B152 anti-hyperglycosylated human chorionic gonadotropin free ß-Subunit. A new, possible treatment for cancer.

OBJECTIVE: To investigate the ability of B152 to block cancer growth in cell lines in vivo and in nude mice in vitro. STUDY DESIGN: We examined JAR, JEG-3, and NTERA trophoblastic cancer cell lines and KLE, Hec-1A, SCaBER, and T24 nontrophoblastic cancer cell lines. JEG-3 cells were transplanted into 8 nude mice. Four nude mice were administered B152 antibody, and 4 were administered control non-specific IgG. Two studies were completed: first with antibody treatment started 2 weeks after cancer transplantation, and second with antibody treatment started at the time of transplantation. RESULTS: In 3 trophoblastic cancer lines and 4 non-trophoblastic cancer cell lines, B152 suppressed the growth of cancer cells, forcing cells into a state of regression. When B152 was administered to nude mice with tumor xenographs, the antibody blocked cancer cell growth and invoked oncostasis. When B152 was administered to nude mice starting at time of xenograph transplantation, the antibody prevented tumor growth completely. CONCLUSION: B152 suppresses tumor growth by seemingly blocking hyperglycosylated human chorionic gonadotropin (hCG) free ß-subunit effects. Thus, highly specific antibodies against hCG such as B152 may form part of a novel adjuvant treatment regimen against hCG-producing tumors in humans. This may form a new treatment for humans.

Proportion hyperglycosylated hCG: a new test for discriminating gestational trophoblastic diseases.

INTRODUCTION: Hyperglycosylated human chorionic gonadotropin (hCG) is a variant of hCG with large oligosaccharide side chains. Although hCG is produced by syncytiotrophoblast cells, hyperglycosylated hCG marks cytotrophoblast cell. Hyperglycosylated hCG signals placental implantation. METHODS: Total hCG in serum and urine is measured by the Siemens Immulite hCG pregnancy test; the result is in milli-international unit per milliliter. Hyperglycosylated hCG is determined by the B152 microtiter plate assay; the result is in nanogram per milliliter. Hyperglycosylated hCG results can be converted to milli-international unit per milliliter equivalents by multiplying by 11. The test measures proportion hyperglycosylated hCG, hyperglycosylated hCG / total hCG. RESULTS: Proportion hyperglycosylated hCG marks cases intent on developing persistent hydatidiform mole (68% detection at 17% false detection). Proportion hyperglycosylated hCG also marks persistent hydatidiform mole (100% detection at 5.1% false detection). Proportion hyperglycosylated hCG distinguishes choriocarcinoma and gestational trophoblastic neoplasm cases, absolutely discriminating aggressive cases and minimally aggressive cases. Proportion hyperglycosylated hCG identifies quiescent gestational trophoblastic disease cases. It recognizes quiescent cases that become persistent disease (100% detection at 0% false positive). DISCUSSION: Proportion hyperglycosylated hCG is an invaluable test for discriminating gestational trophoblastic diseases.

Familial hCG syndrome: production of variable, degraded or mutant forms of hCG.

OBJECTIVE: To examine the properties of the unique degraded forms of hCG produced in familial hCG syndrome and to describe 15 cases referred to the USA hCG Reference Service. STUDY DESIGN: Total hCG was detected by Immulite total hCG assay. The molecules missing the beta-subunit C-terminal peptide were detected by the Centaur total hCG assay; the proportion of molecules missing the beta-subunit C-terminal peptide was determined as Immu-lite assay minus Centaur assay. Free beta-subunit was detected in the FBT11 free beta-subunit assay with 5008 anticore-hCGbeta tracer. RESULTS: In all cases the syndrome was confirmed by either a mother,father, or sibling exhibiting ectopic hCG production. Serum hCG ranges in cases from 1-216 mIU/mL and urine hCG from 1.5-527 mIU/mL. It was estimated that 48-100% of molecules were missing the beta-subunit C-terminal peptide. Serum hCG free beta-subunit was measured, accounting for 52-79% of the total hCG immunoreactivity. Molecules missing the C-terminal peptide and free beta-subunit mark this syndrome. Serial serum samples were examined in 4 cases; hCG concentrations varied widely with time from < 1 to 182 mIU/mL. CONCLUSION: The proportion of molecules missing the beta-subunit C-terminal peptide, 48-100%, is extraordinarily high. Epitope studies and gel filtration studies indicate that the C-terminal peptide may not actually be missing, suggesting that the beta-subunit may be a mutant blocking C-terminal peptide recognition.

