Effect of chronic estradiol administration on vimentin and GFAP immunohistochemistry within the inner ear.

Recent data show that hormone replacement therapy, involving estrogen together with progestin, can promote hearing loss (Guimaraes, P., Frisina, S.T., Mapes, F., Tadros, S.F., Frisina, D.R. and Frisina, R.D., 2006. Progestin negatively affects hearing in aged women. Proc. Natl. Acad. Sci. USA. 103, 14246-14249.). But long-term estradiol treatment, which induces hyperprolactinemia in guinea pigs, results in hearing loss and bone dysmorphology of the otic capsule-without much hair cell loss (Horner, K.C., Cazals, Y., Guieu, R., Lenoir, M. and Sauze, N., 2007. Experimental estrogen-induced hyperprolactinemia results in bone-related hearing loss in the guinea pig. Am. J. Physiol., Endocrinol. Metab. 293, E1224-1232.). Since estrogen receptor beta can protect the mouse cochlea against acoustic trauma (Meltser, I., Tahera, Y., Simpson, E., Hultcrantz, M., Charitidi, K., Gustafsson, J.A. and Canlon, B., 2008. Estrogen receptor beta protects against acoustic trauma in mice. J. Clin. Invest. 118, 1563-1570.), we hypothesized that estradiol might activate protective glial-like elements in the inner ear. Immunohistochemistry showed down-regulation of vimentin within the lateral wall and upregulation within the spiral limbus. Glial fibrillary acid protein was increased in the inner sulcus, Hensen cells and Claudius cells. Furthermore, there was increased expression of vimentin in type II cells of the spiral ganglion and type I vestibular hair cells. The observations suggested that estradiol treatment may affect the inner ear ionic homeostasis but protection may be afforded via activated intermediate filaments.

Stress hormones in Ménière's disease and acoustic neuroma.

Stress has been postulated to trigger or contribute to inner ear pathologies but there is little objective evidence. We investigated stress hormones in Ménière's patients and patients with acoustic neuroma. Data were compared with those from a control group of patients with facial spasm. We assayed classic stress hormones including adrenocorticotropic hormone, cortisol, growth hormone and prolactin. We found a strong positive correlation between cortisol and adrenocorticotropic hormone in Ménière patients and patients with acoustic neuroma but no correlation in patients with facial spasm. The data also revealed in female patients with Ménière's disease or with acoustic neuroma an unexpected significant positive correlation between cortisol and prolactin. The data showed the expected negative correlation or no correlation between cortisol and prolactin associated with males and females in the other patient groups. Both cortisol and prolactin increases are known to represent alternative strategies to cope with stress, and our data point to prolactin being possibly more dominant in Ménière's disease and cortisol in acoustic neuroma. These data provide further evidence for modification of different stress hormones in audiovestibular pathologies, which might provide a valuable diagnostic or prognostic tool in the future.

Hyperprolactinemia in some Meniere patients even in the absence of incapacitating vertigo.

Stress can be a significant factor influencing ear pathologies and is often reported to trigger the symptoms of Meniere's disease. Both physiological and psychological stress provokes the release of prolactin from the pituitary thus allowing the classification of prolactin as a major stress hormone. We investigated the level of the stress hormone prolactin in a Swedish population with early symptoms of Meniere's disease. The median prolactin level in the Meniere patients (n=33) was not significantly different from that of non-Meniere patients (n=23). However, in the Meniere group one female (90 year old) had prolactin levels in the upper normal range for women, one male (77 year old) had prolactin levels above the normal limit for men, and a third patient (76 year old female) presented hyperprolactinemia with more than twice the normal level. MRI confirmed a pituitary adenoma in this patient. This study provides further support for the recent report of hyperprolactinemia in some patients with long-standing Meniere's disease and presenting incapacitating vertigo in France. The data emphasize the likely implication of stress in this pathology where the stress hormone prolactin is likely to represent one actor in a complex hormonal imbalance affecting the inner ear.

Prolactinoma in some Ménière's patients--is stress involved?

Dizziness is a common complaint in primary care clinics and can enter the diagnostic profile of different pathologies spanning from psychiatric problems to vestibular dysfunction. Episodes of vertigo in Ménière's patients are often reported to be triggered by stress but no physiological data are available to account for the subjective link. The study involved 42 Ménière's patients hospitalized for neurectomy of the vestibular nerve for relief of incapacitating vertigo. In addition 18 patients with neurinoma of the vestibular nerve and 12 patients with facial spasm, who underwent surgery, served as controls. A blood sample was taken on the day of surgery in order to determine the level of battery of different stress hormones. The most striking observation was the presence of hyperprolactinemia (above 20 microg/l) in 14 Ménière's patients. The presence of prolactinoma was confirmed by MRI in six cases out of six investigated and the others have not yet been followed up in this retrospective study. These observations are clearly indicative for systematic determination of prolactin levels before opting for surgery in Ménière's patients.

Similar half-octave TTS protection of the cochlea by xylazine/ketamine or sympathectomy.

