- Email: [email protected]
Effects of ovarian reserve and hormone therapy on hearing in premenopausal and postmenopausal women: A cross-sectional study
Accepted Manuscript Title: Effects of ovarian reserve and hormone therapy on hearing in premenopausal and postmenopausal women: a cross-sectional study Authors: Jingfei Zhang, Tingyue Zhang, Lisheng Yu, Qianying Ruan, Lingxue Yin, Dong Liu, Haicheng Zhang, Wenpei Bai, Zhenghong Ren PII: DOI: Reference:
S0378-5122(17)30904-0 https://doi.org/10.1016/j.maturitas.2018.01.019 MAT 6954
To appear in:
Maturitas
Received date: Revised date: Accepted date:
17-9-2017 24-12-2017 20-1-2018
Please cite this article as: Zhang Jingfei, Zhang Tingyue, Yu Lisheng, Ruan Qianying, Yin Lingxue, Liu Dong, Zhang Haicheng, Bai Wenpei, Ren Zhenghong.Effects of ovarian reserve and hormone therapy on hearing in premenopausal and postmenopausal women: a cross-sectional study.Maturitas https://doi.org/10.1016/j.maturitas.2018.01.019 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Effects of ovarian reserve and hormone therapy on hearing in premenopausal and postmenopausal women: a cross-sectional study Jingfei Zhanga&, Tingyue Zhangb&, Lisheng Yuc, Qianying Ruand, Lingxue Yind, Dong
a
IP T
Liue, Haicheng Zhangf, Wenpei Baia*and Zhenghong Reng
Department of Obstetrics and Gynecology, Beijing Shijitan Hospital, Capital Medical
b
SC R
University, Beijing, China
Department of Clinical Medicine, Xiangya School of Medicine, Central South
University, Hunan, China c
Department of Otorhinolaryngology, Peking University People's Hospital, Beijing,
Department of Audiology, Beijing Shijitan Hospital, Capital Medical University,
N
d
U
China
Beijing, China
Department of life science, Peking University, Beijing, China
f
Department of Cardiology, Peking University People's Hospital, Beijing, China
g
Department of public health, Peking University, Beijing, China
M
A
e
ED
Corresponding author: Wenpei Bai, MD, PhD, Department of Obstetrics and Gynecology, Beijing Shijitan Hospital, Capital Medical University, 10 Tieyi Road,
PT
Haidian District, Beijing, China
CC E
Email: [email protected]
Abbreviations: AMH, anti-Mullerian hormone; BMI, body mass index; KMI,
A
Kupperman menopausal index; FSH, follicle-stimulating hormone; LH, luteinizing hormone; E2, estradiol; T, testosterone; AFC, antral follicle count; OF group, ovarian failure group; NOF group, ovarian non-failure group; HT group, hormone therapy group; OR, odds ratio
1
Highlights
To our knowledge, this is the first study in which ovarian reserve has been categorized by the anti-Mullerian hormone level to evaluate the effect of ovarian reserve on hearing.
To determine the early changes in hearing loss among pre- and postmenopausal women, we performed extended high-frequency audiometry. A decline in ovarian function is associated with hearing loss in women, especially in relation to extended high-frequency air conduction of the right ear.
IP T
Preserving ovarian function and reducing earphone use are important measures to
U
SC R
protect women’s hearing.
Abstract
N
Objectives: To observe the hearing function around menopause, to analyze the effects
A
of ovarian reserve and hormone therapy on hearing, and to study factors related to
M
hearing loss among women around menopause.
Study Design: In this cross-sectional study, we evaluated 109 women around
ED
menopause aged 45 to 55 years, including 40 women with ovarian failure, 48 with ovarian non-failure, and 21 receiving hormone therapy. All women underwent an audiologic evaluation, and hormone blood testing was performed. The general
PT
condition, reproductive history, medical history, lifestyle, and menopausal symptoms were collected through a questionnaire.
CC E
Main outcome measure: The auditory threshold and anti-Mullerian hormone level. Results: Women in the ovarian failure group presented with a decreased hearing level in all frequency bands compared with those in the ovarian non-failure group; the significant differences occurred at 8000Hz, 10 000 Hz, 12 500 Hz, and 16 000 Hz in
A
the right-ear air conduction. The auditory threshold was lower in the hormone therapy group than in the ovarian failure group, but the difference was statistically significant only in the right-ear air conduction at 10 000Hz. There were two risk factors for hearing loss: an anti-Mullerian hormone level <0.01 ng/mL (odds ratio [OR]=2.624) and frequent earphone use (OR=3.846). Conclusions: A decline in ovarian function is associated with hearing loss in women, 2
especially in relation to extended high-frequency air conduction of the right ear. Preserving ovarian function and reducing earphone use are important measures to protect women’s hearing. However, the effect of hormone therapy on hearing requires further investigation.
IP T
Keywords: Anti-Mullerian Hormone; Ovarian Reserve; Menopause; Audiometry,
SC R
Pure-tone
1. Introduction
U
With age, hearing loss is a common disorder with important consequences for
N
quality of life. Population studies have estimated that more than half of individuals
A
aged over 60 years and 75% of those aged 70 years or older have hearing impairment, whereas the prevalence of hearing disability in those aged 60-80 years was 21-27%
M
[1-5]. Hearing loss in old age has a significant impact on everyday living and can lead to communication difficulties, cognitive impairment and depression [6]. Menopause is
ED
an important period of transition into old age for women, and it is often associated with menopausal vasomotor symptoms, neurological symptoms, physical symptoms, and
PT
urinary tract symptoms; however, few people have concerns about their hearing status. In recent years, some scholars have noticed that estrogen and its receptors play an important role in the development of the inner ear, and hearing and balance system
CC E
function. For example, newborn girls’ hearing was more sensitive than that of newborn boys [7]; women with Turner syndrome, who were biologically estrogen-deficient, were often associated with having hearing problems [8]; auditory function was
A
influenced by the ovarian cycle [9,10]; the effects of estrogen on hearing have been also validated in animal experiments [11,12]; there was an association between low serum estrogen levels and hearing loss in menopausal women [13], and estrogen replacement therapy may preserve hearing [14-16]. Epidemiological studies have shown that age-related hearing decline starts after 30 years in men but not until after 50 years in women, which coincides with the menopausal transition in most women [17]. 3
There have been sporadic reports about the effect of menopause on hearing [18-20]. The decline of ovarian function is the main cause of metabolic changes and clinical symptoms around menopause. Among previous studies concerning the relationship between menopause and hearing decline, few investigations have evaluated the effect of ovarian reserve function on one’s hearing condition. As ovarian reserve cannot be quantified directly in vivo or indirectly with the menstrual status, hormonal and
IP T
ultrasonographic assays have been developed as indirect markers, including estradiol (E2), follicle-stimulating hormone (FSH), inhibin B, anti-Mullerian hormone (AMH), and the antral follicle count (AFC) [21]. Among them, the serum AMH level along
SC R
with AFC have been proven to be the most accurate in reflecting the pool of antral follicles, indirectly reflecting the remaining ovarian reserve made of primordial follicles and predicting reproductive lifespan [22,23].
The present study focused on analyzing the effect of ovarian reverse function
U
decline on hearing. To reflect the early changes of hearing loss, we performed
N
extended high frequency audiometry, and to the best of our knowledge, this is the first
A
time ovarian function has been categorized by the AMH level to evaluate the effect of ovarian reserve function on hearing. This study aimed to answer the following
M
questions: (1) how does hearing change with ovarian reserve failure? (2) if ovarian reserve function is a key factor affecting hearing, how does hormone therapy affect
ED
women’s hearing? and (3) what are the risk factors for hearing loss around menopause?
