
Human chorionic gonadotropin or human
chorionic gonadotrophin (hCG) is a glycoprotein
hormone
produced during pregnancy that is made by the developing embryo after conception and later by the syncytiotrophoblast (part of the placenta).[1][2]
Some cancerous tumors produce this hormone; therefore, elevated levels measured
when the patient is not pregnant can lead to a cancer diagnosis. However, it is
not known whether this production is a contributing cause or an effect of tumorigenesis.
The pituitary analog of hCG, known as luteinizing hormone (LH), is produced in the pituitary
gland of males and females of all ages.[1][3]
As of December 6, 2011, the FDA has prohibited the sale of hCG diet products
and declared them fraudulent and illegal.[4][5][6]
Structure
Human chorionic gonadotropin is a glycoprotein
composed of 244 amino acids with a molecular
mass of 36.7 kDa.[7]
It is heterodimeric,
with an α (alpha) subunit identical to that of luteinizing hormone (LH), follicle-stimulating hormone
(FSH), thyroid-stimulating hormone
(TSH), and β (beta) subunit that is unique to hCG.
- The α (alpha) subunit
is 92 amino acids long. The sequence of the alpha unit can be found on
UniProtKB with ID: P01215[25-116].
- The β-subunit of hCG gonadotropin contains 145
amino acids, encoded by six highly-homologous genes that are
arranged in tandem and inverted pairs on chromosome
19q13.3 - CGB (1, 2,
3, 5, 7, 8). The sequence of the beta
unit can be found on UniProtKB with ID: P01233[21-165].
The two subunits create a small hydrophobic
core surrounded by a high surface area-to-volume ratio: 2.8 times that of a
sphere. The vast majority of the outer amino acids are hydrophilic.[7]
Function
Human chorionic gonadotropin interacts with the LHCG
receptor and promotes the maintenance of the corpus
luteum during the beginning of pregnancy,
causing it to secrete the hormone progesterone.
Progesterone enriches the uterus with a thick lining
of blood
vessels and capillaries so that it can
sustain the growing fetus.
Due to its highly-negative charge, hCG may repel the immune cells of the
mother, protecting the fetus during the first trimester. It has also been
hypothesized that hCG may be a placental link for the development of local
maternal immunotolerance. For example, hCG-treated endometrial cells induce an
increase in T cell apoptosis (dissolution of T-cells). These results suggest
that hCG may be a link in the development of peritrophoblastic immune
tolerance, and may facilitate the trophoblast invasion, which is known to
expedite fetal development in the endometrium.[8]
It has also been suggested that hCG levels are linked to the severity of morning
sickness in pregnant women.[9]
Because of its similarity to LH, hCG can also be used
clinically to induce ovulation in the ovaries as
well as testosterone
production in the testes.
As the most abundant biological source is women who are presently pregnant, some
organizations collect urine from pregnant women to extract hCG for use in fertility treatment.[10]
Human chorionic gonadotropin also plays a role in
cellular differentiation/proliferation
and may activate apoptosis.[11]
Production
Like other gonadotropins,
hCG can be extracted from urine or by genetic modification. Pregnyl, Follutein,
Profasi, Choragon and Novarel use the former method, derived from the urine of
pregnant women. Ovidrel,
on the other hand, is a product of recombinant
DNA. hCG is produced from the syncytiotrophoblast cell layer.
Testing
Levels of hCG may be measured in the blood or urine. Most
commonly, this is done as a pregnancy
test, intended to indicate the presence or absence of an implanted embryo. Testing for hCG may
also be done when diagnosing or monitoring germ
cell tumors and gestational
trophoblastic disease.
Most tests employ a monoclonal antibody, which is
specific to the β-subunit of hCG (β-hCG). This procedure is employed to
ensure that tests do not make false positives by confusing
hCG with LH and FSH. (The latter two are always present at varying levels in
the body, whereas the presence of hCG almost always indicates pregnancy.)
- The urine
test may be a chromatographic immunoassay
or any of several other test formats, home-, physician's office-, or
laboratory-based.[12]
Published detection thresholds range from 20 to 100 mIU/ml, depending on
the brand of test.[13]
Early in pregnancy, more accurate results may be obtained by using the
first urine of the morning (when hCG levels are highest). When the urine
is dilute (specific gravity less than 1.015), the hCG
concentration may not be representative of the blood concentration, and
the test may be falsely negative.
