{"paper_id":"2257ad1b-baef-4739-8ef1-b9e0968eec88","body_text":"ISSN 2077-4214. Вісник проблем біології і медицини – 2024 – Вип. 1 (172) / Bulletin of problems in biology and medicine – 2024 – Issue 1 (172)\n69\nОГЛЯДИ ЛІТЕРАТУРИ / LITERATURE REVIEWS\nimprove the process of diagnosis and treatment of the specified category of patients, which will contribute to the \nimprovement of the reproductive health of the future generation.\nKey words: reproductive health, reproductive potential, adolescent girls, abnormal uterine bleeding.\nORCID and contributionship: / ORCID автора та його внесок до статті:\nPliekhova O. O.: https://orcid.org/0000-0003-3183-8183 ABCDEF\n________________________________________________________________\nCorresponding author / Адреса для кореспонденції\nPliekhova Olesia Oleksandrivna / Плєхова Олеся Олександрівна\nKharkiv National Medical University / Харківський національний медичний університет\nUkraine, 61000, Kharkiv, 4 Nauky avenue / Адреса: Україна, 61000, м. Харків, проспект Науки 4 \nTel.: +380682609073 / Тел.: +380682609073\nE-mail: plehovaolesja@gmail.com\n________________________________________________________________A  – Work concept and design, B – Data collection and analysis, \nC – Responsibility for statistical analysis, D – Writing the article, E – Critical review, F – Final approval of the article / A  – концепція роботи та \nдизайн, В  – збір та аналіз даних, С  – відповідальність за статичний аналіз, D  – написання статті, Е  – критичний огляд, F  – остаточне за-\nтвердження статті.\nReceived 20.08.2023 / Стаття надійшла 20.08.2023 року\nAccepted 01.02.2024 / Стаття прийнята до друку 01.02.2024 року\nDOI 10.29254/2077-4214-2024-1-172-69-75\nUDC 618.17-008.8-06:616.018.2-007.1]-08-055.26\nRakytianskyi I. Yu.\nCURRENT STATE OF THE PROBLEM OF MENSTRUAL CYCLE DISORDERS IN WOMEN \nOF REPRODUCTIVE AGE WITH UNDIFFERENTIATED CONNECTIVE TISSUE DYSPLASIA \n(LITERATURE REVIEW)\nKharkiv National Medical University (Kharkiv, Ukraine)\nigorrakytianskyi@gmail.com\nConnection of the publication with planned re-\nsearch works. \nThe study was carried out within the scientific \ndirection of the department of obstetrics, gynecology, \npediatric gynecology and medical genetics of KhNMU \n“Optimization of clinical-diagnostic and therapeutic \napproaches to the management of gynecological \npatients taking into account age and the presence \nof extragenital disorders”, state registration number \n0122U000257.\nIntroduction. \nMenstrual cycle (MC) is a natural event and a unique \nexperience of women of reproductive age [1]. MC \noccurs during the reproductive period of a woman’s \nlife, characterized by cyclicity and rhythm. Menstrual \ncycle disorders (MCD) is one of the most common \nBased on the analysis of information from available sources of scientific literature, the article provides an over -\nview of the problem of menstrual cycle disorders (MCD) in women of reproductive age and the impact of connec-\ntive tissue diseases. MCD is the most common gynecological problem of reproductive health, and connective tissue \ndiseases occur in up to 90% of cases in women of all ages. The pathogenic mechanism of these abnormalities can be \npresented as a connection between sex hormones and immunity. Undifferentiated connective tissue dysplasia (UCTD) \nhas been shown to exert a negative effect on the course of pregnancy and the likely development of fetal disorders, \nto which the vast majority of research is devoted. The relationship between the pathological course of pregnancy of \nmothers whose daughters had menstrual disorders and phenotypic signs of connective tissue diseases is shown. In \nyoung women with connective tissue diseases, the most common menstrual dysfunction (MD) is dysmenorrhea and \nabnormal uterine bleeding (AUB), caused by immune dysregulation, autoimmune changes, and inflammation. The \nmodern approach to the treatment of such patients involves the elaboration of individual treatment tactics taking \ninto account concomitant diseases, current test results, pathogenic features of development and the course of MCD. \nTreatment involves the use of hormonal (synthetic and natural estrogens, gonadotropin hormones, progesterone, \ngonadotropin-releasing hormone analogues) and non-hormonal (nonsteroidal anti-inflammatory drugs, tranexamic \nacid) drugs, as well as non-drug methods (correction of lifestyle, physical activity, rational nutrition ). UCTD remains \nan understudied problem due to its clinical heterogeneity, lack of uniform terminology, generally accepted criteria for \ndiagnosis and assessment of severity. There is a lack of standardization of diagnostic methods and diagnostic criteria \nfor UCTD compared to the criteria used for various forms of connective tissue diseases. Management of patients \nwith connective tissue diseases and disorders of menstrual function is a complex problem, involving assessment of \ngynecological conditions (menstruation, fertility, sexuality) and an interdisciplinary approach (rheumatology, gyne-\ncology, etc.).\nKey words: menstrual cycle irregularities, women of reproductive age, undifferentiated connective tissue dyspla-\nsia, abnormal uterine bleeding, dysmenorrhea.\n\nISSN 2077-4214. Вісник проблем біології і медицини – 2024 – Вип. 1 (172) / Bulletin of problems in biology and medicine – 2024 – Issue 1 (172)\n70\nОГЛЯДИ ЛІТЕРАТУРИ / LITERATURE REVIEWS\ngynecological problems of reproductive health, which is \na combination of one or more pathological symptoms \nof MC, which strongly affects a woman’s daily life and \nleads to infertility and other pathological conditions \n[2]. MCDs affect 75% of young women in developed \nand developing countries and constitute the majority \nof diseases of women of childbearing age [3]. These \nconditions, especially menorrhagia, are a serious \nreason for consulting a doctor [4]. MCDs not only \nimpair the reproductive capacity of young women, but \nare associated with various pathological conditions, in \nparticular with anemia, thyroid gland dysfunction, etc. \n[5, 6].