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Endocrine Journal 2015, 62 (6), 557-560

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Serum human chorionic gonadotropin levels and thyroid


hormone levels in gestational transient thyrotoxicosis: Is the
serum hCG level useful for differentiating between active
Graves disease and GTT?
Ai Yoshihara, Jaeduk Yoshimura Noh, Koji Mukasa, Miho Suzuki, Hidemi Ohye, Masako Matsumoto,
Yo Kunii, Natsuko Watanabe, Nami Suzuki, Toshiaki Kameda, Kiminori Sugino and Koichi Ito
Ito Hospital, Tokyo 150-8308, Japan

Abstract. Gestational transient thyrotoxicosis (GTT) is defined as transient thyrotoxicosis caused by the stimulating effect
of human chorionic gonadotropin (hCG) during pregnancy. We attempted to identify the serum hCG level that causes GTT,
and we compared the serum hCG levels and thyroid hormone levels of GTT patients according to whether they had a
background of thyroid disease. We also evaluated serum hCG as a parameter for differentiating between active Graves
disease (GD) and GTT. We reviewed the 135 cases of pregnant women who came to our hospital to be evaluated for
thyrotoxicosis during their 7th to 14th week of pregnancy, and their serum hCG level was measured at that time. Among
the 135 pregnant women with thyrotoxicosis; 103 of the women had GTT, and the other 32 women had active GD. There
were no correlations between their serum hCG levels and free thyroid hormone levels. There were no significant differences
in thyroid hormone levels or hCG levels among the GTT groups with different thyroid disease backgrounds; i.e., the GTT
group without thyroid disease, GTT group with chronic thyroiditis, GTT group with non-functioning thyroid nodules, and
GTT group with GD in remission. The serum hCG level of the GTT group was significantly higher than in the active GD
group, but it was not a good parameter for differentiating between the two groups. The FT3/FT4 ratio of the active GD was
significantly higher than in GTT group, and was a better parameter for differentiation.
Key words: Human chorionic gonadotropin, Gestational transient thyrotoxicosis, Graves disease

Gestational transient thyrotoxicosis (GTT) is


defined as transient thyrotoxicosis caused by the stimulating effect of human chorionic gonadotropin (hCG)
on the TSH receptor in the first trimester of gestation.
The prevalence of GTT has been reported to be 5.5%
in the Japanese population [1] and 11% in Singapore
[2]. GTT is characterized by an elevated serum thyroid hormone level and low or undetectable serum TSH
level in the absence of TSH receptor antibody. It is
very important to differentiate between GTT and active
Graves disease (GD) during pregnancy in GD patients
in remission, and having additional parameters besides
the serum TRAb titer as a means of making the differential diagnosis would be very helpful in clinical practice.
In the present study we investigated the hCG levels of
Submitted Dec. 9, 2014; Accepted Mar. 10, 2015 as EJ14-0596
Released online in J-STAGE as advance publication Mar. 29, 2015

Correspondence to: Ai Yoshihara, M.D., Ito Hospital, 4-3-6


Jingumae, Shibuya-ku, Tokyo 150-8308, Japan.
E-mail: a-yoshihara@ito-hospital.jp
The Japan Endocrine Society

GTT patients and whether the serum hCG levels of the


GTT patients correlated with their thyroid hormone levels. We also compared the characteristics of GTT according to whether the patients had a background of thyroid
disease, and more specifically whether they had a background of inactive GD, chronic thyroiditis, or non-functioning thyroid nodules. We compared the serum hCG
levels and FT3/FT4 ratios of patients with active GD and
GTT patients to determine which was a better parameter
for differentiating between active GD and GTT.
Patients
We reviewed the cases of pregnant women who
came to our hospital during their 7th to 14th weeks of
pregnancy to be evaluated for thyrotoxicosis between
November 1, 2005 and December 31, 2012, and their
serum hCG level was measured at that time. Patients
who had been treated with drugs that affect thyroid
function, including antithyroid drugs and levothyroxine, at the time of the blood tests were excluded as

558

Yoshihara et al.

