Hormones and the auditory system: A review of physiology and pathophysiology

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Neuroscience 153 (2008) 881–900

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ORMONES AND THE AUDITORY SYSTEM: A REVIEW OF
HYSIOLOGY AND PATHOPHYSIOLOGY
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. AL-MANA,a,d B. CERANIC,b* O. DJAHANBAKHCHc

ND L. M. LUXONa,d

Department of Neuro-Otology, The National Hospital for Neurologynd Neurosurgery, Queen Square, London WC1N 3BG, UK

Department of Audiology, St. George’s Hospital, Blackshaw Road,ondon SW17 0QT, UK

Newham University Hospital, Academic Department of Obstetrics &ynaecology, Barts and The London Queen Mary’s School of Medi-ine and Dentistry, Glen Road, London E13 8SL, UK

Academic Unit of Audiological Medicine, University College London,nstitute of Child Health, 30 Guilford Street, London WC1N 1EH, UK

bstract—This review explores the potential role of hor-ones in modulating the auditory function. The review de-

cribes four groups of hormones (the hormones of the circa-ian cycle, reproduction, stress response and the fluid andlectrolyte balance), their physiological variations, interac-ions, as well as the physiological basis for their effect on theuditory system. Possible contribution of hormones toathophysiology of auditory dysfunctions, including hyper-cusis, tinnitus, Menière’s disease and pre-menstrual audi-ory dysfunction, has also been discussed. Published bylsevier Ltd on behalf of IBRO.

ey words: auditory, hearing, hormones.

Contentsunctional anatomy of the auditory system 882Anatomy and physiology 882Modulation of the auditory system 882

ow the different hormones may influence the auditory system883

Reproductive steroids 883Estrogen 884Progesterone 884

Stress-related hormones 884Glucocorticoids 884

Corresponding author. Tel: �44-0-20-8725-1195; fax: �44-2-8725-874.-mail address: [email protected] (B. Ceranic).bbreviations: ABR, auditory brain stem–evoked response; ADH, an-

idiuretic hormone; ART, acoustic reflex threshold; CN, cochlear nu-leus; DPOAE, distortion product otoacoustic emission; ER, estrogeneceptor; FSH, follicular stimulating hormone; GnRH, gonadotrophineleasing hormone; GR, glucocorticoid receptor; HIOMT, hydroxyin-ole-O-methyltransferase; HRT, hormone replacement therapy; IHC,

nner hair cell; LH, luteinizing hormone; LL, lateral leminiscus; MGB,edial geniculate body; MOC, medial olivocochlear system; NAT,-acetyltransferase; OAE, otoacoustic emission; OC, oral contracep-

ives; OCB, olivary cochlear bundle; OHC, outer hair cell; OVX, oo-horectomized; PMDD, premenstrual dysphoric disorder; PMS, pre-
enstrual syndrome; SCN, suprachiasmatic nucleus; SOAE, sponta-eous otoacoustic emission; SOC, superior olivary complex.
306-4522/08$32.00�0.00 Published by Elsevier Ltd on behalf of IBRO.oi:10.1016/j.neuroscience.2008.02.077

881

Catecholamines and endogenous opioids 884Hormones regulating fluid and electrolyte balance 885

Aldosterone 885Vasopressin 885

Melatonin 885hysiological variation in hormones and the effects on auditory

function 885Circadian cycle and auditory function 886Gender differences in auditory function 886The ovarian cycle and auditory function 887

� Auditory thresholds 889� SOAEs 889� Transient OAEs 890� ABR 890

Menopause and auditory function 890Pregnancy and auditory function 891Stress and auditory function 891

uditory pathology and hormones 892Hyperacusis and tinnitus 892Menière’s disease and endocrine system 893Reproductive hormones 893Stress-related hormones 893Fluid and electrolyte related hormones 893Pre-menstrual syndrome and auditory function 893onclusion 894eferences 894

onsiderable anecdotal evidence and limited informationrom previous studies suggest that auditory function may benfluenced by hormones. Recent advances in the fields ofeuroendocrinology and neuropharmacology, together with

he development of new assessment techniques have pro-ided insights into the contribution of hormones in the regu-

ation of the circadian cycle, reproduction, stress responsesnd the maintenance of fluid and electrolyte balance. In thisontext, this review examines the potential role of hormones

n modulating the auditory system and in the development ofathological conditions in the auditory system.

Four areas will be considered:

he functional anatomy of the auditory system. description of the groups of hormones and their interac-

tions, together with the physiological basis and proposedmechanisms of effects of hormones on auditory function.

hysiological hormonal variations, including gender differ-ences, and possible implications for the auditory sys-tem.

ossible contribution of hormones to pathophysiology of
auditory dysfunction, including hyperacusis, tinnitus,
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D. Al-Mana et al. / Neuroscience 153 (2008) 881–900882

Menière’s disease and pre-menstrual auditory dys-function.

FUNCTIONAL ANATOMY OF THE AUDITORYSYSTEM

natomy and physiology

he auditory system consists of a variety of anatomicaltructures, from the cochlea to the auditory cortex, includ-ng both ascending (afferent) and descending (efferent)athways (Ceranic B, Luxon LM, in press) (Fig. 1).

The inner hair cells (IHC) of the organ of Corti trans-orm the mechanical energy of sound waves to electricalnformation that passes to the type I auditory afferent fi-ers. The outer hair cells (OHC) on the other hand, are

hought to act as a modulator and amplifier capable ofne-tuning the receptive function of the cochlea (Santos-acchi, 2001). The auditory signal from the organ of Corti

hen travels through the auditory nerve to the ipsilateralochlear nucleus (CN) and from there the majority of thefferent auditory fibers project to the contralateral superiorlivary complex (SOC), the lateral lemniscus (LL), inferiorolliculus (IC), medial geniculate body (MGB) to the audi-ory cortex (Chermak and Musiek, 1997).

The efferent auditory pathway is less well understood.

ig. 1. Schematic illustration of the afferent (left) and efferent (right)uditory pathways: The afferent pathway originates at the cochlear

evel, from the outer cells (OHCs), which feed mechanical oscillation tohe inner hair cells (IHCs. Neural signals are conveyed via the auditoryerve to the cochlear nuclei (CN). The fibers from the CN projectredominantly contralaterally to the superior olivary complex (SOC)nd further via the lateral lemniscus (LL), the inferior colliculus (IC) andhe medial geniculate body (MGB) to the auditory cortex. The efferentathway runs in parallel to the afferent pathway, from the cortex to theochlea, allowing multiple feedback loops, with illustrated in moreetails the most distal part: the olivocochlear bundle (OCB) consistsrom the medial bundle (MB), which projects predominantly contralat-ral fibers from the superior olivary complex (SOC) directly onto theHCs, and the lateral bundle (LB), which projects indirectly to the

HCs. (Ceranic B, Luxon LM, in press. Reproduced by permission ofdward Arnold, Publishers, Ltd.)

t arises in the auditory cortex and descends into the

rainstem to reach the cochlea (Suga et al., 2000). Theistal pathway is its best known part, the olivary cochlearundle (OCB), which originates from the SOC and projectso the cochlea through two main pathways (reviewed by

arr, 1992):

● Medial olivocochlear system (MOC) which projectsmainly to the contralateral cochlea and terminatesdirectly on the OHCs.

● Lateral olivocochlear system (LOC) which projectsmainly to the ipsilateral cochlea, and ends on the typeI afferent dendrites that terminate at the IHCs.

The exact function of the efferent auditory system isot fully understood, but it seems to act as an autoregula-ory feedback mechanism, with a predominantly inhibitorynfluence, but it may also be excitatory at different levelsnd so adjusts and improves the processing of the auditoryignal (Suga et al., 2000).

odulation of the auditory system

he baseline activity of the auditory system can be mod-lated by different mechanisms, such as the cardiovascu-

ar system, drugs, various neurotransmitter systems andxtra-auditory structures, i.e. the other structures of theNS with direct or indirect inputs to the auditory system.or the purpose of this review only the following will beonsidered:

. Neurotransmitters

The neurotransmitters identified in the auditory systemre summarized in Table 1.

These neurotransmitters are a potential target for hor-onal modulation of auditory function (see Hormones).

