Human chorionic gonadotropin (hCG) is a hormone produced during pregnancy by the placenta. It provides nourishment to the egg after it has been fertilized and attached to the uterine wall.
HCG is used to detect pregnancy as well as to monitor it. It is also elevated in certain cancers, hence is used as a tumor marker for their diagnosis.
HCG receptors have been found in sperm and fallopian tubes suggesting pre-pregnancy communication.
HCG receptors have been found in the brain too.
During pregnancy, hCG levels have been related to morning sickness. Higher the hCG levels, greater the severity of nausea and vomiting during pregnancy.
Production of Human Chorionic Gonadotropin
Gestational and nongestational trophoblasts are by far the most common sources of hCG. A small amount of the hormone may also be produced by the pituitary gland and nontrophoblastic malignancies.
Structure of hCG
Human chorionic gonadotropin is a member of the glycoprotein hormone family that includes the pituitary hormones – luteinizing hormone (LH), follicle-stimulating hormone (FSH), and thyroid-stimulating hormone (TSH).
It is composed of 237 amino acids and has a molecular weight of 36.7 kDa.
It is a heterodimer composed of two dissimilar subunits, α and β which are joined together by noncovalent bonds. The two subunits are arranged in such a manner that a small hydrophobic core is formed in the center while the majority of the outer amino acids are hydrophilic.
The α-subunit is similar to the pituitary glycoprotein hormones. It is composed of 92 amino acids linked by five disulfide bridges.
The β-subunit is unique to hCG and distinguishes it from the other glycoprotein hormones. It is composed of 145 amino acids linked by six disulfide bridges. These amino acids are encoded by six highly homologous genes that are arranged in tandem and inverted pairs on chromosome 19q13.3
There are different forms of endogenous hCG which can be measured separately. These include total hCG, C-terminal peptide total hCG, intact hCG, free β-subunit hCG, β-core fragment hCG, hyperglycosylated hCG, nicked hCG, alpha hCG and pituitary hCG
Functions of hCG
Maintenance of Corpus Luteum
The primary function of hCG is to help in the maintenance of the corpus luteum during early pregnancy. The corpus luteum secretes the hormone progesterone which in turn maintains the endometrial lining and sustains the growing fetus.
Maintenance of the uterine lining provides a place for embryonic development. The embryo is totally dependent on the uterine lining until the placenta is fully formed, usually during the fourth month of pregnancy.
By maintaining the corpus luteum that surrounds the egg, hCG helps to sustain a pregnancy if an egg is fertilized. In a non –pregnant person, when the corpus luteum surrounding an unfertilized egg dies, levels of progesterone fall causing the uterine lining to slough, which results in a menstrual period.
Immuno-suppression [Blockage of Phagocytosis of Invading Trophoblast Cells]
HCG repels the immune cells of the mother and promotes maternal immunotolerance, thereby protecting the fetus during the early months of pregnancy.
- Angiogenesis of Uterine Vasculature
- Differentiation of Cytotrophoblast
- Promotion of uterine growth with of Uterus in Accordance with Fetal Growth
- Quiescence of Uterine Muscle Contraction
- Promotes growth and Differentiation of fetal organs
- Umbilical cord growth and development
Normal Levels of Human Chorionic Gonadotropin
Levels in Children
- Birth-3 months – 50 mIU/mL or less
- 3 months-18 years – 0.8 mIU/mL or less
Pediatric females are
- Birth-3 months – 50.0 mIU/mL or less
- 3 months-18 years – 2.3 mIU/mL or less
- Non-pregnant females: 0 – 5 mIU/mL
- Males: 0 – 5 mIU/mL
- Postmenopausal females: 0 – 8 mIU/mL
Maternal Blood Levels
[in weeks from LMP (last menstrual period) or gestational age]
HCG can first be detected in a blood sample about 11 days after conception or 3 weeks after the first day of last menstrual period. Levels continue to double every 48 to 72 hours to reach their peak at around 8 to 12 weeks. After that, the values start declining and level off, remaining steady for the rest of the pregnancy.
Here are the weekly levels in mIU/mL
- 3 weeks: 5 – 50
- 4 weeks : 5 – 426
- 5 weeks : 18 – 7,340
- 6 weeks : 1,080 – 56,500
- 7 – 8 weeks : 7, 650 – 229,000
- 9 – 12 weeks : 25,700 – 288,000
- 13 – 16 weeks : 13,300 – 254,000
- 17 – 24 weeks : 4,060 – 165,400
- 25 – 40 weeks : 3,640 – 117,000
Presence of twins approximately doubles hCG concentration.
Clinical Uses of hCG
Diagnosis and Confirmation of pregnancy
Since hCG levels start rising immediately after successful conception, its level in blood and urine can be used to diagnose and confirm pregnancy. Women can test positive for pregnancy owing to hCG production several days before a missed period. Detection of hCG in urine forms the basis of home pregnancy detection kits.
Serum level of hCG < 5 mIU/ml indicates no pregnancy.
Levels > 25 mIU/ml indicate a positive test result for pregnancy while levels between 5 – 25 mIU/ml indicate an indeterminate result and need to be repeated again.
Detection of ectopic pregnancy
A slow increase in hCG (<66% in 48 hours during first 40 days of pregnancy) indicates ectopic pregnancy in the majority of cases.
