Introduction

The human chorionic gonadotropin (hCG) is recognized as a term to describe four 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 non-trophoblastic 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, signals the endometrium of impending implantation, supports the growth and differentiation of the umbilical cord, as well as promotes 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 non-trophoblastic 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 effects of the luteinizing hormone (LH).[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 the time of implantation to the completion of pregnancy at various levels. As previously mentioned, one of the most important functions of hCG is to promote the production of progesterone as it protects the endometrial lining during pregnancy. hCG has also been implicated in the regulation of uterine growth, implantation, trophoblast differentiation, and angiogenesis and vasculogenesis in the uterine walls.[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 non-pregnant female, LH promotes progesterone production.[10][5][11]

The hCG hormone is a dimer made of an alpha and beta subunit. The alpha subunit is common to all isomers, as mentioned earlier of hCG except for the free beta-subunit form of the hormone.[8] The alpha subunit is also present on other hormones such as LH, follicle-stimulating hormone (FSH), and thyroid-stimulating hormone (TSH). The beta subunit is what confers a structural differentiation from hormones like LH, though all forms of hCG and LH bind to a common receptor. The marked distinction between the two hormones besides the absence of a beta subunit in LH 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 the maintenance of an optimal intrauterine environment.[8][4][13]

Studies done over recent years have shown hCG to be involved in a plethora of functions supporting the placenta, uterus, and fetus throughout pregnancy. These functions include the promotion of angiogenesis, immunosuppression, and blockage of phagocytosis of invading trophoblasts, promotion of growth and differentiation of fetal organs, and involvement in the adult brain and brainstem.[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 the prevention of 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.[10][19][9]

Maternal hCG has implications in 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.[13][5][11]

Researchers have found hCG receptors in various areas of the adult female brain, including the hippocampus, hypothalamus, and brain stem. Speculation is that the presence of these receptors in the brain are involved in the pathophysiology of hyperemesis gravidarum. Other contributing factors may involve a combination of rising hormone levels overall, including estrogen, progesterone, and serum thyroxine, in addition to elevated hCG.[5][11][20]

Mechanism

hCG achieves many of its functions through the regulation of 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 both pathological and normal development of the fetus. 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 in fetal growth restriction.[10][7][13][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 support fetal development and growth properly. The intrauterine conditions are dependent 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 producing a mass of multiple vesicles with little evidence of fetal and embryonic development. A partial hydatidiform mole is usually triploid due to dispermic 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 as a result of 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, as well as 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 pre-term 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]