. Extra-auditory structures with inputs to the auditorysystem

The main extra-auditory connections are:

● The limbic system regulates instinctive behavior andemotions and connects with the auditory system viathe MGB. It is thought to be important in attachingemotional significance to acoustic stimuli (LeDoux etal., 1984; LeDoux, 1993). The limbic system alsoexpresses hormone receptors which include stress-related hormone and reproductive hormone receptors(Gray and Bingaman, 1996; Jennes and Langub,2000).

● The hypothalamus, is the integrator center for theendocrine and autonomic systems and is linked withthe auditory system through the IC (Adams, 1980),although, its effect on the auditory function is unclear.The hypothalamus contains the suprachiasmatic nu-cleus (SCN) which is thought to regulate the circadianrhythm (Halasz, 2000; Levine, 2000), and expressesa wide range of hormone receptors (reviewed byJennes and Langub, 2000).

● The reticular system is concerned with the behavioral
state of arousal and alertness and projects serotoner-

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D. Al-Mana et al. / Neuroscience 153 (2008) 881–900 883

gic fibers to most levels of the auditory system fromthe cochlea (Gil-Loyzaga et al., 2000) to the auditorycortex (Juckel et al., 1997). The ascending reticularsystem reacts more to “important” than to “unimpor-tant” stimuli, and this may be related to hearing innoise and selective attention (Chermak and Musiek,1997). The reticular formation is involved in the stressresponse and expresses adrenal steroid receptors(Jennes and Langub, 2000). The presence of noise orother stressful stimuli was found to modulate theserotonergic system, by increasing the release of5-HT (Singewald et al., 1998). 5-HT was also found tocontrol the gain the IC neural responses, either in apositive or negative direction depending on the typeof auditory stimuli, thus influencing auditory process-ing (reviewed by Hurley et al., 2002). Animal andhuman studies suggest that the serotonergic systemis sexually dimorphic, i.e. there is a gender difference.It has been reported that there is an increase in 5-HTactivity in the female rat brain compared with the male(Carlsson and Carlsson, 1988) and a decrease in thewhole brain 5-HT synthesis in women compared with

able 1. Neurotransmitters of the afferent and efferent auditory syste

evel Afferent auditory system

Neurotransmitter Possible function

HC Glutamate Physiologically excitatory (Puel, 1Le Prell et al., 2001)

and pathologically neurotoxic(acoustic trauma and/or ischeminjury) (Janssen et al., 1991;Eybalin, 1993)

HC ? ?

N Glutamate, aspartate Excitatory

Acetylcholine

GABA, glycine Inhibitory (Musiek and Hoffman,1990)

OC GABA, glycine Inhibitory

Glutamate, NMDA Excitatory (Musiek and Hoffman,1990)

L GABA ? Inhibitory (Moore and Moore, 1C Glycine, GABA Inhibitory

Glutamate Excitatory (Faingold et al., 1989;Musiek and Hoffman, 1990)

GB ? ?

C Acetylcholine, opioids Not clear (Musiek and Hoffman,1990)

AC, auditory cortex; IC, inferior colliculus; LOC, lateral olivocochlea

men (Nishizawa et al., 1997). It seems that estrogen e

contributes to dimorphism, as it may either enhanceor decrease 5-HT binding, depending on the site ofthe receptors in the brain (reviewed by Rubinow et al.,1998).

Hormones may modulate auditory function indirectlyhrough their action on the extra-auditory structures thatonnect with the auditory system.

HOW THE DIFFERENT HORMONES MAYINFLUENCE THE AUDITORY SYSTEM

. Reproductive steroids

. Stress-related hormones

. Hormones regulating fluid and electrolyte balance

. Melatonin

eproductive steroids

he reproductive (gonadal) hormones regulate reproduc-ive behavior, but also modulate the activity of hypotha-amic and extrahypothalamic noradrenergic, dopaminergicnd serotonergic neurons (Scholtz et al., 1998; Genazzani

Efferent auditory system

Neurotransmitter Possible function

Acetylcholine Excitatory (Felix and Ehrenberger, 1992)

GABA Inhibitory (Eybalin, 1993; Le Prell et al.,2001)

Dopamine, enkephalin

Dynorphin (via LOC) Inhibitory (Gil-Loyzaga, 1995; Pujol,1994; Le Prell et al., 2001)

Excitatory (Sahley and Nodar, 1994;Sahley et al., 1999)

Acetylcholine Mainly inhibitory (Eybalin, 1993; Dalloset al., 1997; Le Prell et al., 2001)

GABA (via MOC) Inhibitory (Eybalin, 1993; Le Prell et al.,2001)

GABA Inhibitory (Thompson and Schofield,2000)

Glutamate Excitatory (Thompson and Schofield,2000)


? GABA Inhibitory (Campos et al., 2001)

? ?Glutamate Excitatory (Thompson and Schofield,

2000)GABA, glycine Inhibitory (Huffman and Henson, 1990)


? Glutamate Excitatory (Thompson and Schofield,2000)

; NMDA, N-methyl-D-aspartate; ?, not known; N/A, not applicable.

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Estrogen. Estrogens influence physiological func-ions of many organs and systems in both females (Nilssont al., 2001) and males (Sharpe, 1998; Lombardi et al.,001), including the skeletal, cardiovascular and the ner-ous systems, as well as the male urogenital tract, mam-ary glands and female reproductive organs.

Estrogen may influence the auditory system at differentevels, at the cochlear and more proximal levels:

At the cochlear level, estrogen receptors alpha (ER�)nd beta (ER�) have been identified in the inner ear (in-luding spiral ganglion type I cells, the stria vascularis andochlear blood vessels) in both humans (Stenberg et al.,001) and animal models (rats and mice) (Stenberg et al.,999) by immunohistochemistry, while previously, Nathant al. (1999) did not find the mRNA that encodes ERs in theat cochlea. These conflicting results may be the result ofhe small number of receptors and/or the low stability of theRNA. The presence of the receptors in the spiral gan-lion and outer and IHCs, suggests that estrogen may

nfluence auditory transmission, while the receptors in thetria vascularis may affect fluid electrolyte balance in theochlear fluids (Lee and Marcus, 2001).

Additionally, the ERs in the cochlear blood vesselsay influence auditory function by modulating cochlearlood flow (Laugel et al., 1987).

Stenberg and co-workers (2003) have reported thatreating oophorectomized rats with tamoxifen (a specificR modulator and generally acts as an ER antagonist) fordays did not affect the ER content of the cochlea. A

ecent study by Thompson and colleagues (2006) demon-trated that tamoxifen treatment for 3 months in youngdult female CBA mice have led to changes in their audi-ory function, although this does not necessarily mean thathese changes occurred through the cochlear receptors.he potential difference between the two studies could bettributed to the difference in the length of treatment.hompson et al. (2006) speculated that blocking ER had

ed to a decline in suppression of distortion product oto-coustic emissions (DPOAEs), as a result of a reduction ofhe MOC suppression. This decline could be similar tohat occurs with aging and precedes the onset of age-

elated hearing loss (Guimaraes et al., 2004) which mayuggest that estrogen has a protective role on auditoryunction, in conjunction with its neuroprotective effect. Itas been observed that the decrease in estrogen levels,.g. after menopause or in Turner’s syndrome, is associ-ted with an increased frequency of neurodegenerativeisorders. One mechanism of this protective effect coulde based on the “genomic” (steroid hormone actions cane delayed in onset and prolonged in duration and involveene expression and thus described as a genomic effectMcEwen and Alves, 1999)) action of estrogen on its alphaER�) and beta (ER�), possibly membrane receptors, as aegulator of the electrical activity of neurons, promotingynaptogenesis and the expression of nerve growth fac-ors. Another proposed mechanism would implicate estro-en as a free radical scavenging antioxidant (Behl and
anthey, 2000; Garcia-Segura et al., 2001). a
In the proximal auditory system, specific ERs have noteen reported. However, from what is known about theffect of estrogen on the CNS (Kuiper et al., 1998; McEwennd Alves, 1999), theoretically, estrogen may influence theuditory function at different levels of the CNS, through itsnown action as a modulator of the GABA-ergic, seroto-ergic, and glutamatergic systems (Woolley et al., 1997).

