From Wikipedia, the free encyclopedia
Human chorionic gonadotropin (hCG) is a hormone for the maternal recognition of pregnancy produced by trophoblast cells that are surrounding a growing embryo (syncytiotrophoblast initially), which eventually forms the placenta after implantation. The presence of hCG is detected in some pregnancy tests (HCG pregnancy strip tests). Some cancerous tumors
produce this hormone; therefore, elevated levels measured when the
patient is not pregnant may lead to a cancer diagnosis and, if high
enough, paraneoplastic syndromes, however, it is not known whether this production is a contributing cause, or an effect of carcinogenesis. The pituitary analog of hCG, known as luteinizing hormone (LH), is produced in the pituitary gland of males and females of all ages.
Various endogenous
forms of hCG exist. The measurement of these diverse forms is used in
the diagnosis of pregnancy and a variety of disease states. Preparations of hCG from various sources have also been used therapeutically, by both medicine and quackery. As of December 6, 2011, the United States Food and Drug Administration has prohibited the sale of "homeopathic" and over-the-counter hCG diet products and declared them fraudulent and illegal.
Beta-hCG is initially secreted by the syncytiotrophoblast.
Structure
Human chorionic gonadotropin is a glycoprotein composed of 237 amino acids with a molecular mass of 36.7 kDa, approximately 14.5kDa αhCG and 22.2kDa βhCG.
It is heterodimeric, with an α (alpha) subunit identical to that of luteinizing hormone (LH), follicle-stimulating hormone (FSH), thyroid-stimulating hormone (TSH), and a β (beta) subunit that is unique to hCG.
- The α (alpha) subunit is 92 amino acids long.
- The β-subunit of hCG gonadotropin (beta-hCG) 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). It is known that CGB7 has a sequence slightly different from that of the others.
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.
beta-hCG is mostly similar to beta-LH,
with the exception of a Carboxy Terminus Peptide (beta-CTP) containing
four glycosylated serine residues that is responsible for hCG's longer
half-life.
Function
Human chorionic gonadotropin interacts with the LHCG receptor of the ovary and promotes the maintenance of the corpus luteum for the maternal recognition of pregnancy at the beginning of pregnancy. This allows the corpus luteum to secrete the hormone progesterone during the first trimester. Progesterone enriches the uterus with a thick lining of blood vessels and capillaries so that it can sustain the growing fetus.
It has 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. It has also been suggested that hCG levels are linked to the severity of morning sickness or Hyperemesis gravidarum in pregnant women.
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 in women who are
presently pregnant, some organizations collect urine from pregnant women
to extract hCG for use in fertility treatment.
Human chorionic gonadotropin also plays a role in cellular differentiation/proliferation and may activate apoptosis.
Production
Naturally, it is produced in the human placenta by the syncytiotrophoblast.
Like any other gonadotropins, it can be extracted from the urine of pregnant women or produced from cultures of genetically modified cells using recombinant DNA technology.
In Pubergen, Pregnyl, Follutein, Profasi, Choragon and Novarel, it is extracted from the urine of pregnant women. In Ovidrel, it is produced with recombinant DNA technology.
hCG forms
Three
major forms of hCG are produced by humans, with each having distinct
physiological roles. These include regular hCG, hyperglycosylated hCG,
and the free beta-subunit of hCG. Degradation products of hCG have also
been detected, including nicked hCG, hCG missing the C-terminal peptide
from the beta-subunit, and free alpha-subunit, which has no known
biological function. Some hCG is also made by the pituitary gland with a pattern of glycosylation that differs from placental forms of hCG.
Regular hCG is the main form of hCG associated with the majority
of pregnancy and in non-invasive molar pregnancies. This is produced in
the trophoblast
cells of the placental tissue. Hyperglycosylated hCG is the main form
of hCG during the implantation phase of pregnancy, with invasive molar
pregnancies, and with choriocarcinoma.
Gonadotropin preparations of hCG can be produced for pharmaceutical use from animal or synthetic sources.
Testing
Blood or urine tests measure hCG. These can be pregnancy tests. hCG-positive can indicate an implanted blastocyst and mammalian embryogenesis or can be detected for a short time following childbirth or pregnancy loss. Tests can be done to diagnose and monitor germ cell tumors and gestational trophoblastic diseases.