\nResearchers found general consequences of \nmenstrual disorders, manifested by limitations in \neducation or work due to a decrease in attention and \nconcentration, the need to reduce normal physical \nactivity [7]. So, the negative impact of menstrual \ndysfunctions on the quality of life of young women is \nobvious. At the same time, disorders of the menstrual \nfunction are manifested at the initial stage by such \ndiseases of the reproductive system as uterine fibroids, \nendometriosis, adenomyosis [8].\nOften MCDs are associated with other diseases, for \nexample, connective tissue. Connective tissue dysplasia \n(CTD) causes a violation of the formation of connective \ntissue in many organs and systems. This abnormality \noccurs in up to 90% of cases in women of various ages \n[9]. Undifferentiated connective tissue dysplasia (UCTD) \nis diagnosed when the set of phenotypic features does \nnot correspond to any of the differentiated diseases [9]. \nAmong the disorders associated with this syndrome, \nin recent years, disorders of the reproductive system \noccupy a certain place, which constitutes an actual \nmedical problem. There are well-known studies of the \nsexual function of women suffering from connective \ntissue diseases, which show the relationship between \nsexual and mental health and the underlying disease \n[10, 11]. All of the above cannot fail to affect the \nimplementation of the reproductive plans of women \nwith disorders of menstrual function and CTD. Violations \nof the reproductive system against the background of \nUCTD can be explained both by chronic inflammation, \nhormonal imbalance and the influence of medication, \nand by psychological problems [12]. The researchers’ \nattention was mostly drawn to the issue of the \nrelationship between the underlying disease and sexual \nproblems, their impact on women’s mental health, as \nwell as vaginal symptoms, such as dryness of the vaginal \nmucous membranes [12, 13]. However, limited data \nare available on violations related to MC in the case of \nUCTD [12], which prompted us to pay attention to this \nproblem.\nThe aim of the study.\nConsidering the available sources of literature, \nto analyze the state of the problem of menstrual \ncycle disorders in women of reproductive age with \nundifferentiated connective tissue dysplasia.\nObject and research methods. \nThis review was conducted using PubMed, Medline, \nand the Cochrane Library databases. Key terms such \nas “problems of menstrual disorders”, “women \nof reproductive”, “abnormal uterine bleeding”, \n“dysmenorrhea”, “undifferentiated connective tissue \ndysplasia” were used to search for relevant studies \npublished within 10 years. We have analyzed the \nabstracts of articles related to disorders of the menstrual \ncycle of women of reproductive age and the impact of \nconnective tissue diseases on the functioning of the \nreproductive system of young women. Reference lists \nof publications on the topic and recent reviews on this \nissue were also studied.\nResearch results and their discussion. \nThe pathogenic mechanism of menstrual disorders \nin patients with UCTD can be presented as a connection \nbetween sex hormones and immunity. Autoimmune \nconnective tissue diseases have been shown to more \noften affect women, so the issue of hormonal influence \non the risk of developing connective tissue diseases \nattracts the attention of researchers [13, 14]. Women are \nknown to have enhanced immunoreactivity against men \ndue to a higher level of immunoglobulins and increased \nproduction of antibodies to antigenic stimulation. In \nwomen, the immune response is dominated by type \n2 T-helpers, in contrast to men, who have a type 1 \nT-helper response [15]. At the same time, sex hormones \nestrogen, androgen and prolactin increase the \nsusceptibility to autoimmune diseases by modulating \nthe immune response through androgen and estrogen \nreceptors [16]. The interaction of sex hormones is \ncomplex, affecting susceptibility to disease. Thus, \ncholesterol is a precursor to hormones such as estrogen, \nprogesterone, and testosterone, and their common \nintermediate metabolites dehydroepiandrosterone and \nestradiol also interact with the immune system [17]. \nThe study of the level of sex hormones is difficult due \nto the fact that it is not determined whether the disease \nitself or its treatment affects the level of hormones, and \ninformation about the level of hormones before the \ndisease is not always known [18].\nThe level of sex hormones that circulate in women \nand men represent the relative transformation \nof androgens and estrogens [19]. Estrogen and \nprogesterone levels decline with age, with the rate \nof decline increasing during premenopause and \nmenopause, while progesterone levels decline faster \nthan estrogen levels. Estrogen and prolactin are known \nto be pro-inflammatory hormones, which may explain \nthe high prevalence of autoimmune disorders in women.\nThe prevalence of this disorder in women of \nreproductive age, which negatively affects obstetric and \nperinatal outcomes, also attracts attention.\nAn analysis of the specialized scientific literature \non the problem of menstrual cycle disorders in women \nwith UCTD revealed a large number of studies on the \npeculiarities of the course of pregnancy in women with \nconnective tissue diseases. It has been established that \nUCTD has a negative effect on the course of pregnancy. \nD. Zucchi et al. [20] in a retrospective study found that \n11% of pregnancies ended in miscarriage in the first \ntrimester, and 29% in complications during pregnancy: \npreeclampsia was noted in 10%, intrahepatic cholestasis \nof pregnancy in 3%, premature rupture of membranes \nin 2%, gestational diabetes, TELA in 1%, in 10% of cases \nbabies were born with low gestational weight. According \nto A. Spinillo et al. [21], the number of pregnancy \ncomplications in women with UCTD was 39 % against \n13.4 % of healthy pregnant women.