PT
2. Methods
2.1 Study design and sample
CC E
All women aged 45 to 55 years (N=338) without occupational noise exposure who were undergoing health checkups which included an otoscopic examination by an otorhinolaryngology specialist, at Beijing Shijitan Hospital between March and September 2016 were invited to complete a medical questionnaire. Among them, 140
A
failed to return the questionnaire or refused to participate in the study. In total, 198 questionnaires were returned, and 89 were excluded because of exclusion criteria or missing items. Therefore, 109 questionnaires were valid and included in this study. All participants underwent an audiologic evaluation that included pure-tone audiometry at conventional and extended high frequencies and impedance audiometry test. Blood
4
samples were obtained to determine the levels of AMH, FSH, luteinizing hormone (LH), E2, and testosterone (T). 2.2 Inclusion and exclusion criteria Since the average age of menopause for Chinese women is 50 years [24], women were included in the sample if they were aged 45 to 55 years and in good health; and had regular menstruation, oligomenorrhea, or had been postmenopausal for less than 5
IP T
years. Participants were divided into three groups according to AMH level and whether they received hormone therapy. The ovarian failure group (OF group), i.e., those with a serum AMH level <0.01 ng/mL, did not receive any hormone therapy previously; the
SC R
ovarian non-failure group (NOF group), i.e., those with a serum AMH level ≥0.01
ng/mL, did not receive any hormone therapy previously; and the hormone therapy group (HT group) were treated with sex hormones over the course of 1 year.
Individuals were excluded if they had previous otologic symptoms, any neurological
U
disease or systemic diseases that could affect their hearing, or premature ovarian
N
failure, and those who previously had used ototoxic drugs. Otoscopic examination and
A
the impedance audiometry test were all normal. 2.3 Questionnaire
M
A questionnaire composed of 10 items on 9 pages was developed and took about 30 minutes to complete. It included questions on general information (e.g., age, education
ED
level, and income), menstrual and reproductive history, previous or current diseases, anthropometric data (e.g., height, weight, body mass index [BMI], blood pressure,
PT
heart rate, and waist and hip circumference), lifestyle (e.g., smoking history, and exercise and dietary habits), and hearing condition (e.g., a history of otitis media,
CC E
sudden deafness, noise exposure and exposure to ototoxic drugs, a family history of deafness, and habit of wearing earphones). Additionally, the Kupperman Menopausal Index (KMI) was used to evaluate menopausal symptoms.
A
2.4 Hormone testing Four milliliters of peripheral blood samples were obtained on the second, third, or
fourth day of the menstrual cycle for women with regular menses, whereas blood samples were obtained randomly for women with oligomenorrhea and menopause. Serum was separated, frozen, and stored at -80°C for batch determination. All samples were analyzed at the laboratory of The First Hospital of Peking University. Levels of the AMH, FSH, LH, E2, and T were determined using fully automated 5
electrochemiluminescence immunoassay (Roche Diagnostics, USA). 2.5 Audiologic evaluation Pure-tone audiometry at conventional and extended high frequencies and impedance audiometry were separately performed for all participants in a soundproof booth by the same audiometry technician, who was blinded to the participants’ hormonal and medication statuses. Frequencies at octave intervals from 125 to 16 000 Hz were tested
IP T
for air conduction, and from 250 to 8000 Hz for bone conduction. The testing was performed using the GSI-61 audiometer (Grason-Stadler Instruments, USA) and Titan impedance meter (Interacoustics, Denmark). TDH 50P circumaural earphones
SC R
(Telephonics, USA) were used for low frequencies, and HDA 200L circumaural earphones (Sennheiser, Germany) were used for high frequencies. 2.6 Statistical analyses
Data were double entered by EPIDATA 3.0 (The EpiData Association Odense) and
U
analyzed by SPSS 23.0 (IBM Corp.). All normally distributed values are expressed as
N
means ± standard deviation. Medians (interquartile range) are provided in case of
A
non-normally distributed data. Analysis of variance and Kruskall– Wallis tests were used as appropriate to compare means and medians of continuous variables depending
M
on the normality and homogeneity of variance of data, respectively. Chi-square test and Fisher exact probability test were used to compare proportions. Multiple logistic
ED
regression analysis was used to estimate odds ratios (ORs) for the association of hearing loss and the various factors. P values <0.05 indicate statistical significance.
PT
3. Results
3.1 Characteristics of the sample
CC E
In this cross-sectional study, 109 women were enrolled. Characteristics of these women, combined and stratified by ovarian reserve function and whether they received hormone therapy, are shown in Table 1. There were no differences among the three groups in age; menarche age; BMI; pregnancy; medical history; family history of
A
deafness; history of noise exposure; smoking history; headphone use; exercise habits; the intake of vitamins and a calcium supplement; use of health care products; and intake of milk, egg, soy products, meat, nuts, vegetables, fruits, cereals, and potatoes. There were differences among the three groups of ovarian function in the FSH, LH, and E2 levels. Additionally, the HT group had a higher KMI score than the NOF group.
6
Table 1. Baseline characteristics of the three groups.
Age(years)a Menarche age(years)a BMI(kg/m2)a KMI scorea LH(IU/L)b FSH(IU/L)b E2(pg/mL)b T(ng/dL)a
OF-group （n=40） 50.70±1.74 13.78±2.11 24.04±3.68 13.00±8.28 28.74(15.32) 67.97(38.91) 28.50(23.75) 1.12±0.29
NOF-group （n=48） 49.65±2.79 13.16±1.25 24.00±3.87 10.18±7.71 5.14(18.79) 9.31(24.91) 87.00(119.00) 1.13±0.17
HT-group （n=21） 50.76±3.21 13.10±1.94 23.51±2.61 15.76±7.87 27.79(18.22) 51.84(33.41) 40.00(49.00) 1.11±0.24
P 0.062 0.167 0.849 0.028 † <0.001*† <0.001*† <0.001* 0.920
For the OF group and NOF group
†
For the NOF group and HT group
a
Compared using one-way analysis of variance with LSD post-hoc test
b
Compared using Kruskal-Wallis test followed by all pairwise multiple comparisons
SC R
IP T
*
OF, ovarian failure; NOF, ovarian non-failure; HT, hormone therapy; BMI, body mass index; KMI, Kupperman Menopausal Index ; LH, luteinizing hormone; FSH,
U
follicle-stimulating hormone; T, testosterone; continuous data as mean ± standard
A
N
deviation or median (interquartile range) as appropriate.
3.2 Comparison of hearing among the groups
M
A comparison of the air and bone conduction thresholds of both ears at the tested frequencies among the three groups is presented in Figure 1. There was a statistically
ED
significant difference among the three groups in the right ear air conduction at 8000 Hz (P =0.048), 10 000 Hz (P=0.039), 12 500 Hz (P =0.019), and 16 000 Hz (P =0.018).
PT
Multiple comparison tests showed difference was statistically significant between OF group and NOF group.
CC E
In the HT group, 21 women received sex hormones (3, femonston; 4, climen; 10, estradiol and progesterone /dydrogesterone; 4, tibolone); the details are shown in Table 2. The results showed that the HT group had better hearing than that of the OF group, but the difference was statistically significant only in the right ear air conduction at 10
A
000Hz.
