Original Article

Do prenatal and postnatal hypothyroidism affect the craniofacial structure?:

An experimental study
Mine Gecgelen Cesura; Gokhan Cesurb; Mert Ogrenimc; Afra Alkand
ABSTRACT
Objective: To investigate the effect of experimental prenatal and postnatal hypothyroidism (HT) on
the craniofacial structure in rats.
Materials and Methods: Female Wistar albino rats were mated with males for fertilization.
Pregnant rats were divided into three groups. Group 1 (methimazole [MMI]-induced prenatal
hypothyroidism group) mother rats were given MMI water during and after pregnancy. Group 2
(MMI-induced postnatal hypothyroidism group) mother rats were given MMI water after pregnancy.
After the breast-feeding period, group 1 and 2 rat pups received the same water as their lactating
mothers drank. Group 3 (control group) pregnant rats and rat pups were given normal tap water.
When the rat pups were 90 days of age, lateral cephalometric and posteroanterior films were taken
under anesthesia.
Results: Posteroanterior radiographs revealed that palatal, cranial, bizygomatic arch, and bigonial
width measurements were significantly shorter in prenatal HT and postnatal HT groups compared
to the control group (P , .001). Intragroup comparisons in lateral cephalometric radiographs
showed that, nearly all of the comparisons were statistically significant (P , .05), with the exception
of the Co-Gn, E-Pg/S-Gn measurements between the prenatal and postnatal HT groups.
Conclusions: Sagittal and transverse measurements showed that untreated HT has detrimental
effects on the growth of the maxilla and mandible. (Angle Orthod. 2016;86:983990.)
KEY WORDS: Hypothyroidism; Craniofacial structure

INTRODUCTION

Thyroid diseases are common, and their effects on

craniofacial, dental, and oral structures are defined in
the literature. Severe HT causes subnormal growth of
the maxilla and mandible and a decrease in the facial
dimensions. HT has detrimental effects on tooth development and eruption, which leads to prolonged
retention of deciduous teeth and impaction of permanent
teeth, resulting in malocclusion.46 Oral effects of HT
include enlargement of the tongue, thick lips, dysgeusia,
poor periodontal health, and delayed wound healing.2,5,7
HT can occur either as a congenital or as an
acquired condition.4,8 In prenatal HT, linear growth at
birth is normal, but the development of bone and teeth
is retarded. After birth, HT disturbs normal growth,
resulting in growth deficiency or complete cessation of
growth is also seen at athyroidism. Growth of the
craniofacial structures is retarded and brachycephalic
facial features develop.9
To the best of our knowledge, no study has been
reported that involved investigation of craniofacial
measures in cases of HT. Here we aim to evaluate
the effect of experimental prenatal and postnatal HT
on the craniofacial structure in rats.

Hypothyroidism (HT) is defined as a metabolic

condition that is caused by a deficiency in thyroid
hormone (TH) production and gland function.1,2 THs
(triiodothyronine-T3 and thyroxine-T4) are very important regulators of the growth, bone maturation, energy
metabolism, and turnover of cells.2,3

a
Assistant Professor, Adnan Menderes University, Faculty of
Dentistry, Department of Orthodontics, Aydn, Turkey.
b
Associate Professor, Adnan Menderes University, Faculty of
Medicine, Department of Physiology, Aydn, Turkey.
c
Research Assistant, Adnan Menderes University, Faculty of
Dentistry, Department of Orthodontics, Aydn, Turkey.
d
Research Assistant, Yldrm Beyazt University, Faculty of
Medicine, Department of Biostatistics, Ankara, Turkey.
Corresponding author: Dr Mine Gecgelen Cesur, Assistant
Professor, Adnan Menderes University, Faculty of Dentistry,
Department of Orthodontics, Aydn, Turkey
(e-mail: minegecgelen@hotmail.com)

Accepted: November 2015. Submitted: August 2015

Published Online: January 12, 2016
G 2016 by The EH Angle Education and Research Foundation,
Inc.
DOI: 10.2319/080315-521.1

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CESUR, CESUR, OGRENIM, ALKAN

Figure 1. Location of cephalometric landmarks on lateral radiographs.

