Download Lipodystrophy in Patients with Acromegaly Receiving Pegvisomant

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ARTICLE
R e p o r t
Lipodystrophy in Patients with Acromegaly Receiving
Pegvisomant
Vivien S. Bonert, Laurence Kennedy, Stephan Petersenn, Ariel Barkan, John Carmichael, and
Shlomo Melmed
Department of Medicine (V.S.B., J.C., S.M.), Cedars-Sinai Medical Center, David Geffen School of Medicine at University of California,
Los Angeles, Los Angeles, California 90048; Department of Medicine (L.K.), University of Florida, Gainesville, Florida 32610; Division of
Endocrinology (S.P.), Medical Center, University of Duisburg-Essen, 47048 Duisburg, Germany; and Department of Neurosurgery and
Division of Metabolism, Endocrinology, and Diabetes (A.B.), University of Michigan Medical Center, Ann Arbor, Michigan 48105
Context: Pegvisomant, a GH receptor antagonist, suppresses serum IGF-I levels into the normal
range in more than 95% of patients with acromegaly. Documented side effects in the initial
registration studies included headache, injection-site reactions, flu-like syndrome, and reversible
elevation of hepatic enzymes.
Objective: We report seven patients with acromegaly treated with pegvisomant who developed
lipodystrophy at the site of injection (anterior abdominal wall, thigh, buttock, and upper arm). This
side effect resulted in discontinuation of pegvisomant in four patients, with subsequent regression
of lipohypertrophy.
Subjects: Six female and one male patient with acromegaly, aged 24 –59 yr, are reported. All patients
had undergone prior transsphenoidal surgery, and four received subsequent radiotherapy. Four patients had been treated with maximal doses of somatostatin analogs with partial suppression of IGF-I
levels before initiation of pegvisomant therapy. Pegvisomant suppressed IGF-I levels into the normal
range in five of seven subjects, before discontinuation of the drug. Two of seven patients received
pegvisomant as first-line medical therapy, without prior somatostatin analog treatment, and one
received combination therapy with a long-acting somatostatin analog and weekly pegvisomant injections. One patient experienced an erythematous superficial injection-site reaction that responded
to application of steroid cream before the onset of lipohypertrophy.
Conclusions: We report seven patients with acromegaly who developed lipohypertrophy at the
pegvisomant injection site. Pegvisomant was discontinued due to dissatisfaction with lipohypertrophy by four patients. Lipohypertrophy regressed in all patients when the medication was discontinued. Lipohypertrophy recurred when two patients were rechallenged with pegvisomant.
Patients receiving pegvisomant should undergo frequent examination of injection sites for
lipohypertrophy. (J Clin Endocrinol Metab 93: 3515–3518, 2008)
M
edical treatment of patients with acromegaly is indicated
as either primary or adjunctive therapy after pituitary
tumor resection with or without radiation. Somatostatin analogs
bind to pituitary tumor somatostatin receptors and suppress tumor GH secretion with normal serum IGF-I levels achieved in
more than 65% of patients. These analogs have been the mainstay of effective and well tolerated medical therapy for acro-
megaly for 20 yr (1). Most frequently reported adverse events
of these generally safe peptide analogs include transient, mild
gastrointestinal side effects including gas, abdominal cramps,
diarrhea, and steatorrhea. Twenty percent of patients develop
gallbladder sludge, of whom 20% develop frank asymptomatic gallstones. Injection-site reactions, bradycardia, and alopecia occur rarely (1).
0021-972X/08/$15.00/0
Abbreviations: LAR, Long-acting release; MRI, magnetic resonance imaging.
Printed in U.S.A.
Copyright © 2008 by The Endocrine Society
doi: 10.1210/jc.2008-0833 Received April 17, 2008. Accepted June 26, 2008.
First Published Online July 8, 2008
J Clin Endocrinol Metab, September 2008, 93(9):3515–3518
jcem.endojournals.org
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Bonert et al.
Lipodystrophy and Pegvisomant
J Clin Endocrinol Metab, September 2008, 93(9):3515–3518
TABLE 1.
