==== Front J Funct Morphol Kinesiol J Funct Morphol Kinesiol jfmk Journal of Functional Morphology and Kinesiology 2411-5142 MDPI 10.3390/jfmk5020036 jfmk-05-00036 Article Craniomandibular Disorders in Pregnant Women: An Epidemiological Survey Fichera Grazia 1 https://orcid.org/0000-0001-6717-8899Polizzi Alessandro 1* https://orcid.org/0000-0002-3331-3914Scapellato Simone 12 Palazzo Giuseppe 1 Indelicato Francesco 1 1 Department of General Surgery and Surgical-Medical Specialties, University of Catania, 95124 Catania, Italy; graziafichera@hotmail.it (G.F.); simonescapellato@hotmail.com (S.S.); gpalazzo@unict.it (G.P.); indelicato@policlinico.unict.it (F.I.) 2 Department of Biomedical, Odontostomatological Sciences and of Morphological and Functional Images, University of Messina, 98125 Messina, Italy * Correspondence: alexpoli345@gmail.com 04 6 2020 6 2020 5 2 3606 4 2020 01 6 2020 © 2020 by the authors.2020Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).Temporomandibular joint (TMJ) disorder has been reported to be 1.5 to two times more common in women than men. Such a gender-based difference could be attributed to behavioral, hormonal, anatomical, and psychological characteristics. Physiological hormonal differences between genders could be one of the possible explanations for the higher incidence of temporomandibular disorder (TMD) in women. As the plasma level of certain female hormones increases during gestation, it could be assumed that there is a higher prevalence of dysfunctional signs and symptoms in pregnant women. We performed an epidemiological survey based on screening for TMD in a group of 108 pregnant women and found that 72% of young women reported significant signs of TMJ disorders, 9% of the young women reported mild signs of TMJ disorders, and 19% of the included subjects reported no signs or symptoms of TMD. The presence of estrogen receptors in the temporomandibular joint of female baboons could be the basis of an explanation for the increased prevalence of dysfunction in young women reported in the literature and the high feedback we have seen of joint noises in pregnant women. On the basis of the present findings, it could be assumed that gestation period could represent a risk factor for craniomandibular dysfunctions. temporomandibular jointpregnancytemporomandibular disordergrowthclinical trial ==== Body 1. Introduction Dysfunction of the masticatory system, including the temporomandibular joint (TMJ), muscular and dental system, and the supporting bones, is called temporomandibular disorder (TMD) [1]. Adults are more affected by TMD as compared with children in a range of between 40% and 70%, however, a relevant high incidence of TMD has been found among subjects in mixed dental dentition [1,2,3]. Ethnicity, age, geographical location, and time of assessment influence the prevalence, causes, and factors that affect TMD, as well as the signs and clinical symptoms [4,5,6,7]. According to previous findings, TMD is generally reported to be 1.5 to two times more common in women as compared with men, and this difference is attributed to behavioral, hormonal, anatomical, and psychological factors [8,9]. In general, women are more affected than men by craniomandibular dysfunctions with a ratio of 4 to 1 [10,11,12,13,14]. The prevalence of clicks, headaches, teeth tightening, hypomobility, difficulty in chewing, and neuromuscular symptoms has been shown to be significantly higher among young women (<30 years) [15,16,17,18,19,20]. Moreover, there was a significant correlation between the severity of symptoms and age among women, and a relative reduction in clinical symptoms with age in both sexes [10,11,12,13,15,16,21,22]. Previous evidence reported that estrogen receptors are localized in the TMJ tissues, such as chondroid tissue of condyle and retrodiscal tissues [6,17,18,23,24,25,26,27]. In this respect, the hormone, estrogen, could influence the incidence of TMD, and its levels can affect the development, restitution, and metabolism of the temporomandibular joint, bone, and associated structures [7,23,25,28,29,30,31,32,33,34]. Estrogen can be related to TMD by regulating the pain mechanisms in the expressions of TMD [35]. For example, receptors for estrogens were found in both the peripheral and central nervous systems which would suggest that estrogens are capable of modifying pain signaling [36]. Moreover, estrogen receptors (ERα, ERβ) were also reported in the dorsal root ganglion (DRG) and in the trigeminal nerve nucleus. Estrogen can act as a pro- and anti-nociceptive, depending on the pain signaling type. In physiological pain, estrogen decreases pain, whereas, in inflammatory pain, the effect of estrogen depends on the inflammation type. In acute inflammatory pain, estrogen has an anti-nociceptive effect. On the contrary, in chronic inflammatory pain, this hormone has been documented to have a pro-nociceptive effect due to the presence of its receptors in tissues of both the peripheral and central nervous systems [36,37,38,39]. Thus, physiological hormonal differences between males and females could be one of the possible explanations for the higher incidence of TMD in the female. Given that the plasma level of some female hormones increases during gestation, it could be postulated that there is a higher prevalence of dysfunctional signs and symptoms in pregnant women than the frequencies reported in the literature for the same sex. In this respect, the aim of the present study was to assess the presence of TMJ disorders in a cohort of pregnant women. 