\nSince women are not always aware of the \nabnormality of uterine bleeding and do not seek \n\nISSN 2077-4214. Вісник проблем біології і медицини – 2024 – Вип. 1 (172) / Bulletin of problems in biology and medicine – 2024 – Issue 1 (172)\n71\nОГЛЯДИ ЛІТЕРАТУРИ / LITERATURE REVIEWS\nmedical help, a thorough history is of great importance \nin identifying its cause. The relationship between the \npathological course of pregnancy of mothers whose \ndaughters had menstrual disorders and phenotypic \nsigns of connective tissue diseases is shown. In this \ncase, the most threatening factors are termination of \npregnancy, premature birth, preeclampsia and asphyxia \nof the newborn [22].\nF. Beneventi et al. [23] conducted a prospective co-\nhort study and found during dopplerography more fre-\nquent presence of blood flow disorders in uterine arter-\nies in pregnant women with UCTD in the first, second \nand third trimesters compared to the control group. The \nfindings show that inadequate trophoblast invasion is \ncommon in pregnant women with UCTD. In addition, the \ndetected disorder was associated with poor pregnancy \noutcomes. According to A. Spinillo et al. [24], antibodies \nare directly related to defective placentation and are the \ncause of adverse pregnancy outcomes. Also, antinuclear \nantibodies affect the quality of oocytes and the patho -\nlogical development of the embryo due to the activation \nof the complement cascade [25]. The presence of an-\ntinuclear antibodies causes disruption of uterine blood \nflow in non-pregnant women who have experienced \nrepeated pregnancy loss, which has been experimen-\ntally confirmed [26, 27]. Placentation defect in pregnant \nwomen with UCTD has been shown to be triggered by \nendothelial dysfunction and cytokine imbalance [28]. \nThe researchers came to the conclusion that antinuclear \nantibodies and inflammation negatively affect the func-\ntion of platelets, the balance of coagulation and antico-\nagulation mechanisms, causing a prothrombotic state, \nendothelial dysfunction, resulting in violation of remod-\neling of spiral arteries and development of the placenta, \nincrease in the risk of preeclampsia, fetal development \ndelays in pregnant women with UCTD, and a risk of pre-\nmature birth [29].\nUCTD is one of the causes of isthmic-cervical \ninsufficiency due to a decrease in collagen and an \nincrease in the mass of muscle tissue. Such an imbalance \nis characteristic of connective tissue diseases [30].\nThat is why, in recent years, experts in the medical \nfield have been talking about the importance of \npregnancy planning and pre-pregnancy preparation \nof women with connective tissue diseases, since \ncomplications of pregnancy and newborn impairments \nare mostly found in patients who are not sufficiently \nprepared for this [31].\nWhile studying the problem of reproductive \nfunction in women with CTD, we have drawn attention \nto the small number of studies and limited information \non disorders associated with MC and connective tissue \ndiseases. The most common gynecological symptom \nassociated with menstruation is dysmenorrhea — pain \ndue to pathological contraction of the uterus [32].\nAccording to López-Liria R, Bakhsh H et al., \ndysmenorrhea affects about half of women of \nchildbearing age and adolescent girls [33, 34]. \nDysmenorrhea is characterized by painful spasms \nbefore or during menstruation due to cyclic shedding \nof the inner lining of the uterus. Approximately 34 % \nof women rated the pain as 7–10 points on the VAS \nscale (visual analog scale) [35], which negatively affects \nthe intellectual abilities and psychosocial existence \nof a significant number of adolescent girls and young \nwomen [36, 37].\nA number of studies suggest that dysmenorrhea is \na clinical manifestation of dysmorphic connective tissue \ndisorders [38]. And according to M. Orlandi et al. [39], \n72% of women of reproductive age with connective \ntissue diseases suffer from moderate or severe \nmenstrual pain. A study conducted by N. Shigesi et al. \n[40], found a connection between connective tissue \ndisorders and endometriosis. Endometriosis is often \nthe cause of secondary dysmenorrhea due to ectopic \nlocalization of endometrial cells [41]. Quite often, a \nwoman considers such menstrual pain “normal”, so \npatients with connective tissue diseases are a high-risk \ngroup for the development of endometriosis, especially \nif dysmenorrhea is established [39]. O. Yakubova et al. \n[42] concluded that there is a relationship between \nhypomagnesemia and connective tissue diseases in \ngirls with primary dysmenorrhea. Since collagen fibers \nare the main component of connective tissue, their \ndestruction occurs due to magnesium deficiency.\nAbnormally heavy or prolonged menstrual bleeding \nwas found in 38% of women of reproductive age and \n52% of adolescent girls with connective tissue diseases \n[39].\nMenstrual disorders in women with connective tissue \ndiseases are pathogenically related to sex hormones and \nimmunity: estrogens and progesterone are involved in \nthe modulation of immune system signals, which affects \nthe maturation of lymphocytes, activation and synthesis \nof antibodies and pro-inflammatory cytokines. At the \nsame time, immune dysregulation and inflammation \nplay a significant role in the development of some \ngynecological disorders (endometriosis, adenomyosis), \nwhich affects the development of menstrual disorders \nin women with connective tissue diseases [43, 44].