RU2752541C1 - Method of treating a thin endometrium in preparation for an ivf-program - Google Patents

Abstract

FIELD: medicine; gynecology; obstetrics.SUBSTANCE: gas mixture of 5 % carbon dioxide and 95 % nitrogen is used, which is introduced through a catheter with a rounded tip at the distal end. On the outer surface of the catheter, a sucker is arranged to move along the catheter, wherein during introduction of the catheter through an airtight lining in the latter an opening is made for free passage of the catheter, then the suction cup is fixed with an airtight lining. Airtight spacer is fixed around the labia before the catheter is introduced, or during insertion of the catheter.EFFECT: method provides higher clinical effectiveness in the treatment of thin endometrium when preparing the patient for the IVF program, reduces the gas mixture loss during the procedure, and also enables the outpatient procedure.1 cl, 4 dwg

Description

The invention relates to medicine, gynecology and obstetrics and can be used for the therapeutic treatment of the thin endometrium in preparation for the IVF program.

The problem of female infertility is becoming more and more urgent all over the world and has no tendency to decrease. According to official data, the number of infertile marriages in Russia is up to 17.5%, but in reality, it can be much higher, since statistics on infertile marriages in small and remote from the center settlements are almost absent. About 6 million married couples are infertile, of which 3 million are in need of IVF.

The effectiveness of the IVF method is quite high and reaches up to 30.7% of pregnancy per cycle. However, a large number of failures in the IVF program forces researchers to study this problem more and more deeply and look for new methods in the application of IVF.

In gynecological practice, in order to achieve the desired pregnancy, it is necessary to combine a normal embryo and a receptive endometrium, to which the embryo is able to implant. That is why a thin endometrium is a frequent cause of a significant decrease in the possibility of pregnancy [1-5]. In 1991, Gonen et al. for the first time proposed to use the minimum thickness of the endometrium (6 mm) as a prognostic criterion for the possible development of pregnancy in the natural cycle. Since that time, the concept of the minimum thickness of the endometrium for the possible development of pregnancy has been widely used by various researchers.

It is believed that an endometrial thickness of less than 7 mm gives the minimum chance of productive conception. Therefore, the search for new methods of treatment of this pathology is relevant and necessary.

The reasons why the endometrium becomes thin can be due to a number of pathological factors. This can be a violation of the blood supply in the uterus, which is inherent in both hereditary (congenital) and acquired factors (after inflammation, induced abortion, trauma, with a disease of the body of the uterus or neighboring organs). In addition, pathology can form against the background of genital infantilism, or as a result of hormonal imbalance. Until now, it is not clear why a thin endometrium is an unfavorable factor for the onset of embryo implantation. Some researchers speculate that the thin layer of the endometrium results in abnormally high oxygen concentrations in epithelial cells, which leads to the excessive generation of reactive oxygen species (free radicals), which can be toxic to cellular structures. The condition and thickness of the endometrium is clearly visible during ultrasound, and its permissible value should be at least 6 mm, and only then a successful pregnancy is possible.

Treatment can be both medication with a predominance of hormonal therapy, and surgical with direct removal of the endometrial layer.

The search for alternative methods of treating thin endometrium is relevant and timely.

There are certain methods for improving blood flow in the uterine arteries. These include:

1. Low doses of aspirin, which suppress the synthesis of thromboxane A2, without affecting the synthesis of a simple cycle and on, which explains the increase in blood flow velocity in the uterine and ovarian arteries.

2. L-arginine (nitric oxide donor) improves uterine blood flow in the endometrium. In addition, oral administration of L-arginine increases the thickness of the endometrium.

3. Sildenafil (Viagra) enhances the effect of nitric oxide on the dilation of vascular smooth muscles. Vaginal sildenafil may be effective in improving blood flow to the endometrium.

The role of carbon dioxide (CO ₂ ) in the life of the body is very diverse.

Here are just some of its main properties:

CO ₂ is an excellent vasodilator;

is a soothing (tranquilizer) of the nervous system, which means an excellent

anesthetic;

participates in the synthesis of amino acids in the body;

CO ₂ plays an important role in the excitation of the respiratory center;

Increasing the _CO2 level enhances small arteries (tone which determines the number of functioning capillaries) and increase blood flow. Carbon dioxide is a powerful vasodilator.

