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The Journal of Clinical Endocrinology & Metabolism 91(8):2960 –2966 Copyright 2006 by The Endocrine Society Pegvisomant for the Treatment of gsp-Mediated Growth
Hormone Excess in Patients with McCune-Albright
Syndrome

Sunday O. Akintoye, Marilyn H. Kelly, Beth Brillante, Natasha Cherman, Sarah Turner,John A. Butman, Pamela G. Robey, and Michael T. Collins Craniofacial and Skeletal Diseases Branch (S.O.A., M.H.K., B.B., N.C., P.G.R., M.T.C., S.T.) and Diagnostic RadiologyDepartment (J.A.B.), Clinical Center, National Institutes of Health, Department of Health and Human Services, Bethesda,Maryland 20892 Context: GH excess affects approximately 20% of the patients with
in serum IGF binding protein-3 (IGFBP-3), improvement of fatigue McCune-Albright syndrome (MAS). MAS is caused by sporadic, and sweating, and reduction in markers of bone metabolism and bone postzygotic, activating mutations in the GNAS gene, which codes for the cAMP-regulating protein, G ␣ (gsp oncogene). These same mu- tations are found in approximately one third of the sporadic cases of Results: Combined mean changes in serum IGF-I at 6 and 12 wk were
Ϫ236.4 ng/ml (53%, P Ͻ 0.005) and Ϫ329.8 ng/ml (62%, P Ͻ 0.001),respectively. IGFBP-3 decreased by 0.8 mg/liter (24%, P Ͻ 0.01) and Objective: We examined efficacy of the GH receptor antagonist,
2.9 mg/liter (37%, P Ͻ 0.005), respectively. There were no significant pegvisomant, in controlling gsp oncogene-mediated GH excess and changes in signs and symptoms of acromegaly or markers of bone skeletal disease (fibrous dysplasia of bone) associated with MAS.
metabolism and bone pain, nor was there a significant change inpituitary size. Retrospective comparison of the degree of control Setting and Patients: Five MAS patients with GH excess were
achieved with pegvisomant vs. other medications (long-acting oct- treated with 20 mg/d sc injection of pegvisomant for 12 wk in a reotide Ϯ dopamine agonist) in the same group showed that the two randomized, double-blind, placebo-controlled crossover study at the Conclusions: Pegvisomant effectively reduced IGF-I and IGFBP-3
Main Outcome Measures: The primary measure of efficacy was
levels in gsp-mediated GH excess but had no effect on fibrous normalization of IGF-I. Secondary outcome measures were reduction dysplasia. (J Clin Endocrinol Metab 91: 2960 –2966, 2006)
MCCUNE-ALBRIGHT SYNDROME (MAS) is classi- ever, the diagnosis of GH excess in MAS is sometimes dif- cally defined clinically by the triad of polyostotic ficult. In children with MAS, rapid linear growth as a sign of fibrous dysplasia of bone (FD), cafe´-au-lait skin pigmenta- GH excess is often ascribed to PP, which is seen in the tion, and hyperfunctioning endocrinopathies, such as pre- majority of patients with MAS. And whereas patients with cocious puberty (PP), GH excess (acromegaly), hyperthy- PP would be expected to have diminished final height, those roidism, hypercortisolism, and renal phosphate wasting with concomitant GH excess often attain (or exceed) the associated with rickets/osteomalacia (1–3). The underlying predicted midparental height. Therefore, normal stature in a molecular etiology of MAS is a postzygotic mutation of the person with MAS and PP can be a sign of GH excess (8).
GNAS gene (R201H,C,S,G) that encodes for the ␣-subunit of Additionally, the diagnosis is often delayed or missed be- the stimulatory heterotrimeric G protein complex, G ␣ cause the characteristic coarsening of the face, frontal boss- These result in a constitutive activation of the adenylyl cy- ing, and prognathism evolve insidiously and may be ob- clase enzyme signal transduction pathway and dysregulated scured or attributed to the progression of the fibrous production of cAMP (6). The constellation of phenotypic dysplastic bone lesions in the skull, which themselves can presentations seen in MAS is an example of mosaicism and lead to some degree of dysmorphism in the absence of GH results from the involvement of cells in the affected tissues excess. It is important to diagnose and treat GH excess in that harbor the gsp mutation and respond to the hormone- MAS because GH excess is a risk factor for loss of vision and sensitive adenylyl cyclase signal transduction pathway.
hearing (due to GH-fueled expansion of FD) as well as dra- About 20% of MAS patients have GH excess (7, 8). How- matic macrocephaly and dysmorphism (8, 9).
