Key Words
central auditory processing disorder - menopause
INTRODUCTION
Estrogen has been found to play an integral role in many organ systems including the
auditory system. The auditory system comprises a peripheral component, which generally
includes the outer, inner, and middle ear, and a central component, which consists
of structures within the central nervous system. In this auditory system, estrogen
receptors have been shown to be present in the pathways of mice and rats, which suggests
that estrogen may play an important role in hearing ([Stenberg et al, 1999]). It has been demonstrated in rats that ovariectomy negatively affects auditory
brainstem responses (ABR) and middle latency responses (MLR) ([Coleman et al, 1994]). Estrogen replacement therapy may reverse the neurophysiological changes in these
rats following ovariectomy ([Coleman et al, 1994]). In songbirds such as the white-throated sparrow, auditory processing has been
shown to be dependent on levels of estradiol, which subsequently affects females’
behavioral responses to male songs during breeding season ([Maney et al, 2006]). In female rhesus monkeys, administration of exogenous estrogen resulted in shorter
ABR latencies ([Golub et al, 2004]).
In humans, estrogen receptors have been identified in the inner ear ([Stenberg et al, 2001]). Estrogen has been found to be produced in the human brain by auditory neurons
themselves and has an important direct effect on neurotransmission ([Pinaud and Tremere, 2012]). Estrogen has an effect on neurotransmission by acting as a neuromodulator thereby
directly influencing synaptic physiology by suppressing presynaptic γ-aminobutyric
acid (GABA) release—in addition to estrogen-dependent genomic transcription in auditory
neurons ([Pinaud and Tremere, 2012]). Although less direct, estrogen has also been shown to influence cochlear blood
flow, which may play a role in auditory function ([Laugel et al, 1987]).
Because of estrogen’s role in the auditory system, postmenopausal (Post-M) women may
suffer auditory processing disorders due to decreased production of the hormone. Women
consistently have shorter latencies and larger amplitudes on ABR compared with men
between the ages of 20 and 79 ([Jerger and Hall, 1980]). However, older Post-M women have similar latencies as men of the same age ([Wharton and Church, 1990]). Thus, female ABR latencies, which are normally shorter compared with men, may
prolong after menopause to the point that female latencies are similar to male latencies
([Wharton and Church, 1990]). Administration of hormone replacement therapy (HRT) in Post-M women has been shown
to improve ABR latencies ([Caruso et al, 2000]; [Caruso et al, 2003]; [Khaliq et al, 2003]). Turner’s syndrome, an estrogen deficient state, is associated with earlier onset
of high-frequency hearing loss in addition to other auditory problems associated with
the condition, such as recurrent otitis media, sensorineural hearing loss, conductive
hearing loss, or inner ear malformations ([Hultcrantz and Sylven, 1997]; [Hultcrantz et al, 2006]). In addition, it has been shown that estradiol therapy may delay hearing loss in
Post-M women ([Kilicdag et al, 2004]). These findings support the notion that the hormonal changes accompanying menopause
have an effect on hearing.
Hearing loss is an exceedingly common disorder in the United States. As many as 20%
of Americans aged 12 years and older have hearing loss and the prevalence increases
with every decade of age ([Lin et al, 2011]). Although hearing loss is not associated with mortality, this condition substantially
affects the quality of life of elderly individuals. Hearing loss in the elderly has
been associated with dysfunction in emotional states, social interactions, and communications
and many consider these dysfunctions to be severely handicapping ([Mulrow et al, 1990a],[b]). Although the focus of hearing loss has been primarily on peripheral involvement,
central deficits are less commonly studied but can negatively influence quality of
life as well.
Many Post-M women report abnormal auditory perceptions, complaining of difficulty
in hearing or tinnitus but demonstrate no deficits in peripheral hearing sensitivity
as reflected on the pure-tone audiogram. It has been shown that participants with
these auditory complaints but normal audiometry may have an underlying central auditory
processing disorder (CAPD) ([Shinn et al, 2016]). Although there is extensive research examining estrogen and hearing loss using
animal models, there is little research examining these relationships between humans
and auditory processing. The aim of this study was to evaluate relationships between
hormonal changes and hearing as it relates to higher auditory function in premenopausal
(Pre-M) and Post-M females.
MATERIALS AND METHODS
Participants
A prospective, group comparison study was conducted on 28 adult women between the
ages of 18 and 70 at the University of Kentucky between September 2015 and April 2017.
