Beta-Human Chorionic Gonadotropin, Quantitative, Serum
Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test
Human chorionic gonadotropin (hCG) is a glycoprotein hormone (molecular weight [MW] approximately 36,000 Dalton [Da]) consisting of 2 noncovalently bound subunits. The alpha subunit (92-amino acids; "naked" protein MW 10,205 Da) is essentially identical to that of luteinizing hormone (LH), follicle-stimulating hormone, and thyroid-stimulating hormone (TSH). The alpha subunit is essential for receptor transactivation. The different beta subunits of the above hormones are transcribed from separate genes, show less homology, and convey the receptor-specificity of the dimeric hormones. The chorionic gonadotropin, beta gene (coding for a 145-amino acid, "naked" protein MW 15,531 Da, glycosylated subunit MW approximately 22,500 Da) is highly homologous to the beta subunit of LH and acts through the same receptor. However, while LH is a classical tropic pituitary hormone, hCG does not usually circulate in significant concentrations. In pregnant primates (including humans) it is synthesized in the placenta and maintains the corpus luteum and, hence, progesterone production, during the first trimester. Thereafter, the placenta produces steroid hormones, diminishing the role of hCG. hCG concentrations fall, leveling off around week 20, significantly above prepregnancy levels. After delivery, miscarriage, or pregnancy termination, hCG falls with a half-life of 24 to 36 hours, until prepregnancy levels are reached.
Outside of pregnancy, hCG may be secreted by abnormal germ cell, placental, or embryonal tissues, in particular seminomatous and nonseminomatous testicular tumors; ovarian germ cell tumors; gestational trophoblastic disease (GTD: hydatidiform mole and choriocarcinoma); and benign or malignant nontesticular teratomas. Rarely, other tumors including hepatic, neuroendocrine, breast, ovarian, pancreatic, cervical, and gastric cancers may secrete hCG, usually in relatively modest quantities.
During pathological hCG production, the highly coordinated secretion of alpha and beta subunits of hCG may be disturbed. In addition to secreting intact hCG, tumors may produce disproportionate quantities of free alpha-subunits or, more commonly, free beta-subunits. Assays that detect both intact hCG and free beta-hCG, including this assay, tend to be more sensitive in detecting hCG-producing tumors.
With successful treatment of hCG-producing tumors, hCG levels should fall with a half-life of 24 to 36 hours, and eventually return to the reference range.
Monitoring patients for retained products of conception
An aid in the diagnosis of gestational trophoblastic disease (GTD), testicular tumors, ovarian germ cell tumors, teratomas, and, rarely, other human chorionic gonadotropin (hCG)-secreting tumors
Serial measurement of hCG following treatment to:
-Monitor therapeutic response in GTD or in hCG-secreting tumors
-Detect persistent or recurrent GTD or hCG-secreting tumors
After delivery, miscarriage, or pregnancy termination, human chorionic gonadotropin (hCG) falls with a half-life of 24 to 36 hours, until prepregnancy levels are reached. An absent or significantly slower decline is seen in patients with retained products of conception.
Gestational trophoblastic disease (GTD) is associated with very considerable elevations of hCG, usually above 2 multiples of the medians for gestational age persisting or even rising beyond the first trimester.
Serum hCG levels are elevated in approximately 40% to 50% of patients with nonseminomatous testicular cancer and 20% to 40% of patients with seminoma. Markedly elevated levels of hCG (>5,000 IU/L) are uncommon in patients with pure seminoma and indicate the presence of a mixed testicular cancer.
Ovarian germ cell tumors (approximately 10% of ovarian tumors) display elevated hCG levels in 20% to 50% of cases. Teratomas in children may overproduce hCG, even when benign, resulting in precocious pseudopuberty. Levels may be elevated to similar levels as seen in testicular cancer.
Among nonreproductive tumors, hepatobiliary tumors (hepatoblastomas, hepatocellular carcinomas, and cholangiocarcinomas) and neuroendocrine tumors (eg, islet cell tumors and carcinoids) are those most commonly associated with hCG production.
Many hCG-producing tumors also produce other embryonic proteins or antigens, in particular alpha fetoprotein (AFP). AFP should, therefore, also be measured in the diagnostic workup of such neoplasms.
Complete therapeutic response in hCG-secreting tumors is characterized by a decline in hCG levels with an apparent half-life of 24 to 36 hours and eventual return to concentrations within the reference range. GTD and some tumors may produce hyperglycoslated hCG with a longer half-life, but an apparent half-life of >3 days suggests the presence of residual hCG-producing tumor tissue.
A rise in hCG levels above the reference range in patients with hCG-producing tumors that had previously been treated successfully, suggests possible local or distant metastatic recurrence.
