YBJOM-4312; No.

of Pages 5
ARTICLE IN PRESS
Available online at www.sciencedirect.com

British Journal of Oral and Maxillofacial Surgery xxx (2014) xxxxxx

Is the incidence of temporomandibular disorder increased in

polycystic ovary syndrome?
Sidika Sinem Soydan a, , Kagan Deniz b,1 , Sina Uckan a,2 , Asl Dogruk Unal c,3 ,
Neslihan Bascl Tutuncu d,4
a Department of Oral and Maxillofacial Surgery, 11. Sokak no:26 Bahcelievler, Ankara, Trkiye
b Department of Oral and Maxillofacial Surgery, Kskl Caddesi Oymac Sokak No:7 Altunizade, skdar Istanbul, Trkiye
c Endocrinology Department, Kskl Caddesi Oymac Sokak No:7, Altunizade, skdar Istanbul, Trkiye
d Endocrinology Department, Maresal Fevzi CakmakCaddesi, 10. Sokak no:45, Ankara, Turkey

Accepted 18 July 2014

Abstract

The prevalence of temporomandibular disorders is higher among women than men (ratio 3:1 -9:1). Polycystic ovary syndrome(PCOS) is the
most common endocrine disorder in women, which is characterised by chronic low-grade inflammation and excess of androgenic hormones
that lead to metabolic aberrations and ovarian dysfunction. Increased activities of various matrix metalloproteinases (particularly MMP-
2 and 9) in the serum of these patients has been reported, and it has been hypothesised that high activities of MMP may contribute to
loss of matrix and chronic inflammation of the fibrocartilage in temporomandibular disorders. Our aim was to evaluate the incidence of
temopormandibular dysfunction in women with PCOS compared with an age-matched, disease-free, control group. We studied 50 patients
with previously diagnosed PCOS and 50 volunteers who had normal menstrual cycles. We made a comprehensive clinical examination of the
temporomandibular joint (TMJ) and muscles of mastication in both groups and recorded the Visual Analogue Scores (VAS) for pain. There
were significant differences (p < 0.001) in the incidence of temporomandibular disorders (n = 43 (86%) in the PCOS group compared with
n = 12 24% in the control group), muscle tenderness(n = 32 (64%) in the PCOS group compared with n = 14 (28%) in the control group) and
pain in the TMJ (mean (SD) VAS 2.9 (2.61) compared with 0.3 (1.56). We confirm the higher incidence and severity of disorders of the TMJ
in patients with PCOS and suspect that chronic low-grade inflammation may play a part in the aetiology of the disease.
2014 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.

Keywords: Polycystic ovary syndrome; Temporomandibular joint disorder; Temporomandibular pain; Internal derangement; Matrix metalloproteinase

Corresponding author. Baskent University, Faculty of Dentistry, Depart-
ment of Oral and Maxillofacial Surgery, 11. Sokak no:26 Bahcelievler,
Ankara, Turkiye. Tel.: +903122151336; fax: +903122152962.
E-mail addresses: sdksoydan@yahoo.com (S.S. Soydan),
kgndeniz@yahoo.com (K. Deniz), suckan@yahoo.com (S. Uckan),
aslidogruk@yahoo.com (A.D. Unal), neslibascil@yahoo.com
(N.B. Tutuncu).
1 Tel.: +903122151336 Fax:+903122152962.
2 Tel.: +903122151336 Fax:+903122152962.
3 Tel: +903122122912 Fax: +903122154216.
4 Tel. +903122122912 Fax: +903122154216.
Introduction
The high female:male predominance of degenerative joint
diseases is well-known and well- documented,1 and the
potential effect of female sex hormones (oestrogen, proges-
terone, and relaxin) on the development of degenerative joint
disorders (together with the presence of the receptors of these
hormones in the cartilage of the temporomandibular joint
(TMJ)) have been described.25
The modulation of the remodelling activities of the extra-
cellular matrix by oestrogen, progesterone, and relaxin may

http://dx.doi.org/10.1016/j.bjoms.2014.07.100
0266-4356/ 2014 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.

