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Review |
hCG Reference Laboratory, 308 FMB, Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, CT 06520. Fax 203-785-6367; e-mail laurence.cole{at}yale.edu
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Abstract |
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 Top Abstract IntroductionStructure and Metabolism of...hCG and Related Molecule...Persistent Low Concentrations of...Free Subunit and ss-Core...Stability of hCG, Free...hCG and Related Molecule...Summary and RecommendationsReferences |
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-subunit, large free -subunit, free ß-subunit, nicked free
ß-subunit, and ß-core fragment. Over 100 immunoassays are sold for
quantifying hCG-related molecules in serum or urine. Each measures
nonnicked hCG and one of seven combinations of the other hCG-related
molecules. This is the source of interassay discordance in hCG
determinations. Whereas minor variations are noted in different kit
results in normal pregnancy samples (more than twofold variation), much
larger variations may be found in two immunoassay results in irregular
gestations (spontaneous abortion, aneuploidy, preeclampsia, cancers,
and trophoblast disease). Care is needed in choosing an immunoassay.
What the assay measures may be more important than its cost or speed.
This article reviews the structure of hCG and related molecules. It
examines the stability and degradation of hCG, and recognition of
hCG-related molecules by different types of immunoassay. Also reviewed
are new assays for specifically detecting these other hCG-related
molecules. |
Introduction |
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TopAbstractIntroductionStructure and Metabolism of...hCG and Related Molecule...Persistent Low Concentrations of...Free Subunit and ss-Core...Stability of hCG, Free...hCG and Related Molecule...Summary and RecommendationsReferences |
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This review article examines the presence of nicked and otherwise degraded hCG molecules, free subunits, and fragments in normal and abnormal pregnancies, and their effect on the hCG immunoassay. I start by examining the structure and metabolism of hCG; the stability of hCG, free subunits, and metabolites in samples; and the effect of the molecular heterogeneity of hCG on the immunodiagnosis of pregnancy. Particular problems with hCG measurement are addressed. Potential problems with detecting hCG in aneuploid pregnancies, trophoblast disease, and cancer are discussed. The difficulty measuring clearing concentrations of hCG and the interpretation of persistent low concentrations of hormone are elucidated. The different hCG immunoassay calibrators are described. New commercial assays are described for specifically measuring degraded or dissociated hCG molecules, and potential clinical applications are discussed.
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Structure and Metabolism of hCG |
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TopAbstractIntroductionStructure and Metabolism of...hCG and Related Molecule...Persistent Low Concentrations of...Free Subunit and ss-Core...Stability of hCG, Free...hCG and Related Molecule...Summary and RecommendationsReferences |
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and ß, joined noncovalently. It is produced by trophoblast tissue
in pregnancy and trophoblast disease, and in small amounts by certain
poorly differentiated cancers. The -subunit of hCG is similar to
that of the pituitary glycoprotein hormones. It is composed of 92 amino
acids linked by five disulfide bridges. The -subunit has two
N-linked oligosaccharide side chains, attached at amino acid residues
52 and 78. The ß-subunit is unique, and distinguishes hCG from the
other glycoprotein hormones. It is composed of 145 amino acids linked
by six disulfide bridges. The ß-subunit contains two N-linked
oligosaccharide side chains, attached to residues 13 and 30. It also
has four O-linked oligosaccharide units, located in the unique proline-
and serine-rich C-terminal extension (residues 122 to 145). A
two-dimensional representation of the structure of hCG is illustrated
in Fig. 1
.
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Serum and urine concentrations of biologically active hCG (nonnicked
hCG) rise exponentially in the first trimester of pregnancy, doubling
every 48 h, to a peak at about 10 weeks of gestation (weeks since
last menstrual period). Concentrations decrease from the 10th to the
16th week of gestation, reaching approximately one-fifth of peak
concentrations, and remain around this concentration until term (Fig. 2
) (1). The hormone is present in pregnancy serum
and urine samples, along with a variety of dissociated or degraded
hCG-related molecules that have little or no biological activity
(1)(2)(3)(4)(5)(6).
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Nicked hCG has a single cleavage in the ß-subunit peptide, between
residues 47 and 48, or less commonly between 43 and 44 or 44 and 45
(Fig. 1
). Nicked hCG concentrations peak at the same time as nonnicked
hCG concentrations, at around 10 weeks of pregnancy. Nicked hCG
molecules account for approximately 9% of hCG molecules (mean
proportion) in serum in the 2nd month of gestation. Proportions rise to
21% of hCG molecules (mean proportion) in the 9th month of normal
pregnancy (Fig. 2
). Similar proportions of nicked hCG are observed in
urine samples (1). Although these percentages are low,
they can vary very greatly among individuals (Fig. 2
). In a previous
study of 176 first-trimester pregnancy serum samples, between 0% and
59% nicking was detected (2).
