Qureshi AC et al. (2007) The influence of the route of oestrogen administration on serum levels of cortisol-binding globulin and total cortisol. Clin Endocrinol (Oxf) 66: 632–635

Most cortisol that circulates in the blood is bound to proteins such as cortisol-binding globulin (CBG). Direct measurement of the 'free' (biologically active) form in the serum is difficult, but salivary cortisol levels are relatively easy to determine and are a marker of blood free cortisol levels. Oral estrogen preparations are known to increase CBG levels, thereby increasing total blood cortisol levels. As well as the potential physiological consequences of this, the increased cortisol affects assessment of the hypothalamic–pituitary–adrenal (HPA) axis. This single-center cross-sectional study compared effects of transdermal (n = 8) and oral (n = 14) estrogen therapy on salivary cortisol levels, and serum total cortisol and CBG levels in women. Controls (n = 15) were not taking estrogens.

Total serum cortisol and CBG levels were higher in subjects taking oral estrogens than in controls (P <0.001); however, levels in subjects taking transdermal estrogen were similar to controls. Salivary cortisol levels were similar in all three groups.

The authors conclude that oral estrogen administration markedly increases serum levels of total cortisol and CBG; however, salivary cortisol levels were not affected. Further work is needed to assess whether this reflects serum free cortisol levels. Because transdermal estrogen seems not to affect cortisol levels, there appears no need to discontinue therapy in the weeks before assessing the HPA axis, which is the procedure currently used for people taking oral estrogens.