Translational implications of the interactions between hormones and age-related hearing loss

Abstract

Provocative research has revealed both positive and negative effects of hormones on hearing as we age; with in some cases, mis-regulation of hormonal levels in instances of medical comorbidities linked to aging, lying at the heart of the problem. Animal model studies have discovered that hormonal fluctuations can sharpen hearing for improved communication and processing of mating calls during reproductive seasons. Sex hormones sometimes have positive effects on auditory processing, as is often the case with estrogen, whereas combinations of estrogen and progesterone, and testosterone, can have negative effects on hearing abilities, particularly in aging subjects. Too much or too little of some hormones can be detrimental, as is the case for aldosterone and thyroid hormones, which generally decline in older individuals. Too little insulin, as in Type 1 diabetics, or poor regulation of insulin, as in Type 2 diabetics, is also harmful to hearing in our aged population. In terms of clinical translational possibilities, hormone therapies can be problematic due to systemic side effects, as has happened for estrogen/progestin combination hormone replacement therapy (HRT) in older women, where the HRT induces a hearing loss. As hormone therapy approaches are further developed, it may be possible to lower needed doses of hormones by combining them with supplements, such as antioxidants. Another option will be to take advantage of emerging technologies for local drug delivery to the inner ear, including biodegradeable, sustained-release hydrogels and micro-pumps which can be implanted in the middle ear near the round window. In closing, exciting research completed to date, summarized in the present report bodes well for emerging biomedical therapies to prevent or treat age-related hearing loss utilizing hormonal strategies.

Keywords: Aldosterone; Animal model; Estrogen; Human; Presbycusis; Testosterone.

Figure 1.

Females show better hearing throughout life, but the difference declines in old age. (a) Low frequency range (5.6–12 kHz): the males presented with a progressive decline of DPOAE amplitude from young adult to middle-aged groups. The females maintained their DPOAE amplitudes through middle-aged and then showed a significant decline from middle to old age. The sex differences for the low frequencies using a two-way ANOVA proved to be significant (F=4.2, P<0.05). (b) Middle frequency range (13–25 kHz): the pattern in this graph was similar to that of the previous one. The females had high DPOAE amplitudes through middle age, with declines from middle age to old age. The males presented with a progressive decline throughout life. The two-way ANOVA confirmed this sex difference (F=4.57, P<0.05). (c) High frequency range (26–45 kHz): the age by sex findings were like those of the previous graphs (a,b). The two-way ANOVA was also significant (F=4.89, P<0.05). (From Guimaraes et al. 2004, Fig. 3; with permission).

Figure 2.

Auditory brainstem response thresholds over the course of hormone treatments as well as during the recovery period. (a) Estrogen-treated (E) females show no significant signs of ARHL over the course of hormone therapy, thus indicating that E possesses protective properties for auditory function. (b) Progestin-treated (P) females show significantly poorer hearing at almost all of the tested frequencies. (c) The E + P-treated group of females displayed elevations in ABR thresholds as early as 3 months. Notable worsening of hearing could be seen in this group over time. (d) Placebo control females’ (Pb) thresholds changed drastically over the 6-month time period. Significant ARHL changes were observed for all frequencies. (e) Changes observed in the male group, more specifically during the recovery period (8 months), could be attributed to ARHL. (f) Recovery period group comparison shows that E-treated animals had lower thresholds at 12, 16, 20, 24, and 32 kHz compared to all the other HRT animals. Pb females had higher thresholds among the HRT groups at 24 and 32 kHz. These data suggest that the results of long-term HRT on ABR thresholds are permanent. No statistical differences were seen among the hormone groups during the recovery period. It should be noted that statistical differences for (a) through (e) are a comparison between the baseline and recovery. Statistical test: 2-way ANOVA followed by Bonferroni; *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001. From Williamson et al. 2019, Fig. 2; with permission.

Figure 3.

