The reproductive hormones and hearing: The gender difference Borka Ceranic MD ENTspec PhD Department of Audiology and Neuro-otology St George’s Hospital, London

Effects of reproductive hormones Cognitive function Hampson, 2002 Neural excitability Smith et al, 2002

Effects of reproductive hormones on behaviour Ovulatory shifts in human female ornamentation:  Women dress to impress Haselton et al, 2007

Effects of reproductive hormones on sensory processes Around the time of ovulation … Greater visual sensitivity, Eisner et al, 2004 Better colour discrimination, Giuffre et al, 2007 More sensitive sense of smell, Grillo et al, 2001

Reproductive hormones and hearing: Animal studies Midshipman fish are more responsive to male mating calls during the breeding season than at other times Sisneros et al, 2003 Treatment with oestradiol of female midshipman fish during the non-breeding season makes their auditory nerves more sensitive to the frequency of the male mating call Sisneros et al, 2004

Reproductive hormones and auditory system in humans The hormones allow “system setting”…by modulating auditory function to either facilitate or inhibit auditory information Physiological basis for interaction between ovarian hormones and the auditory system Al-Mana, Ceranic, Djahanbakhch and Luxon; Neuroscience, 2008

Oestrogen and the auditory system: Physiological pathways Cochlea:  Receptors ER  and ER  are detected in the cochlea (Stenberg et al, 1999, 2001)  Oestrogen receptors in cochlear blood vessels (Laguel et al, 1987)  E2 influence the the balance of electrolytes in the cochlear fluids (Lee & Marcus, 2001) CNS:  Modulates GABA-ergic, serotonergic and glutamatergic systems ( Woolley et al, 1997)  Excitatory effect on neural fibers (Smith et al, 2002 )

Progesterone and the auditory system: Physiological pathways Cochlea:  Cross-reacts with other steroid receptors (e.g. glucocorticoid receptors) Lang et al, 1990; Nathan et al, 1999 CNS:  Interacts with steroid binding sites on the GABA-A receptors, leading to a rapid modulation of CNS excitability Majewska et al, 1986  Mainly inhibitory action on the CNS and balance oestrogen action Katzenellenbogen, 2000; Smith et al, 2002

Aim To compare the auditory function in relation to changes in hormone levels in a group of women during the normal ovarian cycle and a group of men over a similar period of time

29 consecutive volunteers with normal hearing 16 women age 31.4 (± 8) years cycle 28.5 (± 1.6) days 13 men age 31.8 (± 7.6) years Subjects

 Cochlear function Recording of otoacoustic emissions  Efferent feedback system which controls the cochlea Medial olivo-cochlear suppression test  Auditory nerve conduction Auditory brainstem responses – to evaluate sound transmission (latencies) through the auditory pathways in the brainstem Auditory Tests

Otoacoustic emissions (OAEs) OAEs generated by the cochlea and they reflect vibrations of the cochlear outer hair cells Kemp, 1978

Recording of otoacoustic emissions (OAEs) A standard recording setup Evoked OAEs (dB SPL) Higher levels of OAEs = Higher cochlear gain  better hearing sensitivity

Medial olivo-cochlear suppression test  To measure the magnitude of suppression of the efferent feedback system which controls the cochlea

The auditory system Olivo-cochlear pathway Feedback mechanism Cortex Inferior colliculus

Medial olivo-cochlear suppression test Contralateral stimulation of the olivo-cochlear system and recording OAEs following ipsilateral stimulation: Ipsilateral stimulation (linear click) Contralateral stimulation (broadband noise) OAEs Recording of OAEs with and without contralateral noise

Auditory Brainstem Responses (ABR) A diagram illustrating the auditory pathway and the anatomical locations; the traces of the ABR

Auditory Brainstem Response (ABR) Short latency potentials from the scalp: Wave I  Spiral ganglion Wave III  CN and SOC Wave V  upper pons (LL and IC) Adapted from: Duane (1977)

Protocol E 2 : oestrogen, P: progesterone, LH: lutenizing hormone, FSH: follicular stimulating hormone Women: Auditory tests 4 times during one ovarian cycle with blood samples E2 all 4 sessions P last 2 sessions Men: Auditory tests once a week for 4 weeks

Results

Alteration in TEOAE during the ovarian cycle 1- Early follicular phase 15.3 dB spl 2 - Late follicular phase 16.5 dB spl 3 - Early luteal phase 16.0 dB spl 4 - Late luteal phase 15.0 dB spl

TEOAE inter-session levels Women Men TEOAE amplitude significantly larger in the women (F= 15.7; p<0.001*)

MOC Suppression in four sessions MOC Suppression (mean  SD) Session 4Session 3Session 2F; p 1.47        1.2 Women (n=32) Men (n=26) F=3.2; p= 0.03* F=7.4; p= 0.3 Session  1.1 no significant difference between the level of MOC suppression between the women and men (F=1.9; p=0.17)

The correlation between OAE amplitudes and Oestradiol levels

The correlation between MOC suppression and Oestradiol levels

ABR women and men

Auditory brainstem responses Wave V * Longer wave V latency in the follicular phase Wave V latency (mean  SD) Session 4Session 3Session 2F; p 5.55 ± ± ± ± ± ± ± 0.1 Women (n=32) Men (n=26) F=3.9; p=0.01* F=0.93; p=0.4 Session ± 0.2

Summary I  Larger OAE amplitudes in women - suggest more acute hearing in women  OAE amplitudes largest in the late follicular/early luteal phase and Positive OAE and Oestradiol level correlation - imply even more sensitive hearing around the time of ovulation.

Summary II Changes in MOC suppression  with  E2   with presence of P   when both E2 and P are low. - Excitatory effect of E2 during the follicular phase and - Inhibitory effect of P in the luteal phase ABR - shorter latencies in women - Excitatory effect of E2 (facilitates neural transmission of the acoustic signal) E2 facilitates, while P inhibits auditory processing

Modulation in auditory function during the ovarian cycle is a part of intricate processes in different systems, which enhances one of the most fundamental body functions - reproduction and preservation

Study collaborators: Professor Ovrang Djahanbakhch St Bartholomew’s Hospital, Queen Mary’s School of Medicine, University of London Dr Deena Al-Mana and Professor Linda M. Luxon The National Hospital for Neurology & Neurosurgery, University College London