Estradiol in Temporomandibular Joint Disorders: A Historical and Present-Day Perspective
Authors: Ai Huang* Robert S. Glickman**
Mentor: Robert S. Glickman**
*Visiting Scholar, Department of Oral and Maxillofacial Surgery, New York University College of Dentistry, New York, NY.
**Professor and Chair, Department of Oral and Maxillofacial Surgery, New York University College of Dentistry, New York University Langone Medical Center, and Bellevue Hospital Center, New York, NY.
Temporomandibular Joint Disorders (TMDs) are the most common cause of facial pain seriously impacting jaw function and quality of life. Medication is often the main method of managing pain from TMDs but many adverse reactions are common with chronic use. More narrowed targets and optimal timing of treatments might be more effective. Abundant evidence from recent epidemiologic studies clearly demonstrates that women are at greater risk for TMDs. To explain this obvious female susceptibility, estradiol, which is the major female sex hormone, has gained more and more attention from scientists and clinicians. Therefore, it seems timely to review this literature about estradiol and TMDs and map out potential opportunities for further understanding of the mechanism of pain and provide clinicians inspiration for TMD prevention, diagnosis and treatment. This review focuses on the role of estradiol in TMDs nerve, cartilage, bone and inflammation, as well as physiological estradiol level changes during menstrual cycle and menopause in female bodies and their effects on TMDs. The review concludes with a discussion of possible biopsychosocial mechanisms that menstrual cyclic fluctuation of estradiol level may underlie best timing of TMD treatment, as well as considerations for future research.
Key words: Estradiol; Temporomandibular Joint Disorders; Pain; Inflammation; Menstrual cycle; Menopause
Temporomandibular disorders（TMDs）are the most common cause of facial pain and can cause chronic or recurrent pain and dysfunction in the jaw joints，associated muscles and supporting tissues. Approximately 5 to 12% of the population suffer from TMDs, with an annual cost estimated at $4 billion in US 1.Medication is the main method of managing pain in TMDs. Opiate, non-steroidal anti-inflammatory drug(NSAIDs), and others may be prescribed, and adjunct medication including antidepressants and anticonvulsants can also be used. Due to the potential for medication side effects more selective and effective treatments are needed to be improved.
The prevalence of TMDs seems to be 2–5 times higher in women than men in community samples, and pain onset tends to occur after puberty and peak in the reproductive years, with the highest prevalence occurring in women age from late teens to 45 years old2. Severe problems are much more common among women in clinical populations, and the ratio between women and men who seek treatment for TMDs is about 8:13. Scientists and clinicians try to find explanation of this obvious female susceptibility. Estradiol, which is the major female sex hormone, has gained more attention and may explain some of this prevalence in women.
Estradiol (E2), aka oestradiol, is the primary biologically active estrogen produced especially within the ovaries. Estradiol acts via binding to its receptors，alpha (ERα) ,beta (ERβ), and G-protein coupled estrogen receptor 1 (GPER1) 4. Estradiol is involved in the regulation of the menstrual cycles and essential for the development of female secondary sexual characteristics as well as the maintenance of female reproductive tissues. TMJ also can be an estradiol target tissue. Intense estradiol receptors were localized in the synovial lining cells, stromal cells in the articular disc, chondrocytes and retro-discal tissues in the TMJ, in both symptomatic and asymptomatic males and females5.
How does estradiol affect TMD? The effect is complicated and multi-faceted. Sometimes the results of different studies are even contradictory. This review focuses on the role of estradiol in TMDs nerve, cartilage, bone and inflammation, to get a clearer scientific image of how estradiol acts on TMDs. Besides, the review includes estradiol level changes in female bodies and their effects on TMDs, to provide clinicians inspiration for TMD prevention, diagnosis and treatment.
Effects of estradiol on TMDs
Fig. 1. Shown is a summary of the known interactions. Estradiol acts on TMDs via its effects on the peripheral nervous system (PNS), central nervous system (CNS), cartilage, bone, inflammation, and others. Estradiol’s influences are diverse, tissue-specific in multiple systems.
Estradiol level change
Fig.2 Combined graph of data from three articles. Blood estradiol fluctuation during a menstrual cycle is modified from Häggström M’s article6. Saliva estradiol fluctuation during a menstrual cycle is modified from Saibaba’s article7. TMD pain fluctuation during a menstrual cycle is modified from LeResche L’s article8.
The effect of estradiol depends on its level, time of exposition and rapid or cyclic changes9. Estradiol level fluctuates regularly during the normal menstrual cycle as shown in Fig.2. Although related researches cannot reach a perfectly consistent result, what we may conclude from them is that TMD pain varies during one menstrual cycle and is highly related with estradiol level change. LeResche L et al’ s research showed that TMD pain in women is highest at times of lowest estradiol, but rapid estradiol change may also be associated with increased pain8. Research which monitors daily estradiol level and pain level during a complete menstrual cycle is necessary to verify the relationship between estradiol level change and TMD pain, and magnetic resonance imaging(MRI) and molecular analysis may help understand this correlation.
Menopause occurs due to the sharp decrease of estradiol and progesterone produced by the ovaries. The changes in circulating estradiol at menopause affect TMJ, decreasing the possibility of getting TMD10. Besides, in postmenopausal women, disk displacement disorders tend to be more common with aging11.
Not only the estradiol produced in the body, but also the hormone replacement therapy(HRT) during post-menopause is worth noting. It is important to find out whether the onset of TMD symptoms is related to the initiation of HRT, which has no answer yet.
Clinical studies suggest that estradiol level changes may influence TMD treatment outcome12. To make TMD treatment as effective as possible, it is necessary to determine the best timing of treatment, which can benefit a huge number of female TMDs patients. As shown in Fig. 2, estradiol level and TMD pain both regularly fluctuate in every menstrual cycle. We assume a possible biopsychosocial mechanism that menstrual cyclic fluctuation of estradiol level may underlie best timing of TMD treatment. If we can confirm the correlation of different menstrual cycle phases during which TMD treatments are conducted and the treatments outcomes, the certain phase of menstrual cycle may be a good indication for TMD treatments, which may help clinicians in case selection and optimize treatment outcome.
The correlation can be determined via retrospective and prospective clinical studies. Saliva estradiol level assessment, which is cheaper, more convenient, totally non-invasive and partly reflecting serum levels, shows great potential to be the best alternative to track daily estradiol levels7. After finding out the best timing of the TMD treatments, molecular analysis of the TMJ synovial fluid， MRI of TMJ structures and some other evaluations may help explain the biopsychosocial mechanisms under the best timing and assist to narrow treatment targets, making the treatments more efficient and targeted.
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