Human chorionic gonadotrophin (hCG)

hCG Overview

Human Chorionic Gonadotropin (hCG) is a hormone produced primarily during pregnancy by cells that form the placenta (specifically, the syncytiotrophoblast). It plays a crucial role in maintaining the corpus luteum during early pregnancy, ensuring the continued production of progesterone necessary to support the pregnancy.

Measurement of hCG levels in blood (serum) or urine is the basis for most pregnancy tests. Additionally, hCG serves as an important tumor marker for certain types of cancer, particularly gestational trophoblastic diseases and some germ cell tumors.

hCG Biology and Structure

hCG is a glycoprotein hormone composed of two dissimilar subunits, designated alpha (α) and beta (β), linked non-covalently.

• The alpha (α) subunit is structurally very similar (nearly identical) to the alpha subunits of other pituitary glycoprotein hormones: Luteinizing Hormone (LH), Follicle-Stimulating Hormone (FSH), and Thyroid-Stimulating Hormone (TSH).
• The beta (β) subunit is unique to hCG and confers its specific biological activity and immunological identity. Most quantitative blood tests and sensitive pregnancy tests are designed to detect the specific β-subunit (beta-hCG or β-hCG) to avoid cross-reactivity with LH, FSH, and TSH.

hCG contains carbohydrate components, including sialic acid (neuraminic acid), which influences its biological half-life and activity. Removal of these carbohydrate components reduces its activity.

Clinical Indications for hCG Testing

Testing for hCG (usually beta-hCG) is performed for several key reasons:

1. Pregnancy Diagnosis and Monitoring:
   • Confirmation of early pregnancy (detection in serum or urine).
   • Monitoring the viability and progression of early pregnancy (quantitative serum levels typically double every 48-72 hours).
   • Diagnosis of ectopic pregnancy (abnormally low or slow-rising levels).
   • Screening for potential miscarriage or threatened abortion (falling or inappropriately low levels).
   • Part of prenatal screening for chromosomal abnormalities (e.g., Down syndrome, often measured in combination with other markers like PAPP-A or AFP/estriol).
2. Tumor Marker:
   • Diagnosis, staging, monitoring treatment effectiveness, and detecting recurrence of Gestational Trophoblastic Disease (GTD), which includes:
     • Hydatidiform mole (molar pregnancy - complete or partial)
     • Choriocarcinoma (placental or testicular/ovarian origin)
     • Placental site trophoblastic tumor (PSTT)
     • Epithelioid trophoblastic tumor (ETT)
   • Diagnosis, staging, monitoring, and detecting recurrence of certain Germ Cell Tumors (GCTs), often in conjunction with Alpha-fetoprotein (AFP):
     • Testicular GCTs (especially non-seminomatous types like choriocarcinoma, embryonal carcinoma, mixed GCTs; sometimes mildly elevated in pure seminomas).
     • Ovarian GCTs (e.g., choriocarcinoma, embryonal carcinoma, dysgerminomas sometimes).
     • Extragonadal GCTs (e.g., in the mediastinum or retroperitoneum).

hCG in Pregnancy

hCG production begins shortly after implantation of the fertilized egg. It can typically be detected in maternal serum as early as 6-10 days after fertilization (around the time of the missed menstrual period) and in urine 1-2 days later.

Serum hCG levels rise rapidly and exponentially during the first trimester, typically doubling every 48-72 hours, reaching a peak around 8-11 weeks of gestation. After this peak, levels gradually decline during the second and third trimesters but remain detectable throughout the pregnancy.

Abnormal patterns of hCG levels in early pregnancy can indicate problems:

• Lower than expected levels or slow rise: May suggest an ectopic pregnancy or an impending miscarriage (threatened abortion).
• Very high levels for gestational age: May suggest multiple gestation (twins, etc.), molar pregnancy, or Down syndrome.
• Falling levels: Suggest failing pregnancy or completed miscarriage.

hCG levels in amniotic fluid generally correlate with serum levels but are much lower.

hCG as a Tumor Marker

In non-pregnant individuals (men and women), detectable or elevated levels of hCG (specifically beta-hCG) are almost always abnormal and strongly suggest the presence of an hCG-producing tumor.

