hCG used to be thought about as one molecule. Today we know that it is not. The term hCG refers to a combination of 5 independent structurally-similar molecules, and a variety of blood and urine breakdown products. As illustrated in the Table below, their are 5 functionally-independent forms of hCG.
|Parameter||hCG||Sulfated hCG||Hyperglycosylated hCG||Fetal hCG||Hyperglycosylated hCGß|
|Source cell for synthesis||Syncytiotrophoblast||Gonadotrope||Cytotrophoblast||Fetal kidney/liver||Malignancy|
|Mode of action||Endocrine||Endocrine||Autocrine||Endocrine||Autocrine|
|Total Molecular weight||37,180||36,150||42,800||Unknown||27,600|
|Site of action||LH/hCG receptor||LH/hCG receptor||TGFß antagonism||Fetal organs||TGFß antagonism|
|Amino acids α-subunit||92||92||92||Unknown||–|
|Amino acids ß-subunit||145||145||145||Unknown||145|
|Peptide molecular weight||26,200||26,200||26,200||Unknown||16,000|
|Molecular weight sugars||10,980||9,950||16,600||Unknown||11,600|
As illustrated in the Table, there is “hCG” the endocrine or hormone made by placental syncytiotrophoblast cells. This performs numerous function in pregnancy. “hCG” promotes progesterone production by corpus luteal ovarian cells at 3-7 weeks of gestation, promotes growth of uterine spiral arteries and umbilical vessels to meet at hemochorial placentation, promotes growth of the uterus in line with fetal growth, suppresses macrophage and immune system rejection of foreign fetal and placental tissues invading mother, and suppresses uterine contraction during pregnancy.
Hyperglycosylated hCG is made by placental cytotrophoblast cells during pregnancy. This overly-glycosylated or overly-sugarized form of hCG is not a hormone, it is an autocrine. It antagonizing a TGFß receptor on these same cell. This antagonism promotes growth of the root placenta cells, leading to placenta growth during pregnancy. It also promotes a cancer-like invasion of these placental cells into the uterus (implantation). Hyperglycosylated hCG is essential for pregnancy, shortages cause biochemical pregnancy and miscarriages. Deficiency during the second trimester of placental cause preeclampsia and pregnancy-induced hypertension.
Multiple authors have demonstrated higher concentrations of hCG in a pregnancy fetus. Receptor have found indicating site of growth promoting action in fetal lungs, kidney, pancreas, small and large intestine and adrenal tissues. Studies also show that this is an independent hCG to that made by the placenta made by fetal liver or kidney. Nobody has as yet been able to find sufficient fetal hCG to permit any structure studies.
The pituitary gland in men and woman produces a small concentration of sulfated hCG. Sulfated means that some oligosaccharide sugar sugar side chains terminate with a sulfate residues instead of the acidic sugar residue sialic acid. Sulfated hCG is made by pituitary gonadotrope cells, the cells that make luteinizing hormone (LH) and follicle stimulating hormone (FSH). Examining the gene on chromosome 19, 8 back to back genes all code for hCG ß-subunit, and one on the end codes for LH ß-subunit. To make pituitary LH, the hypothalamic hormone gonadotropin releasing hormone (GnRH) acts on this solitary end LH ß-subunit gene to promote LH production. It appears that it incidentally or accidentally also promotes the neighboring hCG ß-subunit genes and sulfated hCG is made. Both hCG ß-subunit and LH ß-subunit rapidly associate with the excess of common alpha subunit to form hCG and LH dimeric hormone.
Science papers shows that approximately 1/50th of the LH concentration made by the pituitary gland in males and females corresponds to sulfated hCG. The problem is that Birken et al. showed that sulfated hCG is approximately 50-fold more potent that pituitary LH. As such, the two hormones produced by pituitary gonadotrope cells both have equal activities at the joint LH/hCG receptors in promoting steroidogenesis in men and women, promoting progesterone (luteal phase of menstrual cycle) and androstenedione (follicular phase) in women and testosterone in men. In women, it is fair to say that both sulfated hCG and LH promote ovultation.
When a woman reaches peri-menopause and menopause her ovaries produce reduced amounts of estrogens and stop producing estrogen. With the limited estrogen feedback to the hypothalamus, stronger and stronger pulses of GnRH are made by the hypothalamus and act on the pituitary gonadotrope cells. As a result, sky high levels of FSH and LH are made by the pituitary gonadotrope cells. While the low levels of sulfated hCG are hardly detectable during the menstrual cycle, the higher levels produced in menopause are very detectable (up to serum concentration of 39 mIU/ml). This is a cause of hCG production outside of pregnancy.
As discussed on the home page link “D1 hCG The Root of Human Evolution” hCG and hyperglycosylated hCG evolved as super-promoters to promote placental growth and placental implantation as a key part of human evolution. Unfortunately, human cancers seem to misuse these super-promoters to drive human malignancies. As understood, human malignancies make hyperglycosylated hCG and it free ß-subunit. Both are secreted by cancer cells into the blood and act as autocrines, feeding back to the cancer cells. The feed back antagonizes a TGFß receptor on cancer cells. This antagonism cause promotion of cancer cell growth, blockage of cancer cell apoptosis, and promotion of production of metalloproteinases and collagenases, the digestive enzymes of invasion by the cancer cells (go to go link “G. Dr. Cole’s Pertinent hCG Publication” to read mare about this science). Dr. Cole hopes that in the future human antibodies can be made to hyperglycosylated hCG and it free ß-subunit, and used to treat and block or possible cure advanced cancers.
When hCG, hyperglycosylated hCG and sulfated hCG are secreted a breakdown procedure starts. Leukocytes and macrophages, which may gather around placental and cancer tissue, produce an enzyme called leukocycte elastase, which quckly nicks or cleaves secreted hCG, cutting the molecules at ß-subunit residue 47-48. Once nicked, hCG becomes unstable, and rapidly splits into a nicked free ß-subunit and free alpha-subunit. Leukocyte elastase attacks the hCG molecules further, cleaving off the ß-subunit C-terminal peptide (residues 93-145). When the remaining molecules are filtered through the kidney, further degradation occurs to make ß-core fragment (ß6-40 Cys linked linked to ß55-92) the terminal degradation product of the ß-subunit. In summary, a pregnancy blood samples may contain: hCG, hyperglycosylated hCG, nicked hCG, nicked hyperglycosylated hCG, nicked hCG missing the C-terminal peptide, nicked hyperglycosylated hCG missing the C-terminal peptide, nicked hCG free ß-subunit, nicked hyperglycosylated free ß-subunit, nicked hCG free ß-subunit missing the C-terminal peptide and nicked hyperglycosylated hCG missing the C-terminal peptide. Or a wild mixture of 10 hCG-related molecules. A urine sample may contain these same 10 molecules plus principally ß-core fragment, the terminal degradation product of hCG ß-subunit. Through much of pregnancy (7 weeks to term), ß-core fragment is the principal hCG variant detected in urine.