Pharmacological Management of Acromegaly: a Current Perspective

Home , Lanreotide, Pasireotide, Pegvisomant

Neurosurg Focus 29 (4):E14, 2010

Pharmacological management of acromegaly: a current perspective

Su n i l Ma n j i l a , M.D.,1 Osmo n d C. Wu, B.A.,1 Fa h d R. Kh a n , M.D., M.S.E.,1 Me h ree n M. Kh a n , M.D.,2 Ba h a M. Ar a f a h , M.D.,2 a n d Wa rre n R. Se l m a n , M.D.1 1Department of Neurological Surgery, The Neurological Institute, and 2Division of Clinical and Molecular Endocrinology, University Hospitals Case Medical Center, Cleveland, Ohio

Acromegaly is a chronic disorder of enhanced growth hormone (GH) secretion and elevated insulin-like growth factor–I (IGF-I) levels, the most frequent cause of which is a pituitary adenoma. Persistently elevated GH and IGF-I levels lead to substantial morbidity and mortality. Treatment goals include complete removal of the tumor causing the disease, symptomatic relief, reduction of multisystem complications, and control of local mass effect. While transsphenoidal tumor resection is considered first-line treatment of patients in whom a surgical cure can be expected, pharmacological therapy is playing an increased role in the armamentarium against acromegaly in patients unsuitable for or refusing surgery, after failure of surgical treatment (inadequate resection, cavernous sinus invasion, or transcap- sular intraarachnoid invasion), or in select cases as primary treatment. Three broad drug classes are available for the treatment of acromegaly: somatostatin analogs, dopamine agonists, and GH receptor antagonists. Somatostatin analogs are considered as the first-line pharmacological treatment of acromegaly, although efficacy varies among the different formulations. Octreotide long-acting release (LAR) appears to be more efficacious than lanreotide sustained release (SR). Lanreotide Autogel (ATG) has been shown to result in similar biological control as octreotide LAR, and there may be a benefit in switching from one to the other in some cases of treatment failure. The novel multireceptor somatostatin analog pasireotide, currently in Phase II clinical trials, also shows promise in the treatment of acromegaly. Dopamine agonists have been the earliest and most widely used agents in the treatment of acromegaly but have been found to be less effective than somatostatin analogs. In this class of drugs, cabergoline has shown greater efficacy and tolerability than bromocriptine. Dopamine agonists have the advantage of oral admin- istration, resulting in increased use in select patient groups. Selective GH receptor antagonists, such as pegvisomant, act by blocking the effects of GH, resulting in decreased IGF-I production despite persistent elevation of GH serum levels. Thus far, tumor growth has not been a concern during pegvisomant therapy. However, combination treatment with somatostatin analogs may counteract these effects. The authors discuss the latest guidelines for biochemical cure and highlight the efficacy of combination therapy. In addition, the effects of pharmacological presurgical treatment on surgical outcome are explored. (DOI: 10.3171/2010.7.FOCUS10168)

Ke y Words • acromegaly • octreotide • lanreotide • pasireotide • pegvisomant • growth hormone

c r o m e g a l y is a chronic disorder characterized by mortality. Complications of acromegaly include, but are elevated GH secretion with a resultant increase not limited to, acral growth, cardiovascular disease, in- in serum IGF-I level. A pituitary adenoma is the sulin resistance and diabetes, arthritis, hypertension, and Amost common cause of the disorder. Persistently elevated sleep apnea. All of these adverse complications individu- levels of GH and IGF-I lead to significant morbidity and ally and collectively lead to a shortened life span. With GH-secreting tumors being the most common cause of Abbreviations used in this paper: ATG = Autogel; GH = growth acromegaly, other symptoms related to the tumor itself hormone; GHRH = GH-releasing hormone; IGF = insulin-like are often present in patients with these lesions. These growth factor; LAR = long-acting release; SC = subcutaneous; SR symptoms include headaches and visual disturbances = sustained release. due to the mass effect on the optic nerve and chiasm.

