Effects of hormone replacement therapy on insulin-like growth factor (IGF)-I, IGF-II and IGF binding protein (IGFBP)-1 to IGFBP-4: implications for cardiovascular risk.
OBJECTIVE
Hormone replacement therapy (HRT) in postmenopausal women is controversial, with an elevated cardiovascular event rate for combined estrogen-progestogen but no adverse cardiovascular effect and possible cumulative benefit for estrogen alone. Here we measured the effects of differing estrogen/progestogen combinations on the insulin-like growth factor (IGF)/IGF binding protein (IGFBP) system which has been implicated in the pathophysiological mechanisms underlying cardiovascular disease, higher IGFBP-1 levels having been linked with a reduced cardiovascular risk.


METHODS
Oral conjugated equine estrogens (CEE) alone, or in combination with the increasingly androgenic progestogens medroxyprogesterone acetate, desogestrel or norethisterone, were given in a randomized triple crossover fashion to 35 healthy postmenopausal women. Serum concentrations of IGFs and the principal circulating IGFBPs were measured.


RESULTS
Circulating IGF-I, IGFBP-3 and IGF-I/IGFBP-3 molar ratio were significantly reduced by CEE. These effects were reversed by progestogens according to their androgenicity. Plasma IGFBP-1 concentration increased from baseline to CEE alone. This rise was opposed by progestogens of increasing androgenicity. IGFBP-2 levels fell and IGFBP-4 increased with CEE, with no further change with addition of progestogens. CEE increased the proportional contribution of IGFBP-1 and IGFBP-4 to total IGFBP binding and decreased the IGFBP-3 contribution. This was reversed by progestogens.


CONCLUSIONS
There are marked changes in molar ratios of the IGFBPs in relation to estrogen/progestogens in HRT. The effect of progestogens on IGF bioavailability could be an important determinant of the longer-term risks of specific HRT preparations by opposing the potentially beneficial effects of CEE alone on cardiovascular risk.
Heald
Adrian
A
Department of Diabetes and Endocrinology, University of Manchester, Salford Royal Hospitals University Trust, Salford, UK. aheald@fs1.ho.man.ac.uk
Kaushal
Kalpana
K
Anderson
Simon
S
Redpath
Mark
M
Durrington
Paul N
PN
Selby
Peter L
PL
Gibson
Martin J
MJ
D001786:Blood Glucose / Q000032:analysis; D002318:Cardiovascular Diseases; D017135:Desogestrel / Q000008:administration & dosage; D015914:Estrogen Replacement Therapy / Q000009:adverse effects*; D004966:Estrogens, Conjugated (USP) / Q000008:administration & dosage; D005260:Female; D006801:Humans; D007328:Insulin / Q000097:blood; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000097:blood; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000097:blood; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000097:blood; D018974:Insulin-Like Growth Factor Binding Protein 4 / Q000097:blood; D018969:Insulin-Like Growth Factor Binding Proteins / Q000097:blood*; D007334:Insulin-Like Growth Factor I / Q000032:analysis*; D007335:Insulin-Like Growth Factor II / Q000032:analysis*; D017258:Medroxyprogesterone Acetate / Q000008:administration & dosage; D008875:Middle Aged; D009640:Norethindrone / Q000008:administration & dosage; D017698:Postmenopause; D011372:Progestins / Q000008:administration & dosage; D012307:Risk Factors
D001786:Blood Glucose; D004966:Estrogens, Conjugated (USP); D007328:Insulin; D018970:Insulin-Like Growth Factor Binding Protein 1; D018971:Insulin-Like Growth Factor Binding Protein 2; D018972:Insulin-Like Growth Factor Binding Protein 3; D018974:Insulin-Like Growth Factor Binding Protein 4; D018969:Insulin-Like Growth Factor Binding Proteins; D011372:Progestins; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D017135:Desogestrel; D017258:Medroxyprogesterone Acetate; D009640:Norethindrone