2. Materials and Methods 2.1. Study Design This study followed the Helsinki Declaration on medical protocols and ethics and received positive response by the Approval Board of the School of Dentistry, University of Catania (protocol no. 14/19). The study sample included subjects followed at a private practice specialized in gynecology and gynecologic radiology, in Catania (Italy), between January 2016 and March 2020. For the investigation, subjects were recruited base on the following inclusion criteria: subjects at the sixth month of pregnancy, aged between 19 and 35 years, and absence of severe dental pathology potentially affecting the perception of TMD and craniofacial dysmorphism. The anamnestic data were collected using yes-no questionnaires in compliance with the Helkimo anamnestic dysfunction index (Ai) (Figure 1) and subjects were classified as Ai 0 (no symptoms), I (mild symptoms), and II (severe symptoms) based on the information obtained. Screening for craniomandibular dysfunctions was done by following the Helkimo dysfunction index guidelines (Figure 2) [40,41,42]. All examinations were performed by the same expert, blinded gnathologist. In particular, clinical examination of masticatory apparatus was performed using the Helkimo clinical dysfunction index (Di), which is based on five domains each evaluating one of the following signs of TMJ dysfunction: limited TMJ mobility, limited TMJ function, jaw muscle pain to palpation, TMJ pain to palpation, and pain during mandibular movement. Jaw movements were evaluated in order to highlight the presence of any limitations. The temporomandibular joint was examined for the diagnosis of joint noise, taking into account possible deviations and deflections of the lower median line over three chewing cycles. Palpation of the chewing muscles and the temporomandibular joint was carried out, and the mandible excursions were examined to assess the presence of pain. Scores for each of the domains were based on the three-level scale of severity, i.e., 0 (no symptoms), 1 (mild symptoms), and 5 (acute symptoms) and were summed up to obtain a total dysfunction score ranging from 0 to 25 points, with a high score indicating a higher temporomandibular dysfunction. In order to obtain comparative assessment, data of the study group were matched with a control sample of female subjects living in the same geographic area who had been referred to the same gynecology clinic for routine controls. The recruitment of the control group was based on the same inclusion criteria as the study group except for the pregnancy status. 2.2. Power Sample Analysis A preliminary evaluation of sample size power was performed on 20 subjects (10 in the study group and 10 in the control group), the analysis suggested that 79 patients for each group were required to reach the 80% power to detect a mean difference of 7.2% [43] of incidence of clinically assessed joint click between study and control groups, with a confidence level of 95% and a beta error level of 20%. However, according to the inclusion criteria, it included 108 subjects in the study group and 90 subjects in the control group which increased the robustness of the data. 2.3. Statistical Analysis The Kolmogorov–Smirnov test was preliminarily performed to test the normality of the data. Since the data showed homogeneous variance, parametric tests were used to evaluate and compare measurements. For those subjects reporting positive values from the anamnestic index, data obtained from the dysfunction index were recorded on a specific spreadsheet. Datasets were analyzed using SPSS® version 24 Statistics software (IBM Corporation, 1 New Orchard Road, Armonk, New York, USA). The incidence of TMD was detected as percentage values within the sample size. Chi-square test coefficient was used to compare the distribution data obtained from the anamnestic and dysfunction forms between each group. The level of significance was set at p < 0.05. 