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Progressive expansion of GH-secreting tumors can also megaly have been recently elucidated. Development and lead to loss of pituitary function and variable degrees differentiation of somatotrophs, GH-producing cells in of hypopituitarism. In children, in whom the epiphyseal the anterior pituitary, are influenced by a gene named growth plate is not closed, excessive GH secretion leads the Prophet of Pit-1 (PROP1), which is responsible for to progressive linear growth as the predominant symp- the embryological development of the cells of the Pit-1 tom, clinically manifesting as gigantism. (POU1F1) transcription factor lineage. The binding of The goals of treatment should include complete tumor Pit-1 to the GH promoter in the cell nucleus results in removal, alleviation of symptoms, and control of complica- development and growth of somatotrophs and subsequent tions.13 Control of excessive GH secretion can be achieved GH transcription. Growth hormone is a 191–amino acid through surgical removal of the tumor, radiotherapy, and polypeptide synthesized and secreted in a pulsatile fash- medical treatment.27 In this review, we examine the phar- ion by the anterior pituitary. Growth hormone–releasing macological management of acromegaly, with a focus on hormone (GHRH) stimulates the synthesis and secretion the efficacy and side-effect profile of medical therapy. of GH while somatostatin inhibits GH release, with both Pathophysiology of Acromegaly traveling in the portal vein and acting on somatotroph- specific transcription factors (Fig. 1). The effects of GH The molecular genetics of tumorigenesis in acro- are mediated by GH receptors found primarily in the liv-

Fig. 1. Hypothalamic-pituitary axis: control of GH secretion. Reproduced with permission from Melmed S: Medical progress: acromegaly. N Engl J Med 355:2558–2573, 2006. Copyright © 2006 Massachusetts Medical Society. All rights reserved.

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Fig. 2. Causes of acromegaly: excessive GH or GHRH. Reproduced with permission from Melmed S: Medical progress: acromegaly. N Engl J Med 355:2558–2573, 2006. Copyright © 2006 Massachusetts Medical Society. All rights reserved. er and cartilage. Activation of the GH receptor results in GHRH production by central hypothalamic tumors or phosphorylation of the receptor and Janus kinase 2 (JAK2) peripheral neuroendocrine tumors (Fig. 2).27 followed by the binding of signal transducer and activa- tor of transcription (STAT) proteins to the complex. The STAT proteins then become phosphorylated, translocate Biochemical Criteria for Diagnosis of Acromegaly into the cell nucleus, and initiate transcription of target Acromegaly is diagnosed by finding an elevated IGF- proteins, such as IGF-I, which induces cell proliferation I level compared with the age- and sex-adjusted normal and inhibits apoptosis. The development of a GH-secret- range and a failure to suppress GH in response to an oral ing tumor is the result of variables that affect the develop- glucose tolerance test (OGTT). Unlike normal subjects, ment and growth of somatotrophs and their hormone pro- patients with acromegaly do not suppress GH secretion to duction. Approximately 40% of tumors appear to harbor very low levels with a glucose load. A post-OGTT GH level a mutation in the a-subunit of the Gs protein that results of less than 1.0 mg/L is the most recent cutoff level used to in constitutive activation of cyclic AMP. Overexpression separate individuals without acromegaly from those with of the pituitary tumor–transforming gene (PTTG) pro- the disorder. As newer and more sensitive immunological tein and lost expression of the growth arrest and DNA assays become available, the cutoff points to define acro- damage-inducible (GADD) 45g protein, a proapoptotic megaly may need to be adjusted accordingly.13,18 factor, has been demonstrated in GH-secreting pituitary adenomas. Overproliferation of somatotrophs and the re- Overview of the Management of Acromegaly sultant excessive secretion of GH results in acromegaly.27 The majority of somatotroph tumors are macroade- Treatment of this disease requires optimal interaction nomas, but there have been rare instances of pituitary car- between the management team members. Our focus in this cinomas. Up to 40% of GH-secreting pituitary adenomas article will be on patients with GH-secreting adenomas cosecrete other pituitary hormones, especially prolactin because they represent more than 98% of cases of acro- and thyrotropin, leading to additional clinical manifesta- megaly. All authorities in the field believe that surgery by tions. Other rare causes of primary GH excess include an experienced neurosurgeon is the treatment of choice for familial syndromes, such as Carney syndrome, multiple GH-secreting adenomas. In experienced hands, this treat- endocrine neoplasia Type I, McCune-Albright syndrome, ment leads to disease control in 50% of patients. Some and familial acromegaly. Extrapituitary causes of excess patients, however, might refuse surgery or could be poor GH can result from ectopic hypersecretion of GH by pan- candidates for this procedure. In addition, there are a large creatic islet-cell tumors or lymphoma. Finally, GH excess number of patients in whom surgery is not curative and can result from somatotroph hyperplasia due to excess who would require additional treatment. Available options

