Clinical Chemistry 43: 2155-2163, 1997;
(Clinical Chemistry. 1997;43:2155-2163.)
© 1997 American Association for Clinical Chemistry, Inc.
Disappearance of human chorionic gonadotropin and its 
- and ß-subunits after term pregnancy
Juha Korhonena,
Henrik Alfthan,
Pekka Ylöstalo,
Johannes Veldhuis1 and
Ulf-Håkan Stenman
Department of Obstetrics and Gynecology and Department of Clinical Chemistry, Helsinki University Central Hospital, Haartmaninkatu 2, FIN-00290 Helsinki, Finland.
1
Department of Internal Medicine, University of Virginia
Health Sciences Center, and National Science Foundation Center for
Biological Timing, Charlottesville, VA 22908.
a Author for correspondence. Fax 358-9-4714801; e-mail ulf-hakan, stenman{at}huch.fi
 |
Abstract
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We have used high-specificity and precision
immunofluorometric assays to measure the elimination
half-times of human chorionic gonadotropin (hCG), hCG
, and hCGß in
serum over 21 days after delivery in six women with term pregnancies.
Baseline concentrations and half-times were calculated with the use of
a curve-fitting algorithm for multiexponential decay. In contrast to
the two-component model, a three-component exponential function with
baseline provided a fit for which predicted values could not be
distinguished from the observed values by analysis of variance. Median
half-times were 3.6, 18.0, and 53.0 h for hCG; 1.0, 23.4, and
194 h for hCGß; and 0.6, 6.2, and 21.9 h for hCG. The
mean ratio of hCG to hCG decreased rapidly from 36.9% to 3.3% on
day 3; thereafter it increased to 64.3% 21 days after delivery because
of a higher baseline concentration of hCG. hCGß had the slowest
total elimination rate, and the ratio of hCGß to hCG in serum
increased from 0.8% before delivery to 26.7% after 21 days. If the
metabolism of hCG and hCGß is similar in patients with trophoblastic
disease, the ratio of hCGß to hCG must be evaluated with caution in
samples taken several days after initiating therapy. We conclude that
the disappearance of hCGß from plasma is slower than previously
recognized and that the ratios of hCGß or hCG to intact hCG vary
as a function of postpartum time. Such information may be important in
clinical studies of pregnancy disorders.
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Introduction
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Human chorionic gonadotropin
(hCG)1
is a
heterodimer composed of two highly glycosylated subunits, called
and ß, that are noncovalently joined. The -subunits of all
glycoprotein hormones of pituitary origin, including
follicle-stimulating hormone, luteinizing hormone, and
thyroid-stimulating hormone, are virtually identical, but the
ß-subunits are different and thus confer biological specificity of
the hormones.
In early pregnancy the concentrations of hCG in serum start to increase
7–11 days after ovulation, corresponding to 21–25 days after the last
menstrual period (1)(2). After in vitro
fertilization and embryo transfer, an increase of serum hCG can be
observed 9 days after ovum retrieval, corresponding to 7 days after
embryo transfer (3). The increase is exponential, with a
doubling time of 1.5 days during the first 6 weeks (4).
Serum hCG reaches peak concentrations of ~100 000 IU/L (in relation
to the First International Reference Preparation) at 8–10 weeks after
the last menstrual period. The concentrations start to decrease after
week 12 and stay fairly constant at about ~30 000 IU/L from the 20th
week until term (5).
In addition to hCG, serum and urine from pregnant women and patients
with trophoblastic disease contain free -subunits (hCG) and
ß-subunits (hCGß). The profile of the serum concentrations of
hCGß during pregnancy resembles that of hCG, but the concentrations
are lower. During gestation, the molar ratio of hCGß to hCG is
1.5–4% in early pregnancy and decreases to 0.2–1% after the 10th
week (3)(6). In patients with benign
trophoblastic disease, the ratio is similar to that in pregnancy,
whereas higher ratios are observed in trophoblastic cancer. Thus the
ratio may aid in differentiating between malignant and benign
trophoblastic tumors (7)(8)(9)(10).