MATERIALS AND METHODS

Experimental Design
In this prospective, randomized study, 6-month
female Wistar albino rats weighing 250300 g were
mated with males for fertilization. Vaginal smears were
performed for the determination of pregnancy. When
semen was detected in the vaginal smears, rats were
thought to be pregnant and were followed. Pregnant
rats were divided into three groups, as follows:
Group 1 (methimazole [MMI]-induced prenatal hypothyroidism group): The pregnant rats were fed ad
libitum with MMI water during and after pregnancy.
MMI (SC-205747A, Santa Cruz Biotechnology Inc,
Dallas, Tex; 0.025% wt/vol) was given daily in drinking
water starting from pregnancy. Rat pups were fed with
breast milk from their lactating mothers. After weaning
(1922 days), pups drank the same MMI water that
their lactating mothers drank until day 90. Group 2
(MMI-induced postnatal hypothyroidism group): The
pregnant rats were fed ad libitum with water during
pregnancy. The mother rats were given the same dose
of MMI daily in drinking water from birth. Offspring were
fed with breast milk from their mothers. After weaning
(1922 days), pups drank the same MMI water that
their lactating mothers drank until day 90. Group 3
(control group): The pregnant rats were fed ad libitum
with normal tap water (without MMI). Rat pups were fed
with breast milk from their lactating mothers. After
weaning and until they were 90 days of age, they were
fed ad libitum with regular water, as were their mothers.
Angle Orthodontist, Vol 86, No 6, 2016

This protocol and dosage of MMI administration is

typically used for the production of HT rats.1012
The rats were restricted separately in plastic cages
under artificial lighting from fluorescence lamps, with
a 12-hour light:12-hour dark photoperiod. The room
temperature was set at 25uC. When the rat pups were
90 days of age, 10 female and 10 male rats from each
group (total 5 60 rats) were used. Permission was
obtained from the University of Adnan Menderes,
Local Ethics Committee for Animal Experiments
(reference No, 64583101/2014/036). The experiments
were carried out in the Department of Experimental
Animals at the Research and Development Center.
Cephalometric Technique and Data Analysis
Rats were anesthetized with intraperitoneal injections of 100 mg/kg and 20 mg/kg xylazine and
ketamine combination, respectively. A 1-mL xylazine
+ ketamine combination was prepared per kilogram of
rat. Lateral and posteroanterior cephalometric radiographs were taken with a Comed X-ray machine
(Comed Medical System, Seongnam Si Jungwon-gu
GYEONGGI-DO, Korea) at a setting of 2 mAs at 70 Kv.
Dentofacial parameters were measured using
a cephalometric analysis program (Romexis 3.2.0.R;
Planmeca, Helsinki, Finland). Cephalometric landmarks were marked and digitized by one author. All
of the measurements were repeated 2 weeks later to
determine the measurement error.
Fifteen cephalometric landmarks were identified
(Figure 1), and 21 measurements (17 linear, 3

985

EFFECT OF HYPOTHYROIDISM ON CRANIOFACIAL STRUCTURE

Table 1. Definition of Cephalometric Landmarks and Measurements Used on the Lateral Radiographs
Landmarks and Measurements
A
N
E
Po
Ba
Co
Go
Mn
Gn
Il
S
Ml
Mu
Iu
Pg
Po-N, (mm)
N-A, (mm)
Po-A, (mm)
S-E, (mm)
S-Ba, (mm)
Ml-Il, (mm)
Go-Mn, (mm)
Go-Pg, (mm)
Co-Gn, (mm)
S-Gn, (mm)
E-Pg, (mm)
E-Pg/S-Gn
E-Mu, (mm)
Po-Ba, (mm)
Co-Pg, (mm)
Co-Iu, (mm)
Co-II, (mm)
Mu-Iu, (mm)
SNIu, (u)
SNPg, (u)
SN-PgGn, (u)