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44 include various forms of irradiation and medical therapy. the somatostatin receptor subtypes sst1–3 and sst5. Since While radiation therapy can be effective, it takes years to most GH-secreting pituitary adenomas predominantly show its benefits in controlling GH secretion. Thus, even express sst2 and sst5 receptor subtypes, pasireotide may patients given all forms of radiation therapy would re- potentially be more effective than octreotide and lan- quire additional treatments to control GH secretion until reotide at suppression of GH secretion. radiation effects become apparent. With the availability The reported biochemical efficacy of somatostatin of newer and more effective agents, the focus on medical analogs in the treatment of acromegaly varies greatly by therapy has intensified to the point that some researchers study. In an extensive meta-analysis by Freda and col- and practitioners advocate it to be the primary therapy in leagues,17 results from 44 trials were analyzed, compar- most patients. The following section will address available ing the efficacy of octreotide LAR and lanreotide SR. The medical therapies and their efficacies, advantages, and dis- authors concluded that the efficacy of octreotide LAR is advantages. greater than that of lanreotide SR among patients unse- lected for prior somatostatin analog responsiveness. It Somatostatin Analogs was also shown that efficacy was similar when treatments First introduced in the 1980s, somatostatin analogs were given as primary or secondary therapy. In their re- have been widely used in the treatment of acromegaly. view of somatostatin analog formulations, Murray and The concept is to mimic the physiological inhibitory ac- Melmed32 found that octreotide LAR was slightly more tion of somatostatin on the anterior pituitary gland. Two effective than lanreotide SR in the biochemical control of endogenous, biologically active forms of somatostatin acromegaly. Lanreotide ATG is the primary formulation are formed by the cleavage of prosomatostatin: SRIF-14 of lanreotide currently used clinically, but there are only a and SRIF-18.27 Five different somatostatin receptor sub- handful of studies comparing the efficacies of octreotide types, sst1–5, have been characterized. These subtypes are LAR and lanreotide ATG. Results from nonrandomized 7–transmembrane domain G-protein–coupled receptors.38 open-label studies have suggested that lanreotide ATG is The importance of delineating the subtypes becomes ap- at least as effective as octreotide LAR.2,4,42 A randomized parent when one considers the expression profile in nor- crossover trial by Andries and colleagues3 further sup- mal pituitary gland and pituitary adenomas as well as the ports the findings of equal efficacy between octreotide receptor selectivity of drugs. Studies have shown that the LAR and lanreotide ATG. Additionally, their study sug- human pituitary gland primarily expresses the sst1, sst2, gests that some patients who experience treatment failure 30,37 sst3, and sst5 receptors. Additionally, GH secretion by or adverse effects may benefit from a switch between the human fetal somatotroph cells appears to be regulated 2 drugs. Pasireotide, which is currently in Phase II clini- 47 by the sst2 and sst5 receptors. When pituitary adenomas cal trials, has demonstrated biochemical