First Published Online May 23, 2006
present in the adenomatous tissue of approximately one Abbreviations: FD, Fibrous dysplasia of bone; IGFBP, IGF binding third of the patients with sporadic acromegaly, suggesting protein; LAR, long-acting sandostatin; MAS, McCune-Albright syn- that these mutations may also be the molecular etiology in drome; MRI, magnetic resonance imaging; OGTT, oral glucose tolerance those sporadic cases of sporadic acromegaly. GH plays a central role in skeletal development and maintenance, both JCEM is published monthly by The Endocrine Society (http://www.
endo-society.org), the foremost professional society serving the en-

through direct effects and those mediated by IGF-I (10). IGFs docrine community.
circulate by binding to six different types of IGF binding Akintoye et al. • Pegvisomant for gsp-Mediated GH Excess J Clin Endocrinol Metab, August 2006, 91(8):2960 –2966 TABLE 1. Demographics and clinical and molecular characterization of the study cohort
n/a, Not applicable; HT, hyperthyroidism; LT, Leydig cell tumor of testes; RPW, renal phosphate wasting; ST, Sertoli cell tumor of the testes; a Substitution of the amino acid cysteine (Cys) or histidine (His) for arginine at position 201 determined from bone specimen.
b See Ref. 14.
c (30), 30 mg/month; DA, dopamine agonist; (), dose of cabergline per week.
proteins (IGFBPs), of which IGFBP-3 is the most abundant MAS in normalizing serum IGF-I and, secondarily, its ability (11, 12) and in some cases may be a sensitive marker for GH to decrease serum IGFBP-3, signs and symptoms of GH ex- cess, bone pain and markers of bone metabolism in the FD Conventional treatments of GH excess include surgery, medications, and radiotherapy. However, in patients withMAS, transphenoidal surgery is often not possible due to Patients and Methods
massive thickening of the skull base with FD, and radiation therapy is avoided because FD is prone to sarcomatous trans- The study was a double-blinded, placebo-controlled, crossover study.
formation after radiation (13). Therefore, medical therapy is Before enrollment, there was a 12-wk washout period during which all often the only reasonable choice. Medical options include medications for the treatment of GH excess were discontinued. Subjects short- and long-acting analogs of somatostatin, dopamine were randomized to either drug or placebo for 12 wk, after which there receptor agonists, and more recently the GH receptor antag- was a 6-wk washout period. Subjects were then crossed over to placeboor drug for the final 12 wk. The primary measure of pegvisomant efficacy onist, pegvisomant. Somatostatin analogs and/or dopamine was the age- and gender-specific normalization of serum IGF-I. Sec- receptor agonists are not always effective in MAS (8), and it ondary measures of efficacy were normalization of serum level of is unclear whether controlling GH excess affects FD. In ad- IGFBP-3, improvement in signs and symptoms of GH excess (sweating dition, there has not been a report on the efficacy of a medical and fatigue), decrease in serum and urine markers of bone metabolism, treatment of GH excess in a population of patients whose and a decrease in bone pain. Serum and urine samples were collectedat baseline and wk 6, 12, 18, 24, 30, and 36. Liver function tests, hemo- disease is of a single molecular etiology. Therefore, we tested gram, and electrocardiogram were performed to monitor for adverse the efficacy of pegvisomant in a population of patients with effects. Change in pituitary size was assessed as a measure of drug safety IGF-I and head circumference. There was a sig-nificant association between head circumference(expressed as percent of the age- and gender-spe-cific upper limit of normal) and baseline serumIGF-I. This is a reflection of macrocephaly, a GHexcess-related morbidity in MAS.
J Clin Endocrinol Metab, August 2006, 91(8):2960 –2966 Akintoye et al. • Pegvisomant for gsp-Mediated GH Excess FIG. 2. Percent change of serum IGF-I during the course of the study.
The change in the serum IGF-I in comparison with the baseline (study entry) value during the pegvisomant treatment (filled squares) andplacebo (open circles) phases are shown. During the pegvisomantphase, the serum IGF-I decreased an average of 63% from baseline.
Patient 4 experienced a 57% increase in serum IGF-I during the course of the placebo phase of the study.
with magnetic resonance imaging (MRI) scanning at baseline and 1 yr.
Pegvisomant was kindly provided by Pfizer Inc. (New York, NY; Phar- macia at the initiation of the study) as single-use, 20-mg strength ly- ophilized powder that was reconstituted with 1 ml saline for injection.
