The GH–IGF–IGFBP axis is changed in Turner syndrome: Partial normalization by HRT

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• 作者：Claus Hø ; jbjerg Gravholt ; Jian-Wen Chen ; Claus Oxvig ; Michael T. Overgaard ; Jens S ; ahl Christiansen ; Jan Frystyk ; Allan Flyvbjerg
• 关键词：Turner syndrome ; IGF-I ; IGFBP-3 proteolysis ; Acid-labile subunit ; Ternary complex ; 17β ; -Estradiol ; Insulin-like growth factor-binding proteins
• 刊名：Growth Hormone & IGF Research
• 出版年：2006
• 出版时间：October-December 2006
• 年：2006
• 卷：16
• 期：5-6
• 页码：332-339
• 全文大小：283 K

文摘

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.

Material

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. 17β-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.

Conclusion

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.