control in 27% were investigated, the sst1, sst2, sst3, and sst5 receptor sub- of patients after 3 months of treatment in a recent study. types were also shown to be expressed. Additionally, most As the authors of this randomized multicenter trial have human GH-secreting pituitary tumors primarily express reported, the study was not designed or powered to com- 50 the sst2 and sst5 receptors. pare the efficacy of pasireotide to octreotide, which was Octreotide SC was the first somatostatin analog first self-administered for 28 days. However, pasireotide available for clinical use. Initial dosage is 100 mg injected shows promise as a new treatment for acromegaly.39 subcutaneously 3–4 times daily, titratable to a maximum Another important parameter to consider in the medi- of 1.5 mg/day. The dosing regimen of 3–4 times daily is cal management of acromegaly is the effect on tumor required to maintain therapeutic serum levels because of shrinkage. A number of studies have investigated the an- the 2-hour half-life. To reduce the inconvenience of mul- titumor effects of somatostatin analogs, and their data tiple injections per day and increase compliance, long- has been examined in various reviews. From a total of 22 acting formulations have been developed. Octreotide studies, Bevan8 found that 217 (45%) of 478 patients who LAR was the first long-acting formulation and is based were treated with octreotide SC had significant tumor on octreotide delivered in polymeric microspheres.19 The shrinkage. It was also noted that tumor shrinkage was starting dosage is 20 mg intramuscular injection every 4 seen in 110 (51%) of 217 patients treated primarily with weeks and can be titrated up to 40 mg. Octreotide has been octreotide SC compared with 22 (27%) of 82 patients who 49 shown to act primarily at the sst2 receptor subtype. Lan- received octreotide adjunctively after surgery and/or radia- reotide was the second long-acting somatostatin analog tion treatment. Freda and colleagues17 showed that, of 468 developed and is available in 2 formulations: lanreotide patients treated with octreotide SC, 40.8% had significant SR and lanreotide ATG. Lanreotide ATG is currently the decreases in tumor size. In considering studies involving only formulation available in the US. Lanreotide SR con- octreotide LAR treatment, tumor size reduction was shown sists of lanreotide packaged in a biodegradable polymer in 103 (57%) of 180 patients. As with octreotide SC, pri- microparticle and is given as a 30-mg intramuscular in- mary treatment with octreotide LAR resulted in a higher jection every 7–14 days. Lanreotide ATG, on the other percentage of patients with tumor shrinkage than second- hand, consists of lanreotide acetate in an aqueous solution ary treatment did (80% vs 28%). Studies of lanreotide SR packaged in prefilled syringes for deep SC injection. It showed decreases in tumor size in 62 (24%) of 263 patients. is available in 60-, 90-, and 120-mg mixtures. Like oc- As with the other drugs, primary therapy with lanreotide treotide, lanreotide appears to be sst2-preferential. Pasi- SR showed a greater degree of tumor-size reduction than reotide (SOM230), the newest somatostatin analog, is a secondary therapy (31% vs 9%). The caveat is that, in a few novel multireceptor ligand analog with high affinity for of the octreotide LAR studies, patients were preselected

