Human chorionic gonadotropin (HCG)

What is Human Chorionic Gonadotropin (HCG)

Human chorionic gonadotropin (hCG) is a glycoprotein hormone synthesized in early pregnancy in trophoblast cells; then from the placenta.

It is a substance created from trophoblast tissue, a tissue typically found in early embryos, and which will eventually form part of the placenta.

Measurement of hCG levels can be useful in identifying a normal pregnancy, a pathological pregnancy, and can also be useful after an aborted pregnancy.

Measuring it can also be useful to discover the possible presence of tumors, including choriocarcinoma and extrauterine neoplasms.

Etiology and epidemiology

Human chorionic gonadotropin (hCG) is a hormone produced during pregnancy primarily by syncytiotrophoblastic cells of the placenta.

This hCG stimulates the corpus luteum to produce progesterone  for pregnancy. Small amounts of hCG are also produced in the pituitary gland, liver and colon.

As mentioned, some malignant tumors can also produce hCG or hCG-related hormone. Trophoblastic tumors (hydatidiform mole, choriocarcinoma, and germ cell tumors) are associated with high serum levels of hCG-related molecules.

Human chorionic gonadotropin (hCG) is a glycoprotein consisting of an alpha subunit and a beta subunit. There are several forms of hCG in the serum and urine during pregnancy, each with distinct physiological roles including the intact hormone and each of the free subunits*. Although approximately 20% is excreted in the urine, HCG is primarily catabolized by the liver. The beta subunit is degraded in the kidney to form a core fragment which is measured by urine hCG testing.

Urine and blood tests

Urinalysis
Urine to be tested should not be collected after a person has drunk large quantities of fluids as a diluted urine sample may result in a false negative test. 
However, blood in the urine can cause a false positive test result.

Serum Test
Peripheral blood can be obtained for a serum hCG test.

Diagnostic tests

Serum tests for hCG are immunometric. It means that they use two antibodies that bind to the hCG molecule: a fixed antibody and a radiolabeled antibody, which adhere to different sites on the molecule, enveloping and immobilizing the molecule to make it detectable.

Tests that involve washing out excess serum components, and measuring the remaining amount of labeled hCG, to provide a quantitative result.
More than 100 different tests are commercially available, and this causes a significant variability in the values ​​detected.

Urine tests are similar, although many have total hCG levels above 20 mIU/mL. Many tests ;bench; in urine do not detect hyperglycosylated hCG, which accounts for the majority of hCG in early pregnancy, resulting in a wide range of sensitivity of these tests.

The serum test is much more sensitive and more specific than the urine test.
However, the urine test is cheaper and more comfortable to use. They have fast response times (5 to 10 minutes) and do not require a prescription.

Test procedures

Urine tests

• Urine is placed in or on a urine container: most commercially available medical tests and those available at *Point of Care Testing *i.e. near or at places of care.
• If the test is positive, an indicator will appear together with a control line/symbol: usually a colored line or symbol.
• If the test is negative, an isolated control line/symbol will be highlighted.

Blood tests

• The serum hCG test uses a peripheral blood sample. They are made in laboratories equipped with suitable machinery.
• If a hook effect/gestational trophoblastic disease is suspected, the laboratory should make a dilution prior to testing.

Interference factors

There are several reasons why an hCG test (whether blood or urine) can give a false result.
While not common, false positive hCG tests can lead to unnecessary medical treatment and/or irreversible surgical procedures.

False negative tests can also be equally concerning and lead to delays in treatment or diagnostic evaluations.
However, here is a rundown of potential causes of false results.

Serological tests: false positives (from 1/1,000 to 1/10,000)

• Ectopic production of hCG (hydatidiform mole, choriocarcinoma and germ cell tumors, as well as multiple myeloma, stomach, liver, lung, bladder, pancreatic, breast, colon, cervical and endometrial cancers).
• Heterophile antibodies (autoantibodies and antibodies formed after exposure to animal products that interact with test antibodies).
• Rheumatoid factors (may also bind the antibodies in the assay.
• IgA deficiency.
• Chronic renal failure or ESRD on hemodialysis (rare).
• Red blood cells or blood plasma transfusions with hCG present have been reported.
• Exogenous preparations of hCG for slimming, assisted reproduction, doping.