Direct analysis of hCGßcf glycosylation in normal and aberrant pregnancy by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry.

The analysis of human chorionic gonadotropin (hCG) in clinical chemistry laboratories by specific immunoassay is well established. However, changes in glycosylation are not as easily assayed and yet alterations in hCG glycosylation is associated with abnormal pregnancy. hCGß-core fragment (hCGßcf) was isolated from the urine of women, pregnant with normal, molar and hyperemesis gravidarum pregnancies. Each sample was subjected to matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI TOF MS) analysis following dithiothreitol (DTT) reduction and fingerprint spectra of peptide hCGß 6-40 were analyzed. Samples were variably glycosylated, where most structures were small, core and largely mono-antennary. Larger single bi-antennary and mixtures of larger mono-antennary and bi-antennary moieties were also observed in some samples. Larger glycoforms were more abundant in the abnormal pregnancies and tri-antennary carbohydrate moieties were only observed in the samples from molar and hyperemesis gravidarum pregnancies. Given that such spectral profiling differences may be characteristic, development of small sample preparation for mass spectral analysis of hCG may lead to a simpler and faster approach to glycostructural analysis and potentially a novel clinical diagnostic test.

hCG, the wonder of today's science.

BACKGROUND: hCG is a wonder. Firstly, because hCG is such an extreme molecule. hCG is the most acidic glycoprotein containing the highest proportion of sugars. Secondly, hCG exists in 5 common forms. Finally, it has so many functions ranging from control of human pregnancy to human cancer. This review examines these molecules in detail. CONTENT: These 5 molecules, hCG, sulfated hCG, hyperglycosylated hCG, hCG free beta and hyperglycosylated free beta are produced by placental syncytiotrophoblast cells and pituitary gonadotrope cells (group 1), and by placental cytotrophoblast cells and human malignancies (group 2). Group 1 molecules are both hormones that act on the hCG/LH receptor. These molecules are central to human menstrual cycle and human pregnancy. Group 2 molecules are autocrines, that act by antagonizing a TGF beta receptor. These molecules are critical to all advanced malignancies. CONCLUSIONS: The hCG groups are molecules critical to both the molecules of pregnancy or human life, and to the advancement of cancer, or human death.

Minimally-aggressive gestational trophoblastic neoplasms.

INTRODUCTION: We have previously defined a new syndrome "Minimally-aggressive gestational trophoblastic neoplasms" in which choriocarcinoma or persistent hydatidiform mole has a minimal growth rate and becomes chemorefractory. Previously we described a new treatment protocol, waiting for hCG rise to >3000 mIU/ml and disease becomes more advanced, then using combination chemotherapy. Initially we found this treatment successful in 8 of 8 cases, here we find this protocol appropriate in a further 16 cases. Initially we used hyperglycosylated hCG, a limited availability test, to identify this syndrome. Here we propose also using hCG doubling rate to detect this syndrome. METHODS: Minimally aggressive gestational trophoblastic disease can be detected by chemotherapy resistance or low hyperglycosylated hCG, <40% of total hCG. It can also be identified by hCG doubling rate, with doubling time greater than 2 weeks. RESULTS: Nineteen new cases were identified as having minimally aggressive gestational trophoblastic disease by hyperglycosylated hCG and by hCG doubling test. All were recommended to hold off further chemotherapy until hCG >3000mIU/ml. One case died prior to the start of the study, one case withdrew because of a lung nodule and one withdrew refusing the suggested combination chemotherapy. The remaining 16 women were all successfully treated. DISCUSSION: A total of 8 plus 16 or 24 of 24 women were successfully treated using the proposed protocol, holding back on chemotherapy until hCG >3000mIU/ml.

