By Jeffrey T. Jensen, MD, MPH, Editor
Leon Speroff Professor and Vice Chair for Research, Department of Obstetrics and Gynecology, Oregon Health & Science University, Portland
Dr. Jensen reports that he is a consultant for and receives grant/research support from Bayer, Abbvie, ContraMed, and Merck; he receives grant/research support from Medicines 360, Agile, and Teva; and he is a consultant for MicroChips and Evofem.
SYNOPSIS: Data from the prospective Nurses’ Health Study demonstrate a weak association between menopause onset after age 50 years and use of hormone therapy and hearing loss. The most likely explanation is “noise.”
SOURCE: Curhan SG, Eliassen AH, Eavey RD, et al. Menopause and postmenopausal hormone therapy and risk of hearing loss. Menopause 2017; May 8. doi: 10.1097/GME.0000000000000878. [Epub ahead of print].
Hearing loss affects more than 48 million Americans, and the prevalence increases with age. Whether postmenopausal hormone therapy (HT) influences the progression of hearing loss is controversial. Curhan et al conducted the Conservation of Hearing Study (CHEARS) to explore the question using the Nurses’ Health Study (NHS) II database. An ongoing cohort study, the NHS II enrolled 116,430 U.S., female, registered nurses aged 25 to 42 years in 1989. Nurses in the cohort received biennial mailed questionnaires that elicited updated information on diet, lifestyle, and various health outcomes; the follow-up rate over 24 years exceeds 90% of the eligible person-time. The CHEARS study limited the cohort to women who provided information on hearing on the 2009 or 2013 questionnaire and excluded women who reported an onset of hearing loss prior to 1991 and women who reported HT use prior to menopause. The primary outcome of the study was self-reported hearing loss determined based on the response to the 2009 and 2013 questionnaires, with an incident date after 1991. Since the prospective nature of the NHS design allowed investigators to relate the date of hearing loss to the onset of menopause and HT, they could calculate incidence rates and provide relative risk estimates adjusted for known confounders (e.g., history of occupational or recreational noise exposure, demographic characteristics, nutritional factors, etc.). The authors examined the independent relations between menopause and postmenopausal HT and risk of self-reported hearing loss.
After exclusions, the cohort comprised 80,972 women who contributed 1,410,928 person-years of follow-up. A total of 18,558 women in the cohort reported hearing loss. The authors found no significant overall association between menopausal status, natural or surgical, and risk of hearing loss. However, older age at natural menopause (≥ 50 compared to < 50 years) was associated with higher risk (multivariable-adjusted relative risk [MVRR], 1.10; 95% confidence interval [CI], 1.03-1.17). The authors also found HT (predominantly oral estrogen therapy or estrogen plus progestogen therapy) was associated with a higher risk of hearing loss, and that greater duration of HT increased the risk (MVRR 1-1.9 years, 1.10 [CI, 1.00-1.21]; 2-4.9 years, 1.08 [CI, 1.00-1.16]; 5-9.9 years, 1.15 [1.06-1.24]; > 10 years, 1.21 [1.07-1.37]; P for trend 0.001).
Based on these associations, the authors concluded that women who undergo menopause at an older age or use hormonal therapy have a higher risk of hearing loss.
COMMENTARY
Over coffee one morning, my wife commented aloud about the many advertisements for hearing aids in our newspaper. After I responded with the cheap laugh line (“What?”), we talked about the changing demographics of the newspaper business. People over the age of 50 are more likely to receive a daily newspaper, and we know hearing loss increases with age. Whether hormonal therapy increases or decreases this important health concern has not been established. Unfortunately, the association of long-term HT use with hearing loss described in the paper by Curhan et al does not improve our understanding. This paper made the rounds in the newspapers (probably to the delight of those companies marketing hearing aids) and television news as yet another “risk associated with hormones.” Since this usually results in phone calls, let’s examine the data.
The Nurses’ Health Studies have provided a treasure trove of data to evaluate numerous health outcomes in women. The original NHS enrolled a cohort of 121,700 married registered nurses, aged 30 to 55 years in 1976. These women received follow-up questionnaires every two years. A second cohort, NHS II, enrolled women in 1989 (marriage no longer required!), and enrollment for NHS3 (both men and women) using a web-based approach is ongoing. The establishment of a cohort allows ascertainment of baseline health status, demographic characteristics, and potential risk factors and exposures. The periodic questionnaires provide information on changes in health status and exposures. This allows researchers to assess incidence data and construct relative risks in a prospective design, and to adjust these risks for known confounders. Other strengths include the large sample size that provides impressive statistical power. However, the design is “prospective” only when the data are collected prospectively. While this sounds obvious, investigators sometimes bend the rules to add in new questions later that require recall. This takes away our assumption of good baseline assessment of confounders and should increase our interest in understanding the potential for bias.
The assessment of hearing loss requires comment. A new series of questions added in 2009 and 2013 asked women in the cohort about hearing loss that occurred any time beginning after 1991, a recall interval of more than two decades. In the paper, the authors defended the approach as robust by citing papers that reported sensitivity/specificity estimates of around 75% for self-reported hearing loss evaluated by a single question.1,2 Although this lack of precision in assessment of the primary outcome alone is concerning, we also can’t assume that effect is non-differential. For example, could women concerned about hearing loss have been more likely to start HT or use it longer?
Biologic plausibility always helps me gauge the potential for association. Hearing loss may reflect changes occurring in the inner, middle, or outer ear. Both estrogen receptor-alpha and -beta are expressed in the cochlea, suggesting a role for estrogen in hearing.3 Although progesterone receptor is not expressed in the inner ear, progesterone receptor-beta occurs in the cochlear bone.4 Estrogen action influences bone remodeling of the otic capsule, and the development of otosclerosis may be related to downregulation of estrogen response by progestogens or to elevated prolactin levels.5 If so, one could hypothesize that unopposed estrogen might protect against hearing loss, and combined HT could worsen hearing. No such effect was reported by Curhan et al. Furthermore, we have no mechanism to understand why an early menopause would protect against hearing loss.
The most likely explanation for the observed associations? Noise! While statistically significant because of the extremely large sample size of the NHS II, the observed associations are very weak (MVRR, 1.1-1.23), with CIs including 1.0 for many comparisons, and clinically unimportant. Bias provides the most likely explanation for associations like these. Don’t let noise like this interfere with your discussion of potential important benefits of HT, like fracture prevention and reduction in cardiovascular risk.
REFERENCES
- Ferrite S, Santana VS, Marshall SW. Validity of self-reported hearing loss in adults: Performance of three single questions. Rev Saude Publica 2011;45:824-830.
- Sindhusake D, Mitchell P, Smith W, et al. Validation of self-reported hearing loss. The Blue Mountains Hearing Study. Int J Epidemiol 2001;30:1371-1378.
- Stenberg AE, Simonoska R, Stygar D, et al. Effect of estrogen and antiestrogens on the estrogen receptor content in the cochlea of ovariectomized rats. Hear Res 2003;182:19-23.
- Bonnard A, Sahlin L, Hultcrantz M, Simonoska R. No direct nuclear effect of progesterone in the inner ear: Other possible pathways. Acta Otolaryngol 2013;133:1250-1257.
- Horner KC. The effect of sex hormones on bone metabolism of the otic capsule—An overview. Hear Res 2009;252:56-60.
Data from the prospective Nurses’ Health Study demonstrate a weak association between menopause onset after age 50 years and use of hormone therapy and hearing loss. The most likely explanation is “noise.”
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