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Show detailsIntroduction
The human chorionic gonadotropin (hCG) is recognized as a term that describes 4 separate isoforms, each with a distinct biological function and produced by a different type of cell within the body.[1] These include synthesis from villous syncytiotrophoblasts, multiple primary nontrophoblastic malignancies or tumors, the anterior pituitary gland, and cytotrophoblast cells.[1][2] The principal functions of hCG synthesized from villous syncytiotrophoblastic cells include promoting progesterone production by the corpus luteal cells and subsequent growth of cytotrophoblast cells. The actions of hCG allow a coordinated growth of the fetus and uterus, signal the endometrium of impending implantation, support the growth and differentiation of the umbilical cord, and promote fetal growth and organogenesis.[1][2][3][4][5][6]
Hyperglycosylated forms of hCG from cytotrophoblastic cells promote growth and invasion of these cells, thus contributing to the pathogenesis of choriocarcinoma cells. A similar mechanism can occur in hCG-free beta-subunits synthesized by nontrophoblastic tumors. The detection of the free-beta subunit hCG is suggestive of malign cancer and poor prognosis.[7] hCG synthesized by the anterior pituitary gland is produced at low levels throughout the menstrual cycle and mimics the luteinizing hormone (LH) effects.[4]
Development
hCG is a pregnancy-specific hormone that is critical for the development of the fetus and placenta. Villous syncytiotrophoblasts and trophoblastic cells mainly produce hCG from implantation to the completion of pregnancy at various levels. As previously mentioned, one of the most important functions of hCG is to promote progesterone production, as it protects the endometrial lining during pregnancy. hCG has also been implicated in regulating uterine growth, implantation, trophoblast differentiation, angiogenesis, and vasculogenesis in the uterine walls.[4][5][8][4][5][9]
Importantly, hCG stimulates the production of endocrine gland-derived vascular endothelial growth factor (EG-VEGF), which acts on cytotrophoblastic cells. Through this action, the trophoblasts can form plugs that prevent maternal blood from bleeding into the intervillous spaces during early pregnancy.[4][5][6]
Function
The most well-known function of hCG is the promotion of progesterone production during pregnancy. hCG stimulates ovarian corpus luteal cells to produce progesterone, thus reinforcing the endometrial walls and preventing menstrual bleeding. This promotion of progesterone production is active in approximately 10% of the total length of the pregnancy or around 3 to 4 weeks following implantation. In a nonpregnant female, LH promotes progesterone production.[10][5][11]
The hCG hormone is a dimer made of an alpha and beta subunit. As mentioned earlier, the alpha subunit is common to all isomers of hCG except for the free beta-subunit form of the hormone.[8] The alpha subunit is also present in other hormones such as LH, follicle-stimulating hormone (FSH), and thyroid-stimulating hormone (TSH). The beta subunit confers a structural differentiation from hormones like LH, though all forms of hCG and LH bind to a common receptor. Besides the absence of a beta subunit in LH, the marked distinction between the 2 hormones is the difference in half-life. With a pI of 8.0, LH has a half-life of approximately 25 to 30 minutes, while hCG has a pI of 3.5 and a much longer half-life at 37 hours.[12][5] This difference in half-life is critical to hCG’s function as a type of "super LH" during pregnancy to support maintaining an optimal intrauterine environment.[8][4][13]
Studies over recent years have shown that hCG is involved in many functions supporting the placenta, uterus, and fetus throughout pregnancy. These functions include promoting angiogenesis, immunosuppression, and blockage of phagocytosis of invading trophoblasts, promoting growth and differentiation of fetal organs, and involvement in the adult brain and brainstem.[9][10][9]
hCG promotes angiogenesis and vasculogenesis through the upregulation of EG-VEGF.[6] Uterine spinal arteries have hCG receptors that, when acted upon by hCG, undergo growth and support the adequate blood supply and nutrition to the placenta. hCG also promotes the fusion of cytotrophoblast cells and their subsequent differentiation into syncytiotrophoblasts.[5][9]
Several studies have supported the function of hCG in preventing fetoplacental tissue rejection through inhibitory immune-mediated mechanisms.[14][15] Some groups have shown that an anti-macrophage inhibitory factor is upregulated by hCG activity during pregnancy, thus reducing macrophage activity at the uterine-placental interface.[16][17][18] Other studies support a more proximate mechanism of action in which hCG directly suppresses immune actions taken against the fetus.[9][10][19][9]