Estrogen may have an excitatory action on auditoryerve fibers, as it has been found to be mainly excitatory toeurons in other areas of the CNS (Smith et al., 2002), and

t could have a neuroprotective effect, as mentionedbove.

Progesterone. Progesterone is an ovarian hormoneecreted by the corpus luteum during the luteal phase ofhe ovarian cycle (see below) and it is also produced in thedrenal glands and the CNS. Progesterone is a precursoro other steroid hormones and acts as a neurosteroidBaulieu, 1998). Specific progesterone receptors have noteen identified in the in the auditory system, but proges-erone may cross-react with other steroid receptors (suchs glucocorticoid and mineralocorticoid receptors) present

n the cochlea or more proximal areas of the auditoryystem (Lang et al., 1990; Nathan et al., 1999). Proges-erone and its metabolites may also influence the auditoryystem through its interaction with the steroid binding sitesn GABA-A receptors acting as a GABA-A agonist, whichre present throughout the auditory system (Follesa et al.,001). Progesterone was found to decrease 5-HT levelsreviewed by Birzniece et al., 2006) and this may affectuditory processing indirectly. In general, progesteroneas a mainly inhibitory action on the CNS which mayalance the mainly excitatory action of estrogen (Katzenel-

enbogen, 2000).

tress-related hormones

Glucocorticoids. Cortisol (a steroid-based hormone)s the main glucocorticoid secreted from the adrenal cortexn response to stress, and acts through glucocorticoid re-eptors (GR) which are widely distributed in the CNSJennes and Langub, 2000) and other organs. GR havelso been identified in the inner ear of animals (Rarey etl., 1993; Zuo et al., 1995; Shimazaki et al., 2002) andumans (Rarey and Curtis, 1996), more in the cochlearhan the vestibular tissue. Within the cochlea, they areresent in the sensory (the organ of Corti’s hair cells andupporting cells) and non-sensory (spiral ligament andtria vascularis) tissues, suggesting both a possible role inomeostasis of inner ear fluids and signal transductionreviewed by Horner, 2003). Glucocorticoids may also in-uence the auditory function by interacting with their re-eptors found in the brainstem nuclei, including the mes-ncephalic raphe nuclei and locus ceruleus, which containerotonergic and noradrenergic neurons (Jennes and Lan-ub, 2000).

Catecholamines and endogenous opioids. Catechol-mines (adrenalin and nor-adrenalin) and endogenouspioids (such as �-endorphin, enkephalins, dynorphins)
re released in response to stress from the adrenal me-

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ulla and act mainly through the nervous system. Cat-cholamines are the main neurotransmitters of the sym-athetic nervous system, which is activated during stressBrook and Marshall, 2001). The opioids are also releasedrom the pituitary and the limbic system during stressSapolsky, 2002).

Endorphins and enkephalins act as analgesics androduce a euphoric state (Brook and Marshall, 2001). Opi-id binding of mu (�) and delta (�) opioid receptors com-only leads to neural inhibition (Crain and Shen, 1998),ut may also lead to neural excitation especially throughynorphin sensitive kappa (�) opioid receptors (Mains andipper, 1999), and these receptors have been identified in

he mammalian cochlea (Jongkamonwiwat et al., 2003,006). Enkephalins and dynorphins are thought to act aseurotransmitters in the auditory system (see Table 1),hile the nor-adrenalin fibers of the sympathetic innerva-

ion of the cochlea, that surround the labyrinthine arterynd the modiolar branches, control cochlear blood flowBrown, 2001). Sympathetic innervation is also seen inther auditory structures including the CN (Thompson,003) and the SOC (Mulders and Robertson, 2001) and,hus, has a potential to modulate higher levels of theuditory system.

ormones regulating fluid and electrolyte balance

Aldosterone. Aldosterone (a steroid-based hormone)s the main mineralocorticoid secreted from the adrenalortex. It is predominantly involved in regulating sodiumomeostasis, and indirectly volume homeostasis, but islso released during stress. Mineralocorticoid receptorsMR) are distributed in the CNS, but to a lesser degreehan GR (Jennes and Langub, 2000), and have beendentified within the cochlea (Rarey and Luttge, 1989) inhe marginal cells of the stria vascularis and spiral ganglionells (Furuta et al., 1994). Aldosterone increases sodiumeabsorption mainly by regulating the enzyme Na�, K�-TPase (Brook and Marshall, 2001), which has been iden-

ified in the inner ear epithelium. This suggests possibleormonal modulation of endolymph secretion and fluidomeostasis (Ferrary and Sterkers, 1998), although thection on spiral ganglion cells remains unknown. The ab-ence of circulating adrenal hormones does not lead tolectrophysiological changes in inner ear fluids (Ferrary etl., 1996) but to a decrease in endolymph volume (Lohuist al., 2000).

Aldosterone treatment in mice with autoimmune hear-ng loss has been reported to demonstrate a similar effecto prednisolone in improving hearing thresholds and re-ersing the pathology in the stria vascularis (Trune et al.,000). Tadros and colleagues (2005) found that aged mennd women with lower levels of aldosterone (but still in thelinically normal range) had worse hearing thresholds thanubjects with aldosterone levels in the upper middle of theormal range. Thus, aldosterone may play a protective role

n the cochlea.

Vasopressin. Vasopressin, also known as antidi-
retic hormone (ADH), is involved in fluid homeostasis in a 6
imilar way to aldosterone and is also released duringtress (Halasz, 2000). Vasopressin may play a role inegulating the cochlear fluids by regulating the enzymedenylate cyclase which has been identified in the innerar epithelium (Ferrary and Sterkers, 1998). Vasopressinas found to stimulate potassium secretion and increaseater permeability in the cochlea (Ferrary et al., 1996).asopressin receptors V1a and V2 have been identified

hroughout the developing rat cochlea, but only in the spiralanglion and spiral ligament of the adult cochlea. It isurrently thought to be important in cochlear developmentFuruta et al., 1998). The vasopressin receptor V1a isxpressed widely in the CNS, in the frontal and piriformortex, olfactory system, hippocampus, and throughout theidbrain, pons and medulla (Jennes and Langub, 2000)nd may therefore, directly or indirectly modulate the au-itory system.

elatonin

elatonin is a neuroactive substance derived from 5-HT byhe melatonin forming enzyme 5-HT N-acetyltransferaseNAT) and hydroxyindole-O-methyltransferase (HIOMT)nd secreted from the pineal gland. Melatonin is alsoynthesized in the guinea-pig cochlea by melatonin-form-

ng enzymes, NAT and HIOMT, and is detectable in thergan of Corti, the basilar membrane and to a lesseregree in the cochlear nerve and stria vascularis, includinghe spiral ligament (Biesalski et al., 1988). The concentra-ion of melatonin in the cochlea is affected by light, andorrelates with the peripheral concentration of melatoninLopez-Gonzalez et al., 1997). Melatonin was found torolong the postmortem activity of OHC in rats (Lopez-onzalez et al., 1999). Otoacoustic emissions (OAEs), asn expression of the OHC activity, can be recorded fromats for a few minutes postmortem, i.e. after clinical death,hen the cells of different tissues, including OHCs, stillhow activity. The treatment with melatonin before killinghe animal seems to prolong this activity up to seven timesompared with control animals (Lopez-Gonzalez et al.,999). It was also observed that melatonin ameliorates thetotoxicity of aminoglycosides and cisplatinum in ratsLopez-Gonzalez et al., 2000a,b). These findings suggesthat melatonin may have a protective role on the cochlea.

Melatonin has multiple effects on the CNS including annticonvulsant and anxiolytic action by enhancing GABAGolombek et al., 1996) and benzodiazepine functionGuardiola-Lemaitre et al., 1992). Therefore, theoretically,t may also have an effect on GABA-ergic fibers of theuditory system.

PHYSIOLOGICAL VARIATION IN HORMONESAND THE EFFECTS ON AUDITORY FUNCTION

. Circadian cycle

. Gender differences

. The ovarian cycle

. Menopause

. Pregnancy

. Stress

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The levels of hormones vary in response to endoge-ous and exogenous stimuli and many vary in a cyclic

ashion. The hypothalamus acts as the neural control cen-er of the endocrine system and regulates the physiologicalariation in hormones (Halasz, 2000).