The hCG assay or pregnancy test.

This review examines human chorionic gonadotropin (hCG) or pregnancy tests from multiple perspectives. It first investigates the molecule hCG and shows that the term represents five independent molecules differing in carbohydrate and meric structure that share a common amino acid sequence. The review goes on to show that multiple degradation produces also the need to be tested for an hCG or pregnancy test to be optimally efficient. The review then carefully examines the literature showing the sensitivity and specificity of automated laboratory tests. Point-of-care pregnancy tests are then investigated along with over-the-counter pregnancy tests. Appropriate detection of hyperglycosylated hCG, nicked hCG, nicked hCG missing the ß-subunit C-terminal peptide and nicked hyperglycosylated hCG is a limitation on all pregnancy tests. In the opinion of the author, just one automated laboratory test, the Siemen's Immulite, one point-of-care test, the Beckman-Coulter Icon 25, and one brand of over-the-counter device, First Response, are suitable for early pregnancy detection and possibly other applications.

Individual deviations in human chorionic gonadotropin concentrations during pregnancy.

BACKGROUND: Serum and urine human chorionic gonadotropin (hCG) vary greatly during the course of pregnancy. We investigated the cause of this variation. STUDY DESIGN: Eighty-two women provided daily urine samples during the first 6 weeks of gestation. First-void urine samples were monitored for luteinizing hormone (LH) and hCG. RESULTS: Variation was wide when pregnancy hCG anchoring to the last menstrual period (variation 677 ± 786-fold) or to LH peak (variation 810 ± 936-fold). When pregnancy was anchored to the day of implantation (variation 187 ± 123-fold) variation was significantly reduced (P < .00005). Individual differences in the rate of hCG production were examined. hCG production ranged from 1.52-fold to 2.92-fold per day. Rate differences in hCG were also a major source of hCG variation. CONCLUSION: Two factors are responsible for the wide fluctuation in hCG concentrations, first dating pregnancies to the start of the last menstrual period rather than the timing of implantation and second, individual pregnancy differences in the rate of hCG production.

The utility of six over-the-counter (home) pregnancy tests.

BACKGROUND: The home pregnancy market is rapidly evolving. It has moved from detection of pregnancy on the day of missed menstrual bleeding, to detection claims 4 days prior. It is moving from all manual tests to digital tests, with a monitor reading the bands and informing women they are pregnant. A thorough study is needed to investigate the validity of claims and evolving usefulness of devices. METHODS: Studies were proposed to examine the sensitivity and specificity of home tests and their abilities to detect pregnancy. Methods examined the abilities of tests to detect human chorionic gonadotropin (hCG), hyperglycosylated hCG, free ß-subunit, a mixture of these antigens in 40 individual early pregnancy urines. RESULTS: Using a mixture of hCG, hyperglycosylated hCG and free ß-subunit typical for early pregnancy, the sensitivity of the First Response manual and digital tests was 5.5 mIU/mL, while the sensitivities of the EPT and ClearBlue brand manual and digital tests was 22 mIU/mL. On further evaluation, the First Response manual and digital tests both detected 97% of 120 pregnancies on the day of missed menstrual bleeding. The EPT manual and digital devices detected 54% and 67% of pregnancies, respectively, and the ClearBlue manual and digital devices detected 64% and 54% of pregnancies, respectively. CONCLUSIONS: First Response manual and digital claim >99% detection on the day of missed menses. The results here suggest similar sensitivity for these two tests. The EPT and ClearBlue manual and digital test make similar >99% claims, the data presented here disputes their elevated claim.

Biological functions of hCG and hCG-related molecules.