Case
Age
(yr)
Gender
Year of
diagnosis
TSS
(date)
1
2
3
4
22
50
28
46
F
M
F
F
1999
2001
1998
2002
1999
2001
1998
2003
5
6
7
46
56
36
F
F
F
1999
2003
1997
1999
2004
1997
RT (date)
Hormone replacement,
[drug (date)]
External beam (1999)
Stereotactic radiosurgery (2005)
Levothyroxine (2000)
RT (2006)
Levothyroxine, hydrocortisone
(2000)
Levothyroxine (2000)
␥-Knife (2001)
Levothyroxine
(Continues)
Pegvisomant, a pegylated GH analog, competes with endogenous GH ligand and functions as a peripheral GH receptor
antagonist, blocking hepatic IGF-I production (2). Ninety-seven
percent of patients with acromegaly achieved normal serum
IGF-I levels when treated with pegvisomant for 12 months or
longer (3). Pegvisomant was approved by the U.S. Food and Drug
Administration in 2004, and long-term surveillance is currently
underway to monitor drug safety. Although serum GH levels
initially increase after initiation of therapy and then plateau after
about 2 wk (2), pegvisomant is detected in conventional GH
assays, which could result in falsely elevated estimation of serum
GH concentrations. Adverse effects including headache (26% of
patients), injection-site reactions (11%), pain (23%), and flulike syndrome (21%) were reported in the initial 12-wk pegvisomant study (2). Pegvisomant therapy enhances insulin sensitivity, improves glucose tolerance (4), and lowers glycosylated
hemoglobin levels, suggesting a beneficial effect of the drug on
glucose homeostasis in acromegaly patients both with and without diabetes (5).
Although increased pituitary tumor size due to disrupted
IGF-I inhibitory feedback on the pituitary is a potential adverse
effect of pegvisomant therapy, stable tumor volumes were reported in 131 patients treated for 12 months (3). Reversible
increased serum hepatic transaminase levels were documented in
two of 112 patients treated with pegvisomant for 3 months (2).
Drug-induced hepatitis was observed in a patient receiving combined treatment with pegvisomant and octreotide; hepatic enzymes returned to normal after discontinuation of pegvisomant
and recurred after drug rechallenge (6). A recent surveillance
study reported discontinuing pegvisomant treatment in six of
142 patients because of elevated transaminases (7).
We report here reversible focal lipohypertrophy developing
shortly after initiation of pegvisomant therapy in seven patients
with acromegaly.
Patients
Clinical history
Six female and one male patient (aged 24 –59 yr) with acromegaly,
managed between 1997 and 2008 (Table 1), underwent transsphenoidal
pituitary tumor resection, and four then received radiotherapy. Five pa-
tients subsequently received somatostatin analog therapy with suboptimal control of IGF-I levels and were then treated with sc pegvisomant
injections (10 – 40 mg/d). Pegvisomant was initiated directly after surgery
in two patients without prior somatostatin analog therapy. One patient
received monthly octreotide long-acting release (LAR) 30 mg together
with weekly pegvisomant 15 mg sc. Lipohypertrophy developed 1–12 wk
after initiating pegvisomant therapy. A total of 60 patients have received
pegvisomant therapy in our centers.
Patient 1 developed extensive, firm anterior abdominal wall swelling
that interfered with her ability to dress with her jeans. She had also
injected pegvisomant into her thighs and buttocks and noted swelling at
these sites. On discontinuation of pegvisomant, lipohypertrophy regressed with minimal residual swelling. Nine months later, pegvisomant
therapy was reinitiated to suppress elevated IGF-I levels. Pegvisomant 10
mg sc was initially injected every 3 d into the buttock, and after a month,
increased to alternate-day injections. After 5 months, firm nontender
bilateral buttock swelling developed. A suboptimal IGF-I response necessitated increasing the pegvisomant dose to 30 mg on alternate days
with continued resistance of IGF-I levels. Buttock lipodystrophy persisted, and she elected to discontinue pegvisomant whereupon the lipodystrophy regressed over 2 months.
Patient 2 developed anterior abdominal wall lipohypertrophy
within a week of starting 10 mg daily pegvisomant administered in the
abdomen. Injection site was switched to the thighs with regression of
anterior abdominal wall lipohypertrophy, but swelling developed at
the thigh injection sites. Pituitary-directed stereotaxic radiosurgery
resulted in normal serum IGF-I levels, and pegvisomant was discontinued. Two months later, IGF-I levels increased, pegvisomant therapy was restarted, and lipohypertrophy recurred at the abdominal
injection site.
Patient 3 received pegvisomant (20 mg/d), rotating the injection
site between the thighs and arms, but developed swellings at the arm
and thigh injection sites within 3 months of initiating pegvisomant
therapy. Because the swellings were unsightly, the patient elected to
discontinue pegvisomant after 12 months, despite attaining normal
serum IGF-I levels, and the swellings slowly regressed over the subsequent 6 months.