Serological tests: false negatives

• Early measurement after conception.
• The hook effect, which can occur when hCG levels are around 500,000 mIU/mL. This is because there are so many hCG molecules that saturate both the tracer and the antibodies separately and this does not allow for the tracer-hCG antibody interplay necessary for measurement. It means that all complexes are washed away, giving a false negative result. If gestational trophoblastic disease is suspected, the laboratory should perform a dilution before testing.

Urine tests: false positives

• Blood or protein in the urine.
• Human error in interpreting results.
• Ectopic production of hCG.
• exogenous hCG.
• Drugs: aspirin, carbamazepine, methadone, elevated urinary pH and semen.

Urine tests: false negatives

• Early measurement after conception.
• Diluted urine sample.
• ;Hook effect;, as noted above.

Findings, reports, critical findings

HCG levels are reported in milliinternational units of hCG hormone per milliliter of blood, or mIU/mL. The international unit of measurement for liter (IU/L) can also be used.

Urine hCG tests are qualitative in that they report a positive or negative result . Tests detect hCG levels typically as low as 20 to 50 (reportedly 6.3 to 12.5) mIU/mL, corresponding to levels about 4 weeks after conception.

Serum tests can measure beta-hCG as low as 1-2 mIU/mL.

Clinical meanings

Pregnancy

HCG is an important hormone in pregnancy, and its clinical utility is mainly focused on its initial detection, but also later in relation to pregnancy-related complications.

In women with normal pregnancies, hCG levels can vary widely.
As a rule, in the first trimester of pregnancy, serum and urine concentrations of hCG increase exponentially, doubling approximately every 24 hours during the first 8 weeks.

The peak usually occurs around 10 weeks of gestation.
Then, the levels decrease until about the 16th week where they remain fairly constant until the end.

Women who have hCG levels that stabilize before 8 weeks or fail to double commonly have a nonviable pregnancy, either intrauterine or ectopic.
Extrauterine (ectopic) pregnancies usually have a low rate of increase without the typical doubling.
However, given the wide range of normal hCG levels and the inconsistent rates of elevation of this hormone, monitoring of serum levels is usually associated with ultrasound evaluation to improve sensitivity and specificity. [20]

After delivery or termination of pregnancy, the return of hCG to zero occurs between 7 and 60 days. [21]
The tendency for hCG levels to fall may be important in the termination of molar pregnancies and also after termination of normal or ectopic pregnancies in order to ensure that therapy has been successful.

It is noteworthy that they are used in ;commercial; many different combinations of antibodies.
This results in heterogeneous results, with up to 50-fold differences in immunoassay results. 
This fact is clinically relevant, particularly when comparing results from different laboratories in different facilities/hospitals, and when looking at values ​​after abortion or trophoblastic disease.

Gestational trophoblastic disease

Detection of hCG is also useful in the evaluation of trophoblastic disease, including complete and partial hydatidiform mole, postmolar tumor, gestational choriocarcinoma, testicular choriocarcinoma, and placental site trophoblastic disease.

All of these entities produce hCG whose varying levels are reported on commercial tests.
For example, in early pregnancy, a total hCG level above 100,000 mIU/mL is highly suggestive of a complete hydatidiform mole, although many normal pregnancies can reach this level at its peak around weeks 8-11 of gestation.

Accurate hCG measurements are important for assessing: tumor burden, success of treatment of malignancy, and for testing for disease recurrence or persistence.

Non-pregnant women

In non-pregnant women, serum HCG increases with age. A cut-off of 14 mIU/mL has been suggested for interpretation of results in women over 55 years of age.

In all nonpregnant women, hCG testing should be evaluated as a source of persistent positivity for ovarian cancer, bladder cancer, or other malignancies.