The endocrine changes related to reproductive func-ion (ovarian cycle, pregnancy, and menopause), dailyhythm (circadian) and exposure to stressful stimuli couldn turn affect auditory function. Additionally, there are mul-iple interactions between the hormones involved in thesehysiological changes (Fig. 2) and this enhances the pos-ible multidirectional effects on the auditory system.

ircadian cycle and auditory function

elatonin, cortisol and vasopressin show a clear circadianattern. The circadian pacemaker in mammals is found inhe paired SCN of the hypothalamus, which also controlshe rhythm of melatonin synthesis through a multi synapticathway (Urbanski, 2000). Cortisol levels are highest atawn and low at dusk (Despopoulos and Silbernagl, 1991),hile vasopressin levels are higher during the night (Kos-

oglou-Athanassiou et al., 1998a). The SCN rhythm isntrained by light via the retino-hypothalamic tract (Blockt al., 2000). In subterranean animals, such as the mole,

he IC (with auditory information) projects to the SCN, anday have a similar function to the retino-hypothalamic tract

n other mammals (Kudo et al., 1997). In humans, a recenttudy has found that auditory stimuli led to a phase shift inircadian rhythms (Goel, 2005). This finding implies that aonnection between the auditory pathways and the SCNlso exists in humans, which may enable a direct effect ofircadian cycle on auditory function and vice versa.

Diurnal changes in OAE, which reflect cochlear OHCunction, have been reported (Wit, 1985; Bell, 1992; Hag-erty et al., 1993). Wit (1985) measured spontaneous

ig. 2. Hypothalamic pituitary adrenal and gonadal axis and the cir-adian cycle. Light effect on the SCN leads to inhibition of melatoninynthesis from the pineal gland. * The inhibitory effect of melatonin onnRH is only seen before puberty and in certain pathological condi-

ions in humans (Silman, 1991; Kadva et al., 1998). Solid lines: Exci-atory effect, Dashed lines: inhibitory effect. CRF: corticotropin releas-ng factor, E2: estrogen, Prog: progesterone, ACTH: adrenocorticotropicormone, Endo: �-endorphin, Dyn: dynorphin, ACh: acetylcholine, Ad:drenalin and, NA: nor adrenalin. (Italics indicate inhibitory action.)

toacoustic emissions (SOAEs) in two volunteers on 10

ifferent days, twice and three times daily for the femalend male volunteer respectively. The SOAE frequencyas shown to shift significantly to a lower frequency in thefternoon compared with the morning sessions. This find-

ng was confirmed by Bell (1992) who calculated a 1%hange in SOAE frequency, with no amplitude fluctuation.aggerty et al. (1993) also noted a significant 24-h vari-bility in SOAEs frequency but reported that there was lesshan 1% change.

These changes suggest that the SOAE generator maye synchronized with the biological circadian rhythm. Theeripheral auditory structures may be less inhibited alongith other subcortical structures during sleep (Lancel,993), resulting in an increase in SOAE levels.

The auditory evoked potentials arising from more prox-mal, cortical structures, such as the P300 seem to beffected by the time of day (Polich and Kok, 1995). Thisay be attributed to circadian changes in cognitive func-

ion that contribute to the P300 (Wesensten et al., 1990).

ender differences in auditory function

eproductive hormones have been implicated in genderifferences in sensorimotor (Becker, 2002) and cognitiveHampson, 2002) functions in animals and humans. Expo-ure to reproductive hormones during development leadso sexual dimorphism in CNS structures (de Courten-My-rs, 1999; Rhodes and Rubin, 1999). This may be thenderlying cause for gender differences and may alsoffect the auditory system. Indeed, sexual dimorphism haseen noted in auditory structures, such as the cochlea inemales which may have a larger number of OHC (Wrightt al., 1987) and is shorter than the cochlea in males (Satot al., 1991). The sexually dimorphic structure of the sero-onergic system (Rubinow et al., 1998) as mentionedbove, may also modulate neural transmission in the au-itory brain stem and cortical structures. The differences ineproductive hormones during development and in adult-ood may explain gender effects in auditory function, spe-ifically the theoretical possibility that auditory function isbetter” in females than males due to the excitatory androtective effects of estrogen. This notion could be sup-orted by the following:

� Several studies have reported that adult femaleshave more sensitive hearing in higher frequencies(measured by pure tone audiometry) compared withmales (Jerger and Hall, 1980; Davis, 1995; McFadden,1993, 1998) which is also noted in carefully screenedpopulations for noise exposure (Johansson and Ar-linger, 2002). It was also observed in school-agedchildren, that girls tend to have lower audiometricthreshold compared with boys, however the differ-ence was not statistically significant (Roberts andHuber, 1970; Haapaniemi, 1996).

� OAE are thought to originate from the OHCs reflect-ing cochlear function (Kemp et al., 1990), and areassociated with good hearing sensitivity (Probst et
al., 1991). Females tend to have OAEs with larger

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amplitudes compared with men (McFadden, 1993;Hall, 2000) and are more likely to have recordableSOAEs (75% of females compared with 58% ofmales (Penner and Zhang, 1997). The gender differ-ence is also seen in neonates (Kei et al., 1997) andolder children (Lamprecht-Dinnesen et al., 1998;O’Rourke et al., 2002) which may be due to prenatalhormonal exposure.

� Oral contraceptives (OC) suppress the endogenouslevels of estrogen, and females using OC displayOAEs which are closer to males’ results than fe-males not using OC (McFadden, 2000).

� The excitatory effect of estrogen and sexual dimor-phism in the CNS and auditory system may affect theneural transmission in the auditory brainstem leadingto gender differences in auditory brain stem–evokedresponses (ABR). Female adults were found to haveshorter ABR wave latencies and larger wave V am-plitude compared with males (Jerger and Hall, 1980;Jerger and Johnson, 1988; Trune et al., 1988; Dehanand Jerger, 1990). The same findings were alsonoted in neonates (Chiarenza et al., 1988; Stuart andYang, 2001), but to a lesser extent in older children(Trune et al., 1988; Hall, 1992).

The effect of reproductive hormones on the auditoryunction may be more clearly noted in the endocrinehanges that occur during the menstrual cycle.

he ovarian cycle and auditory function

he secretion of estrogen and progesterone fluctuatesuring the ovarian cycle, with the estrogen level risinguring the first, proliferative (follicular) phase of the cycleeaching a peak just before the luteinizing hormone (LH)urge, while progesterone secretion starts to rise in theecond, luteal phase of the cycle, following the LH surgend ovulation (Djahanbakhch et al., 1981) (Fig. 3).

The higher level of estrogen during the follicular phases also associated with a rise in other hormone levels. Theasal ACTH plasma level seems to rise in the late follicularhase (Genazzani et al., 1975; Mauri et al., 1990) possiblyue to the enhancing effect of estrogen on corticotropineleasing factor gene transcription in the hypothalamusKirschbaum et al., 1999). The rise of ACTH during the lateollicular phase is not associated with higher free cortisolevel, due to estrogen induced changes in corticosteriod-inding protein levels (Kirschbaum et al., 1999; Altemus etl., 2001). The lower level of free cortisol may affect thehysiological response to stress during this phase of theenstrual cycle.

Vasopressin levels also tend to be higher during theollicular phase of the cycle compared with the mid-lutealhase (Kostoglou-Athanassiou et al., 1998b). The en-ancement of vasopressin secretion is possibly due tostrogen, which was found to increase vasopressin levels

n females who had undergone oophorectomy (Forsling etl., 1996). This may lead to fluid retention or redistributionhich occurs in some women in the pre-menstrual period
f the menstrual cycle (Tollan et al., 1993) and may also t
ffect the fluid balance in the cochlea and thus affectuditory function.