\nIn patients with autoimmune diseases, the expression \nof sex hormones changes, which is one of the factors of \nimmune dysregulation. The causes of menstrual cycle \ndisorders can be autoimmunity and inflammation, \neven independent of connective tissue diseases. At the \nsame time, menstrual disorders can cause a hormonal \nimbalance, which affects the contractility of the uterus, \nthe condition of the endometrium [45]. Considering \nthis, women with CTD represent a population associated \nwith the risk of menstrual cycle disorders.\nTreatment of women with MC disorders and \nconnective tissue diseases is a difficult task for \nspecialists. Scientific literature has a large amount \nof information on the specifics of MCD treatment \nin patients with extragenital impairments. The main \nprinciple of treatment of gynecological disorders in \nthese cases is the treatment of the underlying disease \n[46, 47]. At the same time, little attention has been paid \nto the problem of treatment of women with menstrual \ncycle disorders and UCTD, so we can talk about the \nlack of specific treatment recommendations. The \nmodern approach to solving this problem consists in \nthe development of individual treatment tactics taking \ninto account concomitant diseases, current test results, \npathogenic features of MCD development and course \n[48]. The principles of therapy consist in the use of \nmedicinal and non-medicinal methods.\nThe basis of medication is the use of hormonal and \nnon-hormonal drugs. Among the latter, non-steroidal \n\nISSN 2077-4214. Вісник проблем біології і медицини – 2024 – Вип. 1 (172) / Bulletin of problems in biology and medicine – 2024 – Issue 1 (172)\n72\nОГЛЯДИ ЛІТЕРАТУРИ / LITERATURE REVIEWS\nanti-inflammatory drugs (NSAIDs) are prescribed, \nwhich act on the endometrium and reduce the level \nof prostaglandins due to inhibition of the enzyme \ncyclooxygenase [49]. NSAIDs are used only during \nmenstruation to reduce pain in case of dysmenorrhea. \nAt the same time, it was found that in 75% of women, \nthese drugs reduce blood loss by 25–35% [50]. NSAIDs \nare quite well tolerated, but there are contraindications \nfor them in case of blood coagulation disorders, gastric \nulcer disease, kidney diseases [51].\nThe antifibrinolytic agent tranexamic acid reduces \nmenstrual blood loss by 26–50 %, but has a minimal \neffect on dysmenorrhea [52, 53]. This medicine is \nused independently and with NSAIDs. But unlike \nNSAIDs, tranexamic acid does not increase the risk of \nthromboembolic events [54].\nThe main method of treatment of abnormal \nuterine bleeding (AUB) is hormonal therapy, the choice \nof which depends on the nature of their disorders. \nEstrogens of synthetic and natural origin, gonadotropin \nhormones, progesterone, analogues of gonadotropin-\nreleasing hormone are widely used [55]. Estrogen, \nprogesterone, and combined oral contraceptives are \nused for MC irregularity, amenorrhea, oligomenorrhea, \nand anovulatory bleeding [56, 57]. Ovulatory bleeding \nis managed by intrauterine systems releasing hormones \nwith levonorgestrel [58] and antifibrinolytic drugs [59].\nManagement of patients with UCTD involves \nadherence to a diet rich in protein, trace elements, \nunsaturated fatty acids, vitamins and minerals, and \ncollagen-forming elements. The selection of the diet \nshould be individualized, taking into account the level \nof deficiency of these substances confirmed by the \ntests. Thus, vitamin D3 is additionally recommended for \nnormalizing phosphorus-calcium metabolism in patients \nwith UCTD, as it has powerful immunomodulatory \nproperties. Some researchers even believe that the \ndeficiency of this vitamin in patients with UCTD may \ncontribute to the progression of the specified disorder \nto well-defined connective tissue diseases [60]. Given \nthe availability of vitamin D3, it should be noted that \nthere is a lack of evidence-based recommendations for \nthe treatment of UCTD.\nPhysical activity is an important part of the \ntreatment of connective tissue diseases, because with \nthe simultaneous normalization of body weight, which \ncontributes to the regularity and quality of menstrual \nfunction, muscle tone improves, which compensates for \nthe insufficient development of connective tissue [61, \n62].\nConclusions.\nSummarizing the information presented in the review, \nit can be noted that young women with UCTD show a \nhigh prevalence of various gynecological symptoms and \ndiseases. MCDs significantly affect a woman’s quality of \nlife and health, so this issue needs attention. With a view \nto clinical practice, a more complete understanding of \nthe underlying phenomena associated with menstrual \ndysfunction will help to achieve the goals of personalized \ntreatment. UCTD remains an understudied problem due \nto its clinical heterogeneity, lack of uniform terminology, \ngenerally accepted criteria for diagnosis and assessment \nof severity. Summing up, attention should be paid \nto the lack of standardization of diagnostic methods \nand diagnostic criteria for UCTD. Solving this problem \nwill create an opportunity to determine the degree \nof clinical manifestations of dysplasia, select a set of \ntreatment measures, assess the prognosis of the course \nof the disease and the possibility of complications that \nnegatively affect the reproductive function of young \nwomen. Therefore, the management of patients with \nUCTD is a complex problem of modern medicine, \nwhich consists in the assessment of gynecological \nconditions (menstruation, fertility, sexuality) and an \ninterdisciplinary approach (rheumatology, gynecology, \netc.).