Ectopic pregnancy is suspected when hCG levels are in the range of 1500-2000 mIU/mL but no gestational sac is seen on transvaginal sonography. It is also to be considered If the level is about 6500 mIU/mL and no gestational sac is visible on abdominal ultrasonography. High or rising level of hCG post endometrial curettage is also indicative of ectopic pregnancy.
Monitoring viability of pregnancy
Since, hCG levels keep on rising in early pregnancy, serial monitoring of this hormone is used to assess whether the pregnancy is viable or not. In case, the levels start decreasing or do not rise in proportion to the gestational age, it indicates a non-viable fetus.
More than the level at any gestational age, it is the change in the level over a period of time that is more relevant. HCG doubling time over two to three days can give a strong indication of whether or not the pregnancy is progressing.
Used as a tumor marker
It can be used as a tumor marker in following malignancies for screening, diagnosis, disease monitoring and to assess response to treatment.
- Gestational trophoblastic diseases
- Hydatidiform mole
- Invasive Mole
- Placental site trophoblastic tumor
- Epithelioid trophoblastic tumor
- Germ cell tumors of the ovary and testis
- Embryonal carcinoma
- Seminoma (few cases)
Role in Prenatal Screening
Levels of hCG can identify women having increased risk of fetal abnormalities. Usually done at 15-20 weeks of gestation, the test is called triple marker as levels of human chorionic gonadotropin are tested along with levels of AFP and free estriol.
When inhibin A is also used along with, the term quadruple marker is used.
Increased level of hCG is associated with increased risk of Down Syndrome while reduced level indicates increased risk of Trisomy 18.
Very high unexplained levels are associated with fetal chromosomal abnormalities, molar pregnancy, multiple gestation or chorangiosis of the placenta.
Prevention of Miscarriage
Human chorionic gonadotropin is administered to patients for reducing the risk of miscarriage. It is given in cases of impending miscarriage or in patients having a history of repeated abortions.
Treatment of Female Infertility
HCG mimics some of the effects of luteinizing hormone (LH) due to similarities between the two.
Luteinizing hormone normally stimulates ovulation, but if LH levels are low, injections of hCG have similar stimulatory effects.
Thus in women whose ovaries form eggs but fail to release, human chorionic gonadotropin can stimulate ovulation and help improve fertility.
The ovulation usually occurs between 38 and 40 hours after a single hCG injection. Therefore, the procedures such as intrauterine insemination or IVF need to be planned in accordance.
Treatment of Male Infertility
Human chorionic gonadotropin is used to increase sperm production in men having low testosterone levels. hCG stimulates the Leydig cells of the testes to synthesize testosterone.
HCG is also used in
- Treatment of
- undescended testes in young men
- Undeveloped sexual traits in girls.
Use in Sports and Diet
Used by bodybuilders and athletes
[HCG is included in some sports’ illegal drug lists.]
- Taken at the end of the anabolic-androgenic steroid dosing
- Aimed at increasing testosterone production
- Exogenous steroids shut down testosterone production and cause testicular atrophy.
- HCG used during and after steroid cycles to maintain and restore testicular size and increase testosterone production.
HCG was proposed as an adjunct to an ultra-low-calorie weight-loss diet based on assumption that it causes body fat to burn rather than muscles. However, the research has not substantiated this further.
How to test for Human Chorionic Gonadotropin
HCG can be measured both in blood as well as in urine. A positive result usually indicates an implanted blastocyst and embryogenesis.
Method of Testing
Most hCG immunoassays are based on the sandwich principle which uses a monoclonal antibody, specific to the β-subunit of hCG (β-hCG). The antibodies to hCG are labeled with an enzyme or a conventional or luminescent dye. This procedure prevents false positive results as it avoids confusion of hCG with luteinizing hormone (LH) and follicle stimulating hormone (FSH).
HCG Test in Urine
The urine test employs chromatographic immunoassay and is based on lateral flow technique. It is a qualitative test. Pregnancy urine dipstick tests [Commmon Pregnancy Test Kit] are based on this method. It is very convenient and can be performed at home, physician’s office or at a laboratory.
The detection thresholds range from 20 to 100 mIU/ml, depending on the brand of test.
In early pregnancy, when the levels of hCG are low, a positive result may be obtained by using the first urine of the morning (which is most concentrated).
HCG Test in Blood
The blood test employs a chemiluminescent or fluorimetric immunoassay technique. It is a quantitative test that can detect βhCG levels as low as 5 mIU/ml. It requires about 2-4ml of venous blood.
An elevated hCG level may be physiologic, pathophysiologic from a tumor or an artifact from a false-positive hCG test.
Clinical correlation helps to identify the significance.
False-negative pregnancy results
A negative result usually indicates that the patient is not pregnant. However if performed in early pregnancy, the hCG level may be quite low and not detectable by conventional tests. In such cases, it is advised to repeat the test after 48-72 hours.
False-positive Pregnancy Test Results
- Exogenous hCG being administered. After hCG is administered, it increases the level for up to two to three weeks after the drug has been administered.
- Improper usage of Home detection kits
- Not following label instructions
- Defective Pregnancy Test Kit
- Chemical Pregnancy
- Positive pregnancy test but the embryo or fetus does not develop.
- Early miscarriage
- Presence of certain rare conditions
- Pancreas islet-cell tumors
- Bladder cancer
- Lung cancer
- Medications – methadone, chlordiazepoxide, or promethazine
- Psychological condition
- Patient falsely believes that she is pregnant
- Slightly increased hormone levels due to the involvement of pituitary hypothalamus axis
- Can give a false positive blood test result
- Not detected in urine though
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