Best Practice & Research Clinical Endocrinology & Metabolism

Vol. 18, No. 2, pp. 249–265, 2004

doi:10.1016/[Link].2004.03.010
available online at [Link]

Physiological and pathological aspects

of the effect of human chorionic
gonadotropin on the thyroid

Jerome M. Hershman* MD
Endocrinology-111D, VA Greater Los Angeles Healthcare Center, 11301 Wilshire Blvd, Los Angeles, CA 90073, USA

Human chorionic gonadotropin (hCG) is a glycoprotein hormone that has structural similarity to
TSH. At the time of the peak hCG levels in normal pregnancy, serum TSH levels fall and bear a
mirror image to the hCG peak. This reduction in TSH suggests that hCG causes an increased
secretion of T4 and T3.
Women with hyperemisis gravidarum often have high hCG levels that cause transient
hyperthyroidsm. In the vast majority of such patients, there will be spontaneous remission of the
increased thyroid function when the vomiting stops in several weeks. When there are clinical
features of hyperthyroidism, it is be reasonable to treat with antithyroid drugs or a beta-
adrenergic blocker, but treatment is rarely required beyond 22 weeks of gestation.
Hyperthyroidism or increased thyroid function has been reported in many patients with
trophoblastic tumors, either hydatiditform mole or choriocarcinoma. The diagnosis of
hydatidiform mole is made by ultrasonography that shows a ‘snowstorm’ appearance without
a fetus. Hydatidiform moles secrete large amounts of hCG proportional to the mass of the tumor.
The development of hyperthyroidism requires hCG levels of . 200 U/ml that are sustained for
several weeks. Removal of the mole cures the hyperthyroidism. There have been many case
reports of hyperthyroidism in women with choriocarcinoma and high hCG levels. The principal
therapy is chemotherapy, usually given at a specialized center. With effective chemotherapy, long-
term survival exceeds 95%.
A unique family with recurrent gestational hyperthyroidism associated with hyperemesis
gravidarum was found to have a mutation in the extracellular domain of the TSH receptor that
made it responsive to normal levels of hCG.

Key words: human chorionic gonadotropin; thyrotropin; pregnancy; hyperemesis gravidarum;

hydatidiform mole; choriocarcinoma; mutant thyroid-stimulating hormone receptor.

* Tel.: þ 310-268-3852; Fax: þ 310-268-4879.

E-mail address: jhershmn@[Link] (J.M. Hershman).

1521-690X/$ - see front matter Published by Elsevier Ltd.

250 J. M. Hershman

HCG BIOCHEMISTRY AND PHYSIOLOGY

Biochemistry

Human chorionic gonadotropin (HCG) is a member of the glycoprotein hormone

family that is composed of a common a-subunit and a hormone-specific b-subunit, non-
covalently associated.1 The a-subunit of HCG, that is common to the pituitary
hormones, thyroid-stimulating hormone (TSH), follicle-stimulating hormone (FSH) and
luteininzing hormone (LH), consists of a polypeptide chain of 92 amino acid residues
containing two N-linked oligosaccharide side-chains. The hCG b-subunit consists of
145 residues with two N-linked and four O-linked oligosaccharides. Figure 1 shows the
structure of the HCG subunits. The TSH b-subunit is composed of 112 residues and
one N-linked oligosaccaride. The b-subunits of both possess 12 half-cysteine residues
at highly conserved positions. Three disulphide bonds form a cystine knot structure,
identical in both hormones and essential for binding to the receptor.2 HCG and LH bind
to the same receptor.
A single gene on chromosome 6 encodes the a-subunit.3 The genes that encode the
b-subunits are in a cluster on chromosome 19. There are eight genes for the b-subunit
of HCG/LH. One gene codes for LH, and seven genes code for HCG, but only three are
actively transcribed. Only primates and horses have genes for b-HCG. A single base
deletion in the b-LH gene caused a read-through mutation of a stop signal in the b-LH
gene, resulting in the extended carboxyteminal 33 amino acid sequence of b-HCG.
HCG, molecular weight 36 700, contains 30% carbohydrate, the highest
carbohydrate content of any human hormone. In contrast with the approximate
1 hour plasma half-life of LH, that of HCG is about 24 hour because of its high sialic acid
content that prevents uptake and degradation by the liver. The complete hCG molecule
is synthesized primarily in the syncytiotrophoblast. Small amounts of the a and b
subunits are also secreted.