Cochlear efferents, sympathetic control and stress conditions have been shown to influence sound-induced hearing loss. These factors are also known to be modified by sedation/anesthesia. We tested here the effect of sedation/anesthesia on temporary threshold shift (TTS) compared to that in the same awake animals. The effect of sympathectomy was also tested. We employed awake guinea pigs with a chronically implanted electrode on the round window of each of the cochleae. Each ear was tested for its sensitivity to TTS induced by a 1 min or a 10 min exposure to an 8 kHz pure tone at 96 dB sound pressure level. After an intramuscular injection of xylazine or ketamine together with xylazine, TTS at half-octave frequencies was reduced compared to that in awake animals. The second half-octave frequencies were less affected. This specific pattern of protection was also observed here after surgical ablation of a superior cervical ganglion. The data lead to the speculation that protection from TTS under sedation/anesthesia might be due to diminished sympathetic influence. Xylazine is a pre-synaptic alpha2-adrenoreceptor agonist which blocks noradrenaline release from the sympathetic system. Ketamine is a N-methyl-D-aspartic acid receptor antagonist which could reduce glutamate excitotoxicity as well as reduce sympathetic activity.

Receptors for leptin in the otic labyrinth and the cochlear-vestibular nerve of guinea pig are modified in hormone-induced anorexia.

Metabolic syndromic inner ear pathology is a recognized condition in clinical practice but the possible causes remain controversial. We have previously reported that chronically-implanted estrogen implants in guinea pig results in hyperprolactinemia and hearing loss together with otic bone dysmorphology. The animals also present with anorexia. The hormone leptin has major roles in the regulation of satiety as well as bone metabolism and so we hypothesized that leptin might contribute to pathology of the otic labyrinth. We employed immunohistochemistry to investigate leptin receptor (ObR) expression. In control animals, ObR immunolabeling was not detected in the bone of the otic capsule but immunolabeling was observed in the cochlear-vestibular nerve. The labeling was associated with the astrocytic glial dome area, which marks the transition between central and peripheral parts of the nerve. In estrogen-treated animals, positive-ObR immunolabeling was observed in osteoblasts in new bone of the otic capsule and the ObR labeling was reduced in the cochlear-vestibular nerve compared to controls. The data provide evidence that leptin may target the labyrinth - affecting the bone and the nerve - and so could contribute to ongoing protection of the inner ear. Leptin disturbance might contribute to metabolic syndromes involving the audiovestibular system.

The effect of sex hormones on bone metabolism of the otic capsule--an overview.

Bone resorption, which can occur after the menopause, has long been considered to due to the decrease of estrogen and so estrogen and estrogen/progestin treatment in women has been employed with the aim of slowing down the process. Other important factors have recently been considered, including follicle-stimulating hormone. The hormonal control of bone metabolism has taken on a new dimension since the description, within the last decade, of a major osteoclast inhibiting control system. The receptor activator of nuclear factor-kappaB (NF-kappaB) ligand (RANKL) produced by osteoblastic lineage cells, must bind with its receptor RANK, located on osteoclasts, in order to allow the maturation and activation of osteoclasts. The potential continuous bone loss is controlled by the decoy receptor osteoprotegerin (OPG) which competitively binds to RANKL and hence blocks the interaction of RANKL-RANK. Estrogen contributes to bone protection since it decreases the response of osteoclasts to RANKL and induces osteoclast apoptosis. But estrogen, alone and especially in synergy with progesterone, is a potent stimulator of prolactin release. Prolactin affects calcium metabolism and hyperprolactinemia associated with pregnancy, lactation, antipsychotic drug treatment, or aging is reflected in decreased bone mineral density. Long-term estrogen treatment in guinea pig results in hyperprolactinemia and has been shown to lead to hearing loss as well as bone dysmorphology of the otic capsule. Recent data show that prolactin decreases OPG and increases RANKL. OPG has been shown to be expressed at high levels in the cochlea and OPG knock-out mice have indeed abnormal remodeling of the otic capsule and resorption of the auditory ossicles. So estrogen-induced hyperprolactinemia could oppose estrogen protection by the knock-down of the OPG bone protection system. This might explain why oral contraception treatment and hormone replacement therapies, involving estrogen together with progestin, increases the risk of otosclerosis and vestibular disorders. Hyperprolactinemia associated with pregnancy and lactation might also underlie the association of increased risk of otosclerosis with multiple pregnancies.

Experimental estrogen-induced hyperprolactinemia results in bone-related hearing loss in the guinea pig.

Our group (Horner KC, Guieu R, Magnan J, Chays A, Cazals Y. Neuropsychopharmacology 26: 135-138, 2002) has earlier described hyperprolactinemia in some patients presenting inner ear dysfunction. However, in that study, it was not possible to determine whether hyperprolactinemia was a cause or an effect of the symptoms. To investigate the effect of hyperprolactinemia on inner ear function, we first developed a model of hyperprolactinemia in estrogen-primed Fischer 344 rats and then performed functional studies on pigmented guinea pigs. Hyperprolactinemia induced, after 2 mo, a hearing loss of approximately 30-40 dB across all frequencies, as indicated by the compound action potential audiogram. During the 3rd mo, the hearing loss continued to deteriorate. The threshold shifts were more substantial in males than in females. Observations under a dissection microscope revealed bone dysmorphology of the bulla and the cochlea. Light microscopy observations of cryostat sections confirmed bone-related pathology of the bony cochlear bulla and the cochlear wall and revealed morphopathology of the stria vascularis and spiral ligament. Scanning electron microscopy revealed loss of hair cells and stereocilia damage, in particular in the upper three cochlear turns and the two outermost hair cell rows. The data provide the first evidence of otic capsule and hair cell pathology associated with estrogen-induced prolonged hyperprolactinemia and suggest that conditions such as pregnancy, anti-psychotic drug treatment, aging, and/or stress might lead to similar ear dysfunctions.