Description
The most anterior point on the nasal bone
A point on the nasofrontal suture
The intersection of the frontal bone and floor of anterior cranial fossa
The most posterior and superior point on the skull
The most posterior and inferior point on the occipital condyle
The most posterior and superior point on the mandibular condyle
The most posterior point on the mandibular ramus
The most concave portion of the concavity on the inferior border of the mandibular corpus
The most inferior point on the ramus that lies on a perpendicular bisector of the line Go-Mn
The most anterior and superior point on the alveolar bone of the mandibular incisor
The intersection of the most anterior tympanic bulla and the superior border of the sphenoid bone
The junction of the alveolar bone and the mesial surface of the first mandibular molar
The junction of the alveolar bone and the distal surface of the third maxillary molar
The most anterior-inferior point on the maxilla posterior to the maxillary incisors
The most inferior point on the lower border of the mandible
Cranial vault length
Nasal bone length
Total skull length
Anterior cranial base length
Posterior cranial base length
Anterior corpus length
Posterior corpus length
Mandibular corpus length
Mandibular ramus length
Posterior facial height
Anterior facial height
Anterior/posterior facial height ratio
Midfacial length
Occipital bone height
Effective mandibular length
Effective maxillary length
Total mandibular length
Palatal length
The sagittal position of the maxilla relative to cranial base
The sagittal position of the mandible relative to cranial base
Mandibular plane angle

angular, and one proportional) were performed on

lateral radiographs (Table 1). Eight cephalometric
landmarks and four linear cephalometric measure-

ments were identified on posteroanterior radiographs

(Figure 2; Table 2).
At the end of the radiograph acquisition period,
blood samples were collected from the heart under
general anesthesia and serum levels of total T4 were
analyzed using enzyme-linked immunosorbent assay.
Statistical Analysis

Figure 2. Location of cephalometric landmarks on posteroanterior

radiographs.

The distributions of the measurements taken on the

lateral and posteroanterior radiographs were examined
by Shapiro-Wilks test. Normal distributed measurements were shown as mean 6 standard deviation
(mean 6 SD), and nonnormal ones were expressed
with a median (Interquartile Range).
The intraclass correlation coefficient (ICC) was
calculated to evaluate the intrarater agreement. Since
all ICCs were greater than 0.900 and significant, the
first measurements were analyzed.
Total T4 serum levels of control, prenatal, and
postnatal HT groups were compared by Kruskal-Wallis
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CESUR, CESUR, OGRENIM, ALKAN

Table 2. Definition of Cephalometric Landmarks and Measurements Used on the Posteroanterior Radiographs
Landmarks and Measurements

Description

Z1 & Z2
Go1 & Go2
P1 & P2
C1 & C2
Go1-Go2
C1-C2
P1-P2
Z1-Z2

The points on the lateral portion of the zygomatic arch that produce the widest width
The points on the angle of the mandible that produce the widest width
The most anterior and medial points within the temporal fossae that produce the most narrow palatal width
The points on the cranium that produce the widest cranial width
Bigonial width
Maximum cranial width
Palatal width
Bizygomatic width

