RU2759168C1 - Method for activating ovarian function with reduced ovarian reserve - Google Patents

Abstract

FIELD: medicine; reproductive gynecology.

SUBSTANCE: invention relates to medicine, namely to reproductive gynecology; it can be used in patients with infertility and low ovarian reserve to activate ovarian function. A method for stimulating ovarian function with a reduced ovarian reserve includes the injection of 2 ml of autoplasm enriched with thrombocytes into the brain substance of the ovary at a distance of at least 5 mm from main vessels, and fractionally, of 0.5 ml at each of four injection points; plasma is injected into the ovary under conditions of step-by-step needle traction under visual control using technical diagnostic tools.

EFFECT: possibility of obtaining one’s own egg in programs of assisted reproductive technologies and/or the onset of spontaneous pregnancy in patients with low and extremely low ovarian reserve, as well as the possibility to go without the use of donor oocytes.

1 cl, 1 dwg, 4 tbl

Description

The present invention is applicable in the medical field, in particular in the field of reproductive medicine.

The prior art discloses a method of stimulating folliculogenesis (patent RU №2629871), providing two-fold subcutaneous injection formulation containing the chimeric protein suspension with a water-insoluble enzymatically inactive chloramphenicol without 10 C-terminal amino acid, an amino acid spacer (Sp) _n, where n = 1, 2, 4, 8, and somatostatin-14 with the amino acid sequence AGCFWKTFTSC in refined vegetable oil with the addition of pyrogen-free water for injection, at the rate of 25-50 μg of the specified chimeric protein per 1 kg of live body weight with an interval of 14 days between injection, or at the rate of 100-250 mg of the specified chimeric protein per 100 ml of refined vegetable oil, including 5.0-10.0 wt. % pyrogen-free water for injection. The introduction of chimeric protein and somatostatin-14 promotes an increase in the activity of sex hormones (testosterone, progesterone, estradiol) in the blood serum and induction of complex rearrangements of adaptive genesis, expressed in structural transformations of the organs of the reproductive system, and aimed at stimulating the reproductive potential.

It is also known from the prior art (patent RU No. 2418604) about the use of somatostatin (a hormone antagonist of somatotropin) or one of its agonist analogs for the preparation of a drug that is intended to inhibit the growth of resting follicles in ovarian tissue.

In addition, there is a known method for in vitro activation of ovarian follicles and oocytes, including the use of PTEN inhibitors (patent RU No. 2492866), where the PTEN inhibitor is selected from the group including Bisperoxo (bipyridine) oxovanadate, Bisperoxo (1,10-phenanthroline) oxovanadate, Bisperoxo (picolinato) oxovanadate, Bisperoxo (5-hydroxypyridine-2-carboxyl) oxovanadate, Di- (picolinate) oxovanadate, Di- (3-hydroxypicolinate) oxovanadate, Bisperoxo (phenylbiguanide) oxovanadine-isphenylate acid) oxovanadate. The method may include incubating follicles and / or oocytes in a physiologically acceptable medium containing one or more PTEN inhibitors. The medium may additionally contain a gonadotropin such as FSH and / or CG.

The disadvantages of the known methods are: a slight anti-inflammatory, anti-edematous, analgesic and stimulating the regeneration of a number of tissues effect, as well as the lack of the possibility of using in patients with physiologically low ovarian reserve associated with age-related changes or premature ovarian failure.

The problem posed during the creation of the invention is to develop an effective and safe method for stimulating ovarian function in patients with low ovarian reserve, including women with "poor response" in IVF programs, as well as with premature ovarian failure.

The technical result consists in the possibility of obtaining one's own egg in programs of assisted reproductive technologies (ART) and / or the onset of spontaneous pregnancy in patients with low and extremely low ovarian reserve, as well as the ability to do without the use of donor oocytes.

The essence of the invention lies in the transvaginal intraovarial administration of platelet-rich plasma into the ovarian tissue.