Maternal hCG has implications for the development of fetal organs during development. There are hCG receptors in the fetal liver and kidney that are completely absent in adult organs. hCG has also been shown to support the growth and development of the umbilical cord.[5][11][13][11]
Researchers have found hCG receptors in various areas of the adult female brain, including the hippocampus, hypothalamus, and brain stem. Speculation is that these receptors in the brain are involved in the pathophysiology of hyperemesis gravidarum. Other contributing factors may involve a combination of rising hormone levels, including estrogen, progesterone, and serum thyroxine, in addition to elevated hCG.[5][11][20]
Mechanism
hCG achieves many of its functions by regulating the expression of EG-VEGF and its receptors.[6] The EG-VEGF receptors are GPCRs, prokineticin 1 (PROKR1), and prokineticin 2. EG-VEGF is an angiogenic factor specific to endocrine tissues, including the placenta. EG-VEGF expression peaks around the same time as the peak of hCG concentration at approximately 8 to 11 weeks gestation.[6] As an angiogenic factor, EG-VEGF expression increases in conditions of hypoxia. EG-VEGF and its receptors are regulators of the fetus's pathological and normal development. EG-VEGF, PROKR1, and PROKR2 levels are significantly higher in fetal growth-restricted patients. Some have proposed that increases in EG-VEGF expression and its receptors brought on by increased levels of hCG are a form of compensation for fetal growth restriction.[7][10][11][13][11][11]
Clinical Significance
Abnormal levels of hCG are associated with adverse pregnancy outcomes such as molar pregnancies and fetal growth restrictions. The intrauterine environment must be maintained with certain conditions to properly support fetal development and growth. The intrauterine conditions depend upon placental function, as the placenta is the main source of fetal nourishment. Suboptimal conditions due to an atrophic placenta may contribute to the risk of low birth weight. Several studies support the correlation between low birth weight and the risk of developing chronic conditions such as diabetes and hypertension later in life.[5][21][22][23]
A molar pregnancy, or hydatidiform mole, is a tumor arising from the trophoblast, which surrounds a blastocyst and subsequently develops into the chorion and amnion.[23][24] This condition may manifest as a complete or partial molar pregnancy. A complete hydatidiform mole is usually diploid with a 46 XX karyotype. There is trophoblastic hyperplasia, which produces a mass of multiple vesicles with little evidence of fetal and embryonic development. A partial hydatidiform mole is usually triploid due to dispermous fertilization or fertilization with an unreduced diploid sperm. In contrast to the complete mole, there is usually evidence of fetal development with an enlarged placenta.[10][23]
The development of molar pregnancy correlates with fluxes in the levels of free beta-subunit of hCG. In a complete molar pregnancy, it is not uncommon to see large theca-lutein cysts due to increased stimulation of the ovaries by excess free beta-subunit hCG.[22][23][24]
Patients with a history of prior molar pregnancy are at a 10-fold greater risk of a second hydatidiform pregnancy compared to the general population. The recommendation is that these women have their hCG levels monitored throughout pregnancy and undergo evaluation by early ultrasonography.[5][23][24]
Several clinical studies support the association of hCG concentration abnormalities with adverse fetal outcomes. This association varies with gestational age as hCG levels fluctuate throughout the pregnancy.[22][24][23]
In the first trimester, low levels of hCG have correlated with spontaneous abortion and preeclampsia. Some studies have shown an association between low hCG concentrations (especially of the free beta-subunit of hCG) during the latter half of the first trimester and low birth weight due to attenuated fetal growth. Interestingly, some studies show that higher maternal hCG concentrations at the end of the first trimester are associated with fetal growth acceleration only in female-sex fetuses.[21][22]
In the second trimester, high levels of hCG have associations with gestational hypertension, spontaneous abortion, preeclampsia, fetal growth restriction (low birth weight), and preterm delivery; this is in contrast to the association of low levels of hCG and low birth weight observed in the first trimester of pregnancy.[7][22]
References
- 1.
- Cole LA, Laidler LL. Inherited human chorionic gonadotropin. J Reprod Med. 2010 Mar-Apr;55(3-4):99-102. [PubMed: 20506668]
- 2.