analysis of variance (ANOVA) and one-way ANOVA

for males and females, respectively. The sample sizes
in each combination of gender and groups were near
10, and the lateral and posteroanterior radiographic
measurements did not satisfy the homogeneity of the
variances. Therefore, two-way ANOVA could not be
applied. The analyses were carried out for gender and
group categories separately. In each gender category,
the groups were compared by one-way ANOVA. For
each group category, the genders were compared by
an independent-sample t-test. All p values obtained by
these ANOVA and t-tests were adjusted by the
Bonferroni-Holm correction method. Groups were
compared generally by Kruskal-Wallis ANOVA with
respect to the Go-Mn measurements and by one-way
ANOVA with respect to all other measurements.
F-statistics or Welchs statistics were provided and
Tukey honestly significantly different or Games Howell
post hoc tests were applied depending on the Levene
test results. x2 statistics were written, and the MannWhitney U-test with Bonferroni correction was applied
as a result of the Kruskal-Wallis ANOVA. A P values
of less than .05 were accepted as statistically
significant.
All analysis and calculations were performed in IBM
SPSS 21.0 (IBM Corp, Released 2012, IBM SPSS
Statistics for Windows [Version 21.0], Armonk, N.Y.).
RESULTS
The rats did not show any signs of systemic disease
during the study period. The body weight of rats on the
last day of the study period is given at Table 3. Total T4
hormone levels showed that experimental intervention
(administration of MMI) effectively produced the
expected condition of HT in the prenatal and postnatal
HT groups (Table 4).

Significant agreement was found between the two

sets of measurements on the lateral and posteroanterior radiographs (P , .001), indicating excellent
intrarater reliability (all ICC . 0.900).
When we evaluated the male lateral cephalometric
radiographs for control prenatal and postnatal HT
groups, S-Ba, Co-Gn, and E-Pg/S-Gn measurements
did not show significant differences between the
prenatal and postnatal HT groups (P . .05) (Table 5).
There were not significant differences in Snlu, SNPgGn, and MI-II measurements between the control
and postnatal HT groups (P . .05) (Table 5). Comparisons of female lateral cephalometric radiograph
measurements showed that S-Ba, Go-Mn, E-Pg/SGn, SNIu, SN-PgGn, and Ml-II measurements were not
statistically different between the prenatal and postnatal HT groups (P . .05) (Table 5). There were significant differences between groups with respect to the
other measurements except these ones (P , .05)
(Table 5).
Intragroup comparisons in lateral cephalometric
radiographs showed that N-A, S-Ba, Po-A, Go-Mn,
Go-Pg S-Gn, E-Pg, and Mu-Iu measurements for the
control group; S-Ba, Co-Gn, and E-Pg/S-Gn measurements for the prenatal HT group; and Po-N, Go-Mn,
Go-Pg, Co-Gn, E-Pg, Co-Pg, Co-Iu, SnPg, SN-PgGn,
Co-II, and Mu-Iu measurements for the postnatal HT
group were statistically significant between the sexes
(P , .05) (Table 5).
When the sex differences were ignored, nearly all
of the comparisons were statistically significant
(P , .001), except for the Co-Gn, E-Pg/S-Gn measurements between the prenatal and postnatal HT
groups (P . .05) (Table 6).
Comparisons of posteroanterior cephalometric radiograph measurements for control, prenatal, and

Table 3. The Body Weight (g) of Control, Prenatal, and Postnatal Hypothyroidism (HT) Group

Male
Female
a

Control Group

Prenatal HT Group

Postnatal HT Group

Mean 6 SDa

Mean 6 SDa

Mean 6 SDa

256.00 6 15.23
211.30 6 13.87

37.53 6 4.83
33.80 6 3.42

81.80 6 9.44
70.00 6 8.50

SD indicates standard deviation.

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EFFECT OF HYPOTHYROIDISM ON CRANIOFACIAL STRUCTURE

Table 4. Comparison of Total T4 Serum Levels (ng/mL) of Control, Prenatal, and Postnatal Hypothyroidism (HT) Groupsa

Male
Median (IQR)a
Female
Mean 6 SD

Control Group

Prenatal HT Group

Postnatal HT Group

Test Statistics

56.35 (1.78)1,3

24.90 (1.78)1,2

36.40 (2.30)2,3

x2 5 25.939

54.51 6 1.51a,c

26.35 6 2.28a,b

36.50 6 1.42b,c

F 5 668.729

Adjusted P

df
2

,.001

2; 27

,.001

IQR indicates interquartile range.

