Obesity and metabolic disease are associated with reduced fertility and alterations in several markers of reproductive health, including plasma concentrations of sex hormone-binding globulin. Low levels of sex hormone-binding globulin are common in those with obesity and are predictive of cardiovascular disease and type 2 diabetes risk, although it is unclear how glucose and insulin regulation affect sex hormone-binding globulin levels. A group of investigators recently performed a series of experiments with the aim of identifying mechanisms of sugar metabolism and sex hormone-binding globulin production.

Sex hormone-binding globulin, which is produced by liver, transports sex hormones in the blood and regulates their uptake by sensitive tissues. Hepatocyte nuclear factor-4α, also produced by the liver, stimulates sex hormone-binding globulin production and increases serum testosterone by decreasing its half-life. De novo lipogenesis, the process by which the liver converts excess sugar into fatty acids, suppresses hepatocyte nuclear factor-4α activation and sex hormone-binding globulin production.

In the first experiment, the researchers used transgenic mice whose genomes had been altered to express the human sex hormone-binding globulin gene. They fed these mice a diet high in either sucrose, glucose, or fructose (three types of simple sugars) for one week and measured blood levels of sex hormone-binding globulin. In a second experiment, the researchers exposed human liver cells to varying amounts of insulin and to high concentrations of either glucose or fructose and measured gene expression. Finally, they exposed the same type of liver cells to varying concentrations of glucose and fructose and to the fatty acid palmitate and measured gene expression.

After five days a high fructose diet reduced sex hormone-binding globulin levels in the mice by fructose 80 percent. Sex hormone-binding globulin levels decreased by 40 percent on a high glucose diet and 50 percent on a high sucrose diet. Insulin exposure did not affect sex hormone-binding globulin production in mice. In liver cells, glucose and fructose exposure over five days reduced sex hormone-binding globulin accumulation by 50 percent. This change corresponded to a three- to fourfold reduction in the expression of hepatocyte nuclear factor-4α. Additionally, glucose or fructose exposure over five days resulted in a two- to threefold increase in palmitate production (due to de novo lipogenesis), which corresponded to reductions in sex hormone-binding globulin. Finally, exposure to varying amounts of palmitate over five days reduced hepatocyte nuclear factor-4α expression and sex hormone-binding globulin production.

The authors of this comprehensive study concluded that excess sugar intake resulted in increased de novo lipogenesis, which led to a suppression of hepatic HNF-4α activity, which in turn attenuated sex hormone-binding globulin expression. This work provides a detailed explanation of why sex hormone-binding globulin is a sensitive biomarker of metabolic syndrome and why simple sugars, especially fructose, decrease fertility.

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