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.

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.^[31]

See also

• Equine chorionic gonadotropin
• Human placental lactogen
• Triple test - a screening test in pregnancy

References

1.       ^ ^{a b} Cole LA (2009). "New discoveries on the biology and detection of human chorionic gonadotropin". Reprod. Biol. Endocrinol. 7: 8. doi:10.1186/1477-7827-7-8. PMC 2649930. 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). "Evidence for the presence of human chorionic gonadotropin (hCG) and free beta-subunit of hCG in the human pituitary". J. Clin. Endocrinol. Metab. 71 (1): 179–86. doi:10.1210/jcem-71-1-179. PMID 1695224.

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.

9.       ^ Askling J, Erlandsson G, Kaijser M, Akre O, Ekbom A (December 1999). "Sickness in pregnancy and sex of child". Lancet 354 (9195): 2053. doi:10.1016/S0140-6736(99)04239-7. PMID 10636378.

10.   ^ Moedersvoormoeders.nl - a Dutch organization that collects urine from pregnant women to extract hCG.^{[unreliable medical source?]}

11.   ^ Michels KB, Xue F, Colditz GA, Willett WC (April 2007). "Induced and spontaneous abortion and incidence of breast cancer among young women: a prospective cohort study". Arch. Intern. Med. 167 (8): 814–20. doi:10.1001/archinte.167.8.814. PMID 17452545.

12.   ^ ^{a b} Richard A. McPherson, Matthew R. Pincus, (2006). Henry's 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 implantation of the conceptus and loss of pregnancy". New England Journal of Medicine 340 (23): 1796–1799. doi:10.1056/NEJM199906103402304. PMID 10362823.

15.   ^ Butler SA, Khanlian SA, Cole LA (2001). "Detection of early pregnancy forms of human chorionic gonadotropin by home pregnancy test 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.