Patient 4 started pegvisomant therapy after transsphenoidal surgery. She had received preoperative somatostatin analog therapy with
poor control of serum IGF-I levels. Pegvisomant was injected into the
anterior abdominal wall, and the dose was increased to 40 mg/d. She
experienced a dramatic increase in abdominal fat over the 3-month
treatment period, beginning a few weeks after initiation of injections.
Abdominal magnetic resonance imaging (MRI) at the level of the
umbilicus showed increased sc fat tissue thickness.
Patient 5 developed lipohypertrophy of the abdomen while receiving combination therapy with octreotide LAR and weekly pegvisomant injections. She received LAR 30 mg monthly into the buttocks
for 3 months, with partial suppression of IGF-I levels from 849 ng/ml
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TABLE 1. (Continued)
SRIF analog therapy
Starting IGF-I
[ng/ml (date)]
Maximum
dose (mg)
1280 (1999)
LAR 40
1135 (1998) (nl, ⬍380)
616 (2002)
849 (2006) (nl, 60 –304)
LAR 20
LAR 30
LAR 30
653 (2001) (nl, 114 – 492)
LAR 30
Pegvisomant therapy
Nadir IGF-I
(ng/ml)
Starting IGF-I
[ng/ml (date)]
595 (2002) (nl, ⬍492)
440 (2004) (nl, ⬍360)
970
1380 (1998) (nl, ⬍380)
600
712 (2003) (90 –360)
479 (2006) (nl, 88 –249) 479 (nl, 88 –249)
562 (2005) (nl, 71–290)
369 (nl, 115–307)
518 (2006) (nl, 109 –284)
369 (nl, 115–307)
Maximum
dose (mg/d)
10
15
20
40
15
10
15
Nadir IGF-I
(ng/ml)
Imaging
320 (nl, ⬍492)
111 (nl, ⬍360)
150 (nl, ⬍380)
379 (90 –360)
MRI abdomen
410 (nl, 88 –249)
110 (nl, 71–290)
MRI abdomen
142 (nl, 109 –284)
F, Female; M, male; nl, normal; RT, radiotherapy; SRIF, somatostatin; TSS, transsphenoidal surgery.
(60 –304) to 479 ng/ml (88 –249). Subcutaneous weekly pegvisomant
(10 mg) was injected in her thighs. After a month, serum IGF-I levels
were 330 ng/ml (88 –249), and the pegvisomant dose increased to 15
mg weekly. Injection sites were rotated between thigh and abdomen.
After 2 wk on the increased pegvisomant dose, lipohypertrophy of the
anterior abdominal wall and thighs developed. Pegvisomant was
discontinued.
Patient 6 (Fig. 1) noticed swelling of the anterior abdominal wall
4 months after starting pegvisomant (10 mg/d), rotating injection sites
around the umbilicus. The injection site was changed to the thighs
with partial resolution of abdominal lipodystrophy. She did not
develop thigh lipodystrophy and elected to continue pegvisomant
therapy.
Patient 7 developed erythema, pruritus, and injection-site swelling
3 wk after starting pegvisomant (15 mg daily) injected into rotating
sites around the umbilicus. Symptoms resolved with local application
of 1% hydrocortisone cream. Five weeks later, she experienced anterior abdominal wall swelling and then injected the drug into her
thighs, buttocks, and upper arms, with subsequent swelling in all these
areas. Despite no further injections of pegvisomant into the anterior
abdominal wall, the lipohypertrophy persists. She continues to inject
pegvisomant into the buttocks, arms, and legs, and serum IGF-I levels
are normal.
Patients 5 and 7 experienced other side effects while receiving
pegvisomant, including persistent pituitary tumor enlargement on
serial MRI examinations and erythematous superficial injection-site
reaction that responded to topical steroid cream before onset of
lipohypertrophy.
Discussion
Two classes of drugs available to manage patients with acromegaly and GH oversecretion (1) include somatostatin analogs acting primarily at the level of the pituitary tumor and
pegvisomant acting at the periphery to block GH action. Both
these therapies are efficacious and generally safe, and their use
is determined by individual patient clinical needs.
Lipodystrophy, a disorder of adipose tissue involving selective loss or gain of fat cells can be localized and acquired in
association with parenteral drug administration (8). Localized
adipose tissue changes secondary to drug administration result in
depressed skin areas (lipoatrophy) or areas of fat overgrowth
(lipohypertrophy). Before the advent of recombinant insulin, lipoatrophy was commonly associated with insulin administration, likely attributable to a local immune reaction to crystals of
impure insulin preparations (9). Localized lipoatrophy has been
reported as a complication of im injection of benzathine penicillin (10, 11) and steroids (11). After administration of sc octreotide for 2– 6 yr (12), three female patients with acromegaly
developed injection-site lipoatrophy (upper arms, thighs, and
abdomen). After therapy was changed to im octreotide LAR
injection, lipoatrophy regressed in one patient after 12 months
but persisted after 8 and 12 months of therapy in two patients.