The level of �-endorphin peaks 2–4 days before ovu-ation followed by a dip in levels postovulation and thenhere is a gradual rise again during the late luteal phase,bout 24 h before the next menses (Vrbicky et al., 1982;ang et al., 1987; Ferrer et al., 1997). Women with poly-ystic ovarian disease and amenorrhea have levels of-endorphin lower than in normal women (Martinez-Guisa-ola et al., 1999). There is also evidence that estrogentimulates opioid receptor expression and stabilizes the

evels of �-endorphins that tend to decreases after meno-ause (surgical or spontaneous). This may be associatedith mood changes that can be helped by estrogen treat-ent, which increases �-endorphin levels in plasma

Genazzani et al., 2000). Estrogen also affects mood byacilitating the function of enkephalin that is also importantor reproductive behavior (Pfaff et al., 2000). It is not clearf the changes seen in �-endorphin are the result of anntrinsic role in the regulation of the ovarian cycle or are theffect of estrogen.

Progesterone alone had no effect on �-endorphin lev-ls in the hypothalamus and pituitary of oophorectomizedOVX) rats. However, treatment with both estrogen androgesterone reverses the effect of estrogen alone on-endorphin levels in the pituitary, and increases the levelsf �-endorphin in the hypothalamus (Genazzani et al.,000).

The fluctuation of hormones during the ovarian cycleay potentially lead to fluctuation in auditory function andther sensory processes (Parlee, 1983). The auditory sys-em may be more sensitive during the peak of estrogenirculation due to its excitatory and protective effect in theNS. Correspondingly, the low levels of hormones during

he pre-menstrual phase may relate to less sensitive au-itory function. A recent study (Sisneros and Bass, 2003)oted that the auditory nerve fibers of a midshipman fish (aocal seasonally breeding fish) are more responsive toale mating calls during the breeding season and not atther times. Treatment with estradiol of female midship-an fish during the non-breeding season makes their au-itory nerves respond more to male mating calls (Sisnerost al., 2004). No studies have reported these changes inther vertebrates, but these findings may imply auditoryodulation in the presence of reproductive steroids.

Auditory function in women during the ovarian cycleas been previously investigated, with inconsistent find-

ngs (Table 2). Fluctuation in auditory function during dif-erent stages of the cycle has been demonstrated, but thetudies lacked precise timing of the cycle, together withxact correlation between hormonal levels and auditoryunction. Only a few studies monitored ovarian steroidevels during the cycle, and these examined only auditoryrainstem-evoked responses.

No studies have reported auditory symptoms duringhe ovarian cycle. However, a few case reports in theiterature have described women who had fluctuating hear-ng loss associated with the ovarian cycle, that occurred in
he late luteal phase and improved after the onset of men-

Table 2. Studies of auditory function and menstrual cycle and the effect of reproductive hormones

Study Subjects Auditory test andmethodology

Documentation of ovulatorycycle

Findings

(Cox, 1980) 12 �13 �OC

PTA (Bekesy) at 0.5,1 and 2 kHz

Daily BBT ● No significant change in auditory sensitivity between groups● Poorer thresholds in the menstrual phase for all● Negative middle ear pressure during the menstrual phase in all

(Swanson and Dengerink, 1988) 10 �10 � OC

PTA (Bekesy) at 4and 6 kHz

Daily BBT ● � 4 kHz Threshold was lowest during ovulation (cycle days13–14) and highest during menses (cycle days 2–3)

● � 4 kHz Threshold during ovulation was significantly lower thanOC group and �

12 � Cervical mucus changes ● No significant change was found in 6 kHz threshold or differencebetween the groups

(Bell, 1992) 4 � SOAE History and daily BBT in 2subjects only

● 3 Out of 4 had a clear variation in SOAE frequency● 2 In the frequency before menses and 1 time of ovulation

(cycle day not mentioned)(Haggerty et al., 1993) 8 � SOAE History ● 6 Females had monthly variation in SOAE

2 � ● 2 Had 1 in frequency variation before menses● 5 Had 2 in the frequency before menses and 1 time of

ovulation (cycle day not mentioned)(Penner, 1995) 1 � (NMC, FA, OC) SOAE Daily BBT ● During NMC 2 in the frequency of SOAE before menses and 1

near the time of ovulation● Less fluctuation in SOAE frequency was noted during

amenorrhea and the use of OC(Yellin and Stillman, 1999) 13 � SOAE, DPOAE,

TEOAEDaily BBT ● SOAEs dominant early in the cycle, gradually decreased and

least prevalent before menses● No cyclic changes in TEOAEs or DPOAEs were found

(Amit and Animesh, 2004) 15 � TEOAE History ● TEOAE amplitude significantly higher during menses (cycle days1–3) and lowest during the luteal phase (cycle days 22–25)

● TEOAE amplitude significantly lower during midcycle (days 12–15)compared to during menses but higher than the luteal phase

● 3 Subjects did not have TEOAE responses during midcycle andluteal phase

(Fagan and Church, 1986) 10 � ABR at 50 dBnHL Daily BBT ● No fluctuation in ABR latencies during MC(Dehan and Jerger, 1990) 10 � ABR at 80 dBnHL Blood (E2, P, FSH and LH) ● Wave V latency 1 just before ovulation and 2 at PP and pre-

menstrual period (cycle day not mentioned)(Elkind-Hirsch et al., 1992a) 9 � ABR at 70 dBnHL Blood (E2, P, FSH and LH) ● Significant 1 in wave III, V and I–V latency associated with 1

E2 during mid-cycle phase (cycle days 12–15)9 � OC ● No significant changes in ABR latencies in the OC group

(Elkind-Hirsch et al., 1992b) 5 � POF on HRT ABR at 70 dBnHL Blood (E2, P, FSH and LH) ● HRT led to fluctuation in ABR as seen in NMC● Wave V and I–V latency significantly 1 during the E2 only

replacement compared to P and E2 replacement phase(Elkind-Hirsch et al., 1994) 5 �

9 �9 � OC

ABR at 70 dBnHL Blood (E2, P, FSH, LH,DHEAS and T)

● Wave V latency in descending order: �, � PCOD (higherandrogen levels), then � POF, � OC and �

5 � POF5 � PCOD

● Significant 1 in wave V latency during E2 only replacement forPOF and midcycle in �

(Tasman et al., 1999) 19 � ABR at 70 dB Daily urine LH and BBT ● Wave V and III--V latency 1 in follicular phase (cycle day notmentioned)

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es (Miller and Gould, 1967; Andreyko and Jaffe, 1989).iller and Gould (1967) described two women with this

ondition, one of whom had worse hearing when givenrogesterone. A similar case was reported by Andreykond Jaffe, (1989). Their patient’s fluctuating hearing loss

mproved during pregnancy, while she was breast-feedingshe had amenorrhea) and with the use of nafarelin (go-adotrophin releasing hormone (GnRH) agonist that leadso ablation of sex steroids by downregulation of GnRHeceptors and decreases secretion of follicular stimulatingormone (FSH) and LH leading to anovulation and amen-rrhea). On the other hand, Souaid and Rappaport (2000)escribed a case of a 45-year-old woman who had bilateralearing loss with the onset of menses with right ear block-ge and tinnitus that improved later on during the cycle.hey also reported that she had an abnormal ABR re-orded in the middle of her ovarian cycle (prolonged III–V

nter-peak interval on the left and delayed wave V withrolonged I–V inter-peak interval on the right). She wasreated with diuretics, which improved her symptoms, andhe ABR results of the right ear but the ABR results of theeft ear were the same as before, and her hormonal pro-le was within normal limits. These cases suggest that theuditory system in some women is more sensitive to theuctuation of hormones during the ovarian cycle.

The following alterations in the auditory system duringhe ovarian cycle have been reported (as summarized inhe Table 2):

� Auditory thresholds. The less sensitive auditoryhresholds during the menstrual phase observed by Cox1980) and Swanson and Dengerink (1988) are unex-lained. However, the associated negative middle earressure observed during the menstrual phase in someubjects could contribute to this. An increase in interstitialuids (possibly due to progesterone; Pechere-Bertschi etl., 2002; Tollan et al., 1993), affects the eustachian tubeunction and, thus may lead to poorer thresholds during theenstrual phase of the cycle. Another explanation may be

hat a fluctuation in hormones affects higher areas of au-itory processing and thus leads to changes in auditoryhresholds, similar to the findings documented in otherensorimotor and cognitive functions (Hampson, 2002).