3. Results One hundred and eight pregnant females (mean age 27.4 ± 3.8) were finally recruited to participate in the survey of the present investigation and 72% of young women reported significant signs of TMJ disorders. Thus, they were allocated to belong to the DII group (moderate dysfunctional) according to the anamnestic Helkimo index; 9% of young women reported slight signs of TMJ disorders and were allocated to the DI group (slightly dysfunctional). Consequently, 19% of the included subjects did not report signs or symptoms of TMD and were allocated to the the D0 group. Ninety female subjects were enrolled in the control group (mean age 26.2 ± 4.5) and 41% of young women reported significant signs of TMJ disorders. Thus, they were allocated to the DII group (moderate dysfunctional) according to the anamnestic Helkimo index; 11% of young women reported slight signs of TMJ disorders and were allocated to the DI group (slightly dysfunctional). Consequently, 48% of the included subjects did not report signs or symptoms of TMD and were allocated to the D0 group. Table 1 shows the distribution of data obtained with the anamnestic Helkimo index and assessed using the Chi-square test (p < 0.05). Table 2 shows the distribution of data obtained with the Helkimo dysfunction index and assessed using the Chi-square test. In both groups, all subjects in the DII group reported TMJ click, whereas subjects in the DI group reported muscular pain (p < 0.05). 4. Discussion From the literature review, it can be seen that the incidence of craniomandibular dysfunctions, except for a few exceptions, shows no gender differences in school-age patients, whereas, for adults, prevalence of signs is observed dysfunctional in the female sex. It can be hypothesized with great certainty that, after adolescence, physiological, psychological, and morphological differences are taking over. With regard to physiological differences, in addition to the effects of hormonal regulation of metabolic activities, women are much more susceptible to pulp stimulation pain. Men tolerate deep pain much more readily than women, and pain tolerance in general and the threshold of skin pain are lower in women than in men [44,45,46]. Patients with craniomandibular dysfunction, and especially women, similar to periodontitis [28,47,48,49,50,51,52,53] have a lower pain tolerance than the control group [42,54], and a lower pain threshold [55,56]. In addition, emotional stress increases pain by accelerating activities in the neural system, which is, in turn, stimulated by harmful impulses. Anxiety, depression, anger, induce autonomous, visceral and skeletal activities, and the interactions between these biological systems are illustrated in the pain-anxiety-tension cycle proposed by some authors to explain some forms of acute pain, and often observed in pathologies affecting the skeletal-muscular system [57,58,59,60,61]. Pain causes anxiety, which induces both prolonged muscle spasms at pain sites and trigger points, as well as vasoconstriction, ischemia, and release of pain-mediating substances. Similarly, depression has a profound effect on peripheral symptoms, interacting through the thalamus and hypothalamus. Catecolo-methyltransferases (COMT) is an important enzyme that inactivates neurotransmitters and regulators of the central and peripheral nervous system. Patients with craniomandibular dysfunction have a low erythrocyte level of COMT as compared with control subjects, and therefore appear to be predisposed to depression. With a few exceptions, women suffer much more than men from depression and this psychophysiological difference could explain the results of his studies [62]. Depression is easier to match among young women and usually decreases with age; however, symptoms of depression are less common among young males [24]. This could justify the significant correlation between the severity of symptoms and age for women, and the decrease in the number of symptoms for both sexes previously found [21,63,64]. The authors also saw that young women have a high incidence of clicks, headaches, teeth tightening, hypomobility, difficulty in chewing, and neuromuscular symptoms. This could be explained by the fact that women are much more susceptible to tissue alterations and, in particular, to those of the condyle-disc complex [24,64]. The teeth tightening found in young women would represent a functional expression of specificity of response originating from the activity of large muscles and high residual muscle tension. Chronic muscle hyperactivity with the maintenance of high residual muscle tension could initiate numerous pathophysiological mechanisms [49,65,66,67]. It must also be said that women from puberty to menopause have a hormonal structure that varies cyclically in a physiological way. During pregnancy, this situation changes further, as, after fertilization, the lute body remains active, magnifying large amounts of estrogen and progesterone. After the third month, it is no longer essential for the continuation of pregnancy, as its endocrine function changes to the placenta, so it regresses. The placenta, as well as an organ responsible for the exchanges between the fetus and the mother, is also an endocrine