MECHANISMS IN ENDOCRINOLOGY: Clinical and pharmacogenetic aspects of the growth hormone receptor polymorphism

Abstract

Pharmacogenetics aims to maximize the beneficial effects of a medical therapy by identifying genetic finger prints from responders and non-responders and, thereby improving safety and efficacy profile of the drug. Most subjects who are deficient in growth hormone (GHD) are candidates for recombinant human GH (rhGH) therapy. To date, it is well established that even after adjustments for several clinical variables, such as age, gender, body composition and the age at onset of the GHD, response to rhGH treatment is highly variable among individuals, part of which is believed to be due to genetic factors within the GH system. As the first genetic variant to potentially influence the individual response to rhGH therapy in children with growth disorders, polymorphism in the GH receptor (GHR) has attracted a great interest as a target for pharmacogenetics. Studies have been conducted to compare the functional and molecular effects of the full-length GHR (fl-GHR) isoform with the exon 3 deleted (d3-GHR) isoform in children and adults treated with rhGH therapy. Additionally, the impact of the GHR polymorphism has been investigated in relation to the clinical status and response to medical treatment in acromegaly, especially to the GHR antagonist drug pegvisomant. We have performed a narrative review of the studies performed to date on the association of GHR polymorphism with rhGH response in children and adults, and its potential influence in the medical management of acromegaly. In addition, data from studies on the general population and in other chronic diseases examining a role of this genetic variant in the regulation of growth and metabolism are summarized. The growth hormone receptor (GHR)Growth hormone (GH) exerts its biological effects by binding to the GH receptor (GHR). The GHR protein is positioned at the cell membrane of almost every cell in the human body and contains a 246 amino acids long extracellular (GH-binding) domain, a transmembrane domain and a 350 amino acids long intracellular (cytoplasmic) domain. In total, the GHR protein is composed of 638 residues (1). Binding of GH to the GHR induces a series of subtle conformational events within a receptor homodimer, rather than a simple receptor dimerization, promoting a realignment of the two receptors both by relative rotation and by closer apposition just above the cell membrane (2). The parallel receptor transmembrane domains are converted into a rotated crossover orientation and the lower parts of the transmembrane helices are separated. GHR activation

Molecular targets in acromegaly

“…A novel drug in development, Cimdelirsen (IONIS-GHR-LRx; ISIS 766720), which is an antisense molecule that acts by reducing GHR synthesis in the liver, has also shown promise in treating acromegaly ( 33 ). Polymorphisms in GHR, such as d3-GHR, has been studied in acromegaly but correlation with clinical features or therapeutic outcomes has not been consistent ( 34 ).…”

Personalized approach to growth hormone replacement in adults

“…dose titration, adherence), in patients who were homozygous for the full-length receptor (33). Other studies, however, did not show any impact of GH receptor polymorphism on treatment response (32).…”

“…It was initially shown in a pediatric study that patients carrying the d3-receptor had a better growth response to GHRT than those with the full-length receptor (31). Since then, several studies in both children and adults have been performed in an attempt to further investigate the impact of the GH receptor isoforms on clinical response to GHRT and their findings have been detailed in a recent review (32). In summary, trials with a duration longer than 6 months showed that patients carrying the d3-receptor isoform had a marginally larger serum IGF-1 response, i.e.…”

Treatment with Growth Hormone for Adults with Growth Hormone Deficiency Syndrome: Benefits and Risks

“…GHRs belong to the class I cytokine receptor family along with prolactin, erythropoietin, leptin and interleukins receptor [ 86 , 87 ]. The GHR receptor polymorphism has been extensively studied [ 88 ]. The GHR is a membrane receptor composed of 638 amino acids with three cellular domains: an extracellular, a transmembrane and an intracellular domain.…”

“…Taking into account the studies published to date, there is little evidence that GHR polymorphism have an important impact in the clinical manifestations of the syndrome of adult GHD. The importance of the d3-GHR variant on the response of adult GHD patients to GH replacement is unclear at the present time [ 88 , 110 ].…”