Each vial of pegvisomant or placebo also contained 1.36 mg glycine, 36mg mannitol, 1.04 mg sodium phosphate, dibasic (anhydrous), and 0.36mg monobasic sodium phosphate. Both pegvisomant and placebo ap- peared similar in color after reconstitution. When a patient was on pegvisomant, the first dose was a loading dose of 40 mg followed by daily sc administration of 20 mg. The study was approved by the In- stitutional Review Board of the National Institute of Dental and Cranio- facial Research, National Institutes of Health.
Five patients were studied. There were 10 patients (adults and chil- dren) in the NIH cohort who were eligible for enrollment. Five declined enrollment for personal reasons, which included unwillingness to dis- continue medical treatment for the washout period. MAS was diagnosed by a combination of clinical history; characteristic radiographic and histological features of FD; endocrine testing; and, when necessary, analysis of GNAS gene mutation. The age range was 13–39 yr, with a mean of 28 yr (Table 1). GH excess was diagnosed by clinical signs and symptoms of GH excess, elevated serum GH and IGF-I levels, but the key criterion for the diagnosis was a serum GH that did not suppress less than 1 ng/ml at 60 min on a standard oral glucose tolerance test (OGTT). Patient 2 (Table 1) had a normal IGF-I at baseline but a GH that did not suppress on OGTT and complications known to be associated with GH excess; one optic nerve decompression, and six facial/sinus operations. None of the patients had had pituitary surgery, due to the fact that either a pituitary adenoma was not visualized or they were considered inoperable due to the thickness of the skull base. None of the patients had prior radiotherapy because radiotherapy is a risk factor for transformation of FD to a malignancy (13) and is used only as a last resort. All patients had significant skeletal disease burden of FD (14).
Four of the five patients had a history of other endocrine disorders, but only three had a demonstrable pituitary adenoma by MRI (Table 1).
Serum IGF-I and IGFBP-3 were measured by RIA (Esoterix Inc., Austin TX). Serum lGF-I Z-scores were computed using reference ranges specific for the IGF-I assay. Serum GH was measured using a commercial immunochemiluminometric assay (Mayo Medical Laboratories, Roch- ester, MN) that was modified to avoid cross-reactivity with pegviso- mant. Antipegvisomant antibodies were measured by MDS Pharma Akintoye et al. • Pegvisomant for gsp-Mediated GH Excess J Clin Endocrinol Metab, August 2006, 91(8):2960 –2966 FIG. 3. Sweating, fatigue, and pain scores. Patients keptweekly logs and recorded sweating and fatigue scores (A)and pain scores (B). The mean score Ϯ 1 SD for each patienton drug (filled bars) and placebo (open bars) are shown. Astandardized, validated tool for the assessment of sweatingand fatigue was used (see Refs. 15 and 16), and the BriefPain Inventory was used to assess pain. As a group, therewere no differences in sweating, fatigue, or pain, but twopatients had significantly more pain on drug than placebo.
Services (Montreal, Canada). Patients kept a weekly diary to record circumference were compared with age and gender-matched controls subjective impressions of fatigue and sweating using a visual analog (18), Z-scores were calculated using assay-specific age and gender- scale ranging from 0 (none) to 10 (worst) (15, 16). Physical examination matched reference values (8), and Pearson’s linear regression was used was performed at baseline and wk 12, 18, 30, and 36. Patients were to evaluate correlations and degree of significance. Statistical analyses followed up for at least 12 months after the end of the drug and placebo were two sided, and P Ͻ 0.05 was regarded statistically significant. All analyses were performed with JMP Windows NT 5.1 statistical package Secondary skeletal effects of pegvisomant on FD were assessed by measuring markers of bone metabolism and bone pain. Bone pain wasmeasured using a validated, subjective self-assessment tool developedby the American Pain Society, the Modified Brief Pain Inventory (17).
Bone metabolism markers (serum alkaline phosphatase, bone-specific Pfizer Inc. (Pharmacia), manufacturer of pegvisomant, limited its role alkaline phosphatase, osteocalcin, urine N-telopeptides of collagen, pyr- to supply of drug, placebo, and funds for patient travel and certain idinoline, and deoxypyridinoline cross-links) were measured by stan- assays. Study design, coordination, patient care and testing, data anal- dard commercially available assays (Mayo Medical Laboratories).
ysis, and manuscript preparation were the sole responsibilities of the Pituitary volume was assessed by T1-weighted noncontrast and post- contrast MRI of the brain performed at baseline and 12 months afterenrollment. From sagittal and coronal sequences, anterior-posterior,superior-inferior, and medial-lateral measurements were recorded at the maximum dimension to estimate pituitary gland volume.