Please cite this article in press as: Soydan SS, et al. Is the incidence of temporomandibular disorder increased in polycystic ovary syndrome?
Br J Oral Maxillofac Surg (2014), http://dx.doi.org/10.1016/j.bjoms.2014.07.100
YBJOM-4312; No. of Pages 5
ARTICLE IN PRESS
2 S.S. Soydan et al. / British Journal of Oral and Maxillofacial Surgery xxx (2014) xxxxxx
be one of the key mechanisms by which joints are predisposed
to degenerative changes. Oestrogen induces the expression
of matrix metalloproteinases (MMP) -3, -9, and -13 in vari-
ous cells, including fibrocartilaginous cells.6,7 Progesterone
produces a dose-dependent receptor-mediated decrease in
MMP-9 expression in trophoblasts.8 Relaxin increases the
turnover of fibrocartilage by the extracellular matrix, and
induces MMP-1 (collagenase-1) and -3 (stromelysin-1),
which are paralleled by loss of collagen and proteogly-
can from the fibrocartilaginous tissue of the disc of the
TMJ.9
Polycystic ovary syndrome (PCOS) is the most com-
mon endocrinopathy in women during the premenopausal
period, and is defined as clinical or biochemical (or both)
hyperandrogenism, hyperinsulinaemia, oligomenorrhoea or
anovulation, and polycystic ovaries, according to the Rotter-
dam criteria.10 In women, androgens are necessary to make
oestrogen, but women with PCOS have concentrations in the
high normal range. It is marked by a decrease in female sex
hormones and hormonal imbalance,11 and is a state of chronic
low-grade inflammation that might be responsible for the
development of ovarian dysfunction and metabolic abnor-
malities. The presence of certain cytokines in women with
the syndrome correlates with obesity and insulin resistance.12
Visceral adiposity is closely associated with insulin resistance
and may be attributed to dysfunctioning adipocytes and the
low-grade inflammation.13
A number of studies have shown that activities of MMP-2
and 9 are increased in the follicular fluid and serum of women
with PCOS.14 It may be speculated that increased activities
of these MMP may be one of the most important factors that
lead to the increased incidence of disorders of the TMJ among
women, particularly those with PCOS. To our knowledge
the incidence of such disorders has not yet been evaluated
in women with PCOS. Our aim therefore was to evaluate
the incidence of disorders of the TMJ in these women and
compare it with that in an age-matched, disease-free, control
group.
Patients and Methods
One hundred premenopausal women were included in this
prospective study. They were divided into 2 groups, PCOS
and control. The PCOS group consisted of 50 women who
had previously been diagnosed with PCOS at the endocrinol-
ogy department. The control group included 50 randomised
healthy women who had regular menstrual cycles and were
not taking any medication. The control group comprised
students and staff of Baskent University Faculty of Den-
tistry. All subjects gave informed consent to participate in the
study.
Exclusion criteria were: age over 40 years, known cardio-
vascular disease, thyroid disease, smoking, diabetes mellitus,
hypertension (blood pressure > 140/90 mm Hg), renal impair-
ment (serum creatinine > 150 mol/l), craniofacial syndromes,
Please cite this article in press as: Soydan SS, et al. Is the incidence of temporomandibular disorder increased in polycystic ovary syndrome?
Br J Oral Maxillofac Surg (2014), http://dx.doi.org/10.1016/j.bjoms.2014.07.100
history of head and neck trauma, isolated muscular tender-
ness, or previous operation on the TMJ.
The TMJ and the masticatory muscles were evaluated
by the same clinician. Patients described symptoms such as
preauricular pain, limited mouth opening, deviation or deflec-
tion during mouth opening, and joint sounds. All patients
were assessed using Okesons Muscle and temporomandibu-
lar joint examination and treatment outcome form.15 This
form records (for both TMJ) tenderness and pain in the
masseter, temporalis, lateral pterygoid, medial pterygoid,
sternocleidomastoid, trapezius, splenius capitis, and digastric
muscles, as well as maximum interincisal distance, restric-
tion of laterotrusive and protrusive movements, joint sounds,
deviation or deflection during mouth opening, and the visual
analogue score (VAS) for pain in the TMJ.
In addition, any history of the following disorders was
recorded: rheumatological disease, neurological disease,
familial disease, muscular disease, history of closed lock or
dislocation of the TMJ, bruxism, single-sided chewing, and
limited mouth opening. Objective assessment of muscular
tenderness, interincisal opening (mm), and VAS for pain in
the TMJ were also recorded. Magnetic resonance imaging
was used to support management where this was indicated,
but was not used for the purposes of this study.
Statistical analysis
With the aid of SPSS (version 18.0, SPSS Inc, Chicago), and
the independent two samples t test we compared the demo-
graphic data of the two groups. The proportional Z test was
used to compare the significance of differences in the inci-
dence of disorders of the TMJ, incidence of pain in the TMJ,
and muscular tenderness in the two groups. The results of the
VAS were compared using the non-parametric Mann Whitney
U test.
Results
The mean (SD) age of the PCOS group was 27 (6) and 26 (5)
in control group. There was no significant difference between
the mean ages of two groups (t (93) = -1.06, p = 0.29). The
mean (SD) interincisal distance in the PCOS group was 44
(7) mm and in the control group 46 (5) mm. There was also no
significant difference between interincisal opening in the 2
groups (t (64) = 1.617, p = 0.11). The incidence of disorders
of the TMJ did, however, differ significantly (p = = 0.001)
being higher in the PCOS group (86%) than the control group
(24%). There was also a significant difference in the incidence
of pain in the TMJ (p = 0.002) in the PCOS group (72%) com-
pared withthe control group (28%) and also in the severity of
the pain as measured by VAS (p = 0.001), being 2.9 (SD:2.61)
in the PCOS group and 0.3 (SD:1.56)in the control group
(Table 1). The incidence of tenderness in one or more muscle
was also significantly greater (p = 0.002) in the PCOS group
(64%) than in the control group (28%) (Fig. 1).
YBJOM-4312; No. of Pages 5
ARTICLE IN PRESS
S.S. Soydan et al. / British Journal of Oral and Maxillofacial Surgery xxx (2014) xxxxxx 3