7
IP T SC R U N A M ED PT
Figure 1. Pure-tone thresholds in the frequency range from 125 to 16000Hz for air
CC E
conduction and from 250 to 8000 Hz for bone conduction are displayed as box plots for each frequency of the three groups. Boxes indicate median and inter quartile range, and whiskers represent minimum and maximum values. OF, ovarian failure; NOF, ovarian non-failure; HT, hormone therapy; LAC, left ear air conduction; RAC,
A
right ear air conduction; RBC, right ear bone conduction; LBC, left ear bone conduction. Data were analyzed using one way analysis of variance with LSD post-hoc test or the Kruskal-Wallis nonparametric test followed by stepwise step-down comparisons depending on the normality of data. Differences between OF and NOF group, between OF and HT group are marked with * and # respectively.
8
Table 2. Details of sex hormones
Climen Estrogen plus progestin Tibolone
IP T
Composition and usage 17ß-estradiol (1 mg/day, 28 days) /continuously and dydrogesterone (10 mg/day, 14 days) /sequentially estradiol valerate (2 mg/day, 21 days) / continuously and cyproterone acetate (1 mg/day, 10 days) /sequentially, followed by 7 days off estradiol valerate (1-2 mg/day, 21-28 days) / continuously and progesterone (200 mg/day, 10-14 days) or dydrogesterone (10 mg/day, 10-14 days) /sequentially, followed by 2 -7 days off tibolone (2.5 mg or 1.25 mg, daily) /continuously
Femonston
3.3 Factors associated with hearing loss
Hearing was considered abnormal if the hearing threshold was ≥25 dB at any test
SC R
frequency (125-8000 Hz), i.e., the hearing loss group (n=39); hearing was considered normal if the hearing threshold was <25 dB at all test frequencies, i.e., the normal hearing group (n=70). We built a multivariate model that included the following independent variables: age (years), AMH level (<0.01/≥0.01 ng/mL), FSH level, LH
U
level, E2 level, T level, BMI, symptoms of menopause (yes/no), KMI score, pregnancy,
N
parity, receipt of hormone therapy (yes/no), frequency of sexual activity in the past 6
A
months (≥8 times per month/4-7 times per month/≤3 times per month/ none), medical history (yes/no), a family history of deafness (yes/no), a history of noise exposure
M
(yes/no), smoking history (never/current/past), passive smoking (yes/no), frequent earphone use (yes/no), exercise habits (number of exercises per week), diet (frequency
ED
of taking vitamins and a calcium supplement; health care products; and intake of milk, eggs, soy products, meat, nuts, vegetables, fruits, grains and potatoes per week).
PT
Logistic regression of univariate analysis showed a significant correlation between hearing loss and ovarian function failure (AMH level <0.01 ng/mL), menopausal
CC E
symptoms, and frequent earphone use (P<0.05, all). There was no correlation with age, medical history, diet, exercise habits, receipt of hormone therapy, and other factors (P>0.05). Multivariable logistic regression analysis showed that ovarian function failure (AMH level <0.01 ng/mL) and frequent earphone use were risk factors (OR>1,
A
P<0.05), as shown in Table 3.
Table 3. Multiple logistic regression analysis of hearing loss. Variable
AMH level
9
B
0.965
SE
0.481
Wald
4.028
P-value
0.045
OR
2.624
95% CI Lower
Upper
1.023
6.732
Menopausal symptoms
0.335
0.484
0.480
0.488
1.398
0.542
3.610
Frequent earphone use
1.347
0.515
6.833
0.009
3.846
1.401
10.559
SE, standard error; OR, odds ratio; CI, confidence interval; AMH, anti-Mullerian hormone 4. Discussion This study observed the effect of ovarian reserve function on hearing by grouping ovarian function by the AMH level, and we performed conventional and extended high
IP T
frequency audiometry. The decline of ovarian reserve function is the main cause of metabolic changes and clinical symptoms in the perimenopausal period. AMH is
SC R
majorly secreted by preantral follicles and antral follicles without fluctuation during
the menstrual cycle, and the AMH level cannot be measured during menopause or 3-5 days after bilateral oophorectomy, which is a good and early marker of ovarian reserve decline compared to FSH and inhibin B levels, and AFC [25]. In our study, 82.5% of
U
women in the OF group were in menopause, 15% had oligomenorrhea, and 2.5% had
N
regular menses. In the NOF group, 83.3% had regular menses, 14.6% had oligomenorrhea, and 2.1% were in menopause. There was good consistency between
A
the AMH level and ovarian function. Therefore, the serum AMH level was used to
M
evaluate ovarian reserve function in this study. The results showed that the OF group had a poorer hearing threshold in binaural air conduction at each frequency than the
ED
NOF group; the significant difference was particularly reflected by the extended high frequency in the right ear. Moreover, the median hearing threshold in right ear air
PT
conduction at 8000 Hz was the same among the three groups, but the inter quartile range was different, with a P-value of 0.048, which is very close to 0.05; therefore, in future research, we will increase the sample size to validate this conclusion. In addition
CC E
to the traditional air conduction pathway, voice can also be transmitted through bone conduction to the inner ear, and sound stimulates the inner ear lymph by bypassing the external and middle ears through skull vibration. Therefore, bone conduction
A
thresholds were measured. However, the results showed no difference among the groups. Some studies have demonstrated a strong relationship between menopause and
hearing decline. However, most of them only performed conventional pure-tone audiometry restricted to 125-8000 Hz frequencies, which has great limitations in detecting early auditory organ damage, as the extended high frequencies of hearing are affected early and lower frequencies of hearing are affected gradually. Johan et al. [18] 10
followed the hearing condition of 100 perimenopausal women for 10 years; they found a continuous hearing decline at all frequencies during the follow-up, and the rate of decline during the menopausal period was higher than that of reference period for the same age group. Köşüş et al. [19] reported that postmenopausal women with and without tibolone therapy had poorer hearing thresholds than those who were still menstruating at the same age; it was considered that menopause is the key factor
IP T
affecting hearing function, and estrogen had a crucial influence on hearing function. An animal experiment demonstrated that auditory brainstem response latency was prolonged after ovariectomy in rats and reversed by estrogen treatments [11].
SC R
Additionally, it has been reported that estrogen deficiency in early menopause may not lead to an increase in the hearing threshold [26]. However, the sample size was small and extended high frequency audiometry was not performed, so the findings did not reflect the early changes of hearing loss.
U
We discovered that low ovarian reserve function and frequent earphone use were
N
main risk factors of hearing loss in conventional pure-tone audiometry (≤8000 Hz).
A
Thus, to protect women’s hearing, we suggest preserving ovarian function and reducing earphone use. As the normal range of extended high-frequency hearing
M
(>9000 Hz) has no uniform standard, we could not group participants by extended high frequency hearing and discuss it as an influencing factor. Interestingly, this study
ED
suggests that the decline of hearing in menopausal women is more pronounced in the right ear, which is different from that reported by Hederstierna et al. [20]. The
PT
expression of estrogen receptors in the inner ear and brain may be a prerequisite for ovarian function to affect hearing, and it has been reported that decreased bone mineral
CC E
density may be related to age-related sensorineural hearing loss in postmenopausal women [27]. The mechanism of ovarian function influencing hearing requires further research.
Hormone therapy is an important way to improve menopausal symptoms in women.
A
Estrogen plays an important role in cell differentiation, memory storage, bone growth, etc. Whether estrogen can affect the development of the ear and hearing function has not yet been determined. There are many studies about the effects of estrogen and progesterone on hearing function. Most scholars believe that estrogen has a protective effect on hearing, and estrogen replacement therapy may delay hearing loss in menopausal women [14,28], whereas progesterone may have a negative effect on the 11
peripheral and central auditory system [29]. Köşüş et al. [30] reported a discrepancy in improvement of hearing loss between the left and right ears after postmenopausal hormone therapy, which was more prominent on the right side. Our study showed that the hearing level in the HT group was better than that in the OF group, but the difference was not statistically significant except in the right air conduction at 10 000Hz.