- Cole LA, Butler S. Detection of hCG in trophoblastic disease. The USA hCG reference service experience. J Reprod Med. 2002 Jun;47(6):433-44. [PubMed: 12092011]
- 3.
- Kohorn EI. What we know about low-level hCG: definition, classification and management. J Reprod Med. 2004 Jun;49(6):433-7. [PubMed: 15283049]
- 4.
- Faiman C, Ryan RJ, Zwirek SJ, Rubin ME. Serum FSH and HCG during human pregnancy and puerperium. J Clin Endocrinol Metab. 1968 Sep;28(9):1323-9. [PubMed: 5679995]
- 5.
- Cole LA. Biological functions of hCG and hCG-related molecules. Reprod Biol Endocrinol. 2010 Aug 24;8:102. [PMC free article: PMC2936313] [PubMed: 20735820]
- 6.
- Berndt S, Blacher S, Perrier d'Hauterive S, Thiry M, Tsampalas M, Cruz A, Péqueux C, Lorquet S, Munaut C, Noël A, Foidart JM. Chorionic gonadotropin stimulation of angiogenesis and pericyte recruitment. J Clin Endocrinol Metab. 2009 Nov;94(11):4567-74. [PubMed: 19837939]
- 7.
- Butler SA, Ikram MS, Mathieu S, Iles RK. The increase in bladder carcinoma cell population induced by the free beta subunit of human chorionic gonadotrophin is a result of an anti-apoptosis effect and not cell proliferation. Br J Cancer. 2000 May;82(9):1553-6. [PMC free article: PMC2363404] [PubMed: 10789723]
- 8.
- Cole LA, Dai D, Butler SA, Leslie KK, Kohorn EI. Gestational trophoblastic diseases: 1. Pathophysiology of hyperglycosylated hCG. Gynecol Oncol. 2006 Aug;102(2):145-50. [PubMed: 16631920]
- 9.
- Toth P, Li X, Rao CV, Lincoln SR, Sanfilippo JS, Spinnato JA, Yussman MA. Expression of functional human chorionic gonadotropin/human luteinizing hormone receptor gene in human uterine arteries. J Clin Endocrinol Metab. 1994 Jul;79(1):307-15. [PubMed: 8027246]
- 10.
- Iles RK. Ectopic hCGbeta expression by epithelial cancer: malignant behaviour, metastasis and inhibition of tumor cell apoptosis. Mol Cell Endocrinol. 2007 Jan 02;260-262:264-70. [PubMed: 17069968]
- 11.
- Toth P, Lukacs H, Gimes G, Sebestyen A, Pasztor N, Paulin F, Rao CV. Clinical importance of vascular LH/hCG receptors--a review. Reprod Biol. 2001 Nov;1(2):5-11. [PubMed: 14666164]
- 12.
- Rao CV. Differential properties of human chorionic gonadotrophin and human luteinizing hormone binding to plasma membranes of bovine corpora lutea. Acta Endocrinol (Copenh). 1979 Apr;90(4):696-710. [PubMed: 34964]
- 13.
- Strott CA, Yoshimi T, Ross GT, Lipsett MB. Ovarian physiology: relationship between plasma LH and steroidogenesis by the follicle and corpus luteum; effect of HCG. J Clin Endocrinol Metab. 1969 Sep;29(9):1157-67. [PubMed: 5808525]
- 14.
- Akoum A, Metz CN, Morin M. Marked increase in macrophage migration inhibitory factor synthesis and secretion in human endometrial cells in response to human chorionic gonadotropin hormone. J Clin Endocrinol Metab. 2005 May;90(5):2904-10. [PubMed: 15687332]
- 15.
- Herrmann-Lavoie C, Rao CV, Akoum A. Chorionic gonadotropin down-regulates the expression of the decoy inhibitory interleukin 1 receptor type II in human endometrial epithelial cells. Endocrinology. 2007 Nov;148(11):5377-84. [PubMed: 17702847]
- 16.
- Matsuura T, Sugimura M, Iwaki T, Ohashi R, Kanayama N, Nishihira J. Anti-macrophage inhibitory factor antibody inhibits PMSG-hCG-induced follicular growth and ovulation in mice. J Assist Reprod Genet. 2002 Dec;19(12):591-5. [PMC free article: PMC3455831] [PubMed: 12503892]
- 17.
