1 Department of Microbiological Science and Gynecological Science, 2 Research Group for Sexology, Department of Microbiological Science and Gynecological Science and 3 Department of Otorhinolaryngology, School of Medicine, University of Catania, Italy 4 To whom correspondence should be addressed at: Ospedale S.Bambino, Via Torre del Vescovo, 95124 Catania, Italy. e-mail scaruso{at}mbox.unict.it
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Abstract |
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Key words: Auditory brainstem response/auditory evoked potentials/hearing/menstrual cycle/oral contraceptives
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Introduction |
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Advances in electronic and computing technology and their physiological application have made possible the detection of small biological signals arising from within the nervous system. Since the brainstem potentials were first described during the 1970s (Jewett and Williston, 1971; Sohmer and Feinmesser, 1974
), interest has continued to increase, both in the audiological and neurological fields (Nuwer, 1998
). The auditory brainstem response (ABR) is a measure of the electrical activities generated in the brainstem auditory pathways after auditory stimulation and recorded superficially from the surface of the scalp. Classification of these auditory-evoked potentials has been based primarily on their latencies in relation to a previous stimulus. The response consists of five waves, designated IV. The preponderance of experimental and clinical evidence suggests that wave I is generated by action potentials of the cochlear nerve, wave II by the cochlear nucleus, wave III by the superior olivary complex, wave IV by the nucleus of the lateral lemniscus, and wave V by the inferior colliculus (Jewett and Williston, 1971
). Data demonstrate that post-menopausal women show increased ABR wave latencies and inter-peak intervals than do younger women or men (Jerger and Hall, 1980
; Dehan and Jerger, 1990
; Wharton and Church, 1990
), and it has been hypothesized that ABR latencies could change with age (ODonovan et al., 1980
; Rosenhamer et al., 1980
; Jerger and Johnson, 1988
). The source of the malefemale related differences could also be factors such as hormones (McFadden, 1998
), head size, skin thickness or gender-dependent sizes of the external acoustic meatus (Trune et al., 1988
), or even metabolic differences (Baker and Weiler, 1977
). Hormones influencing the brain structures responsible for sexual orientation can provoke differences in ABR. Homosexual and bisexual females, and homosexual males have respectively masculinized and hypermasculinized ABRs, probably due to exposures to androgens during development (McFadden, 2002
). It has also been reported that there is a fluctuation in behavioural auditory thresholds during the menstrual cycle (Haggard and Gaston, 1978
; Fagan and Church, 1986
; Elkind-Hirsch et al., 1992b
). Ovulatory women seem to have significant cyclic fluctuation in auditory sensitivity during the follicular, periovular and luteal phases of menstrual cycle, and less temporary threshold shifts during menstrual phase than women using the pill (Swanson and Dengerink, 1988
).
One of the variables associated with changes in female hormonal status is oral contraceptive (pill) intake. There are currently 400 million contraceptive users worldwide, with approximately one-sixth taking the pill. Use of the pill declines with age; 75% of users are aged 1930 years. A review of medical literature shows that research is being carried out on ABR in oral contraceptive users (Swanson and Dengerink, 1988
; Elkind-Hirsch et al., 1992a,
b, 1994; McFadden, 2000
). The results of this research are not always in agreement, though this may be due to the use of non-standardized methodologies.
A prospective, within-subject study was designed to test whether ABRs are affected by oral contraceptives with respect to the different phases of the menstrual cycle.
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Materials and methods |
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Subjects
A total of 118 healthy volunteers (mean age 26.9 ± 5.7 years; range 1938 years) who were attending the Family Planning Centre and planning to take oral contraceptives, participated in the study. None of the subjects had ever used any oral contraceptive or any other hormonal contraceptive or treatment. Each woman reported not having hearing loss or hearing disorders, nor any nose or throat problems. Subjects with tobacco use and/or drug abuse were excluded from the study. Moreover, the women enrolled in the study did not report any dysendocrinism or metabolic or neoplastic pathologies. Inclusion criteria required a normal gynaecological history and examination, with normal menstrual cycles (mean cycle length 28.3 ± 3.3 days).
To confirm ovulation, sonography was performed on days 10, 12 and 15 of the cycle, and serum progesterone concentrations were measured on days 21 and 25. Serum hormone concentrations were measured using commercially available enzyme-linked immunosorbent assay (ELISA) kits (Roche, Monza, Italy). The menstrual cycle was defined as ovulatory when the serum progesterone level was >18 IU/ml. Of the 118 women screened, 14 were excluded from the study for medical problems: nine had metabolic problems and five had hearing pathologies. Moreover, during enrolment, 10 women with both sonography aspects of anovulatory cycles, and serum progesterone levels <18 IU/ml were also excluded from the study. Therefore, the sample consisted of 94 women of mean age 27.9 ± 6.1 (range 2038) years. The mean body mass index (BMI) of the participating women (24.4 ± 1.3 kg/m2) was within the normal range (18.525.9 kg/m2).