All patients had signs and symptoms of GH excess in- cluding macrocephaly, the degree of which correlated withbaseline IGF-I levels (R ϭ 0.91, P Ͻ 0.05, Fig. 1). The mean Pegvisomant and placebo primary efficacy data were accessed as baseline IGF-I for the group was 491 ng/ml.
percentage change from baseline and compared using Fisher’s exact testor the ␹2 test for the comparison of proportions. Continuous measures A daily dose of 20 mg pegvisomant for 12 wk successfully were compared using the two sample t test. Measurements of head reduced serum IGF-I in all patients at 6 wk [combined mean TABLE 3. Serum GH and pegvisomant levels, and anti-pegvisomant antibodies
Mean change in GH compared with baseline (%) P value (differences between placebo and pegvisomant) J Clin Endocrinol Metab, August 2006, 91(8):2960 –2966 Akintoye et al. • Pegvisomant for gsp-Mediated GH Excess TABLE 4. Markers of bone metabolism
Normal range is in parentheses in first column. n/a, Not available.
a No mean changes from baseline were statistically significant.
difference Ϫ263.4 ng/ml (Ϫ53%; P Ͻ 0.005)] and 12 wk Successful medical treatment in this group is especially im- [combined mean difference of Ϫ329.8ng/ml (Ϫ63%; P Ͻ portant because these patients are usually not good candi- 0.001, Table 2)]. The differences in serum IGF-I between dates for surgery due to massive thickening of the skull base baseline or placebo and drug treatment for each patient, with FD, and they are not good candidates for radiation shown as percent changes from baseline, are depicted in Fig.
because FD can undergo sarcomatous transformation with 2. The decrease in IGFBP-3 at 6 wk was significant (combined radiation treatment. The urgency for successful medical mean difference 0.8 mg/liter (24%; P Ͻ 0.01), and 12 wk treatment is intensified by the fact that GH excess in FD is an [combined mean difference Ϫ2.0 mg/liter (37%; P Ͻ 0.001, independent risk factor for the development of disfiguring Table 2)], suggesting that serum IGF-I may be a better mea- macrocephaly as well as vision and hearing loss, presumably sure of pegvisomant efficacy. There was no significant dif- due to GH-stimulated expansion of FD lesions.
ference in the degree of the acromegalic symptoms of fatigue We show here that pegvisomant, a GH receptor antago- and sweating between the drug and placebo phases (Fig. 3), nist, is an effective treatment for GH excess in patients with nor was there a correlation between the severity of these MAS. It significantly lowered both serum IGF-I and IGFBP-3 symptoms and the degree of IGF-I elevation (data not in all patients and normalized these values in all but one shown). Average weekly bone pain score was significantly patient. Whereas this was not a head-to-head trial comparing higher in two patients during pegvisomant treatment, but as the efficacy of pegvisomant with other therapies, the efficacy a group there was no overall effect on pain (Fig. 3).
of pegvisomant was retrospectively compared with that of There was no change in random serum GH at 6 or 12 wk, LAR Ϯ cabergoline. As a group there was no difference in the antibodies to pegvisomant were undetectable throughout degree of control, but one patient (patient 4) whose IGF-I had the study, and serum pegvisomant levels confirmed com- not been normalized by a combination of LAR ϩ cabergoline pliance with study drug use (Table 3).
was controlled on pegvisomant alone (Table 5). The single The levels of the markers of bone metabolism were quite patient whose IGF-I was not normalized by pegvisomant high, but there was no significant effect of treatment on either (patient 1) went on to be treated with a combination of both markers of bone formation (alkaline phosphatase and osteo- LAR and pegvisomant, and even with this combination, the calcin) or resorption (N-telopeptide, pyridinoline, and de- IGF-I did not normalize. This is different from what was seen oxypyridinoline cross-links; Table 4).
One patient had an increase in pituitary volume over a 12-month period, but as a group, there was no change inpituitary volume (Fig. 4). All the patients completed thestudy with no adverse events.
The efficacy of pegvisomant on lowering serum IGF-I was compared with the efficacy of the regimen patients were onbefore the study. Before the study, all patients were treatedwith long-acting sandostatin (LAR) Ϯ cabergoline. The meanpercent decreases in IGF-I by the pretrial regimen and thepegvisomant were 52 and 63%, respectively (Table 5). Onepatient who had not been controlled by LAR ϩ cabergolinewas controlled by pegvisomant alone.
