human chorionic gonadotropin

Chorionic gonadotropin, beta polypeptide
PDB rendering based on 1hcn.
Available structures: 1hcn, 1hrp, 1qfw
Identifiers
Symbols	CGB; CGB3; hCGB; HCG; MGC119822
External IDs	OMIM: 118860 HomoloGene: 37338
Gene ontology Molecular function: • hormone activity Cellular component: • extracellular region
Orthologs
	Human	Mouse
Entrez	1082	n/a
Refseq	NM_000737 (mRNA) NP_000728 (protein)	n/a (mRNA) n/a (protein)
Pubmed search	[1]	n/a

Human chorionic gonadotropin (hCG) is a glycoprotein hormone produced in pregnancy that is made by the developing embryo soon after conception and later by the syncytiotrophoblast (part of the placenta). Its role is to prevent the disintegration of the corpus luteum of the ovary and thereby maintain progesterone production that is critical for a pregnancy in humans. hCG may have additional functions; for instance, it is thought that hCG affects the immune tolerance of the pregnancy. Early pregnancy testing, in general, is based on the detection or measurement of hCG. Because hCG is produced also by some kinds of tumor, hCG is an important tumor marker, but it is not known whether this production is a contributing cause or an effect of tumorigenesis.

Structure

Human chorionic gonadotropin is a glycoprotein composed of 244 amino acids with a molecular mass of 36.7 kDa. Its total dimensions are 75×35×30 angstroms (7.5×3.5×3 nanometers).

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 and has dimensions 60×25×15 angstroms (6×2.5×1.5 nm).

• The β-subunit of hCG gonadotropin contains 145 amino acids and has dimensions 6.5×2.5×2 nm, 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 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.

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.^[1] It has also been suggested that hCG levels are linked to the severity of morning sickness in pregnant women.^[2]

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.

Human chorionic gonadotropin also plays a role in cellular differentiation/proliferation and may activate apoptosis.^[3]

Production

Like other gonadotropins, hCG can be extracted from urine or by genetic modification. Pregnyl, Follutein, Profasi, and Novarel use the former method, derived from the urine of pregnant women. Ovidrel, on the other hand, is a product of recombinant DNA.

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.^[4] Published detection thresholds range from 20 to 100 mIU/ml, depending on the brand of test.^[5] 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^[4] 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 IU/ml is strongly indicative of an ectopic pregnancy.

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.)

• 3 weeks since LMP: 5 - 50 mIU/ml
• 4 weeks since LMP: 5 - 426 mIU/ml
• 5 weeks since LMP: 18 - 7,340 mIU/ml
• 6 weeks since LMP: 1,080 - 56,500 mIU/ml
• 7 - 8 weeks since LMP: 7, 650 - 229,000 mIU/ml
• 9 - 12 weeks since LMP: 25,700 - 288,000 mIU/ml
• 13 - 16 weeks since LMP: 13,300 - 254,000 mIU/ml
• 17 - 24 weeks since LMP: 4,060 - 165,400 mIU/ml
• 25 - 40 weeks since LMP: 3,640 - 117,000 mIU/ml
• Non-pregnant females: <5.0 mIU/ml
• Postmenopausal females: <9.5 mIU/ml

Uses

Tumor marker

The β subunit of human chorionic gonadotropin is secreted also by some cancers including choriocarcinoma, germ cell tumors, hydatidiform mole formation, teratoma with elements of choriocarcinoma (this is rare), 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 IU/ml.

Fertility

Human chorionic gonadotropin is extensively used as a parenteral fertility medication 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 about 36-48 hours after the injection of hCG, procedures can be scheduled to take advantage of this time sequence. Thus, patients that undergo IVF, in general, receive hCG to trigger the ovulation process, but have their eggs retrieved at about 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.

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.^[6]

Weight loss

A controversial usage of hCG is as an adjunct to the British endocrinologist Dr. A.T.W. Simeons' ultra-low-calorie weight-loss diet.^[7] Simeons, while studying pregnant women in India on a calorie-deficient diet, and “fat boys” with pituitary problems treated with low-dose hCG, discovered 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 fœtus, and proceeded to use low-dose daily hCG injections (125 mg) in combination with a customized ultra-low-calorie (500 cal/day, high-protein, low-carbohydrate/fat) diet to help obese adults lose dramatic amounts of adipose tissue without loss of lean, at a Salvator Mundi International Hospital in Rome, Italy, clinic mainly for celebrities. After Simeons’ mysterious death, the diet started to spread to specialized centers and via popularization by such as the controversial popular author Kevin Trudeau (search for hCG in that article for more details).

The controversy proceeds from warnings by the Journal of the American Medical Association^[8] and the American Journal of Clinical Nutrition^[9] that hCG is not safe,^[8] indeed ineffective, as a weight-loss aid^[10] on its own; yet its usage as cited above to increase testosterone production contradicts this assertion, since much late-life male obesity is associated with estrogen dominance and deficient testosterone in the mis-named, so-called andropause. Furthermore, in the Simeons protocol, it is, as in any diet, the ultra-low-calorie component (caloric deficit) that results in weight loss, if the protocol is followed strictly. hCG’s role is supposedly to trigger the hypothalamic lean-protection mechanisms Simeons thought he saw, thus promoting mobilization and consumption of abnormal, excessive adipose deposits, while protecting normal adipose and lean tissue from being consumed, with the assumption that these protective hypothalamic mechanisms exist in males as well as females, to be acted upon by hCG.

Anabolic steroid adjunct

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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 AAS are put into a male body, the body's 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 of a dose, the resulting rise in natural testosterone will eventually inhibit its own production via negative feedback on the hypothalamus and pituitary.

See also

• Human placental lactogen
• Triple test - a screening test in pregnancy

References

External links

• MeSH Chorionic+Gonadotropin