This study was approved by the University of Kentucky Institutional Review Board (IRB
#15-0623-P2H). Participants were separated into Pre-M and Peri/Post-M groups. There
were 14 participants in each group, respectively. Perimenopausal participants were
grouped with Post-M participants due to lack of perimenopausal participants enrolling
in the study (a total of three were enrolled). Participants were recruited via flyers
and word of mouth. The average age of the Pre-M group was 30 years old and the average
age of the Peri/Post-M group was 54 years old. Pre-M was defined as having regular
cycles, perimenopausal was defined as having irregular cycles between three and 11
months, and Post-M was defined as having at least one year of amenorrhea. Inclusion
criteria were defined as normal hearing (pure-tone audiological thresholds better
than 25 dB HL at 500, 1000, 2000, and 4000 Hz), right handed, and no active otologic
or neurologic involvement. The audiogram and word recognition results are depicted
in [Table 1] for each group. Participants were excluded if they had any of the following characteristics:
left-handedness, hearing loss, history of neurologic involvement per participant report,
active otologic involvement per participant report. Additional exclusionary criteria
included actively taking glucocorticoids, pregnant or suspicion of pregnancy, history
of hysterectomy, use of HRT within the past three months, use of birth control within
the past three months, or use of estrogen-based medications for other conditions.
Table 1
Audiogram and Word Recognition Results
|
Group
|
Ear
|
Mean Pure-Tone Thresholds (dB)
|
WR (%)
|
|
500 Hz
|
1000 Hz
|
2000 Hz
|
4000 Hz
|
|
Pre-M
|
Left
|
3.9
|
4.3
|
3.9
|
6.4
|
98.0
|
|
Right
|
5
|
5
|
6.1
|
7.5
|
99.4
|
|
Post-M
|
Left
|
7.5
|
9.3
|
6.8
|
12.9
|
98.9
|
|
Right
|
6.8
|
8.6
|
7.1
|
12.1
|
98.3
|
WR = mean word recognition percent correct.
Procedures
Behavioral Measures
All behavioral testing was completed in a sound-treated suite. Each participant underwent
a comprehensive audiological evaluation. A traditional audiological evaluation including
pure-tone air conduction and speech audiometry was completed using a GSI AudioStar
Pro (Grason-Stadler, Eden Prairie, MN). The behavioral auditory processing battery
consisting of dichotic digits (DD) test, duration patterns test, Listening in Spatialized
Noise Test–Sentences (LiSN-S) test, and the Speech Perception In Noise-Revised (SPIN-R)
test. Test stimuli were administered on an iPad and passed through a diagnostic audiometer
to supra-aural headphones earphones. The LiSN-S is administered via computer and stimuli
are delivered through Sennheiser HD 215 headphones (Sennheiser, Old Lyme, CT). The
stimuli were presented at 50-dB sensation level re: pure-tone average to each ear.
All participants were given practice items, which were placed at the beginning of
the test to insure the task was understood. Participants were asked to verbally repeat
what they heard and the tests were manually scored by the examiner (DD, duration patterns,
and SPIN) or by the computer program (LiSN). The DD test is a well-established test
of binaural integration ([Musiek, 1983]). This is a low linguistic measure involving the simultaneous presentation of two
numbers to each ear (four in total) and participants were asked to repeat all four
numbers. Percent correct scores were recorded. The duration pattern test was selected
to further evaluate participants’ temporal processing ability with respect to ordering
using a low linguistic measure ([Musiek et al, 1990]). Participants were presented with stimuli that are either long or short in duration
and asked to repeat the pattern. This test was administered in the sound field and
was scored as a percent correct. The R-SPIN evaluates participant ability to process
auditory information in the presence of background noise (multitalker babble with
a +8 dB signal-to-noise ratio) ([Bilger et al, 1984]). The R-SPIN presents participants with 50 sentences per list that are either high
or low predictability. Participants were evaluated in the sound field and scores were
calculated for both the low and high predictability sentences as a percent correct
score. The LiSN-S is a clinical measure which uses virtual reality to measure speech
perception in noisy environments ([Cameron and Dillon, 2007]). The LiSN-S was administered in four test conditions: same speaker with masker
at 0° azimuth, same speaker ±90° azimuth, different speaker 0° azimuth, and different
speaker ±90° azimuth. The LiSN-S is scored as the participant’s speech reception threshold.
The order of behavioral testing was pseudorandomized with standardized instructions
read to participants before each test.