IP T
It should be noted that this study has a few limitations. The study was relatively small, and the effect of hormone therapy on hearing needs to be further explored. In addition, the expression of estrogen receptors in the inner ear and brain may be a
SC R
prerequisite for ovarian function to affect hearing, and its underlying mechanism warrants further study.
In conclusion, this study identified that ovarian function decline was associated with hearing loss in women, especially in extended high frequency air conduction of the
A
N
important measures to protect women’s hearing.
U
right ear. Additionally, preserving ovarian function and reducing earphone use were
M
Contributors
Jingfei Zhang and Tingyue Zhang participated in the study design, participant
equally to the work.
ED
recruitment, data collection and analyses, and manuscript preparation and contributed
design.
PT
Lisheng Yu, Dong Liu and Haicheng Zhang participated in the study conception and
CC E
Qianying Ruan and Lingxue Yin participated in the auditory test. Wenpei Bai participated in the study design, study funding, and supervision of this
work.
A
Zhenghong Reng participated in the data analyses and manuscript revision. All authors saw and approved the final version of the manuscript.
Conflict of interest The authors declare that they have no conflict of interest.
12
Funding This work was supported by the Youth Fund of Beijing Shijitan Hospital (grant number 2016-q26) and the Beijing Municipal Science & Technology Commission
IP T
(grant number Z131107002213088).
SC R
Ethical approval
This study was approved by the Beijing Shijitan Hospital ethics committee (SJTH
Provenance and peer review
M
A
This article has undergone peer review.
N
U
2016NO.34), and all participants provided informed consent.
Research data (data sharing and collaboration)
ED
The data set will be available from 16 September 2019 at https://data.mendeley.com/datasets/59g6dv9ty8/draft?a=e198509b-ea59-4bf2-abc1-3
CC E
PT
4ca7ea3c576.
References
[1] M.A. Rooth, The prevalence and impact of vision and hearing loss in the elderly, N C Med J. 78(2017)118-120.
A
[2] F. Cacciatore, C. Napoli,P. Abete, et al., Quality of life determinants and hearing function in an elderly population: Osservatorio Geriatrico Campano Study Group, Gerontology. 45(1999)323-328. [3] A. Ciorba, C. Bianchini, S. Pelucchi, A. Pastore, The impact of hearing loss on the quality of life of elderly adults, Clin Interv Aging. 7(2012) 159-163.
13
[4] A. Hogan, K. O'Loughlin,P. Miller, H. Kendig, The health impact of a hearing disability on older people in Australia, J Aging Health. 21(2009)1098-1111. [5] S. Monini, C. Filippi, R. Baldini, M. Barbara, Perceived disability from hearing and voice changes in the elderly, Geriatr Gerontol Int. 15(2015)147-155. [6] M. Cherko, L. Hickson, M. Bhutta, Auditory deprivation and health in the elderly, Maturitas. 88(2016) 52-57.
IP T
[7] A.W.K. Snihur, E. Hampson, Sex and ear differences in spontaneous and click-evoked otoacoustic emissions in young adults, Brain Cogn. 77(2011)40-47.
[8] C. Hederstierna, M. Hultcrantz, U. Rosenhall, Estrogen and hearing from a clinical
SC R
point of view;characteristics of auditory function in women with Turner syndrome, Hear Res. 252(2009)3-8.
[9] S.J. Swanson , H.A. Dengerink, Changes in pure-tone thresholds and temporary threshold shift s as a function of menstrual cycle and oral contraceptives,
U
J Speech Hear Res. 31(1988)569-574.
N
[10] D. Al-Mana, B. Ceranic, O. Djahanbakhch, L.M. Luxon, Alteration in auditory
A
function during the ovarian cycle, Hear Res. 268(2010)114-122. [11] J.R. Coleman, D. Campbell, A. Cooper, et al., Auditory brainstem response after
M
ovariectomy and estrogen replacement in rat, Hear Res. 80(1994)209-215. [12] I. Meltser, Y. Tahera, E. Simpson, et al., Estrogen receptor β protects against
ED
acoustic trauma in mice, J Clin Invest. 118(2008)1563-1570. [13] S.H. Kim, B.H. Kang, H.D. Chae, C.H. Kim, The association between serum
PT
estradiol level and hearing sensitivity in postmenopausal women, Obstet Gynecol. 99(2002)726-730.
CC E
[14] S. Caruso, L. Maiolino, C. Agnello, et al., Effects of patch or gel estrogen therapies on auditory brainstem response in surgically postmenopausal women: a prospective, randomized study, Fertil Steril. 79(2003)556-561. [15] E.B. Kilicdag, H. Yavuz,T. Bagis, et al., Effects of estrogen therapy on hearing in
A
postmenopausal women, Am J Obstet Gynecol. 190(2004)77-82. [16] C. Hederstierna, M. Hultcrantz, A. Collins, U. Rosenhall, Hearing in women at menopause. Prevalence of hearing loss, audiometric configuration and relation to hormone replacement therapy, Acta Otolaryngol. 27(2007)149-155. [17] A. Davis, Hearing in adults, Whurr Publishers Ltd, London. (1995)102-103.
14
[18] S. Johan, B. Rusana, H. Malou, H. Christina, Hearing decline in menopausal women- a 10-year follow-up, Acta Otolaryngol. 135(2015)807-813. [19] N. Köşüş, A. Köşüş, NÖ. Turhan, H. Kurtaran, Hearing levels in menopausal women and the effect of tibolone on audiological functions, J Obstet Gynecol. 32 (2012)294-297. [20] C. Hederstierna, M. Hultcrantz, A. Collins, U. Rosenhall, The menopause
IP T
triggers hearing decline in healthy women, Hear Res. 259(2010)31-35. [21] T.S. Domingues, A.M. Rocha, P.C. Serafini, Tests for ovarian reserve: reliability and utility, Curr Opin Obstet Gynecol. 22(2010)271-276.
SC R
[22] S.L. Broer, F.J. Broekmans, J.S. Laven, B.C. Fauser, Anti-mulleria hormone:
ovarian reserve testing and its potential clinical implications. Hum Reprod Update. 20(2014)688-701.
[23] D. Dewailly, C.Y. Andersen, A. Balen, et al., The physiology and clinical utility
U
of anti-Mullerian hormone in women, Hum Reprod Update. 20(2014)370-385.
N
[24] L. Li, J. Wu, D. Pu, et al. Factors associated with the age of natural menopause and
A
menopausal symptoms in Chinese women, Maturitas. 73(2012)354-360. [25] Q. Yu, Menopause, People's Medical Publishing House, Beijing. (2013)76-78.
M
[26] F. Oghan, H. Coksuer, Comparative audiometric evaluation of hearing loss between the premenopausal and postmenopausal period in young women, Am J
ED
Otolaryngol. 33(2012)322-325.
[27]J.Y. Kim, S.B. Lee, C.H, Lee, H.M. Kim, Hearing loss in postmenopausal women
PT
with low bone mineral density, Auris Nasus Larynx. 43(2016)155-160. [28] E.B. Kilicdag, H. Yavuz, T. Bagis,et al., Effects of estrogen therapy on hearing in
CC E
postmenopausal women, Am J Obstet Gynecol. 190(2004)77-82. [29] P. Guimaraes, S.T. Frisina, F. Mapes, et al., Progestin negatively affects hearing in aged women, Proc Natl Acad Sci USA. 103(2006)14246-14249. [30] N. Köşüş, A. Köşüş, NÖ. Turhan, Discrepancy in improvement of hearing loss
A
between left and right ears after postmenopausal hormone therapy, Med Hypotheses. 76(2011)447-449.