� SOAEs. The fluctuation in SOAEs with the men-trual cycle implies that there may be a link betweenochlear function and the pituitary–gonadal axis. Thereater frequency variation of SOAEs near the time ofvulation (Bell, 1992; Haggerty et al., 1993; Penner, 1995),ith a shift toward a higher frequency, may suggest anxcitatory effect of estrogen on the SOAE generator andhe frequency shift toward a lower frequency and lessrequency variation in SOAEs near menstruation may re-ect low levels of estrogen and progesterone. Estrogenay be implicated in this frequency change, as the level is

owest in the late luteal phase (before menses) and peaksear ovulation. Moreover the peak has been associatedith an increase in neuronal excitability and inhibition of

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� Transient OAEs. Only twostudiesevaluatedTEOAEsuring the ovarian cycle (Yellin and Stillman, 1999; Amitnd Animesh, 2004). Yellin and Stillman (1999) did notbserve any change in TEOAE responses during the cy-le. On the other hand, Amit and Animesh (2004) reportedhat the TEOAE responses tend to decrease during theycle and that three of their subjects did not have record-ble TEOAEs in two testing sessions (see Table 2). Thisould have been confounded their results because theirubjects could have had a cochlear dysfunction. Moretudies are needed to clarify TEOAE results.

� ABR. The studies that measured hormone levelsnd ABR produced conflicting findings (see Table 2). Thehorter ABR latencies reported by Caruso et al. (2003a)nd Serra et al. (2003) during the periovulatory phase ofhe cycle may suggest that the high estrogen level isssociated with shorter ABR latencies, as had been found

n estrogen treatment of young OVX rats (Coleman et al.,994). The higher level of estrogen may alter the speed ofensory neurotransmission in the brain stem by modulat-ng glutamate transmission (Behl and Manthey, 2000). Onhe other hand, the possible effect on neurosteroids mayxplain the results of Dehan and Jerger (1990) and Elkind-irsch et al. (1992a,b, 1994) of longer ABR latencies dur-

ng the periovulatory phase. The higher levels of estrogenay result in an increase in neurosteroids (such as allo-regnalone) which facilitate GABA inhibition in the auditoryidbrain (Disney and Calford, 2001). The estrogen treat-ent of OVX rats increases the level of allopregnaloneoth centrally and peripherally in a dose dependent fash-

on (Stomati et al., 2002). The difference between the ABRatencies in the periovulatory phase and luteal phaseould be compatible with progesterone blunting the ef-

ect of estrogen, by inhibiting its action in the auditoryrainstem.

Further larger studies on the effect of the ovarian cyclen auditory functions are needed to clarify the results

ound in the previous studies.

enopause and auditory function

hanges in auditory function have been noted in post-enopausal women attributed in part to the lower levels ofvarian hormones.

The following findings raise the suspicion that theenopause leads to a decline of the auditory function:

� The onset of age-related hearing loss is later inwomen compared with men (Pearson et al., 1995)and seem to coincide with the menopause (Murphyand Gates, 1997). The sex difference in age relatedhearing loss is also seen in mice models of agerelated hearing loss (CBA mice) (Guimaraes et al.,2004), with a decline in DPOAE amplitudes occur-ring earlier in the males. In female CBA mice thegreatest decline in DPOAE amplitudes occurred inolder age mice following the mouse menopause.This finding suggests that estrogen may have a pro-
tective role on the cochlea and OHC function.
� A few studies explored the possible association ofhearing loss assessed by pure tone audiometry inpost-menopausal women. Kim et al. (2002) sug-gested that a lower level of serum estradiol impedeshearing sensitivity in post-menopausal women. Kilic-dag and co-workers (2004) reported that post-meno-pausal women using estrogen therapy had betterpure tone thresholds compared with those who didnot use it. A recent study by Hederstierna et al.(2007) evaluated the hearing thresholds in a group ofwomen around the time of menopause and foundthat 40% had some degree of hearing loss. Theyreported that a subgroup of women who were notusing hormone replacement therapy (HRT) had atendency of poorer hearing threshold levels com-pared with pre- and peri-menopausal and post-menopausal women who were using HRT.

These studies suggests that HRT and in particularstrogen therapy may have a beneficial effect on hearingensitivity.

� In a recent study, Guimaraes and colleagues (2006)reported that post-menopausal women who weretaking the combined estrogen and progesteroneHRT had poorer pure tone auditory thresholds, lowerlevels of high frequency DPOAE, and poorer perfor-mance in the hearing-in-noise test compared withpost-menopausal women who were either on estro-gen only replacement therapy or not taking any HRT.These results suggests that progestin (a syntheticprogesterone in combined HRT) may have a nega-tive effect on both peripheral (DPOAE) and central(hearing-in-noise test) auditory function and supportthe positive role of estrogen on hearing function.

� The low levels of estrogen and progesterone mayalter nerve conduction times as seen in carpal tunnelsyndrome (Pascual et al., 1991) and, thus, may alsoaffect ABR latencies. ABR latencies tend to increasewith age, and post-menopausal women have pro-longed ABR wave latencies and interpeak latenciescompared with younger females of a significantlygreater degree than that seen in men of matchedage groups (Jerger and Hall, 1980; Wharton andChurch, 1990). These findings in women cannot besolely age-related changes and hormones maytherefore be of importance. Indeed, HRT, in post-menopausal women, brings ABR latencies closer tothe values seen in pre-menopausal women (Carusoet al., 2000). ABR latencies were also found to besignificantly shorter in postmenopausal women afterthe use of different forms of HRT; tibolone (a syn-thetic steroid with combined estrogenic, progesto-genic and androgenic action) (Sator et al., 1999),combined estrogen and progesterone (Khaliq et al.,2003), trans-dermal estrogen therapy (Carusoet al., 2003a), and oral estrogen therapy (Khaliq et al.,2005). Moreover, the effect of HRT in post-meno-pausal women on ABR latencies is similar to what is
seen in females with premature ovarian failure (POF)

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after treatment (Elkind-Hirsch et al., 1992b) and es-trogen treatment in animal studies (Coleman et al.,1994; Cooper et al., 1999). These findings suggestthat ovarian hormones may have an effect on syn-aptic transmission in the auditory brainstem.

regnancy and auditory function

uring pregnancy the levels of both ovarian hormones areigher than usual, and there are other complex physiolog-

cal changes (Hadley, 2000). These changes lead to fluidetention and a hyperdynamic circulation, which may im-act upon the circulation in the cochlea and cochlear fluidomeostasis.

Auditory symptoms such as aural fullness, changes inuditory sensitivity or tinnitus (Gurr et al., 1993; Tsunoda etl., 1999) have been reported in pregnancy. The results ofpostal questionnaire by Gurr et al. (1993) showed that

he prevalence of tinnitus in pregnant females (25%) wasigher than non-pregnant women (11%). Tsunoda et al.1999) noted that 25% of pregnant women in their surveyeported otologic symptoms, including tinnitus and auralullness that resolved after giving birth but no changes inure tone or impedance audiometry were noted comparingregnant and non-pregnant women. However, Sennaroglund Belgin (2001) found that pregnant women had higherTA thresholds at 125, 250 and 500 Hz, than postpartumnd non-pregnant women, but were still within the normalange (less than 20 dB HL), and pregnant women in thehird trimester had significantly lower uncomfortable loud-ess level compared with postpartum and non-pregnantubjects. These findings suggest that the physiologicalhanges in pregnancy may affect auditory function mim-cking the auditory dysfunction seen in Menière’s disease,.e. low frequency elevated thresholds, with lowering ofncomfortable loudness levels.

