The role of estrogen receptors in the auditory system

Both laboratory and clinical studies have previously demonstrated estrogenic effects on auditory function. The overall scope of this study was to investigate the physiological and molecular involvement of estrogens and estrogen receptors alpha (ERα) and beta (ERβ) in hearing physiology. ERα and ERβ were localized in a number of central auditory structures in mice, and their differential localization suggested distinct roles in auditory processing. ER expression was assessed in young, prepubertal and aged mice with diverging levels of estrogens. Changes in the expression patterns were not uniform between groups, suggesting that region-specific mechanisms regulate ERs expression. Neither age group showed sex differences in ER expression. Chronic 17β-estradiol treatment in ovariectomized mice resulted in molecular changes in the central (inferior colliculus) and peripheral (cochlea) auditory structures. Down-regulation of ERα mRNA in the cochlea and inferior colliculus may be a direct effect of estrogen-induced feedback inhibition of ERα transcription. No changes were noted for ERβ mRNA levels, suggesting that ERβ is constitutively expressed, rather than directly regulated by circulating hormones. Concurrent with these molecular changes, auditory-related behavioral parameters were altered by 17β-estradiol treatment. Improved prepulse inhibition of the acoustic startle response after 17β-estradiol treatment, suggested an estrogenic modulation of sensorimotor gating. Investigation of mice deficient in ERα (ERKO mice), ERβ (BERKO mice) and aromatase (ARKO mice) suggested a protective role for ERβ in the auditory system against acoustic trauma. Brain derived neurotrophic factor (BDNF), which is a neuroprotective peptide that can be induced by estrogens, increased in the cochlea after treatment with an ERβ-selective agonist, whereas it was decreased in the cochlea of BERKO and ARKO mice. ERβ-mediated neuroprotective mechanisms against noise exposure involving neurotrophic factor BDNF, were suggestive of estrogens’ supportive contributions to the auditory function. Analysis of ERα, ERβ and BDNF levels in the cochlea during the reproductive cycle, revealed regulation of ERα but not ERβ or BDNF by endocrine activity. ERα levels were lower in high-estrogen conditions, suggesting that ERα expression in the peripheral auditory system is regulated by circulating sex hormones and acts as an interface between endocrine activity and the auditory system. Taken together, these results suggest an involvement of estrogens and their receptors along with neurotrophic factors in the physiology of the mammalian auditory system. Unraveling the distinct roles of estrogen receptors in the auditory system may provide novel treatment strategies and pharmacological targets for the support of hearing

Steroid receptor expression in the fish inner ear varies with sex, social status, and reproductive state

<p>Abstract</p> <p>Background</p> <p>Gonadal and stress-related steroid hormones are known to influence auditory function across vertebrates but the cellular and molecular mechanisms responsible for steroid-mediated auditory plasticity at the level of the inner ear remain unknown. The presence of steroid receptors in the ear suggests a direct pathway for hormones to act on the peripheral auditory system, but little is known about which receptors are expressed in the ear or whether their expression levels change with internal physiological state or external social cues. We used qRT-PCR to measure mRNA expression levels of multiple steroid receptor subtypes (estrogen receptors: ERα, ERβa, ERβb; androgen receptors: ARα, ARβ; corticosteroid receptors: GR2, GR1a/b, MR) and aromatase in the main hearing organ of the inner ear (saccule) in the highly social African cichlid fish <it>Astatotilapia burtoni</it>, and tested whether these receptor levels were correlated with circulating steroid concentrations.</p> <p>Results</p> <p>We show that multiple steroid receptor subtypes are expressed within the main hearing organ of a single vertebrate species, and that expression levels differ between the sexes. We also show that steroid receptor subtype-specific changes in mRNA expression are associated with reproductive phase in females and social status in males. Sex-steroid receptor mRNA levels were negatively correlated with circulating estradiol and androgens in both males and females, suggesting possible ligand down-regulation of receptors in the inner ear. In contrast, saccular changes in corticosteroid receptor mRNA levels were not related to serum cortisol levels. Circulating steroid levels and receptor subtype mRNA levels were not as tightly correlated in males as compared to females, suggesting different regulatory mechanisms between sexes.</p> <p>Conclusions</p> <p>This is the most comprehensive study of sex-, social-, and reproductive-related steroid receptor mRNA expression in the peripheral auditory system of any single vertebrate. Our data suggest that changes in steroid receptor mRNA expression in the inner ear could be a regulatory mechanism for physiological state-dependent auditory plasticity across vertebrates.</p