treated with PEG-V, reported that only 3 of the 8 patients initially reported as having an increase in tumour-size indeed had a small, but significant increase in tumour size after PEG-V initiation (12). In another 3 of the 8 subjects, the increase in tumour size was already present before the initiation of PEG-V therapy (12). Finally, the 2 remaining patients appeared to have a rebound phenomenon after cessation of LA SRIF analogues (12). In a Spanish study, it was reported that 6.7% (5 out of 75) of patients had pituitary tumour size increase (51). Before patients switched to PEG-V monotherapy, they all used LA-SRIF analogues. Just after LA-SRIF analogues were discontinued, baseline size of the tumour was assessed by MRI. Patients that showed an increase in tumour size had a shorter preThe observed increase in tumour size could be well explained by a rebound phenomenon after cessation of the LA-SRIF analogue treatment. Continuation of LA-SRIF analogues


treatment period with LA-SRIF analogues and had not received radiotherapy in the past (51).



8

during PEG-V treatment could be an alternative to prevent this rebound phenomenon. In a large cohort of 141 patients on combination treatment, it was reported that only 1 patient had an increase in tumour size while in 17% patients a decrease of more than 20% in tumour size was observed (4). Another study on the efficacy of combined treatment with PEG-V and LA-SRIFs observed that 1 out of 11 patients showed a significant increase in tumour size (26). However, prior to study entry some subjects in this study received high dose octreotide LAR treatment (30 mg every 2 weeks). Tumour size data prior to study entry were unavailable and the study also included a period of monotherapy with PEG-V. Therefore, it is impossible to determine if the changes in tumour size can be explained by a rebound phenomenon after cessation or reduction in the dose of LA-SRIF analogues or by the natural course of the pituitary adenoma. In conclusion Of all medical interventions possible in acromegaly pegvisomant has the highest efficacy. However unlike surgery it does not cure acromegaly and is costly. Generally it is used as a second line therapy after inadequate biochemical control with long-acting somatostatin analogues. Combined with long-acting somatostatin analogues the dose of pegvisomant is lower while maintaining a similar high efficacy as during PEG-V monotherapy. The addition of pegvisomant to controlled patients with a poor quality of life during long-acting somatostatin analogues can improve quality of life. Side effects are rare and mainly transient. Elevated transaminases seem to be more common during combination treatment, but no predisposing factors are known.

1. Melmed S. Medical progress: Acromegaly. The New England journal of medicine. 2006;355(24):255873. 2. Dekkers OM, Biermasz NR, Pereira AM, Romijn JA, Vandenbroucke JP. Mortality in acromegaly: a metaanalysis. The Journal of clinical endocrinology and metabolism. 2008;93(1):61-7. 3. Holdaway IM, Bolland MJ, Gamble GD. A meta-analysis of the effect of lowering serum levels of GH and IGF-I on mortality in acromegaly. European journal of endocrinology / European Federation of Endocrine Societies. 2008;159(2):89-95. 4. Neggers SJ, Franck SE, de Rooij FW, Dallenga AH, Poublon RM, Feelders RA, et al. Long-term efficacy and safety of pegvisomant in combination with long-acting somatostatin analogues in acromegaly. The Journal of clinical endocrinology and metabolism. 2014:jc20142032. 5. Neggers SJ, van der Lely AJ. Somatostatin analog and pegvisomant combination therapy for acromegaly. Nature reviews Endocrinology. 2009;5(10):546-52. 6. Neggers SJ, van der Lely AJ. Combination treatment with somatostatin analogues and pegvisomant in acromegaly. Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society. 2011;21(3):129-33. 7. Kopchick JJ, Parkinson C, Stevens EC, Trainer PJ. Growth hormone receptor antagonists: discovery, development, and use in patients with acromegaly. Endocrine reviews. 2002;23(5):623-46.


