The GH-IGF-IGFBP axis is changed in Turner syndrome: partial normalization by HRT.
BACKGROUND
We recently described increased insulin-like growth factor binding protein 3 (IGFBP-3) proteolysis in the circulation in adult Turner syndrome (TS), with normalization during sex hormone replacement therapy (HRT), suggesting the presence of a sex hormone regulated IGFBP-3 proteolytic activity.


OBJECTIVE
To study the GH-IGF-IGFBP axis in TS without and during HRT, and to further characterize the nature of the IGFBP-3 proteolytic activity.


METHODS
23 women with TS before and during HRT, and 24 healthy age-matched women.


METHODS
The study included measurements of the acid-labile subunit (ALS), IGFBP-1, -2 and -3 (immunoreactive and Western ligand blot (WLB)), IGFBP-4 (WLB) and IGF-I bioactivity. To determine the molecular distribution of IGFBP-3, serum from patient and controls was subjected to neutral size-exclusion chromatography followed by determination of the IGFBP profile by WLB and immunoassay. Finally, the inhibitor characteristic of in vitro IGFBP-3 proteolytic activity in serum was determined.


RESULTS
Immunoreactive IGF-I was normal, while IGF-I bioactivity was decreased in TS. Immunoreactive IGFBP-1, -2 and -3 were normal, while WLB-IGFBPs were all reduced, but increased in response to HRT. The IGFBP-3 ternary complex was significantly reduced in TS, and increased in response to HRT, while the non-ternary complexed IGFBP-3 remained unaffected by treatment. In vitro IGFBP-3 proteolytic activity in serum was abolished by aprotinin, while EDTA and zinc chloride had no inhibitory effects, suggesting the presence of a serine protease. 17beta-estradiol had no direct inhibitory effect on the IGFBP-3 proteolytic activity in vitro. Size-exclusion chromatography showed that the protease had a molecular mass of more than 500 kDa.


CONCLUSIONS
The GH-IGF-IGFBP axis is profoundly disturbed in TS, with a partly normalizing effect of HRT. A sex hormone-dependent IGFBP-3 proteolytic activity (serine protease) leads to destabilization of the 150 kDa IGFBP-3 ternary complex in TS. During HRT both IGFBP-3 proteolytic activity and ternary complex formation is normalized.
Gravholt
Claus Højbjerg
CH
Medical Department M (Endocrinology and Diabetes) and Medical Research Laboratories, Aarhus Sygehus NBG, Aarhus University Hospital, Norrebrogade 44, DK-8000 Aarhus C, Denmark. ch.gravholt@dadlnet.dk
Chen
Jian-Wen
JW
Oxvig
Claus
C
Overgaard
Michael T
MT
Christiansen
Jens Sandahl
JS
Frystyk
Jan
J
Flyvbjerg
Allan
A
D000328:Adult; D007611:Aprotinin / Q000494:pharmacology; D002352:Carrier Proteins / Q000097:blood; D016022:Case-Control Studies; D015914:Estrogen Replacement Therapy; D005260:Female; D006023:Glycoproteins / Q000097:blood; D019382:Human Growth Hormone / Q000097:blood*; D006801:Humans; D066298:In Vitro Techniques; 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; D018974:Insulin-Like Growth Factor Binding Protein 4 / Q000097:blood; D018969:Insulin-Like Growth Factor Binding Proteins / Q000037:antagonists & inhibitors / Q000097:blood*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D014424:Turner Syndrome / Q000097:blood* / Q000188:drug therapy* / Q000235:genetics
D002352:Carrier Proteins; D006023:Glycoproteins; C032231:IGFBP1 protein, human; C515497:IGFBP3 protein, human; 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; C075944:insulin-like growth factor binding protein, acid labile subunit; D019382:Human Growth Hormone; D007334:Insulin-Like Growth Factor I; D007611:Aprotinin