Pattern of secretion

Secretion of HCG begins very early in pregnancy and peaks at 9– 11 weeks of

pregnancy (Figure 2). Peak levels are in the range 30 –100 U/l and last for only a few
days, then gradually decline to a nadir of 5 –10 U/l at about 20 weeks, where they
remain throughout the latter half of pregnancy. The peak levels bear a relation to the
mass of the placenta. Peak levels are higher and more prolonged when there are
multiple fetuses.

Glycoprotein hormone receptors

The glycoprotein hormone receptors are members of the large superfamily of G-protein-
coupled seven-transmembrane receptors. They share a high degree of homology (, 70%)
in their transmembrane domains.4 The main differences are found in the large amino-
terminal extracellular domain involved in binding of the hormone. In the extracellular
domain, the LH/CG receptor has 45% homology with the TSH receptor.4 – 6

Function of HCG
The best known biological function of hCG is the maintenance of the function of the
corpus luteum, resulting in continued progesterone production. However, progesterone
Effect of human chorionic gonadotropin on the thyroid 251

α-subunit
20
Pro Glx Ser Phe Phe Pro
Gly Asx
Ala
Glx

Pro
1
H2N Ala Pro Glx Glx
Pro
Asx 7
Val 10 Leu
Glx
Asx Cys Cys Thr
Ile
28
Leu 40
Gln Cys Met Gly Cys Cys Phe Ser Arg Ala Tyr Pro Thr Pro
31 32 Leu
Asn Tyr Ser Lys Ala 59 Arg
Arg Val Cys
Val Cys
Thr Ser
60
Thr Ser
70 Val Glx Lys
Cys Tyr
Met Ser
Thr 87 Tyr Lys
Thr
Gly Ser Hls Arg
90 Lys Val
Gly 81 Cys Thr
Ser COOH
Val Asn Ser
Pha 82 Met
Thr Lys
Lys Cys CHO Gln
70 CHO Leu Lys
Val Ala Hls
Val Thr 50 Val
Hls
Met Glx Asn 80 Lys
Gly

Gly Pro Leu Val Thr

hCG β-subunit Ala
Leu 50 Gly
Phe
Pro Gln
Lys Gln
Leu
Val Val
57 Val
Arg Tyr Asn Cys
Glx Asp
Val
Val
Pro Thr
Arg Cys Arg
Thr Met
Phe Tyr 38
Asn Pro Val Glu
Val
Ser Val Gly
Gly Ile Ser
80 Tyr
Arg Arg Ala Ala
Val Gln
Leu Ala
Pro Pro Cys 34 93 Arg
Leu Arg eu
Gly Ser Ile Cys Ser
Cys
CHO Thr
26 Leu Thr
Pro Thr Cys 90
Val Cys Ile Thr Val Asn
88 Gln Ala
30 Cys
23 Thr
Gly Pro AspAsp CysThr Asp
Arg Leu Pro
Phe 110 Hls Asp Arg CysArg Lys Pro Gly Gly Cys
Glu Pro ProArg
Lys Ile 9 100
Leu
Glu Asn Pro
A Val Ala Ala Gln
Asp Leu Thr Lys
Val Ser CHO Ser
Ser H2N
Gly 120 Ser
CHO Ser
Arg Lys
Ala CHO CHO
72 Pro CHO 130 140
Pro Pro Gln COOH
ProSer Leu Pro Ser Pro Ser Arg Leu Pro Gly Pro Ser Asp Thr Pro Ile Leu Pro
Cys 145

Pro Val Cys 90

Cys Ile Thr Val Asn
Cys Gln Ala
30 88 Cys
23 Thr
Gly Pro Asp Asp Cys Thr Asp
Arg Leu Lys Pro Gly Gly Cys
Pro Hls Asp
Phe 110 Arg Cys Arg
Glu Pro Arg
Pro 100
Lys Ile 9 Leu
Glu Asn Pro
Gln Val Ala Gln
Asp Ala Leu Thr Lys
Ser CHO Ser
Ser H2N
1
120 Ser
CHO Ser
Lys
Ala CHO CHO
Pro CHO 140
130 COOH
Pro Gln
Ile Leu Pro
Pro Arg Leu Pro Gly Pro Ser Asp Thr Pro
Ser Leu Pro Ser Pro Ser 145

