Hormone replacement therapy diminishes hearing in peri-menopausal mice

Abstract

We recently discovered that progestin in hormone replacement therapy (HRT) for post-menopausal women has detrimental effects on the ear and central auditory system [Guimaraes, P., Frisina, S.T., Mapes, F., Tadros, S.F., Frisina, D.R., Frisina, R.D., 2006. Progestin negatively affects hearing in aged women. Proc. Natl. Acad. Sci. - PNAS 103, 14246-14249]. To start determining the generality and neural bases of these human findings, the present study examined the effects of combination HRT (estrogen+progestin) and estrogen alone on hearing in peri-menopausal mice. Specifically, auditory brainstem responses (ABRs-sensitivity of the auditory system) and distortion-product otoacoustic emissions (DPOAEs-cochlear outer hair cell system) were employed. Middle age female CBA mice received either a time-release, subcutaneous implanted pellet of estrogen+progestin, estrogen alone, or placebo. Longitudinal comparisons of ABR threshold data obtained at 4 months of treatment revealed statistically significant declines in auditory sensitivity over time for the combined estrogen+progestin treatment group, with the estrogen only group revealing milder changes at 3, 6 and 32 kHz. DPOAE testing revealed statistically significant differences for the estrogen+progestin treatment group in the high and middle frequency ranges (15-29 and 30-45 kHz) after as early as 2 months of treatment (p<0.01 and p<0.001, respectively). Statistically significant changes were also seen at 4 months of treatment across all frequencies for the combined HRT group. These data suggest that estrogen+progestin HRT therapy of 4 months duration impairs outer hair cell functioning and overall auditory sensitivity. These findings indicate that estrogen+progestin HRT may actually accelerate age-related hearing loss, relative to estrogen monotherapy; findings that are consistent with the clinical hearing loss observed in aging women that have taken combination HRT.

Figure 1

Longitudinal comparisons among groups revealed statistically significant changes to ABR thresholds at 4 mon of treatment when compared to baseline, across 6–48 kHz for the E+P group. The estrogen only treatment group revealed statistically significant changes at 3, 6 and 32 kHz only, with no corresponding changes in either the placebo or male groups. Error bars represent standard error of the mean (SEM).

Figure 2

A) Comparisons of ABR absolute threshold changes at 4 mon of treatment revealed a general trend toward increasing threshold changes with increasing frequency with the largest trend seen in the E+P treatment group. A two way ANOVA for HRT treatment at 4 mon revealed significant differences in ABR thresholds when comparing E+P vs. Placebo at 32 and 48 kHz, and for Placebo vs. Male at 48 kHz. B) A one-way ANOVA for HRT treatment at 4 mon treatment revealed statistically significant differences in otoacoustic emissions amplitudes when comparing the E+P vs. Estrogen only, Placebo and male groups within the high frequency range (dashed vertical lines). DP – DPOAE amplitude; NF – noise floor amplitude. Error bars represent standard error of the mean (SEM).

Figure 3

Longitudinal comparisons of otoacoustic emissions amplitudes among groups revealed statistically significant changes across: A) low (5–15 kHz), B) middle (15–30 kHz) and C) high (30–45 kHz) frequency ranges for the E+P treatment group at 4 mon of treatment, and as early as 2 mon in the middle and high frequency ranges. Less significant changes were seen within the middle frequency range at 4 mon for the placebo and male groups. Error bars represent standard error of the mean (SEM).