Currently, medical scientists look at carbon dioxide as a powerful physiological factor in the regulation of numerous body systems: respiratory, transport, vasomotor, excretory, hematopoietic, immune, hormonal, etc.

It has been proven that the local effect of carbon dioxide on a limited area of tissues is accompanied by an increase in volumetric blood flow, an increase in the rate of oxygen extraction by tissues, an increase in their metabolism, restoration of receptor sensitivity, an increase in reparative processes and activation of fibroblasts. Increasing the level of CO ₂ in the tissue promotes the expansion of small arteries (tone which determines the number of functioning capillaries) and increase blood flow. So, it becomes clear that carbon dioxide in our body performs numerous and very important functions.

For example, in the invention RU 2066216 "Method for restoring patency of fallopian tubes", it is said about a method and device for restoring patency of fallopian tubes using carbon dioxide to expand the uterine cavity. In the invention RU 2200453 "Method for the treatment of intra-abdominal bleeding with pneumoperitoneum" refers to stopping intra-abdominal bleeding by injecting carbon dioxide up to 16-18 mm Hg. under the control of a laparoscope. The method allows you to stop bleeding in a minimally invasive way. In the invention RU 2352262, a method of necrsequestrectomy for pancreatonecrosis is described, characterized in that the removal of necrosis and sequesters is carried out through a mini-laparotomic incision of 4-6 cm with a stream of carbon dioxide at a pressure of 25 atm through a nozzle with a diameter of 0.05 cm. lack of intraoperative blood loss. In the invention related to medicine and, in particular, emergency surgery, entitled "Method for laparoscopic treatment of peritonitis" patent RU 2205602, it is said about the sanitation of the abdominal cavity in conditions of carboxyperitoneum and subsequent desufflation of carbon dioxide. The method allows to reduce the contamination of anaerobic and aerobic microflora in the abdominal cavity.

The invention related to veterinary medicine "Method for the treatment of gynecological diseases of cows using medicinal solutions based on carbonated water" (patent RU 2329795) refers to the treatment of gynecological diseases by intrauterine administration of an antiseptic solution saturated with carbon dioxide, which makes the drug highly therapeutic.

In the last 2 years, the method of carboxytherapy has entered aesthetic cosmetology. Thus, the use of carbon dioxide occurs in various fields of medicine and is an effective factor in the treatment of a number of diseases.

The invention RU 2203625 describes a method for determining the strength of sutures imposed on the uterus by pneumopression, characterized in that in the experimental animal, after ligation of the fallopian tubes, carbon dioxide is introduced through the vagina into the uterine cavity, recording the pressure at the time of violation of the integrity of the sutures, determined by the color change indicator paper overlaid on the seam line. Nitrogen in the body is one of the main biogenic elements that make up the most important substances of living cells, proteins and nucleic acids. Nitrogen is an element necessary for the existence of animals and plants, it is part of proteins (16% -18% by weight), amino acids, nucleic acids, nucleoproteins, hemoglobin, etc. All the most important parts of cells (for example, protoplasm and nucleus) are built from protein substances. Without protein, there is no life, and without nitrogen, there is no protein. Protein in the body has a number of functions, the most important of which are: plastic, hormonal, catalytic, protective, transport, energy, etc. nucleic acids. Consequently, a lack of nitrogen reduces all of the above functions of proteins. Until now, in modern literature and in modern medical practice, we have not met data on the treatment of women with a thin endometrium by treating the endometrium with a mixture of gases (CO ₂ + N ₂ ) under the influence of which there is a significant increase in blood circulation in the mucosa and, consequently, an increase in the thickness of the basal and functional layers.

The closest analogue is the application RU 2013151641, A61M 35/00, publ .: 05/27/2015. It describes a method of treating a hypoplastic (thin) endometrium in preparation for an IVF program, characterized by stimulating the blood supply to the endometrium, by injecting carbon dioxide into the uterus under pressure, characterized in that the blood supply to the endometrium is stimulated using a gas mixture of carbon dioxide and nitrogen (CO ₂ and N). During the introduction of the gas mixture, the woman's labia are fixed with an airtight gasket. The composition of the gas mixture is selected based on the ratio of carbon dioxide - 6%, nitrogen - 94%. The technical problem of the prototype is the free exit of gas, even despite the fact that the woman's labia are fixed with an airtight gasket, since a large percentage of the gas mixture comes out through the labia, and there is no tight sealing in them. Large gas losses reduce the effectiveness of treatment.

