No 11 (2020)

Anticancer chemotherapy is one of the main treatments for cancers. Moreover, in addition to its high efficiency, the chemotherapy has a gonadotoxic effect that worsens quality of life in patients, most of whom are reproductive aged at the time of diagnosis. The review includes data from Russian and foreign articles published in the PubMed database over the past 5 years. To reduce the pathological effect of anticancer therapy on the ovaries, several categories of drugs (gonadotropin-releasing hormone agonists, continuous oral contraceptives) are used. The efficacy of these drugs in preserving the reproductive and endocrine functions of the ovaries has not yet been proven. That is the reason that the search for new agents to protect the ovaries is now underway. The degree of damage to the ovarian reserve during treatment and the efficiency of ovarian protection are known to depend on many factors. Nevertheless, prescribing criteria and tactics have not been developed even for already existing drugs. Conclusion. This scientific literature review shows that it is necessary to assess the clinical significance of the methods used to protect the ovaries and to elaborate new approaches.

Implantation, a process that reflects the blastocyst-endometrium interaction, is a key step to achieve desired pregnancy. Many studies of endometrial receptivity have been conducted in recent decades; however, a universal marker that is able to predict successful implantation has not yet been established. Analysis of the data available in the literature may lead to the conclusion that none of the existing ultrasound-based approaches, including the assessment of the endometrial thickness, pattern, and volume, and the features of endometrial vascularization, provides any opportunity to fully assess the receptive ability of the endometrium. Molecular studies of endometrial receptivity also cannot be recognized to be highly effective at the moment. In this connection, it can be noted that it is important to avoid searching for a single receptivity marker, preferring to develop the diagnostic panels that combine the most effective markers, the complex analysis of which will have a higher diagnostic value. The review includes data from the foreign and Russian articles published in the SCOPUS, Web of Science, MEDLINE, Cochrane Library, Embase, Global Health, CyberLeninka, and PubMed databases over the past 10 years Conclusion. Considering a set of indicators that take into account thickness, volume, echo structure, blood flow, morphological features, and molecular markers that characterize these parameters in the endometrium, it seems possible to approximate to the understanding of complex, multicomponent processes in the receptive endometrium.

Standard ovarian stimulation regimens use gonadotropin in combination with gonadotropin-releasing hormone (GnRH) analogues to prevent the premature luteinizing hormone (LH) surge that improves the outcomes of assisted reproductive technology (ART) programs, by optimizing the number of extracted oocytes and the synchronization of the endometrium to embryo transfer. However, GnRH analogues have many disadvantages: uneasiness to use (the drug must be accurately prepared and be subcutaneously injected), cost, and different side effects. This has aroused interest in searching for medical alternatives. Current cryopreservation technologies, cycle segmentation strategy for delayed embryo transfer allow one to consider new approaches to ovarian stimulation without the limitations associated with endometrial effects and risks associated with ovarian hyperstimulation syndrome. At present, an ovarian stimulation strategy has been proposed, when gestagen is prescribed instead of a GnRH analogue, while oocyte (embryo) vitrification eliminates possible adverse effects on endometrial susceptibility. The advantage of this approach is ease of use, oral administration, affordability, and no adverse reactions. Conclusion. The use of gestagens to suppress endogenous LH release may become the first choice for ovarian stimulation with planned oocyte or embryo cryopreservation, preimplantation genetic testing, in donor cycles, as well as in ovarian stimulation protocols for the luteal phase of the menstrual cycle or in double superovulation stimulation, which always require subsequent cryopreservation of biological material.

This review describes the importance of telomeres and telomerase for human reproduction. It considers the impact of concomitant diseases on telomere length in females and males. It also describes telomerase activity and telomere length at different stages of ontogenesis: from spermatogenesis and oogenesis to subsequent embryonic development. There is information from various studies conducted within the framework of ART programs showing the relationship between telomere length, telomerase activity, and fertility. Many studies have shown that the length of telomeres in human germ cells has a positive effect on the formation and further development of embryos. The relationship between the length of telomere regions and fertility has also been demonstrated. For example, males with shorter telomeres have lower-quality embryos than those with longer sperm telomeres. Males with higher sperm DNA fragmentation are also observed to have a shorter telomere length. In women, the short telomere length is associated with different diseases. The presence of elongated telomeres in the oocytes has shown that the probability of forming good-quality embryos increases. Conclusion. The role of telomere length and telomerase activity in the germ cells can make it possible to predict the effectiveness of ART programs and to introduce new analyses aimed at finding the causes of male and female infertility in future.