15
S0378-5122(17)30904-0 https://doi.org/10.1016/j.maturitas.2018.01.019 MAT 6954
To appear in:
Maturitas
Received date: Revised date: Accepted date:
17-9-2017 24-12-2017 20-1-2018
Please cite this article as: Zhang Jingfei, Zhang Tingyue, Yu Lisheng, Ruan Qianying, Yin Lingxue, Liu Dong, Zhang Haicheng, Bai Wenpei, Ren Zhenghong.Effects of ovarian reserve and hormone therapy on hearing in premenopausal and postmenopausal women: a cross-sectional study.Maturitas https://doi.org/10.1016/j.maturitas.2018.01.019 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Effects of ovarian reserve and hormone therapy on hearing in premenopausal and postmenopausal women: a cross-sectional study Jingfei Zhanga&, Tingyue Zhangb&, Lisheng Yuc, Qianying Ruand, Lingxue Yind, Dong
a
IP T
Liue, Haicheng Zhangf, Wenpei Baia*and Zhenghong Reng
Department of Obstetrics and Gynecology, Beijing Shijitan Hospital, Capital Medical
b
SC R
University, Beijing, China
Department of Clinical Medicine, Xiangya School of Medicine, Central South
University, Hunan, China c
Department of Otorhinolaryngology, Peking University People's Hospital, Beijing,
Department of Audiology, Beijing Shijitan Hospital, Capital Medical University,
N
d
U
China
Beijing, China
Department of life science, Peking University, Beijing, China
f
Department of Cardiology, Peking University People's Hospital, Beijing, China
g
Department of public health, Peking University, Beijing, China
M
A
e
ED
Corresponding author: Wenpei Bai, MD, PhD, Department of Obstetrics and Gynecology, Beijing Shijitan Hospital, Capital Medical University, 10 Tieyi Road,
PT
Haidian District, Beijing, China
CC E
Email: [email protected]
Abbreviations: AMH, anti-Mullerian hormone; BMI, body mass index; KMI,
A
Kupperman menopausal index; FSH, follicle-stimulating hormone; LH, luteinizing hormone; E2, estradiol; T, testosterone; AFC, antral follicle count; OF group, ovarian failure group; NOF group, ovarian non-failure group; HT group, hormone therapy group; OR, odds ratio
1
Highlights
To our knowledge, this is the first study in which ovarian reserve has been categorized by the anti-Mullerian hormone level to evaluate the effect of ovarian reserve on hearing.
To determine the early changes in hearing loss among pre- and postmenopausal women, we performed extended high-frequency audiometry. A decline in ovarian function is associated with hearing loss in women, especially in relation to extended high-frequency air conduction of the right ear.
IP T
Preserving ovarian function and reducing earphone use are important measures to
U
SC R
protect women’s hearing.
Abstract
N
Objectives: To observe the hearing function around menopause, to analyze the effects
A
of ovarian reserve and hormone therapy on hearing, and to study factors related to
M
hearing loss among women around menopause.
Study Design: In this cross-sectional study, we evaluated 109 women around
ED
menopause aged 45 to 55 years, including 40 women with ovarian failure, 48 with ovarian non-failure, and 21 receiving hormone therapy. All women underwent an audiologic evaluation, and hormone blood testing was performed. The general
PT
condition, reproductive history, medical history, lifestyle, and menopausal symptoms were collected through a questionnaire.
CC E
Main outcome measure: The auditory threshold and anti-Mullerian hormone level. Results: Women in the ovarian failure group presented with a decreased hearing level in all frequency bands compared with those in the ovarian non-failure group; the significant differences occurred at 8000Hz, 10 000 Hz, 12 500 Hz, and 16 000 Hz in
A
the right-ear air conduction. The auditory threshold was lower in the hormone therapy group than in the ovarian failure group, but the difference was statistically significant only in the right-ear air conduction at 10 000Hz. There were two risk factors for hearing loss: an anti-Mullerian hormone level <0.01 ng/mL (odds ratio [OR]=2.624) and frequent earphone use (OR=3.846). Conclusions: A decline in ovarian function is associated with hearing loss in women, 2
especially in relation to extended high-frequency air conduction of the right ear. Preserving ovarian function and reducing earphone use are important measures to protect women’s hearing. However, the effect of hormone therapy on hearing requires further investigation.
IP T
Keywords: Anti-Mullerian Hormone; Ovarian Reserve; Menopause; Audiometry,
SC R
Pure-tone
1. Introduction
U
With age, hearing loss is a common disorder with important consequences for
N
quality of life. Population studies have estimated that more than half of individuals
A
aged over 60 years and 75% of those aged 70 years or older have hearing impairment, whereas the prevalence of hearing disability in those aged 60-80 years was 21-27%
M
[1-5]. Hearing loss in old age has a significant impact on everyday living and can lead to communication difficulties, cognitive impairment and depression [6]. Menopause is
ED
an important period of transition into old age for women, and it is often associated with menopausal vasomotor symptoms, neurological symptoms, physical symptoms, and
PT
urinary tract symptoms; however, few people have concerns about their hearing status. In recent years, some scholars have noticed that estrogen and its receptors play an important role in the development of the inner ear, and hearing and balance system
CC E
function. For example, newborn girls’ hearing was more sensitive than that of newborn boys [7]; women with Turner syndrome, who were biologically estrogen-deficient, were often associated with having hearing problems [8]; auditory function was
A
influenced by the ovarian cycle [9,10]; the effects of estrogen on hearing have been also validated in animal experiments [11,12]; there was an association between low serum estrogen levels and hearing loss in menopausal women [13], and estrogen replacement therapy may preserve hearing [14-16]. Epidemiological studies have shown that age-related hearing decline starts after 30 years in men but not until after 50 years in women, which coincides with the menopausal transition in most women [17]. 3
There have been sporadic reports about the effect of menopause on hearing [18-20]. The decline of ovarian function is the main cause of metabolic changes and clinical symptoms around menopause. Among previous studies concerning the relationship between menopause and hearing decline, few investigations have evaluated the effect of ovarian reserve function on one’s hearing condition. As ovarian reserve cannot be quantified directly in vivo or indirectly with the menstrual status, hormonal and
IP T
ultrasonographic assays have been developed as indirect markers, including estradiol (E2), follicle-stimulating hormone (FSH), inhibin B, anti-Mullerian hormone (AMH), and the antral follicle count (AFC) [21]. Among them, the serum AMH level along
SC R
with AFC have been proven to be the most accurate in reflecting the pool of antral follicles, indirectly reflecting the remaining ovarian reserve made of primordial follicles and predicting reproductive lifespan [22,23].
The present study focused on analyzing the effect of ovarian reverse function
U
decline on hearing. To reflect the early changes of hearing loss, we performed
N
extended high frequency audiometry, and to the best of our knowledge, this is the first
A
time ovarian function has been categorized by the AMH level to evaluate the effect of ovarian reserve function on hearing. This study aimed to answer the following
M
questions: (1) how does hearing change with ovarian reserve failure? (2) if ovarian reserve function is a key factor affecting hearing, how does hormone therapy affect
ED
women’s hearing? and (3) what are the risk factors for hearing loss around menopause?
