www.elsevier.com/locate/ajog

American Journal of Obstetrics and Gynecology (2004) 190, 77e82

Effects of estrogen therapy on hearing inpostmenopausal women

Esra Bulgan Kilicdag, MD,a Haluk Yavuz, MD,b Tayfun Bagis, MD,a,* Ebru Tarim, MD,a

Alper Nabi Erkan, MD,b Ferah Kazanci, MDa

Departments of Obstetrics and Gynecologya and Oto-Rhino-Laryngology,b Baskent University Faculty of Medicine,Adana, Turkey

Received March 16, 2003; revised May 29, 2003; accepted June 13, 2003

––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––Objective: This study was undertaken to investigate how hormone therapy affects hearing in post-

menopausal women.Study design: This prospective study involved 109 postmenopausal women. Twenty of the womenwere using estrogen therapy (ET group), 30 women were using hormone therapy (HT group), and59 had not received hormone therapy of any kind (control group). Otoscopic examination revealed

normal tympanic membranes in all 109 subjects. Each individual was tested with low- (250-2000Hz) and high-frequency audiometry (4000-16000 Hz). Duration of hormone therapy was recorded,and patient characteristics (age, type of menopause, time since onset of menopause), body mass in-

dex (BMI), and hearing test results in the ET, HT, and control groups were compared.Results: There were no statistically significant differences between the treatment (ET and HTgroup) and control groups with respect to age, BMI, or time since onset of menopause. The mean

time on HT and ET was 4.13G 2.41 years and 3.35G 2.20 years, respectively. The mean air con-duction results at low frequencies (250, 500, 1000, and 2000 Hz) in the ET group were signifi-cantly higher than the corresponding findings in the control group (P! .001) and than the HT

group (P! .001). When the same comparisons were made between the HT group and the controlgroup, none of the differences was statistically significant (PO .05). The mean air-conduction re-sults at high frequencies (4, 6, 8, 10, 12, 14, and 16 kHz) in the ET group were significantly higherthan the corresponding results in the HT group (P! .008). ET versus controls and HT versus

controls at high frequencies revealed no significant differences (PO .05). The mean bone conduc-tion results in the ET group were significantly higher than the corresponding findings in the con-trol group (P! .016). Analysis of the same comparisons between the HT-ET and HT-control

groups revealed no significant differences (PO .05).Conclusion: Estrogen therapy may slow down hearing loss in aging postmenopausal women; how-ever, further studies of larger series are needed to confirm this, and the sites of hormonal action

must also be explored.� 2004 Elsevier Inc. All rights reserved.

KEY WORDSEstrogen therapyHormone therapy

Hearing lossPostmenopausal

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*Reprint requests: Tayfun Bagis, Guzelyali Mah. Adnan Kahveci

Bul 15.Sok, Bilgin Apt Kat: 6 No. 11, Seyhan-Adana, Turkey.

E-mail: bagistayfun@hotmail.com

0002-9378/$ - see front matter � 2004 Elsevier Inc. All rights reserved.

doi:10.1016/j.ajog.2003.06.001

78 Kilicdag et al

The prevalence of hearing impairment rises duringthe midlife years in humans and increases even moreduring old age. An epidemiologic study conducted byDavis1 in the United Kingdom showed that 80% ofhearing-impaired people older than 18 years are in thecategory of 60 years and older.

Research has demonstrated estrogen receptors in theinner ear of humans, mice, and rats, and some studieshave suggested that estrogen, which is known to acton neurons of the limbic-hypothalamic axis, may influ-ence sensory processing, including the auditory sys-tem.2,3 Turner’s syndrome is an interesting conditionthat may demonstrate the relationship between estrogenand hearing. It is known that the women with Turner’ssyndrome have aging-related hearing loss (presbyacusis)develop prematurely and they do not lack estrogen re-ceptors but rather the effect of estrogen.3-5 This suggeststhat lack of this hormone may play a role in the hearingdisorder in this patient group.

