Authority evoked responses during different phases of menstrual cycle
ASHA YADAV*, O.P. TANDON AND NEELAM VANEY
Department of Physiology
University College of Medical Sciences & GTB Hospital
Dilshad Garden, Delhi – 110 095
*Corresponding Author
(Received on March 18, 2002)

Abstract: The electrophysiological correlates of changes in sensory function during menstrual cycle has already been studied and attributed to the hormonal influence. Effects of estrogen and progesterone on waves of auditory brainstem responses (ABR) have been reported and a hypothesis has been proposed that sex steroids have more influence on central auditory pathways. As mid-latency responses (MLRs) and slow vertex responses (SVRs) are better indicators of central auditory pathways, so MLRs and SVRs were also recorded besides ABRs in he present study.

Wave of ABRs, MLRs & SVRs were recorded in 20 normal cycling females in 4 different phases of menstrual cycles from Cz-A1 and Cz-A2 position with alternating 90dB sound pressure click stimuli. Contralateral ear was masked with a white noise of –40 dBHL. With the same setting by changing the number of click stimuli, intervals of stimuli and filter bandpass the above 3 recordings were taken. The evoked responses in females having ovulatory cycles were compared within the four phases using ANOVA test. There is a trend of increase in peak latencies of ABR waves III and V and IPL I-V in estrogen-peak mid-cycle while decrease in latencies in progesterone-peak (interpeak latency) midluteal phase. Peak latencies of MLR waves No, Po, Na, Pa and Pb alo show a same trend. SVR waves P2 and N2 are significantly delayed in mid-cycle (178.80 ± 20.49, 276.65 ± 18.32) while conduction is faster in midluteal phase (166.45 ± 17.41, 261.95 ± 21.07). Smallest latencies of all the waves are occurring during menstruation. These findings are suggesting that normal cyclical variations in the levels of estrogen and progesterone during menstrual cycle do effect the auditory pathways and effects are better seen on the central component.

Key words: menstrual cycle                 ABR         MLR         SVR

Introduction
Methods
Results
Discussion
References

INTRODUCTION

Sex hormones are known to exert regulatory influences on the central nervous system in different ways. They result in sexual differentiation of the brain, pattern of neural connections and organizations of their circuits in specific parts of the brain (1). Clinical observations strongly suggest that changes in gonadal function modify auditory, olfactory and taste thresholds (2). Thresholds for light, touch and two-point discrimination have also been found to vary during follicular and luteal phases (3). Similarly gonadal hormones have also been reported to influence palatability and spontaneous ingestion of sweet solutions. Pleasantness for glucose increases during ovulation (4).

EEG findings during menstrual cycle have shown that a wave frequency increases at the time of ovulation (5,6). Several researchers have reported that changes in auditory acquity occur during menstrual cycle (7). Due to their water and sodium retention property, female sex hormone influence the axonal conduction time in premenstrual period (8,9). Numerous tasks including visual and auditory threshold vary systematically throughout the menstrual cycle with reduction in threshold during menstruation which imply that withdrawal of sex hormones improve hearing threshold. Variations in different hormonal levels especially estrogen and progesterone across the menstrual cycle have been proposed to be responsible for the latency changes of the waves of auditory evoked potentials (10, 11).

Waves of Auditory Brainstem Response (ABR) represent volume conducted electrical activity from auditory nerve to inferior colliculus in midbrain. Mid Latency Response (MLR) waves represent the conduction through thalamocrotical portions and SVR waves represent the conduction and processing of information in primary auditory cortex and temporoparietal and frontocentral association areas (12-14).

