Figure 1. Obesity trends. The graph shows trends in the age-adjusted prevalence of obesity for adults aged 20-74 years in the United States from 1960-2000 (Ref. 2) as percentage of the total population. Measured weight and height data have been collected for nationally representative samples of adults since 1960. These data, which were collected in the National Health and Nutrition Examination Survey by the National Center for Health Statistics (for further information, see the online links box), allow valid comparisons of trends over time. The prevalence of overweight (body-mass index (BMI) >/= 25 kg/m²) and obesity (BMI >/= 30 kg/m²) in adults aged 20-74 was relatively stable from 1960-1980. This situation changed markedly in the 1980s and 1990s when large increases in the prevalence of both overweight and obesity occurred nationally in men and women. By the year 2000, 64.5% of adults in the United States were overweight or obese, and 30.5% were obese. Within the population of adults, 4.7% were morbidly obese (BMI >/= 40kg/m²; not shown).

Figure 2. Effects of obesity on growth-factor production. In obesity, increased release from adipose tissue of free fatty acids (FFA), tumour-necrosis factor-α (TNFα) and resistin, and reduced release of adiponectin lead to the development of insulin resistance and compensatory, chronic hyperinsulinaemia (see "The Insulin-Resistance Syndrome or Metabolic Syndrome"). Increased insulin levels, in turn, lead to reduced liver synthesis and blood levels of insulin-like growth factor binding protein 1 (IGFBP1), and probably also reduce IGFBP1 synthesis locally in other tissues. Increased fasting levels of insulin in the plasma are generally also associated with reduced levels of IGFBP2 in the blood. This results in increased levels of bioavailable IGF1. Insulin and IGF1 signal through the insulin receptors (IRs) and IGF1 receptor (IGF1R), respectively, to promote cellular proliferation and inhibit apoptosis in many tissue types. These effects might contribute to tumorigenesis.

Figure 3. Effects of obesity on hormone production. Adipose tissue produces the enzymes aromotase and 17ß-hydroxysteroid dehydrogenase (17ß-HSD). So in obese individuals, there is typically an increased conversion of the androgens δ4-androstenedione (δ4A) and testosterone (T) into the oestrogens oestrone (E1) and oestradiol (E2), respectively, by aromatase. 17ß-HSD converts the less biologically active hormones δ4A and E1 into the more active hormones T and E2, respectively. In parallel, obesity leads to hyperinsulinaemia, which in turn causes a reduction in the hepatic synthesis and circulating levels of sex-hormone-binding globulin (SHBG). The combined effect of increased formation of oestrone and testosterone, along with reduced levels of SHBG, leads to an increase in the bioavailable fractions of E2 and T that can diffuse to target cells, where they bind to oestrogen and androgen receptors. The effects of sex steroids binding their receptors can vary, depending on the tissue types, but in some tissues (for example, breast epithelium and endometrium) they promote cellular proliferation and inhibit apoptosis.

Figure 4. Obesity, hormones and endometrial cancer. Obesity can increase risk of endometrial cancer through several parallel endocrine pathways. Obesity is associated with increased insulin levels, which lead to increases in insulin-like growth factor 1 (IGF1) activity and, in some individuals, an increased androgen production by the ovaries. An excessive increase in ovarian androgen production inhibits ovulation (chronic anovulation), which leads to progesterone deficiency. Increased adiposity also increases aromatase activity, leading to increased levels of bioavailable oestrogen levels in postmenopausal women. Oestrogens increase endometrial cell proliferation and inhibit apoptosis, partially by stimulating the local synthesis of IGF1 in endometrial tissue. Progesterone normally counteracts these effects through various mechanisms, in part by promoting synthesis of IGF-binding protein 1 (IGFBP1) -- the most abundant IGFBP in endometrial tissue. Among premenopausal women, the lack of progesterone, because of ovarian androgen production and continuous anovulation, leads to reduced production of IGFBP1 by the endometrium. Loss of progesterone production therefore seems to be the most important physiological risk factor for cancer in premenopausal women. After menopause (and in the absence of exogenous oestrogen production), when ovarian progesterone synthesis has ceased altogether, the more central risk factor seems to be obesity-related increases in bioavailable oestrogen levels. In addition to oestrogens and progesterone, insulin itself could also promote endometrial cancer development by reducing concentrations of sex-hormone-binding globulin (SHBG) in the blood, which would increase the levels of bioavailable oestrogens that can diffuse into endometrial tissue. Figure modified from Ref. 35.