4 Neurosurg Focus / Volume 29 / October 2010 Unauthenticated | Downloaded 10/02/21 08:04 PM UTC Pharmacological treatment of acromegaly for drug responsiveness, which could falsely elevate the treatment is associated with valvular heart disease. While response rate. When data were combined from all the stud- cardiac abnormalities have not been demonstrated in pa- ies, 382 (42%) of 920 patients had a decrease in tumor size. tients with pituitary adenomas on cabergoline, monitoring Again, primary therapy showed a more pronounced effect patients receiving higher than regular doses is recommend- on tumor shrinkage than secondary therapy did (52% vs ed.28 21%). 8 The meta-analysis by Freda and colleagues17 sup- Chimeric Compounds ports the general finding that primary treatment results in Dopamine agonists have been reported to suppress higher rates of tumor shrinkage than secondary treatment. 20 Melmed and colleagues29 reported similar findings in a GH levels in some patients with acromegaly. Further- review, noting that significant tumor reduction was found more, the combination of a somatostatin analog and a dopamine agonist has been suggested to work synergisti- in 36.6% of 424 patients receiving primary somatostatin 16,24 41 treatment. Bevan8 suggested that this observation may be cally. Rocheville and colleagues subsequently demon- the result of alterations in tumor anatomy, such as fibrosis strated that somatostatin and dopamine receptors can form or scarring, caused by prior surgery or radiotherapy. Over- hetero-oligomers with enhanced receptor activity. Several all, among the different somatostatin analogs, octreotide chimeric molecules with both somatostatin and dopamine LAR has shown greater rates of tumor size reduction than receptor affinity have been developed. BIM23A387, which octreotide SC and lanreotide SR.8 has selective binding to sst2 and D2 receptors in cultured The side-effect profile and safety of somatostatin somatotropic tumor cells, has been shown to have greater GH suppression compared with an individual agonist or a analogs has been well studied. Generally, they are well 43 tolerated and fairly safe. Among the side effects, gastro- combination. To date, there have been no published clini- intestinal symptoms, including nausea, diarrhea, and ab- cal studies for BIM23A387. Another chimeric molecule, dominal pain, are the most commonly reported. Biliary BIM23A760, has an affinity for sst2, sst5, and D2 receptors. It has demonstrated more potent inhibition of GH secretion tract abnormalities, such as biliary sludge and cholelithia- 21 sis, have also been known to occur. In addition, soma- than sst2, sst5, and D2 agonists and pasireotide. A variety tostatin analogs have the potential to impair the secretion of other novel chimeric molecules have been investigated and show potential for treatment.22 of insulin, which is of particular concern in acromegaly, a condition that already has an increased risk of impaired Growth Hormone Receptor Antagonists glucose tolerance and diabetes.6,48 Pegvisomant represents the first in a novel class of Dopamine Agonists drugs that act on GH receptors. It is a genetically engi- Like somatostatin analogs, the dopamine agonists in- neered, pegylated analog of human GH that functions as a hibit GH secretion in pituitary tumors but do so by bind- selective GH receptor antagonist. Pegvisomant competes ing to D2 receptors. Dopamine receptors exist in 5 sub- with physiological GH for binding, thus preventing re- types with specific distribution in tissue. 