Estrogen and the inner ear: megalin knockout mice suffer progressive hearing loss.

Megalin, the largest member of the low-density lipoprotein receptor-related protein family, functions as an endocytic receptor for a variety of essential lipophilic metabolites, including the steroid hormone estrogen. In the cochlea, megalin is strongly expressed within the marginal cells of the stria vascularis, and previous studies demonstrated that beta-estrogen receptors are also expressed in megalin-expressing marginal cells. In the present study, we demonstrate that homozygous megalin mutant mice exhibit profound hearing loss at 3 months of age associated with features of presbycusis, enrichment of lipofuscin granules, and a reduced number of microvilli in marginal cells of the stria vascularis. FITC-labeled beta-estrogen is taken up into the strial marginal cells; however, in megalin-deficient mice the uptake of FITC-labeled beta-estrogen is reduced. This highlights beta-estrogen as a possible carrier-bound candidate ligand for megalin and supports the concept that estrogen may function via megalin within the inner ear. A crucial role of megalin in hearing should be considered and the megalin/estrogen interaction needs to be discussed in the context of early presbycusis in estrogen-deficient humans and mice.