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Influence of Growth Hormone Receptor d3 and Full-Length Isoforms on Biochemical Treatment Outcomes in Acromegaly

Division of Endocrinology (A.B., V.C., A.P., L.D.M.) and Internal Medicine (R.P., F.A.), Catholic University School of Medicine, 00168 Rome, Italy; and Department of Medical and Surgical Sciences (A.G.), University of Brescia, 25121 Brescia, Italy

Address all correspondence and requests for reprints to: Dr. Antonio Bianchi, Division of Endocrinology, Catholic University, School of Medicine, Largo A. Gemelli, 8, 00168 Rome, Italy. E-mail: abianchi69{at}yahoo.it.

Context: In acromegaly, a discrepancy between what are defined as "normal" levels of GH and IGF-I for every given patient is observed in up to 35% of subjects at diagnosis and during the follow-up.

Objective: The aim of the study was to evaluate the impact of GH receptor (GHR) polymorphism on the biochemical assessment of the treatment of acromegaly and on prevalence of discordant levels of GH and IGF-I.

Setting: The study was performed in an institutional referral center at a tertiary care hospital.

Design, Patients, and Methods: We studied prospectively and retrospectively 84 consecutive acromegalic patients with active disease after neurosurgery and treated them with somatostatin analogs. The GHR genotype (flfl, fld3, or d3d3) was determined from peripheral blood.

Results: Lack of exon 3 of GH receptor (d3-GHR) was found in 40 of 84 patients (47.6%). After neurosurgery, 67 subjects (79.8%) of the study population, concordant active acromegalic patients, had high IGF-I and mean GH levels above 2 ng/ml, whereas the remaining 17 patients (20.2%, discordant active acromegalic patients) showed discordance between these two parameters (high IGF-I and GH levels 2 ng/ml). Overall, 70.6% of discordant patients were carriers of the d3-GHR. After somatostatin analogs, discordant active acromegalic patients increased to 30.9%, 69.2% of whom were carriers of the d3-GHR. Logistic regression analysis demonstrated that d3-GHR carriers maintained the significant correlation with discordant GH and IGF-I values either after neurosurgery or after somatostatin analog treatment, independently of the effects of age, sex, duration of acromegaly, serum GH, and IGF- I values either at diagnosis of acromegaly or after neurosurgery.

Conclusion: The GHR polymorphism seems to have a relevant impact on the posttreatment biochemical assessment of acromegaly. Moreover, the d3-GHR isoform could be an independent predictor of GH and IGF-I discrepancy during the follow-up in acromegaly.