The concentrations of hCG increase throughout pregnancy from <1
µg/L (69 pmol/L) (11) to 100–300 µg/L (6900–20 700
pmol/L) in the third trimester (12)(13). The
hCG to hCG ratio is <10% during the first trimester and increases
to 30–60% at term (6).
When hCG is injected into humans, it reportedly has a biphasic
disappearance curve with an initial fast half-time of ~5 h and a slow
one of 24–32 h (14)(15)(16). Injected hCG and hCGß are
cleared from circulation much more rapidly than hCG
(16)(17). hCG has a rapid half-time of 13
min and a slow one of 76 min. The corresponding times for hCGß are 41
and 236 min, respectively (18)(19).
Serial hCG estimations are used for detecting pregnancy-related
disorders such as spontaneous abortion and ectopic pregnancy as well as
following-up patients with ectopic pregnancy. In ectopic pregnancy
patients selected for expectant management, decreasing concentrations
usually indicate spontaneous resolution, but one-third of these still
require surgery within 1–24 days (20). Thus a decreasing
hCG concentration alone is not a reliable indicator for spontaneous
resolution of an ectopic pregnancy.
Because hCG and hCGß have been reported to have much shorter
half-times than hCG, they might more rapidly reflect changes in
placental function such as an impending abortion. Changes in the ratio
of the subunits to intact hCG potentially could be used to evaluate
trophoblastic activity in pregnancy-related disorders, e.g., a low
subunit to hCG ratio might indicate the cessation of hCG production
because the ratio may be expected to decrease rapidly when the
production ceases such as during an abortion or after delivery.
|
Materials and Methods
|
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patients
Six women with term pregnancies were included in the study, which
was approved by the local institutional review committee. One of the
patients had a twin pregnancy, one had gestational diabetes
(non-insulin-dependent glucose intolerance of pregnancy), and one had
diabetes mellitus (insulin-dependent diabetes with nephropathy). The
mean age was 37 years (range 32–48 years) and mean gestational age
38 ± 4 weeks (range 37 + 3 to 39 + 5 weeks). In
singleton pregnancies the mean birth weight was 3862 g (range
3270–4360 g) and the mean placental weight 678 g (range 600–770
g). In the twin pregnancy the birth weights were 2970 g and
3325 g and placental weights 560 g and 685 g,
respectively.
The first blood sample was drawn from a cannula inserted in the
right cubital vein 15 min before an elective caesarean section,
performed under spinal anesthesia. Infusion of saline solution was
started in the opposite arm to stabilize the hemodynamics during
anesthesia before the beginning of spinal anesthesia. The infusion was
continued in some individuals, depending on the blood pressure. At the
time of the first sample, ~500 mL of saline solution had been infused
and at the time of delivery ~1000 mL. The effect of saline infusion
on the serum concentration of hCG and its subunits and consequently on
the half-times was analyzed in one case (patient 5 in Table 3
), in
which blood samples were drawn before fluid infusion and after infusion
of 1 L of saline. After delivery, blood samples were drawn at 5, 10,
15, 20, 30, 40, 60, 120, 180, 360, and 720 min during the first day and
every 24 h thereafter for 6 days. Additional blood samples were
obtained from all patients 14 to 16 days after delivery and from 4 of
those patients 21 days after delivery. Serum samples were stored at
-20 °C before assay.
immunoassays
Serum hCG, hCGß, and hCG were determined by time-resolved
immunofluorometric assays (DELFIA®, Wallac). The detection
limit for hCG was 0.3 IU/L. The assays for hCGß and hCG are newly
developed time-resolved immunofluorometric assays and are described in
detail elsewhere. The detection limit for hCGß was 0.3 pmol/L (0.01
µg/L) (conversion factor: 1 µg/L = 45.5 pmol/L) and that for
hCG 2.8 pmol/L (0.04 µg/L) (conversion factor: 1 µg/L = 69
pmol/L). Cross-reaction of hCG in the subunit assays was studied after
separation of hCG and the subunits in pregnancy serum (3).
