title: Effects of raloxifene and estrogen on bioactive IGF1 in GH-deficient women.
abstract: BACKGROUND
  GH action is attenuated by estrogens and selective estrogen receptor modulators (SERMs) administered orally. During GH therapy in hypopituitary women, co-treatment with raloxifene, a SERM, induced a smaller gain in lean body mass (LBM) compared with estrogen, despite an equal reduction in IGF1. As a higher IGF-binding protein-3 (IGFBP3) level was observed with raloxifene co-treatment, we hypothesize that an increase in IGFBP3 reduced IGF1 bioactivity causing the attenuated anabolic effect.
  
  
  OBJECTIVE
  To assess the effects of 17β-estradiol (E₂) and raloxifene on bioactive IGF1.
  
  
  METHODS
  In study 1, 12 GH-deficient (GHD) women were randomized to raloxifene 120 mg/day or E₂ 4 mg/day for 1 month. In study 2, 16 GHD women were randomized to 1 month GH treatment alone (0.5 mg/day) and in combination with raloxifene (60 mg/day) or E₂ (2 mg/day). We measured bioactive IGF1, immunoreactive IGF1 and IGF2, and IGFBP3 immunoreactivity and fragmentation.
  
  
  RESULTS
  Raloxifene and estrogen suppressed (P<0.05) total IGF1 equally in GHD and GH-replaced hypopituitary women. In GHD patients, neither raloxifene nor estrogen affected bioactive IGF1. GH significantly increased IGF1 bioactivity, an effect attenuated by co-treatment with raloxifene (Δ -23 ± 7%, P<0.01) and estrogen (Δ -26 ± 3%, P=0.06). Total IGF1 correlated (r(2)=0.54, P<0.001) with bioactive IGF1, which represented 3.1 ± 0.2% of the total IGF1, irrespective of the treatments. Total IGF2 was unchanged by raloxifene and estrogen treatment. IGFBP3 was significantly higher during raloxifene administration, whereas no differences in IGFBP3 fragmentation were observed.
  
  
  CONCLUSIONS
  Raloxifene effect on bioactive IGF1 is similar to that of estrogen despite higher IGFBP3 levels during raloxifene administration. We conclude that the observed different effects on LBM between raloxifene and estrogen treatments cannot be explained by differences in IGF1 bioactivity.
authors.affiliation: Department of Endocrinology, Garvan Institute of Medical Research, St Vincent's Hospital, Sydney, New South Wales, Australia.
authors.forename: Vita
authors.initials: V
authors.lastname: Birzniece
authors.forename: Nils Erik
authors.initials: NE
authors.lastname: Magnusson
authors.forename: Ken K Y
authors.initials: KK
authors.lastname: Ho
authors.forename: Jan
authors.initials: J
authors.lastname: Frystyk
mesh_terms: D000328:Adult; D004958:Estradiol / Q000627:therapeutic use*; D005260:Female; D057809:HEK293 Cells; D019382:Human Growth Hormone / Q000172:deficiency* / Q000627:therapeutic use; D006801:Humans; D007018:Hypopituitarism / Q000188:drug therapy; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D007335:Insulin-Like Growth Factor II / Q000378:metabolism; D008875:Middle Aged; D020849:Raloxifene Hydrochloride / Q000627:therapeutic use*
chemical_list: C035170:IGF2 protein, human; C515497:IGFBP3 protein, human; D018972:Insulin-Like Growth Factor Binding Protein 3; D019382:Human Growth Hormone; D020849:Raloxifene Hydrochloride; D004958:Estradiol; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II