Concentrations are commonly reported in thousandth international
units per milliliter (mIU/mL). The international unit of hCG was
originally established in 1938 and has been redefined in 1964 and in
1980. At the present time, 1 international unit is equal to approximately 2.35×10−12 moles, or about 6×10−8 grams.
It is also possible to test for hCG to have an approximation of the gestational age.
Methodology
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.)
Many hCG immunoassays are based on the sandwich principle, which uses antibodies to hCG labeled with an enzyme or a conventional or luminescent dye.
Pregnancy urine dipstick tests are based on the lateral flow technique.
- The urine test may be a chromatographic immunoassay or any of several other test formats, home-, physician's office-, or laboratory-based. Published detection thresholds range from 20 to 100 mIU/mL, depending on the brand of test.
Early in pregnancy, more accurate results may be obtained by using the
first urine of the morning (when urine is most concentrated). 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 that can detect βhCG levels as low as 5 mIU/mL and allows quantification of the βhCG concentration.
Reference levels in normal pregnancy
The following is a list of serum hCG levels. (LMP is the last menstrual period dated from the first day of the last menstrual period.) The levels grow exponentially after conception and implantation.
| weeks since LMP |
mIU/mL
|
| 3 |
5 – 50
|
| 4 |
5 – 428
|
| 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
|
If a pregnant woman has serum hCG levels that are higher than expected, they may be experiencing a multiple pregnancy
or an abnormal uterine growth. Falling hCG levels may indicate the
possibility of a miscarriage. hCG levels which are rising at a slower
rate than expected may indicate an ectopic pregnancy.
Interpretation
The ability to quantitate the βhCG level is useful in monitoring germ cell and trophoblastic tumors, follow-up care after miscarriage, and diagnosis of and follow-up care after treatment of ectopic pregnancy. The lack of a visible fetus on vaginal ultrasound after βhCG levels reach 1500 mIU/mL is strongly indicative of an ectopic pregnancy. Still, even an hCG over 2000 IU/L does not necessarily exclude the presence of a viable intrauterine pregnancy in such cases.
As pregnancy tests, quantitative blood tests and the most
sensitive urine tests usually detect hCG between 6 and 12 days after
ovulation.
It must be taken into account, however, 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. A rise of 35% over 48 hours is proposed as the minimal rise consistent with a viable intrauterine pregnancy.
Gestational trophoblastic disease like hydatidiform moles ("molar pregnancy") or choriocarcinoma may produce high levels of βhCG (due to the presence of syncytiotrophoblasts
- 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.
A study of 32 normal pregnancies came to the result that a gestational sac of 1–3 mm was detected at a mean hCG level of 1150 IU/L (range 800–1500), a yolk sac was detected at a mean level of 6000 IU/L (range 4500–7500) and fetal heartbeat was visible at a mean hCG level of 10,000 IU/L (range 8650–12,200).
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, teratoma with elements of choriocarcinoma, other germ cell tumors, hydatidiform mole, 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 injection is extensively used for final maturation induction 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, procedures can be scheduled to take advantage of this time sequence, such as intrauterine insemination or sexual intercourse. Also, patients that undergo IVF, in general, receive HCG to trigger the ovulation process, but have an oocyte retrieval performed at about 34 to 36 hours after injection, 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, including during testosterone replacement
therapy to restore or maintain fertility and prevent testicular atrophy.
Several vaccines against human chorionic gonadotropin (hCG) for the prevention of pregnancy are currently in clinical trials.
HCG Pubergen, Pregnyl warnings
In the case of female patients who want to be treated with HCG Pubergen, Pregnyl:
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 drug
have a higher risk of multiple pregnancy.
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 Pubergen, 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
Pubergen, Pregnyl is known to regularly lead to increased production of
androgen. Therefore: Patients who have overt or latent cardiac failure,
hypertension, renal dysfunction, migraines, or epilepsy might not be
allowed to start using this medicine or may require a lower dose of HCG
Pubergen, Pregnyl. This drug should be used with extreme caution in the
treatment of prepubescent
teenagers in order to reduce the risk of 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 Pubergen, Pregnyl: (1)
Hypersensitivity to this drug 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.
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.
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 and estrogen would eventually inhibit
endogenous production of luteinizing hormone 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 and a 4-game ban from the NFL for Brian Cushing for a positive urine test for HCG. Mixed Martial Arts fighter Dennis Siver was fined $19,800 and suspended 9 months for being tested positive after his bout at UFC 168.
