RU-2861643-C1 - METHOD FOR TREATING REPEATED EMBRYO IMPLANTATION FAILURES IN INFERTILE PATIENTS

Abstract

FIELD: medicine. SUBSTANCE: invention relates to obstetrics and gynaecology, and can be used for treating repeated embryo implantation failures in infertile patients. A single subcutaneous injection of a depot form of a gonadotropin-releasing hormone agonist (GnRH agonist) at a dose of 3.75 mg is given on the 2nd-3rd day of the menstrual cycle, followed by administration of oestradiol and progesterone. Oestradiol is administered transdermally at a dose of 3-4.5 mg per day 28 days after the GnRH agonist injection. When an endometrial thickness of at least 7 mm is achieved, progesterone is administered subcutaneously at a dose of 25 mg per day and micronised progesterone is administered intravaginally at 200 mg twice a day, while continuing oestradiol administration. On the 6th day from the start of progesterone administration, a thawed embryo is transferred. Progesterone and oestradiol therapy is continued at the same doses until the 8th week of pregnancy. EFFECT: possibility of increasing the pregnancy rate in patients with combined gynaecological pathology by achieving an adequate level of the hormone in both the endometrial tissue and the systemic bloodstream. 1 cl, 2 ex

Inventors

• Ziganshin Aidar Mindiiarovich
• Giniiatullina Alfiia Nailevna
• Maksiutova Alina Albertovna

Dates

Publication Date

20260506

Application Date

20250926

Claims (1)

1. A method for treating repeated embryo implantation failures in infertile female patients comprising a single subcutaneous administration of a depot form of a gonadotropin-releasing hormone agonist (GnRH agonist) at a dose of 3.75 mg on days 2-3 of the menstrual cycle followed by administration of estradiol and progesterone, characterized in that estradiol is administered transdermally at a dose of 3-4.5 mg per day 28 days after administration of GnRH agonist, when the endometrial thickness reaches at least 7 mm, progesterone is administered subcutaneously at a dose of 25 mg per day and micronized progesterone is administered intravaginally at 200 mg twice per day, while continuing administration of estradiol; on the 6th day from the start of progesterone administration, a thawed embryo is transferred, therapy with progesterone and estradiol is continued in the same doses until the 8th week of pregnancy.

Description

The invention relates to medicine, in particular to obstetrics and gynecology in the field of assisted reproductive technologies (ART), and can be used in the treatment of infertility in patients with repeated implantation failures. Recurrent implantation failure (RIF) remains one of the most serious and poorly understood problems in assisted reproductive technologies. According to estimates by Russian and international researchers, up to 10% of couples worldwide experience this phenomenon. However, there are still no unified diagnostic criteria or universal method for determining this condition due to the high heterogeneity of this patient group [Ma J, Gao W, Li D. Recurrent implantation failure: A comprehensive summary from etiology to treatment. Front Endocrinol (Lausanne). 2023 Jan 5;13:1061766]. According to the European Society of Human Reproduction and Embryology (ESHRE) working group's guideline "Good Practice Recommendations on Recurrent Implantation Failure," RIF is a condition in which repeated transfers of presumably viable embryos fail to result in pregnancy. Key factors influencing implantation are the quality of the embryo and endometrium, as well as the synchronized interaction between them. Although the diagnosis of embryo euploidy based on the morphological and functional characteristics of the endometrium is now well established, endometrial receptivity remains controversial. There are isolated data in the literature that the cancellation of fresh transfer and the policy of embryo cryopreservation may have a positive effect on subsequent embryo implantation due to the absence of the negative effect of induction and superovulation on the endometrium. Magdi et al. (2017) confirmed this information in their study, obtaining a higher implantation rate in the cryopreservation group - 44.2% compared to the fresh transfer group - 15.8%; OR 2.80; 95% CI, 2.00-3.92 [Magdi Y, El-Damen A, Farm AM, et al. Revisiting the management of recurrent implantation failure through freeze-all policy. Fertil Steril. 2017 Jul; 108(l):72-77]. Recently, there has been increasing interest in studying the potential positive effect of gonadotropin-releasing hormone agonists (GnRH agonists) and subcutaneous forms of progesterone on increasing endometrial receptivity in ART programs [MacLean JA, Hayashi K. Progesterone Actions and Resistance in Gynecological Disorders. Cells. 2022 Feb 13;11(4):647]. In this regard, the development and clinical implementation of new complex therapeutic approaches for patients with infertility and repeated implantation failures is of particular importance, which remains one of the priority tasks of modern reproductive medicine. A method for treating repeated implantation failures is known, characterized by the fact that embryo transfer is carried out against the background of cyclic hormone therapy (CHT) with the introduction of GnRH agonists in the luteal phase of the cycle on the 4th and 6th day of progesterone intake [Gogce M, Benchaib M, Hadj S, et al. Administering GnRH Agonists in the luteal phase of Artificial Cycle Frozen-Thawed Embryo Transfers. A prospective randomized study. Gynecol ObstetFertil. 2015 Nov; 43(11):728-34. French.]. A disadvantage of this method is its limited effectiveness compared to protocols that include pre-treatment of the endometrium with depot forms of GnRH. This is particularly relevant for patients with concomitant reproductive pathologies, such as endometriosis and polycystic ovary syndrome, in whom pre-treatment of the endometrium can facilitate synchronization with the implantation window and increase pregnancy rates. A known method for treating repeated implantation failures involves embryo transfer against the background of cyclophosphamide therapy with preliminary preparation of the endometrium using a depot form of GnRH agonist [Xu B, Nou Z, Liu N, et al. Pretreatment with a long-acting GnRH agonist for frozen-thawed embryo transfer cycles: how to improve live birth? J Ovarian Res. 2023 Sep 25; 16(1)]. A disadvantage of this method is the exclusive use of vaginal progesterone to support the luteal phase of the cycle. This approach primarily delivers progesterone locally to the endometrium and does not always result in adequate hormone levels in the systemic circulation. This method is particularly relevant for patients with repeated implantation failures, who often have reduced serum progesterone levels, which can negatively impact the likelihood of pregnancy. A prototype method for preparing the endometrium for the transfer of cryopreserved embryos was selected. This method involves preliminary hormonal suppression using a single subcutaneous administration of a long-acting GnRH agonist (leuprorelin at a dose of 3.75 mg) on days 2-3 of the menstrual cycle. After 14-21 days, when the endometrial thickness reaches at least 5 mm and the progesterone level is <1.0 ng/ml, estradiol valerate is administered at a dosage of 8 mg per day for at least 9