\r\n\t(i) Quantum dots of very high-quality optical applications, Quantum dot light-emitting diodes (QD-LED) and ‘QD-White LED’, Quantum dot photodetectors (QDPs), Quantum dot solar cells (Photovoltaics).
\r\n\r\n\t(ii) Quantum Computing (quantum bits or ‘qubits’), (vii) The Future of Quantum Dots (broad range of real-time applications, magnetic quantum dots & graphene quantum dots), Superconducting Loop, Quantum Entanglement, Quantum Fingerprints.
\r\n\r\n\t(iii) Biomedical and Environmental Applications (to study intracellular processes, tumor targeting, in vivo observation of cell trafficking, diagnostics and cellular imaging at high resolutions), Bioconjugation, Cell Imaging, Photoelectrochemical Immunosensor, Membranes and Bacterial Cells, Resonance Energy-Transfer Processes, Evaluation of Drinking Water Quality, Water and Wastewater Treatment, Pollutant Control.
",isbn:"978-1-80356-594-1",printIsbn:"978-1-80356-593-4",pdfIsbn:"978-1-80356-595-8",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,isNomenclature:!1,hash:"0dd5611c62c91569bd2819e68852002a",bookSignature:"Prof. Jagannathan Thirumalai",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11756.jpg",keywords:"LED, Organic LEDs, Dyes & Pigments, Solar Cells, Laser Photonics, Electronic Switching Devices, Qubits, Josephson Junction, Bioconjugation, Cell Imaging, Photoelectrochemical Immunosensor, Membranes, and Bacterial Cells",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"March 16th 2022",dateEndSecondStepPublish:"May 27th 2022",dateEndThirdStepPublish:"July 26th 2022",dateEndFourthStepPublish:"October 14th 2022",dateEndFifthStepPublish:"December 13th 2022",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"a month",secondStepPassed:!0,areRegistrationsClosed:!1,currentStepOfPublishingProcess:3,editedByType:null,kuFlag:!1,biosketch:"Dr. J. Thirumalai received his Ph.D. from Alagappa University, Karaikudi, He was also awarded the Post-doctoral Fellowship from Pohang University of Science and Technology (POSTECH), the Republic of Korea. His research interests focus on luminescence, self-assembled nanomaterials, and thin-film optoelectronic devices. He has published more than 60 SCOPUS/ISI indexed papers and 11 book chapters, edited 4 books, and member of several national and international societies like RSC, OSA, etc. His h-index is 19.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"99242",title:"Prof.",name:"Jagannathan",middleName:null,surname:"Thirumalai",slug:"jagannathan-thirumalai",fullName:"Jagannathan Thirumalai",profilePictureURL:"https://mts.intechopen.com/storage/users/99242/images/system/99242.png",biography:"Dr. J. Thirumalai received his Ph.D. from Alagappa University, Karaikudi in 2010. He was also awarded the Post-doctoral Fellowship from Pohang University of Science and Technology (POSTECH), Republic of Korea, in 2013. He worked as Assistant Professor of Physics, B.S. Abdur Rahman University, Chennai, India (2011 to 2016). Currently, he is working as Senior Assistant Professor of Physics, Srinivasa Ramanujan Centre, SASTRA Deemed University, Kumbakonam (T.N.), India. His research interests focus on luminescence, self-assembled nanomaterials, and thin film opto-electronic devices. He has published more than 60 SCOPUS/ISI indexed papers and 11 book chapters, edited 4 books and member in several national and international societies like RSC, OSA, etc. Currently, he served as a principal investigator for a funded project towards the application of luminescence based thin film opto-electronic devices, funded by the Science and Engineering Research Board (SERB), India. As an expert in opto-electronics and nanotechnology area, he has been invited as external and internal examiners to MSc and PhD theses, invited to give talk in some forum, review papers for international and national journals.",institutionString:"SASTRA University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"10",totalChapterViews:"0",totalEditedBooks:"6",institution:null}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"17",title:"Nanotechnology and Nanomaterials",slug:"nanotechnology-and-nanomaterials"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"347258",firstName:"Marica",lastName:"Novakovic",middleName:null,title:"Ms.",imageUrl:"//cdnintech.com/web/frontend/www/assets/author.svg",email:"marica@intechopen.com",biography:null}},relatedBooks:[{type:"book",id:"5348",title:"Luminescence",subtitle:"An 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Firstly, it is difficult to find its clinical standardized definition, despite the various articles on the topic. There is no agreement on issues, such as the number of embryo transfer failures, the embryo development stage, its morphology and aneuploidy, in order to define RIF [1]. There are also inconsistencies on the definition of implantation. Some authors consider it a failure when the gestational sac is not seen after the embryo transfer. Others claim that it happens when the β-hCG test is negative [1]. In 2014, some researchers proposed the following definition: it is the transfer of at least four good morphologic quality embryos, with at least three fresh or frozen transfers to women below 40 years old. This is the most accepted definition up to date [2]. However, an international common understanding is necessary to standardize the definition in order to create more consistent scientific studies.
The embryo implantation is a key stage during
The anatomic causes constitute an important factor for RIF, although they are usually manageable. Fibroids and polyps can cause endometrial cavity distortion. Adhesions that form after surgery or infection can hinder the process of embryo implantation. Besides that, mullerian abnormalities such as septate or bicornuate uterus should be considered in patients with RIF.
According to the American Society of Reproductive Medicine (ASRM), the presence of hydrosalpinx can negatively affect implantation rates, either by alteration on the fluid nutrients or even by mechanically affecting embryo implantation.
In this chapter, we will address the main anatomic causes that can affect the implantation rates in patients undergoing to IVF as well as recommendations on the management and treatment.
Submucosal fibroids can affect embryo implantation due to different mechanisms, resulting in subsequent increased uterine contractility, abnormal endometrial vascularity, chronic endometrial inflammatory response and changes in local cytokines profile.
Fibroids which distort the endometrial cavity are associated with lower implantation and pregnancy rates among women who tried a natural pregnancy as well as among those who are undergoing IVF treatment [2].
Uterine fibroids investigation among women with RIF can be done through the following methods:
Transvaginal ultrasound scan: non-invasive method performed routinely in women undergoing IVF treatment [2, 3].
Hysteroscopy procedure: it is considered a gold standard method in the diagnosis and treatment of intrauterine pathologies which cannot be seen during a transvaginal ultrasound scan, such as for example submucosal fibroids. A guideline published recently shows that the incidence of abnormal hysteroscopic findings in women with RIF ranges from 14–51%, including the submucosal fibroids. The author mentions a large and well conducted multicenter randomized clinical trial (RCT) - the TROPHY study - which discusses the role of hysteroscopy in RIF investigation among women with normal basal transvaginal ultrasound scan results. He found uterine alterations in 24% of women in the hysteroscopy group. However, only 4% showed an incidence of surgically treated alterations. Besides that, there was no statistical difference in live births rate among the two groups after surgical correction. Therefore, the above-mentioned guideline states that the routine hysteroscopy among RIF patients with normal basal transvaginal ultrasound scan is not recommended (recommendation strength: strong; evidence level: high) [1, 4]. Hysteroscopy must be considered before a new treatment cycle if the basal transvaginal ultrasound scan shows uterine pathology.
Hysterosonography: although studies about cavity evaluation in RIF patients refer mainly to hysteroscopy, hysterosonography is a recommended and acceptable choice [1].
Hysterosalpingography: it has a limited value for detection of intrauterine pathology and should not be used routinely for this purpose [2].
Regarding the management of submucosal fibroids in women with RIF, one advocates their surgical removal, regardless the size, since evidence shows that their removal can improve clinical pregnancy rates [2, 3].
Prior to the surgery, the size and number of fibroids and the depth of intramural extension should be carefully assessed. Resection of a solitary submucous fibroid less than 5 cm in diameter and with little intramural extension should not pose significant difficulties. However, a submucous fibroid more than 5 cm in diameter or more than 50% embedded in the intramural part of the uterus may require removal in two stages. In the case of multiple submucosal fibroids, there is an increased risk of intrauterine adhesion formation after the procedure. Some surgeons advocate the removal of the anterior wall and posterior wall fibroids on separate occasions to reduce the risk of intrauterine adhesions [2, 3].
Unlike what happens to fibroids that distort the uterine cavity, there is no consensus regarding the removal of intramural fibroids in women with RIF. Some authors suggest adverse effects of intramural fibroids on implantation and pregnancy rates in women undergoing to IVF, particularly those larger than 4 cm, while other authors could not demonstrate such association [2].