Table 1 of closed lock: 0.03), deviation during mouth opening, (p

Comparison of the two groups. Data are number (%) of patients except where value of deviation during mouth opening:0.002) and unilat-
otherwise stated.
eral or bilateral clicking (p value of unilateral clicking: 0.048
Variable PCOS Control p value p value of bilateral clicking: 0.036) were significantly greater
group group
(n = 50) (n = 50)
in the PCOS group. The incidence of displacement of the disc
without reduction and deflection during mouth opening was
Incidence of 43 (86) 12 (24) 0.001
temperomandibular disease
similar.
Incidence of 36 (72) 14 (28) 0.001
temporomandibular pain
Mean (SD) VAS of pain in the 2.9 (2.61) 0.3 (1.56) 0.002 Discussion
temporomandibular joint
Incidence of muscular 32 (64) 14 (24) 0.002
tenderness This study has shown that the incidence and severity of dis-
orders of the TMJ is higher in patients with PCOS than in
PCOS = polycystic ovary syndrome. VAS = 0 (no pain) to 10 (worst pain controls. Our most important and new finding was that in
imaginable).
women with PCOS the incidence is 4 times that of controls.
Table 2 This may be related to an increase in MMP or proinflamatory
Incidence of symptoms of dysfunction of the temporomandibular joint in cytokines, but this requires more detailed study. We did not
the two groups. Data are number (%) of patients. study the incidence of PCOS in patients with disorders of the
Variable PCOS Control TMJ, but this may also be a topic for further study.
group group The high predominance of these disorders in women (ratio
(n = 50) (n = 50) between 3:1 and 9:1) is well-known.3 PCOS is the most
Unilateral internal derangement of disc 34 (68) 10 (20) common endocrine disorder in women with a prevalence
Bilateral internal derangement of disc 9 (18) 2 (4) between 6% and 15%. It is typically first identified during the
Displacement of disc with reduction 40 (80) 10 (20)
Displacement of disc without reduction 3 (6) 2 (4)
early reproductive years and its aetiology remains obscure.11
History of closed lock 9 (18) 0 Increase activity of MMP might be related to cardiovascu-
Deviation during mouth opening 34 (68) 10 (20) lar abnormalities, remodelling of the ovarian extracellular
Deflection during mouth opening 3 (6) 2 (4) matrix, formation of multiple cysts, and chronic anovulation
Unilateral clicking 16 (32) 11 (22) noted in women with PCOS.14 MMP are known acute phase
Bilateral clicking 8 (16) 0
reactants the activity of which increase during inflammation,
PCOS = polycystic ovary syndrome. and factors that stimulate their production such as oxidative
stress and the presence of inflammatory cytokines are also
Clinical signs are shown in Table 2. The incidence of present in PCOS.16
unilateral and bilateral internal derangements of the disc Female sex hormones (oestrogen, progesterone, and
(p:o.oo2 and p:0.036), displacement of the disc with reduc- relaxin) induce the expression of the various types of MMP
tion (p value of the difference of displacement of disc with in the fibrocartilagenous tissue of TMJ and lead to degen-
reduction is 0.001), history of closed lock (p value of history erative disorders of the TMJ.68 The overexpression and

Figure 1. Histogram showing the muscular tenderness in the PCOS and control groups Dark columns = polycystic ovary syndrome, and pale columns = controls.