\nProspects for further research. \nSince menstrual cycle disorders in women of \nreproductive age remain an urgent problem of \nmodern medicine, and connective tissue diseases are \na widespread abnormality, it is advisable to continue \nstudying the links of the pathogenesis of these im-\npairments in order to develop acceptable treatment \nmethods that will contribute to strengthening the \nreproductive health of young women.\nReferences\n1. Brantelid IE, Nilvér H, Alehagen S. Menstruation during a lifespan: A qualitative study of women’s experiences. Health Care Women Int. \n2014;35(6):600–16. DOI: 10.1080/07399332.2013.868465.\n2. Odongo E, Byamugisha J, Ajeani J, Mukisa J. Prevalence and effects of menstrual disorders on quality of life of female undergraduate \nstudents in Makerere University College of health sciences, a cross sectional survey. BMC Womens Health. 2023;23(1):152. DOI: 10.1186/\ns12905-023-02290-7. \n3. Anikwe CC, Mamah JE, Okorochukwu BC, Nnadozie UU, Obarezi CH, Ekwedigwe KC. Age at menarche, menstrual characteristics, and \nits associated morbidities among secondary school students in Abakaliki, southeast Nigeria. Heliyon. 2020;6(5):e04018. DOI: 10.1016/j.\nheliyon.2020. e04018.\n4. Lebduska E, Beshear D, Spataro BM. Abnormal Uterine Bleeding. Med Clin North Am. 2023;107(2):235–246. DOI: 10.1016/j.\nmcna.2022.10.014.\n5. Zeru AB, Gebeyaw ED, Ayele ET. Magnitude and associated factors of menstrual irregularity among undergraduate students of Debre \nBerhan University, Ethiopia. Reprod Health. 2021;18(1):101. DOI: 10.1186/s12978–021–01156–1. \n6. Rajiwade SR, Sagili H, Soundravally R, Subitha L. Endocrine Abnormalities in Adolescents with Menstrual Disorders. J Obstet Gynaecol \nIndia. 2018;68(1):58–64. DOI: 10.1007/s13224–017–1035-y.\n7. Nyirenda T, Nyagumbo E, Murewanhema G, Mukonowenzou N, Kagodora SB, Mapfumo C, et al. Prevalence of dysmenorrhea and \nassociated risk factors among university students in Zimbabwe. Womens Health (Lond). 2023;19:17455057231189549. DOI: \n10.1177/17455057231189549.\n8. Maybin JA, Critchley HO. Menstrual physiology: implications for endometrial pathology and beyond. Hum Reprod Update. 2015;21(6):748–\n761. DOI: 10.1093/humupd/dmv038.\n9. Marwa K, Anjum F. Undifferentiated Connective Tissue Disease [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 [updated 2023 \nApr 27]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK572061/.\n10. Wiśniewski M, Zabłocka-Żytka L. Sexual and mental health of woman suffering from selected connective tissue diseases: an original \npaper. Clin Rheumatol. 2021;40(8):3319–3327. DOI: 10.1007/s10067–021–05611-z. \n11. Alia F, Rim BS, Miladi S, Ouenniche K, Kassab S, Chekili S, et al. Comparison of sexual function in Tunisian women with rheumatoid \narthritis and healthy controls. Clin Rheumatol. 2019;38(12):3361–3365. DOI: 10.1007/s10067–019–04726–8.\n\nISSN 2077-4214. Вісник проблем біології і медицини – 2024 – Вип. 1 (172) / Bulletin of problems in biology and medicine – 2024 – Issue 1 (172)\n73\nОГЛЯДИ ЛІТЕРАТУРИ / LITERATURE REVIEWS\n12. Østensen M. Sexual and reproductive health in rheumatic disease. Nat Rev Rheumatol. 2017;13(8):485–493. DOI: 10.1038/\nnrrheum.2017.102. \n13. Desai MK, Brinton RD. Autoimmune Disease in Women: Endocrine Transition and Risk Across the Lifespan. Front Endocrinol (Lausanne). \n2019;10:265. DOI: 10.3389/fendo.2019.00265. \n14. Kronzer VL, Bridges SL Jr, Davis JM 3rd. Why women have more autoimmune diseases than men: An evolutionary perspective. Evol Appl. \n2020;14(3):629–633. DOI: 10.1111/eva.13167.\n15. Cutolo M, Straub RH. Sex steroids and autoimmune rheumatic diseases: state of the art. Nat Rev Rheumatol. 2020;16:628–44. DOI: \n10.1038/s41584–020–0503–4.\n16. Fuentes N, Silveyra P. Estrogen receptor signaling mechanisms. Adv Protein Chem Struct Biol. 2019;116:135–170. DOI: 10.1016/\nbs.apcsb.2019.01.001.\n17. Buendía-González FO, Legorreta-Herrera M. The Similarities and Differences between the Effects of Testosterone and DHEA on the \nInnate and Adaptive Immune Response. Biomolecules. 2022;12(12):1768. DOI: 10.3390/biom12121768.\n18. Tang J, Chen LR, Chen KH. The Utilization of Dehydroepiandrosterone as a Sexual Hormone Precursor in Premenopausal and \nPostmenopausal Women: An Overview. Pharmaceuticals (Basel). 2021;15(1):46. DOI: 10.3390/ph 15010046.\n19. Xing E, Billi AC, Gudjonsson JE. Sex Bias and Autoimmune Diseases. J Invest Dermatol. 2022;142(3.B):857–866. DOI: 10.1016/j.\njid.2021.06.008.\n20. Zucchi D, Tani C, Monacci F, Elefante E, Carli L, Parma A, et al. Pregnancy and undifferentiated connective tissue disease: outcome and \nrisk of flare in 100 pregnancies. Rheumatology (Oxford). 2020;59(6):1335–1339. DOI: 10.1093/rheumatology/kez440.\n21. Spinillo A, Beneventi F, Epis OM, Montanari L, Mammoliti D, Ramoni V, et al. Prevalence of undiagnosed autoimmune rheumatic diseases \nin the first trimester of pregnancy. Results of a two-steps strategy using a self-administered questionnaire and autoantibody testing. BJOG. \n2008;115(1):51–57. DOI: 10.1111/j.1471–0528.2007.01530.x.\n22. Shavazi NN, Nurmukhamedova DU. Menstrual function disorders in adolescent girls with dysplasia of connective tissues. Galaxy int. \ninterdiscip. res. j. 2022;10(4):206–211. Available from: https://internationaljournals.co. in/index.php/giirj/article/view/1649.\n23. Beneventi F, Locatelli E, Ramoni V, Caporali R, Montecucco CM, Simonetta M, et al. Uterine artery Doppler velocimetry and obstetric \noutcomes in connective tissue diseases diagnosed during the first trimester of pregnancy. Prenat Diagn. 2012;32(11):1094–101. DOI: \n10.1002/pd.3964.\n24. Spinillo A, Beneventi F, Locatelli E, Ramoni V, Caporali R, Alpini C, et al. Early, Incomplete, or Preclinical Autoimmune Systemic Rheumatic \nDiseases and Pregnancy Outcome. Arthritis Rheumatol. 2016;68(10):2555–62. DOI: 10.1002/art.39737.\n25. Veglia M, D’Ippolito S, Marana R, Di Nicuolo F, Castellani R, Bruno V, et al. Human IgG Antinuclear Antibodies Induce Pregnancy Loss \nin Mice by Increasing Immune Complex Deposition in Placental Tissue: In Vivo Study. Am J Reprod Immunol. 