Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving oxidoreductase
Patent
1995-09-21
1997-06-03
Gitomer, Ralph
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving oxidoreductase
435806, 436817, C12Q 132
Patent
active
056353669
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to an assay which is predictive of the outcome of in vitro fertilisation (IVF) in mammals including humans.
BACKGROUND OF THE INVENTION
The technique of IVF has been used in human patients with infertility problems successfully since 1978. Despite extensive research it is still a difficult procedure and even in the best IVF clinics a success rate of only 30% is generally achieved.
IVF is an expensive procedure and can also be psychologically traumatic for a patient. Surgical procedures are required to collect eggs for IVF and following fertilization, further surgery is required to implant fertilised eggs in the womb. The recipient must then wait for a period of time before it can be determined whether or not pregnancy has been established. In some cases, pregnancy may never be established despite repeated attempts and these cases represent a considerable expense to society, both in financial and human terms.
Therefore, until success rates of IVF can be improved, it would be desirable to be able to identify recipients for whom IVF is unlikely to be successful prior to treatment, so that such patients avoid the abovementioned costs of the IVF procedure.
The adrenal steroid hormone, cortisol, is believed to influence maturation of the female germ cell (the oocyte) and the development of ovarian cells in culture (Orly & Sato (1979) Cell 17,295; Patino & Thomas, (1990) J. Exp. 2006 255,97). Recently, Fateh et al (1989, Fertil. Steril. 51,538-541) have reported that there is an association between the concentration of cortisol in follicular fluid and oocyte maturity.
The enzyme 11.beta.-hydroxysteroid dehydrogenase (EC 1.1.1.146) converts cortisol to its inactive form, cortisone. Benediktsson et al (J. Endocrinology (1992) 135, 53-58) report the presence of 11.beta.-hydroxysteroid dehydrogenase (11.beta.-HSD) in rat oocytes. The results of Benediktsson et al suggest a role for 11.beta.-HSD in modulating ovarian function. Two isoforms of 11.beta.-HSD have been characterised; a hepatic form and a renal form. Our initial findings suggest that both isoforms are expressed in ovarian tissue. In the present invention, reference to 11.beta.-HSD includes both isoforms.
DESCRIPTION OF THE INVENTION
Studies such as those mentioned above have tended to focus upon the relationship between oocyte maturity or hormone levels and the success of fertilization in vitro. However, we have surprisingly found that once fertilisation has been achieved and the second part of the IVF procedure is performed, namely implantation, there is a strong inverse correlation between levels of 11.beta.-HSD in the environment of the oocyte at the time of collection and the subsequent establishment of pregnancy. This correlation exists regardless of the maturity of the oocyte or other factors which may affect fertilization.
The present invention thus relates to assay methods and assay kits which can be used to predict the outcome of IVF in a female patient. The invention also relates to such methods and kits for use in a method of diagnosis in order to determine the outcome of IVF or the suitability of a female patient for IVF treatment. Although our invention described below has been developed from research on human female patients, it will be applicable to any mammalian female and can be used to increase the success of, for example, captive breeding programs of endangered species or commercial breeding by IVF of livestock such as cattle or horses.
Thus in one aspect the invention comprises a method for predicting the outcome of IVF which comprises: (11.beta.-HSD) in a biological sample from a female subject; and establishing pregnancy in said subject by IVF.
With regard to step (i), the sample may be a body fluid or a tissue such as the tissue from the environment of the oocyte such as the granulosa-lutein cells or follicular cells recovered for example from the ovarian follicles of women undergoing oocyte recovery for in vitro fertilization and embryo transfer. Alternatively the sample may be follicular aspirate
REFERENCES:
patent: 4815835 (1989-03-01), Corona
patent: 5173404 (1992-12-01), DiZerega
Fateh, M., Cortisol Levels in Human Follicular Fluid, Fertility and Sterility 51(3) 538-541. Mar. 1989.
McAllister, J., Proliferating Human Granulosa Lutein Cells in Long Term Monolayer Culture: Expression of Aromatase, Cholesterol Side-Chain Cleavage, and 3betaHydroxysteroid Dehydrogenase, J of Clinical Endo and Metabolism, 71(1) 26-33.1990.
Benediktsson, R., 11betaHydroxysteroid Dehydrogenase in the Rat Ovary: High Expression in the Oocyte, J of Endocrinology 135 53-58. 1992.
The Lancet, vol. 342, No. 8873, Sep. 18, 1993, pp. 711-712. Michael et al, `Ovarian 11Betahydroxysteroid dehydrogenase: potential predictor of conception by in-vitro fertilisation and embryo transfer`.
Journal of Endocrinology, vol. 135, 1992 pp. 53-58, Benediktsson et al. `11ss-Hydroxysteroid dehydrogenase in the rat ovary: high expression in the oocyte`.
The Journal of Clinical Endocrinology & Metabolism vol. 71 No. 5, Nov. 1990, pp. 1375-1376, Anderson `Levels of Steroid-Binding Proteins and Steroids in Human Preovulatory Follicle et al.`.
Fertility and Sterility vol. 51 No. 3, Mar. 1989 pp. 538-541, Fateh et al, `Cortisol levels in human follicular fluid`.
Clinical Endocrinology, vol. 38, 3 Jun. 1993, pp. 641-644, Michael et al, `Direct inhibition of ovarian steroidogenesis by cortisol and the modulatory role of 11Beta-hydroxysteroid dehydrogenase`.
Cooke Brian
Michael Anthony
Gitomer Ralph
Royal Free Hospital School of Medicine
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