On a molar basis, the cross-reaction of hCG in the hCGß assay was
0.05% and that in the hCG assay <0.1%. The upper reference limits
of hCG, hCGß, and hCG in nonpregnant premenopausal women were 2.9
IU/L, 1.6 pmol/L (21), and 31 pmol/L, respectively [H.
Alfthan, unpublished finding]. The assays measure equally intact and
nicked forms of hCG and hCGß [H. Alfthan, unpublished finding].
calibrator preparations and conversion factors
The hCG assay was calibrated against the WHO 3rd International
Standard (75/569), 1 mg corresponding to 9286 IU, and hCGß and hCG
against the 1st International Standard, 75/551 and 75/569,
respectively. For conversion of IU to molar units, molecular masses of
36 700, 22 000, and 14 500 Da were used for hCG, hCGß, and hCG,
respectively (22). The conversion factor of hCG to SI unit
was 1 IU/L = 2.93 pmol/L.
calculations and statistical analysis
The ratio of the subunits (hCG or hCGß) to total hCG was
calculated on the basis of the molar concentration of each subunit
relative to the concentration of subunit + hCG. Percentiles, means,
SDs, and 95% confidence limits for the concentrations of hCG, hCGß,
and hCG and the ratios of the concentrations to the initial values
were calculated for each time point. The individual subject's
concentration values were used for calculations of base-line
concentrations and half-times for hCG, hCGß, and hCG with the use
of a curve-fitting algorithm for multiexponential decay (Microsoft
Excel®). An iterative approach was used to calculate the
combination of basal concentration and two or three exponential
functions providing the best fit of the observed concentration values.
The algorithm minimizes the fitted variance, which is the sum of the
squares of the differences between the calculated curve and the
observed values.
The mathematical model for the decay curve is defined as
 | (1) |
where Ci is a coefficient (decay amplitude) and
Ri is a rate constant (min-1).
t is the time after delivery, and A is the
baseline concentration. By choosing n between 1 and 3, sums of up to 3
exponential terms can be used (23). Untransformed
concentration data over time are fit, such that a triphasic decay curve
is defined as
 | (2) |
and a biphasic decay curve is defined as
 | (3) |
The half-times are calculated as t1/2 =
(ln2/Ri). The integrated contribution of each
exponential component to the overall disappearance curves of hCG,
hCGß, and hCG was calculated on the basis of the area under the
curve (AUC) by
 | (4) |
Significant differences between triphasic and biphasic half-time
fits were evaluated by comparing the fitted variances (above) via
F ratio testing with Bonferroni/Dunn correction. We
estimated whether the time course over which the measurements were made
affected the half-times by analyzing time intervals of 0–6 days, 0–1
day, 0–12 h, and 0–6 h. The longest half-times were not calculated
when the time interval was shorter than the longest half-time
component.
|
Results
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The mean serum concentration of hCG before delivery was 32 275
IU/L (94 566 pmol/L) (range 1631–84 995 IU/L). The corresponding
value for hCGß was 729 pmol/L (range 48–2198 pmol/L) and for hCG
35 862 pmol/L (range 17 432–68 145 pmol/L). The mean concentrations
of hCG, hCGß, and hCG are shown in
Figs. 1–3
,
and the ratios of hCGß and hCG to total hCG and the ratios
of hCG to hCGß are shown in Table 1
.
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Figure 1. Observed disappearance of hCG (mean + SD) and
estimated triphasic exponential half-times of hCG and their combined
curve.
