Growth hormone receptor polymorphism and the effects of pegvisomant in acromegaly Antonio Bianchi Æ Gherardo Mazziotti Æ Laura Tilaro Æ Vincenzo Cimino Æ Flora Veltri Æ Eleonora Gaetani Æ Giovanni Pecorini Æ Alfredo Pontecorvi Æ Andrea Giustina Æ Laura De Marinis Published online: 17 December 2008 Ó Springer Science+Business Media, LLC 2008 Abstract Background Sensitivity to pegvisomant therapy is highly variable in patients with acromegaly but determinants of this variability are still unknown. Lack of exon 3 (d3-) of the growth hormone (GH) receptor (GHR) has been associated with increased biological activity of GH. Objective To assess whether the presence of d3- GHR haplotype may have a role in predicting dose regimen and response to pegvisomant in acromegaly. Design Case series. Setting Institutional referral center at a ter- tiary care hospital. Patients Ninenteen acromegalic patients with active disease after unsuccessful neurosurgery and somatostatin analog therapy. Measurements before and 1, 3, 6 and 12 months after treatment with pegviso- mant, IGF-I; GH receptor genotype, determined from peripheral blood by polymerase chain reaction. All patients started treatment with pegvisomant at 10 mg/daily and then increased the dose, according to a fixed schedule, during a 12-month follow-up until normalization of IGF-I levels. Results d3-GHR patients required a significant lower dose of pegvisomant and shorter treatment time to nor- malize IGF-I. Conclusion the GHR genotype could be useful in predicting dose and individual response to peg- visomant in acromegaly. Keywords Growth hormone Á Acromegaly Á Growth hormone receptor (GHR) Á Exon 3 Á Pegvisomant Introduction Pegvisomant, a pegylated recombinant analog of human growth hormone (GH) which acts functionally as a GH receptor antagonist is used in patients with acromegaly resistant to neurosurgery and somatostatin analogs [1–3]. Sensitivity to pegvisomant is highly variable in acro- megaly; in fact, normalization of serum IGF-I levels, which is obtained in up to 97% of patients, may require dramat- ically variable amount of drug (from 10 to 80 mg/daily) [4, 5]. Multiple factors have been so far hypothesized to influence the dose of pegvisomant required to normalize IGF-I such as baseline serum GH and IGF-I, previous radiotherapy, sex and body weight [6]. However, interest- ingly, to date there is no specific recommendation on how to adjust the dose in each patient with acromegaly. The GH receptor (GHR) is a single peptide chain, containing an extracellular hormone-binding, a transmem- brane and a cytoplasmic domain [7]. The GHR gene consists of nine exons that encode the receptor and several additional untranslated exons [8, 9]. Two messenger ribo- nucleic acid (mRNA) transcripts, differing in the coding part of the GHR, have been identified for the human GHR: one, the wild type, homozygous for the full length GHR isoform, (fl/fl or fl-GHR), and the other lacking exon 3 (d3-GHR), either homozygous (d3/d3) or heterozygous, (fl/d3) [10, 11]. The frequency of the d3-GHR genotype is quite high (about 50% of the general population). Origi- nally, studies in children suggested that the presence of the d3-GHR polymorphism confers a greater sensitivity to exogenous rhGH administration [12–14]. Moreover, lack A. Bianchi (&) Á L. Tilaro Á V. Cimino Á F. Veltri Á A. Pontecorvi Á L. De Marinis Division of Endocrinology, School of Medicine, Catholic University, Largo A. Gemelli, 8, 00168 Rome, Italy e-mail: abianchi69@yahoo.it G. Mazziotti Á A. Giustina Department of Medical and Surgical Sciences, University of Brescia, Brescia, Italy E. Gaetani Á G. Pecorini Internal Medicine, School of Medicine, Catholic University, Rome, Italy 123 Pituitary (2009) 12:196–199 DOI 10.1007/s11102-008-0157-8