This investigation has attempted to generalize and systematize knowledge about the cytoplasmic embryo fragmentation phenomenon, to reveal the causes and mechanisms of its occurrence, and to describe its impact on embryo viability and clinical outcomes of IVF programs. Since human embryo fragmentation is most common during the embryological stage of IVF programs, the phenomenon itself has not been studied suff iciently. Rare attempts to investigate this phenomenon have narrowly focused on the association of the fragmentation with apoptosis. The reasons for this limited knowledge were ethical obstacles and practical difficulties associated with the use of human eggs and embryos for experiments. The lack of a suitable model among animal embryos and the relatively low occurrence and significance of fragmentation in experimental embryology (in mouse embryos) also contributed to the exclusion of the fragmentation phenomenon as a worthy object of investigation. The review included the data obtained over a fairly extensive period and an attempt was undertaken to comprehensively cover the topic of embryo fragmentation. Conclusion. Despite the fact that the effect of a low fragmentation fraction (<10%) on the effectiveness of ART programs is insignificant, a significant fragmentation fraction (> 25-30%) reduces embryo viability. The results of studies investigating the microsurgical removal of cytoplasmic fragments and its positive impact on the viability of embryos and the clinical outcomes of IVF programs are controversial and require further confirmation.

Aim. To investigate the demand and effectiveness of algorithms for the management of infertility using IVF and surgical methods in women with ovarian endometriotic cysts (OEC) on a case-by-case basis, taking into account the OEC manifestations and clinical presentations associated with age, ovarian reserve, and concomitant indications for IVF. Materials and methods. The study analyzed clinical spectrum OEC in 532 infertile women regarding the distribution of patients by age, ovarian reserve, and the presence of concomitant indications for IVF. The study compared the demand and effectiveness of three algorithms selected based on the OEC characteristics and clinical status affecting the reproductive potential. Results. The most popular algorithm (80.3%) for the management of infertility in women with OEC was IVF’s initial administration, which resulted in a cumulative pregnancy rate (PR) of 86.7%. Algorithms with the initial use of surgery to create conditions for spontaneous pregnancy or to prepare for urgent IVF were in demand in 11.4% and 8.3% of cases, respectively. They had 93.4% and 36.4% cumulative PR, respectively. Conclusion. The selection of the optimal algorithm for the management of infertility using IVF and surgical methods in women with OEC requires considering the age, ovarian reserve, and concomitant indications for IVF and the features of the detected OECs. The widespread use of cryopreservation technology allows the re-transfer of embryos without ovarian stimulation (thus reducing the program’s overall cost). It implies the possibility of continuing fertility treatment in cases of surgical menopause after OEC removal.

Aim. To develop a differentiated management strategy for cancer patients referred for retrieval and cryopreservation of reproductive material based on the structure of oncological diseases by referral, oncological and reproductive status, individual patient characteristics, and the planned/conducted treatment. Materials and methods. We analyzed cancer patients’ medical records, including a complete description of the disease, the stage of the process, and the examination results. The planned treatment, prognosis for the course, and curability of the disease were outlined. Patients referred during stable remission had detailed medical case notes describing the treatment, the results of the examination, and the oncologist's conclusion about the feasibility of therapy to achieve pregnancy. Clinical evaluation at admission included assessing the patient's reproductive system, ovarian reserve, general and gynecological health. Based on the totality of analyzed data, individual treatment algorithms were developed. Results. Between February and December 2019, 259 patients were consulted at the V.I. Kulakov NMRC for OG&P to determine the feasibility and methods of retrieval and preservation of reproductive material and assess the prospects for achieving pregnancy during stable remission. Fifty-six patients completed cancer treatment, and 203 were planned to have gonadotoxic therapy and/or radical treatment. Eighty-five controlled ovarian stimulation programs were conducted, including 68 before the onset of gonadotoxic therapy and 17 after cancer treatment completion. Sixty-one patients underwent retrieval and cryopreservation of ovarian tissue with the collection of immature oocytes, followed by in vitro maturation of oocytes and conservation, or fertilization, and embryo cryopreservation. Treatment was not administered to 113 referred patients due to a sharp decrease in the ovarian reserve and the inability to obtain their oocyte or for other reasons. Conclusion. There is no doubt in need for joint counseling of cancer patients wishing to preserve fertility or in cases when oncologists allow a woman to become pregnant after treatment. The retrieval of reproductive material before the onset of cancer treatment undoubtedly increases patients' chances for subsequent childbirth, including, if necessary, using a surrogate mother. The choice of programs aimed at retrieval and cryopreservation of reproductive material was made on a case-by-case basis taking into account the location, type, and stage of the malignancy and the state of the patient's ovarian reserve.