1
P , .001.
2,3
P , .05.
a,b,c
P , .001.

Table 5. Comparison of Male and Female Rat Lateral Cephalometric Film Measurements Between the Control, Prenatal, and Postnatal
Hypothyroidism (HT) Groups

Male
Po-N
N-A
Po-A
S-E
S-Ba
Go-Mn
Go-Pg
Co-Gn
S-Gn
E-Pg
EPg/S-Gn
Po-Ba
Co-Pg
Co-Iu
SNIu, u
SnPg, u
SN-PgGn, u
E-Mu
Co-II
Ml-II
Mu-Iu
Female
Po-N
N-A
Po-A
S-E
S-Ba
Go-Mn
Go-Pg
Co-Gn
S-Gn
E-Pg
EPg/S-Gn
Po-Ba
Co-Pg
Co-Iu
SNIu, u
SnPg, u
SN-PgGn, u
E-Mu
Co-II
Ml-II
Mu-Iu

Control Group

Prenatal HT Group

Postnatal HT Group

Mean 6 SD

Mean 6 SD

Mean 6 SD

Test Statistics (F)

df

Adjusted P

26.38
16.44
42.08
14.08
12.00
9.72
18.08
11.05
9.33
19.48
2.10
8.48
20.59
26.50
97.11
55.82
46.27
12.04
21.61
5.17
18.48

6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6

0.98
0.721
1.032
1.38
0.923
0.524
1.085
0.70
0.646
0.507
0.13c
0.28
1.19
1.20
2.40e
3.01
2.99f
0.45
0.68
0.27g
0.42

21.00
9.48
29.90
10.63
9.36
3.12
10.59
9.52
6.25
13.90
2.23
6.27
13.95
19.11
92.08
44.82
57.94
10.18
16.25
4.09
13.70

6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6

0.65
0.68
1.08
0.74
0.72a
0.34
0.92
0.69b
0.23
0.47
0.10c,d
0.42
0.73
0.75
1.59
2.47
3.17
0.79
0.59
0.50
1.04

24.21
12.14
35.82
11.86
9.94
6.64
14.09
9.27
7.25
16.44
2.28
7.65
17.01
22.69
96.18
50.43
48.14
10.91
18.58
4.69
16.11

6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6

0.92
1.11
1.56
0.71
1.03a
0.741
0.992
1.023,b
0.61
0.554
0.17d
0.42
0.845
0.98
3.02e
3.196
2.807,f
0.36
0.83
0.67g
0.80

137.165
220.618
316.197
43.065
30.864
475.536
189.660
17.604
129.220*
400.287
5.850*
155.644
174.024
192.273
17.570
48.617
61.454
35.072
171.465
14.707
114.065

2;
2;
2;
2;
2;
2;
2;
2;
2;
2;
2;
2;
2;
2;
2;
2;
2;
2;
2;
2;
2;

38
38
38
38
38
38
38
38
19.069
38
23.245
38
38
38
38
38
38
38
38
38
38

,.001
,.001
,.001
,.001
,.001
,.001
,.001
,.001
,.001
,.001
.045
,.001
,.001
,.001
,.001
,.001
,.001
,.001
,.001
,.001
,.001

25.97
15.50
40.72
13.46
11.16
8.36
16.63
11.33
8.70
18.69
2.15
8.38
20.49
26.18
98.43
55.58
45.16
11.58
21.55
5.33
17.26

6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6

0.42
0.291
0.872
0.59
0.353
0.484
0.755
0.36
0.326
0.407
0.08j,k
0.40
0.44
0.67
1.93
3.61
2.84
0.72
1.21
0.89
0.738

20.55
9.47
29.58
10.65
9.02
3.14
10.43
9.31
6.08
13.58
2.30
6.07
13.60
19.05
92.89
43.53
56.59
9.90
16.02
3.80
13.21

6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6

0.47
0.64
0.49
0.37
0.65h
0.30i
0.61
0.40
0.56
0.35
0.2j,l
0.47
0.36
0.40
1.69m
1.91
2.52n
0.24
0.49
0.52o
0.43