Chronic exogenous GH administration to GH-deficient children
results in a relative increase in gluteal relative to abdominal sc fat, presumably due to
decreased sensitivity to the antilipolytic action of insulin (13).
Focal lipohypertrophy of the anterior abdominal wall associated with pegvisomant
has been reported in two patients with acromegaly (14). A biopsy of the mass performed in one patient (15) showed normal
sc adipose tissue devoid of inflammatory
cells or fat necrosis.
Increased fat mass and decreased lean
body mass evident in GH-deficient adults
(16) is reversible with GH administration
(16), highlighting the important role GH
plays in maintenance of adult body composition. Acute GH administration promotes
FIG. 1. Anterior abdominal wall lipohypertrophy in patient 6 at 4 months after injection of pegvisomant.
lipolysis and decreases adiposity (17). FurAbdominal MRI shows increased sc fat in the region of clinical lipohypertrophy in the patient (arrow).
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Lipodystrophy and Pegvisomant
thermore, GH also regulates adipocyte differentiation, although
discrepant results have been reported between preadipocyte cell
lines and primary adipocyte cultures (18). The average size and
lipid content of sc adipocytes in GH-deficient patients is greater
than in GH-replete subjects, and GH therapy decreases both
adipocyte size and lipid content in these patients (19). Our observations suggest that local antagonism of GH action by pegvisomant may result in abrogated GH signaling at the injection site,
with unopposed insulin effects resulting in lipogenesis and increased local adiposity.
Interestingly, six of the seven patients experiencing lipohypertrophy were female, despite the fact that the gender ratio is
approximately 50:50 in acromegaly (20). Furthermore, the three
reported patients with lipohypertrophy associated with octreotide were female (15) as well as one of the two previously
reported cases of lipohypertrophy associated with pegvisomant
(16). The observed female preponderance may be attributable to
a greater female accumulation of sc adipose tissue or may be a
gender-specific adipocyte response.
Localized lipohypertrophy developed at the site of injection (anterior abdominal wall, upper arms, thigh, and buttock) in seven
patients from 1–12 wk after initiating therapy. Four patients moved
the injection site, and all experienced lipohypertrophy at the new
site of injection. Four patients discontinued pegvisomant therapy,
because the lipohypertrophy was unsightly, and experienced regression of the swelling. Two patients were rechallenged with pegvisomant and developed recurrent lipohypertrophy. Whether the development of lipohypertrophy is related to the dose or frequency of
pegvisomant injection has not been determined. However, lipohypertrophy was apparent at lower doses of pegvisomant and even
during combination with somatostatin analog in one patient. Potential antagonism of the effects of GH on local adipocyte lipid
metabolism could result in this newly recognized side effect. Although lipohypertrophy does not appear to have major detrimental
clinical implications, it is a significant side effect, because patient
dissatisfaction or discomfort results from pegvisomant therapy. Patients should be instructed to diligently rotate GH injection sites.
Injection sites of patients with acromegaly receiving pegvisomant
should be monitored for early signs of lipohypertrophy and patients
advised that regression is likely after drug discontinuation.
Acknowledgments
Address all correspondence and requests for reprints to: Vivien Bonert,
M.D., Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los
Angeles, California 90048. E-mail: [email protected].
Disclosure Statement: V.S.B., J.C., and S.M. have nothing to declare.
A.B. and S.P. consult for Pfizer. A.B., S.P., and L.K. have received lecture
fees from Pfizer.
