Hamilton-Fairley, Diana; (1996) Regulation of sex hormone binding globulin and insulin-like growth factor binding protein-1. Doctoral thesis (M.D), UCL (University College London).

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Abstract

Women with polycystic ovary syndrome (PCOS) present most commonly with hirsutism and/or anovulation. The prevalence of hirsutism and/or menstrual irregularity is increased in obese women with PCOS compared with lean women with PCOS. It is, therefore, possible that factors associated with obesity exacerbate the symptoms and the underlying hormonal abnormality of this condition. Sex hormone binding globulin (SHBG) and insulin-like growth factor binding protein-1 (IGFBP1) concentrations are reduced in PCOS and decline during puberty in boys and girls. The regulation of sex hormone binding globulin has been thought to be primarily by the sex steroid hormones and that of IGFBP1 by insulin. The hypothesis of this thesis is that dietary factors are more important than the sex steroids in the regulation of hepatic SHBG production and that this is of relevance in understanding the relationship between obesity and hirsutism in women with polcystic ovary syndrome. In addition insulin also regulates hepatic IGFBP1 production implying that the two binding proteins may be co-regulated. The role of sex steroids in the regulation of IGFBP1 is not known. The regulation of hepatic production of SHBG and IGFBP1 by insulin, IGF-1 and the sex steroids was studied in-vitro by cell culture experiments on Hepatocarcinoma G2 cells. The relationship of dietary factors on androgen metabolism and circulating SHBG and IGFBP1concentrations was investigated in three separate studies. In the first two studies women with PCOS were studied before and after calorie restriction and during an oral glucose tolerance test (OGTT). A third study conducted over a 24 hour period investigated the diurnal variation in SHBG and IGFBP1 related to that of insulin and IGF-1. The cell culture experiments demonstrated a role of insulin and IGF-1 as inhibitors of hepatic SHBG production but only insulin inhibited the secretion of IGFBP1. The effect of the sex steroids was less clear since testosterone increased SHBG production while oestradiol had no effect. The sex steroids had no effect on IGFBP1 production. Weight loss following a four week very low calorie diet was associated with a significant increase in SHBG and IGFBP1 concentrations mirrored by a decrease in insulin and IGF-1. This resulted in a decrease in free testosterone although the total testosterone concentration did not change. The inverse relationship of SHBG and IGFBP1 with insulin was further confirmed in the OGTT and 24 hour study although the role of IGF-1 was less clear. The time course of the changes was significantly longer for SHBG than IGFBP1. These studies demonstrate that insulin is a primary regulator of SHBG and IGFBP1 synthesis by the liver. The two binding proteins may be co-regulated by insulin but other factors including the sex steroids may alter their half-lives in the circulation and therefore their serum concentration under various physiological and pathological conditions.

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