PT
2. Methods
2.1 Study design and sample
CC E
All women aged 45 to 55 years (N=338) without occupational noise exposure who were undergoing health checkups which included an otoscopic examination by an otorhinolaryngology specialist, at Beijing Shijitan Hospital between March and September 2016 were invited to complete a medical questionnaire. Among them, 140
A
failed to return the questionnaire or refused to participate in the study. In total, 198 questionnaires were returned, and 89 were excluded because of exclusion criteria or missing items. Therefore, 109 questionnaires were valid and included in this study. All participants underwent an audiologic evaluation that included pure-tone audiometry at conventional and extended high frequencies and impedance audiometry test. Blood
4
samples were obtained to determine the levels of AMH, FSH, luteinizing hormone (LH), E2, and testosterone (T). 2.2 Inclusion and exclusion criteria Since the average age of menopause for Chinese women is 50 years [24], women were included in the sample if they were aged 45 to 55 years and in good health; and had regular menstruation, oligomenorrhea, or had been postmenopausal for less than 5
IP T
years. Participants were divided into three groups according to AMH level and whether they received hormone therapy. The ovarian failure group (OF group), i.e., those with a serum AMH level <0.01 ng/mL, did not receive any hormone therapy previously; the
SC R
ovarian non-failure group (NOF group), i.e., those with a serum AMH level ≥0.01
ng/mL, did not receive any hormone therapy previously; and the hormone therapy group (HT group) were treated with sex hormones over the course of 1 year.
Individuals were excluded if they had previous otologic symptoms, any neurological
U
disease or systemic diseases that could affect their hearing, or premature ovarian
N
failure, and those who previously had used ototoxic drugs. Otoscopic examination and
A
the impedance audiometry test were all normal. 2.3 Questionnaire
M
A questionnaire composed of 10 items on 9 pages was developed and took about 30 minutes to complete. It included questions on general information (e.g., age, education
ED
level, and income), menstrual and reproductive history, previous or current diseases, anthropometric data (e.g., height, weight, body mass index [BMI], blood pressure,
PT
heart rate, and waist and hip circumference), lifestyle (e.g., smoking history, and exercise and dietary habits), and hearing condition (e.g., a history of otitis media,
CC E
sudden deafness, noise exposure and exposure to ototoxic drugs, a family history of deafness, and habit of wearing earphones). Additionally, the Kupperman Menopausal Index (KMI) was used to evaluate menopausal symptoms.
A
2.4 Hormone testing Four milliliters of peripheral blood samples were obtained on the second, third, or
fourth day of the menstrual cycle for women with regular menses, whereas blood samples were obtained randomly for women with oligomenorrhea and menopause. Serum was separated, frozen, and stored at -80°C for batch determination. All samples were analyzed at the laboratory of The First Hospital of Peking University. Levels of the AMH, FSH, LH, E2, and T were determined using fully automated 5
electrochemiluminescence immunoassay (Roche Diagnostics, USA). 2.5 Audiologic evaluation Pure-tone audiometry at conventional and extended high frequencies and impedance audiometry were separately performed for all participants in a soundproof booth by the same audiometry technician, who was blinded to the participants’ hormonal and medication statuses. Frequencies at octave intervals from 125 to 16 000 Hz were tested
IP T
for air conduction, and from 250 to 8000 Hz for bone conduction. The testing was performed using the GSI-61 audiometer (Grason-Stadler Instruments, USA) and Titan impedance meter (Interacoustics, Denmark). TDH 50P circumaural earphones
SC R
(Telephonics, USA) were used for low frequencies, and HDA 200L circumaural earphones (Sennheiser, Germany) were used for high frequencies. 2.6 Statistical analyses
Data were double entered by EPIDATA 3.0 (The EpiData Association Odense) and
U
analyzed by SPSS 23.0 (IBM Corp.). All normally distributed values are expressed as
N
means ± standard deviation. Medians (interquartile range) are provided in case of
A
non-normally distributed data. Analysis of variance and Kruskall– Wallis tests were used as appropriate to compare means and medians of continuous variables depending
M
on the normality and homogeneity of variance of data, respectively. Chi-square test and Fisher exact probability test were used to compare proportions. Multiple logistic
ED
regression analysis was used to estimate odds ratios (ORs) for the association of hearing loss and the various factors. P values <0.05 indicate statistical significance.
PT
3. Results
3.1 Characteristics of the sample
CC E
In this cross-sectional study, 109 women were enrolled. Characteristics of these women, combined and stratified by ovarian reserve function and whether they received hormone therapy, are shown in Table 1. There were no differences among the three groups in age; menarche age; BMI; pregnancy; medical history; family history of
A
deafness; history of noise exposure; smoking history; headphone use; exercise habits; the intake of vitamins and a calcium supplement; use of health care products; and intake of milk, egg, soy products, meat, nuts, vegetables, fruits, cereals, and potatoes. There were differences among the three groups of ovarian function in the FSH, LH, and E2 levels. Additionally, the HT group had a higher KMI score than the NOF group.
6
Table 1. Baseline characteristics of the three groups.
Age(years)a Menarche age(years)a BMI(kg/m2)a KMI scorea LH(IU/L)b FSH(IU/L)b E2(pg/mL)b T(ng/dL)a
OF-group （n=40） 50.70±1.74 13.78±2.11 24.04±3.68 13.00±8.28 28.74(15.32) 67.97(38.91) 28.50(23.75) 1.12±0.29
NOF-group （n=48） 49.65±2.79 13.16±1.25 24.00±3.87 10.18±7.71 5.14(18.79) 9.31(24.91) 87.00(119.00) 1.13±0.17
HT-group （n=21） 50.76±3.21 13.10±1.94 23.51±2.61 15.76±7.87 27.79(18.22) 51.84(33.41) 40.00(49.00) 1.11±0.24
P 0.062 0.167 0.849 0.028 † <0.001*† <0.001*† <0.001* 0.920
For the OF group and NOF group
†
For the NOF group and HT group
a
Compared using one-way analysis of variance with LSD post-hoc test
b
Compared using Kruskal-Wallis test followed by all pairwise multiple comparisons
SC R
IP T
*
OF, ovarian failure; NOF, ovarian non-failure; HT, hormone therapy; BMI, body mass index; KMI, Kupperman Menopausal Index ; LH, luteinizing hormone; FSH,
U
follicle-stimulating hormone; T, testosterone; continuous data as mean ± standard
A
N
deviation or median (interquartile range) as appropriate.
3.2 Comparison of hearing among the groups
M
A comparison of the air and bone conduction thresholds of both ears at the tested frequencies among the three groups is presented in Figure 1. There was a statistically
ED
significant difference among the three groups in the right ear air conduction at 8000 Hz (P =0.048), 10 000 Hz (P=0.039), 12 500 Hz (P =0.019), and 16 000 Hz (P =0.018).
PT
Multiple comparison tests showed difference was statistically significant between OF group and NOF group.
CC E
In the HT group, 21 women received sex hormones (3, femonston; 4, climen; 10, estradiol and progesterone /dydrogesterone; 4, tibolone); the details are shown in Table 2. The results showed that the HT group had better hearing than that of the OF group, but the difference was statistically significant only in the right ear air conduction at 10
A
000Hz.
7
IP T SC R U N A M ED PT
Figure 1. Pure-tone thresholds in the frequency range from 125 to 16000Hz for air
CC E
conduction and from 250 to 8000 Hz for bone conduction are displayed as box plots for each frequency of the three groups. Boxes indicate median and inter quartile range, and whiskers represent minimum and maximum values. OF, ovarian failure; NOF, ovarian non-failure; HT, hormone therapy; LAC, left ear air conduction; RAC,
A
right ear air conduction; RBC, right ear bone conduction; LBC, left ear bone conduction. Data were analyzed using one way analysis of variance with LSD post-hoc test or the Kruskal-Wallis nonparametric test followed by stepwise step-down comparisons depending on the normality of data. Differences between OF and NOF group, between OF and HT group are marked with * and # respectively.