organ, which separates at least four types of hormones, i.e., a gonadotropin, estrogen, progesterone, and relaxin [67]. The effects of sex hormones in target tissues are varied and very significant. They stimulate collagen and protein synthesis, increased vasal reactivity, alteration of endothelial permeability, and prostaglandins synthesis [67,68,69,70]. They also have an effect on the immune system, having a role in antibody formation and in stem cell differentiation and proliferation. They inhibit leucocyte proliferation in rats and, in humans, suppress the transformation of lymphocytes. Estrogens also tend to increase the immune response, as opposed to androgens [71]. The presence of estrogen receptors in the temporomandibular joint of female baboons [16,71] could be the basis of an explanation for the higher prevalence of the dysfunction in young women reported in the literature [72,73,74,75,76,77,78,79,80,81,82,83], and the high feedback we have noted of joint noises in pregnant women. Relaxin, which is mainly found in serum and mammalian tissues, especially during pregnancy, has a series of actions that together promote gestation and prepare the female reproductive apparatus for childbirth. The connective tissue of pubic symphyses causes the transformation from cartilage to the more fluid and flexible with ligament formation between the two pubic bones. They increase collagen texture and extensibility [83,84,85] and dilate and makes the cervix softer. On the basis of previous evidence confirming the prevalence of TMD in female [24,26,72], our findings would suggest that pregnancy can be more susceptible from TMD and that gestation is a predisposing factor for craniomandibular dysfunctions [58,59,60,61,62,63]. The hypothesis that relaxin, reaching high levels during pregnancy, affects the tenderness of joint tissues, including the TMJ [74,75], could explain the high incidence of clicks in the pregnant young women found in the present study. Further studies, based on this assumption, are warmly required in order to provide new information on the potential effects of hormone levels on the development of TMD. The limitation of this study is the absence of a quantitative distinction between physical assessment and psychological assessment of TMD and further studies should include this comparative evaluation in the methodology. 5. Conclusions Female subjects in pregnancy status could be more susceptible to TMD due to a physiological increment of estrogenic hormones levels. However, further studies are needed to better understand the role of TMD during pregnancy. Author Contributions G.F. has drafted the work and performed segmentations; A.P. and S.S. has performed the experimental procedures; G.P. and F.I. has validated the results. All authors have read and agreed to the published version of the manuscript. Funding This research received no external funding. Conflicts of Interest The authors declare no conflict of interest. Figure 1 Example of the anamnestic Helkimo index. Figure 2 Example of the Helkimo clinical dysfunction index questionnaire filled out by one included patient. jfmk-05-00036-t001_Table 1Table 1 Data distribution from the anamnestic form (Helkimo’s index). Significance set at p < 0.05 according to the Chi-Square test. TMJ Disfunction Positive Negative Total Study Group Observed 87 21 108 p < 0.05 Percentage (%) 81 19 100 Study Group Observed 47 43 90 Percentage (%) 52 48 100 jfmk-05-00036-t002_Table 2Table 2 Data distribution from the anamnestic form (Helkimo’s index). Significance set at p < 0.05 according to the Chi-Square test. Articular Signs Muscular Pain Total Study Group Observed 87 0 87 p < 0.05 Percentage (%) 100 0 100 Study Group Observed 37 10 47 Percentage (%) 79 21 100 ==== Refs References 1. Furquim B.D. Flamengui L.M. Conti P.C. TMD and chronic pain: A current view Dent. Press J. Orthod. 2015 20 127 133 10.1590/2176-9451.20.1.127-133.sar 25741834 2. Castelo P.M. Gaviao M.B. Pereira L.J. Bonjardim L.R. Relationship between oral parafunctional/nutritive sucking habits and temporomandibular joint dysfunction in primary dentition Int. J. Paediatr. Dent. 2005 15 29 36 10.1111/j.1365-263X.2005.00608.x 15663442 3. Mackie A. Lyons K. The role of occlusion in temporomandibular disorders--a review of the literature N. Z. Dent. J. 2008 104 54 59 18672830 4. Okeson J.P. Management of Temporomandibular Disorder and Occlusion -E -Book Elsevier Health Sciences Amsterdam, The Netherlands 2008 1 333 10.14219/jada.archive.2013.0022 5. Chisnoiu A.M. Chisnoiu R. Moldovan M. Lascu L.M. Picos A.M. Etiological factors associated with temporomandibular joint disorder - Study on animal model Rom. J. Morphol. Embryol. 