23.35
12.27
35.11
12.18
9.80
3.69
12.74
10.07
7.33
15.78
2.17
7.46
16.17
22.05
95.10
47.76
54.34
10.84
18.00
4.27
15.13

6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6

1.07
1.44
1.34
0.73
0.75h
0.681,i
0.862
0.443
0.65
0.334
0.19k,l
0.51
0.605
0.54
2.24m
2.186
4.987,n
0.54
0.43
0.61o
0.778

357.855*
370.834*
628.747*
53.945
29.948
296.154
171.133
64.182
56.901
528.072
0.948
60.823
491.606
430.984
19.439
55.127
45.606*
24.603
107.857*
13.377
116.942*

2;
2;
2;
2;
2;
2;
2;
2;
2;
2;
2;
2;
2;
2;
2;
2;
2;
2;
2;
2;
2;

20.540
17.507
18.998
31
31
31
31
31
31
31
31
31
31
31
31
31
20.576
31
16.682
31
19.441

,.001
,.001
,.001
,.001
,.001
,.001
,.001
,.001
,.001
,.001
.796
,.001
,.001
,.001
,.001
,.001
,.001
,.001
,.001
,.001
,.001

* Welchs statistics.
1,2,3,4,5,6,7,8
padj , 0.05 (gender comparisons in each group).
a.b,c,d,e,f,g,h,I,j,k,l,m,n,o
padj . 0.05 (group comparisons in each categories of gender).
Angle Orthodontist, Vol 86, No 6, 2016

988
Table 6.

CESUR, CESUR, OGRENIM, ALKAN

Comparison of Lateral Cephalometric Film Measurements Between the Control, Prenatal, and Postnatal Hypothyroidism (HT) Groupsa

Po-N
N-A
Po-A
S-E
S-Ba
Go-Mn
Go-Pg
Co-Gn
S-Gn
E-Pg
EPg/S-Gn
Po-Ba
Co-Pg
Co-Iu
SNIu, u
SnPg, u
SN-PgGn, u
E-Mu
Co-II
Ml-II
Mu-Iu

Control Group

Prenatal HT Group

Postnatal HT Group

Mean 6 SD
Median (IQR)

Mean 6 SD
Median (IQR)

Mean 6 SD
Median (IQR)

Test Statistics
(F)

26.19
16.01
41.46
13.80
11.62
9.11
17.42
11.18
9.04
19.12
2.12
8.43
20.55
26.36
97.71
55.71
45.77
11.83
21.58
5.25
17.93

20.82
9.48
29.77
10.64
9.22
3.11
10.53
9.43
6.19
13.77
2.24
6.19
13.81
19.09
92.40
44.30
57.40
10.07
16.16
3.98
13.50

23.78
12.20
35.47
12.02
9.87
5.27
13.41
9.67
7.29
16.11
2.22
7.55
16.59
22.37
95.64
49.10
51.24
10.87
18.29
4.48
15.62

337.334*
514.566*
736.398*
77.027*
53.910
x2 = 58.505
252.048
41.894
159.250
581.898
5.432*
166.831
421.124
457.305
33.681
93.389
91.225*
56.585
318.027
25.866
147.212

6 0.79
6 0.73
6 1.16
6 1.21
6 0.82
(1.42)
6 1.18
6 0.58
6 0.60
6 0.60
6 0.11
6 0.34
6 0.91
6 0.99
6 2.25
6 3.22
6 2.91
6 0.62
6 0.93
6 0.62
6 0.84

6 0.62
6 0.65
6 0.89
6 0.61
6 0.70
(0.28)
6 0.80
6 0.59a
6 0.40
6 0.45
6 0.15b
6 0.44
6 0.62
6 0.62
6 1.65
6 2.31
6 2.95
6 0.64
6 0.55
6 0.52
6 0.87