- Kamada M, Ino H, Naka O, Irahara M, Daitoh T, Mori K, Maeda N, Maegawa M, Hirano K, Aono T. Immunosuppressive 30-kDa protein in urine of pregnant women and patients with trophoblastic diseases. Eur J Obstet Gynecol Reprod Biol. 1993 Aug;50(3):219-25. [PubMed: 8262299]
- 18.
- Majumdar S, Bapna BC, Mapa MK, Gupta AN, Devi PK, Subrahmanyam D. Pregnancy specific proteins: suppression of in vitro blastogenic response to mitogen by these proteins. Int J Fertil. 1982;27(2):66-9. [PubMed: 6126448]
- 19.
- CEDARD L, VARANGOT J, YANNOTTI S. [The metabolism of estrogens in human placentas artificially maintained in survival by perfusion in vitro]. C R Hebd Seances Acad Sci. 1962 Mar 05;254:1870-1. [PubMed: 13877595]
- 20.
- Lei ZM, Rao CV, Kornyei JL, Licht P, Hiatt ES. Novel expression of human chorionic gonadotropin/luteinizing hormone receptor gene in brain. Endocrinology. 1993 May;132(5):2262-70. [PubMed: 8477671]
- 21.
- Visconti F, Quaresima P, Chiefari E, Caroleo P, Arcidiacono B, Puccio L, Mirabelli M, Foti DP, Di Carlo C, Vero R, Brunetti A. First Trimester Combined Test (FTCT) as a Predictor of Gestational Diabetes Mellitus. Int J Environ Res Public Health. 2019 Sep 28;16(19) [PMC free article: PMC6801433] [PubMed: 31569431]
- 22.
- Barjaktarovic M, Korevaar TI, Jaddoe VW, de Rijke YB, Visser TJ, Peeters RP, Steegers EA. Human chorionic gonadotropin (hCG) concentrations during the late first trimester are associated with fetal growth in a fetal sex-specific manner. Eur J Epidemiol. 2017 Feb;32(2):135-144. [PMC free article: PMC5374189] [PubMed: 27709449]
- 23.
- Cavaliere A, Ermito S, Dinatale A, Pedata R. Management of molar pregnancy. J Prenat Med. 2009 Jan;3(1):15-7. [PMC free article: PMC3279094] [PubMed: 22439034]
- 24.
- Brouillet S, Murthi P, Hoffmann P, Salomon A, Sergent F, De Mazancourt P, Dakouane-Giudicelli M, Dieudonné MN, Rozenberg P, Vaiman D, Barbaux S, Benharouga M, Feige JJ, Alfaidy N. EG-VEGF controls placental growth and survival in normal and pathological pregnancies: case of fetal growth restriction (FGR). Cell Mol Life Sci. 2013 Feb;70(3):511-25. [PMC free article: PMC11113665] [PubMed: 22941044]
Disclosure: Mari Ogino declares no relevant financial relationships with ineligible companies.
Disclosure: Prasanna Tadi declares no relevant financial relationships with ineligible companies.
- Review Biological functions of hCG and hCG-related molecules.[Reprod Biol Endocrinol. 2010]Review Biological functions of hCG and hCG-related molecules.Cole LA. Reprod Biol Endocrinol. 2010 Aug 24; 8:102. Epub 2010 Aug 24.
- Review New discoveries on the biology and detection of human chorionic gonadotropin.[Reprod Biol Endocrinol. 2009]Review New discoveries on the biology and detection of human chorionic gonadotropin.Cole LA. Reprod Biol Endocrinol. 2009 Jan 26; 7:8. Epub 2009 Jan 26.
- Hyperglycosylated human chorionic gonadotropin and human chorionic gonadotropin free beta-subunit: tumor markers and tumor promoters.[J Reprod Med. 2008]Hyperglycosylated human chorionic gonadotropin and human chorionic gonadotropin free beta-subunit: tumor markers and tumor promoters.Cole LA, Butler SA. J Reprod Med. 2008 Jul; 53(7):499-512.
- Review Gonadotropins.[LiverTox: Clinical and Researc...]Review Gonadotropins.. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. 2012
- Physiology, Ovulation.[StatPearls. 2024]Physiology, Ovulation.Holesh JE, Bass AN, Lord M. StatPearls. 2024 Jan
- Physiology, Chorionic Gonadotropin - StatPearlsPhysiology, Chorionic Gonadotropin - StatPearls
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