Vivien Herman-Bonert

BACKGROUND: Patients with acromegaly are currently treated with surgery, radiation therapy, and drugs to reduce hypersecretion of growth hormone, but the treatments may be ineffective and have adverse effects. Pegvisomant is a genetically engineered growth hormone-receptor antagonist that blocks the action of growth hormone. METHODS: We conducted a 12-week, randomized, double-blind study of three daily doses of pegvisomant (10 mg, 15 mg, and 20 mg) and placebo, given subcutaneously, in 112 patients with acromegaly. RESULTS: The mean (+/-SD) serum concentration of insulin-like growth factor I (IGF-I) decreased from base line by 4.0+/-16.8 percent in the placebo group, 26.7+/-27.9 percent in the group that received 10 mg of pegvisomant per day, 50.1+/-26.7 percent in the group that received 15 mg of pegvisomant per day, and 62.5+/-21.3 percent in the group that received 20 mg of pegvisomant per day (P<0.001 for the comparison of each pegvisomant group with placebo), and the concentrations became normal in 10 percent, 54 percent, 81 percent, and 89 percent of patients, respectively (P<0.001 for each comparison with placebo). Among patients treated with 15 mg or 20 mg of pegvisomant per day, there were significant decreases in ring size, soft-tissue swelling, the degree of excessive perspiration, and fatigue. The score fortotal symptoms and signs of acromegaly decreased significantly in all groups receiving pegvisomant (P< or =0.05). The incidence of adverse effects was similar in all groups. CONCLUSIONS: On the basis of these preliminary results, treatment of patients who have acromegaly with a growth hormone-receptor antagonist results in a reduction in serum IGF-I concentrations and in clinical improvement.

Pituitary adenomas result in clinical sequelae and accelerated mortality due to central mass effects or pituitary hormone hypersecretion and/or insufficiency. The low annual incidence and prolonged natural history of these rare tumors has hindered efforts to evaluate long-term clinical outcomes. Care of these patients is often provided by larger tertiary specialist referral centers. A novel evidence-based computerized pituitary tumor registry was developed to systematically evaluate epidemiological, biochemical, and clinical outcome data. Retrospective registration of 371 patients [99 clinically nonfunctioning tumors (CNFTs), 176 acromegalics, and 96 prolactinomas] with radiological, biochemical, and clinical evidence of pituitary tumors was performed. Analysis of this primarily specialist-referred population revealed a female predominance among CNFT (60%) and prolactinoma (69%) patients. Males had a significantly greater frequency of macroadenomas than females for CNFTs (92% vs. (68%) and for prolactinomas (74% vs. 40%). Males with prolactinomas also had higher mean pretreatment serum PRL levels (1206 vs. 219 ng/mL). Concurrent hyperprolactinemia was present in CNFT (47%) and acromegaly (33%) patients. Radiographic cure, defined as absence of visualized tumor, was achieved in 21% of CNFTs, 34% of acromegalies, and 21% of prolactinomas. Biochemical remission, defined by normalization of hormonal tumor markers, was observed in 35% of acromegaly and 39% of prolactinoma patients in the registry, thus reflecting the tertiary referral patterns. Nine premature deaths (patients aged < or =65 yr) occurred in the acromegaly subpopulation, whereas no premature deaths were encountered in nonacromegalic patients. In conclusion, this unique and comprehensive pituitary tumor registry enables identification of diagnostic and prognostic markers and evaluation of long-term clinical outcomes. Prospectively, this registry will improve therapeutic guidelines and cost-effective pituitary tumor management.

Transsphenoidal surgical resection is the primary therapy for acromegaly caused by GH secreting pituitary adenomas. Medical therapy for patients not controlled by surgery includes primarily somatostatin analogs and secondarily dopamine agonists, both of which inhibit pituitary growth hormone secretion. A novel GH receptor antagonist (pegvisomant) binds to hepatic GH receptors and inhibits peripheral insulin-like growth factor-1 generation. Six patients resistant to maximal doses of octreotide therapy received pegvisomant - three received placebo or pegvisomant 30 mg or 80 mg weekly for 6 weeks and three received placebo and pegvisomant 10-20 mg/d for 12 weeks. Thereafter, all patients received daily pegvisomant injections of doses determined by titrating IGF-1 levels. Serum total IGF-1 levels were normalized in all six acromegalic patients previously shown to be resistant to somatostatin analogs via a novel mechanism of peripheral GH receptor antagonism. The GH receptor antagonist is a useful treatment for patients harboring GH-secreting tumors who are resistant to octreotide.