Introduction
Widespread polycystic ovarian syndrome (PCOS) is a polysyndromic disease often associated with infertility. PCOS is the most common endocrine pathology in women of reproductive age both in Russia and abroad. It is characterized by a complex cascade of biochemical processes, hormone imbalance, androgen excess, the development of hirsutism, acne, polycystic ovarian syndrome, irregular menstrual cycle, ovulation disorders and, consequently, infertility. PCOS is diagnosed in up to 50% of women with menstrual and ovulatory dysfunction, and in 5—10% of patients with infertility, and in more than 40% of women PCOS is the cause of anovulatory infertility.
The aim of this work is to analyze the data presented in the current literature on the relationship between insulin resistance (IR) and PCOS.
Material and methods
The review includes data from domestic and foreign studies published in the Medline, PubMed, and eLibrary electronic databases over the past 10 years.
Results
According to the Rotterdam Consensus (2003), PCOS is an ovarian dysfunction syndrome whose specific manifestations include anovulation, hyperandrogenism, and polycystic ovarian morphology confirmed by ultrasound examination. Women with PCOS have a high risk of hypertension, cardiovascular disease, impaired glucose tolerance, type 2 diabetes mellitus and dyslipidemia, abdominal and visceral obesity, delivery complications and psychological stress [1—4]. To date, the pathogenesis of PCOS has not been adequately studied and is considered to be multifactorial, although it is well known that genetic predisposition and the patient's lifestyle are among the main causes of this pathology [5, 6]. In the pathophysiological processes of PCOS development, as well as a number of other diseases manifested by metabolic disorders, the main role is attributed to the development of body tissue IR [2, 4, 7]. Damage of the receptor apparatus provokes an increase in hormone release into the bloodstream, causing hyperinsulinemia. As a consequence of increased serum levels of insulin, the normal functioning of the hypothalamic-pituitary-ovarian system is disturbed: hypothalamic gonadotropin-releasing hormone pulsation rate increases, which in turn increases the production of luteinizing hormone and follicle stimulating hormone (FSH). Insulin affects steroidogenesis, causes an inhibitory response to SHBG (sex hormone-binding globulin) protein and provokes IGFBP-1 (insulin-like growth factor binding protein-1) production [8, 9]. The latter additionally promotes the synthesis of androgens by the ovaries. The described changes in the biochemical profile "draw" the clinical picture of patients with PCOS [10, 11]. Thus, IR, which contributes to hyperinsulinemia, is considered an important factor that affects the imbalance of the hormonal profile of the body and is a "key" in the therapeutic issues of solving the problems of endocrine infertility, reducing the risk of metabolic disorders, gestational diabetes, type 2 diabetes and a number of cardiovascular diseases [2, 4, 10, 12]. PCOS is not only the cause of endocrine infertility in women, but also poses a threat to the health of women in general [8, 13]. Treatment of women with PCOS is based on a comprehensive approach that includes lifestyle changes, dietary intake, normalization of body weight and drug treatment [11, 14]. Pre-vitro preparation helps to identify the risk factors of reproductive losses and ensure their elimination at the beginning of infertility treatment [7]. Insulin receptor signaling defect is closely related to the deficiency of phosphoglycan mediators (inositol-containing substances), which act as secondary messengers in the regulation of hormones, including insulin [8]. Taking this into account, the only theoretically justified approach to the correction of such shifts remains the use of insulin sensitizers. The use of the latter in clinical practice contributes not only to the normalization of insulin levels, but also to the restoration of the balance of genital hormone production and reduction of metabolic syndrome manifestations [3, 5, 10]. Medical recommendations suggest using the positive effect of metformin to increase tissue sensitivity to insulin [15]. However, from the standpoint of evidence-based medicine, a number of doubts have been expressed about the effectiveness of this drug, especially if we are not talking about the therapeutic effect, which results in a reduction of BP and lipid profile modulation, but about cases in which the use of the drug is undesirable, or there are contraindications with the threat of adverse reactions [13, 16, 17].
Articles by foreign researchers published in 2019 and 2021 repeatedly raised the issue of IR as an underestimated factor of PCOS [9, 14]. However, the European Society of Human Reproduction and Embryology (ESHRE) guidelines shifted attention from reproductive problems associated with PCOS to metabolic consequences, hence, the importance of IR is still underestimated. In fact, ESHRE specialists recommend assessing the glycemic status of patients with PCOS by performing an oral glucose tolerance test, which is appropriate for diagnosing impaired glucose tolerance or type 2 diabetes, but not for DI (insulin levels are not measured simultaneously with glucose levels). This recommendation is controversial because most women with PCOS, including underweight patients, do not have type 2 diabetes mellitus, but they are identified as having DI. Consequently, normal results of oral glucose tolerance tests may create a false sense of security in the patient and physician, preventing the initiation of targeted lifestyle changes [15].
