Human chorionic gonadotropin (hCG) is produced in elevated levels during pregnancy as well as with gestational trophoblastic disease and some germ cell tumors. Additionally, hCG concentrations of a pituitary origin are sometimes detected in peri- and post-menopausal women and are not always indicative of pregnancy.

hCG tests are performed on many female patients before performing medical procedures or administering medication that may harm a fetus. The interpretation of low-level hCG elevation in these females is problematic as these elevations might represent gestational trophoblastic disease or other malignancies, or they might be benign.

Pathophysiology

• hCG biochemistry (basic)
  • Sources of hCG
    • Pregnancy
    • Malignancy (gestational trophoblastic neoplasm, testicular cancer)
    • Pituitary
  • hCG variants in serum and urine
    • Intact hCG
    • Nicked hCG (hCGn)
    • Free β subunit (hCGβ)
    • Nicked free β subunit (hCGβb)
    • β core fragment (hCGβcf) – urine only
  • Serum and urine levels are parallel during pregnancy
• Synthesis and function in pregnancy
  • Produced by syncytiotrophoblast cells of the developing placenta
  • Functions to stimulate the corpus luteum in the ovary to synthesize progesterone during the first weeks of pregnancy
  • Elevations seen as early as the day of the expected menstrual period (~2 weeks after fertilization)
  • 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	25,7000-288,000 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

• Synthesis by malignancies
  • Synthesized 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 FSH and LH
  • Hyperstimulation may cause synthesis of hCG

Clinical Presentation

• Clinical uses of hCG tests
  • Determine or rule out pregnancy
  • Diagnose ectopic pregnancy
  • Tumor marker (see gestational trophoblastic disease and testicular cancer)
  • Down syndrome screening (see prenatal screening)

Indications for Testing

• Rule out pregnancy and evaluate for gestational trophoblastic disease

Laboratory Testing

• Serum
  • Quantitative
    • 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 will usually double 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 hCGβcf (core fragment)
• Positive/elevated hCG
  • Positive results should be consistent with clinical picture
    • Consider age, symptoms, etc
      • Goal is to avoid delays in needed treatment and to identify true false positives needing no treatment
    • If inconsistent then rule-out
      • False-positive hCG (interfering antibody)
        • Urine hCG
        • Serial dilution
        • Blocking agents
      • Pituitary hCG
        • Serum FSH
          • FSH >45 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)

Tests generally appear in the order most useful for common clinical situations

General

• Cole LA, Sasaki Y, Muller CY. Normal production of human chorionic gonadotropin in menopause. N Engl J Med. 2007; 356 (11) :1184-1186.PubMed
• Cole LA. Human chorionic gonadotropin tests. Expert Rev Mol Diagn. 2009; 9 (7) :721-747.PubMed
• Cole LA. Phantom hCG and phantom choriocarcinoma. Gynecol Oncol. 1998; 71 (2) :325-329.PubMed
• Gronowski AM, Cervinski M, Stenman UH, Woodworth A, Ashby L, Scott MG. False-negative results in point-of-care qualitative human chorionic gonadotropin (hCG) devices due to excess hCGbeta core fragment. 2009; 55 (7) :1389-1394.PubMed
• Gronowski AM, Fantz CR, Parvin CA, Sokoll LJ, Wiley CL, Wener MH, Grenache DG. Use of serum FSH to identify perimenopausal women with pituitary hCG. Clin Chem. 2008; 54 (4) :652-656.PubMed
• Snyder JA, Haymond S, Parvin CA, Gronowski AM, Grenache DG. Diagnostic considerations in the measurement of human chorionic gonadotropin in aging women. Clin Chem. 2005; 51 (10) :1830-1835.PubMed

ARUP Institute for Clinical and Experimental Pathology®

• Cervinski MA, Lockwood CM, Ferguson AM, Odem RR, Stenman UH, Alfthan H, Grenache DG, Gronowski AM. Qualitative point-of-care and over-the-counter urine hCG devices differentially detect the hCG variants of early pregnancy. Clin Chim Acta. 2009; 406 (1-2) :81-85.PubMed
• Gronowski AM, Grenache DG. Characterization of the hCG variants recognized by different hCG immunoassays: an important step toward standardization of hCG measurements. Clin Chem. 2009; 55 (8) :1447-1449.PubMed

Developmental Delay (DD) or Intellectual Disability (ID) Testing
Gestational Trophoblastic Disease
Ovarian Cancer
Prenatal Screening and Diagnosis
Testicular Cancer