• Gestational Trophoblastic Disease (GTD): These tumors arise from placental trophoblast cells and typically produce large amounts of hCG.
  • Hydatidiform Mole: Often associated with very high hCG levels for gestational age. Monitoring hCG levels after evacuation is crucial to ensure complete removal and detect persistent GTD or choriocarcinoma.
  • Choriocarcinoma: A highly malignant tumor that usually produces very high levels of hCG. Serial hCG monitoring is essential for assessing treatment response (chemotherapy) and detecting relapse. Timely diagnosis and treatment, guided by hCG levels, can lead to high cure rates even in metastatic disease (e.g., 83-95% reported cure rates depending on stage).
• Germ Cell Tumors (GCTs):
  • Testicular Cancer: Elevated beta-hCG is found in many non-seminomatous GCTs (NSGCTs, e.g., choriocarcinoma, embryonal carcinoma components) and sometimes in pure seminomas (usually lower levels). Used for diagnosis, staging, prognosis, and monitoring along with AFP and LDH.
  • Ovarian Cancer: Certain ovarian GCTs produce hCG.
• Other Cancers (Rarely): Ectopic production of hCG or its subunits can occasionally occur in other malignancies, including some lung cancers (approx. 14%), gastrointestinal cancers (up to 60% in some types), urinary tract cancers (approx. 30%), and colorectal cancers (variable). In some cases, like pancreatic adenocarcinoma, primarily the free alpha-subunit might be detected.

The sensitivity of hCG as a marker varies: close to 100% for choriocarcinoma, high for molar pregnancy (97% for chorioadenoma in original text), variable for NSGCTs (48-86%), and lower for pure seminomas (7-14%).

Interpretation of hCG Levels

• Normal Range (Non-pregnant): Typically very low, often < 5 IU/L (or mIU/mL). Levels can be slightly higher in postmenopausal women.
• Pregnancy: Levels vary widely depending on gestational age. Interpretation requires comparison to gestational age-specific reference ranges. Qualitative urine tests typically detect levels around 20-50 IU/L. Quantitative serum tests measure exact levels.
• Tumor Marker: Any detectable or elevated level in a non-pregnant individual warrants investigation for malignancy. The magnitude of elevation often correlates with tumor burden. Serial measurements are crucial for monitoring.

Limitations and Considerations

• Assay Specificity: Tests measuring total hCG might cross-react slightly with high levels of LH (e.g., during ovulation peak or in menopause). Tests specific for the beta-subunit (β-hCG) minimize this.
• Heterophile Antibodies: Rare interference from patient antibodies can cause falsely high or low results in some immunoassays.
• Hook Effect: Extremely high hCG levels (e.g., in molar pregnancy) can sometimes overwhelm certain assays, leading to a paradoxically low ("falsely negative") result. Dilution of the sample may be needed.
• Sample Quality: Hemolysis (broken red blood cells) or lipemia (high fat content) in the blood sample can potentially interfere with some assays, leading to false results.
• Free Subunits: Some tumors may predominantly secrete free alpha or free beta subunits, which may not be detected equally well by all assays designed for intact hCG.
• Pituitary hCG: Very low levels of hCG can be produced by the pituitary gland, especially in postmenopausal women, which is usually clinically insignificant but needs differentiation from malignancy if slightly elevated.

The hCG Test Procedure

• Sample Type: Blood serum or urine. Serum is preferred for quantitative measurement and earlier detection. Urine is commonly used for qualitative point-of-care pregnancy tests.
• Preparation: No special preparation (like fasting) is required for a blood draw. For urine pregnancy tests, a first morning urine sample is often recommended as it is typically more concentrated, but tests are often sensitive enough for use at any time of day.
• Collection: Standard venipuncture for blood; clean-catch urine sample.
• Analysis: Performed using various types of immunoassays (e.g., ELISA, chemiluminescence). Qualitative tests give a positive/negative result; quantitative tests provide a numerical value.

References

1. American College of Obstetricians and Gynecologists (ACOG). (2018). Practice Bulletin No. 193: Tubal Ectopic Pregnancy. *Obstetrics & Gynecology*, 131(3), e91-e103.
2. National Cancer Institute (NCI). (n.d.). Gestational Trophoblastic Disease Treatment (PDQ®)–Patient Version. Retrieved from https://www.cancer.gov/types/gestational-trophoblastic/patient/gtd-treatment-pdq
3. National Cancer Institute (NCI). (n.d.). Testicular Cancer Treatment (PDQ®)–Health Professional Version. Retrieved from https://www.cancer.gov/types/testicular/hp/testicular-treatment-pdq
4. Cole, L. A. (2009). New discoveries on the biology and detection of human chorionic gonadotropin. *Reproductive Biology and Endocrinology*, 7, 8. https://doi.org/10.1186/1477-7827-7-8
5. Mayo Clinic Laboratories. (n.d.). Test ID: HCG - Human Chorionic Gonadotropin (hCG), Quantitative, Serum. Test Catalog. Retrieved from https://www.mayocliniclabs.com/test-catalog/Overview/80678 (Example lab reference)
6. Snyder, J. A., Haymond, S., Parvin, C. A., Gronowski, A. M., & Eby, C. S. (2005). Diagnostic considerations in the measurement of human chorionic gonadotropin in aging women. *Clinical Chemistry*, 51(10), 1830–1835. https://doi.org/10.1373/clinchem.2005.053561 (Discusses pituitary hCG)