6 1.08
6 1.26
6 1.47
6 0.73
6 0.89
(3.27)
6 1.14
6 0.87a
6 0.62
6 0.56
6 0.18b
6 0.47
6 0.84
6 0.84
6 2.67
6 3.00
6 5.07
6 0.45
6 0.71
6 0.66
6 0.92

df
2;
2;
2;
2;
2;
2;
2;
2;
2;
2;
2;
2;
2;
2;
2;
2;
2;
2;
2;
2;

45.907
46.488
45.901
43.599
72
2
72
72
72
72
47.748
72
72
72
72
72
47.375
72
72
72
72

P
,.001
,.001
,.001
,.001
,.001
,.001
,.001
,.001
,.001
,.001
.007
,.001
,.001
,.001
,.001
,.001
,.001
,.001
,.001
,.001
,.001

IQR indicates interquartile range.

* Welchs statistics.
a,b
P . .05.

postnatal HT groups showed that all of the group

comparisons were statistically different from each
other (P , .001) (Table 7). Go1-Go2, C1-C2, P1-P2,
and Z1-Z2 measurements changed as follows: control
group. postnatal HT group . prenatal HT group.

Intragroup comparisons in posteroanterior cephalometric radiographs showed that there were statistically
significant differences between the sexes for Z1-Z2
measurements in the control group (padj 5 0.045); P1P2 measurements in the prenatal group (padj 5 0.009);

Table 7. Comparison of Male and Female Rat Posteroanterior Cephalometric Film Measurements Between the Control, Prenatal and Postnatal
Hypothyroidism (HT) Groups

Male
P1-P2
Z1-Z2
C1-C2
Go1-Go2
Female
P1-P2
Z1-Z2
C1-C2
Go1-Go2
Total
P1-P2
Z1-Z2
C1-C2
Go1-Go2

Control Group

Prenatal HT Group

Postnatal HT Group

Mean 6 SD
Median (IQR)

Mean 6 SD
Median (IQR)

Mean 6 SD
Median (IQR)

8.75
21.71
15.28
18.06

6
6
6
6

0.24
0.51a
0.44
0.54

6.97
15.87
13.08
15.12

6
6
6
6

0.16b
1.04
0.59
0.44

7.82
18.07
14.17
16.19

6
6
6
6

0.17
0.33
0.46c
0.35

278.823
301.042*
65.198
145.198

2;
2;
2;
2;

36
21.810
36
36

,.001
,.001
,.001
,.001

8.91
21.22
14.92
18.05

6
6
6
6

0.36
0.36a
0.54
0.49

6.75
15.57
12.64
14.81

6
6
6
6

0.14b
0.62
0.31
0.30

7.82
17.70
13.70
16.11

6
6
6
6

0.15
0.60
0.23c
0.29

228.265*
278.242
91.793
193.694

2;
2;
2;
2;

17.053
28
28
28

,.001
,.001
,.001
,.001

8.82
21.51
15.13
18.06

6
6
6
6

0.30
0.50
0.51
0.51

6.87
15.74
12.89
14.98

6
6
6
6

0.18
0.87
0.53
0.41

7.82
17.89
13.95
16.15

6
6
6
6

0.16
0.50
0.43
0.31

387.607*
501.141*
122.633
256.127*

2;
2;
2;
2;

42.987
42.637
67
43.309

,.001
,.001
,.001
,.001

* Welchs statistics.
t = 2.263, padj = 0.045
b
t = 3.404, padj = 0.009
c
t = 3.157, padj = 0.018
a