The meta-analysis papers on the topic agree that women with intramural fibroids seem to have decreased implantation rates compared to those without intramural fibroids. However, the myomectomy did not seem to significantly increase clinical pregnancy and live births rates [3]. Therefore, the pros and cons of the myomectomy must be individually assessed. The patients must be aware of the possible complications caused by the procedure such as bladder and bowel injury, hemorrhage, risk of blood transfusion and hysterectomy that occurs in 1% of cases. Other consequences would be the formation of pelvic adhesions leading to infertility due to peritoneal tube factor, and the risk of uterine rupture in subsequent pregnancies. However, one must acknowledge that intramural fibroids can cause not only implantation failure but also some obstetric complications, such as increased risk of premature delivery, premature placental abruption, intrauterine growth restriction, abnormal fetal presentation and intrapartum hemorrhage. The decision-making must be individualized, and it is strongly recommended that an experienced surgeon takes part in the definition of the treatment [2].
In RIF cases with no determinant factors, the surgical removal of large or multiples fibroids is a choice [5]. After all explanations, the decision about the procedure to be taken - expectant conduct or myomectomy – is shared with the patient.
Endometrial polyps are common, affecting more than 25% of women. They can be found within all ages [6, 7], and are common among infertile women with a prevalence up to 32% [8].
The potential mechanisms in which endometrial polyps can adversely affect fertility comprise mechanical interference and the release of molecules which adversely affect the spermatozoid transportation or the embryo implantation. Evidence shows increased levels of aromatase and glycodelin, a glycoprotein which inhibits the Natural Killer (NK) cells activity, resulting in a less receptive endometrium to implantation, inflammatory markers and decreased levels of HOXA-10 and 11 messenger RNA, which are known markers for endometrial receptivity [8, 9].
The investigation of polyps in women with RIF can be done through some of the following methods:
Transvaginal ultrasound scan: An endometrial polyp normally shows as a hyperechoic endometrial mass with regular borders partially or completely occupying the uterine cavity [1]. The ultrasound scan performed in the proliferative phase of the menstrual cycle generally shows more accurate results [10].
Hysterosonography: The addition of intrauterine contrast agent (saline solution or ultrasound gel) increases transvaginal ultrasound diagnostic accuracy [11].
Hysteroscopy: The hysteroscopy is gold standard for the diagnosis of endometrial polyps. They can be identified by hysteroscopy in 16–26% women with unexplained infertility. Hysteroscopy can also facilitate the assessment of several endometrial polyps features, such as size, number and vascular characteristics [11].
Endometrial polyps surgical approach is controversial. The polyp size seems not to significantly affect pregnancy rates [12, 13]. Therefore, some studies have demonstrated that the resection of recently diagnosed polyps during ovarian stimulation cycle can decrease miscarriage rates and increase clinical pregnancy and live births rates, while others do not show such benefits. Lass et al. [14] showed that polyps smaller than 20 mm emerging during IVF can be expectantly managed without compromising clinical gestation and live births rates. However, in patients with RIF there is a recommendation for polypectomy prior to embryo transfer [3].
Congenital uterine anomalies come from failures along any step of the mullerian duct development process during embryo development, either in the formation, fusion or reabsorption. While an arcuate uterus shows a mild form of anomaly, a bicornuate uterus represents total failure. The actual uterine malformation prevalence is difficult to be determined since many of them are asymptomatic although they reach approximately 5.5% of the general population; 8% among infertile women and 13.5% among women with history of recurrent fetal loss [15]. A prospective observational study evaluated the prevalence of congenital uterine anomalies, including arcuate uterus, and their effect on the reproductive outcome among sub fertile women undergoing assisted reproduction. Clinical pregnancy and live births rates were similar among those with congenital uterine anomalies and the control group. There were no differences in the type of delivery, newborn gender or birthweight between the two groups. However, women with congenital uterine anomalies had more chance of premature delivery. After analysis of the anomalies subtypes, pregnancy and live birth rates were similar between arcuate and normal uterus groups. But the group with larger uterine anomalies showed worse reproductive outcomes [16].
Among the congenital uterine anomalies, the septate uterus is the most common and comprises 35% of the malformations. Its prevalence among infertile women (3%) seems to be comparable with the general population (2.3%) [15].
Women with septate uterus show increased risk of spontaneous abortion (2.9 relative risk [RR]; 95% confidence interval [95% CI] 2.0–4.1), premature delivery (2.1 RR; 95% CI 1.5–3.1) and abnormal fetal presentation (6.24 RR; 4.05–9.96 CI). They also have the lowest clinical pregnancy rates (0.86 RR; 95% CI 0.77–0.96) [17].
Little is known about the physiopathology responsible for the negative reproductive outcomes in women with septate uterus. According to a recent systematic literature review, all the eight studies which histologically investigated the septum showed that it consists of endometrial and myometrial tissue, and that most intrauterine septa are vascularized. One explanation for jeopardized reproductive outcomes of embryos implanted in the intrauterine septum could be the different histologic composition of the endometrial septum tissue. The glandular cells and the stroma have different morphologic characteristics: a smaller number of glandular cells and cilium, and incomplete cilium genesis.
Besides that, the endometrial septum contains the lowest levels of vascular endothelial growth fator (VEGF) receptors. It is believed that they have an important role in the early embryo implantation and placentation. In two studies, the HOXA10 gene expression, which is important for the early embryo implantation, seems to be altered in women with septate uterus. These findings can explain the disruptive development of the embryo implanted in the septum. However, since the studies’ results on the issue are conflictive, a more detailed investigation is suggested [18].
The definition of septate uterus has been discussed for a long time. Nowadays, there are three classification systems which are used worldwide. It’s important to have a standardized classification system in order to prevent inappropriate or unnecessary surgical procedures and to compare reproductive results. The original classification system of the ASRM was modified and adapted. It currently uses morphometric criteria, such as the uterus internal indentation angle and internal midline cutout measurements to make a distinction between arcuated and septate uterus. It also uses the depth of uterus external surface to make a distinction between those and the bicornuate uterus. The uterus with indentation angle < 90°, length of midline internal cutout > 1.5 cm and uterine external cutout with less than 1 cm is defined as a septate uterus by the ASRM [19]. In 2012, the European Society of Human Reproduction and Embryology and the European Society for Gynecological Endoscopy (ESHRE/ESGE) published a classification system to replace the subjective criteria of the ASRM classification system by absolute morphometric criteria. Contrary to the American classification, the arcuate uterus is not mentioned and is considered a variant from normality. Septum is defined when the internal indentation is > 50% of the uterine wall thickness and the depth of the external fissure is < 50% of the wall thickness [20]. Women with previous diagnosis of arcuate uterus made by the ASRM (around 58%) would be classified as having a septate uterus when using the ESHRE/ESGE new classification. Thus, there would be an increase on the number of surgical procedures to fix uterine anomalies, with no evidence showing that this practice is beneficial to these women [21]. Recently, a simplified classification was proposed by the Congenital Uterine Malformations Experts (CUME), where the septum is defined as the depth of the internal indentation ≥ 10 mm [22]. It demonstrates the heterogeneity in the classification of mullerian malformations, making it difficult to produce scientific papers on these alterations in a homogeneous way.