Two forms of free -subunit (free ) are present in serum and urine
samples (Fig. 1
). These include a regular free , which is the same
as that -subunit of hCG, and a large free . Large free is
hyperglycosylated, with larger, more-complex N-linked oligosaccharides
(7). The more-complex N-linked oligosaccharides prevent
combination of large free with ß-subunit. As such, large free
is only produced by trophoblast cells as a free subunit, and is not
incorporated into hCG (7). Electrophoresis studies
indicate that the majority of free molecules in pregnancy urine are
large free (7). Currently, there are no immunoassays
that discriminate large free and regular free concentrations.
As such, we have to examine the two analytes together. The serum free
concentration is 5% of the hCG concentration (mean proportion) in
the 2nd month of gestation. Proportions rise to 54% of the hCG
concentration (mean proportion) in the 9th month of pregnancy (mol/mol)
(Fig. 2
). A somewhat higher proportion of free -subunit may be
observed in urine samples (1). The proportion of free
molecules, like the nicked hCG molecules, varies widely (Fig. 2
).
Nicked (nicked as hCG) and nonnicked free ß are also present in serum
and urine samples. Free ß concentrations, like hCG concentrations,
peak at around the 10th week of gestation. The total serum free ß
concentration is very low, 0.9% of the hCG concentration (mean
proportion) in the 2nd month of gestation, declining to 0.5% (mean
proportion) of the hCG concentration in the 9th month of pregnancy
(Fig. 2
) (1). Higher proportions of free ß (9% to 40%
of hCG concentration, data not shown) may be observed in urine samples
(1).
ß-core fragment is the terminal degradation product of hCG. Although
it is the principal hCG ß-subunit-related molecule in pregnancy urine
samples, it is virtually undetectable in pregnancy serum (<0.3% of
hCG concentration) (4)(8). The ß-core
fragment comprises two peptides, ß-subunit residues 6 to 40 and
residues 55 to 92 held together by five disulfide linkages
(4) (Fig. 1
). ß-core fragment (Mr
= 9000) is approximately one-quarter of the size of hCG
(Mr = 36 700) (4). Urine ß-core
fragment concentrations follow the same general course as serum hCG
concentrations, reaching a peak at around 10 weeks of gestation.
ß-core fragment concentrations start off lower than hCG
concentrations. At 5 weeks of gestation they start to increase sharply,
and at 6–7 weeks of gestation they equal hCG concentrations (mol/mol).
ß-core fragment concentrations exceed hCG concentrations thereafter
(data not shown) (1)(2). ß-core fragment
concentrations average 58% of urine hCG concentrations (mean
proportion) in the 2nd month of pregnancy, rising to 305% of hCG
concentrations in the final month of gestation (mean proportion)
(1)(2).
Nonnicked hCG, nonnicked free ß, and large free are secreted by
isolated trophoblast cells in vivo (3)(6)(7)(8)(9).
Nicked hCG, free ß, and ß-core fragment, however, are not secreted
by trophoblast cells (1)(6)(10).
Cell culture and immunohistochemistry studies indicate that hCG is
nicked after secretion by enzymes produced by macrophages associated
with trophoblast cells (1). Nicked hCG is unstable
(1)(12), rapidly breaking up into nicked free
ß and free in serum. The virtual absence of ß-core fragment in
serum (8), and its major presence in urine suggest that
the ß-core fragment is made in the kidney
(4)(8)(9)(10). Kinetic studies indicate that
nicked free ß is the substrate for ß-core fragment synthesis in the
kidney (1)(11). A degradation pathway has been
proposed for hCG: nonnicked hCG 
nicked hCG nicked free ß
ß-core fragment (Fig. 1
)
(1)(11)(12).
Much greater and more variable proportions of nicked hCG, free ß, and ß-core fragment have been detected in Down syndrome pregnancies, preeclampsia, and trophoblast disease urine and serum samples (13)(14)(15)(16). Serum or urine containing entirely nicked hCG or free ß and urine samples containing only ß-core fragment have been found in certain trophoblast disease cases, testicular cancer or bladder cancer patients, and in normal pregnancy patients 3–10 days postpartum (17)(18)(19). Nicking enzyme activity and the hCG degradation pathway are assumed to be more active in abnormal pregnancies, cancer and trophoblast disease, and in the days after clearance of hCG (11)(12)(17).