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Figure 2. Observed disappearance of hCGß (mean + SD) and
estimated triphasic exponential half-times of hCGß and their
predicted overall decay curve.
|
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A three-component exponential function gave the best fit to the
observed hCG decay curves (Fig. 1
). In contrast to a biphasic model,
this resulted in very small deviations from the observed values, and
the differences between triphasic and biphasic models and between the
biphasic model and the observed values were significant (Table 2
). The curve for hCGß was also optimally fit to a
three-component model (Fig. 2
), with significant differences from the biphasic model (Table 2
). The calculated biphasic curve of hCGß fell below the observed
values during the first hour after delivery, rose above the observed
values during the next 12 h, and also deviated thereafter. The
curve for hCG was also best fit to a three-component model (Fig. 3
). It fit to a two-component model only when values from days
0–2 were included in the calculations. When days 3–6, 14, and 21
values were also included, the biphasic model gave a poor fit. There
were no significant differences between calculated values of the
triphasic half-time model and the observed values of hCG, whereas
calculated values of the biphasic model differed significantly from the
observed ones and those of the triphasic model by analysis of variance
(Table 2
). The half-times were virtually identical when calculated for
shorter time intervals.
The median half-time of the most rapid component of hCG was ~6 times
longer than that of hCG and 4 times longer than that of hCGß
(Table 3
). The median half-time of the second component of hCG was 30%
shorter than that for hCGß, but for hCG the second component was 3
times shorter. The median half-time of the third component of hCGß
was almost fourfold that of hCG, and for hCG it was half of that for
hCG (Table 3
). The algorithm used was set to calculate the baseline
concentrations of hCG and its subunits limiting the highest possible
value to the upper reference limit of nonpregnant premenopausal women.
Without this limitation two patients would have had baseline
concentrations for hCG of 3.5 and 5.2 IU/L, two patients baseline
concentrations for hCGß of 2.8 and 2.5 pmol/L, and one patient a
baseline concentration for hCG of 34.2 pmol/L.
In one patient (number 5 in Table 3
) the serum concentrations of hCG,
hCGß, and hCG were measured before and after induction of spinal
anesthesia and infusion of 1 L of saline. The infusion lowered the
serum concentrations by ~22%. When the postinfusion concentrations
were used as initial values, the calculated half-times increased, but
the median effect was small (2.2%, range 0–24%).
The mean concentrations of hCG, hCGß, and hCG on day 21 after
delivery were 2.6 IU/L (7.6 pmol/L) (range 0.7–4.3 IU/L), 3.2 pmol/L
(range 1.2–5.1 pmol/L), and 16 pmol/L (range 9.3–25.0 pmol/L),
respectively. hCGß had the slowest total elimination rate, and
decreased to a mean ± SD concentration of 1.3% ± 1.0% of the
initial value after 14 days and 0.9% ± 0.8% after 21 days. The hCG
concentration decreased to 0.05% ± 0.02% of the initial value at 14
days and 0.02% ± 0.01% within 21 days. hCG reached a
concentration of 0.07% ± 0.03% within 14 days, decreasing only
slightly thereafter to 0.05% ± 0.03% of the initial value on day 21
(Fig. 4
).
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Figure 4. Disappearance of hCG, hCGß, and hCG after delivery.
The values are given as the proportion (mean + SD) of the
concentration before delivery. The SD bars not visible are too small to
be seen at this scale.
|
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The contributions of the various components to the disappearance curves
were calculated on the basis of AUCs. For hCG, the fastest component
represented 13.8% of all hCG and two slower ones were 68.8% and
17.4%, respectively. For hCGß, the corresponding numbers were 3.1%,
78.1%, and 18.9%, and for hCG they were 23.9%, 59.7%, and
16.4%, respectively (Table 4
). hCG contained much more of the most rapid component than
hCGß. Therefore, the total disappearance of hCGß was clearly slower
than that of hCG (Fig. 4
), and after a transient decrease during the
first hour after delivery, the ratio of hCGß to hCG increased
gradually from 0.8% (range 0.6–1.0%) before delivery to 15.8%
(range 7.7–28.3%) after 14 days and 26.7% (range 20.6–36.9%) after
21 days (Fig. 5
).