The uterine septum is the only malformation that can be corrected. There are many discussions about the impact of the septum resection on the reproductive results and if it improves natural conception rates and implantation rates after embryo transfer. Nowadays, the ASRM guidelines for septate uterus management recommend the hysteroscopic resection [18]. In contrast, the ESHRE, the National Institute for Health and Care Excellence (NICE) and the Royal College of Obstetricians and Gynecologists (RCOG) guidelines for recurrent fetal loss associated to septate uterus do not support this procedure until further studies can demonstrate its effectiveness [23, 24, 25]. Lavergne et al. found a retrospective multicentric study which shows that implantation rates after IVF cycle were significantly lower in patients with malformed uterus (septate, bicornuate or unicornuate) in comparison with patients with a normal uterus (6% vs. 12%, p < 0.01). There was significant improvement when the uterine anomaly was corrected (septate uterus) [26]. One study compared gestation and abortion rates after embryo transfer on an IVF cycle in patients with septate uterus before and after septum resection. They were compared to a control group, showing that pregnancy rates before hysteroscopic resection (both in women with septate or subseptate and arcuate uterus) were significantly lower in comparison to the patients in the normal control group [OR 2.9 (P < 0.002) and 2.2 (P < 0.001)], respectively. After surgery, pregnancy rate was comparable to the women with a normal uterus (OR 1.2 and 1.1). The uterine septum size did not influence pregnancy rate. The study conclusion recommends the hysteroscopic resection in order to improve the reproductive outcome, not limited to women with recurrent early fetal loss or premature labor, but it is also recommended to infertile women in order to improve pregnancy and live birth rates, especially if IVF is a choice [27]. Ozgur et al. showed that a history of abortion and IVF failure was frequent among women with untreated incomplete septate uterus in comparison to the infertile general population. After surgical correction of the septum, pregnancy rates in IVF cycle were similar to the group with normal uterine cavity [28]. In a recent article by the SWOT infertility group in Spain, the researchers stated that a septate uterus has been associated to a high prevalence of repeated implantation failure in assisted reproduction and abortion after IVF. In these cases, septum resection seems to be useful to improve IVF pregnancy rates [29]. These studies suggest that the correction of anatomical alterations which distort the uterine cavity, especially the septate uterus, can improve reproductive results.
In other studies, we saw that the septate uterus correction may not bring benefits. In an international multicentric cohort study with women with septate uterus and showing desire for pregnancy (which opted for septum resection or expectant approach), Rikken et al. showed that the septum resection did not increase the chance of live births nor reduced the risk of abortion or premature birth [30]. The only controlled randomized trial assessing the reproductive outcome after uterine septum resection was recently published. Women in reproductive age with a septate uterus and the wish to get pregnant and a history of subfertility, fetal loss or premature birth were selected. The results of this randomized clinical trial showed that the hysteroscopic resection of the septum did not improve live birth rates or other reproductive outcomes in women with septate uterus. In this study, one patient undergoing septum resection had a perioperative uterine perforation. The authors concluded that if there is no proven efficacy, they do not recommend septum resection as a routine procedure in clinical practice. Women with septate uterus need to be informed about this study data. After counseling and according to the principles of shared decision-making, an informed consent must be provided [31].
In relation to other malformations, except septate uterus, surgical correction seems not to bring benefits. Surrey et al. demonstrated that the arcuate uterus does not have an impact on the results of IVF cycle after euploid embryos transfer. Women undergoing IVF with indentation between 4 and 10 mm experience excellent results which are similar to those of women with internal indentation < 4 mm (live birth rate; 68.7% vs. 68.7%). Besides that, there were no differences in the reproductive outcome among those with arcuate or normal uterus, according to Salim et al. Criteria [32]. Chen et al. compared the reproductive outcome between unicornuate and morphologically normal uterus. There were no significant differences in the pregnancy, clinical pregnancy or live births rates. The abortion rates were similar. In single pregnancies, there were no differences in the preterm birth, birthweight or birth size rates. However, prematurity rates, lower birthweight and lower birth size rates as well as higher very low birth rates were found in twin pregnancies with unicornuate uterus. A single embryo transfer is recommended for unicornuate uterus [33].
The difficulty of having an agreement on the scientific studies is due to the impediments to unite mullerian malformations classification, differences on the definition of recurrent embryo implantation failure and a low prevalence of these events. Thus, we suggest the individualization of the cases in which mullerian malformations and recurrent implantation failure appear. Among all the malformations, the septate uterus is the one whose correction is possible in order to improve the reproductive outcome. Nevertheless, further studies are necessary to confirm this statement.
Intrauterine synechiae, intrauterine adhesions or Asherman syndrome are names that define lesions on the endometrial tissue caused after aggressive curettage or any other intrauterine procedure that destroys the endometrium.
It is known that gestational complications such as missed or incomplete abortion and afterbirth bleeding are responsible for approximately 90% of the cases [34]. Nonetheless, infections in a non-pregnant uterus and surgeries such as myomectomies or septoplasty, for example, can lead to synechiae formation [35], causing or not secondary amenorrhea.
In terms of physiopathology, the assessment by electronic microscopy shows that the glandular cells have severe alterations in women with Asherman syndrome. It is mainly due to ribosome metabolism which culminates in ATP depletion and subsequent tissue hypoxia. There is an abnormal expression of different growth factors which leads to the activation of cytokines related to the adhesion and a pro-inflammatory cascade [36]. There are also theories that associate the occurrence, severity and recurrence of intrauterine adhesions to an alteration of the endometrial microbiome, but they lack strong scientific evidence.
The presence of adhesions in the uterine walls can interfere in the embryo implantation impeding the embryo cellular fixation on the endometrial luminal layer. Demirol and Gurgaon found a prevalence of 8.5% of intrauterine synechiae in women with embryo implantation failure, which confirms the importance of a clinical investigation [37].
For 20 years, the hysterosalpingography was the first line exam for the diagnosis of intrauterine synechiae. Today it is still used by many gynecologists for the evaluation of the uterine cavity, since it is a low-cost analysis showing 75% sensitivity [38]. It is similar to the hysterosonography whose sensitivity is of 82% [39]. The transvaginal ultrasound scan is also used to confirm a thin endometrium, but it has low accuracy for the diagnosis of synechiae [40], so that it is not considered the best method of investigation. The 3D hysterosonography has 91.1% sensitivity and 98.8% specificity, which makes it a good examination for the diagnosis of intrauterine adhesions [41]. However, despite the data forementioned, the hysteroscopy is certainly a golden standard for the diagnosis of synechiae, once it allows direct visualization of the uterine cavity [42] and enables treatment. There is concrete evidence that the synechiae lysis during hysteroscopy improves the reproductive outcomes [43].
Before hysteroscopy, cervix dilation and curettage associated with estrogenic therapy and use of IUD ensured 84% success rate in the treatment of Asherman syndrome. However, today we have the hysteroscopy as a golden standard in the diagnosis and treatment of this endometrial complication. It became necessary to define the site and severity of intrauterine adhesions. Classifying the disease process can be important once the severity imposes the prognosis after treatment [44]. The hysteroscopy enables the amplification and general observation of adhesions allowing the viewing of all structures, which decreases the risk of uterine perforation. However, there should be maximum care when using mechanic and electronic section since errors can bring undesirable repercussions [45].
The surgical treatment shows success rate after adhesiolysis ranging between 75 to 100% [46]. This rate can be evaluated by the return of menstrual periods, rates and pregnancy outcome. After a hysteroscopic surgery, around 92 to 96% of women returned to their bleeding pattern prior to the syndrome showing 63% pregnancy rate and 75% live births rate [44]. The most frequent complication in pregnancies after hysteroscopic treatment for uterine adhesions is the abnormal placentation [44].
The intraoperative fluoroscopy and transabdominal ultrasound scan or the laparoscopy are also efficient alternatives [45]. The fluoroscopic guidance enables the surgeon to see endometrium islands behind the scar tissue in an obliterated uterine cavity. The radio opaque dye is injected into a dense scar area in the place where the cavity is obliterated. Some endometrial adhesions can be identified using fluoroscopy. The area can be opened through acute dissection under hysteroscopy. However, this technique is considered limited by the high cost, by technical difficulties or by the requirement for ionizing radiation [46].
The laparoscopic guidance for severe cases of intrauterine adhesiolysis has been advocated for the immediate recognition and treatment of uterine perforation, thus minimizing the extrauterine trauma. The intraoperative ultrasound scan, fluoroscopy or laparoscopy together with the hysteroscopy have been used as guidance to reduce the risk of perforation. Nevertheless, nowadays it is known that these interventions do not prevent uterine perforation or improve the outcome [46].
The stem cell therapy approach is much more efficient due to the potential for multiplication of a single cell and its transformation into undifferentiated forms (self-renovation) and into mature cells. Besides that, it can produce other types of cells, such as totipotent, pluripotent and multipotent cells [35].
In 2016, Tan et al. [47] investigated mesenchymal stem cells derived from bone marrow and stromal cells coming from the menstrual bleeding through transmiometral administration in the subendothelial area, direct installation of stromal cells in the uterine cavity and infusion of cells in spiral arteries through a catheter. Five out of six women with Asherman syndrome recovered their menstrual periods. Others reached adequate endometrial thickness and regular menstruation cycles and were able to get pregnant right after that. In this study, the authors compared some types of stem cells and could observe endometrial regeneration in most of the cases.
