Chorionic gonadotrophin

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Heterodimer of glycoprotein hormones alpha chain and choriogonadotropin subunit beta. Hormone produced by placental tissue and certain tumours. Its detection is the basis of the pregnancy test, but it is also used in monitoring trophoblastic disease and germ cell tumours, e.g. teratomas and certain testicular tumours, so raised levels are not always due to pregnancy.

Post-translational modification means it can be detected as a regular form, a hyperglycosylated form and as the free β-subunit of the hyperglycosylated form. The regular form is produced by placental syncytiotrophoblasts and maintains the myometrium and the placenta blood supply via the decidual spiral arteries. The hyperglycosylated form is produced by the cytotrophoblast and appears to function in an autocrine manner to promote 'invasion' of the placenta.[1] This same hyperglycosylated form is raised in trophoblastic disease as is the free β-subunit of the hyperglycosylated form.[2]

Variants of hCG that have missing residues in the peptide sequence are also recognised ('nicked' hCG) and may account for differences in assays.[3][4]

Contents

Clinical Applications

hCG in Pregnancy Testing

  • HCG is produced once the embryo is implanted (6-12 days).[5] Most commercial urine kits should be able to detect pregnancy as early as first missed period (i.e. 3-4 weeks). The threshold value for detection is ~25 mU/l.
  • HCG falls after the first few weeks of pregnancy as the hormones required to sustain pregnancy are taken over by the placenta. By 20 weeks false negatives are possible as levels fall, although usually still above the 25mIU threshold seen in point-of-care urinary tests.
  • However, in most women, a pregnancy test is not the most useful way of confirming or excluding a 20 week pregnancy.
  • Sustained levels of hCG after week 14 may be seen in gestational trophoblastic disease.
  • Remains elevated after miscarriage or termination for some days (half-life thought to be about 24-48 hours).
  • Rarely, mutations in the hCG may result in negative pregnancy tests.
  • False negatives may also result when very high levels of hCG can overwhelm the antibody present in the kit. This is described as the 'hook' effect, named after the shape of the graph produced from plotting signal to hCG concentration.[6][7][8]

The very first assays for hCG detected the whole dimer, but were sometimes poor at distinguishing between hCG and the structurally similar luteinising hormone (LH), with which it shares the same α-chain. In 1973, an assay specific to the beta sub-unit was developed,[9] though this method has now been superceded by more modern assays that detect the whole unit. Despite this, pregnancy testing is still commonly associated with detection of the β-subunit and 'β-hCG' is often used when it is really the hCG dimer that is intended to be measured.

hCG in Trophoblastic Disease

False positives are rare, but may result from heterophile antibodies. Assay of 'β-hCG' itself, as opposed to the whole hCG molecule, may be relevant in trophoblastic disease.
Anecbubble.pngThe overreliance on a falsely raised hCG level using an assay from Abbott Laboratories resulted in the then 22 year old Jennifer Rufer, an American, having a hysterectomy and lung surgery. Had her doctors tested her urine, it would have tested negative.
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References

  1. Cole LA. Hyperglycosylated hCG. Placenta. 2007 Oct; 28(10):977-86.(Link to article – subscription may be required.)
  2. Cole LA. New discoveries on the biology and detection of human chorionic gonadotropin. Reproductive biology and endocrinology : RB&E. 2009; 7:8.(Epub) (Link to article – subscription may be required.)
  3. Cole LA, Kardana A, Ying FC, Birken S. The biological and clinical significance of nicks in human chorionic gonadotropin and its free beta-subunit. The Yale journal of biology and medicine. 1991 Nov-Dec; 64(6):627-37.
  4. Whittington J, Fantz CR, Gronowski AM, McCudden C, Mullins R, Sokoll L, Wiley C, Wilson A, Grenache DG. The analytical specificity of human chorionic gonadotropin assays determined using WHO International Reference Reagents. Clinica chimica acta; international journal of clinical chemistry. 2010 Jan; 411(1-2):81-5.(Link to article – subscription may be required.)
  5. Wilcox AJ, Baird DD, Weinberg CR. Time of implantation of the conceptus and loss of pregnancy. N Engl J Med. 1999 Jun 10;340(23):1796-9. (Direct link - may require subscription)
  6. 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. Clinical chemistry. 2009 Jul; 55(7):1389-94.(Link to article – subscription may be required.)
  7. Gronowski AM, Powers M, Stenman UH, Ashby L, Scott MG. False-negative results from point-of-care qualitative human chorionic gonadotropin (hCG) devices caused by excess hCGbeta core fragment vary with device lot number. Clinical chemistry. 2009 Oct; 55(10):1885-6.(Link to article – subscription may be required.)
  8. Yadav YK, Fatima U, Dogra S, Kaushik A. Beware of "hook effect" giving false negative pregnancy test on point-of-care kits. Journal of postgraduate medicine. 2013 Apr-Jun; 59(2):153-4.(Link to article – subscription may be required.)
  9. Vaitukaitis JL, Braunstein GD, Ross GT. A radioimmunoassay which specifically measures human chorionic gonadotropin in the presence of human luteinizing hormone. American journal of obstetrics and gynecology. 1972 Jul 15; 113(6):751-8.