J Clin Endocrinol Metab, September 2008, 93(9):3515–3518
References
1. Melmed S 2006 Medical progress: acromegaly. N Engl J Med 355:2558 –2573
2. Trainer PJ, Drake WM, Katznelson L, Freda PU, Herman-Bonert V, van der Lely
AJ, Dimaraki EV, Stewart PM, Friend KE, Vance ML, Besser GM, Scarlett JA,
Thorner MO, Parkinson C, Klibanski A, Powell JS, Barkan AL, Sheppard MC,
Malsonado M, Rose DR, Clemmons DR, Johannsson G, Bengtsson BA, Stavrou
S, Kleinberg DL, Cook DM, Phillips LS, Bidlingmaier M, Strasburger CJ, Hackett
S, Zib K, Bennett WF, Davis RJ 2000 Treatment of acromegaly with the growth
hormone-receptor antagonist pegvisomant. N Engl J Med 342:1171–1177
3. van der Lely AJ, Hutson RK, Trainer PJ, Besser GM, Barkan AL, Katznelson
L, Klibanski A, Herman-Bonert V, Melmed S, Vance ML, Freda PU, Stewart
PM, Friend KE, Clemmons DR, Johannsson G, Stavrou S, Cook DM, Phillips
LS, Strasburger CJ, Hackett S, Zib KA, Davis RJ, Scarlett JA, Thorner MO
2001 Long-term treatment of acromegaly with pegvisomant, a growth hormone receptor antagonist. Lancet 358:1754 –1759
4. Drake WM, Rowles SV, Roberts ME, Fode FK, Besser GM, Monson JP,
Trainer PJ 2003 Insulin sensitivity and glucose tolerance improve in patients
with acromegaly converted from depot octreotide to pegvisomant. Eur J Endocrinol 149:521–527
5. Barkan AL, Burman P, Clemmons DR, Drake WM, Gagel RF, Harris PE,
Trainer PJ, van der Lely AJ, Vance ML 2005 Glucose homeostasis and safety
in patients with acromegaly converted from long-acting octreotide to pegvisomant. J Clin Endocrinol Metab 90:5684 –5691
6. Feenstra J, van Aken MO, de Herder WW, Feelders RA, van der Lely AJ 2006
Drug-induced hepatitis in an acromegalic patient during combined treatment
with pegvisomant and octreotide long-acting repeatable attributed to the use
of pegvisomant. Eur J Endocrinol 154:805– 806
7. Biering H, Saller B, Bauditz J, Pirlich M, Rudolph B, Johne A, Buchfelder M,
Mann K, Droste M, Schreiber I, Lochs H, Strasburger CJ 2006 Elevated transaminases during medical treatment of acromegaly: a review of the German pegvisomant surveillance experience and a report of a patient with histologically proven
chronic mild active hepatitis. Eur J Endocrinol 154:213–220
8. Garg A 2000 Lipodystrophies. Am J Med 108:143–152
9. Reeves WG, Allen BR, Tattersall RB 1980 Insulin-induced lipoatrophy: evidence for an immune pathogenesis. BMJ 280:1500 –1503
10. Kayikcioglu A, Akyurek M, Erk Y 1996 Semicircular lipoatrophy after intragluteal injection of benzathine penicillin. J Pediatr 129:166 –167
11. Dahl PR, Zalla MJ, Winkelmann RK 1996 Localized involutional lipoatrophy:
a clinicopathologic study of 16 patients. J Am Acad Dermatol 35:523–528
12. Atmaca A, Erbas T 2005 Lipoatrophy induced by subcutaneous administration of octreotide in the treatment of acromegaly. Exp Clin Endocrinol Diabetes 113:340 –343
13. Rosenbaum M, Gertner JM, Leibel RL 1989 Effects of systemic GH administration on regional adipose tissue distribution and metabolism in GH-deficient children. J Clin Endocrinol and Metab 69:1274 –1281
14. Maffei P, Martini C, Pagano C, Sicolo N, Corbetti F 2006 Lipohypertrophy in
acromegaly induced by the new growth hormone receptor antagonist pegvisomant. Ann Intern Med 145:310 –312
15. Marazuela M, Dauden E, Ocon E, Moure D, Nattero L 2007 Pegvisomantinduced lipohypertrophy: report of a case with histopathology. Ann Intern
Med 147:741–743
16. Salomon F, Cuneo RC, Hesp R, Sonksen PH 1989 The effects of treatment with
recombinant human growth hormone on body composition and metabolism
in adults with growth hormone deficiency. N Engl J Med 321:1797–1803
17. Gotherstrom G, Bengtsson BA, Bosaeus I, Johannsson G, Svensson J 2007 A
10-year, prospective study of the metabolic effects of growth hormone replacement in adults. J Clin Endocrinol Metab 92:1442–1445
18. Nam SY, Lobie PE 2000 The mechanism of effect of growth hormone on
preadipocyte and adipocyte function. Obes Rev 1:73– 86
19. Brook CG 1973 Effect of human growth hormone treatment on adipose tissue
in children. Arch Dis Childhood 48:725–728
20. Holdaway IM, Rajasoorya C 1999 Epidemiology of acromegaly. Pituitary
2:29 – 41