2015;74(6):542–52. DOI: \n10.1111/aji.12429.\n26. Pietropolli A, Bruno V, Capogna MV, Bernardini S, Piccione E, Ticconi C. Uterine blood flow indices, antinuclear autoantibodies and \nunexplained recurrent miscarriage. Obstet Gynecol Sci. 2015;58(6):453–460. DOI: 10.5468/ogs.2015.58.6.453.\n27. Ferreira AM, Pires CR, Moron AF, Araujo Júnior E, Traina E, Mattar R. Doppler assessment of uterine blood flow in recurrent pregnancy \nloss. Int J Gynaecol Obstet. 2007;98(2):115–119. DOI: 10.1016/j.ijgo.2007.05.006.\n28. Nakken B, Bodolay E, Szodoray P. Cytokine Milieu in Undifferentiated Connective Tissue Disease: a Comprehensive Review. Clin Rev \nAllergy Immunol. 2015;49(2):152–162. DOI: 10.1007/s12016–014–8452–9.\n29. Yang S, Ni R, Lu Y, Wang S, Xie F, Zhang C, et al. A three-arm, multicenter, open-label randomized controlled trial of hydroxychloroquine \nand low-dose prednisone to treat recurrent pregnancy loss in women with undifferentiated connective tissue diseases: protocol for the \nImmunosuppressant regimens for LIving FEtuses (ILIFE) trial. Trials. 2020;21(1):771. DOI: 10.1186/s13063–020–04716–1.\n30. Marder W, Littlejohn EA, Somers EC. Pregnancy and autoimmune connective tissue diseases. Best Pract Res Clin Rheumatol. \n2016;30(1):63-80. DOI: 10.1016/j.berh.2016.05.002.\n31. Klimaszyk K, Wender-Ożegowska E, Kędzia M. Maternal and foetal outcome of pregnancy in women with connective tissue diseases. \nJournal of Medical Science. 2021;90(3):e525. DOI: 10.20883/medical.e525.\n32. Critchley HOD, Babayev E, Bulun SE, Clark S, Garcia-Grau I, Gregersen PK, et al. Menstruation: science and society. Am J Obstet \nGynecol. 2020;223(5):624–664. DOI: 10.1016/j.ajog.2020.06.004.\n33. López-Liria R, Torres-Álamo L, Vega-Ramírez FA, García-Luengo AV, Aguilar-Parra JM, Trigueros-Ramos R, et al. Efficacy of Physiotherapy \nTreatment in Primary Dysmenorrhea: A Systematic Review and Meta-Analysis. Int J Environ Res Public Health. 2021;18(15):7832. DOI: \n10.3390/ijerph18157832. \n34. Bakhsh H, Algenaimi E, Aldhuwayhi R, AboWadaan M. Prevalence of dysmenorrhea among reproductive age group in Saudi Women. \nBMC Womens Health. 2022;22(1):78. DOI: 10.1186/s12905–022–01654–9.\n35. Kural M, Noor NN, Pandit D, Joshi T, Patil A. Menstrual characteristics and prevalence of dysmenorrhea in college going girls. J Family \nMed Prim Care. 2015;4(3):426–431. DOI: 10.4103/2249–4863.161345.\n36. Ali A, Ali A, Eldalo AS, Alotaibi NS, Alsufyan MS i, Alotaibi AJ, et al. Prevalence, impact, and management perception of dysmenorrhea \namong university students: A cross-sectional study. Braz. J. Pharm. Sci. 2022;58:e20458. DOI: 10.1590/s2175–97902022e20458. \n37. Serrahima C, Martínez M. The Experience of Dysmenorrhea. Synthese. 2023;201(173):1–22. DOI: 10.1007/s11229–023–04148–9.\n38. Yakubova O, Ayupova F, Kamalov Z, Negmatshaeva K, Mamarasulova D. Role of Col1a1 and G2046t genes in Uzbeks with juvenile \ndysmenorrhea in the presence of criteria for undifferentiated connective tissue dysplasia. Journal of Critical Reviews. 2020;7(2):391–394. \nAvailable from: https://annalsofrscb.ro/index.php/journal/article/view/832.\n39. Orlandi M, Vannuccini S, El Aoufy K, Melis MR, Lepri G, Sambataro G, et al. Menstruation-Related Disorders-Dysmenorrhea and \nHeavy Bleeding-as Significant Epiphenomena in Women With Rheumatic Diseases. Front Pharmacol. 2022;13:807880. DOI: 10.3389/\nfphar.2022.807880.\n40. Shigesi N, Kvaskoff M, Kirtley S, Feng Q, Fang H, Knight JC, et al. The association between endometriosis and autoimmune diseases: a \nsystematic review and meta-analysis. Hum Reprod Update. 2019;25(4):486–503. DOI: 10.1093/humupd/dmz014.\n41. Chapron C, Marcellin L, Borghese B, Santulli P. Rethinking mechanisms, diagnosis and management of endometriosis. Nat Rev Endocrinol. \n2019;15(11):666–682. DOI: 10.1038/s41574–019–0245-z.\n42. Yakubova O, Isakova D, Rizakova D, Farmankulova Y, Usmanova M, Umarova M. The Relationship of Changes in the State of Connective \nTissue and Hypomagnesemia in Juvenile Dysmenorrhea. Nat. Volatiles & Essent. Oils, 2021;8(5):6805–6810. Available from: https://www.\nnveo.org/index. php/journal/article/view/1893.\n43. Bourdon M, Santulli P, Jeljeli M, Vannuccini S, Marcellin L, Doridot L, et al. Immunological changes associated with adenomyosis: a \nsystematic review. Hum Reprod Update. 2021;27(1):108–129. DOI: 10.1093/humupd/dmaa038.\n44. Králíčková M, Fiala L, Losan P, Tomes P, Vetvicka V. Altered Immunity in Endometriosis: What Came First? Immunol Invest. 2018;47(6):569–\n582. DOI: 10.1080/08820139.2018.1467926.\n45. Critchley HOD, Babayev E, Bulun SE, Clark S, Garcia-Grau I, Gregersen PK, et al. Menstruation: science and society. Am J Obstet \nGynecol. 2020;223(5):624–664. DOI: 10.1016/j.ajog.2020.06.004.\n46. Lavadi RS, Venkatachalaiah R, Prasad M. Double Trouble: A Case Report of Abnormal Uterine Bleeding due to Both Central and Peripheral \nPathology. Int J Appl Basic Med Res. 2022;12(2):134–136. DOI: 10.4103/ijabmr. ijabmr_500_21. \n47. Ueno A, Yoshida T, Yamamoto Y, Hayashi K. Successful control of menstrual cycle-related exacerbation of inflammatory arthritis with \nGnRH agonist with add-back therapy in a patient with rheumatoid arthritis. J Obstet Gynaecol Res. 2022;48(7):2005–2009. DOI: 10.1111/\njog.15287.\n48. Rosenblum E, Wilkinson LD, Brady PH, Gin GT. Female Pelvic Conditions: Abnormal Uterine Bleeding. FP Essent. 2022;515:20–25.\n\nISSN 2077-4214. Вісник проблем біології і медицини – 2024 – Вип. 1 (172) / Bulletin of problems in biology and medicine – 2024 – Issue 1 (172)\n74\nОГЛЯДИ ЛІТЕРАТУРИ / LITERATURE REVIEWS\n49. Bofill Rodriguez M, Lethaby A, Farquhar C. Non-steroidal anti-inflammatory drugs for heavy menstrual bleeding. Cochrane Database Syst \nRev. 2019;9(9):CD000400. DOI: 10.1002/14651858.CD000400.pub4.