Please cite this article in press as: Soydan SS, et al. Is the incidence of temporomandibular disorder increased in polycystic ovary syndrome?
Br J Oral Maxillofac Surg (2014), http://dx.doi.org/10.1016/j.bjoms.2014.07.100
YBJOM-4312; No. of Pages 5
ARTICLE IN PRESS
4 S.S. Soydan et al. / British Journal of Oral and Maxillofacial Surgery xxx (2014) xxxxxx
overactivity of MMP in an inflammatory process results in
the destruction of tissue in the TMJ.17 These degenerative
changes may affect the articular cartilage, articular capsule,
and ligaments, the synovial membrane, and the articular bone.
Degenerative changes in the TMJ alter its physical and func-
tional properties. This leads first to reversible, and finally
to irreversible, changes that make the TMJ unable to with-
stand loading stress.17 Clinically, mild internal derangement
is characterised by displacement of the disc with or without
osseous remodelling. Severe derangement includes perfora-
tion of the disc or its attachments, osseous remodelling, and
osteoarthritic changes.18
Matrix metalloproteinases acting on cartilage collagens
and proteoglycans are mainly responsible for degenerative
and erosive changes.19 Our hypotheses was that high activ-
ities of MMP in the synovial fluid of TMJ in patients with
PCOS may contribute to the degenerative changes in the TMJ
and also reflect further activity of the disease.
It has been shown that the activities of MMP-2, MMP-
3, and MMP-9 are increased in the synovial fluid and on the
condylar surface of the TMJ of patients with internal derange-
ment and osteoarthritis.20 Increased expression of MMP-2,
together with the simultaneous appearance of MMP-9, are
commonly seen in derangements of the TMJ.21,22 Srinivas
et al.23 reported that gelatinases were present inMMP-2 and
MMP-9, and also that collagenases MMP-1, MMP-8, and
MMP-13 were present in the synovial fluid of the TMJ.
These results emphasise the importance of the MMP cas-
cade in the pathogenesis of conditions of the TMJ. The
increased serum activities of MMP in PCOS may contribute
towards the degenerative disorders of the TMJ in women.
The clinical symptoms of internal derangements, such as
pain and clicking, or deviation during mouth opening, were
more common in the PCOS group in the present study
and this result supports the hypothesis of an increased inci-
dence of degenerative disorders of the TMJ in patients with
PCOS.
The increased activities of MMP-9, MMP-2, and MMP-8
in the patients with mild degenerative changes in the TMJ
indicate active tissue destruction during the painful periods
of inflammatory response.17 The incidence and VAS of pain
in the TMJ in the PCOS group was significantly higher than
that in the control group. Although pain in the TMJ may have
many causes, the possible reason for the higher VAS in the
PCOS group may also be the increased activities of MMP.
There was also a significant difference between the inci-
dence of muscular tenderness in the PCOS and control groups
(64% compared with 24%). Chronic musculoskeletal tender-
ness, such as that found in the jaw and neck muscles, is a
common symptom of disorders of the TMJ and has an adverse
effect on the quality of life.24 The muscular damage is asso-
ciated with an inflammatory reaction within the muscles, and
coexists with different degrees of pain and tenderness.25 The
regulation of inflammatory cytokines in PCOS may be con-