2D receptors are ceptor dimerization and signaling, resulting in decreased found in the anterior and intermediate lobes of the pitu- IGF-I production. The mechanism of action blocks the itary. 31 Bromocriptine, a nonselective dopamine agonist, effects of excessive GH instead of inhibiting its secretion was the first to be widely used since it became available and so can function independent of tumor receptor ex- in 1974. Unfortunately, it has been found to be less ef- pression or type.52 Because the drug is pegylated, it has fective when compared with somatostatin analogs. Addi- an increased half-life of approximately 6 days and a re- tionally, acromegaly—as compared with prolactinomas— duced possibility of antibody formation.51 Pegvisomant is requires more frequent and higher doses of bromocriptine available in 10-, 15-, and 20-mg SC injections. The ini- for treatment. Cabergoline, a more selective D2 receptor tial loading dose is a 40-mg SC injection; it is followed agonist, has a longer half-life (62–115 hours) and demon- by maintenance dosages of 10 mg daily, adjustable to a strated better efficacy and tolerability.1,31 Other dopamine maximum maintenance dose of 30 mg daily. agonists, such as lysuride, pergolide, quinagolide, and ter- Trainer and colleagues51 investigated the efficacy of guride, have been studied but were found to be less effec- pegvisomant in a 12-week randomized placebo-controlled tive than bromocriptine and cabergoline. study of 112 patients with acromegaly. They reported a Dopamine agonists, however, have advantages over dose-dependant normalization of serum IGF-I levels, other pharmacological treatments. They can be taken oral- with 89% of patients in the 20-mg daily dose group and ly as opposed to requiring injection, and are perhaps less improvements in clinical symptoms in all pegvisomant- expensive than octreotide. These drugs can be used alone treated groups. Another study found similar results when or as an effective adjunct to somatostatin analog therapy. analyzing the long-term efficacy of pegvisomant in 160 Among all GH-secreting adenomas, dopamine agonists patients treated for up to 18 months. The investigators re- are the most effective in patients with pituitary tumors that port that 87 (97%) of 90 patients treated for at least 12 cosecrete prolactin or thyrotropin.1 months attained normal serum IGF-I levels.51 In a re- Side effects of dopamine agonists include constipa- cent study from the German Pegvisomant Observational tion, nausea, postural dizziness, and nasal congestion. The Study, 76.3% of patients treated with pegvisomant for 24 adverse responses can be minimized if the drug is started months had normal IGF-I levels.45 at a low dose with a slow increase and taken with food. It Because pegvisomant blocks GH from binding to its should be noted that, in patients with Parkinson disease, receptor instead of suppressing GH secretion by the pi- there is evidence that the high dose of cabergoline used for tuitary tumor, there has been concern for potential tumor