It should be noted that, unlike the uterine cavity, which communicates with the external environment through the cervix and vagina, the ovaries are located in the abdominal cavity and do not have contact with the external environment. Therefore, it is especially important for solving the problem and achieving the technical result is the central introduction of plasma into the ovarian medulla at a distance of at least 5 mm from the main vessels (vessels of the ovarian's own ligament and vessels of the funnel-pelvic ligament). To do this, the needle is inserted as distally as possible into the safe zone of the ovary and fractionally, 0.5 ml at each point of injection, the plasma is injected into the ovary, under conditions of step-by-step traction of the needle in the proximal direction. Thus, at four injection sites, at least 0.5 ml is injected into each point with a volume of at least 2.0 ml of plasma for each ovary.

The method of injection described above is due to the following factors:

- safety (vascular injury during manipulation can lead to intra-abdominal bleeding);

- increasing efficiency (the introduction of plasma into the vessel reduces its efficiency);

- the introduction of an injection into the ovarian tissue, and not irrigation or intravascular administration;

- fractional injection of plasma in four stop points of the ovary, which makes it possible to evenly distribute autoplasma in the ovarian medulla, reduces the likelihood of ischemia of the ovarian tissue, as a result of the proposed sequential administration of autoplasma, the possibility of achieving a technical result increases;

After the introduction of autoplasma, the pelvic cavity is carefully examined using ultrasound to exclude the presence of blood as a result of vascular damage.

Brief description of tables and drawings:

FIG. 1 shows the vascular pattern of the ovary in the color Doppler mapping mode.

Table # 1. Clinical and demographic characteristics of patients in the surveyed groups, (n (%)).

Table 2. Dynamics of ovarian reserve indicators in patients with "poor" response in IVF programs.

Table 3. Dynamics of ovarian reserve indicators in patients with premature ovarian failure.

Table 4. Clinical results of intraovarial autoplasma therapy using platelet-rich plasma.

Criteria for evaluating the effectiveness of the proposed method:

- dynamics of the content of follicle-stimulating hormone (FSH), estradiol, anti-Müllerian hormone;

- restoration of ovulatory function of the ovaries;

- the number of oocytes obtained in the course of IVF programs, the onset of pregnancy.

The obtained data on the dynamics of the physiological parameters of the ovarian reserve are presented in tables 2 and 3, demonstrating a significant decrease in FSH, an increase in the values of estradiol and anti-Müllerian hormone within 3 months without significant dynamics when controlled in the 4th menstrual cycle.

Features of hormonal stimulation of superovulation and the results of IVF programs are presented in table 4.

An indication for the use of the proposed method is:

- premature ovarian failure;

infertility, accompanied by unsuccessful attempts at in vitro fertilization (IVF) in history and poor ovarian response.

The presented data demonstrate the fact that intraovarian injection of platelet-rich autoplasma refers to an effective, non-specific stimulation of ovariogenesis and leads to an improvement in ovarian function, contributing to the reactivation of the folliculogenesis process, restoration of the menstrual cycle and improvement of the hormonal profile. The combination of these factors, in turn, leads to the achievement of pregnancy, in some cases by natural conception, in women with a low ovarian reserve, who still have the opportunity to use their own oocytes, refusing to carry out donor programs of assisted reproductive technologies (ART). The claimed method showed the greatest efficiency in the group of patients with physiologically pronounced premature ovarian failure, in comparison with patients over 40 years old and "poor" ovarian response, which is associated with age-related dynamics of the quality of oocytes and, as a consequence, the quality of the embryos obtained, as well as the presence of combined factors infertility in this category of patients.

