A Novel Therapy for Presbycusis

Approximately 30% of adults over the age of 64 years have hearing loss that compromises their ability to communicate and even more have hearing loss that does not yet noticeably affect their daily lives. ¹ Majority of this hearing loss is attributed to presbycusis—age-related decrements in hearing characterized by symmetric loss of auditory perception. ²

Despite the prevalence of presbycusis and its potentially devastating impact on quality of life and professional productivity no pharmacological treatments that reverse or prevent it have come into widespread use. Instead, clinicians rely on symptomatic treatment with hearing amplification. Although advances in this technology have made the devices more effective and discreet, their use remains abysmally low with estimates suggesting only about 15% of eligible patients use them. ³ Commonly cited barriers to hearing amplification include cost, discomfort, lack of perceived benefit, and unpleasing appearance. ⁴ Continued improvements in hearing amplification may address some resistance to these devices, but the strikingly low utilization of this technology necessitates exploration of novel treatment modalities to most effectively care for those afflicted with presbycusis.

Mineralocorticoids represent one such novel treatment modality. Use of these hormones in presbycusis arose as a direct result of developments in the understanding of the pathogenesis of age-related hearing loss that revealed Na–K–Cl cotransporter-1 (NKCC1) and Na–K–ATP channels on the basolateral membrane of the stria vascularis, which create the endocochlear potential required for proper auditory transduction by hair cells, decline with age. ^5,6 Given that this decline correlates with a decline in aldosterone—the mineralocorticoid hormone that regulates NKCC1 and Na–K–ATP channels—supplementation with mineralocorticoids presented itself as an elegantly simple potential means to ameliorate presbycusis. ^5,7

Several studies in mice have shown aldosterone to both slow and reverse presbycusis, and a study by Tadros and colleagues helped confirm the link between aldosterone and presbycusis in humans by demonstrating significantly lower endogenous levels of the hormone in presbycusic adults compared with similarly aged peers with normal hearing. ^5,7,8 Although translational research using mineralocorticoids for presbycusis remains in its infancy, a preliminary randomized controlled trial in humans did show promise.

The study, a 3-month trial published in 2015, consisted of four groups of patients: a control group that received no treatment, a group that received nimodipine (vasodilator), a group that received deflazacort (corticosteroid), and a group that received fludrocortisone (mineralocorticoid). ⁹ Compared with the control group the males in the fludrocortisone group gained 11.49 dB in the right ear (p = 0.00) and 8.94 dB in the left ear (p = 0.28). Females receiving fludrocortisone gained 12.17 dB in the right ear (p = 0.03) and 11.75 dB in left ear (p = 0.00). Males in the deflazacort group gained 6.72 dB in the right ear (p = 0.05) and 6.06 dB in the left ear (p = 0.04). Females in this group gained 10.33 dB in the right ear (p = 0.11) and 8.08 dB in left ear (p = 0.00). The nimodipine group saw more modest gains in hearing acuity, and the control group had negligible changes in hearing over the course of the trial.

Not only do the improvements in the fludrocortisone group support the therapeutic role of mineralocorticoids for presbycusis, but, so too do the results in the deflazacort group as corticosteroids have activity on the mineralocorticoid receptor, the likely mechanism by which deflazacort reversed the patients' hearing loss. ¹⁰ Although encouraging, the results do warrant some skepticism given that the observed improvements are near the test–retest reliability for audiological testing. ¹¹ In addition, the modest nature of the improvements suggest that fludrocortisone may not provide clinically significant benefit as a monotherapy; however, even if ineffective as monotherapy it could still have an important place in a multimodal approach to hearing loss that attains clinical significance through the additive benefit of several therapies that reverse and prevent the degradation of auditory perception.

Over the course of the 3-month trial patients tolerated the fludrocortisone well and only 1 of the 14 patients in the fludrocortisone group dropped out of the study. Although mice studies showed no increases in blood pressure with aldosterone, 5 of the 14 patients receiving fludrocortisone did develop increases in blood pressure requiring an antihypertensive. ^5,7,8 The reason for this discrepancy may rest in the anatomic and physiological differences between humans and mice, but another explanation also seems plausible. This preliminary trial did not limit participation solely to those with presbycusis. Instead, the authors chose sensorineural hearing loss as the only etiological requirement for participation. Given that about 16% of the participants in the study were under the age of 42 years many likely had neither presbycusis nor declining levels of aldosterone, potentially making them especially susceptible to the development of hypertension when given fludrocortisone. A future study that measures aldosterone levels before initiation of fludrocortisone would help clarify if the baseline level of aldosterone affects the risk of developing hypertension.

The hypertension experienced by five of the patients in the preliminary trial and complexities associated with hormone replacement do raise concerns about the feasibility of fludrocortisone as a standard therapy for presbycusis. Because hormones have wide-ranging systemic effects they can cause numerous undesirable and unexpected outcomes, especially in older patients. For example, progestin supplementation appears to negatively affect hearing in postmenopausal women, and thyroid hormone supplementation may actually increase mortality in some subsets of older patients. ^12,13 The most common adverse effects attributed to fludrocortisone include hypertension, edema, and electrolyte abnormalities. ¹⁴ Such adverse effects have the potential to prohibit the widespread use of the therapy, but current investigations into novel means of drug delivery may sufficiently reduce these undesirable effects, preserving the potential of mineralocorticoids to become a routine treatment for presbycusis.

Several animal models have shown the viability of cochlear implants, nanoparticles, hydrogels, magnetic particles, and micropumps for local drug delivery to the inner ear. ^15,16 Hütten et al. even showed in an in vitro model that engineering living cells to produce a desired product can have neuroprotective benefits for spiral ganglion cells. ¹⁷ These novel means of delivery would minimize systemic exposure to fludrocortisone, mitigating its potentially prohibitive adverse effects. Moreover, they would decrease or even obviate the need for the laboratory monitoring, increasing adherence to the therapy and making it more attractive to both clinicians and patients.

Although many unknowns and reasons for caution with the use of mineralocorticoids for presbycusis remain, both animal studies and the first preliminary trial in humans appear to demonstrate that these hormones offer a novel means of reversing hearing loss—a potentially paradigm shifting finding in the treatment of presbycusis that warrants further investigation. Future studies aimed at confirming efficacy and ascertaining the optimal dosing, delivery, and treatment population will be of great interest as the medical community seeks to address the commonest neurodegenerative disorder in our aged population.