2016 57 185 189 27151706 6. Mortazavi S.H. Motamedi M.H. Navi F. Pourshahab M. Bayanzadeh S.M. Hajmiragha H. Isapour M. Outcomes of management of early temporomandibular joint disorders: How effective is nonsurgical therapy in the long-term? Natl. J. Maxillofac. Surg. 2010 1 108 111 22442579 7. Lo Giudice A. Rustico L. Caprioglio A. Migliorati M. Nucera R. Evaluation of condylar cortical bone thickness in patient groups with different vertical facial dimensions using cone-beam computed tomography Odontology 2020 10.1007/s10266-020-00510-2 8. Lo Giudice A. Brewer I. Leonardi R. Roberts N. Bagnato G. Pain threshold and temporomandibular function in systemic sclerosis: Comparison with psoriatic arthritis Clin. Rheumatol. 2018 37 1861 1867 10.1007/s10067-018-4028-z 29445986 9. Ferendiuk E. Zajdel K. Pihut M. Incidence of otolaryngological symptoms in patients with temporomandibular joint dysfunctions Biomed Res. Int. 2014 2014 824684 10.1155/2014/824684 25050373 10. Velly A.M. Schiffman E.L. Rindal D.B. Cunha-Cruz J. Gilbert G.H. Lehmann M. Horowitz A. Fricton J. The feasibility of a clinical trial of pain related to temporomandibular muscle and joint disorders: The results of a survey from the Collaboration on Networked Dental and Oral Research dental practice-based research networks J. Am. Dent. Assoc. 2013 144 e1 e10 10.14219/jada.archive.2013.0022 23283934 11. Leonardi R. Loreto C. Talic N. Caltabiano R. Musumeci G. Immunolocalization of lubricin in the rat periodontal ligament during experimental tooth movement Acta Histochem. 2012 114 700 704 10.1016/j.acthis.2011.12.005 22209395 12. Loreto C. Leonardi R. Musumeci G. Pannone G. Castorina S. An ex vivo study on immunohistochemical localization of MMP-7 and MMP-9 in temporomandibular joint discs with internal derangement Eur. J. Histochem. 2013 57 e12 10.4081/ejh.2013.e12 23807291 13. Musumeci G. Castrogiovanni P. Leonardi R. Trovato F.M. Szychlinska A. Di Giunta A. Loreto C. Castorina S. New perspectives for articular cartilage repair treatment through tissue engineering: A contemporary review World J. Orthop. 2014 18 80 88 10.5312/wjo.v5.i2.80 14. Musumeci G. Trovato F.M. Loreto C. Leonardi R. Szychlinska M.A. Castorina S. Mobasheri A. Lubricin expression in human osteoarthritic knee meniscus and synovial fluid: A morphological, immunohistochemical and biochemical study Acta Histochem. 2014 116 965 972 10.1016/j.acthis.2014.03.011 24932985 15. Cavuoti S. Matarese G. Isola G. Abdolreza J. Femiano F. Perillo L. Combined orthodontic-surgical management of a transmigrated mandibular canine Angle Orthod. 2016 86 681 691 10.2319/050615-309.1 26502299 16. Leonardi R. Perrotta R.E. Almeida L.E. Loreto C. Musumeci G. Lubricin in synovial fluid of mild and severe temporomandibular joint internal derangements Med. Oral Patol. Oral Cir. Bucal. 2016 21 e793 e799 10.4317/medoral.21145 27694778 17. Szychlinska M.A. Trovato F.M. Di Rosa M. Malaguarnera L. Puzzo L. Leonardi R. Castrogiovanni P. Musumeci G. Co-Expression and Co-Localization of Cartilage Glycoproteins CHI3L1 and Lubricin in Osteoarthritic Cartilage: Morphological, Immunohistochemical and Gene Expression Profiles Int. J. Mol. Sci. 2016 17 359 10.3390/ijms17030359 26978347 18. Loreto C. Chiarenza G.P. Musumeci G. Castrogiovanni P. Imbesi R. Ruggeri A. Almeida L.E. Leonardi R. Leonardi R. ADAM10 localization in temporomandibular joint disk with internal derangement: An ex vivo immunohistochemical study Acta Histochem. 2016 118 293 298 10.1016/j.acthis.2016.02.006 26947053 19. Leonardi R. Perrotta R.E. Loreto C. Musumeci G. Crimi S. Dos Santos J.N. Rusu M.C. Bufo P. Barbato E. Pannone G. Toll-like Receptor 4 Expression in the Epithelium of Inflammatory Periapical Lesions. An Immunohistochemical Study Eur. J. Histochem. 2015 59 2547 10.4081/ejh.2015.2547 26708181 20. Leonardi R. Lo Giudice A. Rugeri M. Muraglie S. Cordasco G. Barbato E. Three-dimensional evaluation on digital casts of maxillary palatal size and morphology in patients with functional posterior crossbite Eur. J. Orthod. 2018 40 556 562 10.1093/ejo/cjx103 29474543 21. Lo Giudice A. Fastuca R. Portelli M. Militi A. Bellocchio M. Spinuzza P. Briguglio F. Caprioglio A. Nucera R. Effects of rapid vs slow maxillary expansion on nasal cavity dimensions in growing subjects: A methodological and reproducibility study Eur. J. Paediatr. Dent. 2017 18 299 304 10.23804/ejpd.2017.18.04.07 29380616 22. Koidis P.T. Zarifi A. Grigoriadou E. Garefis P. Effect of age and sex on craniomandibular disorders J. Prosthet. Dent. 1993 69 93 101 10.1016/0022-3913(93)90247-L 8455176 23. Leonardi R. Loreto C. Barbato E. Polimeni A. Caltabiano R. Lo Muzio L. A histochemical survey of the human temporomandibular joint disc of patients with internal derangement without reduction J. Craniofac. Surg. 2007 18 1429 1433 10.1097/scs.0b013e31814fb72a 17993895 24. Cutroneo G. Piancino M.G. Ramieri G. Bracco P. Vita G. Isola G. Vermiglio G. Favaloro A. Anastasi G.P. Trimarchi F. Expression of muscle-specific integrins in masseter muscle fibers during malocclusion disease Int. J. Mol. Med. 2012 30 235 242 10.3892/ijmm.2012.986 22552408 25. Almeida L.E. Pierce