RU2646578C1 - Method for improving efficiency of embryo implantation in natural cycle of conception and in assisted reproductive technology (art) protocols - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to medicine, specifically to gynecology and reproductive medicine. Method employs daily administration of a granulocyte colony-stimulating factor (G-CSF) under the skin of the forearm in a dose of 0.2 ml of the officinal drug solution in a dose of 30,000,000 units per 1.0 ml of the solution, from the second day of the menstrual cycle to the pregnancy test at 28±3 day of the menstrual cycle. Method comprises 4–5 intrauterine installations of G-CSF with an interval of 1–2 days in the follicular phase of the menstrual cycle after the end of menstruation in a volume of 1.0 ml of the official solution for each installation, performed with a catheter for embryo transfer. In "ART protocols", the last intra-uterine administration of G-CSF is performed 1 day before embryo transfer.

EFFECT: method improves efficiency of embryo implantation in the natural cycle of conception and in assisted reproductive technology (ART) protocols.

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Description

The invention relates to medicine, namely to gynecology and reproductology, and can be used as an increase in the efficiency of embryo implantation in the natural cycle of conception and in protocols of assisted reproductive technologies (ART).

Known methods and methods for increasing the efficiency of embryo implantation. Currently, highly proven methods and methods for increasing the efficiency of implantation of embryos are absent. However, in order to increase female fertility (while maintaining male fertility) and in the framework of preparing patients with infertility for ART protocols, combined oral contraceptives, cyclic administration of progestogens [1, 3], antibacterial drugs [3, 4] and antiviral agents [ 2, 3], physiotherapeutic treatment [3], and also directly in the conception cycle (ART protocol) use estrogens, acetylsalicylic acid in low doses, nitric oxide donors in order to change the receptivity of end geometry [3, 5, 8]. However, the available data on the systemic anti-inflammatory effect of granulocyte colony stimulating factor (G-CSF), accompanied by a decrease in the levels of anti-inflammatory cytokines, and its effect on the receptive properties of the endometrium, expressed in a change in the expression of L-selectins and other cell adhesion factors [5, 6]. make it a promising drug in increasing the frequency of implantation of embryos. Also, G-CSF in a dose-dependent manner has an immunomodulating effect, inducing type 2 T-helpers and limiting the local cytotoxic effect of type 1 T-helpers [7]. Violation of the ratio of T-helpers of type 1 and type 2 occurs in the pathology of the endometrium and is one of the reasons for the decrease in fertility in women [6, 8]. Summarizing the data on the properties and dose-dependent effects of G-CSF, its combined administration (subcutaneous at low doses and intrauterine) promotes a change in the receptive properties of the endometrium, a decrease in the secretion of pro-inflammatory cytokines, and a change in the ratio of type 1 and type 2 helper cells in the endometrium, which improves the implantation frequency embryos in ART protocols.

The basis of the invention is the goal of improving fertility in the treatment of infertility in women with endometrial pathology and increasing the frequency of embryo implantation in ART protocols.

The goal is achieved by daily subcutaneous administration of the G-CSF official solution, starting from the second day of the menstrual cycle until the pregnancy test is performed on the 28 ± 3 day of the menstrual cycle), and 4-5 intrauterine irrigation solutions of G-CSF using a catheter for transferring embryos from an interval of 1-2 days in the follicular phase of the menstrual cycle after menstruation. In ART protocols, the last intrauterine administration of G-CSF is carried out 1 day before embryo transfer.

The invention is as follows.

In the cycle of the planned conception (ART protocol), G-CSF is administered subcutaneously (under the skin of the forearm) at a dose of 0.2 ml of the official solution of the drug (30,000,000 units in 1.0 ml of the solution), starting from the second day of the menstrual cycle and continuing daily until quantitative pregnancy test on 28 ± 3 days of the menstrual cycle. In case of a negative pregnancy test, the injections are stopped; in case of a positive pregnancy test, it is possible to continue therapy until ultrasound confirmation of pregnancy. Simultaneously with the subcutaneous administration of G-CSF, 4-5 intrauterine irrigation of G-CSF is carried out with an interval of 1-2 days in the follicular phase of the menstrual cycle after menstruation. Intrauterine irrigation of G-CSF is carried out by introducing into the cavity a catheter for embryo transfer and subsequent administration of an official G-CSF solution in a volume of 1.0 ml through the catheter. In ART protocols, the last intrauterine administration of G-CSF is carried out 1 day before embryo transfer.

Contraindications for the treatment of G-CSF:

- acute inflammatory diseases of the pelvic organs at the time of treatment;

- other acute inflammatory diseases at the time of treatment or within 1 month in history;

- age under 18 years old;

- decompensated forms and terminal stages of chronic diseases.

Bibliography

1. Korhov V.V., Tapilskaya N.I. Gestagens in obstetric and gynecological practice. hands. for doctors / St. Petersburg: SpetsLit, 2005 .-- 144 p.

2. Proshin S. N., Glushakov R. I., Shabanov P. D. et al. Importance of expression of TLR receptors for the choice of pharmacological correction of cervical and endometrial pathology. // Genes and cells. - 2011. - T. 6, No. 1. - S. 91-97.

3. Tapilskaya N.I., Karpeev S.A., Kuznetsova I.V. Chronic endometritis is a subclinical inflammatory disease of the pelvic organs. // Gynecology. - 2014. - T. 16, No. 1. - S. 104-109.

4. Espinoza J., Erez O., Romero R. Preconceptional antibiotic treatment to prevent preterm birth in women with a previous preterm delivery. // Am. J. Obstet. Gynecol. 2006; 194 (3): 630-7.

5. Krikun G., Potter J.A., Abrahams V.M. Human endometrial endothelial cells generate distinct inflammatory and antiviral responses to the TLR3 agonist, Poly (I: C) and the TLR8 agonist, viral ssRNA. // Am J Reprod Immunol. 2013; 70 (3): 190-8.

6. Ledee N., Lombroso R., Lombardelli L. et al. Cytokines and chemokines in follicular fluids and potential of the corresponding embryo: the role of granulocyte colony-stimulating factor. // Hum Reprod. 2008; 23 (9): 2001-9.

7. Lee J.Y., Lee M., Lee S.K. Role of endometrial immune cells in implantation. // Clin Exp Reprod Med. 2011; 38 (3): 119-125.

8. Maybin J.A., Barcroft J., Thiruchelvam U. et al. The presence and regulation of connective tissue growth factor in the human endometrium. // Hum Reprod. 2012; 27 (4): 1112-21.

Claims (2)

1. A method for increasing the efficiency of embryo implantation in the natural cycle of conception and in the “protocols of assisted reproductive technologies (ART)" by the combined use of granulocyte colony stimulating factor (G-CSF), characterized in that daily administration of G-CSF under the skin of the forearm at a dose of 0 is used , 2 ml of the official solution of the drug in a dose of 30,000,000 units in 1.0 ml of the solution, starting from the second day of the menstrual cycle until the pregnancy test is performed on 28 ± 3 days of the menstrual cycle, and 4-5 intrauterine of G-CSF installations with an interval of 1-2 days in the follicular phase of the menstrual cycle after the end of menstruation in a volume of 1.0 ml of the official solution at each installation performed using an embryo transfer catheter. 2. The method according to p. 1, characterized in that in the "ART protocols" the last intrauterine administration of G-CSF is carried out 1 day before embryo transfer.