It has been reported that the auditory brainstem re-sponse (ABR) latencies for several components increasewith age in humans and also vary according to sex, levelof hearing loss, and other variables.6 Hormonal levelsmay contribute to ABR differences that have been ob-served between the sexes in adult rats and adult hu-mans.7,8 Coleman et al2 found that estrogen therapy inyoung adult rats shortened the latencies of electric re-sponses in several auditory pathways.

The aim of this study was to investigate how hor-mone therapy affects hearing in postmenopausalwomen.

Material and methods

This prospective study involved 109 postmenopausalwomen who were referred to the Menopause Unit inthe Gynecology Department of Baskent University Fac-ulty of Medicine between August 1, 2000, and August 1,2001. Fifty of the women had started some form of hor-mone therapy at least 1 year before the study was con-ducted. Twenty of these women were using estrogentherapy (ET group; 2 mg of 17b-estradiol in one tabletof Estrofem daily; Novo Nordisk, Bagsvard, Denmark)and 30 were using continuous combined hormone ther-apy (HT group; 2 mg of 17b-estradiol and 1 mg of nor-ethisterone acetate [NETA] in one tablet of Kliogestdaily; Novo Nordisk, Bagsvaerd, Denmark). The other59 women in the study (control group) had not receivedhormone therapy of any kind.

Postmenopausal status was defined as amenorrheafor at least 1 year, follicle-stimulating hormone levelsgreater than 40 mIU/mL, and estradiol (E2) levels lessthan 30 pg/mL. Patients who had previously had oto-logic symptoms and those who had previously had anyneurologic disease that can affect hearing were excluded.

Duration of hormone therapy was recorded in thetreatment groups, and patient characteristics (age, typeof menopause, time since onset of menopause), bodymass index (BMI), and hearing test results in the ET,HT, and control groups were compared. Otoscopic ex-amination revealed normal tympanic membranes in all109 subjects. All participants had normal middle earfunction, as determined by conventional immittance au-diometry. Each subject was tested with low- (250-2000Hz) and high-frequency audiometry (4000-16000 Hz).The standard battery of hearing tests consisted of puretone, speech, and impedance audiometry. The testingwas performed in standard soundproof rooms (Indus-trial Acoustics Company Inc, Bronx, NY) using anOrbiter 922 Clinical AudiometereVersion 2 (MadsenElectronics, Taastrup, Denmark), an AZ-7 impedancemeter (Interacoustics, Assens, Denmark), MX-41/ARstandard earphones (Madsen Electronics), and SennheiserHDA-200 high-frequency earphones (Madsen Electron-ics). The same audiometry technician performed all audi-ologic examinations in the same audiology laboratory.For each set of tests, mean values of air and bone con-duction at each frequency were calculated for the ET,HT, and control groups, and graphs of decibels versusfrequency were drawn to compare hearing in the threegroups (Figures 1 and 2).

Analysis of variance was used to analyze differencesin baseline data among the three groups. The Mann-Whitney U test was used to compare air-conduction andbone-conduction results in the three groups. P valuesless than .05 were considered to indicate statistical signi-ficance. Data were analyzed with the software SPSSfor Windows version 9.05 (SPSS Inc, Chicago, Ill). Re-sults are expressed as meanG SD.

Results

The characteristics of the subjects in the ET, HT, andcontrol groups are presented in Table I. The mean agesof the women on ET, HT, and the control group were51.11G 3.89 years, 52.58G 4.00 years, and 52.69G 5.0years, respectively. The corresponding mean BMIs were27.85G 3.24 kg/m2, 28.63G 4.74 kg/m2, and 28.73G5.25 kg/m2. The mean times since onset of menopausefor the women on ET, HT, and the controls were6.11G 4.92 years, 4.35G 2.40 years, and 4.44G 3.92years, respectively. There were no statistically signifi-cant differences between the subjects on ET, HT, andthe controls with respect to age, BMI, or time since onsetof menopause. The mean durations of hormone therapyin the HT and ET groups were 3.35G 2.20 years and4.13G 2.41 years, respectively (PO .05). All 20 (100%)subjects taking ET and 11 (18.6%) of the 59 controls werein surgical menopause.

The groups’ air-conduction threshold results at therange of frequencies tested are presented in Table II

Kilicdag et al 79

Figure 2 Comparison of the mean bone-conduction thresholds for the three groups at the frequencies tested. Circles, ET; squares, HT;diamonds, control.