References



9

8. Giustina A, Ambrosio MR, Beck Peccoz P, Bogazzi F, Cannavo S, De Marinis L, et al. Use of Pegvisomant in acromegaly. An Italian Society of Endocrinology guideline. J Endocrinol Invest. 2014;37(10):1017-30. 9. Trainer PJ, Drake WM, Katznelson L, Freda PU, Herman-Bonert V, van der Lely AJ, et al. Treatment of acromegaly with the growth hormone-receptor antagonist pegvisomant. The New England journal of medicine. 2000;342(16):1171-7. 10. van der Lely AJ, Hutson RK, Trainer PJ, Besser GM, Barkan AL, Katznelson L, et al. Long-term treatment of acromegaly with pegvisomant, a growth hormone receptor antagonist. Lancet. 2001;358(9295):1754-9. 11. Brue T, Castinetti F, Lundgren F, Koltowska-Haggstrom M, Petrossians P, investigators A. Which patients with acromegaly are treated with pegvisomant? An overview of methodology and baseline data in ACROSTUDY. European journal of endocrinology / European Federation of Endocrine Societies. 2009;161 Suppl 1:S11-7. 12. Buchfelder M, Schlaffer S, Droste M, Mann K, Saller B, Brubach K, et al. The German ACROSTUDY: past and present. European journal of endocrinology / European Federation of Endocrine Societies. 2009;161 Suppl 1:S3-S10. 13. Sesmilo G, Resmini E, Bernabeu I, Aller J, Soto A, Mora M, et al. Escape and lipodystrophy in acromegaly during pegvisomant therapy, a retrospective multicentre Spanish study. Clinical endocrinology. 2014. 14. Trainer PJ. ACROSTUDY: the first 5 years. European journal of endocrinology / European Federation of Endocrine Societies. 2009;161 Suppl 1:S19-24. 15. van der Lely AJ, Biller BM, Brue T, Buchfelder M, Ghigo E, Gomez R, et al. Long-term safety of pegvisomant in patients with acromegaly: comprehensive review of 1288 subjects in ACROSTUDY. The Journal of clinical endocrinology and metabolism. 2012;97(5):1589-97. 16. Schreiber I, Buchfelder M, Droste M, Forssmann K, Mann K, Saller B, et al. Treatment of acromegaly with the GH receptor antagonist pegvisomant in clinical practice: safety and efficacy evaluation from the German Pegvisomant Observational Study. European journal of endocrinology / European Federation of Endocrine Societies. 2007;156(1):75-82. 17. Gutierrez LP, Koltowska-Haggstrom M, Jonsson PJ, Mattsson AF, Svensson D, Westberg B, et al. Registries as a tool in evidence-based medicine: example of KIMS (Pfizer International Metabolic Database). Pharmacoepidemiology and drug safety. 2008;17(1):90-102. 18. Clemmons DR. Consensus statement on the standardization and evaluation of growth hormone and insulin-like growth factor assays. Clinical chemistry. 2011;57(4):555-9. 19. van der Lely AJ, Bernabeu I, Cap J, Caron P, Colao A, Marek J, et al. Coadministration of lanreotide Autogel and pegvisomant normalizes IGF1 levels and is well tolerated in patients with acromegaly partially controlled by somatostatin analogs alone. European journal of endocrinology / European Federation of Endocrine Societies. 2011;164(3):325-33. 20. Feenstra J, de Herder WW, ten Have SM, van den Beld AW, Feelders RA, Janssen JA, et al. Combined therapy with somatostatin analogues and weekly pegvisomant in active acromegaly. Lancet. 2005;365(9471):1644-6. 21. Neggers SJ, de Herder WW, Janssen JA, Feelders RA, van der Lely AJ. Combined treatment for acromegaly with long-acting somatostatin analogs and pegvisomant: long-term safety for up to 4.5 years (median 2.2 years) of follow-up in 86 patients. European journal of endocrinology / European Federation of Endocrine Societies. 2009;160(4):529-33. 22. Neggers SJ, van Aken MO, Janssen JA, Feelders RA, de Herder WW, van der Lely AJ. Long-term efficacy and safety of combined treatment of somatostatin analogs and pegvisomant in acromegaly. The Journal of clinical endocrinology and metabolism. 2007;92(12):4598-601. 23. Neggers SJ, de Herder WW, Feelders RA, van der Lely AJ. Conversion of daily pegvisomant to weekly pegvisomant combined with long-acting somatostatin analogs, in controlled acromegaly patients. Pituitary. 2011;14(3):253-8. 24. Trainer PJ, Ezzat S, D'Souza GA, Layton G, Strasburger CJ. A randomized, controlled, multicentre trial comparing pegvisomant alone with combination therapy of pegvisomant and long-acting octreotide in patients with acromegaly. Clinical endocrinology. 2009;71(4):549-57. 25. Droste M, Domberg J, Buchfelder M, Mann K, Schwanke A, Stalla G, et al. Therapy of acromegalic patients exacerbated by concomitant type 2 diabetes requires higher pegvisomant doses to normalise IGF1 levels. European journal of endocrinology / European Federation of Endocrine Societies. 2014;171(6):X5. 26. Jorgensen JO, Feldt-Rasmussen U, Frystyk J, Chen JW, Kristensen LO, Hagen C, et al. Cotreatment of acromegaly with a somatostatin analog and a growth hormone receptor antagonist. The Journal of clinical endocrinology and metabolism. 2005;90(10):5627-31.