According to randomized controlled trials evaluating a biochemical panel of patients, the positive effect of metformin, when it can be used, is not inferior to that caused by inositol [16, 17]. Assessment was performed by fasting glycemia, serum insulin, leptin and adiponectin levels, glucose-insulin ratio, HOMA index, and lipid profile [11, 13]. In recent years, an increasing number of studies have focused on the effect of inositol in pre-pregnancy preparation in women with PCOS. Inositol (vitamin B8) is a cyclic six-atom cyclohexane alcohol (C6H12O6) that has 9 stereoisomers [14]. It was first discovered in 1848 by the German scientist J. Liebich. Myo-inositol and D-chiro-inositol are the two major stereoisomers of inositol, which are formed after epimerization of inositol hydroxyl groups and have insulin-sensitizer properties [8, 11]. Myo-inositol is the most common species both in nature and in human cells; it is its deficiency that affects the pathogenetic processes of PCOS development [13]. In the organism, the latter reserves are renewed along with food intake, however, when exogenous sources of inositol are absent or there is a deficiency of them, the sensitivity of specific receptors to insulin is impaired [5]. Myo-inositol is one of the most widely used forms of inositol. It is a substrate for many inositol derivatives formed by epimerase reactions, phosphorylation and methylation of hydroxyl groups [6]. It is in the disruption of a sufficient level of coenzyme-converter synthesis that the essence of changes in the concentration of one or the other active inositol and their derivatives lies. In humans, myo-inositol is synthesized from glucose-6-phosphate into myo-inositol-1-phosphate by the enzyme inositol-3-phosphate synthase, which is further dephosphorylated to form free myo-inositol under the action of the enzyme inositol monophosphate. NAD/NADH epimerase, an insulin-dependent coenzyme, converts myo-inositol to D-chiro-inositol depending on the specific tissue needs for these molecules. Different tissues of the body exhibit different needs in the quantitative ratio of myo-inositol to D-chiro-inositol (in the ovaries, this ratio is 100:1) [5, 8]. As a consequence of ID-induced insufficiency of insulin-dependent coenzyme converters, the ratio of myo-inositol to D-chiro-inositol concentration decreases in patients with PCOS [2, 10]. D-chiro-inositol regulates pyruvate dehydrogenase synthesis, maintaining the level of ATP production in the Krebs cycle. Thus, in the body, myo-inositol activates the work of glucose transporters and glucose utilization, and D-chiro-inositol activates glycogen synthesis. The latter locally, at the ovarian level, regulates insulin-induced androgen synthesis, while myo-inositol affects FSH synthesis. Both stereoisomers are used in complex treatment in women with polycystic ovaries as insulin-sensitizing agents [5].
Uniquely, ovarian tissue, unlike other body tissues, is never insulin-resistant. From this point on, it is possible to misrepresent that patients with PCOS and hyperinsulinemia have elevated levels of epimerase activity and consequently elevated D-chiro-inositol concentrations and myo-inositol deficiency. The well-known "D-chiro-inositol paradox" supports the right to exist hypothesis that only myo-inositol is qualitatively important for ovarian function. This theory was later confirmed by a number of foreign scientific studies. It has been stated that oocyte quality and ovarian response are significantly lower in isolated exogenous administration of D-chiro-inositol alone due to the toxic effect of its high concentrations on body tissues [5, 6, 14]. Inositol with blood enters all cells of the body in a sufficiently high concentration and accumulates in the cell membrane. An important role of inositol in influencing the quality of eggs and pregnancy results has been proved [1, 3, 13]. As a structural basis, myo-inositol plays an important role for the synthesis of many secondary messengers, including phosphatidylinositol-3-kinase as a key messenger of insulin sensitivity.
Myo-inositol derivative — phosphoinositol-3-phosphate promotes glucose transport inside the cell by inducing glucose transporter GLUT-4 translocation to the cell membrane. Another myo-inositol derivative, inositol phosphoglycan, attracts special attention by regulating the release of free fatty acids into the permanent depression mode [13]. As a result of myo-inositol deficiency followed by a deficiency of its derivatives, fatty acid oxidation increases, which decreases glucose utilization due to the development of body tissue IR and increased triglyceride synthesis [8, 11]. Absorption of free inositol by cells is carried out by sodium-dependent co-transport. The pronounced effect of inositol on the reproductive function of women and the development of the embryo has been proved [12]. Inositol plays an important role in the maturation and fertilization of eggs through the regulation of calcium signaling pathways.