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hCG and Related Molecule Antibodies and Immunoassays |
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TopAbstractIntroductionStructure and Metabolism of...hCG and Related Molecule...Persistent Low Concentrations of...Free Subunit and ss-Core...Stability of hCG, Free...hCG and Related Molecule...Summary and RecommendationsReferences |
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Multiple antibody binding sites have been identified on hCG and related
molecules. As many as five separate antibody binding sites have been
identified on nonnicked hCG, four separate sites on nicked hCG, two on
free , six on nonnicked free ß, five on nicked free ß, and as
many as four separate sites on ß-core fragment (Table 1
). Most commercial hCG assays, whether for laboratory, office,
or home use, include multiple antibodies raised to different sites on
hCG and its free subunits (sandwich assays). Often, one monoclonal
antibody is used to capture hCG through a specific site on the hormone.
The immobilized or captured hCG is then detected by a separate antibody
(monoclonal or polyclonal) raised against a distant site on the
hormone. This antibody (tracer antibody) is labeled with a blue dye,
with radioactivity, or with enzyme (for spectrometric or luminescence
detection) to permit measurement of captured hCG. In some assays a
second capture monoclonal antibody is used to capture free ß. Free
ß is then detected by the same labeled antibody that detects hCG.
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Manufacturers use a wide variety of different antibodies in their hCG
immunoassay kits. As a result, not all hCG or hCGß immunoassay kits
measure the same thing. Some assays detect nonnicked hCG only (anti-hCG
dimer capture antibody:anti-common ß1 tracer antibody sandwich
assays), some detect nonnicked hCG and free ß (anti-hCG dimer plus
anti-free ß capture antibodies:anti-common ß1 tracer antibody
sandwich assays), others detect both nicked and nonnicked hCG
(anti-common capture antibody:anti-common ß1 tracer antibody
sandwich assays), and still others measure both forms of hCG and free
ß (anti-common plus anti-free ß capture antibodies:anti-common
ß1 tracer antibody sandwich assays, for instance). Still other assays
detect all forms of hCG, free ß-subunit, and ß-core fragment
(anti-common ß1 competitive immunoassay, and certain anti-common ß1
capture antibody:anti-common ß2 tracer antibody sandwich assays).
Table 2
lists some examples of quantitative serum hCG assays sold in the US, the
antibody combination used, and what they are likely to detect (as
indicated by instruction leaflets, by product management/technical
support personnel, or in publications).
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Our laboratory tested 15 serum samples from normal pregnancy and 15
serum samples from different patients with trophoblast disease, in
seven different commercial hCG assays (2). The assays
included two competitive ßhCG RIAs (Ortho-Clinical Diagnostics
Amerlex M and Diagnostic Products HCG); two anti-common ß1,
anti-common ß2-type sandwich assays (Abbott 15/15 and Biomerica hCG);
one anti-ß C-terminal:anti-common ß1-type sandwich assay (Organon
NML); one anti-common :anti-common ß1-type sandwich assay
(Hybritech Tandem-R); and one anti-hCG dimer plus anti-free
ß:anti-common ß1-type sandwich assay (Serono MAIAclone) (Fig. 4
).
The assays were tested with a common pure hCG calibrator calibrated by
amino acid analysis. The greatest assay-to-assay variation was 1.9-fold
among the 15 pregnancy serum samples (Fig. 3
, upper panel). This was found in sample 2. In this sample, the
Diagnostic Products HCG assay result was 55 IU/L, and the Organon NML
assay value was 102 IU/L. The CV was 9.9% for the 105 pregnancy
determinations with seven assays (Fig. 3
, upper panel). Larger
assay-to-assay variation was found with trophoblast disease samples.
Sample 1 was 1880 IU/L in the Ortho-Clinical Diagnostics Amerlex M and
was 37 IU/L in the Organon NML assay (Fig. 3
, lower panel). This was a
50-fold difference. Two- or more-fold difference in assays values were
found in four of the 15 trophoblast disease samples. The CV was 17%
for 105 determinations with seven assays.
