Chemistry: analytical and immunological testing – Immunochemical pregnancy determination
Reexamination Certificate
1998-06-22
2003-12-09
Romeo, David S. (Department: 1647)
Chemistry: analytical and immunological testing
Immunochemical pregnancy determination
C436S065000, C530S399000, C435S007920
Reexamination Certificate
active
06660531
ABSTRACT:
FIELD OF THE INVENTION
The invention relates generally to the field of assays and methods of treatment. In particular the invention relates to determining relaxin levels and relating the levels to the probability of a successful fertilization of a human female and particularly success in an in vitro fertilization or embryo transfer procedure. The invention further relates to methods of enhancing the probability of obtaining a successful IVF/ET procedure.
BACKGROUND OF THE INVENTION
Reproductive failure is a serious problem that has been addressed clinically by in vitro fertilization (IVF) and embryo transfer (ET). These procedures might be expected to yield exceptionally high conception rates as in vitro fertilization provides an already fertilized ova for transfer into a fully primed recipient. Despite these efforts the success rate of IVF/ET is less than ideal. In the published data for IVF/ET in the United States and Canada in 1994, there were 26,961 initiated cycles of standard IVF. Of these, 86.2% led to a retrieval and of these 90.2% led to a transfer. However, the overall success rate in terms of clinical pregnancies was 22.7% per initiated cycle and a 29.1% pregnancy rate per transfer. Additionally, there appears to be a high incidence of early pregnancy loss after in vitro fertilization with a biochemical pregnancy rate of 18% and a spontaneous abortion rate of 27%. Thus, it appears that the IVF technique has been well optimized but implantation failure may be the cause for a large number of losses with ET and this implantational loss is an area of potential improvement.
The factors which contribute to the success of in vitro fertilization/embryo transfer (IVF/ET) have been extensively studied. In looking at what factors may affect implantation, many studies have reported correlations of hormonal or measurement of other parameters with conception rate. High conception rates have been associated with lowered follicular phase PP14 concentrations, large increases in PP14 concentrations from the day of human chorionic ganadotropin (hCG) stimulation to the day of embryo transfer, high preretrieval concentrations of CA-125, large increases in CA-125 from the day of hCG stimulation to oocyte retrieval, increased uterine blood flow, increased uterine artery impedance, and an inhibition of uterine motility in the periimplantation period. It has also been suggested that lowered estradiol concentrations at the time of ovulation induction lowered progesterone concentrations at the time of hCG stimulation, or the magnitude of the increase in progesterone in response to hCG stimulation have a higher success of conception. These reports generally fail to determine the mechanism by which these observations are translated into impaired conception.
Few studies have examined the relationship between granulosa lutein cell culture and the characteristics of the cycle from which cells were obtained. One group found that decreased granulosa cell 11 beta hydroxysteroid dehydrogenase activity was associated with higher conception rates. It was reasoned that exposure of the oocyte to cortisol was necessary for proper functional maturation and high amounts of enzyme in the cumulus cells could prevent this exposure. Another study was based upon observations that the magnitude of rise in progesterone concentrations in response to hCG stimulation was correlated with implantation success. They found that patients with an increase of 3 fold in response to hCG were more likely to get pregnant (46%) than those with a P4 increase of less than 3 fold who had only a 14% conception rate. Granulosa lutein cell culture (GLCC) from these patients showed differences in hormone production. Patients with a large serum P4 increase had higher progesterone concentrations in culture. Patients with a low P4 increase had more variable estrogen concentrations in culture but the estrogen was more responsive to gonadotropin stimulation.
SUMMARY OF THE INVENTION
A method of predicting the probability of a successful pregnancy resulting from in vitro fertilization (IVF) or embryo transfer (ET) based on relaxin levels is disclosed. The relaxin levels may be determined by culturing granulosa lutein cells (preferably for ten days) extracted from the patient as part of the IVF/ET procedures and/or by measuring relaxin levels in serum. A method of enhancing the rate of successful term pregnancy is provided by administering relaxin in amounts sufficient to raise relaxin levels and/or by modifying conventional procedures so as to increase endogenous relaxin.
An aspect of the invention is to provide a method of determining the probability of obtaining successful in vitro fertilization or embryo transfer.
Another aspect is to determine relaxin concentration of cultured granulosa lutein cells at about 10 days after extraction and relating the level to a standard to determine the probability of a successful IVF/ET procedure.
Another aspect is to determine relaxin levels in serum and relate the level directly to IVF/ET success probability or indirectly by first relating such to relaxin levels of cultured granulosa lutein cells.
Another aspect of the invention is to provide a method for determining the success rate for IVF/ET procedures by assaying for levels of glycodelin, specifically glycodelin released from the endometrium.
Yet another aspect of the invention is to measure levels of hCG and relate the levels to a standard which relates to relaxin levels thereby determining the probability of success with IVF/ET procedures.
Yet another aspect of the invention is to provide a method for predicting the success of an IVF/ET procedure by measuring levels of relaxin, glycodelin, hCG in any combination and relating those levels to a standard.
Yet another aspect of the invention is to provide a method for enhancing the success rate of an IVF/ET procedure by administering into a patient any of relaxin, glycodelin or hCG.
Another aspect is to provide a method for enhancing the success rate for IVF/ET procedures by modifying aspects of conventional procedures to increase endogenous relaxin levels at crucial time periods.
An advantage is that measured relaxin levels are predictive of success rates for conception and for obtaining a term pregnancy.
The assay of the invention shows that relaxin levels at 800 pg/ml or more are highly predictive of resulting in a successful pregnancy.
A feature of the invention is that it requires measurement of only a single hormone.
These and other aspects, advantages and features of the invention will become apparent to those skilled in the art upon reading the disclosure.
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Wilcox et al. Defining and interpreting pregnancy success rates for in vitro fertilization. Fertil Steril. Jul. 1993;60(1):18-25.*
Weiss et al., Elevated first-trimester serum relaxin concentrations in pregnant women following ovarian stimulation predict prematurity risk and preterm delivery. Obstet Gynecol. Nov. 1993;82(5):821-8.
Stewart et al. “Relaxin as a biomarker for human pregnancy detection”, pp. 214-224, in: Progress in relaxin research: 2nd International Congress on the Hormone Relaxin, MacLennan et al. (eds.), River Edge, N.J.: Global Publications Services, 1994.
Yding Andersen et al. Changes induced in serum protein profiles by ovarian stimulation during in-vitro fertilization—embryo transfer treatment: a comparison between conception and non-conception cycles. Human Reproduction, (May 1992) 7 (5) 585-91.*
Lee, Anne, et al., “Shark Cartilag
Stewart Dennis R.
VandeVoort Catherine A.
Romeo David S.
The Regents of the University of California
Townsend and Townsend / and Crew LLP
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