The effectiveness of the claimed method is confirmed by the following experimental data:

to ovarian stimulation for in vitro fertilization: the Bologna criteria//Hum Reprod2011;26(7):1616-24), (n=30); и пациентки с преждевременной яичниковой недостаточностью (возраст менее 40 лет, аменоррея не менее 4 месяцев, уровень ФСГ более 25 Me/мл), (n=30). Из исследования были исключены пациентки с аутоиммунными заболеваниями, воспалительными заболеваниями органов малого таза, хроническим эндометритом, индексом массы тела более 30 и менее 18,5, гипоталамо-гипофизарными расстройствами и предшествующими хирургическими вмешательствами на органах малого таза. Во всех супружеских парах отсутствовал мужской фактор бесплодия. Пациентки с «бедным овариальным ответом» были старше 40 лет, имели «бедный овариальный ответ» в предшествующих программах ЭКО и сниженный овариальный резерв по данным гормонального и ультразвукового исследования. У всех пациенток в анамнезе как минимум одна неудачная попытка программы ВРТ. Пациентки обеих групп получили лечение в соответствии с предложенным способом активации функции яичников. Клинико-демографические характеристики пациенток обеих групп представлены в таблице №1.The study included 60 patients with low ovarian reserve, including patients with a "poor response" in IVF programs according to the Bologna criteria (Ferraretti AR, La Magsa A, Fauser BC et al. ESHRE consensus on the definition of

to ovarian stimulation for in vitro fertilization: the Bologna criteria // Hum Reprod2011; 26 (7): 1616-24), (n = 30); and patients with premature ovarian failure (age less than 40 years, amenorrhea at least 4 months, FSH level more than 25 Me / ml), (n = 30). Patients with autoimmune diseases, inflammatory diseases of the pelvic organs, chronic endometritis, body mass index more than 30 and less than 18.5, hypothalamic-pituitary disorders and previous surgical interventions on the pelvic organs were excluded from the study. In all married couples, the male factor of infertility was absent. Patients with "poor ovarian response" were over 40 years old, had "poor ovarian response" in previous IVF programs, and decreased ovarian reserve on hormonal and ultrasound imaging. All patients have a history of at least one unsuccessful attempt at an ART program. Patients of both groups received treatment in accordance with the proposed method for activating ovarian function. Clinical and demographic characteristics of patients in both groups are presented in Table 1.

Preparation for the application of the claimed method is carried out in several stages:

Preparation of platelet-rich autoplasma is carried out immediately before the infusion. Blood sampling from the patient, at least 40 ml, is performed using a syringe or a butterfly needle, then the blood is mixed by slowly shaking the syringe along a trajectory resembling the number eight for 15 seconds to mix with an anticoagulant, then the blood is placed in a special tube ... To obtain platelet-rich autoplasma, centrifugation is carried out in two stages. At the first stage, centrifugation is carried out with a rotor tilt angle of 45 degrees, 3400 -3600 rpm, time 4 minutes. At the second stage, centrifugation is carried out with an angular rotor, 3400 - 3600 rpm, time is 4 minutes. After the second centrifugation step, platelet-rich plasma is recovered.

Autoplasm is injected through a needle as distally as possible into the safe zone of each ovary, namely into the ovarian medulla at a distance of at least 5 mm from the main vessels, and fractionally, 0.5 ml at each point of injection, plasma is injected into the ovary, under the conditions of step-by-step traction of the needle in the proximal direction ("towards yourself"). The injection of autoplasma is carried out at four points of the ovary, with a volume of at least 0.5 ml of autoplasma at each point. an amount that does not exceed the volume of the ovary, that is, 2 ml. This allows you to avoid the introduction of an excessive amount of plasma and, at the same time, to effectively use the maximum possible amount.

Visual control of the point injection is possible using technical diagnostic tools, for example, using ultrasound examination using color Doppler mapping or using fluoroscopy (angiography).

Claims (1)

A method of stimulating ovarian function with a reduced ovarian reserve by using platelet-rich autoplasma, characterized in that autoplasma is injected into the medulla of each ovary, with a volume of at least 2 ml into each ovary, while the autoplasma is injected fractionally, using step-by-step traction of the needle in the proximal direction, at four points of the ovary, with a volume of at least 0.5 ml of autoplasma at each point; choose the zone of injection of autoplasma into the ovary, located at a distance of at least 5 mm from the main vessels, while performing visual control of the injection of autoplasma using technical diagnostic tools.

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