Objective. To evaluate the effectiveness of additional embryological techniques in frozen-thawed embryo transfer programs. Materials and methods. The study included 288 couples treated for infertility using assisted reproductive technologies (ART) with frozen-thawed embryo transfer. The couples were stratified into two groups depending on the onset of pregnancy: group 1 consisted of couples who achieved pregnancy (pregnancy +, n=92), group 2 included the couples who did not achieve pregnancy (pregnancy -, n=196). The influence of the embryological stage on the effectiveness of ART programs was evaluated. Results. The use of pronase hatching increases the ART effectiveness in patients under 33 years by 3.3 times and the use of pronase hatching reduces the pregnancy rate in patients aged 34 years and older, while laser hatching increases the pregnancy rate by 4.8 times. The use of a culture medium enriched with hyaluronic acid (Embryoglue) increases the pregnancy rate in patients aged 38 years and older and in patients with previous history of three or more ineffective embryo transfer cycles. Prolonged embryo cultivation after thawing and before embryo transfer to the uterine cavity does not influence the effectiveness of frozen-thawed embryo transfer. Conclusion. None of the additional embryological techniques has shown its effectiveness in its regular use. Further research should be aimed at identifying groups of patients who need to be recommended certain modern embryological techniques, as well as their combinations.

Aim. To analyze the association between the levels of heavy metals (cadmium, mercury, lead) in the blood of patients with infertility and the outcomes of assisted reproductive technology (ART) programs. Materials and methods. Infertility treatment by ART was carried out in 301 couples. The levels of mercury, cadmium, and lead were determined in the blood of patients by ICP-MS. The medians of heavy metal levels were evaluated in patients with different outcomes of ART (clinical pregnancy rate, live birth rate, cumulative live birth rate), as well as the ratio between the quartile groups of metals and different outcomes of ART. Results. The levels of cadmium were statistically significantly higher in smoking patients compared to nonsmokers. The median levels of cadmium, mercury and lead did not differ in patients with different outcomes of ART cycles. In different subgroups stratified by quartiles based on cadmium levels, a comparable frequency of clinical outcomes of ART were observed (the rates of clinical pregnancy, live births, cumulative live births). In patients with the highest cadmium level quartile (Q4), no blastocysts for embryo transfer could be obtained significantly more often - OR 2.95 (95% CI 1.22-7.02). When comparing mercury quartile groups, no statistically significant differences were noted. A decrease (but not statistically significant) in the rates of clinical pregnancy and live birth was noted along with an increase in the lead level quartile (Q1-Q4). Conclusion. An increase in cadmium level is associated with a 3-fold increase in the risk of lack of blastocysts for embryo transfer, and an increase in lead level (Q1-Q4) led to a 10% decrease in the rates of the clinical pregnancy and live birth.