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
The purpose to this assay is for following the course of therapy of tumors, such as choriocarcinoma. It is not meant to be used for pregnancy testing.
Despite strenuous efforts at standardization, different human chorionic gonadotropin (hCG) assays show only modest agreements with each other. Therefore, whenever serial monitoring of hCG concentration is required, the same assay should be used for all measurements.
Transient elevations of serum hCG can occur following chemotherapy in patients with susceptible tumors, due to massive tumor cell lysis; these transient elevations should not be confused with tumor progression.
Normal serum levels of hCG do not always exclude tumor persistence since tumors may undergo transition to differentiated teratomas, which may not produce hCG.
In individuals with incomplete or complete primary hypogonadism (eg, menopausal women, XXY males, surgically or medically castrated individuals who are receiving inadequate sex steroid-replacement therapy), increased luteinizing hormone (LH)-gene transcription results in minor "leaky" transcription of hCG, and hCG levels of 3 to 5 IU/L and, in some cases, levels as high as 25 IU/L, may be seen. In postmenopausal women, hCG levels ranging from 3.5 to 32 IU/L have been reported. In these cases, measurements of serum concentrations of sex hormones (LH and follicle-stimulating hormone) might be indicated.
End-stage renal failure is associated with up to 10-fold elevations in serum hCG levels.
Among immunometric assays, hCG assays have been found uniquely susceptible to heterophile antibody interference, resulting in occasional false-positive results. Our current assay has been proven robust in this respect, but rare interferences still occur. Typically, the observed false-positive elevations are modest, ranging from just above the reference range to levels of 50 to 60 IU/L. If such results are seen and are discordant with the clinical picture or other biochemical or imaging tests, then the laboratory should be alerted. Rerunning the specimen in question after additional blocking treatment may resolve the issue. For patients with apparent serum hCG concentrations >15 to 20 IU/L, hCG should also be detectable in urine, if it is truly elevated. Failure to detect urinary hCG in such patients, supports a false-positive serum hCG test.
In rare cases, interference due to extremely high titers of antibodies to analyte-specific antibodies, streptavidin or ruthenium can occur. The laboratory should be alerted if hCG values does not correlate with the clinical presentation.
In patients receiving therapy with high biotin doses (ie, >5 mg/day), no sample should be taken until at least 8 hours after the last biotin administration.
Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.
Birth-3 months: < or =50 IU/L*
>3 months-<18 years: <1.4 IU/L
Birth-3 months: < or =50 IU/L*
>3 months-<18 years: <1.0 IU/L
*hCG, produced in the placenta, partially passes the placental barrier. Newborn serum beta-hCG concentrations are approximately 1/400th of the corresponding maternal serum concentrations, resulting in neonate beta-hCG levels of 10-50 IU/L at birth. Clearance half-life is approximately 2-3 days. Therefore, by 3 months of age, levels comparable to adults should be reached.
Adults (97.5th percentile)
Males: <1.4 IU/L
Premenopausal, nonpregnant: <1.0 IU/L
Postmenopausal: <7.0 IU/L
Pediatric reference values based on:
1. Chen RJ, Huang SC, Chow SN, Hsieh CY: Human chorionic gonadotropin pattern in maternal circulation. Amniotic fluid and fetal circulation in late pregnancy. J Reprod Med 1993;38:151-154
2. Schneider DT, Calaminus G, Gobel U: Diagnostic value of alpha 1-fetoprotein and beta-human chorionic gonadotropin in infancy and childhood. Pediatr Hematol Oncol 2001;18:11-26
Clinical References Provides recommendations for further in-depth reading of a clinical nature
1. Cole LA, Khanlian SA, Muller CY: Detection of perimenopause or postmenopause human chorionic gonadotropin: an unnecessary source of alarm. Am J Obstet Gynecol 2008;198:275.e1-275.e7
2. Schneider DT, Calaminus G, Gobel U: Diagnostic value of alpha 1-fetoprotein and beta-human chorionic gonadotropin in infancy and childhood. Pediatr Hematol Oncol 2001;18(1):11-26
3. Cole LA, Butler S: Detection of hCG in trophoblastic disease. The USA hCG reference service experience. J Reprod Med 2002;40(6):433-444
4. von Eyben FE: Laboratory markers and germ cell tumors. Crit Rev Clin Lab Sci 2003;40(4):377-427
5. Sturgeon CM, Duffy MJ, Stenman UH: National Academy of Clinical Biochemistry laboratory medicine practice guidelines for use of tumor markers in testicular, prostate, colorectal, breast, and ovarian cancers. Clin Chem 2008; 54(12):e11-79