The higher levels of ovarian hormones in pregnancy

ig. 3. Schematic representation of the changes in reproductive hor-ones during the average menstrual cycle, and the associated rise ofther hormones in the periovulatory phase. The graph does not reflecthe pulsatile release of estrogen and LH in the periovulatory phaseDjahanbakhch et al., 1984) but the smoothed out overall changes inormones levels. E2: estrogen, P: progesterone, ACTH: adrenocorti-otropic hormone ADH: ADH (vasopressin), Endo: �-endorphin.

ay shorten ABR wave latencies as seen in previousmH

tudies (see above), but the higher level of progesteroneay blunt this effect. Neural conduction in the brain stemay be slower during pregnancy due to the higher levels of

teroids that facilitate GABA inhibition (Disney and Calford,001). Tandon et al. (1990) found that the absolute wave

atencies were slightly shorter but did not reach signifi-ance in eight pregnant women in the third trimester com-ared with age-matched non-pregnant women. However,he I–III, III–V, and I–V interpeak latencies which indicateeural conduction were significantly longer in pregnantomen. An ABR study of 38 women, 20 in different stagesf pregnancy (including postpartum) and 18 non-pregnantomen by Sennaroglu and Belgin (2001) did not find anyifference. This inconsistency in findings may be attributedo difference in methodology and sample sizes and varyingtates of pregnancy.

tress and auditory function

he presence of emotional or physical stress initiates thendocrine stress response by the release of corticotrophineleasing factor (CRF) which activates the hypothalamicituitary adrenal axis and this leads to the release of cor-isol and adrenalin from the adrenal gland (Fig. 4) and thectivation of the sympathetic nervous system. Acute orhronic stress leads to the inhibition of the reproductiveunction, with the suppression of LH, which is modulatedhrough GRs (McGivern and Redei, 1994; Pfaff et al.,000). GnRH release is suppressed by CRF (Saketos etl., 1993) and dynorphin and �-endorphin through � and �eceptors in the hypothalamus (Petraglia et al., 1986),hich reduces plasma levels of LH, and this may occur inomen with functional hypothalamic amenorrhea. Theuppression of the hypothalamic–pituitary–gonadal axis,

eading to the lower levels of estrogen and progesterone,ay also affect auditory function.

The endocrine response to stress can also be initiatedy strong auditory stimuli such as excessive noiseMichaud et al., 2003; Spreng, 2000). The pathway may behrough the MGB interface between the auditory system

ig. 4. Possible interaction between stress, endocrine and auditoryystems, which may lead to pathology. Rep. H�reproductive hor-
ones, Stress. H�cortisol, catecholamines and opioids, Fluid&E.�aldosterone and vasopressin.

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nd the stress-responsive limbic system. This non-primaryrea of the auditory cortex was found to have more CRFRNA than other areas of the rat’s central auditory system

Imaki et al., 1991). On the other hand, the hormonesnvolved in the response to stress may affect auditoryunction directly by an excitatory effect, which may lead toamage through glutamate induced neurotoxicity (Pujol etl., 1993). The possible interactions between stress and

he auditory system are demonstrated in Fig. 4.Emotional stress has been associated with auditory

henomena such as hyperacusis and an increase in tinni-us and dizziness (Holgers et al., 2000; Katzenell andegal, 2001; Sahley and Nodar, 2001). These phenomenauggest that stress may lead to stimulation and sensitiza-ion of the auditory system, resulting in heightened aware-ess and, thus, more vulnerability to acoustic trauma dueo excitotoxicity (Sahley and Nodar, 2001). The effect ofympathectomy in awake guinea pigs would support thebove hypothesis, as it was found to reduce temporaryhreshold shift by 8.5 dB (Hildesheimer et al., 1991) to 40B (Horner et al., 2001) and permanent threshold shift by.8 dB (Hildesheimer et al., 2002) after sound exposure.n alternative hypothesis is that activation of the sympa-

hetic system causing vasoconstriction (Despopoulos andilbernagl, 1991) may alter the blood flow in the auditoryystem and affect cochlear blood flow leading to ischemicamage following noise exposure.

In animal experiments, supra-physiological amountsf adrenalin were infused to mimic the stress responseJuhn et al., 1991) and this led to an elevation of serumnd perilymph osmolarity and an increase in compoundction potential threshold especially at higher frequen-ies. Chronic administration of adrenalin was also found toause a transient 20–40 dB threshold shift that increasedith time across all frequencies (Juhn et al., 1999). Theseffects are thought to be the result of adrenalin on cochlearlood vessels and inner ear fluid homeostasis.

The effects of stress and glucocorticoid treatment onuditory function have been studied in humans. Fehm-olfsdorf and co-workers (1993) noted that a subset of

ubjects, who presented with raised salivary free cortisolevels after being confronted by stress, had higher con-ralateral acoustic reflex thresholds (ART), while the sameuthors (Fehm-Wolfsdorf and Nagel, 1996) found a non-ignificant trend to higher contralateral ART with glucocor-icoid treatment in a double blind crossover study. Thereas no effect of glucocorticoid treatment on ipsilateralRT, pure tone thresholds and ABR. These findings maye explained on the basis of a multisynaptic contralateraleflex pathway in which both GR and 5-HT are present,oth or either of these may alter function.

AUDITORY PATHOLOGY AND HORMONES

ormones may play a role in the development of patho-ogical conditions of the auditory system, including:

yperacusis and tinnitus s

enière’s diseaseuditory dysfunction in pre-menstrual syndrome

yperacusis and tinnitus

innitus can be defined as an auditory perception in thebsence of any external auditory stimulation, while hyper-cusis has been described as a reduced tolerance tordinary environmental sounds, often associated with tin-itus (Anari et al., 1999; Andersson et al., 2001). It haseen considered that both tinnitus and hyperacusis areesults of a raised rate and/or altered pattern of spontane-us neural activity (Eggermont, 2003). Hence, the mech-nisms which alter spontaneous auditory activity may alsoacilitate the occurrence of tinnitus and/or hyperacusis.

Tinnitus may result from an abnormality/dysfunction atny level of the auditory system. Tinnitus-related activity,s any auditory signal, is, probably, subject to the normalrocess of habituation/adaptation, which protects the au-itory system from overstimulation through the attenuationf repetitive signals. This is supported by the observationhat the intrusiveness of tinnitus declines over time (Tylernd Baker, 1983; Andersson et al., 2001).

The process of habituation involves complex neuronalircuits and multiple transmitter system (Mesulam, 1990;andel, 2001), including acetylcholinergic, dopaminergic,ABA-ergic, nitric oxide and serotonergic systems. The

erotonergic system is thought to play a role in modulatingeuronal responses to repetitive stimulation and to act as“gain-control” between facilitating and inhibitory mecha-

isms (Hegerl and Juckel, 1993). There is also evidenceor the involvement of the serotonergic system in the pro-ess of habituation of sensory stimuli (Gottfries et al.,976; Hegerl and Juckel, 1993). Alterations in these neu-otransmitter systems may lead to a dysfunction of therocess of habituation. Indeed, their dysregulation haseen associated with the pathophysiology of depressionnd mood disorders (Owens and Nemeroff, 1998; Resslernd Nemeroff, 2000; Meyer et al., 2001). 5-HT has alsoeen suggested to play a role in the generation of tinnitusnd hyperacusis (Marriage and Barnes, 1995; Gopal et al.,000; Simpson and Davies, 2000), which may explain theell-recognized co-morbidity of severe tinnitus/hyperacu-is and psychological disorders (Forsling et al., 1996;oger et al., 2001).

The contribution of stress, which activates various bi-logical functions, including the above neurotransmitterystems, may influence the auditory system through differ-nt pathways, particularly in individuals with impairedechanisms of habituation, e.g. in individuals with psycho-

ogical/psychiatric disorders, as outlined above. The linketween stress and tinnitus is well recognized (Erlandssonnd Hallberg, 2000; Holgers et al., 2000). In addition,ysfunction of adrenal stress hormones, such as in Addi-on disease (Henkin et al., 1967; Henkin and Daly, 1968)ay lead to hyperacusis.

The reproductive hormones may also have a role in theccurrence of tinnitus and hyperacusis: both estrogen androgesterone could influence the auditory system, as de-
cribed earlier in this text. Estrogen has been generally

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onsidered to have an excitatory role and to have a neu-oprotective effect, and there is a strong relationship be-ween estrogen and serotoninergic pathways (Rubinow etl., 1998). On the other hand, progesterone and its metab-lites are known to have a potent inhibitory effect, through

he interaction with the GABA receptors. Therefore, alter-tions in these hormones, both physiological and patho-

ogical, may lead to increased susceptibility to developinginnitus.

enière’s disease and endocrine system

enière’s disease is a disease of poorly understood etio-athophysiology. The assumption that hormones couldlay is role in pathogenesis of the disease may be sup-orted by the following data:

● The female to male ratio shows a slight female pre-ponderance (1.3:1) (Schessel et al., 1998), and thepeak incidence for the disease is in the fourth to sixthdecade of life (Paparella, 1991), which spans meno-pause. This may suggest that the alterations in repro-ductive hormone levels may aggravate or initiate thedisease.