Electrophysiological Measures
In addition, participants underwent an electrophysiological evaluation consisting
of ABR and MLR using the Bio-logic® Navigator® Pro. Both the ABR and MLR measure electrical potentials generated by a stimulus as
they travel through the central auditory nervous system, with each wave representing
major generators along the pathway. Electrode montages were identical for both the
ABR and MLR. For each participant, the electrode sites (bilateral mastoid processes
and forehead) were prepped before placement of the electrodes. Impedances were <3
kΩ across the electrode array before the start of the testing.
The ABR was recorded using a 100-µsec rarefaction click stimulus at 80 dB nHL. The
ABR latencies were collected for waves I, III, and V at 23.3 clicks/sec and for wave
V only at 77.7 clicks/sec. The low- and high-frequency filters were set at 100 and
1500 Hz, respectively. A maximum of 2,000 sweeps was collected. The MLR was recorded
using a 100-µsec alternating click stimulus at 70 dB nHL. Amplitudes from baseline
were collected for the Na and Pa waveforms at a rate of 7.1 clicks/sec. A maximum
of 1,000 sweeps was collected. The low- and high-frequency filters were set at 10
and 1500 Hz, respectively. Both ABR and MLR testing consisted of two trials. The average
of the two trials was used for analysis. For each participant, the ABR was conducted
first followed by the MLR. Behavioral and electrophysiological testing were pseudorandomized
between participants.
RESULTS
Participants were separated into Pre-M and Peri/Post-M groups. An analysis of variance
(ANOVA) was performed to address the aims of the study. The ANOVAs had the independent
variable menopausal status (Pre-M versus Peri/Post-M), with the dependent variables
varying by analysis. The dependent variables included the following: percent correct
performance on the DD, duration patterns, and speech recognition in noise tests; signal-to-noise
ratio thresholds on the Listening in Spatialized Noise test; and amplitude and latency
measurements made on the auditory brainstem response and MLR. Trends in the descriptive
statistics were considered when significance was noted.
For duration patterns, DD, and SPIN-R, mean results are depicted in [Figures 1]–[3], respectively. Results for these tests are shown as mean percent correct on each
individual test with error bars representing one standard deviation. DD are subdivided
between right and left ears whereas SPIN-R test is subdivided into high-probability
and low-probability words. In addition, [Figures 4]–[6] show results of the behavioral testing for each individual. Scores below the threshold
lines are considered failing. On ANOVA analysis, no significant differences were detected
between groups in the duration patterns, DD, or SPIN-R tests.
Figure 1 Means for the duration pattern test for pre- vs. postmenopausal women. Error bars
represent one standard deviation. Pre-M = premenopausal; Peri/Post-M = peri-/postmenopausal.
Figure 2 Means for the dichotic digits test for pre- vs. postmenopausal women between ears.
Error bars represent one standard deviation. Pre-M = premenopausal; Peri/Post-M =
peri-/postmenopausal.
Figure 3 Means for the SPIN-R test for pre- vs. postmenopausal women comparing low vs. high
predictability sentences. Error bars represent one standard deviation. Pre-M = premenopausal;
Peri/Post-M = peri-/postmenopausal; High-P = high probability; Low-P = low probability.
Figure 4 Individual results for the duration patterns test with threshold bars representing
normative values. Pre-M = premenopausal; Peri/Post-M = peri-/postmenopausal.
Figure 5 Individual results for the dichotic digits test with threshold bars representing
normative values. Pre-M = premenopausal; Peri/Post-M = peri-/postmenopausal.
Figure 6 Individual results for the SPIN-R test with threshold bars representing normative
values. Pre-M = premenopausal; Peri/Post-M = peri-/postmenopausal; HP = high probability;
LP = low probability.
ANOVA analysis was conducted and significant differences identified in the LiSN-S
test with the Peri/Post-M group performing more poorly in low-cue speech recognition
threshold (SRT) (Pre-M = −1.7231 ± 0.77153 dB, Peri/Post-M = −0.9971 ± 0.89672, p = 0.034), high-cue SRT (Pre-M = −15.515 ± 1.3868 dB, Peri/Post-M = −12.893 ± 1.9105,
p = 0.000), as well as overall performance (Pre-M = −13.7615 ± 1.34073 dB, Peri/Post-M
= 11.8743 ± 1.89315, p = 0.007). The significant results of the LiSN-S test are demonstrated in [Figure 7].
Figure 7 Means for the LiSN-S test for pre- vs. postmenopausal women comparing across the
two conditions. Error bars represent one standard deviation. Pre-M = premenopausal;
Peri/Post-M = peri-/postmenopausal.