\n50. Roy SN, Bhattacharya S. Benefits and risks of pharmacological agents used for the treatment of menorrhagia. Drug Saf. 2004;27(2):75–\n90. DOI: 10.2165/00002018–200427020–00001.\n51. Kontogiannis A, Matsas A, Valsami S, Livanou ME, Panoskaltsis T, Christopoulos P. Primary Hemostasis Disorders as a Cause of Heavy \nMenstrual Bleeding in Women of Reproductive Age. J Clin Med. 2023;12(17):5702. DOI: 10.3390/jcm12175702.\n52. Leminen H, Hurskainen R. Tranexamic acid for the treatment of heavy menstrual bleeding: efficacy and safety. Int J Womens Health. \n2012;4:413–21. DOI: 10.2147/IJWH.S13840.\n53. Marjoribanks J, Lethaby A, Farquhar C. Surgery versus medical therapy for heavy menstrual bleeding. Cochrane Database Syst Rev. \n2016;2016(1):CD003855. DOI: 10.1002/14651858.CD003855.pub3.\n54. Shalaby MA, Maged AM, Al-Asmar A, El Mahy M, Al-Mohamady M, Rund NMA. Safety and efficacy of preoperative tranexamic acid in \nreducing intraoperative and postoperative blood loss in high-risk women undergoing cesarean delivery: a randomized controlled trial. BMC \nPregnancy Childbirth. 2022;22(1):201. DOI: 10.1186/s12884–022–04530–4.\n55. American College of Obstetricians and Gynecologists’ Committee on Clinical Consensus–Gynecology. General Approaches to Medical \nManagement of Menstrual Suppression: ACOG Clinical Consensus No. 3. Obstet Gynecol. 2022;140(3):528–541. DOI: 10.1097/\nAOG.0000000000004899.\n56. Shoupe D. The Progestin Revolution: progestins are arising as the dominant players in the tight interlink between contraceptives and \nbleeding control. Contracept Reprod Med. 2021;6(1):3. DOI: 10.1186/s40834–020–00142–5. \n57. Shoupe D. The progestin revolution 2: progestins are now a dominant player in the tight interlink between contraceptive protection and \nbleeding control-plus more. Contracept Reprod Med. 2023;8(1):48. DOI: 10.1186/s40834–023–00249–5.\n58. Buhur A, Ünal Ö. Treatment of abnormal uterine bleeding using levonorgestrel-releasing intrauterine devices: experience from a Turkish \ntertiary hospital. Eur Rev Med Pharmacol Sci. 2023;27(3):1045–1050. DOI: 10.26355/eurrev_202302_31200.\n59. Bryant-Smith AC, Lethaby A, Farquhar C, Hickey M. Antifibrinolytics for heavy menstrual bleeding. Cochrane Database Syst Rev. \n2018;4(4):CD000249. DOI: 10.1002/14651858.CD000249.pub2.\n60. Zou J, Thornton C, Chambers ES, Rosser EC, Ciurtin C. Exploring the Evidence for an Immunomodulatory Role of Vitamin D in Juvenile \nand Adult Rheumatic Disease. Front Immunol. 2021;11:616483. DOI: 10.3389/fimmu. 2020.616483.\n61. Benito PJ, Alfaro-Magallanes VM, Rael B, Castro EA, Romero-Parra N, Rojo-Tirado MA, et al. Effect of Menstrual Cycle Phase on \nthe Recovery Process of High-Intensity Interval Exercise-A Cross-Sectional Observational Study. Int J Environ Res Public Health. \n2023;20(4):3266. DOI: 10.3390/ijerph20043266.\n62. Purslow PP. The Structure and Role of Intramuscular Connective Tissue in Muscle Function. Front Physiol. 2020;11:495. DOI: 10.3389/\nfphys.2020. 004952023.\nСУЧАСНИЙ СТАН ПРОБЛЕМИ ПОРУШЕНЬ МЕНСТРУАЛЬНОГО ЦИКЛУ У ЖІНОК РЕПРОДУКТИВНОГО ВІКУ З \nНЕДИФЕРЕНЦІЙОВАНОЮ СПОЛУЧНОТКАНИННОЮ ДИСПЛАЗІЄЮ (ОГЛЯД ЛІТЕРАТУРИ)\nРакитянський І. Ю.\nРезюме. На основі аналізу доступних джерел наукової літератури представлено огляд проблеми пору-\nшень менструального циклу у жінок репродуктивного віку та впливу на них захворювань сполучної тканини. \nПорушення менструального циклу вражають 75 % молодих жінок у розвинених країнах і країнах, що розви-\nваються, та становлять більшість захворювань жінок дітородного віку. Патогенез цих станів можна описати як \nстатево-гормонально-імунну асоціацію. Добре відомо, що недиференційована дисплазія сполучної тканини \n(НДСТ) має негативний вплив на перебіг вагітності та можливий розвиток уражень плода. Ця проблема є в \nцентрі уваги більшості досліджень. Виявлено зв’язок між патологічним перебігом вагітності та фенотипічни -\nми ознаками захворювань сполучної тканини в матерів, чиї доньки мають порушення менструальної функції. \nУ молодих жінок із захворюваннями сполучної тканини дисменорея та аномальні маткові кровотечі є най -\nпоширенішими порушеннями менструального циклу, які зумовлені імунною дисрегуляцією, аутоімунними \nпроцесами та запаленням. Сучасний підхід до лікування таких пацієнток полягає в розробці індивідуального \nплану лікування, зважаючи на супутні захворювання, поточні лабораторні показники, патологічні особливос-\nті дебюту захворювання та перебігу порушень менструального циклу. Лікування складається з призначення \nгормональних (синтетичних і природних естрогенів, гонадотропін-рилізинг-гормонів, аналогів прогестерону \nта гонадотропін-рилізинг-гормону) та негормональних засобів (нестероїдних протизапальних препаратів, \nтранексамової кислоти), а також немедикаментозного лікування (модифікація способу життя, фізична актив-\nність, раціональне харчування). На сьогодні відсутня єдина термінологія та загальноприйняті критерії діагнос-\nтики та оцінки тяжкості НДСТ. Діагностичні методи та критерії НДСТ не стандартизовано порівняно з іншими \nзахворюваннями сполучної тканини. Ведення пацієнтів із захворюваннями сполучної тканини та менстру-\nальною дисфункцією є комплексним питанням, відповідь на яке базується на оцінці гінекологічних проблем \n(менструація, фертильність, сексуальність) та мультидисциплінарному підході із залученням фахівців інших \nспеціальностей.\nКлючові слова: порушення менструального циклу, жінки репродуктивного віку, недиференційована дис-\nплазія сполучної тканини, аномальні маткові кровотечі, дисменорея.\nCURRENT STATE OF THE PROBLEM OF MENSTRUAL CYCLE DISORDERS IN WOMEN OF REPRODUCTIVE AGE \nWITH UNDIFFERENTIATED CONNECTIVE TISSUE DYSPLASIA (LITERATURE REVIEW)\nRakytianskyi I. Yu.