The objective of the invention is to eliminate the indicated disadvantages of the prototype.

The technical result is to increase the efficiency in the treatment of thin endometrium in the process of preparing the patient for the IVF program and reduce the loss of the gas mixture, as well as the ability to carry out the procedure on an outpatient basis.

The specified technical result is realized due to the fact that the claimed method of treating a thin endometrium in preparation for an IVF program, characterized by the stimulation of blood supply to the endometrium, which is carried out using a gas mixture of carbon dioxide and nitrogen (CO ₂ and N ₂ ), injected under pressure, and with the introduction of the gas mixture, the woman's labia are fixed with an airtight gasket, characterized in that the gas mixture is introduced through a catheter with a rounded tip at the distal end, on the outer channel of which a suction cup is positioned to move along the channel, while in the process of introducing the catheter through an airtight gasket in the latter a hole for free passage of the catheter, then the suction cup is fixed with an airtight gasket. Preferably, after filling the uterus with a gas mixture, the catheter is withdrawn from the vagina, squeezing the woman's labia and sealing the opening in the airtight seal remaining from the insertion of the catheter.

It is conceivable that the airtight pad is secured around the labia prior to insertion of the catheter, or during insertion of the catheter.

It is permissible that the suction cup has a sticky layer on the inside.

It is possible that the airtight gasket is made consisting of a polyethylene layer, along the edges of which a sticky layer having a removable protective film is placed.

The composition of the gas mixture is preferably selected on the basis of the ratio of carbon dioxide -5%, nitrogen-95%.

Brief Description of Drawings

FIG. 1 shows an example of a device for implementing the method (side view).

FIG. 2 shows the principle of fixing an airtight seal around the labia.

FIG. 3 shows the principle of using the device during the sealing of the suction cup and the airtight pad if the airtight pad is fixed around the labia during catheter insertion.

FIG. 4 shows the principle of operation of the method with the introduction of a catheter into the vaginal cavity. In the drawings: 1 - a cylinder with a compressed gas mixture, designed for many injections (under pressure), 2 - a plastic tip for spraying an air stream, 3 - a distal splitter tip, 4 - a lever for releasing the mixture from the cylinder, 5 - an outlet for the outlet gas jets on the head of the handpiece, 6 - suction cup, 7 - airtight gasket, 8 - sticky layer of the airtight gasket, 9 - protective film, 10 - vagina, 11 - uterine cavity.

Implementation of the invention

A method of treating a thin endometrium in preparation for an IVF program is based on stimulating the blood supply to the endometrium, which is carried out using a gas mixture of carbon dioxide and nitrogen (CO ₂ and N ₂ ), injected under pressure, and when the gas mixture is injected, the woman's labia is fixed with an airtight gasket ... The novelty is that the gas mixture is introduced through a catheter with a rounded tip at the distal end, on the outer channel of which a suction cup is positioned with the possibility of sliding along the channel, while in the process of introducing the catheter through an airtight gasket, an opening is made in the latter for free passage of the catheter, then the suction cup is fixed with an airtight seal. The invention can be implemented, for example, on the basis of a device (see Fig. 1), which consists of a cylinder 1 with a compressed sterile gas mixture (preferred composition: 5% carbon dioxide, 95% nitrogen; selected empirically), designed for multiple injections ... A special disposable sterile or reusable catheter 2 is attached to the balloon, preferably made of a soft material - plastic or silicone, which is pushed onto the balloon head with its tubular end. The gas mixture is supplied by pressing the lever 4 of the cylinder 1.

For greater comfort of the woman, the distal end 3 of the catheter 2 is made with a rounded tip, preferably also having an opening 5 at the end, the purpose of which is to prevent a direct air stream from escaping.

Although hole 5 is located at the end 3 of the catheter 2 in the direction of the uterus and at the base the gas mixture enters the uterine cavity 11 through the cervix 10, the output of gas jets under pressure is partially distributed all the same over the entire cavity of the vagina 10 and uterus 11, including directions back exit to the outside, where it stops with the help of hermetically connected airtight gasket 7 and suction cup 6, which eliminates or reduces the loss of the gas mixture (see Fig. 4). The suction cup 6 can have a sticky layer on the inside or suck to form a reduced pressure inside the suction cup.