- The serum
test, using 2-4 mL of venous blood, is typically a chemiluminescent or
fluorimetric immunoassay[12]
that can detect βhCG levels as low as 5 mIU/ml and allows quantification
of the βhCG concentration. The ability to quantitate the βhCG level is
useful in the monitoring germ
cell and trophoblastic tumors,
followup care after miscarriage, and in diagnosis of and follow-up care
after treatment of ectopic pregnancy. The lack of a visible
fetus on vaginal ultrasound after the βhCG levels have reached 1500
mIU/ml is strongly indicative of an ectopic pregnancy.
As pregnancy tests, quantitative blood tests and
the most sensitive urine tests usually detect hCG between 6 to 12 days after
ovulation.[14]
However, it must be taken into account that total hCG levels may vary in a very
wide range within the first 4 weeks of gestation, leading to false results
during this period of time.[15]
Gestational trophoblastic disease like Hydatidiform
moles ("molar pregnancy") or Choriocarcinoma may produce
high levels of βhCG (due to the presence of syncytialtrophoblasts- part of the
villi that make up the placenta) despite the absence of an embryo. This, as
well as several other conditions, can lead to elevated hCG readings in the
absence of pregnancy.
hCG levels are also a component of the triple
test, a screening test for certain fetal chromosomal abnormalities/birth
defects.
Reference levels
The following is a list of serum hCG levels. (LMP
is the last menstrual period.) The
levels grow exponentially after conception and implantation.
weeks since LMP
|
mIU/mL
|
3
|
5 – 50
|
4
|
5 – 426
|
5
|
18 – 7,340
|
6
|
1,080 – 56,500
|
7 – 8
|
7,650 – 229,000
|
9 – 12
|
25,700 – 288,000
|
13 – 16
|
13,300 – 254,000
|
17 – 24
|
4,060 – 165,400
|
25 – 40
|
3,640 – 117,000
|
Non-pregnant females
|
<5.0
|
Postmenopausal females
|
<9.5
|
Uses
Tumor marker
Human chorionic gonadotropin can be used as a tumor
marker, as its β subunit is secreted by some cancers
including seminoma,
choriocarcinoma,
germ
cell tumors, hydatidiform mole formation, teratoma
with elements of choriocarcinoma, and islet
cell tumor. For this reason a positive result in males can be a test
for testicular cancer. The normal
range for men is between 0-5 mIU/mL. Combined with alpha-fetoprotein,
β-HCG is an excellent tumor marker for the monitoring of germ
cell tumors.
Fertility
Human chorionic gonadotropin is extensively used parenterally
as an ovulation inducer in lieu of luteinizing hormone. In the presence
of one or more mature ovarian follicles, ovulation can be triggered by the
administration of hCG. As ovulation will happen between
38 and 40 hours after a single HCG injection,[16]
procedures can be scheduled to take advantage of this time sequence,[17]
such as intrauterine insemination or
sexual intercourse. Also, patients that undergo IVF, in
general, receive hCG to trigger the ovulation process, but have a oocyte
retrieval performed at about 34 to 36 hours after injection by, a
few hours before the eggs actually would be released from the ovary.
As hCG supports the corpus
luteum, administration of hCG is used in certain circumstances to
enhance the production of progesterone.
In the male, hCG injections are used to stimulate
the leydig
cells to synthesize testosterone.
The intratesticular testosterone is necessary for spermatogenesis
from the sertoli cells. Typical uses
for hCG in men include hypogonadism and fertility
treatment.
During first few months of pregnancy, the transmission
of HIV-1 from woman to fetus is extremely rare. It has been suggested that this
is due to the high concentration of hCG, and that the beta-subunit of this
protein is active against HIV-1.[18]
Weight loss
A controversial usage of hCG is as an adjunct to
the British endocrinologist Albert T. W. Simeons'
ultra-low-calorie weight-loss diet (less than 500 calories). Simeons, while
studying pregnant women in India on a calorie-deficient diet, and “fat boys”
with pituitary problems (Frölich's syndrome) treated
with low-dose hCG, claimed that both lost fat rather than lean (muscle) tissue.