Figure 1. Schematic representations of the alpha and beta subunits of hCG (from Ren SC, Braunstein GD,
Sem. Reprod. Biol. 1992; 10:95 –105, reprinted by permission).
252 J. M. Hershman

1.5 50

40

)
)

1.0

hCG (I.U./Lx1000) (
30
TSH (mU/L) (

20
0.5

10

0
0 10 20 30 40

WEEKS OF GESTATION

Figure 2. Serum hCG and TSH as a function of gestational age. (with permission9). Q 1990 The Endocrine
Society.

synthesis by the corpus luteum begins to decline at about 6 weeks, several weeks before
peak hCG secretion. Until the seventh week of pregnancy, the survival of the pregnancy
depends on the steroids from the corpus luteum.
A second function of HCG is stimulation of fetal testicular secretion of
tesotosterone that attains a maximum at approximately the same time in gestation
when the maximal levels of hCG are attained. Thus, at a critical time in sexual
differentiation of the male fetus, hCG, entering fetal plasma from the syncytiotropho-
blast, stimulates the replication of fetal testicular Leydig cells and testosterone synthesis
to promote male sexual differentiation.

Thyrotropic action in normal pregnancy

At the time of the peak hCG levels in normal pregnancy, serum TSH levels fall and bear
a mirror image to the hCG peak7 – 9 (Figure 2). This reduction in TSH can now be
measured with precision with current sensitive TSH assays. The increase of HCG most
likely causes an increased secretion of T4 and T38,9, but this is difficult to establish with
certainty because the increased thyroxine-binding globulin (TBG) level of pregnancy
may confound the measurement of small changes in free thyroid hormone levels, and
data in the literature are contradictory. Several reports show that free T3 or T4 levels
are significantly elevated at the time when hCG levels are maximal.8 – 11 It is likely that
the HCG-induced thyroid secretion increases free T4 and free T3 levels, albeit
within the normal range. Thyroid-stimulating activity in sera of normal pregnant women
shows a significant correlation with serum hCG levels.12,13 In bioassays, hCG is only
about 1/104 as potent as hTSH during normal pregnancy.14 It is likely that the
thyrotropic activity of hCG during its peak secretion overrides the normal operation of
the hypothalamic-pituitary-thyroid feedback system.8,15
Effect of human chorionic gonadotropin on the thyroid 253

In a systematic survey of pregnant women in Brussels during the first trimester, 20%
had a suppressed serum TSH level and increased serum thyroxine concentration, and in
1% this was associated with clinical features of hyperthyroidism.16 In Asian women in
Singapore at 8 – 14 weeks of pregnancy, 33% had suppressed TSH and 11% had
suppressed TSH and elevated free T4 levels.17

Assays of thyrotropic action of HCG

HCG has thyroid-stimulating activity in bioassays in mice, rats, chicks and men.18 – 20
Administration of single doses of large amounts of commercial HCG to men cause the
release of thyroidal radiodidine, even though the peak HCG levels attained were only
25 –42 U/ml.21 HCG stimulates iodide uptake, adenylate cyclase, and DNA synthesis in
cultured rat thyroid cells.22 HCG stimulates iodide uptake by increasing the mRNA and
protein level of the sodium/iodide symporter.23 In Chinese hamster ovary (CHO) cells
transfected with the human TSH receptor, hCG increased adenylate cyclase and DNA
synthesis.24,25 These studies demonstrated unequivally that HCG activates the TSH
receptor and is a weak thyrotropin. LH and hCG lacking the C-terminal peptide of the
beta subunit were almost ten-fold more active in this system.25 In clinical situations such
as primary hypogonadism, the elevated levels of LH are several orders of magnitude
below those required to activate the TSH receptor.