subjects of this study. Thyroid ultrasonography and


serum tests for the presence of thyroid-related antibodies (anti-TSH receptor antibody [TRAb], thyroglobulin
antibody [TgAb], and anti-thyroid peroxidase antibody
[TPOAb]) were performed, and underlying thyroid disorders were diagnosed.
We diagnosed GTT when the results of the TRAb test
remained negative throughout the hyperthyroid state
and the hyperthyroid state spontaneously improved in
the absence of treatment. Active GD was diagnosed
when the serum TRAb test was positive and antithyroid drugs were required to suppress the thyroid hormone level. Chronic thyroiditis was diagnosed when
the serum TgAb test and/or TPOAb test was positive.
A diagnosis of non-functioning thyroid nodule was
made when ultrasonography showed one or more thyroid nodules and the hyperthyroid state spontaneously
improved to a normal thyroid state in the absence of
treatment. GTT without thyroid disease was diagnosed
when serum TRAb, TgAb, and TPOAb tests were all
negative and thyroid ultrasonography showed normal
findings. This study received approval by the local ethics committee. All participants gave informed consent.
Laboratory methods
Free triiodothyronine (FT3) and free thyroxine (FT4)
levels were measured by an electrochemiluminescence immunoassay (ECLIA) (ECLusys FT4, Roche
Diagnostics GmbH, Mannheim, Germany; manufacturers reference limits: 2.2-4.3 pg/mL, 0.8-1.6 ng/
dL respectively). The TSH level was measured by an
ECLIA (ECLusys TSH; Roche Diagnostics GmbH,
Mannheim, Germany; manufacturers reference limits:
0.2-4.5 mIU/L). Based on the results of our previous
study of a large population, the reference intervals for
FT3, and FT4, and TSH at 4-12 weeks of gestation were
2.01-4.9 pg/mL, 0.77-1.91 ng/dL, and 0.01-3.35 mIU/L,
respectively.
TPOAb and TgAb were determined by an ECLIA
performed with Roche ECLusys Anti-Tg and Anti-TPO
(Roche Diagnostics GmbH, Mannheim, Germany; reference values were: TPOAb, 28 IU/mL; TgAb, 40
IU/mL). Until September 30, 2008, TRAb levels were
determined with a solid-phase immunoradioreceptor assay kit (RSR, Cardiff, UK; TRAb-CT; reference
values <10%), but since October 1, 2008, they have
been determined with an electrochemiluminescence
immunoassay kit (ECLusys TRAb; Roche Diagnostics
GmbH, Mannheim, Germany; reference values <2.0

IU/L). HCG was determined with an enzyme immunoassay kit (Fujirebio Inc., Tokyo, Japan).
Statistical analysis
The statistical analysis was performed with JMP
software, version 11.0.0, (SAS Institute Inc., Cary,
NC). The data were analyzed by the Wilcoxon/
Kruskal-Wallis test for differences between two groups.
Correlations between two parameters were evaluated
by calculating Spearmans rank correlation coefficient.
Tukey-Kramers test and ANOVA were used to compare the hCG levels and thyroid hormone levels among
different groups. A p-value <0.05 was considered significant. Receiver operating characteristic (ROC) curve
analysis was performed to assess the accuracy of serum
hCG levels and FT3/FT4 ratios of patients for differentiating between active GD and GTT.

Results
The 135 hyperthyroid women consisted of 103
women with GTT and 32 women with active GD. Of
the 32 active GD patients, 11 patients had been newly
diagnosed with GD, and the other 21 patients had a
recurrence of GD. The 103 GTT patients consisted
of 30 women with no underlying thyroid disease, 19
women with chronic thyroiditis, 24 women with nonfunctioning thyroid nodule, and 30 women with GD
in remission. None of the women had a hydatidiform
mole or choriocarcinoma. The characteristics of the
GTT group and active GD group are shown in Table 1.
The serum hCG level of the active GD group was significantly lower than in the GTT group (p = 0.0009).
The median serum hCG of the GTT group was 71,000
mIU/mL (range 20,000220,000 mIU/mL) and 51,500
mIU/mL (range 8,900150,000 mIU/mL) in the active
GD group. There were no significant differences
between the serum hCG levels among the GTT group
according to thyroid disease background (no thyroid
disease, chronic thyroiditis, non-functioning thyroid
nodules, GD in remission). There were no correlations between the serum hCG levels and free thyroid
hormone levels (either FT3 or FT4) in either the GTT
group or active GD group (Fig. 1). The serum FT3 level
and FT4 levels of the active GD group were significantly higher than in the GTT group (p < 0.0001), and
the FT3/FT4 ratios were also significantly higher in the
active GD group than in the GTT group (p < 0.0001).
Also, the serum FT3 level and FT4 levels of the active

559

HCG level in gestational thyrotoxicosis

Table 1 Characteristics of the patients in the GTT group and active GD group
Total
GTT
103
Without thyroid disease
30
With chronic thyroiditis
19
With non-functioning thyroid nodule 24
With GD in remission
30
Active GD
32

hCG (mIU/mL)
FT3 (pg/mL)
FT4 (ng/dL)
FT3 / FT4
median (range)
median (range)
median (range)
median (range)
71000 (20000~220000)
5.30 (2.9~17.0)
2.28 (1.91~7.68)
2.32 (1.31~3.76)
62000 (26000~220000)
5.30 (2.9~11.2)
2.21 (1.93~3.90)
2.36 (1.31~2.96)
68000 (20000~160000)
5.35 (3.5~17.0)
2.19 (1.96~7.68)
2.26 (1.77~3.10)
80500 (33000~180000)
6.80 (3.0~13.1)
2.56 (1.91~7.01)
2.42 (1.34~3.76)
73000 (35000~190000)
5.15 (3.5~ 9.2)
2.28 (1.94~3.80)
2.31 (1.65~2.72)
51500* (8900~150000) 9.00** (4.3~32.5) 2.83** (1.95~7.77) 3.03** (2.21~4.18)

