hCG Testing

Human chorionic gonadotropin (hCG) is produced at elevated levels during pregnancy as well as in gestational trophoblastic disease and due to some germ cell tumors. Additionally, hCG concentrations of a pituitary origin are sometimes detected in peri- and postmenopausal women.

Many female patients are tested for hCG before medical procedures or administration of medication that may harm a fetus. The interpretation of low-level hCG elevation in these females is problematic; such elevations might be benign or might represent malignancies such as gestational trophoblastic disease.

Diagnosis

Indications for Testing

Potential pregnancy
- Determine or rule out pregnancy
- Diagnose ectopic pregnancy
- Screen for Down syndrome in pregnant women (see Prenatal Screening)
Suspected gestational trophoblastic disease
Suspected testicular cancer

Laboratory Testing

Serum
- Quantitative – human chorionic gonadotropin (hCG) variant detection
  - Different assays do not all detect the same hCG variants
  - Important to use same assay for serial tests
  - In a viable pregnancy, hCG usually doubles over 48 hours
- Qualitative
  - Rapid but not as sensitive as quantitative
  - Should use quantitative if detection of pregnancy is critical
Urine
- Qualitative only
  - hCG is highest in first morning urine specimen
  - False negatives may occur due to high concentrations of hCG β core fragment (hCGβcf)
Positive/elevated hCG
- Should be consistent with clinical picture – consider age, symptoms, etc.
  - Goal is to avoid delays in needed treatment and to identify true false positives that need no treatment
- If inconsistent, then rule out
  - False-positive hCG (interfering antibody)
    - Urine hCG
    - Serial dilution
    - Blocking agents
  - Pituitary hCG
    - Serum follicle-stimulating hormone (FSH)
      - FSH >45 mIU/mL essentially rules out pregnancy
      - Estrogen replacement for ~2 weeks with repeat testing; if source is pituitary, hCG will be suppressed to ≤2 IU/mL
      - Pituitary hCG should be considered to avoid unnecessary chemotherapy for choriocarcinoma when no true trophoblastic disease is present

Imaging Studies

Pelvic ultrasound to rule out viable pregnancy or possible ectopic pregnancy

Differential Diagnosis

Pregnancy
Gestational trophoblastic disease
Menopause
Germ cell tumor (testicular, ovarian)

Background

Pathophysiology

Human chorionic gonadotropin (hCG) biochemistry (basic)
- Sources of hCG
  - Pregnancy
  - Malignancy (gestational trophoblastic neoplasm, testicular cancer)
  - Pituitary origin
- hCG variants in serum
  - Intact hCG (dimeric)
  - Nicked hCG (hCGn)
  - Free β subunit (hCGβ)
  - Large free α
  - Nicked free β subunit (hCGβb)
  - Free αhCG
- hCG variants in urine
  - Intact hCG (dimeric)
  - hCGn
  - hCGβ
  - Free βhCG
  - Large free α
  - hCGβb
  - Free αhCG
  - β core fragment (hCGβcf) (degradation of nicked free β)
- Levels in serum and urine are parallel during pregnancy

Synthesis and function in pregnancy

Produced by syncytiotrophoblast cells of developing placenta
- Elevations seen as early as first day of expected menstrual period (~2 weeks after fertilization)
Functions to stimulate corpus luteum in ovary to synthesize progesterone during first weeks of pregnancy

Guidelines for serum hCG levels (approximate)

Length of Time from Last Menstrual Period (Gestational Age)	hCG Concentration
3 weeks	5-50 mIU/mL
4 weeks	5-426 mIU/mL
5 weeks	18-7,340 mIU/mL
6 weeks	1,080-56,500 mIU/mL
7-8 weeks	7,650-229,000 mIU/mL
9-12 weeks	25,700-288,000 mIU/mL
13-16 weeks	13,300-254,000 mIU/mL
17-24 weeks	4,060-165,400 mIU/mL
25-40 weeks	3,640-117,000 mIU/mL
Source: Cole, 2009

Synthesis by malignancies
- Produced by placental trophoblastic cells in gestational trophoblastic tumors and some germ cell tumors
- Germ cell tumors may produce hCGβ only
Synthesis by pituitary
- Most common after menopause when sex steroids are decreased
- Pituitary is hyperstimulated to produce follicle-stimulating hormone (FSH) and luteinizing hormone (LH)
- Hyperstimulation may cause synthesis of hCG