In vivo 1-month post-treatment IGF-1R and FoxO3 expression levels. (a) Estrogen-treated (E) females had the highest IGF-1R fold expression levels among the subject groups for stria vascularis (SV) tissue samples. Interestingly, placebo (Pb) and control female (CF) animals had the most significant differences among the groups, relative to E. This implies that lack of HRT during the aging process decreases IGF-1R levels. (b) FoxO3 gene expression was comparatively similar among the SV tissue sample groups. Congruous findings were observed for in vitro FoxO3 experiments. It can be noted that overall the CF group had the lowest expression levels for both genes. (c) Post-treatment IGF-1 concentration levels in the serum of HRT mice showed no significant differences among the female HRT groups. Only E + progestin (P) and Pb groups displayed statistical variances in comparison to the control male animals. Statistical test: 1-way ANOVA followed by Bonferroni; *p < 0.05, **p < 0.01 (E n = 3; P n = 3; E + P n = 3; Pb n = 3, Males n = 3; CF n = 3). Note : The CF group consists of age-matched females with their ovaries intact that did not undergo any type of HRT. From Williamson et al. 2019, Fig. 6; with permission.

Figure 4.

Morphological photomicrographs from: the basal turn of the cochlea in a 3-month-old ER-β−/− mouse (A and B); 12-month-old ER-β−/− mouse (C and D), and 12-month-old WT mouse (E and F). (A) Shows a normal organ of Corti with intact inner hair cell (IHC) and three outer hair cells (OHCs) and in (B) the spiral ganglion is filled with spiral ganglion cells (red arrow). (C) Shows the organ of Corti in a 12-month-old ER-β−/− mouse that has degenerated, resulting in a flat epithelium (red circle) and in (D), there is an extensive loss of ganglion cells in the spiral ganglion, with a red arrow indicating the few cells left. (E) Shows fairly normal organ of Corti in 12-month-old WT mouse and (F) shows the spiral ganglion with loss of spiral ganglion cells (arrow), but in comparison with 12-month-old ER-β−/− mice (D) the loss is not as extensive. From Simonoska et al. 2009, Fig. 2; with permission.

Figure 5.

Age-dependent loss of auditory function in b1/b1 mice; which is a knockout mouse for thyroid receptor β1. A, ABR for +/+ and b1/b1 mice at 1, 2, 4, and 6 months of age, and for b2/b2 mice (b2 is a knockout mouse for thyroid receptor β2) with their own +/+ group at 6 months of age. Responses to click stimulus are shown. Thresholds increased progressively in b1/b1 compared with +/+ mice, whereas b2/b2 mice had no increase compared with their +/+ group at 6 months. For comparison of b1/b1 vs +/+ groups at a given age: *, P < .05; **, P < .01; ***, P < .001; for each b1/b1 group vs its preceding younger group: ##, P < .01; ###, P < .001. B, Representative ABR waveforms for a click stimulus at different intensities (numbers on right, dB SPL) showing loss of specific waveforms by 6 months of age in b1/b1 mice, whereas +/+ mice show only modest shifts in thresholds. In contrast, −/− mice lacked distinct waveforms at younger ages. Waveforms were similar in b2/b2 and +/+ mice at 6 months of age. From Ng et al. 2015, Fig. 4; with permission.

Figure 6.

Loss of hair cells in adult mice lacking thyroid receptor (TR)β1: b1. −/− mice lack both TRβ1 and TRβ2, Histological sections of mid and basal turns of the cochlea at 6 months of age. Brown arrowhead, inner hair cell; white arrowheads, outer hair cells. Loss of hair cells is obvious in b1/b1 and −/− mice but not in +/+ or b2/b2 mice. In b1/b1 and −/− mice, the sensory epithelium has also lost support cells and is flattened, especially in basal regions. Scale bar, 20 μm. B, Counts of hair cells showing loss of outer (oh) and inner hair cells (ih), determined on sections of middle (mid) and basal (base) regions. For a given genotype vs +/+ group: *, P < .005; **, P < .001. C, Immunofluorescent analysis of surface views of the organ of Corti stained for myosin VI (detects inner and outer hair cells, green) and phalloidin (detects filamentous actin, red). Gaps appear in the hair cell array resulting from loss of outer hair cells in this mid-region view of the cochlea in b1/b1 mice at 6 months of age. Scale bar, 10 μm. From Ng et al. 2015, Fig. 6; with permission.