Thus, stem cells therapy has become a new method of treatment for the regenerative medicine, and more specifically, for the regeneration of endometrial diseases with Asherman syndrome and thin endometrium. However, stem cells transplant for Asherman syndrome is far from being common [46].
The biggest challenge for the treatment of Asherman syndrome is to prevent the recurrence of adhesions after the early treatment, which reaches 66% [46]. The treatment is defined by time. There are studies that evaluated the post-operative period comparing the use of intrauterine device (IUD) with intrauterine balloon catheter, Foley catheter, hormonal treatment and barriers such as amniotic membranes. The results are conflicting.
For instance, the copper IUD can provoke inflammation and is contraindicated [44]. Similarly, the hormone IUD have a small surface that limits its capacity to keep the endometrial cavity walls separated during healing [39]. The risk of infection after the insertion of an IUD after surgical resection of intrauterine adhesions is about 8% [44].
The placement of a Foley catheter with an IUD was assessed as a possible adjuvant treatment to prevent the formation of synechiae after hysteroscopy. The authors concluded that the Foley catheter placed one week and a half after adhesiolysis showed 81% success rate while the group which placed an IUD twelve weeks after the adhesiolysis showed 62% success rate [48]. The use of intrauterine hyaluronic gel after hysteroscopic treatment reduces adhesions recurrence [48], but further studies are needed for its incorporation into the treatment [44, 45].
Platelet-rich plasma (PRP) is a form of treatment for intrauterine adhesions after operative hysteroscopy and may be a substitute for the intrauterine balloon. However, randomized controlled trials with large sample sizes are warranted to further confirm the conclusions to compare the efficacy of intrauterine infusions of PRP with intrauterine balloons applied immediately after transcervical resection of the adhesions by hysteroscopy [49].
Clinical treatment with drugs such as aspirin, sildenafil and nitroglycerin have been done to increase endometrial blood flow in an attempt of stimulate cell regeneration. Successful pregnancies were reported after using them. However, more robust and well designed studies are required to confirm it [44].
Hormonal therapy with post-operative estrogen was not standardized in terms of dose, duration, route of administration or a combination with progesterone, Data about its efficacy are limited [44]. The American Association of Gynecologic Laparoscopists (AAGL) guidelines recommend hormonal therapy with estrogen after adhesiolysis, but there is no definition for dose or standard regimen [46]. The combination of this and adjuvant treatments is necessary for a maximum effect on patients with mild to severe adhesions.
As for the therapy with antibiotics, there is a lack of studies addressing the risks and benefits of those before, during and after surgical lysis of intrauterine adhesions. The American College of Obstetrics and Gynecology (ACOG) does not recommend the routine use of antibiotics with this objective [44, 46].
Hysteroscopic adhesiolysis cure infertility in mild, moderate and severe IUA in around 90, 70 and 30%, respectively [50]. Gestational surrogacy remains an alternative for those patients with intrauterine adhesions that stay infertile [51].
Adenomyosis is a benign uterine pathology known by the invasion of glandular endometrial tissue and myometrial stromal tissue which leads to disorders in the myometrial natural architecture [52].
There are some theories explaining the emergence of adenomyosis. The theory of tissue injury and repair (TIAR) as the main mechanism of myometrial invasion has been the most accepted hypothesis. Chronic peristaltic myometrial contractions can lead to micro lesions close to the endometrial-myometrial junction causing inflammation which in turn leads to an increase in local production of estrogen inducing a vicious cycle. Thus, the TIAR theory highlights the importance of tissue damages to the endometrial-myometrial interface supporting the common knowledge that the adenomyosis is associated with multiple births, previous cesarean section and previous uterine surgery [53]. However, it is known that there is a considerable number of macrophages in the ectopic endometrium of patients with endometriosis, fibroids and adenomyosis. Therefore, the potential for embryo implantation can be affected by adenomyosis [54]. This increase in the number of macrophages induced by adenomyosis can cause a hostile immunologic environment for embryos transferred during the implantation process. The interleukin-1 alpha tumor necrosis factor as well as reactive oxygen and nitrogen species are potentially toxic for embryos. It was demonstrated that an increased level of nitric oxygen is related to an adverse development of embryos and low pregnancy rates in the endometrial environment in patients with adenomyosis. Besides that, endometrial biopsies taken from adenomyosis showed that this tissue is composed of a high quantity of antioxidant enzymes as superoxide dismutase, catalase and glutathione peroxidase which are clear signs of oxidative stress caused by excessive ROS production [55].
Other risk factors are age over 40 years, multiple births, previous cesarean sections or other uterine surgeries. The disease is often diagnosed in young and infertile women or those with pain or abnormal uterine bleeding, or both [56].
Adenomyosis is associated with a great variety of symptoms. The common symptoms include pelvic pain (as dysmenorrhea, dyspareunia or chronic pelvic pain), abnormal uterine bleeding and impaired reproductive potential or even infertility itself. However, it is important to observe that 30% of women with adenomyosis have no symptoms [57]. In infertile women with adenomyosis, the topic endometrium shows a great variety of molecular alterations causing altered receptivity. That includes the alteration in the sexual steroid hormone via, increase of inflammatory markers and oxidative stress, decrease on the implantation markers expression, lack of adhesion molecular expression and altered gene function for the embryo development. Not only fertility outcomes are affected, but also pregnancy outcomes [58]. These include premature birth, premature rupture of membranes, postpartum hemorrhage, abnormal fetal presentation, increase on the risk of abortion in the second trimester and abnormal placental position [57].
The diagnosis can be done after case history, clinical evaluation and image assessment with 2D/3D transvaginal ultrasound or magnetic resonance [52]. The transvaginal ultrasound for its facility of access and low cost in relation to other types of screenings has become a very useful tool to the diagnosis. Several ultrasographic criteria have been used to the adenomyosis diagnosis, including uterine size increase, anterior and posterior uterine walls thickness asymmetry, presence of heterogeneous myometrial areas, presence of myometrial anechoic areas, presence of sub endometrial echogenic striations, sub endometrial echogenic nodules, irregular endometrial-myometrial interface, poor definition and thickness of the junctional zone [57].
A meta-analysis about ultrasound accuracy in the diagnosis of adenomyosis demonstrated 82.5% sensitivity (95% CI), 77.5–87.9) and 84.6% specificity (95% CI, 79.8–89.8) with 4.7 positive likelihood ratio (3.1–7.0) and 0.26 negative likelihood ratio (0.18–0.39) which is comparable to the magnetic resonance [59].
The magnetic resonance is a precise and non-invasive technique used to the diagnostic of adenomyosis [60]. Its sensitivity and specificity in this diagnostic range from 88–93% and 67–91%, respectively [57]. The diagnosis of adenomyosis by magnetic resonance is essentially related to junctional zone characteristics, but can also include direct and indirect signs of endometrial glands inside the myometrium and smooth muscle cells hypertrophy [61, 62].
Clinical pregnancy, implantation, and ongoing pregnancy rates were significantly higher in women undergoing frozen embryo transfer after long-term GnRH-analog therapy compared to those not pretreated with GnRH-analog [63].
Tremellen et al. reported that hypothalamic–pituitary- ovarian axis suppression therapy with GnRH agonist can produce a significant decrease in the number of endometrial macrophages, presumably interfering with the estradiol-mediated recruitment of macrophages to the endometrium and a subsequent normalization of embryo implantation rates [64]. Wang et al. showed that patients with normal ovarian reserve who underwent IVF/ICSI, adenomyosis seemed to negatively affect IVF/ICSI outcomes after a long GnRH agonist protocol (subcutaneous administration of short acting GnRH agonist on the dosage of 0.1 mg/day, for 10 days followed by 0.05 mg/day until the day of hCG injection which was started in the mid-luteal phase of the previous cycle), but patients with adenomyosis following an ultra-long GnRH-agonist protocol could experience stronger pituitary inhibition and lower ovarian responses but still could have a better IVF/ICSI outcomes. Ultra-long GnRH agonist protocol was considered the use of a depot injection of the long-acting GnRH agonist, triptorelin acetate (triptorelin) 3.75 mg, intramuscularly, every 28 days for at least 3 months before starting ovarian stimulation [65]. This therapy may produce a window of time with improved implantation rates [66].