S. Zacharias J. Cullinan W. Noronha L. Olandoski M. Tramontina V. Loreto C. Leonardi R. Immunohistochemical analysis of IL-1 beta in the discs of patients with temporomandibular joint dysfunction Cranio 2017 35 233 237 10.1080/08869634.2016.1207911 27415587 26. Leonardi R. Muraglie S. Crimi S. Pirroni M. Musumeci G. Perrotta R. Morphology of palatally displaced canines and adjacent teeth, a 3-D evaluation from cone-beam computed tomographic images BMC Oral Health 2018 18 156 10.1186/s12903-018-0617-0 30180892 27. Almeida L.E. Hresko K. Sorenson A. Butcher S. Tayebi L. Leonardi R. Loreto C. Bosio J. Camejo F. Doetzer A. Immunohistochemical expression of TLR-4 in temporomandibular joint dysfunction Cranio 2019 37 323 328 10.1080/08869634.2018.1446770 29609510 28. Di Rosa M. Szychlinska M.A. Tibullo D. Malaguarnera L. Musumeci G. Expression of CHI3L1 and CHIT1 in osteoarthritic rat cartilage model. A morphological study Eur. J. Histochem. 2014 58 2423 10.4081/ejh.2014.2423 25308850 29. Isola G. Polizzi A. Santonocito S. Alibrandi A. Ferlito S. Expression of salivary and serum malondialdehyde and lipid profile of patients with periodontitis and coronary heart disease Int. J. Mol. Sci. 2019 20 6061 10.3390/ijms20236061 30. Lo Giudice A. Ortensi L. Farronato M. Lucchese A. Lo Castro A. Isola G. The step further smile virtual planning: Milled versus prototyped mock-ups for the evaluation of the designed smile characteristics. A comparative study in the aesthetic area using surface-to-surface matching technique BMC Oral Health 2020 20 166 32503512 31. Isola G. Alibrandi A. Pedulla E. Grassia V. Ferlito S. Perillo L. Rapisarda E. Analysis of the effectiveness of lornoxicam and flurbiprofen on management of pain and sequelae following third molar surgery: A randomized, controlled, clinical trial J. Clin. Med. 2019 8 325 10.3390/jcm8030325 32. Isola G. Matarese G. Alibrandi A. Dalessandri D. Migliorati M. Pedulla E. Rapisarda E. Comparison of effectiveness of etoricoxib and diclofenac on pain and perioperative sequelae after surgical avulsion of mandibular third molars: A randomized, controlled, clinical trial Clin. J. Pain 2019 35 908 915 10.1097/AJP.0000000000000748 31368908 33. Isola G. Perillo L. Migliorati M. Matarese M. Dalessandri D. Grassia V. Alibrandi A. Matarese G. The impact of temporomandibular joint arthritis on functional disability and global health in patients with juvenile idiopathic arthritis Eur. J. Orthod. 2019 41 117 124 10.1093/ejo/cjy034 29878100 34. Loreto C. Filetti V. Almeida L.E. La Rosa G.R.M. Leonardi R. Grippaudo C. Lo Giudice A. MMP-7 and MMP-9 are overexpressed in the synovial tissue from severe temporomandibular joint dysfunction Eur. J. Histochem. 2020 64 10.4081/ejh.2020.3113 32312031 35. Ferlazzo N. Curro M. Zinellu A. Caccamo D. Isola G. Ventura V. Carru C. Matarese G. Ientile R. Influence of MTHFR genetic background on p16 and MGMT methylation in oral squamous cell cancer Int. J. Mol. Sci. 2017 18 724 10.3390/ijms18040724 28353639 36. Puri J. Hutchins B. Bellinger L.L. Kramer P.R. Estrogen and inflammation modulate estrogen receptor alpha expression in specific tissues of the temporomandibular joint Reprod. Biol. Endocrinol. 2009 7 155 10.1186/1477-7827-7-155 20043825 37. Papka R.E. Srinivasan B. Miller K.E. Hayashi S. Localization of estrogen receptor protein and estrogen receptor messenger RNA in peripheral autonomic and sensory neurons Neuroscience 1997 79 1153 1163 10.1016/S0306-4522(97)00076-6 9219974 38. Wang J. Chao Y. Wan Q. Zhu Z. The possible role of estrogen in the incidence of temporomandibular disorders Med. Hypotheses 2008 71 564 567 10.1016/j.mehy.2008.05.011 18597950 39. Bettini E. Pollio G. Santagati S. Maggi A. Estrogen receptor in rat brain: Presence in the hippocampal formation Neuroendocrinology 1992 56 502 508 10.1159/000126267 1475009 40. Castrogiovanni P. Trovato F.M. Szychlinska M.A. Nsir H. Imbesi R. Musumeci G. The importance of physical activity in osteoporosis. From the molecular pathways to the clinical evidence Histol. Histopathol. 2016 31 1183 1194 10.14670/hh-11-793 27311988 41. Helkimo M. Studies on function and dysfunction of the masticatory system. 3. Analyses of anamnestic and clinical recordings of dysfunction with the aid of indices Swed. Dent. J. 1974 67 165 181 42. Lo Giudice A. Nucera R. Leonardi R. Paiusco A. Baldoni M. Caccianiga G. A comparative assessment of the efficiency of orthodontic treatment with and without photobiomodulation during mandibular decrowding in young subjects: A single-center, single-blind randomized controlled trial Photobiomodul. Photomed. Laser Surg. 2020 10.1089/photob.2019.4747 31944878 43. Lo Giudice A. Nucera R. Perillo L. Paiusco A. Caccianiga G. Is Low-level laser therapy an effective method to alleviate pain induced by active orthodontic alignment archwire? A Randomized clinical trial J. Evid. Based Dent. Pract. 