Association between estrogen levels and temporomandibular disorders: a systematic literature review

Introduction

The term ‘temporomandibular disorder’ (TMD) embraces a number of clinical problems that involve the masticatory muscles and/or temporomandibular joints (TMJ) and associated structures. Temporomandibular disorder is the second most prevalent source of orofacial pain [1]. A number of studies have also identified genetic (e.g., COMT, SCN1A) and inflammatory criteria of (e.g., free radicals and cytokines) risk factors that contribute to the development of TMD [2-4]. According to epidemiological data, there is a strong predilection of TMD for women [5]. The prevalence is the highest during reproductive years and the lowest before puberty and after menopause. The male to female ratio of TMD patients is estimated at around 1 : 3 [6]. It is suspected that this predisposition is related to female reproductive hormones, especially estrogen. The effects of estrogen are mediated by binding to its receptors. Three types of estrogen receptors are distinguished, two nuclear – alpha (ER) and beta (ER), and one plasmatic – G-protein coupled estrogen receptor 1 (GPER1) [7]. Since 1986, when estrogen receptors were recognized for the first time in baboon temporomandibular joints, the potential influence of estrogen on TMD has become a matter of interest to many researchers. It is now known that estrogen receptors are localized in many structures of the stomatognathic organ, particularly TMJ tissues, such as chondroid tissue of condyle and retrodiscal tissues [8]. Studies on the effect of estrogen deficiency performed on animal models revealed that estrogen depletion causes structural changes in TMJ. These include an increase in TMJ cartilage thickness, a decrease in subchondral bone volume, flattening of condyles, osteophyte formation or even serial degenerative changes [9-14].
The effect of estrogen on the development, restitution and metabolism of the temporomandibular joint and associated structures is one of the possible mechanisms in which these hormones can influence the incidence of TMD. Another probable mechanism is the modulation of the pain regulative mechanisms by estrogen [15]. The presence of its receptors in tissues of both the peripheral and central nervous systems makes estrogen capable of modifying pain signaling [16, 17]. Estrogen receptors (ER, ER) are found in the dorsal root ganglion (DRG) as well as in the trigeminal nerve nucleus. The influence of estrogen on pain regulatory mechanisms seems to be very complex. Depending on the pain signaling type, estrogen may act as a pro- and anti-nociceptive. In physiological pain, estrogen seems to decrease pain while, in inflammatory pain, estrogen acts differently depending on the inflammation type. In acute inflammatory pain caused by formalin or ATP injection, estrogen has an anti-nociceptive effect. In the chronic inflammatory pain model with complete Freund’s adjuvant (CFA) or carrageen injection, the pro-nociceptive effect of this hormone is seen [18-21]. It is worth noting that blocking estrogen receptors  and  diminishes sex differences in both physiologic and acute inflammatory pain [22]. Recently, some estrogen related genetic factors predisposing to TMD have been discovered. ER gene polymorphism causes receptor overexpression which makes certain allele carriers more susceptible to the effects of estrogen by enhancing processes associated with ER receptor stimulation [23].
The aim of our study is to determine whether the hypothesis that estrogen levels are associated with temporomandibular disorders in humans can be confirmed or contradicted by available literature.

Material and methods

Material for our study consisted of publications identified by searches performed independently by two authors using the Medline/PubMed database, the Cochrane Collaboration database, and the Scopus database. Search strategy is illustrated on the flow-chart (Fig. 1). In order to identify relevant publications, a search using a combination of key words “estrogens” and “temporomandibular joint disorders” (according to Medical Subject Headings – MeSH) was performed.
For the first step of screening, one reviewer read the titles of all 96 papers retrieved from the searches and removed all duplicates and papers unavailable in full text, leaving 72 records. The second step of screening involved abstract reviewing. Full-text articles were obtained for all abstracts except for case reports, reviews, studies on animals, articles which were not addressed to estrogen levels or to our review question and those unavailable in English (Table I). After a manual search of references of identified studies, two more papers were included in our analysis. If after analyzing the full text, the eligibility of an article was still uncertain, the second reviewer undertook a full-text analysis of the article to determine its eligibility. There were no events of disagreement between the reviewers. After evaluation, nine studies were included in our review. All studies were based on the same subject – the influence of estrogen on TMD. How they were focused on different aspects of this issue will be discussed in detail. Aims, methods and material of the studies, as well as results and conclusions, are described in the data extraction tables (Table II-IV). The questions for scoring are based on the “Cochrane Handbook for Systematic Reviews of Interventions 4.2.6 Updated September 2006”, PRISMA 2009 Checklist, “Advice on how to write a systematic review. JM Wardlaw. 14th January 2010” and the quality assessment tool for diagnostic accuracy studies (QUADAS) recommended by the Cochrane Collaboration. Studies were scored according to questions shown in Table V. Each article was scored from 0 to 2 and the scores were tallied up. The methodology of each selected article was evaluated and information placed in Table VI. Scores 0-8 were rated as the poor value of evidence, whereas scores 9-11 and 12-14 were rated as a moderate and high value of evidence.

