title: Progestins abrogate estrogen-induced changes in the insulin-like growth factor axis.
abstract: OBJECTIVE
  We sought to investigate the effect of oral progestins on estrogen-mediated changes in the insulin-like growth factor axis in the peripheral circulation.
  
  
  METHODS
  Oral conjugated equine estrogen alone or in combination with medroxyprogesterone acetate, desogestrel, or norethindrone was given in a randomized triple-crossover fashion to 10 healthy postmenopausal women, and the effects on the insulin-like growth factor axis were determined.
  
  
  RESULTS
  Baseline circulating insulin-like growth factor I levels were significantly reduced by conjugated equine estrogen (359 +/- 54 vs 225 +/- 44 ng/mL; P =.0001). This effect was reversed by progestins (medroxyprogesterone acetate, 254 +/- 44 ng/mL; desogestrel, 266 +/- 50 ng/mL; norethindrone, 286 +/- 48 ng/mL; F = 12.2; P =.0015). Free insulin-like growth factor I was reduced by conjugated equine estrogen (1.00 +/- 0.15 ng/mL vs 2.10 +/- 0.39 ng/mL; P =.004), but addition of progestogens had no further effect. Insulin-like growth factor II and insulin levels were unaffected by conjugated equine estrogen or progestins. Plasma insulin-like growth factor binding protein 1 concentration increased significantly from baseline with conjugated equine estrogen alone (44.1 +/- 6.0 vs 154 +/- 30 microg/L; P =.003). This rise was opposed by progestins of increasing androgenicity (medroxyprogesterone acetate, 130 +/- 26 microg/L; desogestrel, 100 +/- 16 microg/L; norethindrone, 78.0 +/- 12 microg/L; F = 12.5; P =.0015). Insulin-like growth factor binding protein 3 levels fell with conjugated equine estrogen, and this was reversed by progestins (conjugated equine estrogen, 2.17 +/- 0.13 mg/L; vs norethindrone and conjugated equine estrogen, 2.41 +/- 0.12 mg/L; F = 7.6; P =.01). Insulin-like growth factor binding protein 4 levels increased with conjugated equine estrogen with or without progestins, whereas insulin-like growth factor binding protein 2 levels were unchanged.
  
  
  CONCLUSIONS
  Coadministration of androgenic progestins abrogates estrogen-related changes in circulating insulin-like growth factor I, insulin-like growth factor binding protein 1, and insulin-like growth factor binding protein 3. Such hormone replacement therapy-induced changes may have significant consequences for the development of cardiovascular disease and osteoporosis and implications for the use of insulin-like growth factor I in monitoring growth hormone replacement.
authors.affiliation: Endocrine Sciences Research Group, Department of Medicine, University of Manchester, Manchester, United Kingdom.
authors.forename: A
authors.initials: A
authors.lastname: Heald
authors.forename: P L
authors.initials: PL
authors.lastname: Selby
authors.forename: A
authors.initials: A
authors.lastname: White
authors.forename: J M
authors.initials: JM
authors.lastname: Gibson
mesh_terms: D018592:Cross-Over Studies; D017135:Desogestrel / Q000008:administration & dosage / Q000494:pharmacology; D004347:Drug Interactions; D004967:Estrogens / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007328:Insulin / Q000097:blood / Q000494:pharmacology; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000097:blood; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000097:blood; D018974:Insulin-Like Growth Factor Binding Protein 4 / Q000097:blood; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D007335:Insulin-Like Growth Factor II / Q000378:metabolism; D017258:Medroxyprogesterone Acetate / Q000008:administration & dosage / Q000494:pharmacology; D008875:Middle Aged; D009640:Norethindrone / Q000008:administration & dosage / Q000494:pharmacology; D011372:Progestins / Q000008:administration & dosage / Q000494:pharmacology*; D013002:Somatomedins / Q000378:metabolism*
chemical_list: D004967:Estrogens; D007328:Insulin; D018970:Insulin-Like Growth Factor Binding Protein 1; D018971:Insulin-Like Growth Factor Binding Protein 2; D018974:Insulin-Like Growth Factor Binding Protein 4; D011372:Progestins; D013002:Somatomedins; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D017135:Desogestrel; D017258:Medroxyprogesterone Acetate; D009640:Norethindrone