The use of a levonorgestrel-releasing intrauterine device, danazol, or aromatase inhibitors may temporarily induce regression of adenomyosis and oral contraceptive pills, high-dose progestins, and selective progesterone receptor modulators can temporarily improve its symptoms, but these are not used in fertility treatments [66].
Patients with adenomyosis present a higher number of uterine contractions. Oxytocin (OT), a nonapeptide synthesized by neurons of the supraoptic nucleus and released from the posterior pituitary gland, has diverse effects on the female reproductive system. It is known to be a factor causing uterine contractions. It has also been shown in animal models that endometrial cells contain oxytocin receptors (OTRs) and that OT has the capacity to trigger the production of prostaglandin (PG) F2a from these cells. Atosiban, an OTR antagonist, treatment before ET in endometriosis is effective in the priming of the uterus, suitable for embryo implantation [67]. Since uterine contractions in IVF cycles are significantly increased following ovarian stimulation and women with frequent uterine contractions have a lower pregnancy rate, the use of atosiban around embryo transfer may resulted in higher pregnancy rates in women with RIF and adenomyosis. According to Hung Yu et al., the use of atosiban around embryo transfer did not improve the live birth rate in a general population of IVF patients [68].
Hydrosalpinx refers to a condition in which the fallopian tube is filled with fluids following infundibulum obstruction. It is a common condition among infertile women with 10–13% diagnosis rate after ultrasound scan. These numbers can be increased when other diagnostic methods such as hysterosalpingography or laparoscopy are used [69].
Perhaps the real cause for the implantation failure is not known, but studies suggest a decrease in live births rates in patients with hydrosalpinx [70].
The theories regarding hydrosalpinx and implantation failure are about a possible embryo toxicity, changes in the endometrium quality or even embryos washout mechanical effect [71].
The endometrial involvement secondary to hydrosalpinx is related to the presence of fluid inside the uterine cavity, altered endometrial flow, altered in inhibiting factors and increase in the inflammatory response. Besides the endometrial changes and a possible embryo toxicity, the implantation failure can be related to a negative effect on sperm motility and survival.
A history of ectopic pregnancy, pelvic inflammatory disease, endometriosis or previous pelvic surgery increase the suspect of infertility by tubal factors [72]. For patients without risk factors, a negative antibody test for chlamydia indicates that there is less than 15% chance of tubal pathologies [73]. For an accurate diagnosis and an effective treatment of the tubal blockage it is necessary to do exams as the hysterosalpingography (HSG) which uses water or lipids soluble contrast medium. It is a golden standard method to evaluate tubal permeability and can bring some therapeutic benefits. The HSG can document tubal blockage in proximal and distal sites, show salpingitis isthmic nodosa, reveal fimbrial phimosis or peri tubal adhesions [74]. The HSG positive and negative predictive factors are 38% and 94%, respectively [75].
The laparoscopy with chromotubation with methylene blue test (dye test) injected thorough the cervix can demonstrate tubal permeability, proximal or distal tubal occlusion. This surgical route can also identify and correct peritoneal and tubal factors such as fimbriae or peri tubal adhesions which cannot be seen with less invasive methods as the HSG [74].
The techniques used for the treatment of hydrosalpinx are many: laparoscopy or laparotomy for salpingectomy, salpingostomy or even uterine proximal occlusion.
A meta-analysis published in 2020 evaluated the effect of hydrosalpinx on the pregnancy rates, compared different types of treatment and the impact on the ovarian reserve after treatment for hydrosalpinx [70]. They reviewed 17 studies and observed that the hydrosalpinx was associated with a significant decrease in the implantation rate with embryo transfer with 0.41 OR [0.32–0.53]. Besides that, the clinical pregnancy rate per subject and per transference significantly decreased in women with hydrosalpinx (OR = 0.54; [0.32–0.89] and 0.44 [0.27–0.73], respectively) [70].
The hydrosalpinx removal with salpingectomy leads to an improvement of in vitro fertilization outcomes in comparison with no treatment, which turns it into a golden standard management before IVF. This evidence is replicated in other studies, such as Palagiano et al., where the pregnancy rates in patients with hydrosalpinx is lower than the control group [69]. There were negative effects either in fresh or frozen embryo transfers. An increase of two or threefold in abortions in women with hydrosalpinx was observed.
The hydrosalpinx mechanism action is still uncertain. Studies show a negative impact in IVF treatment outcomes, including a decrease in implantation rates, clinical pregnancy and in course pregnancies. Besides that, they show a risk of miscarriages (1.68 OR) and ectopic pregnancy (3.48 OR), according to Capmas et al. [70]. The salpingectomy is the treatment that increases success rate and prevents secondary aggressive factors. According to some authors, it is considered a golden standard. But it can be related to a decrease in the Anti-Mullerian Hormone average of 0.99 ng/ml, as shown the meta-analysis by Capmas et al. [70].
The recurrent implantation failure is a complex clinical condition with a wide variety of etiologies. Its criteria are not still well defined. Despite the lack of consensus, studies strongly show that anatomical factors affecting the uterine cavity contribute to implantation failure. Most of these factors are treatable, though.
Each patient approach must be individualized and offered to women with adequate RIF investigations to eliminate the possibility of all structural causes. The lack of success of an IVF can be devastating for some couples.
Uterine pathologies such as fibroids, adenomyosis, endometrial polyp, congenital abnormalities and synechiae must be considered in the diagnosis of RIF and must be excluded using image exams. Hydrosalpinx is known as a factor for implantation failure and a laparoscopy with salpingectomy or uterine proximal occlusion must be offered as a therapy option.
Even after more than 40 years of IVF procedures worldwide, the causes of RIF remain challenging and controversial. It is necessary to establish a consensus about diagnosis and therapeutic approaches to reduce expensive treatments which are not efficient and are time-consuming for infertile patients.
“The authors declare no conflict of interest.”
Management of PCOS (polycystic ovary syndrome) related to infertility, includes lifestyle changes, ovulation induction by pharmaceuticals, or assisted reproductive technology (ART) as an
Hyperandrogenism, anovulation, and ovarian morphology are the basic determinants in the diagnosis of the polycystic ovarian syndrome (PCOS) according to international guidelines. Given the different clinical presentations in patients, the criteria for the diagnosis of this condition are still discussed, as well as whether the syndrome involves several different diseases with the same clinical picture, as well as discussions about what is really a clinical picture of the polycystic ovary. Therefore, different approaches in the diagnosis and treatment of patients, have been proposed for different phenotypes of PCOS. The criteria for pre-recognition of this condition have been adopted for years by various authoritative bodies at international meetings, such as the National Institute for Health (NIH), Rotterdam consensus, Androgen Excess, and PCO Society, but there has been a constant difference over the mandatory criteria for PCOS [1]. An important starting point in the diagnosis was to exclude diseases of other endocrine glands (pituitary gland, thyroid, and adrenal gland), which give a similar clinical picture and can be confused with PCOS.
Ovulation disorder in the general population of women is estimated at 15% (12–18%) [2]. Regular menstrual cycles are not the exclusive evidence of ovulation, since in some women there is a “subclinical disorder” of ovulation that is proven only by serum values of progesterone in the middle lutein phase of the cycle (21–24.d.c. which must be >5 ng/mL). In the case of PCOS, almost 80% of patients have ovulation disorder [3].
Hyperandrogenism (hyperandrogenemia) implies clinical and/or biochemical evidence of elevated serum androgens, but the incidence in the general population of women is unknown. Hirsutism, androgenic alopecia, and acne are clinical manifestations of hyperandrogenism. The intensity of hirsutism differs ethnically and geographically, and it is desirable to develop population-specific criteria for hirsutism. Almost 70% of women with hirsutism have PCOS, 40% have severely expressed acne, and only 22% have androgenic alopecia [4]. Hyperandogenemia (biochemical hyperandrogenism) is determined by free testosterone and free androgen index (FAI—free androgen index) [5]. A total of 78% of patients with PCOS have hyperandrogenism and 40% in an unselected population of patients with BMI >25 [6].
Polycystic ovary morphology (PCOM) is evaluated by ultrasound examination based on the number of antral follicles (> of 20 per ovary) and/or on the basis of total ovarian volume (> 10 mL), where the frequency of the ultrasonic probe is an extremely important parameter. Based on these international criteria, the prevalence of PCOM in the population is 12.5% [7, 8]. Ultrasonic examination of nonselective population, based only on PCOM, significantly increase the incidence of PCOS and vice versa.