Metabolism of HCG
The hCG immunoreactivity in serum is a mixture of hCG-related molecules, including
intact hCG, nicked hCG (missing the peptide linkage at b44 –45 or b47– 48),
carbohydrate variants of hCG, hCG missing b-C-terminal tail, hCG free a-subunit and
free b-subunit.26 Nicks of the hCG molecule frequently occur in a hydrophobic loop in
the hCG b-subunit, which is held in place by a disulfide link between Cys38 and Cys57
(Figure 1). Nicking of the hCG molecule may result from the deactivation and
degradation pathway of hCG in serum and urine.27 The nicking of the peptide bonds
reduces the binding of hCG to its receptor and causes a loss of 80% of its steriodogenic
activity.28 Nicked hCG preparations, obtained from patients with trophoblastic disease
and by enzymatic digestion of intact hCG, had approximately 1.5 –2-fold the potency of
intact hCG for stimulation of recombinant human TSH receptor.29 Therefore, the
thyrotropic activity of hCG is also influenced by the metabolism of the hCG molecule.

Role of carbohydrate in thyrotropic action of hCG

The biologic activity of glycoprotein hormones is influenced by the number and
structure of the oligosaccharide side chains. Extensive variations are possible in the
branched oligosaccharide structures, contributing to considerable heterogeneity of
glycoprotein hormones.30 Deglycosylation and/or desialylation of hCG enhances its
thyrotropic potency in rat (FRTL-5) thyroid cells.31,32 Basic hCG isoforms with lower
sialic acid content extracted from hydatidiform moles were more potent in activation of
adenylate cyclase, and showed a high ratio of bioactivity/immunoactivity (B/I) in CHO
cells tranfected with human TSH receptors.33 This is consistent with the finding that
the b-C-terminal tail-truncated hCG with higher thyrotropic potency is substantially
deglycosylated and desialylated in the b-subunit in comparison with intact hCG because
all four O-linked glycosylation sites occur within the missing C-terminal extension.25
Although removal of sialic acid from hCG enhances its TSH receptor binding, it also
reduces its plasma half-life because sialic acid blocks the high affinity for and rapid
254 J. M. Hershman

uptake of hCG by hepatic receptors for asialoglycoproteins.34 Therefore, it is likely that

the thyrotropic activity of hCG is regulated by two factors: the amount of desialylated
hCG produced from trophoblast cells and its plasma half-life.25 The precise nature of
the thyrotropic molecular variant of hCG is controversial. HCG that is less sialylated
activates the TSH receptor to a greater extent14, as has been reported in gestational
thyrotoxicosis.14 However, lack of sialic acid reduces its half-life. More acidic variants of
hCG have a longer half-life and, therefore, a more prolonged action.35,36

HYPEREMESIS GRAVIDARUM
Definition and prevalence

Hyperemesis gravidarum occurs in about 1.5% of pregnancies and is probably more

prevalent in Asian women than in Caucasians.37 The incidence is 4.5% in Kuwait.38 It is
characterized by prolonged and severe nausea and vomiting in early pregnancy that
leads to a loss of 5% body weight, dehydration and ketosis.39 It frequently results in
hyponatremia, hypokalemia, hypochloremic alkalosis, and abnormalities of liver
function. Other causes of vomiting must be excluded. There is a correlation between
the degree of vomiting and the serum hCG level (Figure 3).39 Management includes
hospitalization, intravenous fluid and electrolyte replacement, thiamine supplemen-
tation, conventional antiemetics, and psychological support.