Objective. To evaluate the effectiveness of administering the myo-inositol and folic acid complex on the quality of embryos and the pregnancy rate during preconception preparation for in vitro fertilization (IVF) in patients with infertility. Materials and methods. The study included 92 infertile patients planning to undergo IVF, among them 46 women (group I) received the complex of myo-inositol (MI) at a dose of4000 mg and folic acid (FA) at a dose of400 mcg (Fertina, Orion Pharma, Finland) per day for 12 weeks, and 46 women (group II) received only 400 mcg of folic acid per day. The research was performed in accordance with the Order of the Russian Ministry of Health No. 107n dated 30.08.2012. The criteria for evaluating the effectiveness of the complex were the facts of biochemical pregnancy based on the analysis of hCG and clinical pregnancy according to the ultrasound data. Results. The women who took the MI/FA complex before the IVF protocol, in comparison with the women taking only FA, showed the following results: a shorter duration of ovarian stimulation, 9 (9-10) vs. 11 (10-11) days, p=0.04; a lower total dose of gonadotropins, 1470 (1425-1445) vs. 1990 (1775-2150) IU/ml, p=0.01; a larger number of oocytes at MIIstage, 9 (4-17) vs. 6 (3-15) oocytes, p=0.03, respectively. The number of biochemical pregnancies was 19 (68%) vs. 10 (42%), p=0.05, and clinical pregnancies were noted in 15 (53%) vs. 8 (33%) cases, p=0.14, respectively. Conclusion. Administration of the complex MI and FA for three months before IVF has a positive effect on the process of oocyte maturation and pregnancy rate.

Aim. To identify the structure of defects in sperm quality in men in infertile couples and to develop the algorythm for management of such patients. Materials and methods. Clinical laboratory testing of4088 infertile couples (I) without established female factor; the control group - 365fertile men (F), whose spouses became pregnant in the natural cycle for the last 12 weeks. Research type - analytical one-stage multicenter study. Results. The defects in sperm quality in group I were observed more often than in group F: cases of azoospermia - 4,2% and 0% (р<0,001), cryptozoospermia - in 1,6% and 0% (p<0,01), oligozoospermia - 17,4% and 2,2% (р<0,001), asthenozoospermia - 45,5% and 22,1% (р<0,001), teratozoospermia - 27,5% and 11,3% (р<0,001), oligospermia - 5,3% and 1,7% (p<0,05), antisperm antibodies(MAR-IgG>50%) - 12,3% and 4,8% (р<0,001), pyospermia - 17,1% and 8,1% (р<0,001), normal zoospermia - 47,0% and 70,0% (р<0,001) respectively. The medians and ranges of all the parameters of spermogram in group I were significantly worse than in group F (p <0.001), except for the volume and percentage of abnormal forms (p>0,05). In group I, the men with normal zoospermia had defects in sperm function: increased DNA fragmentation (51%), oxidative stress (50%), abnormal acrosomal reaction (46%) andprotamination (30%). Conclusion. In 2/3 of cases, a decrease in male fertility is a consequence of functional disorders of spermatozoa. According to WHO-2010, in fertile men normozoospermia was observed in 70% of cases; this indicates that the ranges reference values vary among the regions. An algorithm for management of patients with various sperm disorders in level 3 healthcare facilities was proposed.

Objective. To study of the biocenosis of the vagina and gastrointestinal tract, weight and growth parameters in the North indigenous small-numbered peoples (NISMP), who have migrated and live in the city of Khanty-Mansiysk, Khanty-Mansi Autonomous Okrug-Yugra. Subjects and methods. Complaints and anamnestic and anthropometric data were prospectively analyzed; as well as the vaginal and intestinal biocenosis was evaluated in 125patients selected using the continuous sampling method. Examinations were made in the women of the indigenous minorities of the Khanty and Mansi, who lived in the urban community Berezovo, in nomad camps, and in Khanty-Mansiysk. The comparison group included female newcomers (Russians, Ukrainians, Tatars, Bashkirs, and others) living in Khanty-Mansiysk. Microbiological examination of vaginal discharge included microscopy of Gram stained smears and real-time PCR (Femoflor). The intestinal microbiota was investigated by real-time PCR (Colonoflor). Statistical processing was performed using the SPSS, Statistica 8.0 software package, as well as the Microsoft Exsel analysis package. Results. The smallest number of deviations in health status was seen in the women of the NISMP, who lived in the rural areas and nomad camps and led a traditional nomadic lifestyle. The deficit of body weight was observed in 10.3% of the women; obese patients were absent in this group. Analysis of the microbiota of vaginal discharge showed that normocenosis was in the majority (87.2%) of the women. No substantial changes were found in the gut microbiota. The urban residents, both newcomers and NISMP, had the greatest number of abnormalities in the biocenosis of the vagina and large bowel. They had frequently combined disorders: bacterial vaginosis and vulvovaginal candidiasis. Conclusion. This makes it possible to recommend Clindacin B prolong (Akrikhin Co., Russia), a combination of clindamycin phosphate, a broad spectrum antibiotic, and butoconazole, an antimycotic from a group of azoles, for treatment. The drug is effective for clinical recovery in a set of inflammatory and non-inflammatory changes in the vagina with vulvovaginal candidiasis.