Thus, on the basis of the described criteria, four PCOS phenotypes with different prevalence in the general and separate population are defined, which are as follows [5]:
Phenotype A (hyperandrogenism, anovulation, PCOM).
Phenotype B (hyperandrogenism, anovulation).
Phenotype C (hyperandrogenism, PCOM), ovulatory PCOS.
Phenotype D (anovulation, PCOM), non-hyperandrogenemic PCOS.
Compared to phenotype C and D, patients with phenotype A and B (classical phenotype) are more often obese, with hirsutism, more likely to have insulin resistance, dyslipidemia, fatty liver, and metabolic syndrome in later life. The frequency of individual phenotype differs significantly in different populations with symptoms of PCOS and also in the general population [9]. Each of the PCOS phenotypes has its own specifics in the treatment of impaired fertility.
The first line of treatment of patients with PCOS is the induction of ovulation with clomiphene citrate or letrozole.
Gonadotropin stimulation in patients with PCOS is associated with the development of a significantly higher number of follicles in the ovaries, as well as oocytes, a significantly higher number of developed embryos and embryos in excess for cryopreservation. Ovarian stimulation in these patients lasts longer and higher doses of gonadotropin are often required, which is associated with disorders of folliculogenesis caused by hyperandrogenism. Estimating the right dose of gonadotropin is the biggest challenge in the phase of ovarian stimulation and is often insufficient. The follicles do not grow, due to hyperandrogenism, and by increasing the dose, the ovary enters in hyperstimulation, which is an extreme of the ovarian response. A newer approach to ovarian stimulation with follitropin delta, based on the patient’s body mass and AMH value, proved to be the best, especially in the PCOS patient population and has a significant reduction in the risk of ovary hyperstimulation. Patients with hyperandrogenism and polycystic ovarian morphology (phenotype A and C) have the highest risk of ovary hyperstimulation [11].
Ovarian hyperstimulation syndrome (OHSS) is an iatrogenic complication of ovarian stimulation, and PCOS patients have the highest risk for complications during the IVF (
The protocol of choice for ovarian stimulation in patients with PCOS and risk for OHSS is an antagonistic protocol that can be fixed or flexible. In this stimulation, it is possible to achieve the final maturation of oocyte with GnRH (gonadotropin-releasing hormone) agonists, thereby avoiding the administration of hCG (human chorionic gonadotropin) injection, which is the basic molecule in the mechanism of development of OHSS in at-risk patients. In this way, the basic mechanism of vascular permeability and compromising circulation by leaking plasma from the vascular system into extracellular spaces are avoided. Those are signs of a more severe form of OHSS. Likewise, the stimulation cycle is abruptly “extinguished.” Menstrual bleeding occurs within a few days after the application of the GnRH agonist. Harvested oocytes are fertilized by IVF/ICSI procedure and developed embryos are cryopreserved, most often in the blastocyst stage, which represents the so-called “freeze-all” strategy that gives safety to the treatment of patients with PCOS. Embryo transfer is planned in the next cycle in which signs of hyperstimulation do not exist. Hormonal preparation of the endometrium, and ovarian stimulation, in this case, is not required.
Additional treatment of PCOS patients involves the use of various medications that have metabolic effects and that could significantly improve the treatment of these patients in IVF procedures by individualizing therapy. The fact is that within the PCOS population with the same PCOS phenotype, an individual woman may have a significantly different response to different types of treatments with respect to the unique hormonal/metabolic status associated with the PCOS phenotype as well. There is a large gap in the literature that indicates the need for new research and the need for an individual approach in the treatment of infertility of these patients.
Spontaneous abortions in patients with PCOS are more common compared to the general population and they are associated with insulin resistance, hyperandrogenism, and obesity. These conditions are very often associated with PCOS, but they are also separate risks for the spontaneous loss of pregnancy. Studies link spontaneous abortion to impaired endometrial receptivity and to more frequent embryo aneuploidy of patients with PCOS. In the Asian population of women with PCOS phenotypes who have hyperandrogenism (A, B, C types), a higher risk for spontaneous miscarriage after IVF procedures was observed than in phenotype D [12]. Impaired glucose and insulin metabolism at the endometrial level and excessive expression of androgen receptors in the endometrium are associated with a signal transduction disorder during the implantation process in patients with PCOS [13]. The causes of more frequent embryo aneuploidy in PCOS patients have not yet been clarified. There are assumptions that impaired glucose metabolism and steroidogenesis lead to DNA molecule instability [14].
During the stimulated IVF cycle, various indicators of quality and success of treatment are monitored. Among other things, these are the total dose of gonadotropin used for stimulation, the number of aspirated oocytes, the number of oocytes in metaphase II, the percentage of fertilization, the number of developed embryos on the 3rd day, the number of developed blastocysts on the 5th day, the number of cryopreserved embryos, the proportion of conceived pregnancies, the number of born children, etc. Since PCOS phenotypes imply hormonal and metabolic differences, the question arises whether the indicators of the course of treatment are different in patients with different PCOS phenotypes.
The results of the studies so far indicate significant differences in treatment between PCOS patients and women who do not have this syndrome and who in studies represent the usual control group. Studies most often follow PCOS patients as a single group. Different criteria for defining PCOS phenotype are associated with problems of analysis and comparison of parameters that monitor the course and outcome of the IVF procedures in different studies [15]. There are two fundamental factors that are most often analyzed and compared in patients with PCOS—hyperandrogenism and PCO morphology of the ovaries, which are clinically very important factors in decision-making during the treatment of infertility by medically assisted fertilization procedures. The role of androgens in folliculogenesis is still unclear and there are conflicting results of studies dealing with this problem. The results of studies analyzing differences in treatment outcomes among defined PCOS phenotypes indicate a negative effect of hyperandrogenism in IVF procedures, and a higher incidence of complications later in pregnancy [16]. In patients with phenotype A and B, for every 1 pg./ml increase in free testosterone concentration, the proportion of clinically confirmed pregnancies decreases by 50–60% as well as the proportion of live births [17]. According to recent findings, the differences between PCOS phenotypes refer only to the number of good embryos for transfer, which is significantly higher in patients with hyperandrogenism and ovulation disorder, but without the typical PCO morphology of the ovaries (phenotype B). The proportion of biochemical and clinically confirmed pregnancies, as well as the number of couples with born children, do not differ significantly among phenotypically different PCOS patients [17, 18]. In addition, studies indicate that the proportion of clinically confirmed pregnancies, is significantly lower in women with PCOS phenotypes A, B and C compared to control patients [17]. The number of children born does not differ in different PCOS phenotypes. In some areas of the world, certain PCOS phenotypes have not been found at all, for example, there are no phenotypes B and C among Vietnamese women with PCOS [19]. Since the anti-Müller hormone (AMH) is often elevated in patients with PCOS, it has become a powerful factor that should have prognostic value in clinically assessing the outcome of treatment with medically assisted fertilization, however, it has been proven useful only in the group of patients with phenotype B. The proportion of clinically confirmed pregnancies and the proportion of babies born increases by 1.3 times for each 1 ng/ml serum AMH concentration increase [17].
PCOS patients’ oocytes quality can be associated with the hormonal and metabolic conditions, and therefore, consequently with the quality of the embryo. Poorer oocyte quality is part of the problem of subfertility in patients with PCOS. There is evidence that oocyte quality depends on PCOS phenotype and accompanying diseases and conditions that are more common in PCOS patients. Oocyte quality is defined by the morphology and morphology of associated structures, such as zona pellucida, cumulus oophorus, and corona radiata. An ovarian microenvironment in which follicles and oocytes grow and mature is exposed to multiple hormonal abnormalities in patients with PCOS. Well-known disruptive mechanisms include elevated concentrations of LH (luteinizing hormone) and FSH (follicle-stimulating hormone), impaired ratio of these hormones, elevated AMH values, impaired insulin-like growth factor secretion, and enzymes involved in the conversion of androgens to estrogens.
Hyperandrogenism interferes with the normal feedback loop between the ovaries, pituitary gland, and hypothalamus, which leads to an increased frequency of excretion of the releasing hormone for gonadotropins, and consecutively results in premature luteinization of granulose cells and abnormal maturation of the oocytes. There is also a direct effect of hyperandrogenism on the oocyte by activating its proapoptotic mechanism [20]. Hyperandogenic ovarium microenvironment interferes with the oocyte in the continuation of meiosis, promotes mitochondrial abnormalities and oxidative stress, and interferes with lipid metabolism in the oocyte [21].