It has been shown that the levels of myo-inositol in blood and follicular fluid are in direct correlation with the quality of oocytes and the frequency of pregnancy. The use of myo-inositol in pre-pregnancy preparation contributes to the influence on oocyte meiosis, which leads to the formation of better quality oocytes and embryos [12].
In F. Caprio et al. (2015) showed that inositol administration to women during pre-vitro preparation for the initiation of superovulation in in vitro fertilization cycles improves the quality of oocytes and embryos, and also reduces the required dose of FSH and the number of days required for the superstimulation process [2].
According to the results of many randomized studies of the effectiveness of myo-inositol use, a reliable improvement of ovarian function in women with PCOS was proved, with decreased testosterone levels and increased progesterone levels, and there were no side effects [3, 8]. According to the 2015 International Consensus on the use of myo-inositol in assisted reproductive technology programs, there is evidence that myo-inositol is an important component of the follicular microenvironment.
Hyperinsulinemia is indirectly associated with PCOS, so the goal of treating patients with PCOS is to restore ovulatory menstrual cycles. Thus, the use of inositol-containing preparations as pregravidarial preparation before assisted reproductive technology (ART) programs improves the expected results in the issue of infertility treatment.
Clinical guidelines approved in 2021 recommend that PCOS patients use lifestyle modifications, including exercise and a balanced diet, to achieve and maintain normal body weight, overall health, and quality of life throughout life.
Achieving goals, such as a 5—10% reduction in body weight over 6 months in overweight patients, leads to significant clinical improvements. Reducing body weight against the background of lifestyle modification in patients with PCOS contributes to the normalization of menstrual function and improvement of a number of metabolic parameters (mainly carbohydrate metabolism), but the response is individual.
If a patient is not planning a pregnancy, it is recommended that therapy with combined hormonal contraceptives: use combined oral contraceptives (according to the anatomical-therapeutic-chemical classification of drugs (ATC) — progestagens and estrogens, fixed combinations), patch, intravaginal ring. For the treatment of patients with PCOS, menstrual irregularities and clinical manifestations of hyperandrogenism (hirsutism and acne), these agents are used as first-line therapy.
According to international clinical guidelines, the nonsteroidal aromatase inhibitor letrozole is the first-line treatment for anovulatory infertility, but in Russia this drug can be prescribed only with the signing of an informed voluntary consent.
Clomiphene is recommended for use in patients with PCOS as first-line therapy for anovulatory infertility.
Women with PCOS who are not interested in pregnancy are allowed any method of contraception, taking into account the WHO criteria for acceptable contraception.
The main indications for laparoscopy in women with PCOS and infertility are clomiphene resistance, other indications for laparoscopic surgery (endometriosis, tubal-peritoneal infertility factor), inability to monitor when using gonadotropins.
The final stage of infertility treatment in PCOS is ART. Patients with this pathology have a high risk of ovarian hyperstimulation, so nowadays a long protocol with gonadotropin-releasing hormone antagonists and recombinant FSH is most commonly used; single embryo transfer is recommended.
The use of inositol balances the metabolic profile and normalizes hormone levels. In this regard, the studies concerning the effect of inositol on increasing the fertility capacity of patients with PCOS have attracted the most attention of specialists. It has been proven that the use of inositol-containing preparations as pregravidarial preparation before ART programs improves the results of infertility treatment.
Conclusion
Polycystic ovarian syndrome remains an urgent problem of modern obstetrics, gynecology and reproductive medicine. Insulin resistance, hyperandrogenism, and dyslipidemia, which are characteristic of polycystic ovarian syndrome, are likely to be critical factors for the processes of trophoblast invasion and placenta, and may also affect maternal and child health. Therefore, it is important to search for new approaches and optimize methods of prenatal preparation of women with this disease. On the basis of the analysis of modern foreign and domestic literature it is established that inositol:
1) plays an important role in the elimination of metabolic disorders and normalization of hormonal background in women with polycystic ovarian syndrome, its use helps to increase high density lipoprotein levels, lower testosterone levels and increase levels of estradiol and progesterone;
2) affects the reproductive function of women (helps normalize the regulation of the menstrual cycle, restore ovulation);
3) has a significant impact on the results of assisted reproductive technologies (it improves the quality of eggs and embryos, increasing the frequency of pregnancy).
Pregravidarial preparation before assisted reproductive technology programs, which includes inositol preparations, provides an opportunity to reduce the doses of recombinant follicle stimulating hormone and the duration of superovulatory stimulation. Prospects for further research lie in the development of a relatively new, effective and adjunctive treatment for polycystic ovarian syndrome, which is associated with endocrine infertility, in the pre-pregnancy preparation process and in assisted reproductive technology protocols.
The authors declare no conflicts of interest.