He reasoned that hCG must be programming the hypothalamus
to do this in the former cases in order to protect the developing fetus by
promoting mobilization and consumption of abnormal, excessive
adipose deposits. Simeons later published a book entitled Pounds and Inches,
designed to combat obesity.[19]
Simeons, practicing at Salvator Mundi International Hospital in Rome, Italy,
recommended low-dose daily hCG injections (125 IU) in combination with a
customized ultra-low-calorie (500 cal/day, high-protein, low-carbohydrate/fat)
diet loss of adipose tissue without loss of lean tissue. After Simeons’ death,
the diet started to spread to specialized centers and via popularization by
individuals, such as the controversial author Kevin
Trudeau, famous for promotion of alternative therapies and
treatments.
The controversy proceeds from warnings by the Journal of the American
Medical Association and the American Journal of Clinical Nutrition[20]
that hCG is neither safe nor effective as a weight-loss aid.[21]
However, recent studies in the Journal
of Clinical Endocrinology and Metabolism show hCG can have an effect
on the lean body mass of older men with androgen deficiency.[22]
A meta analysis found that studies supporting hCG
for weight loss were of poor methodological quality and concluded that
"there is no scientific evidence that HCG is effective in the treatment of
obesity; it does not bring about weight-loss or fat-redistribution, nor does it
reduce hunger or induce a feeling of well-being".[23]
Homeopathic hCG for
weight control
Controversy about, and shortages[24]
of, injected hCG for weight loss have led to substantial Internet promotion of
"homeopathic
hCG" for weight control. The ingredients in these products are often
obscure, but if prepared from true hCG via homeopathic dilution, they contain
either no hCG at all or only trace amounts.
The United States Food and Drug Administration
has stated that this drug is fraudulent and ineffective for weight loss. It is
also not protected as a homeopathic drug and has been deemed an illegal
substance.[25][26]
According to the studies noted above, the weight
loss indicated by individuals on an "hCG diet" can be attributed
entirely to the fact that such diets prescribe a consumption rate of 500-550
calorie per day, or approximately one quarter of what is commonly accepted as
the daily recommended value for a male adult of average build and activity.
Further, double-blind studies note no decrease in appetite by those taking hCG
versus individuals on placebos and have offered no evidence that individuals
taking hCG are more likely to lose fat than lean tissue. Long-term results
caution that unlike individuals participating in a diet of, for example, 1100
calories per day those on a 500 calorie per day diet are unlikely to develop
more appropriate eating habits and will gain weight more quickly after the diet
has completed.
HCG Pregnyl Warnings
In the case of female patients who want to be
treated with HCG Pregnyl:[27]
a) Since infertile female patients who undergo medically assisted reproduction
(especially those who need in vitro fertilization), are
known to often be suffering from tubal abnormalities, after a treatment with
this drug they might experience many more ectopic pregnancies. This is
why early ultrasound confirmation at the beginning of a pregnancy (to see
whether the pregnancy is intrauterine or not) is crucial. - Pregnancies that
have occurred after a treatment with this medicine are submitted to a higher
risk of multiplets. - Female patients who have thrombosis, severe obesity or thrombophilia
should not be prescribed this medicine as they have a higher risk of arterial
or venous thromboembolic events after or during a treatment with HCG Pregnyl.
b)Female patients who have been treated with this medicine are usually more
prone to pregnancy losses.
In the case of male patients: A prolonged
treatment with HCG Pregnyl is known to regularly lead to increased production
of androgen. Therefore: Patients who are suffering from overt or latent cardiac
failure, hypertension, renal dysfunction, migraine or Epilepsy might not be
allowed to start using this medicine or might have to be prescribed a lower
dose of HCG Pregnyl. Also this medicine should be used with extreme cautious in
the case of prepubertal teenagers in order to reduce the risk of experiencing
precocious sexual development or premature epiphyseal closure. This type of
patients’ skeletal maturation should be closely and regularly monitored.