Angle Orthodontist, Vol 86, No 6, 2016

Test Statistics
(F)

df

Adjusted P

989

EFFECT OF HYPOTHYROIDISM ON CRANIOFACIAL STRUCTURE

and C1-C2 measurements in the postnatal group

(padj 5 0.018) (Table 7).
DISCUSSION
Thyroid disorders during development cause major
and minor birth defects. Congenital HT is known to
lead to deficiencies in growth, bone maturation, and
motor development.3 In this study, we aimed to
investigate the effect of prenatal and postnatal HT on
the craniofacial structures in rat models. To the best of
our knowledge, there is no published study that
investigates the effect of HT on craniofacial structures;
therefore, we were unable to compare the results of
this study with the results of others.
HT is caused by iron deficiency, radiation of the
thyroid gland, surgery, and excessive antithyroid
drugs.2,8 MMI is an antithyroid agent and has been
widely used in studies. MMI exposure during the
development process blocks TH synthesis and leads
to growth retardation.10 In this study, we suppressed
the TH synthesis using MMI.
Untreated HT has detrimental effects on the growth
and development of the maxilla and mandibula.13
Loevy et al.13 discussed the dental evaluation of
a patient with untreated congenital HT in their case
report. Their cephalometric radiographs indicate an
overwhelming reduction in the dimensions of the
craniofacial complex, particularly evident in the patients posteroanterior and lateral cephalometric tracings. The findings are similar to those reported by
Bedi and Brook4 in a patient with juvenile HT. In this
study, significant decreases were found in the sagittal
position of the maxilla and mandible effective maxillary
and mandibular length, anterior and posterior cranial
base length, nasal bone length, occipital bone height,
and palatal length between the HT groups and the
control group.
Spiegel et al.14 reported the occurrence of a small
facial height with a tendency to open-bite malocclusion
in HT patients. We have found significant increases in
anterior/posterior facial height ratio and mandibular
plane angle and reduction in anterior and posterior
facial height in each HT group compared with the
control group.
Many linear and angular cephalometric measurements were higher in male than in female lateral and
anteroposterior radiographs, as was the case in
human studies. These results were in accordance with
those of other cephalometric human studies.1518
THs are important for the synthesis of insulin-like
growth factor1 (IGF-1), which promotes bone growth
and differentiation in a variety of tissues.9,19,20 THs
enhance cartilage growth through IGF-1 and by

directly accelerating the differentiation of chondrocytes. HT patients show low serum levels of IGF-I and
reduced IGF bioactivity.9,20
Backeljauw et al.21 reported that children with severe
primary IGF-1 deficiency may have underdeveloped
facial bones (small facial dimensions and a retrognathic
maxilla and mandible). It seems that growth retardation
in HT groups is related to a deficiency of serum IGF-1
levels, and craniofacial growth is under the endocrine
regulation.
Neonatal screening for congenital HT after birth is
important to avoid mentally handicapping conditions
and growth disorders. HT in the newborn period is often
overlooked, and delayed diagnosis leads to the most
severe outcome of HT in developing countries.13 Many
factors, such as lack of awareness about HT among the
health care practitioners and the inaccessibility and
higher cost of the laboratory examinations, play a role
in the limited diagnosis and management of HT.5 This is
especially true for the acquired HT clinical manifestations depend on the age of onset and the length of time
before the disease is effectively treated. Once the HT is
diagnosed, the retardation of skeletal maturity improves quickly after adequate treatment.4 Generally,
the dental development is less responsive to treatments than is skeletal maturity (eg, the height of the
patient). Fortunately, craniofacial growth of HT patients
does not show a modification in growth. Craniofacial
structures are generally affected by the retardation of
growth velocity, which in turn could be treated by an
early orthopedic treatment in early childhood.
In this study, we used two-dimensional imaging to
assess cephalometric parameters in the rats. This
imaging method limits the amount of information to be
gained from analysis, since the three-dimensional
situation is reduced to a two-dimensional projection.
Therefore, future studies should evaluate the relationship using three-dimensional computerized tomography.
CONCLUSIONS
N Palatal, cranial, bizygomatic arch, and bigonial width
measurements were significantly shorter in the prenatal HT and postnatal HT groups compared to the
control group.
N Cephalometric radiographs indicated that statistically
significant differences were present between the
three groups for almost all of the linear and angular
measurements.
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