High concentrations of AMH synthesized by granulosa cells, inhibit the recruitment of follicles, and therefore, the selection of follicles that will ovulate, leading to a vicious cycle of anovulation and hyperandrogenism. In addition, by blocking the action of FSH on follicle growth and blocking the action of aromatase in charge of converting androgens synthesized in theca cells to estrogens in granulosa cells, the chronic state of hyperandrogenism is again supported. There is evidence that in patients with PCOS an increased concentration of AMH in follicular fluid exists along with oocytes of low quality. Molecular mechanisms that lead to disruption in the growth and maturation of oocytes are not known [22]. Significantly lower follicular fluid AMH levels were observed in follicles of fertilized MII oocytes than in non-fertilized non-PCOS patients [23]. Also in our non-PCOS patients with sterility and impaired fertility, gene for the AMH and androgen receptor in human cumulus cells surrounding morphologically highly graded oocytes are underexpressed [24].
Hyperinsulinemia, insulin resistance, and obesity are metabolic disorders associated with PCOS that intertwine with hormonal disorders and further worsen the conditions of oocyte microenvironments. Hyperinsulinemia reduces the synthesis of binding globulin for sex hormones (SHBG), and insulin also competes with androgens for binding sites on this carrier, which means that it promotes hyperandrogenism and all its negative effects. The direct effect of hyperinsulinemia on oocytes has been proven to disrupt the expression of genes associated with the dynamics of the division spindle and the function of centrosomes. In the case of insulin resistance, there is a change in gene expression for glucose carriers in granulose cells, and therefore, a possible decrease in energy sources for the metabolism of the oocyte itself and the processes of meiosis [25].
Based on PCOS phenotype in the population of women being treated with medically assisted reproduction procedures, no difference has been found so far in the proportion of oocytes in metaphase II, percentage of fertilization, or the evaluation of quality embryos for transfer [17, 26]. According to available data to date, patients who have a classic PCOS phenotype (A and B) associated with insulin resistance and obesity also have the highest risk for low-quality oocytes [27].
Besides poor quality oocytes, PCOS patients can have larger numbers of germinal vesicle stages – metaphase I oocyte collected from IVF, due to their elevated antral follicles count. Those are commonly maturated with unsatisfactory results. When optimized maturation procedure will serve, not only for PCOS and infertile patients but also in cancer patients for the preservation of fertility and as a more patient-friendly alternative than standard controlled ovarian stimulation. PCOS patients are not the only ones that could benefit from
The definition of phenotypes of polycystic ovarian syndrome stemmed from a diverse and complex clinical picture of this endocrine disorder. Diagnostic criteria of individual phenotype, contribute to new concepts of research into the effects of obesity, hyperandrogenism, and metabolic disorders on reproduction in humans. According to the outcomes of the treatment of infertility of patients with this disorder, significant differences in the chances of conception compared to the population of infertile women who do not have polycystic ovary syndrome have been clearly proven. Less clear is the difference in infertility treatment outcomes between women with a defined polycystic ovarian syndrome phenotype, which is the area of new research. In cases of classical phenotype polycystic ovarian syndrome (A and B) associated with obesity and insulin resistance, negative effects of this disease on gametes and embryos are possible due to cellular process disorders related to glucose and androgen metabolism.
The publication is supported by H2020: MESOC – measuring the social dimension of culture; under Grant agreement no. 870935. Uniri-biomed-18-161 project: Extracellular vesicles in human follicular fluid: content and role in oocyte maturation and embryo quality.
Authors have no conflict of interest.
IntechOpen offers several publishing options to researchers and research groups looking for a professional partner with a wide, international reach. Our publishing options cover the breadth of scientific publications and ensure an appropriate outlet for your research.
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",coverUrl:"https://cdn.intechopen.com/series/covers/3.jpg",latestPublicationDate:"June 30th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:8,editor:{id:"419588",title:"Ph.D.",name:"Sergio",middleName:"Alexandre",surname:"Gehrke",slug:"sergio-gehrke",fullName:"Sergio Gehrke",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000038WgMKQA0/Profile_Picture_2022-06-02T11:44:20.jpg",biography:"Dr. Sergio Alexandre Gehrke is a doctorate holder in two fields. The first is a Ph.D. in Cellular and Molecular Biology from the Pontificia Catholic University, Porto Alegre, Brazil, in 2010 and the other is an International Ph.D. in Bioengineering from the Universidad Miguel Hernandez, Elche/Alicante, Spain, obtained in 2020. In 2018, he completed a postdoctoral fellowship in Materials Engineering in the NUCLEMAT of the Pontificia Catholic University, Porto Alegre, Brazil. He is currently the Director of the Postgraduate Program in Implantology of the Bioface/UCAM/PgO (Montevideo, Uruguay), Director of the Cathedra of Biotechnology of the Catholic University of Murcia (Murcia, Spain), an Extraordinary Full Professor of the Catholic University of Murcia (Murcia, Spain) as well as the Director of the private center of research Biotecnos – Technology and Science (Montevideo, Uruguay). Applied biomaterials, cellular and molecular biology, and dental implants are among his research interests. He has published several original papers in renowned journals. 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She holds a degree in Dentistry from the Federal University of Alfenas (UNIFAL), while her specialization and professional improvement in Stomatology took place at Hospital Heliopolis (São Paulo, SP). Her qualifications are: a specialist in Dental Imaging and Radiology, Master in Dentistry (Periodontics) from the University of São Paulo (FORP-USP, Ribeirão Preto, SP), and Doctor (Ph.D.) in Dentistry (Stomatology Clinic) from Hospital São Lucas of the Pontifical Catholic University of Rio Grande do Sul (HSL-PUCRS, Porto Alegre, RS). She held a postdoctoral internship at the Federal University from Jequitinhonha and Mucuri Valleys (UFVJM, Diamantina, MG). She is currently a member of the Brazilian Society for Dental Research (SBPqO) and the Brazilian Society of Stomatology and Pathology (SOBEP). 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His passion for teaching then led him to join the faculty of dentistry at University Malaya and he has since became a valuable lecturer and clinical specialist in the Department of Restorative Dentistry. He is currently the removable prosthodontic undergraduate year 3 coordinator, head of the undergraduate module on occlusion and a member of the multidisciplinary team for the TMD clinic. He has previous membership in the British Society for Restorative Dentistry, the Malaysian Association of Aesthetic Dentistry and he is currently a lifetime member of the Malaysian Association for Prosthodontics. Currently, he is also the examiner for the Restorative Specialty Membership Examinations, Royal College of Surgeons, England. He has authored and co-authored handful of both local and international journal articles. 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He has published about ninety scientific papers in peer-reviewed international journals and several papers in national and international conferences. He participated as an invited speaker at thirty international conferences. Prof. Rashed is the editor-in-chief and an editorial board member for several international journals in the fields of chemistry and environment. He is a member of several national and international societies. He received the Egyptian State Award for Environmental Research in 2001 and the Aswan University Merit Award for Basic Science in 2020. 