Our goal is to accurately measure the rate and understand the causes of early pregnancy loss (EPL) and recurrent spontaneous abortion. These infertility problems, especially EPL, can in some instances, be related to exposure to reproductive toxins in the environment. The hypothesis of our preceding proposal was that nicked forms of hCG, which have reduced biological activity, and are poorly detected in many current assays for hCG, might be causal in some losses because of diminished biological activity. Our collaborators and we have discovered that the hCG and EPL subjects does display reduced biological activity. We have determined that the cause of this reduction is not the increased presence of nicked hCG in the loss subjects. The hypothesis to be tested in this proposal is that subjects whose pregnancies succeed produce an early pregnancy isoform of hCG with enhanced biological activity. This hCG isoform is low or absent in pregnancies destined to be lost. We have developed assays (based upon monoclonal antibody B152) which can measure this early pregnancy isoform of hCG. This isoform is present in higher concentrations in early successful pregnancies than the hCG isoform comprising the reference preparations of urinary hCG. This is an unexpected and provocative new observation and we propose to prove our hypothesis by the following specific aims: 1. To determine the time course throughout pregnancy of the isoforms recognized by B152 in urine and blood and to determine the gestational period over which the B152 hCG isoform is replaced by the hCG of later pregnancy. 2. To determine the B152 hCG isoforms present in the blood and urine of women who have a history of recurrent spontaneous abortion and women undergoing embryo implantation. Early loss rate (EPL + spontaneous abortion) is 32% in a normal population and significantly higher in these other populations. 3. To isolate the B152 hCG isoforms from early pregnancy urine and determine their protein and carbohydrate structures. To isolate and compare the structure of third trimester hCG isoforms with hose of early pregnancy. 4. To characterize the biological activities and clearance rates of early pregnancy hCG isoforms as compared to hCG purified form the third trimester and hCG standard reference preparations.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Project (R01)
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Reproductive Endocrinology Study Section (REN)
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Heindel, Jerrold
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Columbia University (N.Y.)
Other Clinical Sciences
Schools of Medicine
New York
United States
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Kovalevskaya, G; Kakuma, T; Schlatterer, J et al. (2007) Hyperglycosylated HCG expression in pregnancy: cellular origin and clinical applications. Mol Cell Endocrinol 260-262:237-43
Kovalevskaya, G; Birken, S; Kakuma, T et al. (2002) Differential expression of human chorionic gonadotropin (hCG) glycosylation isoforms in failing and continuing pregnancies: preliminary characterization of the hyperglycosylated hCG epitope. J Endocrinol 172:497-506
Kovalevskaya, G; Genbacev, O; Fisher, S J et al. (2002) Trophoblast origin of hCG isoforms: cytotrophoblasts are the primary source of choriocarcinoma-like hCG. Mol Cell Endocrinol 194:147-55
Birken, S; Kovalevskaya, G; O'Connor, J (2001) Immunochemical measurement of early pregnancy isoforms of HCG: potential applications to fertility research, prenatal diagnosis, and cancer. Arch Med Res 32:635-43
Mock, P; Kovalevskaya, G; O'Connor, J F et al. (2000) Choriocarcinoma-like human chorionic gonadotrophin (HCG) and HCG bioactivity during the first trimester of pregnancy. Hum Reprod 15:2209-14
Birken, S; Krichevsky, A; O'Connor, J et al. (1999) Development and characterization of antibodies to a nicked and hyperglycosylated form of hCG from a choriocarcinoma patient: generation of antibodies that differentiate between pregnancy hCG and choriocarcinoma hCG. Endocrine 10:137-44
Kovalevskaya, G; Birken, S; Kakuma, T et al. (1999) Early pregnancy human chorionic gonadotropin (hCG) isoforms measured by an immunometric assay for choriocarcinoma-like hCG. J Endocrinol 161:99-106
Kovalevskaya, G; Birken, S; Kakuma, T et al. (1999) Evaluation of nicked human chorionic gonadotropin content in clinical specimens by a specific immunometric assay. Clin Chem 45:68-77
Birken, S; Santoro, N; Maydelman, Y et al. (1999) Differences in urinary excretion patterns of the hLH beta core fragment in premenopausal, perimenopausal, and postmenopausal women. Menopause 6:290-8
O'Connor, J F; Kovalevskaya, G; Birken, S et al. (1998) The expression of the urinary forms of human luteinizing hormone beta fragment in various populations as assessed by a specific immunoradiometric assay. Hum Reprod 13:826-35

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