title: A randomized controlled clinical trial of growth hormone in amyotrophic lateral sclerosis: clinical, neuroimaging, and hormonal results.
abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease with motor neuron degeneration. Riluzole is the only available treatment. Two-thirds of ALS patients present with growth hormone (GH) deficiency. The aim of this study is to determine if add-on of GH to riluzole, with an individually regulated dose based on Insulin-like growth factor 1 (IGF-I) production, was able to reduce neuronal loss in the motor cortex, reduce mortality, and improve motor function of ALS patients. Patients with definite/probable ALS, in treatment with riluzole, aged 40-85 years, and with disease duration ≤3 years were enrolled. The study was randomized, placebo controlled, and double blind. Before treatment, patients were tested with a GH releasing hormone (GHRH) + arginine test. The initial dose of GH was 2 IU s.c. every other day, and was progressively increased to a maximum of 8 IU. Primary endpoint was N-acetylaspartate/(creatine + choline) (NAA/Cre + Cho) ratio in motor cortex assessed by magnetic resonance spectroscopy performed at months 0, 6, and 12. Secondary endpoints were mortality and ALS functional rating scale revised (ALSFRS-R). The NAA/(Cre + Cho) ratio decreased in all patients who completed the trial. No significant difference was noted between treated and placebo group. At baseline, although IGF-I levels were within the normal range, 73% of patients had GH deficiency, being severe in half of them. Compared with bulbar onset, spinal-onset patients showed more depressed GH response to the GHRH + arginine stimulation test (10.4 ± 7.0 versus 15.5 ± 8.1 ng/mL; p < 0.05). Insulin resistance [homeostasis model assessment of insulin resistance (HOMA-IR)] increased from 2.1 ± 1.0 at baseline to 4.6 ± 1.9 at 12 months (p < 0.001). Insulin-like growth factor (IGF) binding protein 3 (IGFBP-3) decreased from 8,435 ± 4,477 ng/mL at baseline to 3,250 ± 1,780 ng/mL at 12 months (p < 0.001). The results show that GH exerted no effect on cerebral NAA or clinical progression assessed by ALSFRS-R. Two-thirds of ALS patients had GH deficit, with higher levels in the bulbar-onset group. During follow-up, patients showed progressive increase in HOMA-IR and decrease in IGFBP-3 levels.
authors.affiliation: Department of Neurological Sciences, University Federico II, Via Pansini, 5, 80131 Naples, NA, Italy. francesco.sacca@unina.it
authors.forename: Francesco
authors.initials: F
authors.lastname: Saccà
authors.forename: Mario
authors.initials: M
authors.lastname: Quarantelli
authors.forename: Carlo
authors.initials: C
authors.lastname: Rinaldi
authors.forename: Tecla
authors.initials: T
authors.lastname: Tucci
authors.forename: Raffaele
authors.initials: R
authors.lastname: Piro
authors.forename: Gaetano
authors.initials: G
authors.lastname: Perrotta
authors.forename: Barbara
authors.initials: B
authors.lastname: Carotenuto
authors.forename: Angela
authors.initials: A
authors.lastname: Marsili
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Palma
authors.forename: Giuseppe
authors.initials: G
authors.lastname: De Michele
authors.forename: Arturo
authors.initials: A
authors.lastname: Brunetti
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Brescia Morra
authors.forename: Alessandro
authors.initials: A
authors.lastname: Filla
authors.forename: Marco
authors.initials: M
authors.lastname: Salvatore
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D001120:Arginine; D002794:Choline / Q000097:blood; D003401:Creatine / Q000097:blood; D004311:Double-Blind Method; D023381:Endpoint Determination; D005260:Female; D006728:Hormones / Q000097:blood*; D019382:Human Growth Hormone / Q000097:blood / Q000627:therapeutic use*; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007333:Insulin Resistance; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000097:blood; D007334:Insulin-Like Growth Factor I / Q000032:analysis; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009044:Motor Cortex / Q000473:pathology; D059906:Neuroimaging; D018696:Neuroprotective Agents / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000627:therapeutic use; D019782:Riluzole / Q000627:therapeutic use
chemical_list: D006728:Hormones; D018972:Insulin-Like Growth Factor Binding Protein 3; D018696:Neuroprotective Agents; D011994:Recombinant Proteins; D019382:Human Growth Hormone; D007334:Insulin-Like Growth Factor I; D019782:Riluzole; D001120:Arginine; D003401:Creatine; D002794:Choline