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BRIEF REPORT |
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
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: Vivian.Bonert{at}cshs.org.
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Abstract |
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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.
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Introduction |
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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 flu-like 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.
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Patients |
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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 patients 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.
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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 (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.
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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.
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Discussion |
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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 lipolysis and decreases adiposity (17). Furthermore, 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.
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Footnotes |
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First Published Online July 8, 2008
Abbreviations: LAR, Long-acting release; MRI, magnetic resonance imaging.
Received April 17, 2008.
Accepted June 26, 2008.
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