Role of Endocytosis in Cellular Uptake of Sex Steroids

Abstract

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 blockade of vagina 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.

Cellular uptake of steroid carrier proteins—Mechanisms and implications

“…In line with this hypothesis, megalin was shown to act as endocytic receptor for human SHBG and rodent ABP in cultured cells (Hammes et al, 2005). When exposed to sex steroids in the presence of physiological concentrations of the carriers, cells were dependent on megalin activity to internalize significant amounts of the hormones.…”

“…In the uterine epithelium, expression of the receptor is tightly regulated during estrus cycle, with strongest expression in met-und diestrus (Hammes et al, 2005). In fact, megalin has been identified as one of the major progesterone target genes in this tissue (Spencer et al, 1999).…”

“…Sex steroid insensitivity was further supported by the fact that megalin-deficient embryos failed to induce regression of the CSL in response to exogenous application of androgens, a response that was readily seen in wild types (Hammes et al, 2005).…”

“…Little steroid hormone uptake was seen in the presence of megalin antagonists or in cell types that lacked receptor expression. SHBG-bound steroids delivered by megalin entered intracellular compartments and acted as inducers of steroid target genes, the hallmark of cellular steroid action (Hammes et al, 2005).…”

Synthesis and biodistribution of fluorine-18-labeled fluorocyclofenils for imaging the estrogen receptor

“…In fact, SHBG has been implicated as a carrier that will facilitate steroid uptake by certain target cells through a membrane receptor for steroid-liganded SHBG [41][42][43]. SHBG has a strong preference for binding certain androgen and estrogen steroidal ligands; by contrast, non-steroidal ligands, including members of the cyclofenil class, typically have very low SHBG binding affinity.…”