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Table 4. Proportions of the various components of hCG, hCG, and
hCGß estimated on the basis of the AUC of each
component.
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Figure 5. Changes in the ratio of hCGß to total hCG (mean +
SD) after delivery.
The values are given as percentages.
|
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hCG had the highest proportion of the rapid component and the lowest
proportion of the slow component, explaining its most rapid total
disappearance (Table 4
and Fig. 4
). The mean ratio of hCG to hCG
before delivery was 36.9% (range 15.3–78.5%). Initially the ratio
decreased rapidly with a nadir of 3.3% (range 1.4–7.9%) on day 3,
but thereafter it increased to 64.3% (range 42.5–83.5%) 21 days
after delivery (Fig. 6
). This resulted from a constant background concentration of
hCG with decreasing hCG concentrations.
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Figure 6. The ratio of hCG to total hCG (mean + SD) after
delivery.
The values are given as percentages.
|
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Discussion
|
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With the use of highly sensitive and specific immunofluorometric
assays, we found in this study that the disappearance of endogenous
hCGß from plasma after delivery is much slower than that observed in
studies with the use of RIA and purified hCGß infused intravenously
(18)(19). Various possible explanations exist
for this. Chemical differences, mainly in the carbohydrate side chains
(24)(25)(26), have been shown to exist between circulating
hCGß and that purified from pregnancy urine, which has been used for
injection (18)(19). The experimental setting
in the present study is not directly comparable with that after
infusion of purified hCGß; i.e., the half-time was measured for
hCGß over a course of 3 weeks, whereas in earlier reports the time
span has been only hours or a few days. However, for comparison, we
also calculated half-times for shorter time frames that were comparable
with those in earlier studies. This did not affect the results
substantially. After pregnancy, some release of small amounts of hCGß
(and hCG) sequestered in tissues could cause an apparent increase in
half-time. Another possibility is that trophoblastic cells remaining in
the body continue to produce hCGß and very little or no hCG.
Trophoblasts persist in the lungs for extended periods of time after
pregnancy (27), but the mass of these cells is very small
in comparison with that of the placenta. Therefore, any production of
hCG and hCGß by persisting trophoblastic cells would not contribute
significantly to the serum concentrations observed the first week after
delivery, when the difference in half-times was already apparent in an
increasing ratio of hCGß to hCG (Fig. 5
).
Dissociation into subunits of the hCG remaining in circulation could
also affect the estimated half-time of hCGß. This mechanism could be
important if the disappearance of hCGß were more rapid than that of
hCG, but the opposite was actually true. Intact hCG is quite stable,
whereas nicked hCG dissociates more rapidly. Especially in
trophoblastic disease (10)(28), nicking may
increase the dissociation of hCG into subunits, which may contribute to
a high ratio of hCGß to hCG. Long incubation times during the assay
of hCGß can cause dissociation of hCG, thus increasing the apparent
concentration of hCGß in the sample. However, with the incubation
times used in the present assay for hCGß, this effect is negligible
(3). Although all these mechanisms could increase the
half-time of hCGß, they probably do not explain why hCGß in all
subjects studied disappeared substantially more slowly than hCG.
Therefore, other explanations need to be considered.
The most likely explanation for the longer half-time of hCGß (vs
intact hCG) is that hCGß circulating in plasma differs from that
isolated by dissociation of urinary hCG into subunits. hCG in urine is
known to be less glycosylated than that in serum (24). The
carbohydrate composition, and especially the presence of terminal
sialic acid, is known to affect the in vivo half-time of hCG
(26). Furthermore, the ß-chain of both hCG and hCGß in
crude urinary hCG preparations has been found to be partially cleaved
or nicked between residues 47 and 48 (25)(29).