10

27. van der Lely AJ, Muller A, Janssen JA, Davis RJ, Zib KA, Scarlett JA, et al. Control of tumor size and disease activity during cotreatment with octreotide and the growth hormone receptor antagonist pegvisomant in an acromegalic patient. The Journal of clinical endocrinology and metabolism. 2001;86(2):478-81. 28. Wurzburger MI, Prelevic GM, Sonksen PH, Balint-Peric LA, Wheeler M. The effect of recombinant human growth hormone on regulation of growth hormone secretion and blood glucose in insulin-dependent diabetes. The Journal of clinical endocrinology and metabolism. 1993;77(1):267-72. 29. Shishko PI, Dreval AV, Abugova IA, Zajarny IU, Goncharov VC. Insulin-like growth factors and binding proteins in patients with recent-onset type 1 (insulin-dependent) diabetes mellitus: influence of diabetes control and intraportal insulin infusion. Diabetes research and clinical practice. 1994;25(1):1-12. 30. Leung KC, Doyle N, Ballesteros M, Waters MJ, Ho KK. Insulin regulation of human hepatic growth hormone receptors: divergent effects on biosynthesis and surface translocation. The Journal of clinical endocrinology and metabolism. 2000;85(12):4712-20. 31. Murray RD, Kim K, Ren SG, Chelly M, Umehara Y, Melmed S. Central and peripheral actions of somatostatin on the growth hormone-IGF-I axis. J Clin Invest. 2004;114(3):349-56. 32. Hodish I, Barkan A, Medscape. Long-term effects of pegvisomant in patients with acromegaly. Nature clinical practice Endocrinology & metabolism. 2008;4(6):324-32. 33. Beauregard C, Truong U, Hardy J, Serri O. Long-term outcome and mortality after transsphenoidal adenomectomy for acromegaly. Clinical endocrinology. 2003;58(1):86-91. 34. Holdaway IM, Rajasoorya CR, Gamble GD, Stewart AW. Long-term treatment outcome in acromegaly. Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society. 2003;13(4):185-92. 35. Holdaway IM, Rajasoorya RC, Gamble GD. Factors influencing mortality in acromegaly. The Journal of clinical endocrinology and metabolism. 2004;89(2):667-74. 36. Swearingen B, Barker FG, 2nd, Katznelson L, Biller BM, Grinspoon S, Klibanski A, et al. Long-term mortality after transsphenoidal surgery and adjunctive therapy for acromegaly. The Journal of clinical endocrinology and metabolism. 1998;83(10):3419-26. 37. Neggers SJ, van Aken MO, de Herder WW, Feelders RA, Janssen JA, Badia X, et al. Quality of life in acromegalic patients during long-term somatostatin analog treatment with and without pegvisomant. The Journal of clinical endocrinology and metabolism. 2008;93(10):3853-9. 38. Neggers SJ, Biermasz NR, van der Lely AJ. What is active acromegaly and which parameters do we have? Clinical endocrinology. 2012;76(5):609-14. 39. Hua SC, Yan YH, Chang TC. Associations of remission status and lanreotide treatment with quality of life in patients with treated acromegaly. European journal of endocrinology / European Federation of Endocrine Societies. 2006;155(6):831-7. 40. Biermasz NR, Pereira AM, Smit JW, Romijn JA, Roelfsema F. Morbidity after long-term remission for acromegaly: persisting joint-related complaints cause reduced quality of life. The Journal of clinical endocrinology and metabolism. 2005;90(5):2731-9. 41. Biermasz NR, van Thiel SW, Pereira AM, Hoftijzer HC, van Hemert AM, Smit JW, et al. Decreased quality of life in patients with acromegaly despite long-term cure of growth hormone excess. The Journal of clinical endocrinology and metabolism. 2004;89(11):5369-76. 42. Bonapart IE, van Domburg R, ten Have SM, de Herder WW, Erdman RA, Janssen JA, et al. The 'bioassay' quality of life might be a better marker of disease activity in acromegalic patients than serum total IGF-I concentrations. European journal of endocrinology / European Federation of Endocrine Societies. 2005;152(2):217-24. 43. Webb SM, Prieto L, Badia X, Albareda M, Catala M, Gaztambide S, et al. Acromegaly Quality of Life Questionnaire (ACROQOL) a new health-related quality of life questionnaire for patients with acromegaly: development and psychometric properties. Clinical endocrinology. 2002;57(2):251-8. 44. Madsen M, Poulsen PL, Orskov H, Moller N, Jorgensen JO. Cotreatment with pegvisomant and a somatostatin analog (SA) in SA-responsive acromegalic patients. The Journal of clinical endocrinology and metabolism. 2011;96(8):2405-13. 45. Bonert VS, Kennedy L, Petersenn S, Barkan A, Carmichael J, Melmed S. Lipodystrophy in patients with acromegaly receiving pegvisomant. The Journal of clinical endocrinology and metabolism. 2008;93(9):3515-8. 46. Maffei P, Martini C, Pagano C, Sicolo N, Corbetti F. Lipohypertrophy in acromegaly induced by the new growth hormone receptor antagonist pegvisomant. Annals of internal medicine. 2006;145(4):310-2. 47. Bernabeu I, Marazuela M, Lucas T, Loidi L, Alvarez-Escola C, Luque-Ramirez M, et al. Pegvisomantinduced liver injury is related to the UGT1A1*28 polymorphism of Gilbert's syndrome. The Journal of clinical endocrinology and metabolism. 2010;95(5):2147-54. 48. Madsen M, Krusenstjerna-Hafstrom T, Moller L, Christensen B, Vendelbo MH, Pedersen SB, et al. Fat content in liver and skeletal muscle changes in a reciprocal manner in patients with acromegaly during