● The symptoms of Menière’s disease often becomemanifest during periods of stress (American Psychi-atric Association, 1994) and the disorder is morecommon in professionals and management occupa-tions (Watanabe et al., 1995) implying that the endo-crine and neural changes associated with the stressresponse may be involved in pathogenesis of thedisease or in its exacerbation.

● Endolymphatic hydrops associated with Menière’sdisease may involve hormones maintaining fluid andelectrolyte balance (Juhn et al., 1991; Naftalin, 1994).

A few studies have tried to explore the relationshipetween the endocrine system and Menière’s disease,specially the possible role of reproductive, stress and fluidnd electrolyte related hormones.

eproductive hormones

� The possible role of a sharp fall in the levels ofreproductive hormones pre-menstrually with an ex-acerbation of Menière’s disease has been noted insome studies. Andrews et al. (1992) found that only6 of 109 women reported this relationship, whileMorse and House (2001) noted that in 11 out of the13 females more symptoms were reported pre-men-strually. Price et al. (1994) reported a case in whichthe patient’s symptoms were exacerbated pre-men-strually but disappeared with leuprolide (GnRH ago-nist that leads to ablation of sex steroids by down-regulation of GnRH receptors and decreases secre-tion of FSH and LH leading to anovulation andamenorrhea) treatment. The symptoms recurredwhen she was prescribed progesterone, but notwhen given estrogen. The fluid retention or redistri-bution that occurs in some women in the pre-men-strual period (Tollan et al., 1993) may also play a role
in exacerbating symptoms. The fluctuation of symp- l
toms during the menstrual cycle in some patientswith Ménière’s disease may imply that variation ineither the reproductive or stress-related hormonesmight be involved in the pathophysiology of this dis-ease.

� The specific influence of menopause, when there isa sharp fall in reproductive hormones, on the onsetor worsening Menière’s disease has not been re-ported in the literature.

� The fluid electrolyte changes and higher levels ofprogesterone seen in pregnancy may also affectMenière’s disease. More attacks have been reportedduring early pregnancy, when the serum osmolarityis low, in a case report by Uchide et al. (1997), whichis possibly related to the sharp rise of hormonesduring the first trimester.

tress-related hormones

� Exacerbation of Menière’s disease tends to occur inrelation to stress and adrenal hormones are thoughtto be involved (Mateijsen et al., 2001).

� Patients with Menière’s disease were found to havehigher levels of cortisol compared with healthy con-trols (van Cruijsen et al., 2005). However, the higherlevels of cortisol are possibly the result of the chroniccourse of the disease, not the cause, as those with alonger history of Menière’s disease had the highestlevels of cortisol.

� Patients with Menière’s disease may have alteredresponse to stress. In comparison with patients withfacial spasm, which is assumed to cause stress butis not contributed to/triggered by stress, the patientswith Menière’s disease displayed a strong positivecorrelation between cortisol and adrenocorticotropichormone, as well as a significant correlation betweencortisol and prolactin (Horner and Cazals, 2005).

luid and electrolyte related hormones

� Altered inner ear fluid homeostasis may be the un-derlying mechanism, as seen in animal models ofendolymphatic hydrops (Juhn et al., 1991; Naftalin,1994; Juhn et al., 1999).

� The possible effect of ADH (vasopressin) inMenière’s disease has also been studied and anincrease in the level of plasma ADH in patients withMenière’s disease has been related to the vertigi-nous attacks (Takeda et al., 1995; Aoki et al., 2005).However, patients with Menière’s were not found tohave abnormal levels of aldosterone compared withcontrols (Mateijsen et al., 2001). Aldosterone levelsmaybe abnormally elevated before or after an attack,which are difficult to measure clinically.

re-menstrual syndrome and auditory function

omen who suffer from premenstrual syndrome (PMS),lso known as premenstrual dysphoric disorder (PMDD),ay have changes in their auditory function.

PMDD is a syndrome occurring specially during the
ate luteal phase of the ovarian cycle and is characterized

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y moderate to severe alteration in mood, behavior andhysical well-being that impairs the personal, professionalnd/or social functions in 5–8% of women during theireproductive years (American Psychiatric Association,994; Yonkers, 1997). The underlying pathophysiology isoorly understood, but may be related to progesterone iniew of the cyclic nature of the symptoms, although noonsistent finding has been documented (Rubinow andchmidt, 1995).

Dysregulation of the stress response and stress-re-ated hormones such as ACTH, �-endorphin and cortisollay a role in mood disorders, such as depression, so theyave also been implicated in the pathogenesis of PMS.ifferences in basal levels of these hormones betweenontrol women and those with PMS have not been firmlystablished (Bloch et al., 1998). However, a recent studyas found that women with PMS have dysregulation of thetress response (activation of the HPA axis in response ton external stressor) compared with those without PMSRoca et al., 2003).

Allopregnalone, a metabolite of progesterone and aotent GABA-A agonist, is also associated with stressBaulieu, 1998), and has a profound anxiolytic effect (Brott al., 1997). Women with PMS may have altered GABAEpperson et al., 2002) and/or allopregnalone (Monteleonet al., 2000; Girdler et al., 2001) functions, thus contribut-

ng to the mood disorder.These alterations in women with PMS have a potential

ffect on the auditory system. Changes in auditory functionave been documented in a study that compared ABR

atencies between women with and without PMS (Howardt al., 1992). Women with severe PMS had longer wave IIInd wave V latencies, while those with moderate PMS had

onger wave III latencies only, compared with women with-ut PMS. Howard et al. (1992) also noted that ABR laten-ies did not change after successful treatment of PMS withuoxetine (a selective 5-HT reuptake inhibitor) suggestinghat the difference in ABR latencies could be due to aeural abnormality at the brainstem level. In addition,hlers et al. (1996) reported that women diagnosed withMS had longer P3 latency of the auditory event–relatedotentials compared with normal controls. The presence ofhese differences in ABR and auditory event–related po-entials between women with and without PMS may sug-est a neurobiological predisposition to PMS.

CONCLUSION

his review highlights the complexity of the effects of hor-ones on the auditory system, with multidirectional andultidimensional interactions. An understanding of the ex-ct mechanism of hormonal influence on auditory functionemains limited. The reproductive steroids, stress-relatedormones and hormones regulating fluid and electrolytealance may all influence auditory function by:

● Direct action through the receptors within the auditorysystem

● Indirect actions
Modulating blood supply to the auditory system
Regulating the fluid electrolyte balance of the co-chlear fluidsModulating the effects of neurotransmitters presentalong the auditory pathwaysEffect through the extra auditory structures in theCNS, through their links with the auditory system

The same hormone may exert its action on the auditoryystem through multiple pathways (modulating blood sup-ly, inner ear fluids, sensory neurotransmission in the co-hlea, brain stem and cortex or through extra-auditoryonnections). For example, estrogen could lead to neuralxcitation and thus facilitate auditory transmission, but theossible increase in neurosteroids in the brainstem mayounteract this effect.

The difficulty in pinpointing the exact effect of a hor-one on the auditory system arises from the complexnatomy of the auditory system and the interactions be-ween the various hormones that occur as the result ofynamic nature of the physiological processes. However,ome general effects can be observed. The reproductiveormones, in general, facilitate auditory function, with arotective effect on the auditory system. Aldosterone andasopressin are mainly involved in maintaining cochlearuid balance. Melatonin possibly has a protective effect onuditory system. The hormones involved in the responseo stress are, generally, excitatory, but in the long run mayead to damage and may play an important role in auditoryathology.

Undoubtedly, there is a need for further studies withetailed analysis of auditory function in different hormonaltates, which may help in the development of:

new pharmacological strategy for the hormone-basedtreatment of some patients with auditory dysfunction;and

on-invasive monitoring of the hormone variations usingauditory tests such as the SOAE during the menstrualcycle.

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(Accepted 2 February 2008)(Available online 15 March 2008)

Hormones and the auditory system: A review of physiology and pathophysiology

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