\nAbstract. Based on the analysis of available sources of scientific literature, an overview of the problem of \nmenstrual cycle disorders in women of reproductive age and the impact of connective tissue diseases on them is \npresented. Menstrual disorders affect 75% of young women in developed and developing countries and constitute \nthe majority of diseases in women of childbearing age. The pathogenesis of these conditions can be described as a \nsex-hormonal-immune association. Undifferentiated connective tissue dysplasia (UCTD) is known to exert a negative \nimpact on the course of pregnancy and the possible development of fetal impairment. This problem is the focus of \nmost research. The relationship between the pathological course of pregnancy and phenotypic signs of connective \ntissue diseases in mothers whose daughters have menstrual disorders was revealed. In young women with connective \n\nISSN 2077-4214. Вісник проблем біології і медицини – 2024 – Вип. 1 (172) / Bulletin of problems in biology and medicine – 2024 – Issue 1 (172)\n75\nОГЛЯДИ ЛІТЕРАТУРИ / LITERATURE REVIEWS\ntissue diseases, dysmenorrhea and abnormal uterine bleeding are the most common menstrual disorders, caused by \nimmune dysregulation, autoimmune processes, and inflammation. The modern approach to the treatment of such \npatients consists in the development of an individual treatment plan, taking into account concomitant diseases, \ncurrent laboratory findings, pathological features of the onset of the disease and the course of menstrual cycle \ndisorders. Treatment consists of prescribing hormonal (synthetic and natural estrogens, gonadotropin-releasing \nhormones, progesterone and gonadotropin-releasing hormone analogues) and non-hormonal agents (nonsteroidal \nanti-inflammatory drugs, tranexamic acid), as well as non-drug treatment (lifestyle modification, physical activity, \nrational nutrition). To date, there is no unified terminology and generally accepted criteria for diagnosing and \nassessing the severity of UCTD. Diagnostic methods and criteria for UCTD are not standardized compared to other \nconnective tissue diseases. Management of patients with connective tissue diseases and menstrual dysfunction is a \ncomplex issue, the answer to which is based on the assessment of gynecological problems (menstruation, fertility, \nsexuality) and a multidisciplinary approach involving specialists from other branches.\nKey words: menstrual cycle irregularities, women of reproductive age, undifferentiated connective tissue \ndysplasia, abnormal uterine bleeding, dysmenorrhea.\nORCID and contributionship:\nRakytianskyi I. Yu.: https://orcid.org/0009-0009-5986-6988 \nABCDEF\n________________________________________________________________\nCorresponding author \nRakytianskyi Igor Yuriyovych\nKharkiv National Medical University\nUkraine, 61000, Kharkiv, 4 Nauky Avenue \nTel.: +380678033564\nE-mail: igorrakytianskyi@gmail.com\n________________________________________________________________\nA  – Work concept and design, B  – Data collection and analysis, C  – Responsibility for statistical analysis, D  – Writing the article, E – Critical \nreview, F  – Final approval of the article. \nReceived 02.09.2023 \nAccepted 14.02.2024 \nDOI 10.29254/2077-4214-2024-1-172-75-81\nUDC 616.61:591.3:546.48:612.6\nShatorna V. F.\nINFLUENCE OF HEAVY METALS ON MORPHO-FUNCTIONAL STATE OF BONE TISSUE\nDnipro State Medical University (Dnipro, Ukraine)\nverashatornaya67@gmail.com\nConnection of the publication with planned re-\nsearch works.\nThe work was carried out in accordance with the sci-\nentific theme of DSMU “Morphological and functional \nfeatures of organs and tissues under the influence of \nexternal and internal factors”, state registration number \n0120U105219.\nIntroduction. \nIncreasing rates of environmental pollution in indus-\ntrialised countries require studying the impact of envi-\nronmental factors on human health. One of the most \nwidespread and dangerous environmental pollutants \nis heavy metals, which, when ingested by the human \nbody, lead to acute and delayed complications, change \nthe balance of trace element systems, cause diseases or \nThe article presents an analysis of scientific literature on the impact of heavy metal compounds on bone and \ncartilage tissue. The most common environmental toxicants in the group of heavy metals are mercury, cadmium and \nlead salts, which, when ingested, accumulate in the body, provoke a hypoxic state and compete with biogenic metals \nfor binding to the active site of many proteins and enzymes, causing a violation of their functions. Modern scientific \nresearch has shown that chronic cadmium intoxication creates an imbalance in the process of bone remodelling, in-\nducing the development of osteopenia and osteoporosis. The ability of the toxicant to accumulate in the extracellular \nbone matrix has been experimentally determined, leading to its bioaccumulation and an increase in the half-life of \nthe metal from the body. The accumulation of cadmium in bone tissue leads to a decrease in calcium and zinc levels, \nwhich disrupts the basic processes of ossification and negatively affects cartilage and joint tissue. Understanding the \nmechanisms of osteo- and chondrotoxicity of cadmium will help to find adequate therapy methods for cadmium-\ninduced osteoporosis and prevent the negative impact of the toxicant on bone and cartilage tissue. Studies of the \naccumulation level of trace elements in bones and their changes under the influence of negative factors are also \nrelevant. It is perspective not only to determine the accumulation level of heavy metal salts but also to search for \npossible bioantagonists of heavy metal salt accumulation.\nKey words: bone tissue, femur, lower jaw, microelements, dyselementoses, cartilage tissue, rats, heavy metals, \ncadmium, zinc, iron, influence, accumulation.","source_license":"CC0","license_restricted":false}