Neurosurg Focus / Volume 29 / October 2010 5 Unauthenticated | Downloaded 10/02/21 08:04 PM UTC S. Manjila et al. growth as a result of an interruption in GH-mediated nega- octreotide improved surgical cure rates in patients with tive feedback inhibition on the tumor. A rise followed by a macroadenomas compared with those who had direct plateau of serum GH levels echoing the reduction in serum surgery without pretreatment (50% vs 16%). However, IGF-I with no significant change in tumor size has been they observed no benefit of pretreatment and possibly an reported during treatment.51,52 A recent prospective multi- adverse effect in patients with microadenomas. Yin and center study designed to investigate tumor volume during colleagues53 reported similar results in patients treated long-term therapy found similar results, with an increase in with octreotide LAR for 3 months prior to transsphenoi- tumor size (> 25%) in only 3 (4.9%) of 61 patients.9 dal tumor resection. In a retrospective study, Colao and Pegvisomant has been found to be generally well tol- colleagues11 concluded that 3–6 months of presurgical erated. One often-reported adverse reaction is elevated octreotide treatment improved clinical symptoms and levels of alanine transaminase and aspartate transami- surgical outcomes and decreased hospitalization time nase. In patients with elevated liver enzyme levels, some postoperatively. Other studies, however, showed no ben- had transient abnormal values that normalized during efit.25,40 Further investigation is needed to define the role treatment while others had enzyme levels that returned to of presurgical pharmacological treatment in acromegaly. normal following discontinuation of pegvisomant.45,51,52 It has been recommended that liver function tests be per- formed regularly during treatment. Injection-site lipohy- Combination Pharmacological Therapy pertrophy has also been experienced, though it resolves Another area of study that shows promise in the man- with more frequent injection-site change.33,45 Other ad- agement of acromegaly is the use of drug combinations. As verse reactions include hypercholesterolemia, infections, discussed earlier, pegvisomant can result in increased se- and self-limited injection-site erythema.45,51,52 rum GH levels. Additionally, there is the concern of tumor growth during therapy. By adding a somatostatin analog to the treatment regimen, one may be able to reduce serum Primary or Secondary Pharmacological Therapy GH levels and reduce tumor size, potentially counteract- According to the recent consensus statement on man- ing the shortcomings of pegvisomant. A recent review by agement by the Acromegaly Consensus Group, transsphe- Neggers and van der Lely34 examined the long-term effi- noidal surgery is still considered first-line treatment for cacy and safety of pegvisomant and somatostatin analog intrasellar microadenomas, noninvasive macroadenomas, combination therapy. They concluded that treatment was and adenomas resulting in compression symptoms.28 Re- effective in normalizing serum IGF-I levels in more than ports indicate that surgical excision achieves normalization 90% of patients. Additionally, they found that combination of serum IGF-I in 75%–95% of patients with microade- therapy resulted in tumor reduction in approximately 20% nomas and 56%–68% of patients with noninvasive mac- of patients, which is not seen in pegvisomant monotherapy. roadenomas.7,15,26,36,46 Remission rates drop when surgical The addition of dopamine agonists to somatostatin analog removal of invasive macroadenomas is considered. Pri- therapy has also been shown to increase the efficacy of mary pharmacological therapy may be indicated in such treatment in some patients (Table 1). patients and in those who are otherwise poor surgical candidates. While studies designed to investigate the use of Cost of Pharmacological Management primary pharmacological therapy are limited, the use of drugs in treatment-naive patients may be efficacious. Previous studies on economic burden in the manage- In a study comparing octreotide as primary treatment of acromegaly have revealed that the cost of medica- ment versus octreotide as secondary therapy after sur- tion represents the greatest contribution (38%) and exceeds gery or radiation, Newman and colleagues35 reported the cost of surgery.23 An accurate comparison of the cost equal efficacy with octreotide as primary or secondary of the various pharmacological agents mentioned above therapy. A retrospective study investigating the efficacy would be extremely difficult due a myriad of reasons: mi- of octreotide LAR as primary and adjunctive therapy croadenoma versus macroadenoma (the latter costs more also found similar efficacy.5 In an open prospective mul- than double the cost of the former), variations in the physi- ticenter trial, Colao and colleagues12 demonstrated that, cian’s choice of drug management, and economic determi- in patients with micro- and macroadenomas, primary oc- nates, such as health care systems and currency value. treotide LAR treatment controlled hormone excess, re- duced tumor volume, and improved symptoms. In another Conclusions study, Colao and colleagues14 investigated the effects of octreotide LAR and lanreotide ATG on tumor-size reduc- Pharmacological management plays a pivotal role in tion in treatment-naive patients. A reduction in tumor size the treatment of acromegaly. Somatostatin analogs, par- of at least 25% was observed in 75.5% of patients after 12 ticularly the long-acting formulations, are considered first months of primary therapy with a somatostatin analog. line in medical therapy and have shown to result in the re- The authors also found that the best predictor of tumor duction and normalization of GH and IGF-I levels. In ad- reduction was the posttreatment serum IGF-I level. dition, they have been found to reduce pituitary tumor size. The use of primary pharmacological treatment also Dopamine agonists, while less effective than somatostatin has the potential to influence surgical outcome posi- analogs, have certain advantages, including oral adminis- tively. In a prospective randomized trial, Carlsen and tration. When added to somatostatin analog therapy, dop- colleagues10 reported that 6-month pretreatment with amine agonists may increase efficacy of treatment. Growth