Increased thyroid function

There are many reports of series of hyperemesis patients whose thyroid function has
been studied. A study in Belgium reported that free thyroxine index was increased in
25 of 33 consecutive hyperemesis patients, of whom six were treated with
methimazole until euthyroid.40 However, free thyroxine index normalized in all
patients, regardless of therapy. A study of 25 patients with hyperemesis in England
found that ten had increased free thyroxine levels.41 Those with increased free
thyroxine had suppressed TSH responses to thyrotropin-releasing hormone. The free
thyroxine levels normalized when the vomiting stopped and remained normal
postpartum. In contrast, a 39 year-old woman presented with severe hyperemesis at 8
weeks pregnancy and very high serum hCG level.42 Although she was treated with
methimazole suppositories until euthyroid at 18 weeks, her vomiting persisted until
delivery, suggesting that the vomiting was not caused by the increased thyroid function.
A study of 71 patients with hyperemesis in Hong Kong revealed that one-third had high
free T4 and one-fifth had high free T3 levels.43 In those with elevated free thyroid
hormone levels, serum hCG was higher. A study in Israel of 41 consecutive admissions
with hyperemesis showed that free thyroxine was increased in 11 patients.44 Four
were treated with propylthiouracil because of tachycardia, two of whom had goiter.
Thyroxine levels returned to normal in the untreated patients when the hyperemesis
abated. A study in Turkey of 24 patients with hyperemesis reported that their free T3,
free T4 and hCG levels were significantly higher than those of controls.45 Twin
pregnancies are more often associated with sustained elevation of hCG and
hyperemesis gravidarum.37,46
A prospective study of 57 consecutive patients with hyperemesis in Los Angeles
compared them with 57 women of similar gestational age.39 In the hyperemesis
patients, TSH was suppressed in 60%, free T4 was increased in 46%, while free T3 index
Effect of human chorionic gonadotropin on the thyroid 255

3.0
NO VOMITING (N-30)
VOMITING (N-27)
2.5
HYPEREMESIS (N-38)
SEVERE HYPEREMESIS (N=19)
2.0
TSH (mU/L)

1.5

1.0

0.5

0.0

40

30
free T4 (nmol/L)

NS

20

10

150
NS
125

100
bCG (IU/mol)

75

50

25

Figure 3. Relation between the severity of vomiting and serum concentratons of TSH, free T4, and hCG
(mean ^ SE). Hormone concentrations differed significantly between each group of patients except as
indicated by NS. (with permission39). Q 1992 The Endocrine Society.
256 J. M. Hershman

was increased in only 12%. The explanation for the relatively lower T3 compared with
T4 may be that caloric deprivation impaired conversion of T4 to T3. Serum HCG levels
were three-fold higher in the hyperemesis patients than in the controls (Figure 3). No
patient in this study had goiter or clinical features of hyperthyroidism. For the entire
group, the degree of biochemical hyperthyoidism and the hCG concentration
correlated with the severity of vomiting (Figure 3). There was an inverse correlation
between the serum HCG and the serum TSH levels and a direct correlation of HCG
with free T4 levels (Figure 4). Thyrotropic activity in the serum, estimated by bioassay,

250

200
Hyperemesis
Control
bCG (IU/ml)

150

100

50

0
0.0 1.0 2.0 3.0 4.0 5.0
TSH (mU/L)

250

200

150
hCG (IU/ml)

100

50

0
5 15 25 35 45 55 65
free T4 (nmol/L)

Figure 4. Correlation of serum hCG vs serum free T4 (r ¼ 0:45; P , 0:001) and serum TSH
(r ¼ 20:48; P , 0:001) in hyperemessis and control subjects. (with permission39). Q 1992 The Endocrine
Society.
Effect of human chorionic gonadotropin on the thyroid 257

140

120
UPTAKE (%)

100

80
125I-IODIDE

60

40

20

0
HYPEREMESIS PREGNANT
GRAVIDARUM CONTROL

200

150
HCG, U/ml

100

50

0
0 50 100 150 200 250 300

IODIDE UPTAKE %

Figure 5. Upper panel, serum thyrotropic activity (measured as iodide uptake in cultured rat cells) in
hyperemeis patients and pregnant controls, mean ^ SE, P , 0:001). Lower panel, correlation of serum hCG
vs serum thyrotropic activity in hyperemesis and pregnant controls, r ¼ 0:50; P , 0:001 (with permission39).
Q 1992 The Endocrine Society.

correlated with the hCG concentration (Figure 5). The authors concluded that hCG
was responsible for the increased hyroid function.

