Birth control pills containing EE have been found to increase circulating SHBG levels by 2- to 4-fold in women and to reduce free testosterone concentrations by 40 to 80%. Birth control pills containing high doses of EE can increase SHBG levels in women by as much as 5- to 10-fold. This is similar to the 5- to 10-fold increase in SHBG levels that occurs during pregnancy. Due to the marked increase in SHBG levels, free testosterone levels become very low during treatment with EE-containing birth control pills. In men, a study found that treatment with a relatively low dosage of 20 μg/day EE for five weeks increased circulating SHBG levels by 150% and, due to the accompanying decrease in free testosterone levels, increased total circulating levels of testosterone by 50% (via upregulation of gonadal testosterone production due to reduced negative feedback by androgens on the hypothalamic–pituitary–gonadal axis). The stimulation of hepatic SHBG production by EE is far stronger than with other estrogens like estradiol, owing to the high resistance of EE to inactivation in the liver and hence its disproportionate effects in this part of the body.