Different investigators have reported different findings of ABRs across the menstrual cycle. On one hand there are reports showing no change in the waves of ABR throughout the menstrual cycle (15, 16). Other hand, reports are showing an increase in wave V latency at the time of ovulation and decrease in latency during luteal phase (17, 18), Other reports are showing an increase in peak latencies of III and V and interpeak latency (IPL) I-V during mid-cycle (19-21). Some researchers have also noticed in women with premature ovarian failure (POF) that during estrogen only replacement phase, the latency of wave V increases while decreases when progesterone was also added (22). All these findings suggested that estrogen and progesterone influence the auditory neural conduction pathway and progesterone is having antagonistic and nullifying effects of estrogen. Estradiol by increasing the availability of GABA and decreasing acetylcholine (Ach) is responsible for depression in auditory neural transmission and hence increase in latency during mid-cycle (23). It has also been postulated that the effects were more pronounced at increasingly rostral brain site as compared to periphery.

Effects of menstrual cycle on brainstem auditory conduction have also been studied by many researchers but their effects on central conduction at the thalamo-cortical level and primary and association auditory areas have not been studied. If female sex steroids have more influence on central auditory pathways then these should affect waves of MLRs and SVRs, which represent central pathways. So we plan to record MLRS and SVRs besides ABRs, thereby tracing the whole auditory pathways across the various phases of normal menstrual cycle in females.
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METHODS

20 females of age group 19-26 years were selected amongst the MBBS students, PG students and paramedical staff for the present study. All of them were having regular menstrual cycle of 27-30 days and were not taking any medication or hormonal pills for the last 6 months. All of them were within the range of ideal body weight. Any ear pathology was ruled out by doing a thorough ENT examination. All had hearing threshold of 0-20 dBHL or better at octave interval frequencies from 250-8000 Hz.

Experimental design: All females charted their basal body temperature (BBT) using the ‘Hanimax’ basal thermometer for 2 months to document the ovulation. Each participant underwent ABR, MLR & SVR testings 4 times in a single cycle:- Menses (1-3 days), Mid-cycle (11-15 days), Mid-luteal (17-22 days) and Pre-menstrual (25-27 days). 

Test procedure: Standardized technique for recording auditory evoked responses was followed (24). Recordings were performed in an air conditioned soundproof room after explaining the details of the procedure to the subject. Recordings were taken by placing Ag/AgCl disc electrodes on vertex at Cz area and left and right ear lobes (A1, A2) after cleaning the site and affixing them with collodion. Grounding was done by placing an electrode on forehead. All electrodes were plugged to a junction box. Skin to electrode impedence was kept below 5 Kohms. The signals picked up by these electrodes from the scalp after a standard click stimuli were filtered, amplified, averaged and displayed on the screen of MEB-5200 (Nihon Kohden, Japan) Evoked Potential Recorder. 

For recording ABR, 2048 click stimuli having intensity 70 dB above the normal hearing threshold were given to each ear independently at the rate of 10/sec and 0.1 msec duration. During testing of one ear, the other ear was masked with a white noise of –40 dBHL. These clicks were generated by passing 0.1 msec squared pulses through shielded headphones with alternating polarity. After filtration (100 Hz and 3 KHz), amplification and averaging, the waves in the first 10 msec of latency were considered for ABR. Peak latencies of waves I, II, III, IV and V interpeak latencies of I-V, I-III and III-V and amplitudes of wave I and V were recorded. The technical details of the ABR testing were similar to those reported earlier from this lab (25). 

Similar procedure was employed for recording MLRs by adjusting the click stimuli 256, latency range 10-50 msec and filters at 1 KHz and 5 Hz. Peak latencies of negative and positive waves No. Po, Na, Pa, Nb and Pb were recorded. 

SVRs were also recorded with the same electrodes by changing the latency range 50-300 msec, average count of 64 stimuli and filters at 30 Hz and 0.5 Hz. Peak latencies of P1, N1, P2, and N2 were recorded for each ear separately. Whole procedure was repeated 4 times in different phases of menstrual cycles. 

Fig.1 click for full view

All the 4 phases were compared for each parameter by using hierarchical ANOVA design and Tukey test was applied to dine out the significance level within phases. 
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RESULTS

Peak latencies of waves of AR, interpeak latencies and amplitudes do not show any significant difference in between the phases as shown by Table I. Waves of MLRs also do not show any significant change across the menstrual cycle (Table II). Both ABRs and MLRs are depicting a trend of increasing latencies in phase-2, decreasing latencies in phase-3 and further increasing in phase-4.