Both male and female patients who have the
following medical conditions must not start a treatment with HCG
Pregnyl:1)Hypersensitivity to this medicine or to any of its main ingredients.
2)Known or possible androgen-dependent tumors for example male breast carcinoma
or prostatic carcinoma.
Anabolic steroid adjunct
In the world of performance-enhancing drugs, hCG
is increasingly used in combination with various anabolic
androgenic steroid (AAS) cycles. As a result, hCG is included in
some sports' illegal drug lists.
When exogenous AAS are put into the male body,
natural negative-feedback loops cause the body to shut down its own production
of testosterone
via shutdown of the hypothalamic-pituitary-gonadal axis (HPGA). This
causes testicular atrophy, among other things. hCG is commonly used during and
after steroid cycles to maintain and restore testicular size as well as normal
testosterone production.[28]
High levels of AASs, that mimic the body's
natural testosterone, trigger the hypothalamus
to shut down its production of gonadotropin-releasing
hormone (GnRH) from the hypothalamus. Without GnRH, the pituitary
gland stops releasing luteinizing hormone (LH). LH
normally travels from the pituitary via the blood stream to the testes,
where it triggers the production and release of testosterone. Without LH, the
testes shut down their production of testosterone.[29]
In males, hCG helps restore and maintain testosterone production in the testes
by mimicking LH and triggering the production and release of testosterone.
If hCG is used for too long and in too high a
dose, the resulting rise in natural testosterone will eventually inhibit its
own production via negative feedback on the hypothalamus and pituitary gland.
Professional athletes who have tested positive
for hCG have been temporarily banned from their sport, including a 50-game ban
from MLB
for Manny
Ramirez in 2009[30]
and a 4-game ban from the NFL
for Brian
Cushing for a positive urine test for hCG.
See also
References
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^ a
b
Cole LA (2009). "New
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PMID 19171054.
2.
^
Gregory JJ, Finlay JL (April 1999).
"Alpha-fetoprotein and beta-human chorionic gonadotropin: their clinical
significance as tumour markers". Drugs 57 (4): 463–7. PMID 10235686.
3.
^
Hoermann R, Spoettl G, Moncayo R, Mann K (July 1990).
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4.
^
Gever, John (December 6, 2011). "FDA
Yanks HCG Weight Loss Agents from Market". MedPage
Today. Retrieved December 7, 2011.
5.
^
"HCG
Diet Products Are Illegal". FDA. December 6, 2011.
6.
^
"FDA,
FTC act to remove 'homeopathic' HCG weight loss products from the market"
(Press release). FDA. December 6, 2011.
Retrieved December 7, 2011.
7.
^ a
b
PDB 1HRP; Lapthorn AJ, Harris DC, Littlejohn A, Lustbader JW, Canfield RE,
Machin KJ, Morgan FJ, Isaacs NW (June 1994). "Crystal structure of human
chorionic gonadotropin". Nature 369 (6480): 455–61. doi:10.1038/369455a0. PMID 8202136.
8.
^
Kayisli U, Selam B, Guzeloglu-Kayisli O, Demir R, Arici A
(2003). "Human chorionic gonadotropin contributes to maternal
immunotolerance and endometrial apoptosis by regulating Fas-Fas ligand
system". J. Immunol. 171 (5): 2305–13. PMID 12928375.
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10.
^
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11.
^
Michels KB, Xue F, Colditz GA, Willett WC (April 2007).
"Induced and spontaneous abortion and incidence of breast cancer among
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(8): 814–20. doi:10.1001/archinte.167.8.814.
PMID 17452545.
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Clinical Diagnosis and Management by Laboratory Methods (21st ed.).
Philadelphia: Saunders. ISBN 1-4160-0287-1.[page needed]
13.
^
Waddell, Rebecca Smith (2006). "FertilityPlus.org".
Home Pregnancy Test hCG Levels and FAQ. Retrieved 2006-06-17.
14.
^
Wilcox AJ, Baird DD, Weinberg CR (1999). "Time of
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15.
^
Butler SA, Khanlian SA, Cole LA (2001). "Detection of
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devices". Clinical Chemistry 47 (12): 2131–2136. PMID 11719477.
16.