Etiology of hyperemesis gravidarum gravidarum

The etiology of hyperemesis gravidarum gravidarum is unknown. It may be related to the

high hCG level and possibly some action of hCG that is still unclear. The increased thyroid
function, or clinical hyperthyroidism, is attributed to the effect of hCG on the TSH
receptor. The vomiting may be related to increased levels of estradiol, or another steroid
induced by hCG. Although estradiol levels in hyperemesis patients were higher than
those of a control group, there was considerable overlap.39 Increased estradiol levels
were found in women with hyperemesis in the US during the first trimester compared
258 J. M. Hershman

with control subjects.47 A recent study in Greece found that higher levels of estradiol
were associated with nausea with or without vomiting up to the 27th week of
pregnancy.48

Syndrome of transient hyperthyroidsm of hyperemesis gravidarum

The syndrome of transient hyperthyroidsm of hyperemesis gravidarum should be

considered in any woman presenting with biochemical evidence of hyperthyroidism
in early pregnancy. In the vast majority of these patients, there will be spontaneous
remission of the increased thyroid function when the vomiting stops in several
weeks. Antithyroid drug therapy is unnecessary. However, some patients with
hyperemesis have frank clinical hyperthyroidism. Because the clinical hyperthyroid-
ism in these patients differs from that of classical Graves’ disease, it has been called
‘gestational thyrotoxicosis’. It has the following characteristics: thyrotoxic symptoms
in early pregnancy, marked increase in serum FT3 and FT4, association with
hyperemesis gravidarum, spontaneous disappearance in the latter half of pregnancy,
negative thyroid peroxidase antibody, negative TSH receptor antibody, usually an
absence of goiter, and circulating hCG with high biological activity.49
It is be reasonable to treat these patients with antithyroid drugs or a beta-adrenergic
blocker, depending on the clinical features, but treatment is rarely required beyond 22
weeks of gestation. However, there are no controlled clinical trials that can be used for
a guide to management.
Hyperplacentosis, a rare condition in which the placenta is enlarged and hCG
concentration is very high, may cause clinical hyperthyroidism that remits promptly
after delivery of the placenta.50

HCG isoforms with thyrotropic activity

Five patients with gestational thyrotoxicosis and hyperemesis were shown to have
circulating asialo-hCG with high thyrotropic bioactivity.51 Another group confirmed
the potent thyrotropic activity of asialo-hCG in a human thyroid follicle bioassay.52 In
contrast, one study reported a preponderance of acidic variants of hCG in the
serum of patients with hyperemesis gravidarum.35 Another study found a similar
distribution of HCG isoforms in sera of hyperemesis patients and controls36,
however, the thyroid hormone concentrations correlated to the absolute HCG
concentration and the proportion of acidic isoforms. The acidic variants with higher
sialic acid content would be expected to have a longer serum half-life. These reports
support the concept that the absolute amount of HCG plays a role in stimulating
thyroid function.

PLACENTAL TUMORS

Hydatidiform mole

Hyperthyroidism or increased thyroid function has been reported in many patients with
trophoblastic tumors, either hydatiditform mole or choriocarcinoma.33,52 – 54 In the US,
hydatidiform mole occurs between 0.5 and 2.5 per 1000 pregnancies.55 It is more
common in Asian and Latin American countries. The prevalence is greatest in women
Effect of human chorionic gonadotropin on the thyroid 259

over 50 or less than age 15. Women who have had a previous mole have a greater risk
of further molar pregnancies.
The mole consists of vesicles of swollen hydropic villi of various sizes, and there is an
absence of fetal tissue. The karyotype is paternal. The usual clinical presentation is that
of a threatened abortion with vaginal bleeding. In one-half of the patients, the uterus is
large for the date of the pregnancy, About one-fifth of the women have hyperemesis,
and 5 – 10% have toxemia, which is unusual in early pregnancy. The diagnosis is made by
ultrasonography that shows a ‘snowstorm’ appearance without a fetus. The current
widespread use of ultrasound for monitoring pregnancy has resulted in earlier
diagnosis when the tumor mass is smaller.56 In one study, moles were evauated at a
mean gestational age of 8.5 weeks during the period 1994– 97 vs 17.0 weeks during
1969 –75.57 Hydatidiform moles secrete large amounts of HCG, and the HCG level is
proportional to the mass of the tumor.
The prevalence of increased thyroid function in patients with hydatidiform mole has
been reported as 25 –64%.54,55 About 5% have clinical hyperthyroidism.58 In a study of
14 women with hydatidiform mole in 1975, nine were hyperthyroid.53 Serum HCG
levels varied from 150– 3000 U/ml. Thyroid-stimulating activity, measured by bioassay
in mice, was found in all sera, and there was a close correlation between this activity,
the serum HCG, and the T3 level. Removal of the mole caused a dramatic fall in serum
levels of T3, T4, HCG and thytropic activity (Figure 6). The data suggested that HCG,
itself, when present in large amounts that are several-fold the peak levels of pregnancy,
stimulates thyroid function and may cause hyperthyroidism.