ducive to neurobiological stimulation of pain and so increase
the muscular tenderness in disorders of the TMJ.
Please cite this article in press as: Soydan SS, et al. Is the incidence of temporomandibular disorder increased in polycystic ovary syndrome?
Br J Oral Maxillofac Surg (2014), http://dx.doi.org/10.1016/j.bjoms.2014.07.100
Conict of Interest
We have no conflict of interest.
Ethics
The study was approved by the institutional Ethics Review
Board.
References
1. Warren MP, Fried JL. Temporomandibular disorders and hormones in
women. Cells Tissues Organs 2001;169:18792.
2. Wang W, Hayami T, Kapila S. Female hormone receptors are differ-
entially expressed in mouse fibrocartilages. Osteoarthritis Cartilage
2009;17:64654.
3. Talwar RM, Wong BS, Svoboda K, et al. Effects of estrogen on chon-
drocyte proliferation and collagen synthesis in skeletally mature articular
cartilage. J Oral Maxillofac Surg 2006;64:6009.
4. Chagin AS, Chrysis D, Takigawa M, et al. Locally produced estro-
gen promotes fetal rat metatarsal bone growth; an effect mediated
through increased chondrocyte proliferation and decreased apoptosis. J
Endocrinol 2006;188:193203.
5. Flake NM, Hermanstyne TO, Gold MS. Testosterone and estrogen have
opposing actions on inflammation-induced plasma extravasation in the
rat temporomandibular joint. Am J Physiol Regul Integr Comp Physiol
2006;291:3438.
6. Khalkhali-Ellis Z, Seftor EA, Nieva DR, et al. Estrogen and pro-
gesterone regulation of human fibroblast-like synoviocyte function
in vitro: implications in rheumatoid arthritis. J Rheumatol 2000;27:
162231.
7. Lu T, Achari Y, Rattner JB, et al. Evidence that estrogen receptor
beta enhances MMP-13 promoter activity in HIG-82 cells and that this
enhancement can be influenced by ligands and involves specific promoter
sites. Biochem Cell Biol 2007;85:32636.
8. Shimonovitz S, Hurwitz A, Hochner-Celnikier D, et al. Expression of
gelatinase B by trophoblast cells: downregulation by progesterone. Am J
Obstet Gynecol 1998;178:45761.
9. Samuel CS, Butkus A, Coghlan JP, et al. The effect of relaxin on collagen
metabolism in the nonpregnant rat pubic symphysis: the influence of
estrogen and progesterone in regulating relaxin activity. Endocrinology
1996;137:388490.
10. Revised 2003 consensus on diagnostic criteria long-term health
risks related to polycystic ovary syndrome. The Rotterdam
ASHRE/ASRM-Sponsored PCOS Consensus Workshop Group.
Fertil Steril 2004;81:1925.
11. Consensus on womens health aspects of polycystic ovary syndrome
(PCOS). The Amsterdam ESHRE/ASRM-Sponsored 3rd PCOS Con-
sensus Workshop Group. Hum Reprod 2012;27:1424.
12. Fulghesu AM, Sanna F, Uda S, et al. IL-6 serum levels and pro-
duction is related to an altered immune response in polycystic ovary
syndrome girls with insulin resistance. Mediators Inamm 2011;2011:
389317.
13. Repaci A, Gambineri A, Pasquali R. The role of low-grade inflamma-
tion in the polycystic ovary syndrome. Mol Cell Endocrinol 2011;335:
3041.
14. Lewandowski KC, Komorowski J, OCallaghan CJ, et al. Increased cir-
culating levels of matrix metalloproteinase-2 and -9 in women with
the polycystic ovary syndrome. J Clin Endocrinol Metab 2006;91:
11737.
15. Okeson JP. Management of temporomandibular disorders and occlusion.
6th ed. St. Louis: Mosby; 2008.
YBJOM-4312; No. of Pages 5
ARTICLE IN PRESS
S.S. Soydan et al. / British Journal of Oral and Maxillofacial Surgery xxx (2014) xxxxxx 5