As seen in [Figures 8] and [9], the two electrophysiological tests conducted were the ABR and MLR. In addition,
[Figure 10] shows the results of the ABR for each individual with threshold bars representing
normative values. On ANOVA analysis, there was a significant difference in Wave V
on the left side only with the Peri/Post-M group having a longer latency on an absolute
scale (Pre-M = 3.7179 ± 0.13239 ms, Peri/Post-M = 3.8486 ± 0.16640 ms, p = 0.030). There were also significant differences between groups in the rate effects
on wave V bilaterally with the Peri/Post-M group having longer latencies both on the
left (Pre-M = 0.3600 ± 0.14676 ms, Peri/Post-M = 0.7285 ± 0.56657 ms, p = 0.027) and on the right (Pre-M = 0.4079 ± 0.08613 ms, Peri/Post-M = 0.5650 ± 0.24951
ms, p = 0.035). The rate effect is calculated as the latency difference of wave V recorded
when the repetition rate is 23.3 clicks/sec versus 77.7 clicks/sec. There were otherwise
no significant differences in ABR variables. Statistically significant differences
were also observed for the MLR. Specifically, the ANOVA analysis demonstrated a significant
difference in the right side Pa amplitude with the Peri/Post-M group demonstrating
a larger amplitude (Pre-M = 0.5707 ± 0.19543 µV, Peri/Post-M = 0.7292 ± 0.15697 µV,
p = 0.029). There were otherwise no significant differences in MLR variables.
Figure 8 Means for the auditory brainstem response rate effect (wave V latency at increased
stimulus rate of 77.7 clicks/sec) for pre- vs. postmenopausal women. Error bars represent
one standard deviation. Pre-M = premenopausal; Peri/Post-M = peri-/postmenopausal.
Figure 9 Means for the middle latency response – right Pa amplitude from baseline for pre-
vs. postmenopausal women. Error bars represent one standard deviation. Pre-M = premenopausal;
Peri/Post-M = peri-/postmenopausal.
Figure 10 Individual results for the auditory brainstem response with threshold bars representing
normative values. Pre-M = premenopausal; Peri/Post-M = peri-/postmenopausal.
DISCUSSION
Although there is evidence detailing the effects of female hormonal changes on the
ABR ([Jerger and Hall, 1980]; [Wharton and Church, 1990]; [Elkind-Hirsch et al 1992a],[b]; [Caruso et al, 2000]; [Caruso et al, 2003]; [Khaliq et al, 2003]; [Serra et al, 2003]), little research has been conducted on other measures of auditory processing in
relation to female hormonal changes. The aim of this study was to compare the effects
of these hormonal changes on auditory processing.
There is increasing interest in studying menopause as a risk factor for hearing loss.
One prospective cohort study analyzing 80,972 women showed that although menopausal
status was not associated with a higher risk of hearing loss, undergoing menopause
at age 50+ years did yield a higher risk ([Curhan et al, 2017]). This study found that, contrary to studies investigating the effects of HRT on
the ABR, Post-M HRT was associated with an increased risk of self-reported hearing
loss ([Curhan et al, 2017]). Hederstierna et al instead examined pure-tone audiometry as a measure of hearing
loss and found that Post-M women not taking HRT had worse hearing at the 2- and 3-kHz
range ([Hederstierna et al, 2007]). Post-M women have also been found to have increased rates of hearing decline on
pure-tone audiometry ([Svedbrant et al, 2015]) and Post-M women with decreased bone mineral density have a higher prevalence of
age-related sensorineural hearing loss ([Kim et al, 2016]). Although the effect of HRT on hearing is controversial, hearing loss defined by
self-report or pure-tone audiometry is clearly only one part of the picture in the
audiological management of Post-M women. None of these studies, however, investigated
central auditory processing as a possible etiology of self-reported hearing loss.
Although the traditional tests of auditory processing did not yield statistically
significant differences, the Peri/Post-M group did significantly worse on the LiSN-S
test, particularly on low-cue SRTs, high-cue SRT, and overall. The LiSN-S test provides
objective data on the participant’s ability to listen in background noise and abnormal
test results may point to CAPDs ([Cameron and Dillon, 2007]). The results of the LiSN-S test show that the Peri/Post-M women have difficulty
listening in background noise when there are neither talker and spatial differences
between target sentences and background noise (low cue) and when there are both talker
and spatial differences (high cue). This aligns with the primary complaint among this
clinical population which is difficulty hearing in noise. All of these women had normal
pure-tone audiograms, therefore these difficulties hearing in noise may be attributed to possible central auditory changes. Although these findings should
not be interpreted, a diagnosis of a central auditory processing deficit, it does
suggest that there are central auditory differences in Pre-M versus Post-M women.