BACKGROUND: hCG is a term referring to 4 independent molecules, each produced by separate cells and each having completely separate functions. These are hCG produced by villous syncytiotrophoblast cells, hyperglycosylated hCG produced by cytotrophoblast cells, free beta-subunit made by multiple primary non-trophoblastic malignancies, and pituitary hCG made by the gonadotrope cells of the anterior pituitary. RESULTS AND DISCUSSION: hCG has numerous functions. hCG promotes progesterone production by corpus luteal cells; promotes angiogenesis in uterine vasculature; promoted the fusion of cytotrophoblast cell and differentiation to make syncytiotrophoblast cells; causes the blockage of any immune or macrophage action by mother on foreign invading placental cells; causes uterine growth parallel to fetal growth; suppresses any myometrial contractions during the course of pregnancy; causes growth and differentiation of the umbilical cord; signals the endometrium about forthcoming implantation; acts on receptor in mother's brain causing hyperemesis gravidarum, and seemingly promotes growth of fetal organs during pregnancy. Hyperglycosylated hCG functions to promote growth of cytotrophoblast cells and invasion by these cells, as occurs in implantation of pregnancy, and growth and invasion by choriocarcinoma cells. hCG free beta-subunit is produced by numerous non-trophoblastic malignancies of different primaries. The detection of free beta-subunit in these malignancies is generally considered a sign of poor prognosis. The free beta-subunit blocks apoptosis in cancer cells and promotes the growth and malignancy of the cancer. Pituitary hCG is a sulfated variant of hCG produced at low levels during the menstrual cycle. Pituitary hCG seems to mimic luteinizing hormone actions during the menstrual cycle.

Hyperglycosylated hCG in the management of quiescent and chemorefractory gestational trophoblastic diseases.

INTRODUCTION: The literature shows that hyperglycosylated hCG is the invasion stimulus in malignant gestational trophoblastic diseases. The USA hCG Reference Service has characterized 2 gestational trophoblastic disease conditions marked by low proportion of hyperglycosylated hCG. These are quiescent gestational trophoblastic disease, defined as inactive or benign invasive disease, and minimally invasive gestational trophoblastic disease, defined as slow growing or chemorefractory disease with hCG increasing very slowly (doubling rate 2-6 weeks). Here we examine the USA hCG Reference Service experience with both diseases. METHODS: Patient were referred to the USA hCG Reference Service, 133 cases shown to have quiescent gestational trophoblastic disease, 35 cases with aggressive and 30 with minimally invasive gestational trophoblastic disease. RESULTS: Quiescent or inactive gestational trophoblastic disease was demonstrated in 133 women. In 127 of these cases, no hyperglycosylated hCG was detected, and in 6 cases 4-27% hyperglycosylated hCG was detected. This is quiescent or inactive disease. Only 1 of 35 cases with aggressive gestational trophoblastic disease (>40% hyperglycosylated hCG) was chemorefractory. In contrast, 30 of 30 minimally invasive cases (<40% hyperglycosylated hCG) were chemorefractory. In chemorefractory cases hyperglycosylated hCG ranged from <1% to 39% of total hCG. The USA hCG Reference Service showed that proportions hyperglycosylated hCG significantly increases as total hCG rises. They recommended in minimally invasive cases to wait to hCG was >3000 IU/L before commencing chemotherapy. This was successful in 10 of 10 minimally invasive cases. DISCUSSION: Measurement of hyperglycosylated hCG or invasiveness is a critical step in management of invasive gestational trophoblastic disease. Quiescent of inactive gestational trophoblastic disease requires no therapy. Minimally invasive disease in chemorefractory. The USA hCG Reference Service experience suggests waiting until hCG exceeds 3000 IU/L before commencing any chemotherapy.

Inherited human chorionic gonadotropin.

OBJECTIVE: To investigate 405 cases of persistent low concentrations of human chorionic gonadotropin (hCG). STUDY DESIGN: The USA hCG Reference Service measured total regular hCG, follicle stimulating hormone and luteinizing hormone (LH) with the Siemens (New York, New York) Immulite 1000 assay. Hyperglycosylated hCG, nicked hCG, C-terminal peptide total hCG, intact regular hCG, free beta-subunit and beta-core fragment were measured in manual microtiter plate assays. RESULTS: Four cases of inherited hCG were identified, with similar hCG production recorded in first degree relatives. All cases produced primarily the regular hCG dimer. In 1 case hCG was detected only in the urine sample. CONCLUSION: Inherited hCG is disclosed as a source of persistent low concentrations ofhCG. It was assumed that this regular hCG is produced by the pituitary gland, either as excess pituitary production beyond that which occurs alongside the LH peak in every menstrual cycle or as a genetic disorder.