2019 19 71 78 10.1016/j.jebdp.2018.11.001 30926104 44. Mayoral V.A. Espinosa I.A. Montiel A.J. Association between signs and symptoms of temporomandibular disorders and pregnancy (case control study) Acta Odontol. Latinoam. 2013 26 3 7 24294817 45. Woodrow K.M. Friedman G.D. Siegelaub A.B. Collen M.F. Pain tolerance: Differences according to age, sex and race Psychosom. Med. 1972 34 548 556 10.1097/00006842-197211000-00007 4644663 46. Procacci P. Zoppi M. Maresca M. Romano S. Studies on the pain threshold in man Adv. Neurol. 1974 4 107 113 47. Perillo L. Isola G. Esercizio D. Iovane M. Triolo G. Matarese G. Differences in craniofacial characteristics in Southern Italian children from Naples: A retrospective study by cephalometric analysis Eur. J. Paediatr. Dent. 2013 14 195 198 24295003 48. Isola G. Alibrandi A. Rapisarda E. Matarese G. Williams R.C. Leonardi R. Association of vitamin D in patients with periodontitis: A cross-sectional study J. Periodontal Res. 2020 10.1111/jre.12746 49. Isola G. Giudice A.L. Polizzi A. Alibrandi A. Patini R. Ferlito S. Periodontitis and tooth loss have negative systemic impact on circulating progenitor cell levels: A Clinical study Genes 2019 10 1022 10.3390/genes10121022 50. Isola G. Matarese G. Ramaglia L. Pedulla E. Rapisarda E. Iorio-Siciliano V. Association between periodontitis and glycosylated haemoglobin before diabetes onset: A cross-sectional study Clin. Oral Investig. 2019 10.1007/s00784-019-03143-0 51. Isola G. Polizzi A. Alibrandi A. Indelicato F. Ferlito S. Analysis of Endothelin-1 Concentrations in individuals with periodontitis Sci. Rep. 2020 10 1652 10.1038/s41598-020-58585-4 32015361 52. Isola G. Polizzi A. Muraglie S. Leonardi R. Lo Giudice A. Assessment of Vitamin C and Antioxidant profiles in saliva and serum in patients with periodontitis and ischemic heart disease Nutrients 2019 11 2956 10.3390/nu11122956 31817129 53. Curro M. Matarese G. Isola G. Caccamo D. Ventura V.P. Cornelius C. Lentini M. Cordasco G. Ientile R. Differential expression of transglutaminase genes in patients with chronic periodontitis Oral Dis. 2014 20 616 623 10.1111/odi.12180 24112124 54. Briguglio F. Briguglio E. Briguglio R. Cafiero C. Isola G. Treatment of infrabony periodontal defects using a resorbable biopolymer of hyaluronic acid: A randomized clinical trial Quintessence Int. 2013 44 231 240 10.3290/j.qi.a29054 23444204 55. Lupton D.E. Psychological aspects of temporomandibular joint dysfunction J. Am. Dent. Assoc. 1969 79 131 136 10.14219/jada.archive.1969.0235 5254542 56. Molin C. Schalling D. Edman G. Psychological studies of patients with mandibular pain dysfunction syndrome. 1. Personality traits in patients and controls Sven. Tandlak. Tidskr. 1973 66 1 13 4510880 57. Matarese G. Curro M. Isola G. Caccamo D. Vecchio M. Giunta M.L. Ramaglia L. Cordasco G. Williams R.C. Ientile R. Transglutaminase 2 up-regulation is associated with RANKL/OPG pathway in cultured HPDL cells and THP-1-differentiated macrophages Amino Acids 2015 47 2447 2455 10.1007/s00726-015-2039-5 26133738 58. Reiter S. Eli I. Mahameed M. Emodi-Perlman A. Friedman-Rubin P. Reiter M.A. Winocur E. Pain catastrophizing and pain persistence in temporomandibular disorder patients J. Oral Facial Pain Headache 2018 32 309 320 10.11607/ofph.1968 29697720 59. Musumeci G. Magro G. Cardile V. Coco M. Marzagalli R. Castrogiovanni P. Imbesi R. Graziano A.C. Barone F. Di Rosa M. Characterization of matrix metalloproteinase-2 and -9, ADAM-10 and N-cadherin expression in human glioblastoma multiforme Cell Tissue Res. 2015 362 45 60 10.1007/s00441-015-2197-5 25948484 60. Piancino M.G. Isola G. Cannavale R. Cutroneo G. Vermiglio G. Bracco P. Anastasi G.P. From periodontal mechanoreceptors to chewing motor control: A systematic review Arch. Oral Biol. 2017 78 109 121 10.1016/j.archoralbio.2017.02.010 28226300 61. Matarese G. Isola G. Anastasi G.P. Favaloro A. Milardi D. Vermiglio G. Vita G. Cordasco G. Cutroneo G. Immunohistochemical analysis of TGF-beta1 and VEGF in gingival and periodontal tissues: A role of these biomarkers in the pathogenesis of scleroderma and periodontal disease Int. J. Mol. Med. 2012 30 502 508 10.3892/ijmm.2012.1024 22692760 62. Lo Giudice A. Caccianiga G. Crimi S. Cavallini C. Leonardi R. Frequency and type of ponticulus posticus in a longitudinal sample of nonorthodontically treated patients: Relationship with gender, age, skeletal maturity, and skeletal malocclusion Oral Surg. Oral Med. Oral Pathol. Oral Radiol. 2018 126 291 297 10.1016/j.oooo.2018.05.001 29937361 63. Sassarini D.J. Depression in midlife women Maturitas 2016 94 149 154 10.1016/j.maturitas.2016.09.004 27823736 64. Iwasaki L.R. Gonzalez Y.M. Liu Y. Liu H. Markova M. Gallo L.M. Nickel J.C. TMJ energy densities in healthy men and women Osteoarthr. Cartil. 