In addition, under the potentially harsh chemical conditions required
to dissociate the subunits, denaturation and appearance of components
with shortened half-times could occur. The hCG heterodimer is unusual
in that it is held together by a loop of the ß-chain embracing the
-chain (30). Disrupting the dimer in vitro might
therefore change the structure of hCGß in comparison with the
circulating form, which probably never has been involved in heterodimer
formation. Free hCG in serum does not reassociate with hCGß
(31)(32).
An increased ratio of hCGß to hCG, in most studies >10%, has been
observed in trophoblastic cancer, and this has been used to
differentiate between malignant and benign trophoblastic disease
(7)(8)(9)(33). In the present study, ratios
>10% were observed in 5 of the 6 patients studied 14 days after
delivery, and in all 4 patients studied 21 days after delivery. If the
metabolism of hCG and hCGß is similar in patients with trophoblastic
disease, our findings suggest that the ratio of hCGß to hCG must be
evaluated with caution in samples taken several days after initiation
of therapy. An increased ratio of hCGß to hCG has actually been
observed several weeks after treatment of trophoblastic disease
(34)(35).
The two most rapid components of hCG had half-times similar to those
observed for hCG injected into humans, i.e., 3.6 and 18 h as
compared with 5 and 24–36 h, respectively (14)(15)(16). In an
earlier study three components with half-times of 15, 27, and 168
h were estimated for hCG after abortion (36). The two
latter half-times support our calculations about the third component
with the half-time of several days (median 53 h for hCG). This
component represented only 17% of total hCG. Therefore, it may not be
detectable after injection unless a large amount of hCG is injected, or
an ultrasensitive assay method is used, or very prolonged observations
are carried out. However, it is possible that this component represents
hCG produced by residual, gradually dying trophoblasts or that is less
abundant in urinary hCG than in plasma. The half-times of the two most
rapid components of disappearance of hCG, hCGß, and hCG were
similar in all the patients studied, but there was more individual
variation in the half-times of the longest component, i.e., from 38 to
64 h for hCG, 103 to 462 h for hCGß, and 15 to 126 h
for hCG. Renal clearance accounts for 20% of the total disposal of
hCG after injection of purified hCG preparations (19). The
slightly impaired kidney function in our patient with diabetes mellitus
(patient 2 in Table 3
) seemed to have no effect on the half-times of
hCG and its subunits.
The algorithm used for calculation of half-times in the present study
was based on the principles described in the EXPFIT program
(23). A two-component model has been used in most earlier
studies to calculate disappearance half-times of hCG and its subunits.
However, the fit of a two-component model was unsatisfactory for hCG,
hCGß, and hCG, whereas a three-component model with baseline
yielded a statistically preferred fit. In contrast to the two-component
model, three exponentials with baseline provided a fit for which
predicted values could not be distinguished from the observed values by
analysis of variance. The baseline concentrations obtained with the
algorithm were in most cases well within the range of the reference
values for nonpregnant premenopausal women (Table 3
) (21).
However, when the follow-up time is insufficient for analysis of the
baseline, it can be restricted in the algorithm.
In conclusion, we have developed a three-component exponential
model with a baseline for calculation of half-times of hCG and its
subunits. Disappearance of endogenous hCGß from plasma after delivery
is slower than previously observed, and the ratios of hCGß or hCG
to intact hCG vary as a function of postpartum time. If the metabolism
of hCG and hCGß is similar in patients with trophoblastic disease,
the ratio of hCGß to hCG must be evaluated with caution in samples
taken several days after initiation of therapy. Ratios of hCGß to hCG
>10%, which are indicative for chorionic cancer, were observed in all
patients 21 days after delivery. However, this needs to be evaluated in
patients with trophoblastic disease. Additional studies will also
reveal whether the half-times are similar in early pregnancy and
whether this can be used to diagnose pregnancy-related disorders.
|
Footnotes
|
|---|
1 Nonstandard abbreviations: hCG, human chorionic
gonadotropin; hCG and hCGß, highly glycosylated subunits of hCG;
AUC, area under the curve. 
|
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Abstract
Introduction
