What is HCG hormone (or beta hCG) and How the FDA is missing the ball with the Pregnancy Test
HCG hormone (Aka Human Chorionic gonadotropin) is a hormone produced in pregnancy by the developing placenta. HCG informs the body that a pregnancy has happened and tells it to start secreting hormones to support the pregnancy and stop producing hormones that bring about the menstrual period. While the placenta produces HCG, sometimes a molar pregnancy, choriocarcinoma or other tumours may also produce HCG.
It has only been within recent years of research that additional discoveries of HCG variants and roles they play during pregnancy, have been made. The three variants are 1) regular HCG (or the principle HCG), 2) Hyperglycosylated HCG and 3) Hyperglycosylated HCG free β. These discoveries shed additional light on a puzzle that has perplexed scientists for many years; scientists thought HCG primary function was only to promote the production of progesterone. According to traditional knowledge, HCG production continues throughout the pregnancy until term, although the HCG stimulation of progesterone is no longer needed by about the 6th week of pregnancy since progesterone (starting the 6th week ) is being made by syncytiotrophoblast cells independent of HCG stimulation. Why then is there the need to keep producing HCG until term?
Regular HCG is a glycoprotein hormone produced by the syncytiotrophoblast cells of the placenta during pregnancy. The regular HCG tells the corpus luteum of the ovary not to self destruct thereby supporting the corpus luteum progesterone production for the initial 6 weeks of pregnancy until the syncytiotrophoblast can produce progesterone on its own. (1)
HCG levels increase at incredible rate as soon as implantation occurs and should double every few days and during normal pregnancy, will decrease after the syncytiotrophoblast of the placenta takes over. The chart below shows Beta-HCG rate levels during pregnancy. (4)
In the recent years research has shown that HCG aside from promoting progesterone production, HCG also supports the fusion of villous cytotrophoblast cells to syncytiotrophoblast, supports hemochorial placentation by helping the maternal blood supply and luteinizing hormone receptors in myometrial blood vessel which promotes expansion and growth of myometrial spiral arteries which in turn give blood supply to the villous tissue. (1) These previously unbeknownst roles of regular HCG are vital in the successful placentation in humans.
The 2nd variant Hyperglycosylated HCG (HCG-H) is formed by cytotrophoblast cells and has a different function from regular HCG, which is to promote invasion, choriocarcinoma or other invading cell malignancies. HCG-H drives the placentation deep into the myometrium for a strong placement and blood supply.
HCG-H by promoting cell invasion , is critical for successful implantation and deter early pregnancy loss or spontaneous abortion. The measurement of HCG-H levels is actually better indicator for problems than regular HCG or Total HCG measurement. Falling levels of HCG-H would indicate ectopic pregnancy, failing pregnancy or spontaneous abortion while rising levels would point to advancing carcinoma or invasive mole.(3) HCG-h is also used as a marker for detecting early trophoblast invasion and Down syndrome. (2)
The 3rd variant Hyperglycosylated HCG free β is produced at the start of implantation of pregnancy and is present until term in low proportions. The Hyperglycosylated HCG free β is widely used as part of a screening test for Down Syndrome. Hyperglycosylated HCG free β has also been found in cancer and other cell malignancies and whether Hyperglycosylated HCG free β is a promoter or just a by product of cell malignancies is yet to be determined.
