Sex steroid hormone receptors : Inner ear & hearing

It is well known that hearing loss is more profound in elderly males than females, regardless of noise exposure. Also, an age-related hearing decline starts much earlier in males, already after the age of 30, while in women, the decline does not start until the age of 50. This coincides with the menopausal transition in most women, when endogenous circulating levels of estrogen in the body are reduced. It is also well known that women with Turner syndrome who are estrogen deficient suffer from early onset of age-related hearing loss already at the age of 35. The overall aim of this thesis was to investigate whether the female sex steroid hormone, estrogen, and its receptors are important in maintaining hearing. The effects of estrogen, estrogen-modulators and anti-estrogen on the estrogen receptors (ERs) in the inner ear were investigated. The expression pattern of estrogen receptors during periods of maximum and minimum hormonal levels such as pregnancy, maturation and development was characterized. The experimental studies were performed using rat and mice animal models. We found that ERs are up and down-regulated in the inner ear depending on the stage of maturation, development and pregnancy. In post-natal rats, ER expression levels appear to be inversely correlated to estrogen levels (e.g. when high levels of estrogen are present, ERs are expressed less in the inner ear). At the time points measured in non-fetal rats, ERα and ERβ expression was highest in three-week-old rats (a known period of fairly low estrogen levels). ER expression reached the lowest levels in pregnant mother rats in late pregnancy (a known period of high estrogen levels). There was no ERα or ERβ identified in the inner ears of the fetuses, at either E8 or E18. No estrogen receptors were found in the cochlea of the developing fetus. These findings suggest that estrogen may have an effect on the cochlea during various stages of life, but seems not to be active during gestation. Treatment of ovariectomized rats with estradiol, tamoxifen, anti-estrogen or vehicle only, did not alter the ER expression pattern significantly in the inner ear. However, a slight down regulation of ERα in the marginal cells of the stria vascularis (involved in ion regulation) was seen in rats that were injected with pure anti-estrogen, suggesting that ERα may be involved in the ion regulation in the cochlea. When investigating estrogen receptor β deficient mice, altered inner ear morphology was found, corresponding to deafness already by one year of age. Also, both ERs are present in the inner ear of wild type (WT) mice at specific localizations suggesting subtype-specific functionality. All together the findings of this thesis strengthen the hypothesis that estrogen has a direct effect on hearing functions and may imply that ERβ is important for the prevention of age-related hearing loss. This study provides a better understanding of the observed positive hearing effects of hormone replacement therapy in patients with low estrogen levels (e.g. postmenopausal women). Several interesting areas for further investigation arose from the work of this thesis including: the protective role of ERβ on hearing along with its possible interactions with ERα; the complex interactions of the reproductive hormones in the inner ear along with their effects on target organ morphology and hearing, and localization and functionality of other reproductive hormone receptors. LIST OF PUBLICATIONS This thesis is based on the following papers, which will be referred to in the text by their Roman numerals. I. Simonoska R, Stenberg AE, Masironi B, Sahlin L and Hultcrantz M. (2009) Estrogen receptors in the inner ear during different stages of pregnancy and development in the rat. Acta Oto-Laryngologica Feb 13: 1-7. II. Stenberg AE, Simonoska R, Stygar D, Sahlin L and Hultcrantz M. (2003) Effect of estrogen and antiestrogens on the estrogen receptor content in the inner ear of ovariectomized rats. Hearing Research 182: 19-23. III. Simonoska R, Stenberg AE, Duan M, Yakimchuk K, Fridberger A, Sahlin L, Gustafsson JA and Hultcrantz M. (2009) Inner ear pathology and loss of hearing in estrogen receptor beta deficient mice. Journal of Endocrinology. In press.