Role of endocytic receptors in cellular uptake of steroid hormones
Thomas Willnow1, Annette Hammes1, Thomas Andreassen2 & Anders Nykjaer2
Androgens and estrogens are transported bound to the sex hormone binding globulin (SHBG). SHBG is believed to keep sex steroids inactive and to control the amount of free hormones that enter cells by passive diffusion. Contrary to the free hormone hypothesis, we demonstrate that megalin, an endocytic receptor in reproductive tissues acts as a pathway for cellular uptake of biologically active androgens and estrogens bound to SHBG. In line with this function, lack of receptor expression in megalin knockout mice results in impaired descent of the testes into the scrotum in males and in blockade of vaginal opening in females. Both processes are critically dependent on sex steroid signaling and similar defects are seen in animals treated with androgen or estrogen receptor antagonists. Thus, our findings uncover the existence of endocytic pathways for protein-bound androgens and estrogens, and their crucial role in development of the reproductive organs.