The airtight pad 7 is fixed around the labia before the insertion of the catheter (see Fig. 2), or during the insertion of the catheter (see Fig. 3). The airtight gasket 7 in can be made consisting of a polyethylene layer, at the edges of which an adhesive layer 8 is placed, having a removable protective film 9.

The gas-filled vagina 10 and uterus 11 create all conditions for stimulating blood supply and endometrial growth.

For greater effect, after filling the uterus 11 with a gas mixture, the catheter 2 is removed from the vagina 10, squeezing the woman's labia, and the opening in the airtight gasket 7 remaining from the introduction of the catheter 2 is sealed in order to prevent the gas mixture remaining in the uterus from escaping. You can seal the hole with tape, for example.

It should be noted that only one of the possible embodiments of the method for introducing the catheter and the principle of gas injection into the uterus are described above. In this case, for example, it is possible to directly introduce the gas mixture into the uterine cavity through a plastic catheter inserted through the cervical canal into the uterine cavity. This process is carried out by a doctor on an outpatient and inpatient basis.

A randomized clinical placebo-controlled study of the effectiveness of the method was carried out on a group of patients planning an IVF procedure with an established diagnosis: thin endometrium - 140 people.

Planned number of observations

120 patients - the application of the claimed method of treatment according to the method in order to increase the thickness of the endometrium and enhance the angioarchitectonics of the uterus and endometrium, confirmed by clinical research methods (ultrasound, Doppler ultrasonography of uterine blood flow, etc.).

20 patients with a placebo-controlled study (ultrasound, Doppler ultrasonography of uterine blood flow, etc.).

Inclusion criteria:

1. Primary or secondary infertility of various origins, in the presence of a diagnosed growth disorder of the thin endometrium.

2. The presence of a thin endometrium in women.

3. Lack of thin endometrial growth in the embryo transfer cycle.

4. Lack of endometrial growth under the influence of hormonal stimulation.

5. Lack of endometrial growth under the influence of physiotherapy treatment.

6. Age 18-45 years old.

7. Women planning IVF.

8. Informed consent to participate in the study. Exclusion criteria:

1. The presence of malignant diseases of the body of the uterus and appendages, tumor formations.

2. Identified diseases that are predominantly sexually transmitted.

3. Submucous uterine myoma.

4. Subfebrile conditions.

5. Genital endometriosis III-IV degree.

6. Polyps of the uterine cavity and cervical canal.

7. The prolapse of the pelvic organs is more than 2-3 degrees.

8. Malformations of the genitals.

9. Severe extragenital pathology.

Survey methods: general examination of women for IVF. Additional examinations are not required.

Research results.

As a result of this study, indications were formulated for the application of the method of exposure to the gas mixture CO ₂ + N ₂ on the process of treating the thin endometrium, and the effectiveness of the applied method was evaluated.

Research Center: Federal State Budgetary Institution "National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. the leader of the Russian Federation).

The method was tested to assess the effectiveness and safety of using an innovative method of treating thin endometrium in the process of preparing patients for the IVF program by improving blood supply and increasing the thickness of the endometrium using a gas mixture (CO ₂ and N ₂ ).

The research methodology was as follows. The thickness of the endometrium (ultrasound) was measured once before the inclusion of patients in the study, and then three times: in the cycle of the procedure and in the next cycle after the procedure. Ultrasound was performed on days 7, 11, 13, 15 of the menstrual cycle with a 28-day cycle in the patient or after 5-7 days of confirmed ovulation with a cycle different from the 28-day cycle.

According to the claimed method, a metered air mixture (carbon dioxide and nitrogen, with the selection of the mixture composition predominantly 5% carbon dioxide, 95% nitrogen with small percentage errors within ± 2% at the technical level of accuracy of filling the balloon with the indicated mixture), which, filling the uterine cavity, affected the endometrium. Due to this, there was an increase in the blood supply in the mucous membrane of the uterine cavity and an increase in the thickness of the endometrium.

The planned procedure was safe, since it uses the guidewire and catheter that are always used during IVF, and the composition of the gas mixture consists of the ingredients used for embryo culture (CO ₂ and N ₂ ). The study included 140 patients of reproductive age (25-40 years) with diagnosed primary or secondary infertility and the presence of a thin endometrium that does not respond to hormonal therapy. All patients underwent clinical and laboratory examination, transvaginal ultrasound scanning.