8
Table 2. Details of sex hormones
Climen Estrogen plus progestin Tibolone
IP T
Composition and usage 17ß-estradiol (1 mg/day, 28 days) /continuously and dydrogesterone (10 mg/day, 14 days) /sequentially estradiol valerate (2 mg/day, 21 days) / continuously and cyproterone acetate (1 mg/day, 10 days) /sequentially, followed by 7 days off estradiol valerate (1-2 mg/day, 21-28 days) / continuously and progesterone (200 mg/day, 10-14 days) or dydrogesterone (10 mg/day, 10-14 days) /sequentially, followed by 2 -7 days off tibolone (2.5 mg or 1.25 mg, daily) /continuously
Femonston
3.3 Factors associated with hearing loss
Hearing was considered abnormal if the hearing threshold was ≥25 dB at any test
SC R
frequency (125-8000 Hz), i.e., the hearing loss group (n=39); hearing was considered normal if the hearing threshold was <25 dB at all test frequencies, i.e., the normal hearing group (n=70). We built a multivariate model that included the following independent variables: age (years), AMH level (<0.01/≥0.01 ng/mL), FSH level, LH
U
level, E2 level, T level, BMI, symptoms of menopause (yes/no), KMI score, pregnancy,
N
parity, receipt of hormone therapy (yes/no), frequency of sexual activity in the past 6
A
months (≥8 times per month/4-7 times per month/≤3 times per month/ none), medical history (yes/no), a family history of deafness (yes/no), a history of noise exposure
M
(yes/no), smoking history (never/current/past), passive smoking (yes/no), frequent earphone use (yes/no), exercise habits (number of exercises per week), diet (frequency
ED
of taking vitamins and a calcium supplement; health care products; and intake of milk, eggs, soy products, meat, nuts, vegetables, fruits, grains and potatoes per week).
PT
Logistic regression of univariate analysis showed a significant correlation between hearing loss and ovarian function failure (AMH level <0.01 ng/mL), menopausal
CC E
symptoms, and frequent earphone use (P<0.05, all). There was no correlation with age, medical history, diet, exercise habits, receipt of hormone therapy, and other factors (P>0.05). Multivariable logistic regression analysis showed that ovarian function failure (AMH level <0.01 ng/mL) and frequent earphone use were risk factors (OR>1,
A
P<0.05), as shown in Table 3.
Table 3. Multiple logistic regression analysis of hearing loss. Variable
AMH level
9
B
0.965
SE
0.481
Wald
4.028
P-value
0.045
OR
2.624
95% CI Lower
Upper
1.023
6.732
Menopausal symptoms
0.335
0.484
0.480
0.488
1.398
0.542
3.610
Frequent earphone use
1.347
0.515
6.833
0.009
3.846
1.401
10.559
SE, standard error; OR, odds ratio; CI, confidence interval; AMH, anti-Mullerian hormone 4. Discussion This study observed the effect of ovarian reserve function on hearing by grouping ovarian function by the AMH level, and we performed conventional and extended high
IP T
frequency audiometry. The decline of ovarian reserve function is the main cause of metabolic changes and clinical symptoms in the perimenopausal period. AMH is
SC R
majorly secreted by preantral follicles and antral follicles without fluctuation during
the menstrual cycle, and the AMH level cannot be measured during menopause or 3-5 days after bilateral oophorectomy, which is a good and early marker of ovarian reserve decline compared to FSH and inhibin B levels, and AFC [25]. In our study, 82.5% of
U
women in the OF group were in menopause, 15% had oligomenorrhea, and 2.5% had
N
regular menses. In the NOF group, 83.3% had regular menses, 14.6% had oligomenorrhea, and 2.1% were in menopause. There was good consistency between
A
the AMH level and ovarian function. Therefore, the serum AMH level was used to
M
evaluate ovarian reserve function in this study. The results showed that the OF group had a poorer hearing threshold in binaural air conduction at each frequency than the
ED
NOF group; the significant difference was particularly reflected by the extended high frequency in the right ear. Moreover, the median hearing threshold in right ear air
PT
conduction at 8000 Hz was the same among the three groups, but the inter quartile range was different, with a P-value of 0.048, which is very close to 0.05; therefore, in future research, we will increase the sample size to validate this conclusion. In addition
CC E
to the traditional air conduction pathway, voice can also be transmitted through bone conduction to the inner ear, and sound stimulates the inner ear lymph by bypassing the external and middle ears through skull vibration. Therefore, bone conduction
A
thresholds were measured. However, the results showed no difference among the groups. Some studies have demonstrated a strong relationship between menopause and
hearing decline. However, most of them only performed conventional pure-tone audiometry restricted to 125-8000 Hz frequencies, which has great limitations in detecting early auditory organ damage, as the extended high frequencies of hearing are affected early and lower frequencies of hearing are affected gradually. Johan et al. [18] 10
followed the hearing condition of 100 perimenopausal women for 10 years; they found a continuous hearing decline at all frequencies during the follow-up, and the rate of decline during the menopausal period was higher than that of reference period for the same age group. Köşüş et al. [19] reported that postmenopausal women with and without tibolone therapy had poorer hearing thresholds than those who were still menstruating at the same age; it was considered that menopause is the key factor
IP T
affecting hearing function, and estrogen had a crucial influence on hearing function. An animal experiment demonstrated that auditory brainstem response latency was prolonged after ovariectomy in rats and reversed by estrogen treatments [11].
SC R
Additionally, it has been reported that estrogen deficiency in early menopause may not lead to an increase in the hearing threshold [26]. However, the sample size was small and extended high frequency audiometry was not performed, so the findings did not reflect the early changes of hearing loss.
U
We discovered that low ovarian reserve function and frequent earphone use were
N
main risk factors of hearing loss in conventional pure-tone audiometry (≤8000 Hz).
A
Thus, to protect women’s hearing, we suggest preserving ovarian function and reducing earphone use. As the normal range of extended high-frequency hearing
M
(>9000 Hz) has no uniform standard, we could not group participants by extended high frequency hearing and discuss it as an influencing factor. Interestingly, this study
ED
suggests that the decline of hearing in menopausal women is more pronounced in the right ear, which is different from that reported by Hederstierna et al. [20]. The
PT
expression of estrogen receptors in the inner ear and brain may be a prerequisite for ovarian function to affect hearing, and it has been reported that decreased bone mineral
CC E
density may be related to age-related sensorineural hearing loss in postmenopausal women [27]. The mechanism of ovarian function influencing hearing requires further research.
Hormone therapy is an important way to improve menopausal symptoms in women.
A
Estrogen plays an important role in cell differentiation, memory storage, bone growth, etc. Whether estrogen can affect the development of the ear and hearing function has not yet been determined. There are many studies about the effects of estrogen and progesterone on hearing function. Most scholars believe that estrogen has a protective effect on hearing, and estrogen replacement therapy may delay hearing loss in menopausal women [14,28], whereas progesterone may have a negative effect on the 11
peripheral and central auditory system [29]. Köşüş et al. [30] reported a discrepancy in improvement of hearing loss between the left and right ears after postmenopausal hormone therapy, which was more prominent on the right side. Our study showed that the hearing level in the HT group was better than that in the OF group, but the difference was not statistically significant except in the right air conduction at 10 000Hz.