Results

Evaluated papers had many limitations, particularly the small sample size and lack of estrogen level assessment. Additionally, some papers did not contain correct exclusion criteria which could have influenced the outcome. Temporomandibular disorders diagnoses in most of the studies were based on clinical examination according to RDC (research diagnostic criteria)/TMD criteria. Papers not based on the RDC/TMD protocol were deemed unsatisfactory for our purposes since they limited the possibility for comparison between studies. Finally, as noted in Table VI, studies varied in the value of evidence. Two papers showed a high value of evidence [24, 25], three papers showed a moderate value of evidence [26-28]; and four papers demonstrated a poor value of evidence [5, 29-31].
The relationship between estrogen levels and TMD was noted in seven out of nine evaluated papers. The results of Nekora Azak et al. and Hatch et al. studies [29, 31], evaluating the relationship between hormone replacement therapy and prevalence of TMD signs and symptoms, did not reveal this relationship. Results from two reports [27, 28] suggest that the high estrogen level is associated with an increased prevalence of TMD. In addition, in one paper [32], it was observed that the use of exogenous estrogen also increases a risk of TMD. According to the studies by Landi et al., pathology of TMJ (group II and/or III RDC/TMD) is associated with high levels of estrogen in both males and females (luteal phase only) [27, 28]. Three papers [25, 27, 28] found a relationship between a low estrogen level and the increase in TMD pain, which seems to be in contrast with the results of other studies [30-32].
In considering the value of evidence and inconsistencies of results in the reviewed publications, we state that there is weak evidence to support the hypothesis that estrogen levels are associated with TMD.

