Mechanisms relating adiposity to cancer risk

Body weight has strong effects on metabolic factors that may subsequently affect cancer risk—in particular, on circulating levels of peptide and steroid hormones and their binding factors. Specific effects vary somewhat by gender and by menopausal status in women and are summarized in Table 2.

A linear increase in circulating levels of insulin occurs with increasing BMI in both men and women. Insulin acts to control the uptake and use of glucose in peripheral tissues. With excessive calorie consumption and weight gain, tissues become insensitive (resistant) to insulin and the body compensates by producing more insulin, resulting in a chronic state of hyperinsulinemia. Obesity—particularly abdominal obesity—is a major determinant of insulin resistance and hyperinsulinemia.

Insulin-like growth factors (IGFs) are mitogens that regulate energy-dependent growth processes (14). IGF-I stimulates cell proliferation and inhibits apoptosis and has been shown to have strong mitogenic affects in a wide variety of cancer cell lines. The synthesis of IGF-I and its main binding protein, IGFBP-3, are regulated primarily by pituitary growth hormone (GH). In the circulation, more than 90% of IGF-I is bound to IGFBP-3. Obesity and other conditions related to chronic hyperinsulinemia result in elevated blood glucose levels, decreased levels of IGF-binding proteins (IGFBP-1 and IGFBP-2) and higher levels of free plasma IGF-I, the small fraction of IGF-I unbound to any binding protein. Obesity does not increase absolute plasma IGF-I levels, and the mild decrease in IGF-I levels observed in obese and hyperinsulinemic individuals can be explained by the negative feedback of free IGF-I on GH secretion, which is also lower in obese individuals.

Insulin and free IGF-I interact with and regulate the synthesis and bioavailability of sex steroids that affect the development and progression of certain cancers (15). Chronic hyperinsulinemia inhibits hepatic synthesis of sex hormone-binding globulin (SHBG), thus increasing bioavailable androgens and estrogens unbound to SHBG. The unbound fraction determines the actual biological activity of androgens and estrogens, hormones

Table 2

Associations of Obesity With Selected Proteins

Hormone or binding globulin Insulin

Insulin-like growth factor-I (IGF-I) Free IGF-I

IGF binding protein-1

IGF binding protein-3

Sex hormone-binding globulin

Total testosterone

Free testosterone

Total estradiol

Free estradiol

Progesterone (premenopausal F)

Obesity vs normal weight i

Nonlinear, peak around BMI 24-27 kg/m2

i or NE

I (M), NE (F); T (PCOS); NE or i(M), T (F) T (M, postmenopausal F), NE (premenopausal F) T (M, postmenopausal F), NE (premenopausal F) NE, or ^ in women with suspectibility to develop ovarian hyperandrogenism

T, increased levels; decreased levels; NE, no observed effect; M, males; F, females; PCOS, premenopausal women with polycystic ovary syndrome; BMI, body mass index. Reproduced with permission from ref. 4.

essential for the growth, differentiation and function of many tissues in both men and women. There is a strong inverse association between the amount and distribution of body fat and circulating levels of SHBG (16,17).

In addition to the effects of insulin on the bioavailability of sex hormones, adipose tissue itself increases the concentration of circulating estrogens in men and postmenopausal women through the aromatization of androstenedione to estrone (16). In postmenopausal women, ovarian production of estrogen falls to very low levels and the adipose is the primary source of circulating estrogen.

Weight loss has been shown to reduce insulin resistance and circulating levels of insulin, glucose, and estradiol, and to increase levels of SHBG (18). In most studies, a 5 to 10% weight reduction is sufficient to improve these metabolic parameters. The influence of weight loss on levels of IGFs and associated binding proteins is less clear. Unfortunately, few studies of the metabolic changes associated with weight loss have measured long-term effects, and there is little empirical evidence regarding the clinical manifestations of weight loss sustained over long periods of time (2,18,19).

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