32 SERUM T4 800
SERUM T3
T4 µg/100 ml

T3 ng/100 ml

24 600

16 400

8 200
4 100
Nal O.R.

600 1200
HCG
Molar TSH µU/ml

HCG U/ml

Molar TSH
400 800

200 400

0 0
1 2 3 4 5 6 7 8 9 10
DAYS

Figure 6. Serum T4, T3, hCG, and molar TSH (measured by bioassay in mice) in a patient with hydatidiform
mole and hyperthyroidism. She was treated with sodium iodide intravenously and then had evacuation of the
mole by hysterectomy (OR). There was a parallel fall in the hCG and molar TSH concentrations. (with
permission53).
260 J. M. Hershman

The diagnosis of hyperthyroidism, or increased thyroid function, is established by

finding elevated serum free T4 and T3 concentrations and suppressed serum TSH level.
Thyroid radioiodine uptake is greatly increased.59 In general, the development of
hysterotomy requires hCG levels of . 200 U/ml that are sustained for several weeks.
HCG extracted from molar tissue showed molecular heterogeneity with a
significant amount of basic molecules containing less sialic acid than normal, highly
purified HCG.33 The more basic, partially desialylated isoforms of hCG had a much
higher ratio of biologic to immunologic activity than the more acidic forms. The partially
desialylated HCG, because of its greater thyrotropic activity, may be responsible for
hyperthyroidism in some patients with trophoblastic disease. Therefore, the
thyrotropic potency of hCG in patients with trophoblastic disease should be
considered not only based on its immunoreactivity but also on its biological activity.
Therapy consists of evacuation of the mole by suction curettage or removal by
hysterotomy. This results in prompt reduction in thyroid hormone levels, hCG and
thyroid-stimulating activity. Monitoring serum HCG is essential in follow-up to detect
persistence of molar tissue or the development of choriocarcinoma.

Choriocarcinoma

Choriocarcinoma occurs in one in 20 000 to one in 40 000 pregnancies in the US and

Europe.60 About half of the cases occur in women with previously diagnosed
hydatidiform moles, but only 3 –5% of women with moles develop choriocarcinoma.
Patients usually present within 1 year of the previous conception. Pathologically, the
tumors consist of large sheets of syncytiotrophoblastic and cytotrophoblastic cells,
hemorrhage, necrosis and absence of hydropic villi. The tumors invade blood vessels
and progress to hemorrhagic metastases. The natural history is rapid progression,
spread to distant organs, especially lungs and vagina, and less commonly the brain and
liver. Without treatment, death occurs within a few months. Patients present with
vaginal bleeding, hemoptysis if there are lung metastases, focal neurologic signs
indicative of brain metastases, and often profound weight loss.
There have been many case reports of hyperthyroidism in women with
choriocarcinoma.61 – 63 In addition, there are 17 cases of choriocarcinoma in men
usually in testicular tumors, less often in extragonadal sites.64 – 66 The precise
prevalence of hyperthyroidism in patients with trophoblastic tumors is unknown. It
was found in five of 20 patients with trophoblastic disease evaluated at a referral center
in 1 year67, three of these five thyrotoxic patients had choriocarcinoma, and two had
hydatidiform moles. In another study, 30 of 52 patients with gestational trophoblastic
tumors were found to be thyrotoxic.68
Less than 3% of the oligosaccharide side chains of hCG derived from a
choriocarcinoma contained sialic acid, whereas that of normal hCG was mostly
sialylated.69 This is consistent with other reports of the preponderance of basic
isoforms of HCG in trophoblastic tumors.
The principal therapy of choriocarcinoma is chemotherapy. Patients should be
referred to a specialized center. With effective chemotherapy, long-term survival is very
high. In the UK, overall long-term survival exceeds 95%.70 In low-risk disesase the cure
rate is virtually 100%, whereas for high-risk patients it is 86%. Cure of the
choriocarcinoma results in a cure of the hyperthyroidism.61 – 63,67
Effect of human chorionic gonadotropin on the thyroid 261