Discussion

In the reviewed studies, only two did not reveal an association between estrogen levels and TMD [29, 31]. Both studies analyzed the effect of exogenous estrogens use on TMD and in our review obtained a poor value from scoring. These results stand in contrast to results of LeResche et al., where the use of exogenous estrogens was also analyzed [32]. Results of Nekora-Azak et al. study can be affected by the fact that time between menopause and introduction of hormone therapy was not considered in allocation to study groups [31]. It seems important because as animal studies show after estrogen depletion by ovariectomy, some TMJ structures can be affected by the lack of estrogen. In patients whose time after menopause was longer, structural abnormalities of TMJ could have developed. Therefore, it would be improper to place them in the same study group with patients with a shorter period between menopause and hormonal therapy. This could be one of the reasons why there were no significant differences between postmenopausal women using and those not using hormone replacement therapy.
Other reviewed papers showed that there is a relationship between estrogen and TMD, but their results are contradictory. Studies by Dao, LeResche, and Sherman showed that a high estrogen level reduced TMD pain [24-26, 30, 32]. The studies by Landi [27, 28] showed that painful TMD, namely RDC/TMD Axis I group II and/or III diagnosis, are associated with high estrogen levels. Based on the study by LeResche it is not possible to determine which subgroups of painful TMD are affected by estrogen due to the lack of sufficient data [32]. Therefore, we can only speculate that estrogen influences TMD pain processing differently than TMJ structures. It is worth noting that in this study it is thought that the increased prevalence of TMD in the studied group may be due to the fact that the study was conducted when hormone replacement therapy, in particular, estrogen replacement therapy, was administered primarily to women who had undergone a hysterectomy [33]. The surgery itself could also have an effect on the temporomandibular joint because endotracheal intubation can cause transient TMD pain [34]. That is why post-surgery patients should have been excluded from the study.
In the studies by Landi et al., where the association of estrogen levels and degenerative joint disease (group II and/or III RDC/TMD) was evaluated, the authors stated that a high estrogen level is associated with an increased prevalence of TMD, which finding can be confirmed by results of studies on animal models [27, 28]. Estrogen can be implied in the development of the degenerative joint disease because of its effect on matrix composition in TMJ fibrocartilage [35]. In studies where the influence of estrogen deficiency on TMJ was evaluated, it was found that lack of estrogen can also induce pathological changes in TMJ. Estrogen reduces sulfated proteoglycan synthesis of articular cartilage in an animal model [36]. It can also influence the synovial membrane through its effect on the collagen and protein content of the TMJ disc [37]. Collagen and elastin make up a great deal of the temporomandibular joint disc’s structure and are often found to be altered in the presence of TMD symptoms. The direct influence of sex hormones on changes in collagen and elastin synthesis is well established [38]. After ovariectomy, an increase in the soft tissue layer and a decrease in bone volume and density in the TMJ is observed [39]. Replacement with estrogen can restore most of the changed histomorphometric parameters of TMJ [14]. It is also interesting that ER receptor polymorphism is associated with the morphology of the face and jaw dimensions [40]. There is still insufficient evidence to support the hypothesis that endogenous and exogenous estrogen and estrogen receptor polymorphisms affect joint health in humans [41].
The decrease in TMD pain in pregnancy reported by LeResche et al. is thought to be associated with an increase in joint laxity in this period, but it is also highly probable that pain regulatory mechanisms may also be implicated, as a similar decrease in pain is seen in pregnant migraine patients [30]. Two reviewed papers [27, 28] found a relationship between a low estrogen level and an increase in TMD pain, which can be partly confirmed by the results of animal studies. As mentioned before, estrogen’s effect on pain signaling is very complex because estrogen can affect different pain mechanisms [21, 42]. Results suggesting that low estrogen increases pain can be confirmed by comparison with the results of animal studies on the effect of estrogen on physiological and acute inflammatory pain.
Estrogen acts as an anti-nociceptive, causing changes in the levels of neurotransmitters in DRG in physiologic pain – an increase in calcitonin gene-related peptide (CGRP) and a decrease in substance P, and, a decrease in the expression of P2X3 receptors in DRG and the trigeminal ganglion. Expression of anti-nociceptive neurotransmitters such as neuropeptide Y, galanin and ghrelin in the trigeminal ganglion changes in the course of the menstrual cycle increasing with estrogen levels. A correlation between high estrogen and decreased physiologic pain is seen. The estrogen-dependent decrease in pain was also observed in humans during menstruation and hormonal therapies [43-47]. On the other hand, estrogen can act as a pro-nociceptive in chronic inflammatory pain. In two reviewed studies [26, 30], patients with a suspected high level of estrogen suffered from myofascial pain, where there is no inflammatory component, so we can suspect that the studies revealed the effect of estrogen on physiological pain processing. It is worth noting that estrogen acting through its receptors, increases activity of N-methyl-D-aspartic acid (NMDA) receptors in DRG, causing release of pro-nociceptive neuropeptides such as substance P, CGRP and brain-derived neurotrophic factor (BDNF). These mechanisms are responsible for sex differences in temporal summation and development of central sensitization [48]. These mechanisms could be associated with chronic forms of TMD pain. In contrast to studies by Landi et al., Dao et al. showed that use of exogenous estrogen does not influence the mean pain intensity in myofascial TMD. However, the levels of pain in patients using oral contraceptives (OCs) are more constant than in non-users. While LeResche et al. did not find differences in the variability of pain between women taking oral contraceptives and normally cycling women [24]. They suggest that any discrepancies may be due to the fact that their subjects suffered from joint pain as well as myofascial pain. Alternately, a larger sample of the study could explain discrepancies. LeResche et al. further suggest that not only estrogen levels, but also rapid changes of hormone levels put women at a higher risk of experiencing pain. This opinion is also shared by other authors. The effect of estrogen depends on its level, time of exposition and rapid or cyclic changes [22, 49].
It is worth noting that other sex hormones can influence TMD pathophysiology and interfere with estrogen. The influence of estrogen on TMD seems to be multi-faceted and it may differently affect certain aspects of TMD. When taking into account that estrogen may be associated only with certain subgroups of TMD or differently affect them, mixed groups of TMD patients may be inappropriate for TMD pain studies and cause difficulties in interpretation of the outcomes. For instance, a combination of group I and II or group II and III (according to RDC/TMD) does not enable the evaluation of a clear association between estrogen and pain regulatory mechanisms. While most of the studies were based on animal models, only a few were performed on human populations. The latest research of Nekora-Azak et al. was published in 2008, which signalizes stagnation in this area of knowledge [31].

Conclusions

Results of reviewed studies were divergent and sometimes contradictory. Thus, we suggest consideration of the dual action of estrogen when planning future studies on its association with TMD.
In our opinion, when planning future studies on influence of estrogen on TMD, it is essential to use a standardized examination method of TMD to enable comparison of outcomes between the studies (e.g. RDC/TMD). Estrogen level assessment should always be provided in order to improve data reliability. When evaluating hormonal therapies, researchers should always indicate the type of therapy used. When creating study groups for explanatory studies, patients with mixed TMD diagnoses should not be included because estrogen has different effects on various components of TMD.

Disclosure

Authors report no conflict of interest.

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