Home | About | Events | Contact | Advisory Board | Writer’s Guidelines | Reprints | Organizations | Advertising
September/October 2019
New Findings in Age-Related Hearing Loss Although hearing loss can stem from various causes, one of the most common is aging. Between one-quarter and one-third of individuals older than 65 suffer from age-related hearing loss, which is characterized by an irreversible, progressive increase in auditory thresholds, particularly in the higher frequency range.1 Fortunately, an array of new research is uncovering factors associated with increased risk. That research, in turn, may enable better identification of vulnerable patients and could help prevent or delay some cases of age-related hearing loss. Osteoporosis Is Significantly Associated With Hearing Loss Although a few studies in recent years have examined the connection between osteoporosis and hearing loss, the findings from those studies have been mixed. One large population-based study of Asian older adults found that those with osteoporosis had a 1.76 higher risk of age-related hearing loss compared with adults without osteoporosis.4 A different study of postmenopausal women likewise found that those with osteoporosis had impaired ability to hear at higher frequencies.5 By contrast, however, a case-control study of postmenopausal Korean women found no association between bone mineral density and hearing loss.6 To untangle the suspected connection between osteoporosis and hearing loss, researchers from Gyeongsang National University Hospital in South Korea recently undertook a new study using data from the Korea National Health and Nutrition Examination Survey, which included 4,861 male and female participants. The team explored whether the bone mineral density of the femur neck and the lumbar spine were correlated with ability to hear pure tones at various frequencies. The group hypothesized that the density of the femur neck would be a better predictor of hearing loss than would the lumbar spine, given that the femur neck is composed of a relatively high percentage of cortical bone, similar to the composition of the ossicles in the ear. The group’s hypothesis proved accurate: Bone mineral density of the lumbar spine was not significantly associated with hearing loss, but there was a significant association with bone mineral density of the femur neck. Specifically, a reduction in bone mineral density of the femur neck was associated with a 1.7-fold increased risk of hearing loss.7 The study, published in the Brazilian Journal of Otorhinolaryngology, was cross-sectional and retrospective in nature, so it can’t establish the direction of causality. But according to Jun-Il Yoo, MD, PhD, a professor of orthopedic surgery at Gyeongsang National University in South Korea, a strength of the study is that it’s based on cohort data representing the population of an entire country and points to a potential means by which age-related hearing loss may occur. “We clinically demonstrated that the metabolism associated with cortical bone loss may be related to the mechanism of hearing loss,” he says. The major implication of the study is that providers should be aware of the risk of hearing loss in osteoporosis patients and vice versa. “Patients with senile osteoporosis, especially those with low hip bone mineral density, should be tested for hearing loss. In addition, there is also a need to consider the risk of osteoporosis in patients with reversible hearing loss,” Yoo says. Exposure to Loud Noise Accelerates Age-Related Hearing Loss For the study, researchers from the University of Castilla-La Mancha in Spain divided 16 young adult rats into two groups—one exposed to noise overstimulation and the other not. During the next 15 months, the first group was exposed to one hour of continuous white noise at a 110-decibel sound pressure level each day for five days of the week. To track what was happening with the rats’ hearing ability, the team recorded the rats’ audio brainstem response at multiple kilohertz at 3, 6, 12, and 18 months. By 6 months of age, the exposed group was already showing an impact on their hearing ability, characterized by an increase in auditory thresholds, decrease in waveform amplitudes, and longer latency times. These impacts were progressively worse at 12 months and again at 18 months. By contrast, the rats that hadn’t been exposed to noise didn’t begin to show hearing loss until 12 months. The auditory thresholds, waveform amplitudes, and latency times in the exposed group at 6 months were comparable to those of the unexposed group at 12 months, and the hearing of the exposed group at 12 months was comparable to the unexposed group at 18 months. This progression suggested that noise exposure was in fact accelerating the processes that would have occurred naturally with age. The team had expected that noise exposure would negatively affect hearing, even with sounds of only short duration, but they were surprised at the strength of the effect. “The functional auditory alterations occurred much earlier than expected and were very apparent,” says Juan Carlos Alvarado, MD, PhD, an associate professor at the University of Castilla-La Mancha. Noise is typically associated only with unpleasant or very loud sounds, Alvarado says. However, even pleasant sounds can be harmful to auditory function if they are sufficiently loud. “A pleasant sound could come from smartphones or game devices but also from any leisure activities. Children, adolescents, and young adults are particularly vulnerable to this type of sound and, therefore, will have a greater risk of suffering from hearing loss,” Alvarado says. Although age-related hearing loss is typically associated with patients older than 60, Alvarado encourages providers to be alert to the fact that some patients will begin showing signs of age-related hearing loss earlier than others, even if they are not yet aware of it, due to previous loud noise exposure. “I would recommend performing annual hearing testing in people over 50 even if they do not report symptoms of hearing loss,” Alvarado says. His group’s findings also underscore the need for individuals of all ages to minimize loud sound exposures wherever possible, even if the noise is pleasant or only lasts for a short period. Hormone Replacement Therapy Helps and Harms More than a decade ago, Frisina and his colleagues at the University of Rochester and Rochester Institute of Technology, where Frisina held faculty posts at the time, published an initial study on that question using clinical data from 124 postmenopausal women.9 That 2006 study had included women who had received combination therapy (estrogen + progesterone), women who had received estrogen alone, and a control group of women who had received no HRT at all. The researchers found that women receiving estrogen alone experienced no effects related to their hearing compared with the control group. But combination therapy was significantly associated with hearing difficulties. “When we compared the hearing tests, some involving simple tones and others involving speech perception in background noise, we discovered that for the women taking combination therapy, there were negative effects on almost every hearing test,” Frisina says. Although this early clinical research study from Frisina’s group found that estrogen-only therapy had a neutral effect, several other studies since