Clinical testing
Before undergoing the audiometric tests, all women underwent ear, nose and throat checks to identify any inflammation of the upper airways. The audiometric thresholds were then measured for each woman at test frequencies of 250, 500, 1000, 2000 and 4000 Hz in an acoustically shielded room using an Amplaid 311 (Amplifon, Milan, Italy). Compliance of the tympanic cavity was evaluated to identify possible inflammation of the middle ear. Stapedial reflex threshold was then measured to evaluate the correct functioning of the neuronal arc (constituted by the acoustic nerve, reticular formation and facial nerve) using an Amplaid 711 (Amplifon) impedance audiometer. Each woman underwent the auditory brainstem test (with her eyes closed) in an electrically and acoustically shielded dark room. The test was performed using an Amplaid MK 12 (Amplifon). The ABR was recorded with three surface electrodes (impedance <5 K). The first was placed on the forehead (20% of nasion-inion length), the second on the ipsilateral mastoid, and the earth lead on the contralateral mastoid. A differential amplifier and a second-stage amplifier recorded the activity received from these electrodes; filters on both amplifiers were set at 100 and 3000 Hz. The acoustic stimuli were 100 dB peak sound pressure level; these were clicks at 11/s produced by delivering a 100-µs electrical square wave to a TDH-49 earphone (Amplifon). Each subject received 2000 stimuli to produce each ABR waveform. The positive peak latencies of waves I, III and V were measured using visual overlay cursors, and the inter-waves IIII, IV and IIIV intervals were calculated for each response. Waves II and IV were not evaluated because of their lesser importance in ABR. Graphic visualization of wave latencies and inter-peak intervals is shown in Figure 1. During the menstrual cycle, each woman underwent three ABR tests, the first at the follicular phase (days 58), the second at the periovular phase (days 1316), and the last at the luteal phase (days 1823). Both ears of each woman were treated as independent samples; thus, ABR waveforms were analysed separately for each ear. The ears were considered as independent samples because the pathways from the two ears are largely separate anatomically and capable of presenting different waveforms in the same individual. An average of latencies extracted from the ABR waveforms collected from both ears was calculated for each woman because the differences were negligible, ranging from 0.01 to 0.02 ms. The duration of a single measuring session was
45 min.
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Statistical analysis
Each statistical analysis was carried out using a software package for Windows 95TM (Glantz, 1997). Using data from previous studies (cited above), the standard deviation was set at 2.2, the mean difference at 0.5 between before and after pill use, and ABR values at P = 0.05; therefore the sample size calculation indicated that 77 subjects would be the minimum number required for the study to have 95% power. The analysis of data was based on an intention to treat approach. Consequently, the effects of the oral contraceptive used by each woman were considered, with the last observation carried forward for patients who prematurely discontinued pill use. The primary objective was the outcome of the ABR values obtained during oral contraceptive intake. The ABR values of each phase of the menstrual cycle were compared with the other phases by analysis of variance. A paired data t-test was used to compare each phase of the menstrual cycle with the oral contraceptive values, and two-sided t-test for independent samples was used to compare the effects of the monophasic oral contraceptives on ABR aspects. Data were analysed using the Bonferroni method of correction for multiple comparisons. All reported values were reported as mean ± SD. A P-value
0.05 was considered statistically significant.
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Results |
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Discussion |
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There are no recent data demonstrating any changes in inter-peak latency changes during the menstrual cycle. Results from one study (Fagan and Church, 1986) suggested that temperature changes during menses could be responsible for the differences noted in ABRs. Also, others (Bruce and Russel, 1962
) have raised the possibility that changes in sodium and potassium metabolism could influence ABRs by changing the axon conduction time and/or the availability of neurotransmitters at synapses. Moreover, these two reports have suggested that there are latency changes of waves related to fluctuating hormone levels, even if the exact mechanism of the hormonal effects is not clear. It was also suggested that estrogen might influence acetylcholine synthesis (Picton et al., 1981
), which was shown recently to be present in the auditory system (Weinberger and Bakin, 1998
).
The ABR fluctuations could depend on the action of the different qualitative and quantitative ovarian steroids either during the menstrual ovulatory cycle, or during pill intake. The present study showed that the increased neural conduction time of the ABR coincides with ovulation, in contrast to the data reported by others (Parlee, 1983; Elkind-Hirsch et al., 1992b
, 1994) who did not find any statistically significant changes in wave latencies and inter-peak intervals among the three phases of the menstrual cycle, though this discrepancy might be attributable to the failure of previous studies to determine the exact time of ovulation. By comparison, ovulation was verified in all of our subjects by the use of sonography and by monitoring serum levels of progesterone.
During the menstrual cycle there are differences in the androgen concentration, with testosterone or free testosterone peak at mid-cycle (Morris et al., 1987). During the present investigation, ABR were not measured at menses (as was the case for other authors; Swanson and Dengerink, 1988
; Elkind-Hirsch et al., 1992b
, 1994), mainly because it was considered that the data available from literature were both sufficient and clear. The level in hearing sensitivity at menses, during which gonadal steroids are at a minimum, is similar to that normally found in the male (McFadden, 1998
). Naturally, at ovulation both androgen and estrogen levels temporarily rise, and during the periovular phase shorter wave latencies in ABR were noted than during both the follicular and luteal phases. Substantially lower levels of free testosterone have been observed among pill users (Bancroft et al., 1991
). Sex hormone-binding globulin levels are increased and, therefore, free testosterone levels appear to be affected by the use of birth control pills (DeCherney, 2000
).
Although the present data have confirmed the existence of changes of ABR in oral contraceptive users with respect to non-users, further studies are required to investigate if the variations of wave latencies and inter-peak intervals of ABR could contribute to variation in the sexual behaviour of the subject, and, if so, in what way.
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Submitted on June 14, 2002; resubmitted on September 3, 2002. accepted on September 11, 2002