New discoveries on the biology and detection of human chorionic gonadotropin.

Human chorionic gonadotropin (hCG) is a glycoprotein hormone comprising 2 subunits, alpha and beta joined non covalently. While similar in structure to luteinizing hormone (LH), hCG exists in multiple hormonal and non-endocrine agents, rather than as a single molecule like LH and the other glycoprotein hormones. These are regular hCG, hyperglycosylated hCG and the free beta-subunit of hyperglycosylated hCG. For 88 years regular hCG has been known as a promoter of corpus luteal progesterone production, even though this function only explains 3 weeks of a full gestations production of regular hCG. Research in recent years has explained the full gestational production by demonstration of critical functions in trophoblast differentiation and in fetal nutrition through myometrial spiral artery angiogenesis. While regular hCG is made by fused villous syncytiotrophoblast cells, extravillous invasive cytotrophoblast cells make the variant hyperglycosylated hCG. This variant is an autocrine factor, acting on extravillous invasive cytotrophoblast cells to initiate and control invasion as occurs at implantation of pregnancy and the establishment of hemochorial placentation, and malignancy as occurs in invasive hydatidiform mole and choriocarcinoma. Hyperglycosylated hCG inhibits apoptosis in extravillous invasive cytotrophoblast cells promoting cell invasion, growth and malignancy. Other non-trophoblastic malignancies retro-differentiate and produce a hyperglycosylated free beta-subunit of hCG (hCG free beta). This has been shown to be an autocrine factor antagonizing apoptosis furthering cancer cell growth and malignancy. New applications have been demonstrated for total hCG measurements and detection of the 3 hCG variants in pregnancy detection, monitoring pregnancy outcome, determining risk for Down syndrome fetus, predicting preeclampsia, detecting pituitary hCG, detecting and managing gestational trophoblastic diseases, diagnosing quiescent gestational trophoblastic disease, diagnosing placental site trophoblastic tumor, managing testicular germ cell malignancies, and monitoring other human malignancies. There are very few molecules with such wide and varying functions as regular hCG and its variants, and very few tests with such a wide spectrum of clinical applications as total hCG.

The quagmire of hCG and hCG testing in gynecologic oncology.

Few molecules have created so much confusion as the hCG series of molecules. Here we present a comprehensive review of hCG as a tumor marker, of hCG and cancer and modern perspectives on the multiplicity of hCG, and its appropriate use in the management of gynecological malignancies and gestational trophoblastic diseases. The complexity of hCG is better understood. There is regular hCG produced by syncytiotrophoblast cells in pregnancy and by hydatidiform moles. This hormone functions to advance uterine angiogenesis and promote progesterone production by corpus luteal cells. Hyperglycosylated hCG is an independent molecule to regular hCG, it varies significantly from hCG in structure and is produced by cytotrophoblast cells. It is an autocrine or cytokine which functions to promote growth, invasion and malignancy. It is an absolute marker of invasive mole and invasive choriocarcinoma. Hyperglycosylated hCG is invaluable in the diagnosis and management of gestational trophoblastic diseases. The free beta-subunit of hCG is also an autocrine or cytokine and is produced in most gynecologic malignancies. Serum free beta-subunit or its urinary degradation product beta-core fragment is produced by 68% of ovarian, 51% of endometrial and 46% of cervical malignancies. Free beta-subunit enhances growth and invasion in all these malignancies leading to poor prognosis. Free beta-subunit and beta-core fragment are good tumor markers for these malignancies. There are few circumstances that create more confusion than the patient presenting with persistent low positive hCG results in the absence of pregnancy and absence of obvious malignancies. The series of hCG molecules as tumor markers will be reviewed to help the clinician best diagnose these often difficult clinical problems.

Normal production of human chorionic gonadotropin in perimenopausal and menopausal women and after oophorectomy.