that time have painted a more complicated picture, suggesting that estrogen alone might actually be protective for hearing. Specifically, estrogen has been shown to improve both distortion product otoacoustic emissions as well as auditory brainstem response amplitudes and latencies.10-15 The findings from this previous research left Frisina with two major questions: Why did combination therapy have such a negative impact, while estrogen by itself produced either neutral or positive impacts? Second, could the hearing damage that occurred with combination therapy be reversed if the treatment was halted? To investigate these questions, Frisina and colleagues at his current university, the University of South Florida-Tampa, recently conducted a study on HRT using a mouse model. For this latest study, published in Aging Cell, they gave the same doses (per body weight) of either combination therapy or estrogen therapy to aging mice that had been given to the women in their earlier clinical study, to examine how specific biomarkers were changing as a result of HRT. The group wanted to look at some of the molecular pathways that changed, including estrogen pathways and inflammatory pathways. They also included a group of mice that received progesterone alone—a therapy that had never been isolated previously to determine its individual effects on hearing. The results: In line with the group’s previous clinical study, the mice receiving combination therapy showed the most deleterious effects on their hearing—worse than that of those who received progesterone alone.16 “One of the new findings in the recent study was that the progesterone by itself isn’t as bad as the combination,” Frisina says, adding that this finding came as a surprise. “So there is some interaction between estrogen and progesterone which is detrimental.” The other major finding: The effects weren’t reversible. “We were hoping that when we discontinued the HRT with the animals, there might be some recovery of hearing in the combination group. There wasn’t any recovery at all,” he says. There were some positive findings, however. As in previous research from other groups, estrogen taken by itself had a positive impact on hearing. “In general, estrogen is like a growth factor. It tends to be good to cells,” Frisina says. Of course, the complication with estrogen is that when this growth factor gets out of hand, it leads to cancer. Still, the positive benefits of estrogen for hearing suggest that estrogen therapy could prove to be a highly useful treatment for various populations in the future. For instance, Frisina envisions that estrogen could have a role in preventing dementia, given that there’s a strong correlation between age-related hearing loss and dementia. Frisina even suggests that estrogen could be used in the future for cancer patients, whose chemotherapy treatments cause hearing damage. “Could you develop a protective agent or mechanism [using estrogen] that would prevent the ototoxic side effects?” Frisina asks. Estrogen treatments would be possible for cancer patients only if researchers could figure out what impact estrogen treatments are having at the cellular level and could determine how to block the carcinogenic effects of the estrogen, but there’s promise in the idea, he says. While the new research underscores the future promise of estrogen-only treatments, it raises new concerns about combination therapy. There are still some women for whom combination hormone therapy is the best option, Frisina says, but the deleterious (and irreversible) impacts of combination therapy on hearing imply a need for caution and careful consideration of what dosage to use. “If a woman has no history of any type of cancer and she has very severe menopausal symptoms, then she might want to go ahead and take it,” Frisina says. “But it’s important for OB/GYNs and the patients to know that it might hurt their hearing as well, so that they can put that into the equation. If they already have hearing loss or they have a family history of breast or ovarian cancer, they might not want to do it.” The Cuticular Plate Plays a Key Role Sensory hair cells are the “antennae” in the inner ear that help sense vibrations in the inner ear. They’re composed of two structures: the hair bundle, which is the antenna itself, and the cuticular plate, which is the foundation on which the antenna sits. While the hair bundle has been studied extensively, few researchers have studied the cuticular plate, so Shin and his colleagues decided to examine it in more detail to determine its role in hearing loss. In their most recent study, published in Nature Communications, Shin and his colleagues homed in on the gene LM07, which codes for protein LM07, a protein the researchers knew is located at the cuticular plate.17 The group deleted this gene in a group of mice, then followed the mice over the next 26 weeks to observe the impacts on their hearing. When the mice’s hearing was first measured at age 2 to 3 months, it was normal—a finding that came as a surprise to Shin, the study’s senior author. “When we deleted this gene, when this protein was gone from this area, we actually thought the effects on hearing would be larger. We knocked out this gene in the mouse by genetic engineering, then we confirmed that this protein was indeed gone, but the sensory hair cells were actually quite normal. You couldn’t really tell a difference.” The mice’s initial ability to hear in spite of the missing gene speaks to the back-up systems that are built into the auditory system, Shin says. “You take out one gene that looks like it should be very important, but probably a lot of compensatory mechanisms kick into place to make up for it.” By six months, however, the mice’s hearing had deteriorated substantially, and they had very severe hearing loss, according to Shin. These results confirmed what the researchers had initially suspected—that the cuticular plate plays a key role in hearing. “We show that if you weaken that foundation, the function of the mechanical antenna deteriorates over time, and that affects the hearing function in these mice,” he says. According to Shin, the findings don’t have any immediate relevance for treatment of age-related hearing loss in that he doesn’t see them as revealing any targets for new drug therapies. But the study does advance basic understanding of how hearing works and the role that the cuticular plate plays. “We have good reason to believe that if we identify a human that has a mutation in the LM07 gene, these humans will be more susceptible to age-related hearing loss,” Shin says. Although his group’s findings don’t point toward immediate solutions for age-related hearing loss, Shin underscores the importance of taking hearing loss seriously and of treating it through available means—namely, hearing aids. While patients might be resistant to being fitted for hearing aids, providers should encourage them not to be intimidated. “Hearing loss is a contributing factor to dementia and Alzheimer’s and so on—this is now proven. And it’s socially very isolating,” Shin says. “If you are deaf, you are just sitting there and you become invisible. This is something the geriatric population needs to be aware of, but also the providers who care for them. The providers in principle know it, but it needs to be driven home.” — Jamie Santa Cruz is a freelance writer based in Englewood, Colorado.