Figure 1 Comparison of the mean air-conduction thresholds for the three groups at the frequencies tested. Circles, ET; squares, HT;diamonds, control.

and Figure 1. At low frequencies (250, 500, 1000, and2000 Hz), the mean air-conduction threshold values inthe ET and HT groups were lower than the correspond-ing results in the control group (lower hearing thresholdmeans better hearing level). The threshold values at lowfrequencies in the ET group were significantly lowerthan the corresponding findings in the control group(P!.001). However, the same comparisons betweenthe HT and control group findings revealed no statisticaldifferences (PO .05). At high frequencies (4, 6, 8, 10, 12,14, and 16 kHz), mean air-conduction threshold values

in the ET group was lower than the corresponding re-sults in the control and HT groups. The ET groupshowed significantly lower mean air-conduction thresh-olds than the HT group (P!.008).

The groups’ bone-conduction threshold results at therange of frequencies tested are presented in Table II andFigure 2. The mean threshold values in the ET groupwere significantly lower than those in the control group(P!.045). There were no significant differences betweenthe HT versus ET and HT versus control group meanthreshold values (PO .05).

80 Kilicdag et al

Table II Comparison of the mean air-conduction thresholds for the 3 groups at different frequencies (lower values indicate betterhearing)

Mean air-and bone-conduction thresholds (dB)

Frequency ET HT Control P value

AC low frequencies (250, 500, 1000, 2000 Hz) 17.31G 5.53 22.34G 10.01 27.90G 15.01 .001*AC high frequencies (4, 6, 8, 10, 12, 14, 16 kHz) 26.23G 6.34 32.45G 6.52 31.92G 10.04 .005y

Bone conduction (500, 1000, 2000, 4000 Hz) 12.88G 7.60 13.51G 7.54 18.90G 11.70 .045z

AC, Air conduction.

* For ET vs control and ET vs HT.y For ET vs HT group.z For ET vs Control group.

Table I The baseline characteristics of the ET, HT, and control groups

ET (n = 20) HT (n = 30) Control (n = 59) P value

Age (y) 51.11G 3.89 52.58G 4.0 52.69G 5.0 NSBMI (kg/m2) 27.85G 3.24 28.63G 4.74 28.73G 5.25 NSTime since onset of menopause (y) 6.11G 4.92 4.35G 2.40 4.44G 3.92 NSDuration of hormone therapy (y) 4.13G 2.41 3.35G 2.20 0 NSSurgical menopause (N [%]) 20 (100%) 0 11 (18.6%)

NS, Not significant.

Comment

Many laboratory data and trends related to estrogenlevels have been published in human epidemiologic stud-ies, but the value of estrogen for protecting againstaging-related diseases in women remains unclear.

The most important roles of estrogen are in growthand in the differentiation and function of the female re-productive tract. However, this hormone also affectsother organ systems.9 For example, evidence suggeststhat estrogen has multiple functions in the brain. It in-fluences development, plasticity, and survival of neurons,which implies links to age-related neuronal degenerativediseases.10-12

The sex and age differences in human hearing func-tion are well documented, and women are known to ex-hibit shorter ABR latencies.6,13 Investigators haveproposed that the sex difference in these latency periodsmay be hormonally influenced.7 Experiments haveshown that estrogen treatment can specifically alterABR latencies.14 A study by Coleman et al2 revealedthat estrogen replacement prolonged ABR latenciesin ovariectomized rats. This suggests that hormonalchanges at menopause may affect hearing.

A number of interesting reports in the literature havenoted an association between cyclical sensorineural hear-ing loss and the luteal phase of the menstrual cycle.15,16

Progesterone is secreted in the second half of menstrualcycle, and this change may be related to the negative ef-fects of this hormone on hearing. In our study, we foundthat, on low-frequency testing, the women on hormonetherapy (both the ET and HT groups) tended to have

better hearing levels than the control group. The findingsin the ET group at these low frequencies were signifi-cantly better than the corresponding findings in the con-trol group (P!.001) and the HT group (P!.001).However, the findings in the HT group at low frequencieswere not statistically important as the corresponding re-sults in the controls (PO .05). These findings suggestthat adding progesterone to estrogen therapy may atten-uate the positive effects of estrogen on hearing.