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Two types of assay gave particularly low or variable results with
trophoblast disease serum samples. The Serono MAIAclone anti-hCG dimer
+ anti-free ß:anti-common ß1 sandwich assay detects nonnicked hCG
molecules (the hormone) and free ß. It gave consistently low results
with trophoblast disease samples (Fig. 3
, lower panel). With this
assay, results for the 15 trophoblast disease samples were 75% (mean)
of those found with the other six assays (mean). Similar low results
have been found with other anti-hCG dimer-based assays
(2)(17). The Organon NML anti-ß
C-terminal:anti-common ß1 sandwich assay, which detects molecules
containing the C-terminal extension, gave sporadic results, in one case
giving values 5.0% of the mean concentration. Similar results have
been found with other anti-ß C-terminal-based assays. Both of these
types of assay gave good results with pregnancy serum, 82% to 96% and
86% to 130% of mean values. We infer that assays involving an
anti-hCG dimer or an anti-ß C-terminal-type antibody, while very
appropriate for detecting pregnancy, may not be optimal for detecting
hCG in patients with trophoblast disease.
Trophoblast disease samples typically contain unduly high proportions
of nicked hCG and free ß (17). Some trophoblast disease
hCG molecules lack the ß-subunit C-terminal extension
(17). It is important when monitoring patients with
trophoblast disease to use an assay that can detect all of these
metabolites (Table 1
). It is also important to tell the laboratory that
very high hCG concentrations may be present (as in trophoblast disease
and other pregnancy disorders). This way multiple dilutions can be used
and the hook effect avoided (saturation of capture and label antibodies
limiting sandwich formation, so that high hCG concentrations can give
low results). Greater and more variable proportions of nicked hCG, free
ß, and ß-core fragment have also been found in Down syndrome
pregnancies, preeclampsia, and testicular and bladder cancer patients
(13)(14)(15)(16). Similar care must be taken in selecting a hCG
assay (or hCG testing center) for samples from these disorders.
Unduly high proportions of nicked hCG, free ß, and ß-core fragment
have been noted in serum and urine samples during clearing of hormone,
3 to 10 days postpartum, or after termination of pregnancy. Similar
care is required in choosing an assay to measure these molecules in
monitoring completeness of evacuation (17). Fig. 4
shows concentrations of nonnicked hCG and of both forms of hCG
after evacuation of a hydatidiform mole (trophoblast disease).
Concentrations determined by an assay measuring nonnicked hCG reached
baseline concentrations (3 IU/L) rapidly (day 25), whereas those
determined with an assay measuring both forms of hCG were still
increased (and may indicate the persistence of trophoblast disease) and
reached baseline concentrations considerably later. Similar results
have now been observed in our laboratory after the evacuation of 13 of
17 hydatidiform moles, after chemotherapy for choriocarcinoma, and
after parturition in four term pregnancies (17). A shift from nonnicked to nicked hCG
is inferred to occur in later weeks after therapy of trophoblast
disease or after normal pregnancy parturition. Whether the residual
nicked hCG represents the presence of trophoblast cells, necrotic
trophoblast cells, or the slow degradation and clearance of hCG remains
to be determined.
ß-core fragment is the principal form of hCG ß-subunit in pregnancy urine samples. It is detected by the anti-common ß1 RIA or enzyme immunoassay, and by certain anti-common ß2:anti-common ß1-type assays (check with manufacturer). Large variation is found in individual results when including or not including ß-core fragment in urine hCG determinations. The addition of ß-core fragment to pregnancy hCG concentrations raises concentrations from as little as 1.02-fold to as much as 26.5-fold (2). In the second month of pregnancy, when most pregnancy tests are performed, the concentration of hCG plus ß-core fragment is approximately twice that of hCG alone (2). It is important to be aware of this large difference, and the incompatibility of both quantitative and qualitative results from tests including and excluding ß-core fragment. Monitoring pregnancy urine with hCG-only tests, and with those including free ß and ß-core fragment are equally valid, but yield very incomparable results. As a general rule, both serum and urine hCG immunoassay results are assay specific. Results from one particular assay, one hospital, or a single testing center should be trusted, and not compared or used in conjunction with those from another immunoassay or site.
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Persistent Low Concentrations of hCG |
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TopAbstractIntroductionStructure and Metabolism of...hCG and Related Molecule...Persistent Low Concentrations of...Free Subunit and ss-Core...Stability of hCG, Free...hCG and Related Molecule...Summary and RecommendationsReferences |
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Trophoblast disease must be considered a possible source for low persistent concentrations of hCG in postpartum women (17). In all nonpregnant individuals, testicular cancer, ovarian cancer, bladder cancer, or other malignancy must be ruled out as a source for low concentrations of serum hCG or free ß, or urine ß-core fragment (23)(24). One explanation for persistent low concentrations of hCG is phantom hCG. Phantom hCG immunoreactivity can be produced by some trypsin-like molecules, cholera toxin, transforming growth factor-ß, or by hCG immunoreactive molecules produced by certain bacteria (25)(26). Generally, phantom hCG does not give a parallel dose–response in hCG immunoassays. Testing multiple serum dilutions in the immunoassay may identify this phenomenon.