Discussion
The medical treatment of a group of patients with GH excess in the context of MAS offers the unique opportunity FIG. 4. Pituitary volume. The pituitary volume was assessed by MRI to study the effects of a drug in a group of acromegalic at baseline and 12 months later. As a group there was no change in patients whose disease is of a single molecular etiology, gsp.
Akintoye et al. • Pegvisomant for gsp-Mediated GH Excess J Clin Endocrinol Metab, August 2006, 91(8):2960 –2966 TABLE 5. Comparison of response to pretrial medication (Rx) and pegvisomant
a LAR, Long-acting somatostatin agonist sandostatin LAR.
b CAB, Dopamine agonist cabergoline.
c P ϭ 0.13 for difference between pretrial medication (Rx) and pegvisomant.
in an earlier study that reported additive effects of pegvi- Given the potential for tumor shrinkage by LAR and the somant in combination with long-acting somatostatin ana- established long-term safety of long-acting somatostatin an- logs (19). It should be noted that this patient’s weight was 127 alogs, our recommendation for the initial treatment of GH kg, and his baseline GH and IGF-I were very high, 75.6 and excess in MAS is a trial of LAR. If this response is inadequate, 734 ng/ml, respectively. Given his large body mass and very high-dose dopamine agonist or pegvisomant may be added.
high baseline GH and IGF-I values, it is possible that the fixed If medical therapy is inadequate, and access to the pituitary dose (by protocol) of pegvisomant may not have been suf- is not prohibited by bone overgrowth, surgery may be an ficient to call this a pegvisomant failure. Interestingly, in this option. However, even in cases wherein it appears that a group of patients, there was not a significant increase in the single, discreet adenoma is the cause of excess GH, the gland serum GH while on pegvisomant (Table 3), as had been is often diffusely involved with areas of somatotroph hy- reported in other studies (20, 21). The reason for this differ- perplasia, and the only option for surgical cure is total hy- ence is not known but could reflect that feedback inhibition phophysectomy. The remaining option is radiation, which is lost at baseline in gsp-mediated acromegaly and that when should also be approached with caution because FD, which IGF-I is lowered by pegvisomant, there is no further loss of always encases the pituitary in MAS, is prone to sarcomatous feedback inhibition and thus no increase in serum GH.
transformation after treatment doses of radiation (13). This Whereas pegvisomant seems to be marginally better than the risk may be minimized with technologies using focused pretrial medical regimen, there was no significant difference in response to therapy in patients with gsp-mediated GH In summary, pegvisomant effectively controlled GH ex- cess in patients with MAS and was at least as effective as LAR Although pegvisomant lowered serum IGF-I and IGFBP-3, it was disappointing that the drug had no effect on the GHexcess-related symptoms of fatigue and sweating. It is pos- Acknowledgments
sible that this lack of effect was due to either the relatively The authors express their gratitude to Ms. Susan Booher and Judith short duration of treatment or the fact that the dose of pegvi- Starling for their professional support. We thank the National Institutes somant was not titrated to relief of symptoms. It was reas- of Health Interinstitute Endocrine Training Program Fellows and the suring that attenuation of the inhibitory feedback effect of nurses of the National Institutes of Health Clinical Center for the su- high IGF-I caused no change in pituitary volume as a group, at least during the period under study. It is possible thatprogression in tumor size that was observed in one patient Received December 8, 2005. Accepted May 16, 2006.
Address all correspondence and requests for reprints to: Sunday O.
may be the result of disease progression. This point may be Akintoye, B.D.S., D.D.S., M.S., University of Pennsylvania, School of a reflection of the relatively short study length; therefore, as Dental Medicine, Department of Oral Medicine, The Robert Schattner in other medical treatments of GH excess, tumor size should Center Room, 209, 240 South 40th Street, Philadelphia, Pennsylvania be monitored in patients on chronic pegvisomant treatment.
19104. E-mail: akintoye@dental.upenn.edu.
This work was supported by the intramural program of the National One of the expectations of this study was that the blockade Institute of Dental and Craniofacial Research, National Institutes of of GH receptors or the secondary lowering of serum IGF-I Health (Bethesda, MD), and Pfizer Inc. (Pharmacia) (New York, NY).
would improve FD symptoms as assessed by a decrease in Current address for S.A.O.: Department of Oral Medicine, University bone pain and/or a decrease in markers of bone metabolism.
of Pennsylvania, School of Dental Medicine, Philadelphia, Pennsylvania.
Whereas there was a trend toward lower levels of markersof bone metabolism, this was not statistically significant, References
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JCEM is published monthly by The Endocrine Society (http://www.endo-society.org), the foremost professional society serving the
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