TSH RECEPTOR MUTATION

A woman with recurrent gestational hyperthyroidism associated with hyperemesis

gravidarum and a TSH receptor mutation was recently reported.71 After two
miscarriages, she had hyperemesis early in pregnancy, along with overt biochemical
hyperthyroidism. She had a small diffuse goiter and no evidence of Graves’ eye
disease. Hyperthyroidism was diagnosed and treated with propylthiouracil through-
out the pregnancy. The drug was discontinued postpartum and normal thyroid
function ensued. During her next pregnancy, she had a recurrence of hyperthyroid-
ism associated with hyperemeis gravidarum, and was again treated with
propylthiouracil.
The patient’s mother had a diagnosis of Graves’ disease during her second and third
gestations. The mother’s first pregnancy was complicated by hyperemesis, and
terminated in miscarriage. During her next pregnancy, she had tremor, tachycardia,
anxiety and hyperemesis. Thyroid function tests revealed hyperthyroidism. She was
treated with antithyroid drugs throughout pregnancy, the hyperemesis resolved, and
she delivered a healthy female baby, the proband. The hyperthyroidism improved in the
postpartum period allowing for discontinuation of antithyroid drugs. The following

80

70

60
Mutant
cAMP Production (pmol/dish)

50

40

30

20 Wild type

10

Mock-transfected cells
0
0 1 33 0 3 10 33 0 0 00
0. 0. 1. 3. 10 30 10
Chorionic Gonadotropin (U/ml)

Figure 7. Functional characteristics of the mutant thyrotropin receptor in COS-7 cells, showing the effect of
stimulation of cAMP production by graded concentrations of hCG in cells transfected with wild-type or
mutant thyrotropin receptor. (with permission71). Q 1998 Massachusetts Medical Society. All rights reserved.
262 J. M. Hershman

pregnancy was also complicated by hyperemesis and hyperthyroidism, requiring

treatment with antithyroid drugs, and followed by recovery of normal thyroid function
postpartum.
Study of the TSH receptor of the patient disclosed the substitution of guanine for
adenine at codon 183 in exon 7 in one allele, resulting in substitution of arginine for
lysine in the middle portion of the extracellular domain of the TSH receptor, a region of
the receptor in contact with the ligand. The patient’s mother was heterozygous for the
same mutation. The mutant TSH receptor was transfected into COS cells and was
shown to be much more sensitive to hCG than the wild-type receptor (Figure 7). It is
likely that the hereditary gestational hyperthyroidism in this family was due to
hypersensitivity of the mutant TSH receptor to hCG. This unique mutation has not yet
been reported in other families.
Recent work has shown that substitution of methionine, asparagjne or glutamine for
the lysine 183 in the TSH receptor increased its affinity toward hCG, the gain of
function was attributed to the release of a nearby glutmate resudue at 157 from a salt
bridge with lysine 183.2

SUMMARY

HCG has thyroid stimulating activity and may cause hyperthyroidism in women with
hyperemesis gravidarum or trophoblastic tumors in women who have high levels of
hCG.
In the vast majority of women with hyperemesis gravidarum, there will be
spontaneous remission of the increased thyroid function when the vomiting stops in
several weeks.
Routine ultrasonography has led to an earlier diagnosis of hydatidiform mole, with a
smaller mass of tumor and lower hCG levels. The development of hyperthyroidism
requires hCG levels of . 200 U/ml that are sustained for several weeks. Removal of the
mole cures the hyperthyroidism. In patients with choriocarcinoma and high hCG levels
causing hyperthyroidsim, the principal therapy is chemotherapy, usually given at a
specialized center.
A unique family with recurrent gestational hyperthyroidism associated with
hyperemesis gravidarum was found to have a mutation in the extracellular domain
of the TSH receptor that made it responsive to normal levels of hCG.

Research agenda
† additional studies should be carried out to characterize the HCG that has
thyroid-stimulating activity in patients with hyperthyroidsm of hyperemesis
gravidarum

ACKNOWLEDGEMENTS

Supported by VA Medical Research Funds.

Effect of human chorionic gonadotropin on the thyroid 263

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