Research paper
The effect of sex hormones on bone metabolism of the otic capsule – an overview

https://doi.org/10.1016/j.heares.2008.12.004Get rights and content

Abstract

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-κB (NF-κB) 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.

Introduction

The aim of the present contribution is not to review the literature on bone metabolism of the otic capsule. The aim is rather to bring together seeming disparate reports – old, new, forgotten or ignored – which in isolation have little impact but when taken together they consolidate todays interest in the influence of sex hormones on the inner ear. In particular, It is hoped that this overview will open the way to further interest in other interacting hormones and, in particular, prolactin which might affect the inner ear.

Section snippets

Sex hormones affect the inner ear

When interested in the effects of hormones and the inner ear, a rapid browse of some recent literature reveals that estrogen and more particularly receptor Β is involved in the protection against acoustic trauma (Meltser et al., 2008) while hormone therapy, including progestin together with estrogen, can damage hearing (Guimaraes et al., 2006). These seemingly conflicting data come years after case reports of irreversible (Okulicz, 1978) or reversible hearing loss (Hanna, 1986), tinnitus (Mitre

Hormones underlie osteoporosis – does prolactin play a role?

Osteoporosis in post-menopausal women has long been associated with the fall in estrogen levels – thus contributing to justification for the continued use of hormone replacement therapy in women. Bone loss in post-menopausal women typically occurs in two phases – a rapid phase, related to the lack of estrogen on bone metabolism, which can last several years, and a slow phase, related to the calcium homeostasis, of indefinite duration (Riggs, 2002). While estrogen is probably a major actor,

Hormones and otosclerosis

Otosclerosis is a chronic inflammatory infection of the otic capsule resulting in bone resorption. The pathology has a complex etiology and the state of the art has been reviewed recently (Arnold, 2007). The measles virus has been pin-pointed as one crucial contributing factor. The virus was first detected by immunohistochemistry in otosclerotic lesions and measle virus specific antibodies have been detected in perilymph (Arnold et al., 1996). While only 1% of the population may develop

Molecular basis of bone metabolism – and the otic capsule

Healthy bone metabolism involves the coupling between bone formation and bone resorption via osteoblasts and osteoclasts respectively. Loss of function of osteoclasts is known as osteopetrosis, gain of function of osteoblasts as osteoclerosis and relative increase of bone resorption over bone formation as osteoporosis. Our present understanding of bone metabolism largely considers the role of three members of the tumor necrosis factor (TNF) and TNF receptor families of proteins (Boyle et al.,

Hormones affect the molecular control of bone metabolism – estrogen versus prolactin

While the RANKL–RANK–OPG system now appears to be determinant in the control of bone metabolism, the system is regulated by hormones. Estrogen has its protective effect on bone because it can inhibit bone resorption by inducing apoptosis of osteoclasts (Kameda et al., 1997) and blocking the maturation of osteoclasts (Pacifici, 1996). Estrogen has now been found to stimulate OPG in osteoblastic cells (Hofbauer et al., 1999) and to decrease the response of osteoclasts to RANKL (Srivastava et al.,

Prolactin is linked to other labyrinthine pathologies

As discussed above pregnancy, lactation, contraceptive pills, and hormone replacement therapy, are conditions affecting bone structure and have, only loosely, been related to different types of labyrinthine dysfunctions. While estrogen is accepted as a possible actor, the same cannot be said for the role of prolactin. However, further supporting evidence for this hypothesis comes from other pathologies.

Ménière’s disease is characterized by hearing loss, tinnitus and vestibular dysfunction. It

Future in molecular bone therapy of the otic capsule

Fundamental studies on molecular mechanisms of bone resorption in the past ten years have given way to therapeutical approaches aimed at inhibiting RANKL and protecting bones (Schwarz and Ritchlin, 2007). For example a single dose of OPG in post-menopausal women was reported to substantially reduce bone turnover and for a sustained period (Bekker et al., 2001). These and other data provide encouraging basis for the development of clinical anti-RANKL therapy for bone diseases (Hofbauer and

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