HCG diet
British endocrinologist Albert T. W. Simeons proposed HCG as an adjunct to an ultra-low-calorie weight-loss diet (fewer 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, observed 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 in 1954 published a book entitled Pounds and Inches,
designed to combat obesity. 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, which was
supposed to result in a loss of adipose tissue without loss of lean
tissue.
Other researchers did not find the same results when attempting
experiments to confirm Simeons' conclusions, and in 1976 in response to
complaints the FDA required Simeons and others to include the following
disclaimer on all advertisements:
These weight reduction treatments
include the injection of HCG, a drug which has not been approved by the
Food and Drug Administration as safe and effective in the treatment of
obesity or weight control. There is no substantial evidence that HCG
increases weight loss beyond that resulting from caloric restriction,
that it causes a more attractive or "normal" distribution of fat, or
that it decreases the hunger and discomfort associated with
calorie-restrictive diets.
— 1976 FDA-mandated disclaimer for HCG diet advertisements
There was a resurgence of interest in the "HCG diet" following promotion by Kevin Trudeau, who was banned from making HCG diet weight-loss claims by the U.S. Federal Trade Commission in 2008, and eventually jailed over such claims.
A 1976 study in the American Journal of Clinical Nutrition concluded that HCG is not more effective as a weight-loss aid than dietary restriction alone.
A 1995 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".
On November 15, 2016, the American Medical Association (AMA) passed policy that "The use of human chorionic gonadotropin (HCG) for weight loss is inappropriate."
There is no scientific evidence
that HCG is effective in the treatment of obesity. The meta-analysis
found insufficient evidence supporting the claims that HCG is effective
in altering fat-distribution, hunger reduction, or in inducing a feeling
of well-being. The authors stated "…the use of HCG should be regarded
as an inappropriate therapy for weight reduction…" In the authors
opinion, "Pharmacists and physicians should be alert on the use of HCG
for Simeons therapy. The results of this meta-analysis support a firm
standpoint against this improper indication. Restraints on physicians
practicing this therapy can be based on our findings."
— American Society of Bariatric Physicians' commentary on Lijesen et al. (1995)
According to the American Society of Bariatric Physicians, no new
clinical trials have been published since the definitive 1995
meta-analysis.
The scientific consensus is that any weight loss reported by
individuals on an "HCG diet" may be attributed entirely to the fact that
such diets prescribe calorie intake of between 500 and 1,000 calories
per day, substantially below recommended levels for an adult, to the
point that this may risk health effects associated with malnutrition.
Homeopathic HCG for weight control
Controversy about, and shortages 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. Moreover, it is
highly unlikely that oral HCG is bioavailable due to the fact that
digestive protease enzymes and hepatic metabolism renders peptide-based
molecules (such as insulin and human growth hormone) biologically inert.
HCG can likely only enter the bloodstream through injection.
The United States Food and Drug Administration
has stated that over-the-counter products containing HCG are fraudulent
and ineffective for weight loss. They are also not protected as
homeopathic drugs and have been deemed illegal substances.
HCG is classified as a prescription drug in the United States and it
has not been approved for over-the-counter sales by the FDA as a weight
loss product or for any other purposes, and therefore neither HCG in its
pure form nor any preparations containing HCG may be sold legally in
the country except by prescription. In December 2011, FDA and FTC started to take actions to pull unapproved HCG products from the market.
In the aftermath, some suppliers started to switch to "hormone-free"
versions of their weight loss products, where the hormone is replaced
with an unproven mixture of free amino acids or where radionics is used to transfer the "energy" to the final product.
Tetanus vaccine conspiracy theory
Catholic Bishops in Kenya are among those who have spread a conspiracy theory asserting that HCG forms part of a covert sterilization program, forcing denials from the Kenyan government.
In order to induce a stronger immune response, some versions of
human chorionic gonadotropin-based anti-fertility vaccines were designed
as conjugates of the β subunit of HCG covalently linked to tetanus toxoid. It was alleged that a non-conjugated tetanus vaccine
used in developing countries was laced with a human chorionic
gonadotropin-based anti-fertility drug and was distributed as a means of
mass sterilization. This charge has been vigorously denied by the World Health Organization (WHO) and UNICEF.
Others have argued that a hCG-laced vaccine could not possibly be used
for sterilization, since the effects of the anti-fertility vaccines are
reversible (requiring booster doses to maintain infertility) and a non-conjugated vaccine is likely to be ineffective.
Finally, independent testing of the tetanus vaccine by Kenya's health
authorities revealed no traces of the human chorionic gonadotropin
hormone.