References 2. Kim J, Koo M. Mass and stiffness impact on the middle ear and the cochlear partition. J Audiol Otol. 2015;19(1):1-6. 3. Sarmento KMA Jr, Sampaio ALL, Santos TGT, Oliveira CACP. High-frequency conductive hearing loss as a diagnostic test for incomplete ossicular discontinuity in non-cholesteatomatous chronic suppurative otitis media. PLoS One. 2017;12(12):e0189997. 4. Yeh MC, Weng SF, Shen YC, et al. Increased risk of sudden sensorineural hearing loss in patients with osteoporosis: a population-based, propensity score-matched, longitudinal follow-up study. J Clin Endocrinol Metab. 2015;100(6):2413-2419. 5. Ozkiriş M, Karaçavuş S, Kapusuz Z, Balbaloğlu O, Saydam L. Does bone mineral density have an effect on hearing loss in postmenopausal patients? Ann Otol Rhinol Laryngol. 2013;122(10):648-652. 6. Jung DJ, Cho HH, Lee KY. Association of bone mineral density with hearing impairment in postmenopausal women in Korea. Clin Exp Otorhinolaryngol. 2016;9(4):319-325. 7. Yoo JI, Park KS, Seo SH, Park HW. Osteoporosis and hearing loss: findings from the Korea National Health and Nutrition Examination Survey 2009-2011 [published online February 18, 2019]. Braz J Otorhinolaryngol. doi: 10.1016/j.bjorl.2018.12.009. 8. Alvarado JC, Fuentes-Santamaría V, Gabaldón-Ull MC, Juiz JM. Age-related hearing loss is accelerated by repeated short-duration loud sound stimulation. Front Neurosci. 2019;13:77. 9. Guimaraes P, Frisina ST, Mapes F, Tadros SF, Frisina DR, Frisina RD. Progestin negatively affects hearing in aged women. Proc Natl Acad Sci U S A. 2006;103(38):14246-14249. 10. Coleman JR, Campbell D, Cooper WA, Welsh MG, Moyer J. Auditory brainstem responses after ovariectomy and estrogen replacement in rat. Hear Res. 1994;80(2):209-215. 11. Curhan SG, Eliassen AH, Eavey RD, Wang M, Lin BM, Curhan GC. Menopause and postmenopausal hormone therapy and risk of hearing loss. Menopause. 2017;24(9):1049-1056. 12. Milon B, Mitra S, Song Y, et al. The impact of biological sex on the response to noise and otoprotective therapies against acoustic injury in mice. Biol Sex Differ. 2018;9(1):12. 13. Price K, Zhu X, Guimaraes PF, Vasilyeva ON, Frisina RD. Hormone replacement therapy diminishes hearing in peri-menopausal mice. Hear Res. 2009;252(1-2):29-36. 14. Zhang J, Zhang T, Yu L, et al. Effects of ovarian reserve and hormone therapy on hearing in premenopausal and postmenopausal women: a cross-sectional study. Maturitas. 2018;111:77-81. 15. Barati B, Abtahi SH, Hashemi SM, Okhovat SA, Poorqasemian M, Tabrizi AG. The effect of topical estrogen on healing of chronic tympanic membrane perforations and hearing threshold. J Res Med Sci. 2013;18(2):99-102. 16. Williamson TT, Ding B, Zhu X, Frisina RD. Hormone replacement therapy attenuates hearing loss: mechanisms involving estrogen and the IGF-1 pathway. Aging Cell. 2019;18(3):e12939. 17. Du TT, Dewey JB, Wagner EL, et al. LMO7 deficiency reveals the significance of the cuticular plate for hearing function. Nat Commun. 2019;10(1):1117. |