BACKGROUND: The normal pituitary production of human chorionic gonadotropin (hCG)alongside luteinizing hormone, and its presence in women after bilateral oophorectomy, during perimenopause and menopause, as measured in serum and urine, has been known for 30 years and is described in numerous publications. Last year our group discussed this finding in a correspondence to the editor in the March 15th issue of New England Journal of Medicine, yet the misinterpretation of low-level hCG in these women seems to have increased in magnitude. METHODS: This is an outcomes study of 36 cases of menopausal hCG referred to the USA hCG Reference Service over a 1-year period, from March 2007 to March 2008. RESULTS: Eight cases occurred in women after oophorectomy, 28 were women in menopause/perimenopause. Surgery was postponed in 5 (14%) of 36 cases, and in 3 cases (8%), chemotherapy was unnecessarily administered. In 2 cases, computed tomography scans were cancelled. The average hCG detected was 10 +/- 7.2 IU/L in cases receiving an oophorectomy and 9.8 +/- 6.7 in perimenopause and 11 +/- 6.2 IU/L in menopause cases. CONCLUSIONS: Low-level hCG production in woman in physiologic perimenopause, in menopause, or in women with prior bilateral oophorectomy is a normal biologic and biochemical phenomenon. Management protocols in all fields need to be changed to accept pituitary hCG as normal and recognize the clinical maneuvers that will secure the diagnosis. Understanding this physiology will avoid needless delays in necessary therapies such as organ transplant procedures and will limit the misadventure of prescribing unnecessary cancer treatments.

Production of human chorionic gonadotropin during the normal menstrual cycle.

OBJECTIVE: To present a comprehensive study of pituitary human chorionic gonadotropin (hCG) production during the menstrual cycle, investigating its occurrence, timing and the possibility of a separate biologic role for pituitary hCG during the normal menstrual cycle. STUDY DESIGN: Daily urine samples were tested from 185 women during 405 normal menstrual cycles. Levels of hCG and luteinizing hormone (LH) were measured daily. RESULTS: hCG levels were detected at LH peak in 84% of menstrual cycles. At this time, hCG levels paralleled LH values. The remaining menstrual cycles (16%) had significantly lower LH levels, suggesting lack of detection of hCG as a result of low concentration of LH or very dilute urines. We infer that hCG is produced in all menstrual cycles. CONCLUSION: hCG is seemingly produced alongside LH in all menstrual cycles. hCG has a much greater circulating half-life compared to LH. It may function to extend the short, sharp LH peak in promoting ovulation or in promoting initial progesterone production by the corpus luteal cells.

Detection of perimenopause or postmenopause human chorionic gonadotropin: an unnecessary source of alarm.

OBJECTIVE: The normal pituitary production of human chorionic gonadotropin alongside luteinizing hormone, measurable in menopausal serum and urine was initially reported over 3 decades ago and has been described in numerous subsequent publications. Unfortunately, delays or cancellations of important medical procedures and use of needless chemotherapy still occurs because of the finding of human chorionic gonadotropin in perimenopausal and postmenopausal woman. We describe the problem and a concise approach to this management dilemma in menopausal women. STUDY DESIGN: This is an outcomes study of 36 cases of perimenopausal and postmenopausal human chorionic gonadotropin evaluated in cases referred to the USA hCG Reference Service. RESULTS: By report of the provided records, in 6 of 36 cases, unneeded chemotherapy was given for assumed recurrent gestational trophoblastic disease. In 9 cases, surgery was cancelled or postponed and in 3 cases renal transplantation was cancelled at the time of locating a matched donor kidney. In all cases the measured human chorionic gonadotropin was due to menopausal production of pituitary human chorionic gonadotropin. The average human chorionic gonadotropin detected in perimenopausal cases was 6.4 +/- 3.2 IU/L, and in postmenopausal cases was 11.6 +/- 7.0 IU/L or significantly higher. In 24 cases, therapeutic doses of high-estrogen birth control pill were used to confirm pituitary origin with 23 cases demonstrating successful human chorionic gonadotropin suppression. CONCLUSION: Low levels of human chorionic gonadotropin production in the perimenopausal and postmenopausal state is a normal physiologic phenomenon. Provider education is warranted and management protocols are suggested in all health-related fields to clarify the normality of low level pituitary human chorionic gonadotropin production. Understanding this physiology will avoid delays in necessary therapies such as organ transplants, and will limit the misadventure of prescribing unnecessary treatments for presumed gestational malignancy.