^
HCG Injection After
Ovulation Induction With Clomiphene Citrate at Medscape. By Peter Kovacs.
Posted: 04/23/2004
17.
^
IVF.com; Ovulation Induction.
Retrieved Mars 7, 2010[unreliable
medical source?]
18.
^
Lee-Huang S, Huang PL, Sun Y, Huang PL, Kung HF, Blithe
DL, Chen HC (March 1999). "Lysozyme
and RNases as anti-HIV components in beta-core preparations of human chorionic
gonadotropin". Proc. Natl. Acad. Sci. U.S.A. 96 (6):
2678–81. doi:10.1073/pnas.96.6.2678. PMC 15828.
PMID 10077570.
19.
^
"Dr.Simeons’
HCG Diet Food Choices". GreenHCG. Retrieved 8 October 2011.
20.
^
Stein MR, Julis RE, Peck CC, Hinshaw W, Sawicki JE, Deller
JJ (September 1976). "Ineffectiveness
of human chorionic gonadotropin in weight reduction: a double-blind study".
Am. J. Clin. Nutr. 29 (9): 940–8. PMID 786001. Retrieved 2009-02-03.
21.
^
Barrett S. "HCG Worthless as
Weight-Loss Aid". Diet Scam Watch. dietscam.org. Retrieved 2009-02-03.
22.
^
Peter Y. Liu, Susan M. Wishart and David J. Handelsman
(2002). "A Double-Blind, Placebo-Controlled, Randomized Clinical Trial of
Recombinant Human Chorionic Gonadotropin on Muscle Strength and Physical
Function and Activity in Older Men with Partial Age-Related Androgen
Deficiency". The Journal of Clinical Endocrinology and Metabolism 87
(7): 3125–3135. doi:10.1210/jc.87.7.3125. PMID 12107212.
23.
^
Lijesen GK, Theeuwen I, Assendelft WJ, Van Der Wal G
(September 1995). "The
effect of human chorionic gonadotropin (HCG) in the treatment of obesity by
means of the Simeons therapy: a criteria-based meta-analysis". Br J
Clin Pharmacol 40 (3): 237–43. PMC 1365103.
PMID 8527285.
24.
^
"Chorionic
Gonadotropin (Human) Injection Shortage". Bulletin. American
Society of Health-System Pharmacists. 2010-10-13. Retrieved 2010-10-23.
25.
^
Phillips J (2011-01-24). "Weight Loss
Drugs Dubbed Fraudulent and Illegal by FDA". Epoch Times. Retrieved 2011-02-03.
26.
^
Hellmich N (2011-01-23). "HCG
weight-loss products are fraudulent, FDA says - USATODAY.com". USA
Today. Retrieved 2011-02-03.
27.
^
"HCG
Pregnyl". 2010-10-13.
Retrieved 2010-10-23.
28.
^
Williams, Lance (May 8, 2009). "Manny
Ramirez suspended; testosterone ratio exceeded limits; fertility drug
reported". San Francisco Chronicle.
29.
^
van Breda E, Keizer HA, Kuipers H, Wolffenbuttel BH (April
2003). "Androgenic anabolic steroid use and severe hypothalamic-pituitary
dysfunction: a case study". Int J Sports Med 24 (3): 195–6. doi:10.1055/s-2003-39089. PMID 12740738.
30.
^
Schmidt, Michael S. (May 8, 2009). "Manny
Ramirez Is Banned for 50 Games". The New York Times.
31.
^
McClain J (2010-05-12). "Cushing
suspended for performance-enhancing drugs". Houston Texans Football.
Houston Chronicle. Retrieved 2010-10-23.

1hcn: STRUCTURE OF HUMAN CHORIONIC GONADOTROPIN AT 2.6 ANGSTROMS RESOLUTION FROM MAD ANALYSIS OF THE SELENOMETHIONYL PROTEIN

1hrp: CRYSTAL STRUCTURE OF HUMAN CHORIONIC GONADOTROPIN

1qfw: TERNARY COMPLEX OF HUMAN CHORIONIC GONADOTROPIN WITH FV ANTI ALPHA SUBUNIT AND FV ANTI BETA SUBUNIT