All patients gave written informed voluntary consent to participate in the study and consent to perform the procedures.

During the first ultrasound, before the start of endometrial gas irrigation, the thickness of the latter varied from 3.1 mm to 5.9 mm.

During subsequent ultrasound, the following was revealed: 2 days after the first irrigation, the thickness of the endometrium increased by 2.7-3.3 mm, two days after the second irrigation - by another 1.8-3.4 mm, and after the third irrigation, the thickness of the endometrium corresponded to 7.3-10.4 mm, which is quite favorable for the transfer and implantation of the blastocyst. Considering that the study involved women who had previously undergone repeated unsuccessful stimulation of endometrial growth with hormonal drugs - there is a clear tendency to increase the thickness of the endometrium under the influence of a gas mixture (CO ₂ + N ₂ ).

The composition of the gas mixture in the ratio of carbon dioxide - 5%, nitrogen - 95% is selected empirically, as a ratio previously approved by the author as optimal and safe for stimulating sperm motility and embryo implantation. These ratios of gases to the achieved result do not have an obvious value for stimulating the growth of the endometrium, since, as follows from the previously described analogs, carbon dioxide is widely used in medicine in its pure form and at high pressure for wound healing during surgical interventions, as well as for resorption of inflammation.

Thus, the ratio of carbon dioxide - 5%, nitrogen - 95% should be considered simply safe for a woman's health and optimal for enhancing the growth of the endometrium.

Sources of information

1. Assessment of endometrial receptivity. Fertil Steril 2011; 96: 522-9. The value of endometrial thickness and morphology before embryo transfer in the IVF program. 18th Annual Meeting in Vienna. Collection of abstracts. Hum Reprod 2002; 17: 157.

2. Leibovitz Z., Grinin V., Rabia R., Degani S, Shapiro I., Tal J., Aybschitz I., Harari O., Paltieli Y., Aharoni, Zeevi J., Ohel G. Evaluation of the endometrium for pregnancy in patients undergoing in vitro fertilization, using the thickness of the endometrium and the myometrium of the uterus, the coefficient of relative echogenicity. Obstet Gynecol 1999; 143: 194-9.

3. Elnashar, Alfaifay, O. Donia. Endometrial thickness and pregnancy in infertile couples undergoing AIH. Benha MJ 1995; 12: 1-9.

4. Ashkenzai J., Yoeli R., Orvieto R., Dekel et al. Significance of increased endometrial thickness in the treatment of reproduction technology. 18th Annual Meeting in Vienna. Collection of abstracts. Hum Reprod 2002; 17: 116.

5. Jinno M., T. Ozaki, Iwashita M., Y. Nakamura, Kuda, Hirano N. Endometrial blood flow measurement - a new way to assess the susceptibility of the uterus to implantation. Fertil Steril 2001; 76: 1168-74.

6. Yuval Y., Lipitz K., Dor. J. and Achiron R. (1999) Relationship between endometrial thickness and blood flow and pregnancy in in vitro fertilization. Hum. Reprod., 14.1067-1071.

Claims (4)

1. A method of treating a thin endometrium in preparation for an IVF program, characterized by stimulating the blood supply to the endometrium, which is carried out using a gas mixture of carbon dioxide and nitrogen - CO ₂ and N ₂ , injected under pressure, and when the gas mixture is injected, the woman's labia is fixed with an airtight gasket characterized in that a gas mixture of 5% carbon dioxide and 95% nitrogen is used, which is injected through a catheter with a rounded tip at the distal end, a suction cup is positioned on the outer surface of the catheter for movement along the catheter, while in the process of introducing the catheter through an airtight gasket in the latter, an opening is made for the free passage of the catheter, then the suction cup is fixed with an airtight gasket, where the airtight gasket is fixed around the labia before the catheter is inserted, or during the catheter insertion. 2. A method according to claim 1, characterized in that after filling the uterus with a gas mixture, the catheter is removed from the vagina, squeezing the woman's labia, and the opening in the airtight seal remaining from the catheter insertion is sealed. 3. A method according to claim 1, characterized in that the suction cup has a sticky layer on the inside. 4. The method according to claim 1, characterized in that the airtight gasket is made up of a polyethylene layer, along the edges of which an adhesive layer having a removable protective film is placed.

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