Estetrol does not bind sex hormone binding globulin or increase its production by human HepG2 cells

Objectives To determine whether human sex hormone binding globulin (SHBG) binds estetrol (E-4), and to assess whether E-4 stimulates the production of SHBG by human hepatocytes. Methods Competitive ligand binding assays have been used to assess the relative binding affinity of E-4 to human SHBG using either [H-3]5 alpha-dihydrotestosterone or [H-3]estradiol as labeled ligands. The effect of E-4 on the production of SHBG has been assessed by a fluoroimmunometric assay in wild-type human HepG2 cells and in human Hep89 cells that over-express the human estrogen receptor (ER) alpha, and compared to the effect of ethinylestradiol, estradiol and estriol. Results There was no detectable binding of E-4 to the human SHBG steroid-binding sites. By contrast, testosterone and estradiol were bound with high affinity and the synthetic estrogen ethinylestradiol was found to bind SHBG with low affinity. Estetrol does not stimulate ER alpha-mediated increases in SHBG production by HepG2 or Hep89 cells, in contrast to ethinylestradiol, estradiol and estriol. Conclusions These data indicate that SHBG has no influence oil the plasma distribution of E-4 or its availability to target tissues. In addition, it is shown that E-4 has no effect on SHBG production by human hepatocytes.