P2 and N2 waves of SVRs are significantly increasing from follicular to mid-cycle (phase-2), decreasing in mild-luteal (phase-3) and again increasing significantly in pre-menstrual phase with the lowest threshold during menstruation. 

TABLE  I: Showing the latencies and amplitudes of ABR in different phases of menstrual cycle. 

TABLE II: Showing the latencies of waves of MLR in different phase of menstrual cycle.

TABLE III: Showing the latencies of waves of SVR in different phases of menstrual cycle.

*P<0.001 when P2 component of SVR is compared in all the phases.

*P<0.001 when N2 component of SVR is compared in all the phases.
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DISCUSSION

The threshold for evoking waves of ABRs doesn’t show any significant difference between phases of menstrual cycle. But there is a trend of increase in peak latencies of all waves in mid-cycle and decrease in latencies in midluteal phase with the smallest latencies occurring during menstruation. Inter-peak latencies and amplitudes of I and V also follow the same trend. This might be due to changes in the circulating levels of female sex hormones-estrogen peak in mid-cycle and progesterone peak in mid-luteal phase. This is in agreement with the suggestion made by Baker and Weiler (1) that the circulating sex steroids affect the functioning of the sensory nervous system in females. It has also been shown that auditory thresholds get reduced during menstruation. Elkind-Hirsch et al (20) have also shown the similar and significant results in wave V and IPL   I-V of ABR through the menstrual cycle. They have also shown that females with POF, estrogen replacement alone increases the peak latency of wave V and IPL I-V while combination of estrogen and progesterone decreases the latencies (22). The source of latency change appeared to be the central auditory pathway rather than peripheral. 

In the present study, the waves of MLR which represent the more central auditory pathways also show same trend as waves of ABRs but not significantly. These might be as a result of low level of hormonal fluctuations during menstrual cycles. In conditions where there is greater hormonal changes like in pregnancy, latencies of ABR waves increase significantly. Effect of pregnancy on ABRs has already been reported from our lab (26). 

The SVR waves which represent the further central processing at the level of auditory cortex and association areas get affected cortex and association areas get affected significantly in the present study. P2 and N2 components which are possibly generated from pericruciate gyrus, antrolateral gyrus and medial suprasylvian gyrus (14) are delayed in mid-cycle and faster in mid-luteal. Our study further support Elkind-Hirsch and others who have presumed that the central auditory pathways are more influenced by sex steroids. 

One hypothesis to explain these effects is that estrogen and progesterone modulate the secretion of GABA in auditory pathway in a counter-regulatory fashion (27). Estradiol may enhance the inhibitory effects of GABA which decreases acetylcholine release in auditory pathways. They may interact with the surface membrane receptors or ion channels to change the excitability of nerve cells in the hypothalamus and hippocampus. They also affect the number or/and affinity of GABA `R’ in rat brain as reported by some authors (28). Physiological fluctuation in ovarian hormonal concentration have also been shown to modify GABA/Benzoidazepine `R’ sites in cerebral cortex and hypothalamus of female mice. Estrogen has also been proposed to be an allosteric antagonist of NMDA `R’ and could be protective against excitotoxicity of glutamate by simply delaying the conduction (28).

From the above results it can be inferred that sex steroids are modulating the whole auditory neural conduction and significantly at the level of polysensory association areas of auditory cortex including pericruciate gyrus, anterolateral gyrus and medial suprasylvian gyrus. In the present study basal body temperature (BBT) was used as an indicator of ovulation which is not a precise method and gets affected by mental stress, lack of sleep and muscular activity. BBT variation could not have been a factor for delaying the conduction in mid-cycle as latency changes still persist in females having no BBT variation (21).

Present study thus supports the hypothesis that variation in levels of female sex hormones during the menstrual cycle significantly affect the central auditory neural conduction. The effects are best seen in SVRs representing cortical processing of auditory stimuli. Further research can better evaluate the significance of changes in MLRs and SVRs across the menstrual cycle.
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