Hyperglycosylated human chorionic gonadotropin and human chorionic gonadotropin free beta-subunit: tumor markers and tumor promoters.

Human chorionic gonadotropin (hCG) is a heterogeneous glycoprotein hormone comprising an alpha-subunit and beta-subunit that can vary in peptide and carbohydrate structure. After conception, hCG produced by early trophoblast cells acts on luteinizing hormone (LH)/hCG receptor corpus luteum cells to promote progesterone production and establish maternal recognition of pregnancy. hCG is not simply 1 molecule, and 2 variants of hCG appear to have independent activities in promoting tumor cell growth, invasion and malignancy. Hyperglycosylated hCG (H-hCG), produced by cytotrophoblast cells, is a marker for cytotrophoblast cells and tumor marker for gestational trophoblastic diseases. H-hCG promotes growth and invasion in these cells during pregnancy implantation, and growth in varying degrees by many nontrophoblastic neoplasms. beta-hCG is a marker of poor prognosis shown to promote growth and invasion in vitro, suggesting autocrine growth factor properties. Vaccines to beta-hCG have been successfully demonstrated, suggesting a potential adjuvant therapy in cancer treatment. Although sufficiently distinct in both structure and occurrence, similarities have been observed between H-hCG and beta-hCG as promoters of cell growth, invasion and malignancy. It is somewhat irregular for 2 structural variants of a molecule to have independent actions, actions very different to the gonadotropic function of the established hormone hCG.

Evolution of the human brain, chorionic gonadotropin and hemochorial implantation of the placenta: insights into origins of pregnancy failures, preeclampsia and choriocarcinoma.

Hyperglycosylated chorionic gonadotropin (CG-H) signals placental cytotrophoblast cell growth and invasion, and chorionic gonadotropin (CG) promotes uterine vascularization. A hypothesis is presented relating the evolution of these molecules to the evolution of human hemochorial implantation and that of the human brain. Deep placental invasion, vascularization and hemochorial placentation, under the influence of CG and CG-H, are a critical part of the nutrition and energy-generating mechanisms needed for human brain development and thus for the evolution of humans. Insufficient CG-H production and the resulting inappropriate implantation is associated with an unduly high incidence of pregnancy failures in humans. Low levels of CG-H and inappropriate hemochorial placentation also appear to be associated with subsequent preeclampsia. It is also of note that human CG-H drives invasion by gestational trophoblastic neoplasms that have been described only in humans.

Blood test for placental site trophoblastic tumor and nontrophoblastic malignancy for evaluating patients with low positive human chorionic gonadotropin results.

OBJECTIVE: To examine utility of measurement of proportions of free beta-subunit of human chorionic gonadotropin (hCG) in diagnosis of placental site trophoblastic tumor (PSTT) and nontrophoblastic neoplasm in patients with persistent low hCG levels and patients with history of gestational trophoblastic diseases. STUDY DESIGN: The USA hCG Reference Service measured proportions of free beta-subunit in 128 cases, 45 with active invasive trophoblastic disease and 83 questionable cases with persistent low hCG levels, with or without history of gestational trophoblastic disease (GTD). RESULTS: High proportions of free beta-subunit (> 30% of total hCG) were identified in 18 of 128 cases, all suspected of having PSTT or nontrophoblastic neoplasm, which was reported to referring physicians. Within 2 months of testing, hysterectomy or tumor biopsy led to histologic proof of PSTT in 13 of the 18 cases and biopsy led to proof of nontrophoblastic neoplasm in 5 of the 18 cases. CONCLUSION: We confirm use of proportion of free beta-subunit (> 30%) as a seemingly absolute test for identifying PSTT and nontrophoblastic neoplasms. It should be used to identify and diagnose these malignancies in women presenting with persistent low hCG levels outside of pregnancy and in secondary evaluation of patients with a history of GTDs.