Most hearing loss that occurs because of presbyacusis,ototoxicity, exposure to noise, or traumatic effects ofmiddle ear surgery is in the high-frequency range; thus,the loss is usually first detected in this range.17,18 Thereare many proposed causes of presbyacusis, ranging fromunavoidable intrinsic degenerative processes to exposureto agents that damage hearing over a person’s life. Thepostulated mechanisms include mechanical, sensorineu-ral, and vascular and biochemical causes.19 Schuknecht20

theorized that genetic factors might influence neuronalloss in the cochlea and in acoustic pathways.

The mechanism by which hormonal changes alter au-ditory thresholds is not clear, but the literature on thephysiologic and biologic effects of sex hormones indi-cates two possible modes of action: (1) direct effectson the cochlea and various pathways in the central audi-tory system and (2) modulation of blood flow in cochleaand brain.2

Direct effects of estrogen

The physiologic actions of estrogens are mediatedthrough estrogen receptors (ERs), which are classified

Kilicdag et al 81

as subtypes a (ERa) and b (ERb). Studies have demon-strated expression of both these types of receptors in theinner ears of normal mice.5 ERas have been detected inthe spiral ganglion and ERb in the stria vascularis.9

Both these brain regions are important for hearingtransmission and inner ear homeostasis. Interaction ofestrogen with ERs increases the secretion of neurome-diators, stimulates the formation of new synapses, andcan activate certain genes that are responsible for pro-duction of antiapoptotic proteins and growth factors.21

Wang et al22 showed that loss of ERb with age is asso-ciated with increased neuronal degeneration in thebrain. Estrogen also has the potential to alter electrolytebalance to some degree in all body tissues,23 and ERahave been detected in the cells of the stria vascularis,which is involved in endolymph ion and fluid balance.24

Normal inner ear function depends on maintenance ofhemostasis in the inner ear fluids and on the biochemicalintegrity of auditory receptor cells. Altered electrolytebalance in these fluids caused by decreased estrogen lev-els and the subsequent osmolality changes that occurmight at least partially explain shifts in auditory thresh-olds in the postmenopausal period. Estrogen therapymay help maintain the ion and fluid balance of the innerear, which is impaired in the postmenopausal period.This hormone also helps regulate neurotransmitter pro-duction by seratonergic, dopaminergic, and cholinergicneurons.25,26 It is thought to enhance cognitive functionby modulating the production of acetylcholine in basalforebrain neurons.

Blood flow effects of estrogen

In addition to potential direct effects, it has also beentheorized that sex hormones alter blood flow in the co-chlea and the brain.2 Estrogen-related changes in cere-bral blood flow may affect the auditory response.There are age-related sex differences in cerebral bloodflow. Before menopause, women have higher cerebralblood flow volume than men of the same age.27 Aftermenopause, the flow volume decreases to parallel thatin age-matched men.28 Estrogen levels affect the reactiv-ity of cerebral arteries to vasoactive stimuli, such as se-rotonin. One study showed that withdrawal of estrogenselectively increased serotonin reactivity in the basilararteries of rabbits.29 Laugel et al30 used laser Dopplerultrasound to measure cochlear blood flow in rats. Theirresults indicated that ovarian steroid-mediated vasculareffects might influence cochlear blood flow. Changes inthe blood flow in this structure can alter the influx ofmetabolites to cells that process acoustic information.

One of the main concerns of both clinicians and pa-tients is that estrogen has unwanted side effects, includ-ing increased risk of uterine cancer. ERb is expressed athigh levels in both neurons and glial cells of the centralnervous system.21,24 Because there is little ERb in the

mature uterus, selective ERb agonists, then they becomeavailable, might be efficient in protecting the hearingfrom presbyacusis without affecting the uterus.

Our results and previously published evidence indi-cate that estrogen may slow down hearing loss in agingpostmenopausal women; however, further studies oflarger series are needed to confirm this, and the sitesof hormonal action must also be explored.

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