Post-M women may present to an audiology clinic with a normal pure-tone audiogram
and variety of auditory complaints such as difficulty hearing (especially in the presence
of background noise), difficulty localizing sound, or difficulty discriminating similar
sounds.
One of the more interesting findings is this study is the electrophysiological results.
The ABR provides a noninvasive way to observe neural conduction in the brainstem in
response to a stimulus, which is a direct look at a portion of the auditory pathways
involved in auditory processing ([Jewett et al, 1970]). The two cohorts demonstrated similarities on the ABR, except for the effects of
stimulus rate on wave V and the left wave III. The Peri/Post-M group had significantly
longer latencies bilaterally with a higher stimulus rate.
The electrophysiological results may be explained by estrogen’s role as a neuromodulator,
particularly its effect on GABA-ergic neurons ([Pinaud and Tremere, 2012]). The increased stimulus rate causes increased synaptic firing of auditory neurons,
which causes release of estrogen as it engages in postsynaptic suppression of inhibitory
GABA-ergic neurons. The Peri/Post-M group, with lower amounts of estrogen, have less
estrogen-derived suppression of inhibitory GABA-ergic neurons during high stimulation
and thus have more inhibition of postsynaptic neurons in the auditory pathway, which
may manifest as longer latencies with higher stimulus rates. There was also a significant
difference in latencies between groups on the left-sided wave III of the ABR. This
may be an artifact of an underpowered study as the Peri/Post-M state is characterized
by a systemic decrease in estrogen production, which should cause bilateral effects,
not unilateral. A similar reasoning may account for the single significant difference
found on the right-sided Pa Amplitude of the MLR. This finding certainly needs further
investigation.
There is evidence in the literature to support the role of estrogen on the ABR. [Elkind-Hirsch et al (1992a)], evaluated how the menstrual cycle influenced the ABR. They found that the ABR is
sensitive to fluctuations in serum estrogen. These authors also demonstrated increased
wave V latencies in young women with premature ovarian failure who were undergoing
estrogen and progesterone replacement therapy. They hypothesized that synaptic conduction
time may be delayed due to inhibition of the GABA synapses and that this may in fact
be exacerbated by progesterone ([Elkind-Hirsch et al, 1992b]). The electrophysiological evidence for subtle differences in auditory function
in Pre-M versus Post-M changes is an important finding and further supports the notion
that we cannot rely solely on the pure-tone audiogram to detect differences or deficits
in auditory processing.
There are several limitations in this study. The study protocol did not screen for
any other risk factors such as hypertension, diabetes, or cholesterol levels. These
have been found to have an association with hearing loss possibly due to a vascular
pathogenesis ([Gates et al, 1993]) and although participants in this study have normal pure-tone audiograms, it does
not exclude the possibility of cerebrovascular disease affecting the auditory processing
pathway. However, age-related vascular changes or age-related processing dysfunction
would be expected in the 6th or 7th decade of life; the Post-M women in our study had a mean age of 54. Thus, age-related
causes of hearing problems would not be expected in our study population. Groups were
classified based on participant-reported menstrual history, which acts as a surrogate
for true estrogen levels.
CONCLUSION
There is some degree of debate regarding “hearing loss” in Post-M women. What one
must consider is how “hearing loss” is defined. Although it may be the case that Post-M
women are not at risk for peripheral hearing loss of sensitivity, it does not rule-out
a CAPD secondary to hormonal changes. Significant differences in auditory processing
tests exist between Pre-M and Peri/Post-M women. This includes listening in noise
and the effect of stimulus rate on wave V of the auditory brainstem response. Post-M
women presenting with auditory complaints but normal hearing thresholds warrant further
audiological evaluation for possible deficits in central auditory processing, a clinical
problem that may otherwise go unrecognized.
Abbreviations
ABR:
auditory brainstem response
ANOVA:
analysis of variance
CAPD:
central auditory processing disorder
DD:
dichotic digits
HRT:
hormone replacement therapy
ILD:
interaural latency difference
LiSN-S:
Listening in Spatialized Noise Test–Sentences
MLR:
middle latency response
Peri-M:
perimenopausal
Post-M:
postmenopausal
Pre-M:
premenopausal
SPIN-R:
Speech Perception in Noise Test Revised
SRT:
speech recognition threshold
