The metabolic effects of oestrogen therapy are influenced by the route of administration. Compared with oral treatment, percutaneous administration may have theoretical advantages with respect to liver metabolism, but there are also potential disadvantages related to the specific kinetics of this route. The increase of SHBG binding capacity is much less pronounced, which might result in excess amounts of unbound, biologically-active steroid during therapy. The serum concentrations of unbound 17 beta-oestradiol were calculated in two groups of postmenopausal women during replacement therapy with equivalent amounts of oral and percutaneous oestrogen. A highly significant and quite similar increase of the free fraction as well as in total 17 beta-oestradiol was found in both groups of women, in spite of the fact that SHBG binding capacity was unchanged during percutaneous therapy. Albumin binding and the total serum concentration of 17 beta-oestradiol were found to be more important for the regulation of unbound steroid concentration than variations in SHBG binding capacity. In conclusion, there was no evidence that percutaneous administration per se would carry an increased risk of over-treatment.