IP T
It should be noted that this study has a few limitations. The study was relatively small, and the effect of hormone therapy on hearing needs to be further explored. In addition, the expression of estrogen receptors in the inner ear and brain may be a
SC R
prerequisite for ovarian function to affect hearing, and its underlying mechanism warrants further study.
In conclusion, this study identified that ovarian function decline was associated with hearing loss in women, especially in extended high frequency air conduction of the
A
N
important measures to protect women’s hearing.
U
right ear. Additionally, preserving ovarian function and reducing earphone use were
M
Contributors
Jingfei Zhang and Tingyue Zhang participated in the study design, participant
equally to the work.
ED
recruitment, data collection and analyses, and manuscript preparation and contributed
design.
PT
Lisheng Yu, Dong Liu and Haicheng Zhang participated in the study conception and
CC E
Qianying Ruan and Lingxue Yin participated in the auditory test. Wenpei Bai participated in the study design, study funding, and supervision of this
work.
A
Zhenghong Reng participated in the data analyses and manuscript revision. All authors saw and approved the final version of the manuscript.
Conflict of interest The authors declare that they have no conflict of interest.
12
Funding This work was supported by the Youth Fund of Beijing Shijitan Hospital (grant number 2016-q26) and the Beijing Municipal Science & Technology Commission
IP T
(grant number Z131107002213088).
SC R
Ethical approval
This study was approved by the Beijing Shijitan Hospital ethics committee (SJTH
Provenance and peer review
M
A
This article has undergone peer review.
N
U
2016NO.34), and all participants provided informed consent.
Research data (data sharing and collaboration)
ED
The data set will be available from 16 September 2019 at https://data.mendeley.com/datasets/59g6dv9ty8/draft?a=e198509b-ea59-4bf2-abc1-3
CC E
PT
4ca7ea3c576.
References
[1] M.A. Rooth, The prevalence and impact of vision and hearing loss in the elderly, N C Med J. 78(2017)118-120.
A
[2] F. Cacciatore, C. Napoli,P. Abete, et al., Quality of life determinants and hearing function in an elderly population: Osservatorio Geriatrico Campano Study Group, Gerontology. 45(1999)323-328. [3] A. Ciorba, C. Bianchini, S. Pelucchi, A. Pastore, The impact of hearing loss on the quality of life of elderly adults, Clin Interv Aging. 7(2012) 159-163.
13
[4] A. Hogan, K. O'Loughlin,P. Miller, H. Kendig, The health impact of a hearing disability on older people in Australia, J Aging Health. 21(2009)1098-1111. [5] S. Monini, C. Filippi, R. Baldini, M. Barbara, Perceived disability from hearing and voice changes in the elderly, Geriatr Gerontol Int. 15(2015)147-155. [6] M. Cherko, L. Hickson, M. Bhutta, Auditory deprivation and health in the elderly, Maturitas. 88(2016) 52-57.
IP T
[7] A.W.K. Snihur, E. Hampson, Sex and ear differences in spontaneous and click-evoked otoacoustic emissions in young adults, Brain Cogn. 77(2011)40-47.
[8] C. Hederstierna, M. Hultcrantz, U. Rosenhall, Estrogen and hearing from a clinical
SC R
point of view;characteristics of auditory function in women with Turner syndrome, Hear Res. 252(2009)3-8.
[9] S.J. Swanson , H.A. Dengerink, Changes in pure-tone thresholds and temporary threshold shift s as a function of menstrual cycle and oral contraceptives,
U
J Speech Hear Res. 31(1988)569-574.
N
[10] D. Al-Mana, B. Ceranic, O. Djahanbakhch, L.M. Luxon, Alteration in auditory
A
function during the ovarian cycle, Hear Res. 268(2010)114-122. [11] J.R. Coleman, D. Campbell, A. Cooper, et al., Auditory brainstem response after
M
ovariectomy and estrogen replacement in rat, Hear Res. 80(1994)209-215. [12] I. Meltser, Y. Tahera, E. Simpson, et al., Estrogen receptor β protects against
ED
acoustic trauma in mice, J Clin Invest. 118(2008)1563-1570. [13] S.H. Kim, B.H. Kang, H.D. Chae, C.H. Kim, The association between serum
PT
estradiol level and hearing sensitivity in postmenopausal women, Obstet Gynecol. 99(2002)726-730.
CC E
[14] S. Caruso, L. Maiolino, C. Agnello, et al., Effects of patch or gel estrogen therapies on auditory brainstem response in surgically postmenopausal women: a prospective, randomized study, Fertil Steril. 79(2003)556-561. [15] E.B. Kilicdag, H. Yavuz,T. Bagis, et al., Effects of estrogen therapy on hearing in
A
postmenopausal women, Am J Obstet Gynecol. 190(2004)77-82. [16] C. Hederstierna, M. Hultcrantz, A. Collins, U. Rosenhall, Hearing in women at menopause. Prevalence of hearing loss, audiometric configuration and relation to hormone replacement therapy, Acta Otolaryngol. 27(2007)149-155. [17] A. Davis, Hearing in adults, Whurr Publishers Ltd, London. (1995)102-103.
14
[18] S. Johan, B. Rusana, H. Malou, H. Christina, Hearing decline in menopausal women- a 10-year follow-up, Acta Otolaryngol. 135(2015)807-813. [19] N. Köşüş, A. Köşüş, NÖ. Turhan, H. Kurtaran, Hearing levels in menopausal women and the effect of tibolone on audiological functions, J Obstet Gynecol. 32 (2012)294-297. [20] C. Hederstierna, M. Hultcrantz, A. Collins, U. Rosenhall, The menopause
IP T
triggers hearing decline in healthy women, Hear Res. 259(2010)31-35. [21] T.S. Domingues, A.M. Rocha, P.C. Serafini, Tests for ovarian reserve: reliability and utility, Curr Opin Obstet Gynecol. 22(2010)271-276.
SC R
[22] S.L. Broer, F.J. Broekmans, J.S. Laven, B.C. Fauser, Anti-mulleria hormone:
ovarian reserve testing and its potential clinical implications. Hum Reprod Update. 20(2014)688-701.
[23] D. Dewailly, C.Y. Andersen, A. Balen, et al., The physiology and clinical utility
U
of anti-Mullerian hormone in women, Hum Reprod Update. 20(2014)370-385.
N
[24] L. Li, J. Wu, D. Pu, et al. Factors associated with the age of natural menopause and
A
menopausal symptoms in Chinese women, Maturitas. 73(2012)354-360. [25] Q. Yu, Menopause, People's Medical Publishing House, Beijing. (2013)76-78.
M
[26] F. Oghan, H. Coksuer, Comparative audiometric evaluation of hearing loss between the premenopausal and postmenopausal period in young women, Am J
ED
Otolaryngol. 33(2012)322-325.
[27]J.Y. Kim, S.B. Lee, C.H, Lee, H.M. Kim, Hearing loss in postmenopausal women
PT
with low bone mineral density, Auris Nasus Larynx. 43(2016)155-160. [28] E.B. Kilicdag, H. Yavuz, T. Bagis,et al., Effects of estrogen therapy on hearing in
CC E
postmenopausal women, Am J Obstet Gynecol. 190(2004)77-82. [29] P. Guimaraes, S.T. Frisina, F. Mapes, et al., Progestin negatively affects hearing in aged women, Proc Natl Acad Sci USA. 103(2006)14246-14249. [30] N. Köşüş, A. Köşüş, NÖ. Turhan, Discrepancy in improvement of hearing loss
A
between left and right ears after postmenopausal hormone therapy, Med Hypotheses. 76(2011)447-449.
15