Human chorionic gonadotropin

Human chorionic gonadotropin (hCG) is a peptide hormone produced in pregnancy that is made by the 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.

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Structure

Human chorionic gonadotropin is an oligosaccharide 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 beta subunit of human chorionic gonadotropin is 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 gravidae to extract hCG for use in fertility treatment.

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

Pregnancy testing

Pregnancy tests measure the levels of hCG in the blood or urine to indicate the presence or absence of an implanted embryo.

In particular, most pregnancy tests employ a monoclonal antibody (MAb), which is specific to the β-subunit of hCG (βhCG). 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 hCG levels are negligible except during 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 (milli International Units per milli-liter), depending on the brand of test.^[5] The urine should be 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 quantitation of the βhCG concentration. The ability to quantitate the βhCG level is useful in the evaluation of ectopic pregnancy and in monitoring germ cell and trophoblastic tumors.

Hydatidiform moles ("molar pregnancy") may produce high levels of βhCG, despite the absence of an embryo. This, as well as several other conditions, can lead to false positive readings of pregnancy tests.

Tumor marker

The β subunit of human chorionic gonadotropin is secreted also by some cancers including choriocarcinoma, 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 cancer.

Main article: tumor marker

Use as medication

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 40-45 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]

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. Novarel and hCG from APP are typically considered generics in the United States.

Use with anabolic steroids

In the world of performance enhancing drugs, hCG is increasingly used in combination with various anabolic androgenic steroid (AAS) cycles.

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-testicular axis (HPTA). 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, causing testicular atrophy.

In males, hCG mimics LH and helps restore and maintain testosterone production in the testes. As such, hCG is commonly used during and after steroid cycles to maintain and restore testicular size as well as endogenous testosterone production. However, 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.

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