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TABLE 1: Pharmacological therapy of acromegaly*

Variable Somatostatin Analogs Dopamine Agonists GH Receptor Antagonists indications 1st-line therapy in cases w/ low expectation of patient preference of oral medication persistent high IGF-I levels despite surgical cure (large extrasellar tumors); & cost factors; patient w/ markedly max treatment w/ other modali- postop/lack of biochem control; to achieve elevated prolactin w/ GH & IGF-I; ties; included in combination partial disease control prior to radiation combination therapy w/ somatosta- therapies therapy for acromegaly tin analogs in refractory cases dosage octreotide SC: 100 μg SC 3 × daily (max 1.5 cabergoline: 1–4 mg orally weekly pegvisomant: 40 mg SC loading mg daily); octreotide LAR: 20 mg IM every 4 dose, 10 mg daily maintenance wks (max 40 mg); lanreotide SR: 30 mg IM dose (max 30 mg daily) every 7–14 days; lanreotide ATG: 60, 90, & 120 mg deep SC every 4 wks biochem control GH < 2.5 mg/L ~70% <15% (cabergoline) ↑ GH (pegvisomant) normalization of IGF-I ~70% <15% (cabergoline) >90% (pegvisomant) onset of response rapid slow rapid tumor mass shrinkage ~ 50% unchanged unchanged adverse effects biliary tract disease (biliary sludge, cholelithia- GI symptoms; postural dizziness; na- ↑ LFTs; injection-site lipohyper- sis); impaired glucose tolerance & diabetes; sal congestion; valvular heart dis- trophy; hypercholesterolemia GI symptoms (nausea, vomiting, ab pain) ease * ab = abdominal; biochem = biochemical; GI = gastrointestinal; IM = intramuscular; LFT = liver function test; ↑ = elevated. hormone receptor antagonists have also shown promise Middleton MA, et al: The efficacy and safety of lanreotide in the control of acromegaly, particularly when combined Autogel in patients with acromegaly previously treated with with a somatostatin analog. Novel chimeric compounds octreotide LAR. Eur J Endocrinol 150:473–480, 2004 with both somatostatin and dopamine receptor affinity 5. Ayuk J, Stewart SE, Stewart PM, Sheppard MC: Efficacy of Sandostatin LAR (long-acting somatostatin analogue) is simi- have demonstrated greater suppression of GH than an ago- lar in patients with untreated acromegaly and in those previ- nist alone or in combination. Several somatostatin analogs ously treated with surgery and/or radiotherapy. Clin Endo- show equal efficacy whether given as primary or second- crinol (Oxf) 60:375–381, 2004 ary therapy but result in greater tumor size reduction with 6. Baldelli R, Battista C, Leonetti F, Ghiggi MR, Ribaudo MC, primary treatment. Further studies are needed to evaluate Paoloni A, et al: Glucose homeostasis in acromegaly: effects the effect of presurgical pharmacological treatment on tu- of long-acting somatostatin analogues treatment. Clin Endo- mor characteristics and operative outcome. crinol (Oxf) 59:492–499, 2003 7. Beauregard C, Truong U, Hardy J, Serri O: Long-term out- Disclosure come and mortality after transsphenoidal adenomectomy for acromegaly. Clin Endocrinol (Oxf) 58:86–91, 2003 The authors report no conflict of interest concerning the mate- 8. Bevan JS: Clinical review: the antitumoral effects of somatosta- rials or methods used in this study or the findings specified in this tin analog therapy in acromegaly. J Clin Endocrinol Metab paper. 90:1856–1863, 2005 Author contributions to the study and manuscript preparation 9. Buhk JH, Jung S, Psychogios MN, Göricke S, Hartz S, Schulz- include the following. Conception and design: Manjila. Acquisition Heise S, et al: Tumor volume of growth hormone-secreting of data: Manjila, Wu. Analysis and interpretation of data: Manjila, pituitary adenomas during treatment with pegvisomant: a Wu. 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somatotropinomas and correlation to in vivo hormonal and 53. Yin J, Su CB, Xu ZQ, Yang Y, Ma WB, Tao W, et al: Effect of tumor volume responses to treatment with octreotide LAR. preoperative use of long-acting octreotide on growth hormone Eur J Endocrinol 158:295–303, 2008 secreting pituitary adenoma and transsphenoidal surgery. 50. Thodou E, Kontogeorgos G, Theodossiou D, Pateraki M: Map- Chin Med Sci J 20:23–26, 2005 ping of somatostatin receptor types in GH or/and PRL producing pituitary adenomas. J Clin Pathol 59:274–279, 2006 51. Trainer PJ, Drake WM, Katznelson L, Freda PU, Herman- Manuscript submitted June 15, 2010. Bonert V, van der Lely AJ, et al: Treatment of acromegaly with the growth hormone-receptor antagonist pegvisomant. N Accepted July 27, 2010. Engl J Med 342:1171–1177, 2000 Address correspondence to: Warren R. Selman, M.D., Depart 52. van der Lely AJ, Hutson RK, Trainer PJ, Besser GM, Barkan ment of Neurological Surgery, The Neurological Institute, Uni AL, Katznelson L, et al: Long-term treatment of acromegaly versity Hospitals Case Medical Center, 11100 Euclid Avenue, with pegvisomant, a growth hormone receptor antagonist. HAN 5042, Cleveland, Ohio 44106. email: Warren.Selman@ Lancet 358:1754–1759, 2001 UHhospitals.org.

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