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Free Subunit and ß-Core Fragment Immunoassays |
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TopAbstractIntroductionStructure and Metabolism of...hCG and Related Molecule...Persistent Low Concentrations of...Free Subunit and ss-Core...Stability of hCG, Free...hCG and Related Molecule...Summary and RecommendationsReferences |
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, and ß-core fragment. Table 2
lists some of these new
commercial assays and their specificities. Over 10 years ago, free ß measurements were shown to be useful in the diagnosis and management of trophoblast disease (18)(19). More recently, raised free ß concentrations have been use to screen pregnancies for Down syndrome fetuses (12)(27). Free ß has also been indicated as a superior tumor marker for testicular cancer (23), and possibly other malignancies (28). Serum nicked free ß has been suggested as an alternative screening test for Down syndrome (29).
ß-core fragment, the urine degradation product of nicked free ß, is being developed as a high-efficiency screening test for Down syndrome pregnancies (14)(15)(30). As a single test, ß-core fragment may be more effective than free ß and the triple screen test, a complex of three tests, for Down syndrome screening (14)(15)(30). ß-core fragment immunoassay kits have been approved in certain countries for use in detecting ß-core fragment as a tumor marker and for following the therapy of ovarian, bladder, or cervical malignancies (23)(31)(32)(33).
Two companies sell immunoassay kits for specifically measuring free
(Table 2
). Few applications have been described, however, for free
measurement. It has been suggested as a marker of Down syndrome
pregnancies. The use in this application, however, may be very limited
(34). hCG free is immunologically indistinguishable
from lutropin, follitropin, and thyrotropin free . This limits the
use of hCG free measurements, and its use a tumor marker or as a
simple pregnancy test.
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Stability of hCG, Free ß, and ß-Core Fragment |
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TopAbstractIntroductionStructure and Metabolism of...hCG and Related Molecule...Persistent Low Concentrations of...Free Subunit and ss-Core...Stability of hCG, Free...hCG and Related Molecule...Summary and RecommendationsReferences |
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, pure nonnicked hCG dissociated at a rate of 14% ± 1.4% per
week in antibiotic-preserved serum at 37 °C. It dissociated at a
much faster rate, however, 34% ± 5.6% per week, in similarly
preserved urine.
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Low temperatures have very little effect on nonnicked hCG concentrations. After 4 weeks at 21 °C or 4 °C, very little change was found in sterile/preserved serum hCG concentrations, 94% ± 3.1% and 94% ± 8.3%, respectively (12). The bulk of the decrease may be attributed to hCG nicking, and more rapid dissociation of nicked hCG to free subunit (12). The hCG calibrator in many commercial immunoassay kits has a significant nicked hCG component. A proportion of these nicked molecules, and those generated by nicking in the refrigerator, will dissociate to free subunits in the refrigerator (12). If your assay detects both forms of hCG and free ß, the results will not be affected by this nicking dissociation process.
Free ß is an extremely minor component of normal pregnancy serum hCG,
<1% of the hCG concentration (Fig. 2
). If your objective is to
measure normal pregnancy hormone, there is no reason to use an assay
detecting free ß, except to accommodate the dissociation of the
nicked or nonnicked hCG to free subunits over a 2-week or longer period
in the refrigerator. Because free ß concentrations are so low in
pregnancy serum, they can be flooded by ß-subunit from the
dissociation of nicked and nonnicked hCG
(12)(36)(37). As shown in Fig. 5
, free ß in normal first-trimester pregnancy serum and urine samples
may be amplified 20- to 30-fold during 1 week of storage or a similar
shipping period at body-like temperatures (in presence of antibiotics)
(36). ß-core fragment is a more stable molecule. No
measurable change was observed in normal first-trimester pregnancy
urine after 7 days at 37 °C (in presence of antibiotics)
(36).