Testing for the HCG hormone and its variants is an important part of establishing pregnancy and detecting possible abnormalities or malignancies. Consequently the first international standard for (HCG) serum gonadtropin was established in 1938 by the League of Nations but when the supplies for the serum was running low in 1961, the World Health Organization (WHO) Expert committee asked the National Institute for Medical Research of London for a replacement of the old standard. They came up with the second international standard which was more potent then the 1st standard and in 1980 an even more pure serum came about and was called International Reference Preparation (IRP)and is twice as potent of the 2nd standard. The second international standard of serum gonadtropin has the rating of 1600 International Units of Potency per ampoule. (6) The IRP then has the rating of 3600 International Units of Potency per ampoule. (5)
Beta HCG is the quantitative measurement of HCG in the blood (actual amount) as opposed to the qualitative HCG test which detects if HCG is present in the blood. Either standard measurement for Beta HCG (the IRP or the 2ndinternational standard) are used today depending on the laboratory’s protocol. For example using the 2nd international standard, a normal gestational sac can be seen when the HCG levels are 1800 mIU/ml or 900 mIU/ml if using the IRP measurement. For many labs, HCG levels between a 1000 to 2000 mUI/ml indicate a normal pregnancy. (4)
Whatever BETA HCG measurement is used, the correlation between HCG levels and menstrual weeks is specific; by a certain menstrual week a certain level of HCG should be present and depending on the time, a specific sonographic fetal landmarks should also be present. For example falling HCG levels usually precede a failed pregnancy or low level HCG relative to the gestational sac development may point to an abnormal pregnancy.
In early pregnancy the use of ultrasound along with Beta HCG testing greatly increases the findings for normal intraurine and abnormal or extraurine pregnancies. For example using a and IRP standard, a gestational sac can be demonstrated at about 1400 mIU/ml and with a transabdominal scanning the IRP would be about 6500 mIU/ml. (5)
The following chart shows Transvaginal ultrasound with IRP standard for Beta HCG levels and the sonographic finding
The fact that transvaginal scanning has a higher resolution then a transabdominal and less dependent on body size (transabdominal gets worse with larger bodies), transvaginal scanning has become the preferred method for early pregnancy. Transabdominal scanning gets more use when the gestational sac grows larger.
In conclusion the combined technique of using ultrasound and Beta HCG tests to confirm pregnancy or discover abnormalities are a vital process today’s healthcare procedures. However the fact is that HCG has many variants (the 3 discussed above and 13 sub-variants not discussed) which should be used to refine current laboratory HCG tests. The fact is that all variants of HCG are lumped together as general HCG to physicians because the FDA only requires the detection of regular HCG. There is no requirement to detect hyperglycosylated HCG or detect free β-subunit which is now known to be the only molecule to be produced by cancer.(1)
The laboratories use tests that confine itself to FDA guidelines, with speed and costs considerations, which preclude a more definitive test using today’s knowledge.
In reality a total HCG assay should include all HCG variants for testing, such as hyperglycosylated HCG for gestational trophoblastic diseases, or hyperglycosylated HCG free β for cancer indicators, would be the ideal, but this will not change until the FDA itself changes it’s guidelines concerning HCG testing.
1)Cole, Laurence A. "New discoveries on the biology and detection of human chorionic gonadotropin." PubMed.gov. 09 Jan. 2009. 28 Nov. 2010 <http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2649930/?tool=pmcentrez>.
2)Guibourdenche,, J., K. Handschuh, V. Tsatsaris, P. Gerbaud, M. C. Leguy, F. Muller, D. Brion, and T. Fournier. "Hyperglycosylated hCG Is a Marker of Early Human Trophoblast Invasion -- Guibourdenche et al. 95 (10): E240." Journal of Clinical Endocrinology & Metabolism. 12 Oct. 2010. 28 Nov. 2010 <http://jcem.endojournals.org/cgi/content/abstract/95/10/E240>.
3)LA, Cole. "Hyperglycosylated hCG." PubMed.gov. 07 Mar. 2007. 28 Nov. 2010 <http://www.ncbi.nlm.nih.gov/pubmed/17346790>.
4) Hagen-Ansert, Sandra L. "Chap 43/Laboratory Values In Early Pregnancy." Textbook of diagnostic ultrasonography. St. Louis, MO: Mosby Elsevier, 2006.
5). "Global Library of Women's Medicine - The Diagnosis of Pregnancy." 2010. DOI 10.3843/GLOWM.10093. 28 November 2010 <http://www.glowm.com/?p=glowm.cml/section_view&articleid=93&SESSID=fgj6g9fktstrddh9bf12kh5sh6>.
6) The Second International Standard for Serum Gonadotrophin
D. R. Bangham and Patricia M. Woodward
Bull World Health Organ. 1966; 35(5): 761–773.
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