16. Boulman N, Levy Y, Leiba R, et al. Increased C-reactive protein levels
in the polycystic ovary syndrome: a marker of cardiovascular disease. J
Clin Endocrinol Metab 2004;89:21605.
17. Israel HA, Saed-Nejad F, Ratcliffe A. Early diagnosis of osteoarthrosis of
the temporomandibular joint: correlation between arthroscopic diagnosis
and keratin sulfate levels in the synovial fluid. J Oral Maxillofac Surg
1991;49:70811.
18. Wilkes C. Arthrography of the temporomandibular joint in patients with
the TMJ pain-dysfunction syndrome. Minn Med 1978;61:64552.
19. Kubota E, Kubota T, Matsumoto J, et al. Synovial fluid cytokines and
proteinases as markers of temporomandibular joint disease. J Oral Max-
illofac Surg 1998;56:1928.
20. Ishimaru JI, Oguma Y, Goss AN. Matrix metalloproteinase and tis-
sue inhibitor of metalloproteinase in serum and lavage fluid of patients
with temporomandibular joint disorders. Br J Oral Maxillofac Surg
2000;38:3549.
21. Marchetti C, Cornaglia I, Casasco A, et al. Immunolocalization of
gelatinase-A (matrix metalloproteinase-2) in damaged human temporo-
mandibular joint discs. Arch Oral Biol 1999;44:297304.
22. Tanaka A, Kawashiri S, Kumagai S, et al. Expression of
matrix metalloproteinase-2 in osteoarthritic fibrocartilage from
human mandibular condyle. J Oral Pathol Med 2000;29:
31420.
23. Srinivas R, Sorsa T, Tjderhane L, et al. Matrix metalloproteinases in
mild and severe temporomandibular joint internal derangement synovial
fluid. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2001;91:
51725.
24. Koutris M, Lobbezoo F, Smer NC, et al. Is myofascial pain in temporo-
mandibular disorder patients a manifestation of delayed-onset muscle
soreness? Clin J Pain 2013;29:7126.
25. Proske U. Muscle tenderness from exercise: mechanisms? J Physiol
2005;564:1.

Please cite this article in press as: Soydan SS, et al. Is the incidence of temporomandibular disorder increased in polycystic ovary syndrome?
Br J Oral Maxillofac Surg (2014), http://dx.doi.org/10.1016/j.bjoms.2014.07.100