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hCG and Related Molecule Standards |
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TopAbstractIntroductionStructure and Metabolism of...hCG and Related Molecule...Persistent Low Concentrations of...Free Subunit and ss-Core...Stability of hCG, Free...hCG and Related Molecule...Summary and RecommendationsReferences |
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International Standards have also been prepared for free and free
ß. These are also weighed out, but with the formula 1 µg = 1
IU (38). They are somewhat incompatible with hCG
standards, since 1 IU of free ß represent 0.045 nmol of free ß, and
1 IU of hCG represents 0.0029 nmol of hCG. As such, 1 IU of free ß
contains 15.5-fold more ß-subunit than 1 IU of hCG. No International
Standard has been established as yet for ß-core fragment.
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Summary and Recommendations |
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TopAbstractIntroductionStructure and Metabolism of...hCG and Related Molecule...Persistent Low Concentrations of...Free Subunit and ss-Core...Stability of hCG, Free...hCG and Related Molecule...Summary and RecommendationsReferences |
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A new labeling system is needed for hCG assays to clarify what they are detecting. Currently, assays are labeled "intact hCG," "total hCG," or "hCGß." This labeling is both confusing and inadequate. Is nicked hCG "intact hCG?" Is hCG missing the ß-subunit C-terminal segment "intact hCG?" Is nonnicked hCG and free ß really "total hCG?" hCG immunoassays could be more clearly labeled "nonnicked hCG only (or hormone only)," "nonnicked hCG plus free ß (or hormone plus free ß)," "nicked and nonnicked hCG (or whole hCG)," "nicked and nonnicked hCG plus free ß (or whole hCG plus free ß)," etc. Using such a system, physicians could better compare immunoassay results from different laboratories, and more correctly order the appropriate test for a problem pregnancy.
New immunoassays are now available, detecting hCG free subunits and ß-core fragment. Applications are emerging for measuring these molecules, particularly in the detection and management of abnormal pregnancies, and as tumor markers. Care is again needed in choosing an assay that measures the molecule in question. Immunoassays should be labeled appropriately. Assays that measure free ß plus ß-core, for instance, should be labeled as such (the Waco ß-core kit, for instance, measures free ß and ß-core equally). Certain manufacturers have given ß-core fragment different names, urinary gonadotropin peptide and urinary gonadotropin fragment. I must admit I had some part in deriving these odd names. When I see papers from different groups calling the same molecule completely different things, I realize that the different names are yet another source of confusion.
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Footnotes |
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, free -subunit; and GnRH, gonadoliberin. 
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References |
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TopAbstractIntroductionStructure and Metabolism of...hCG and Related Molecule...Persistent Low Concentrations of...Free Subunit and ss-Core...Stability of hCG, Free...hCG and Related Molecule...Summary and RecommendationsReferences |
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-subunits of human choriogonadotropin in pregnancy. Endocrinology 1985;117:2218-2228.
and ß subunits of human chorionic gonadotrophin for immunoassay. J Endocrinol 1980;84:295-310.
-subunit and ß-subunit. J Biol Chem 1975;2250:5247-5257.
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 H. J. de Haard, N. van Neer, A. Reurs, S. E. Hufton, R. C. Roovers, P. Henderikx, A. P. de Bruine, J.-W. Arends, and H. R. Hoogenboom A Large Non-immunized Human Fab Fragment Phage Library That Permits Rapid Isolation and Kinetic Analysis of High Affinity Antibodies J. Biol. Chem., June 25, 1999; 274(26): 18218 - 18230. [Abstract] [Full Text] [PDF]
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L. A. Cole, K. M. Rinne, S. Shahabi, and A. Omrani False-Positive hCG Assay Results Leading to Unnecessary Surgery and Chemotherapy and Needless Occurrences of Diabetes and Coma Clin. Chem., February 1, 1999; 45(2): 313 - 314. [Full Text] [PDF]
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G. Kovalevskaya, S. Birken, T. Kakuma, J. Schlatterer, and J. F. O'Connor Evaluation of Nicked Human Chorionic Gonadotropin Content in Clinical Specimens by a Specific Immunometric Assay Clin. Chem., January 1, 1999; 45(1): 68 - 77. [Abstract] [Full Text] [PDF]
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L. A. Cole, T. J. Abbott, and E. G. Armstrong Comment on the Nature and Specificity of Bayer Corporation and Chiron Diagnostics hCG Immunoassays Clin. Chem., September 1, 1998; 44(9): 2001 - 2002. [Full Text] [PDF]
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), nicked hCG (
), free 
) were determined by immunoassay in 300 serum
samples, between 4 weeks and 40 weeks of gestation (
), in the days after therapy for hydatidiform mole.