*p < 0.001, in comparison with the GTT group **p < 0.0001, in comparison with the GTT group p < 0.01, in comparison with the GTT
with GD in remission group p < 0.0001, in comparison with the GTT with GD in remission group
Reference intervals at 4-12 weeks of gestation: FT3 2.01-4.9 pg/mL, FT4 0.77-1.91 ng/dL

Fig. 1 Serum hCG levels and free thyroid hormone levels (FT3 or FT4) in the GTT group and active GD group.

GD group were significantly higher than in the GTT


with GD in remission group (FT3, p < 0.0001; FT4, p =
0.0004), and the FT3/FT4 ratios were also significantly
higher in the active GD group than in the GTT with GD
in remission group (p < 0.0001). There were no significant differences in thyroid hormone levels among
the GTT groups (Table 1). The ROC curve analysis
revealed that the cut-off hCG level for differentiating
between active GD and GTT was 70,000 mIU/mL. The
area under the ROC curve for differentiating between
active GD and GTT was 0.7, and sensitivity was 84%,
and specificity 51%. In addition, the cut-off FT3/FT4
ratio for differentiating between active GD and GTT
was 2.7. The area under the ROC curve was 0.87; sensitivity was 77%, and specificity was 88%.

Discussion
We attempted to identify the serum hCG level that
causes GTT, and we compared the serum hCG levels
and thyroid hormone levels of GTT in patients according to whether they had a background of thyroid disease. HCG shares a common -subunit with TSH and
possesses thyroid stimulating activity [3]. The prevalence of GTT among pregnant woman in Europe has
been estimated to be 2-3% [4], and a higher prevalence
is estimated in Asia [1, 2] Lockwood et al. reported
that hCG concentrations higher than 400,000 IU/L suppresses TSH level and most patients with hCG higher
than 200,000 IU/L lack overt hyperthyroid symptoms [5].
Furthermore, a hydatidiform mole or choriocarcinoma,

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Yoshihara et al.

and twin pregnancies are also known to cause GTT [6,


7].The hCG levels in the GTT group in this study ranged
from 20,000 to 220,000 mIU/mL, and there were no correlations between the serum hCG levels and thyroid hormone levels. In addition, there were no significant differences between the thyroid hormone levels or hCG levels
of the GTT group without thyroid disease, GTT group
with chronic thyroiditis, GTT group with non-functioning thyroid nodules, and GTT group with GD in remission. This result suggests that the characteristics of GTT
do not vary with thyroid disease background.
The exact molecular variants of hCG responsible for
thyrotrophic effects are still unknown. There is one report
of a change in the thyroid stimulating activity of hCG as
a result of a modification of the carbohydrate chain [8].
We also evaluated serum hCG levels as a parameter
for differentiating between active GD and GTT. The thyroid function of most untreated GTT patients becomes
normal by the second trimester, and it is important to
differentiate GTT from GD in order to prevent patients
from undergoing unnecessary ATD treatment.
Tagami et al. evaluated the serum hCG values and
FT3/FT4 ratios of pregnant GD patients and found that
the hCG values were higher and FT3/FT4 ratios were
lower in the GTT group than in the non-GTT group [9].
Our results in the present study were consistent with the
findings in that report. We attempted to identify hCG and
FT3/FT4 ratio cut-off levels for differentiating between
active GD and GTT by performing an ROC curve anal-

ysis. The hCG cut-off level for differentiating between


active GD and GTT was 70000 mIU/mL and the area
under ROC curve for differentiating active GD between
GTT was 0.7. Since the FT3/FT4 ratio cut-off level for
differentiating between active GD and GTT was 2.7,
and the area under the ROC curve was 0.87, we concluded that the FT3/FT4 ratio is a better parameter than
the serum hCG level for differentiating between active
GD and GTT, including GTT with GD in remission. Our
study had the limitations of being retrospective and the
numbers of patients in each group being small. Also,
since hCG was measured only once in every subject,
and the weeks of gestation when the measurements were
made differed from subject to subject, we did not follow
the hCG levels throughout the pregnancy of any of the
subjects. However, the diagnosis of GTT in each subject
was confirmed by reviewing the subjects clinical course.
In conclusion, there was no correlation between the
serum hCG levels and thyroid hormone levels of the
GTT patients, and there were no significant differences
between the thyroid hormone levels or hCG levels of
the GTT groups. The FT3/FT4 ratio was a better parameter than the hCG level for differentiating between
GTT and active GD.

Disclosure Statement
The authors declare that they have no competing
financial interests.

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