Objective. To evaluate the effectiveness of programs using donor gametes and embryos for the treatment of infertility by assisted reproductive technologies (ART). Materials and methods. The investigation used data on the effectiveness of ART cycles using donor sperm (DS), both fresh and cryopreserved donor oocytes (DOs, or donor embryos (DEs), including those after preimplantation genetic testing for aneuploidy (PGT-A). Results. Analysis of the effectiveness of 165 cycles with DS revealed a relationship of the effectiveness of programs using DS to a woman’s age. The analysis of that of299 cycles with DOs showed no significant differences in the programs using fresh and cryopreserved DOs. The results of 32 cycles with DEs suggest their high efficiency. Conclusion. The findings suggest that the use of donor gametes and embryos in the ART programs is highly effective in overcoming infertility. These programs used in accordance with clinical indications allow pregnancy to be achieved in patients who have significant restrictions on the use of their own gametes.

Objective. To present the results of using of various clotrimazole dosage forms (2%, cream and 100 mg vaginal tablets) and its dosage regimens (for 3 and 6 days) in patients with vulvovaginal candidiasis. Subjects and methods. Examinations were made in 60 patients with vulvovaginal candidiasis, who were divided into 3 groups so that each group contained an equal number of people: 1) clotrimazole 2% cream as therapy for 3 days; 2) clotrimazole 2% cream for 6 days; 3) clotrimazole, 100 mg vaginal tablets for 6 days. The diagnosis was confirmed by the presence of Candida blastospores and pseudomycelium on microscopic examination and by the isolation of Candida albicans colonies on Sabouraud agar. The efficiency of therapy was evaluated after its completion, at 14 and 30 days. Results. After completion of therapy, the clinical signs of vulvovaginal candidiasis were absent in 95% of the patients in Group 1, in 100% in Group 2, and in 80% in Group 3; those of Candida pseudomycelium and blastospores were also absent in 18 (90%), 20 (100%), and 15 (75%) patients, respectively. After treatment, elevated leukocyte counts in vaginal discharge persisted only in 2 (10%) patients in Group 3; there was a growth of yeast-like fungi in the patients of Groups 1 (10%) and 3 (20%). The therapy resulted in a significant decrease in the frequency of isolation of opportunistic microorganisms in clinically significant amounts and in the normalization of the vaginal microflora in 90% of the examinees. Conclusion. The optimal profile of antimycotic and antimicrobial efficacy of clotrimazole 2% cream for intravaginal or topical use, which is superior to that when this agent is used as vaginal tablets, makes it possible to recommend it as one of the drugs of choice in the treatment of vulvovaginal candidiasis.

Resistant ovarian syndrome (ROS) is a rare endocrine disease characterized by hypergonadotropic hypogonadism, primary or secondary amenorrhea, generally a normal number of ovarian antral follicles, resistance to endogenous and exogenous gonadotropins, a normal set of chromosomes, and correctly developed secondary sexual characteristics. Patients with this syndrome are included in the third group of the WHO classification of chronic anovulation. Infertility in these patients may be overcome with both donor programs and their own oocytes in assisted reproductive technology programs using in vitro maturation (IVM). This review presents the global experience with IVM technology leading to the birth of healthy babies in women with ROS.

Background. Diminished ovarian reserve is one of the causes of female infertility and a poor response in ovulation induction. Despite advances in clinical embryological approaches and molecular genetic technologies, there are difficulties achieving pregnancy and the birth of a baby with the genetic material from a woman herself with diminished ovarian reserve. Case report. The paper describes a clinical case of the birth of a healthy baby in a patient with diminished ovarian reserve, infertility, and developing premature ovarian failure, who was prescribed dehydroepiandrosterone (DHEA) therapy. Conclusion. The presented clinical case cannot fully demonstrate DHEA treatment success in women with a sharply diminished ovarian reserve. Such situations occur sporadically without DHEA. In the author’s opinion, long-term (9-month) use of DHEA and careful monitoring of the ovaries and hormones are necessary to control treatment efficiency.