11

combination therapy with a somatostatin analog and a GH receptor antagonist: a randomized clinical trial. The Journal of clinical endocrinology and metabolism. 2012;97(4):1227-35. 49. Caron PJ, Bevan JS, Petersenn S, Flanagan D, Tabarin A, Prevost G, et al. Tumor shrinkage with lanreotide Autogel 120 mg as primary therapy in acromegaly: results of a prospective multicenter clinical trial. The Journal of clinical endocrinology and metabolism. 2014;99(4):1282-90. 50. Bevan JS. Clinical review: The antitumoral effects of somatostatin analog therapy in acromegaly. The Journal of clinical endocrinology and metabolism. 2005;90(3):1856-63. 51. Marazuela M, Paniagua AE, Gahete MD, Lucas T, Alvarez-Escola C, Manzanares R, et al. Somatotroph tumor progression during pegvisomant therapy: a clinical and molecular study. The Journal of clinical endocrinology and metabolism. 2011;96(2):E251-9.

Neuroendocrinology (International Journal for Basic and Clinical Studies on Neuroendocrine Relationships) Journal Editor: Millar R.P. (Edinburgh) ISSN: 0028-3835 (Print), eISSN: 1423-0194 (Online)

www.karger.com/NEN Disclaimer: Accepted, unedited article not yet assigned to an issue. The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publisher and the editor(s). The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content. Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center. © 2015 S. Karger AG, Basel


Combined treatment of somatostatin analogues with pegvisomant in acromegaly.

Optimal use of pegvisomant in acromegaly: are we getting there?

Does pegvisomant treatment expertise improve control of resistant acromegaly? The Italian ACROSTUDY experience.

Long-term effects of pegvisomant on comorbidities in patients with acromegaly: a retrospective single-center study.

Escape and lipodystrophy in acromegaly during pegvisomant therapy, a retrospective multicentre Spanish study.

What is the efficacy of switching to weekly pegvisomant in acromegaly patients well controlled on combination therapy?

Bromocriptine treatment of acromegaly.

Medical treatment of acromegaly.

Treatment of acromegaly with bromocryptine.

Treatment of acromegaly with bromocriptine.

Functional treatment of acromegaly by transsphenoidal microsurgery.

The treatment of acromegaly by Yttrium implantation.

Long-term treatment of acromegaly with bromocriptine.

Treatment of acromegaly by transsphenoidal microsurgery.

Acromegaly and its treatment in the McCune-Albright syndrome.

Long-term efficacy and tolerability of octreotide treatment in acromegaly.

Medical treatment of acromegaly in pregnancy, highlights on new reports.

The role of pasireotide in the treatment of acromegaly.

Patterns of pharmacologic treatment in US patients with acromegaly.

Acromegaly.

Acromegaly.

Acromegaly.

Endoscopic versus microscopic approach for surgical treatment of acromegaly.

Treatment of acromegaly by transsphenoidal hypophysectomy with cryoapplication.