2017 25 846 849 10.1016/j.joca.2016.12.027 28064032 65. Huhtela O.S. Näpänkangas R. Joensuu T. Raustia A. Kunttu K. Sipilä K. Self-Reported Bruxism and symptoms of temporomandibular disorders in Finnish University students J. Oral Facial Pain Headache 2016 30 311 317 10.11607/ofph.1674 27792798 66. Isola G. Matarese M. Briguglio F. Grassia V. Picciolo G. Fiorillo L. Matarese G. Eectiveness of Low-Level Laser Therapy during Tooth Movement: A Randomized Clinical Trial Materials 2019 12 2187 10.3390/ma12132187 67. Vannuccini S. Bocchi C. Severi F.M. Challis J.R. Petraglia F. Endocrinology of human parturition Ann. D’endocrinologie 2016 77 105 113 10.1016/j.ando.2016.04.025 68. Isola G. Matarese M. Ramaglia L. Cicciu M. Matarese G. Evaluation of the efficacy of celecoxib and ibuprofen on postoperative pain, swelling, and mouth opening after surgical removal of impacted third molars: A randomized, controlled clinical trial Int. J. Oral Maxillofac. Surg. 2019 48 1348 1354 10.1016/j.ijom.2019.02.006 30853212 69. Goh W.A. Zalud I. Placenta accreta: Diagnosis, management and the molecular biology of the morbidly adherent placenta J. Matern. Fetal Neonatal Med. 2016 29 1795 1800 10.3109/14767058.2015.1064103 26135782 70. Matarese G. Isola G. Ramaglia L. Dalessandri D. Lucchese A. Alibrandi A. Fabiano F. Cordasco G. Periodontal biotype: Characteristic, prevalence and dimensions related to dental malocclusion Minerva Stomatol. 2016 65 231 238 27035270 71. Cannavale R. Matarese G. Isola G. Grassia V. Perillo L. Early treatment of an ectopic premolar to prevent molar-premolar transposition Am. J. Orthod. Dentofac. Orthop. 2013 143 559 569 10.1016/j.ajodo.2012.03.035 72. Isola G. Matarese M. Ramaglia L. Iorio-Siciliano V. Cordasco G. Matarese G. Efficacy of a drug composed of herbal extracts on postoperative discomfort after surgical removal of impacted mandibular third molar: A randomized, triple-blind, controlled clinical trial Clin. Oral Investig. 2019 23 2443 2453 10.1007/s00784-018-2690-9 30311061 73. Leonardi R. Almeida L.E. Trevilatto P.C. Loreto C. Occurrence and regional distribution of TRAIL and DR5 on temporomandibular joint discs: Comparison of disc derangement with and without reduction Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. 2010 109 244 251 10.1016/j.tripleo.2009.09.028 20123409 74. Matarese G. Isola G. Anastasi G.P. Cutroneo G. Favaloro A. Vita G. Cordasco G. Milardi D. Zizzari V.L. Tetè S. Transforming Growth Factor Beta 1 and Vascular Endothelial Growth Factor levels in the pathogenesis of periodontal disease Eur. J. Inflamm. 2013 11 479 488 10.1177/1721727X1301100217 75. Trenti A. Tedesco S. Boscaro C. Trevisi L. Bolego C. Cignarella A. Estrogen, Angiogenesis, immunity and cell metabolism: Solving the puzzle Int. J. Mol. Sci. 2018 19 859 10.3390/ijms19030859 76. Isola G. Anastasi G.P. Matarese G. Williams R.C. Cutroneo G. Bracco P. Piancino M.G. Functional and molecular outcomes of the human masticatory muscles Oral Dis. 2018 24 1428 1441 10.1111/odi.12806 29156093 77. Lo Muzio L. Campisi G. Farina A. Rubini C. Pastore L. Giannone N. Colella G. Leonardi R. Carinci F. Effect of p63 expression on survival in oral squamous cell carcinoma Cancer Investig. 2007 25 464 469 10.1080/07357900701509387 17882659 78. Isola G. Alibrandi A. Curro M. Matarese M. Ricca S. Matarese G. Ientile R. Kocher T. Evaluation of salivary and serum ADMA levels in patients with periodontal and cardiovascular disease as subclinical marker of cardiovascular risk J. Periodontol. 2020 10.1002/JPER.19-0446 79. Aufdemorte T.B. Van Sickels J.E. Dolwick M.F. Sheridan P.J. Holt G.R. Aragon S.B. Gates G.A. Estrogen receptors in the temporomandibular joint of the baboon (Papio cynocephalus): An autoradiographic study Oral Surg. Oral Med. Oral Pathol. 1986 61 307 314 10.1016/0030-4220(86)90407-X 3458137 80. Perillo L. Padricelli G. Isola G. Femiano F. Chiodini P. Matarese G. Class II malocclusion division 1: A new classification method by cephalometric analysis Eur. J. Paediatr. Dent. 2012 13 192 196 22971255 81. Sorenson A. Hresko K. Butcher S. Pierce S. Tramontina V. Leonardi R. Loreto C. Bosio J. Almeida L.E. Expression of Interleukin-1 and temporomandibular disorder: Contemporary review of the literature Cranio 2018 36 268 272 10.1080/08869634.2017.1342890 28629271 82. Isola G. Polizzi A. Iorio-Siciliano V. Alibrandi A. Ramaglia L. Leonardi R. Effectiveness of a nutraceutical agent in the non-surgical periodontal therapy: A randomized, controlled clinical trial Clin. Oral Investig. 2020 in press 7 June 83. Nucera R. Militi A. Lo Giudice A. Longo V. Fastuca R. Caprioglio A. Cordasco G. Papadopoulos M.A. Skeletal and Dental Effectiveness of Treatment of Class II Malocclusion With Headgear: A Systematic Review and Meta-analysis J Evid. Based. Dent. Pract. 2018 18 41 58 10.1016/j.jebdp.2017.07.008 29478681 84. Fiorillo L. Spine and TMJ: A Pathophysiology report J. Funct. Morphol. Kinesiol. 2020 5 24 10.3390/jfmk5020024 85. Fiorillo L. Musumeci G. TMJ Dysfunction and Systemic Correlation J. Funct. Morphol. Kinesiol. 2020 5 20 10.3390/jfmk5010020