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She is now a lecturer at the University of Witwatersrand, South Africa, and a principal researcher at the Health Economics and Epidemiology Research Office (HE2RO), South Africa. Dr. Moolla holds a Ph.D. in Psychology with her research being focused on mental health and resilience. In her professional work capacity, her research has further expanded into the fields of early childhood development, mental health, the HIV and TB care cascades, as well as COVID. She is also a UNESCO-trained International Bioethics Facilitator.",institutionString:"University of the Witwatersrand",institution:{name:"University of the Witwatersrand",country:{name:"South Africa"}}},{id:"419588",title:"Ph.D.",name:"Sergio",middleName:"Alexandre",surname:"Gehrke",slug:"sergio-gehrke",fullName:"Sergio Gehrke",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000038WgMKQA0/Profile_Picture_2022-06-02T11:44:20.jpg",biography:"Dr. Sergio Alexandre Gehrke is a doctorate holder in two fields. The first is a Ph.D. in Cellular and Molecular Biology from the Pontificia Catholic University, Porto Alegre, Brazil, in 2010 and the other is an International Ph.D. in Bioengineering from the Universidad Miguel Hernandez, Elche/Alicante, Spain, obtained in 2020. In 2018, he completed a postdoctoral fellowship in Materials Engineering in the NUCLEMAT of the Pontificia Catholic University, Porto Alegre, Brazil. He is currently the Director of the Postgraduate Program in Implantology of the Bioface/UCAM/PgO (Montevideo, Uruguay), Director of the Cathedra of Biotechnology of the Catholic University of Murcia (Murcia, Spain), an Extraordinary Full Professor of the Catholic University of Murcia (Murcia, Spain) as well as the Director of the private center of research Biotecnos – Technology and Science (Montevideo, Uruguay). Applied biomaterials, cellular and molecular biology, and dental implants are among his research interests. He has published several original papers in renowned journals. In addition, he is also a Collaborating Professor in several Postgraduate programs at different universities all over the world.",institutionString:null,institution:{name:"Universidad Católica San Antonio de Murcia",country:{name:"Spain"}}},{id:"342152",title:"Dr.",name:"Santo",middleName:null,surname:"Grace Umesh",slug:"santo-grace-umesh",fullName:"Santo Grace Umesh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/342152/images/16311_n.jpg",biography:null,institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"333647",title:"Dr.",name:"Shreya",middleName:null,surname:"Kishore",slug:"shreya-kishore",fullName:"Shreya Kishore",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/333647/images/14701_n.jpg",biography:"Dr. Shreya Kishore completed her Bachelor in Dental Surgery in Chettinad Dental College and Research Institute, Chennai, and her Master of Dental Surgery (Orthodontics) in Saveetha Dental College, Chennai. She is also Invisalign certified. She’s working as a Senior Lecturer in the Department of Orthodontics, SRM Dental College since November 2019. She is actively involved in teaching orthodontics to the undergraduates and the postgraduates. Her clinical research topics include new orthodontic brackets, fixed appliances and TADs. She’s published 4 articles in well renowned indexed journals and has a published patency of her own. Her private practice is currently limited to orthodontics and works as a consultant in various clinics.",institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"323731",title:"Prof.",name:"Deepak M.",middleName:"Macchindra",surname:"Vikhe",slug:"deepak-m.-vikhe",fullName:"Deepak M. Vikhe",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/323731/images/13613_n.jpg",biography:"Dr Deepak M.Vikhe .\n\n\t\n\tDr Deepak M.Vikhe , completed his Masters & PhD in Prosthodontics from Rural Dental College, Loni securing third rank in the Pravara Institute of Medical Sciences Deemed University. He was awarded Dr.G.C.DAS Memorial Award for Research on Implants at 39th IPS conference Dubai (U A E).He has two patents under his name. He has received Dr.Saraswati medal award for best research for implant study in 2017.He has received Fully funded scholarship to Spain ,university of Santiago de Compostela. He has completed fellowship in Implantlogy from Noble Biocare. \nHe has attended various conferences and CDE programmes and has national publications to his credit. His field of interest is in Implant supported prosthesis. Presently he is working as a associate professor in the Dept of Prosthodontics, Rural Dental College, Loni and maintains a successful private practice specialising in Implantology at Rahata.\n\nEmail: drdeepak_mvikhe@yahoo.com..................",institutionString:null,institution:{name:"Pravara Institute of Medical Sciences",country:{name:"India"}}},{id:"204110",title:"Dr.",name:"Ahmed A.",middleName:null,surname:"Madfa",slug:"ahmed-a.-madfa",fullName:"Ahmed A. Madfa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204110/images/system/204110.jpg",biography:"Dr. Madfa is currently Associate Professor of Endodontics at Thamar University and a visiting lecturer at Sana'a University and University of Sciences and Technology. He has more than 6 years of experience in teaching. His research interests include root canal morphology, functionally graded concept, dental biomaterials, epidemiology and dental education, biomimetic restoration, finite element analysis and endodontic regeneration. Dr. Madfa has numerous international publications, full articles, two patents, a book and a book chapter. Furthermore, he won 14 international scientific awards. Furthermore, he is involved in many academic activities ranging from editorial board member, reviewer for many international journals and postgraduate students' supervisor. Besides, I deliver many courses and training workshops at various scientific events. Dr. Madfa also regularly attends international conferences and holds administrative positions (Deputy Dean of the Faculty for Students’ & Academic Affairs and Deputy Head of Research Unit).",institutionString:"Thamar University",institution:null},{id:"210472",title:"Dr.",name:"Nermin",middleName:"Mohammed Ahmed",surname:"Yussif",slug:"nermin-yussif",fullName:"Nermin Yussif",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/210472/images/system/210472.jpg",biography:"Dr. Nermin Mohammed Ahmed Yussif is working at the Faculty of dentistry, University for October university for modern sciences and arts (MSA). Her areas of expertise include: periodontology, dental laserology, oral implantology, periodontal plastic surgeries, oral mesotherapy, nutrition, dental pharmacology. She is an editor and reviewer in numerous international journals.",institutionString:"MSA University",institution:null},{id:"204606",title:"Dr.",name:"Serdar",middleName:null,surname:"Gözler",slug:"serdar-gozler",fullName:"Serdar Gözler",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204606/images/system/204606.jpeg",biography:"Dr. Serdar Gözler has completed his undergraduate studies at the Marmara University Faculty of Dentistry in 1978, followed by an assistantship in the Prosthesis Department of Dicle University Faculty of Dentistry. Starting his PhD work on non-resilient overdentures with Assoc. Prof. Hüsnü Yavuzyılmaz, he continued his studies with Prof. Dr. Gürbüz Öztürk of Istanbul University Faculty of Dentistry Department of Prosthodontics, this time on Gnatology. He attended training programs on occlusion, neurology, neurophysiology, EMG, radiology and biostatistics. In 1982, he presented his PhD thesis \\Gerber and Lauritzen Occlusion Analysis Techniques: Diagnosis Values,\\ at Istanbul University School of Dentistry, Department of Prosthodontics. As he was also working with Prof. Senih Çalıkkocaoğlu on The Physiology of Chewing at the same time, Gözler has written a chapter in Çalıkkocaoğlu\\'s book \\Complete Prostheses\\ entitled \\The Place of Neuromuscular Mechanism in Prosthetic Dentistry.\\ The book was published five times since by the Istanbul University Publications. Having presented in various conferences about occlusion analysis until 1998, Dr. Gözler has also decided to use the T-Scan II occlusion analysis method. Having been personally trained by Dr. Robert Kerstein on this method, Dr. Gözler has been lecturing on the T-Scan Occlusion Analysis Method in conferences both in Turkey and abroad. Dr. Gözler has various articles and presentations on Digital Occlusion Analysis methods. He is now Head of the TMD Clinic at Prosthodontic Department of Faculty of Dentistry , Istanbul Aydın University , Turkey.",institutionString:"Istanbul Aydin University",institution:{name:"Istanbul Aydın University",country:{name:"Turkey"}}},{id:"240870",title:"Ph.D.",name:"Alaa Eddin Omar",middleName:null,surname:"Al Ostwani",slug:"alaa-eddin-omar-al-ostwani",fullName:"Alaa Eddin Omar Al Ostwani",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/240870/images/system/240870.jpeg",biography:"Dr. Al Ostwani Alaa Eddin Omar received his Master in dentistry from Damascus University in 2010, and his Ph.D. in Pediatric Dentistry from Damascus University in 2014. Dr. Al Ostwani is an assistant professor and faculty member at IUST University since 2014. \nDuring his academic experience, he has received several awards including the scientific research award from the Union of Arab Universities, the Syrian gold medal and the international gold medal for invention and creativity. Dr. Al Ostwani is a Member of the International Association of Dental Traumatology and the Syrian Society for Research and Preventive Dentistry since 2017. He is also a Member of the Reviewer Board of International Journal of Dental Medicine (IJDM), and the Indian Journal of Conservative and Endodontics since 2016.",institutionString:"International University for Science and Technology.",institution:{name:"Islamic University of Science and Technology",country:{name:"India"}}},{id:"42847",title:"Dr.",name:"Belma",middleName:null,surname:"Işik Aslan",slug:"belma-isik-aslan",fullName:"Belma Işik Aslan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/42847/images/system/42847.jpg",biography:"Dr. Belma IşIk Aslan was born in 1976 in Ankara-TURKEY. After graduating from TED Ankara College in 1994, she attended to Gazi University, Faculty of Dentistry in Ankara. She completed her PhD in orthodontic education at Gazi University between 1999-2005. Dr. Işık Aslan stayed at the Providence Hospital Craniofacial Institude and Reconstructive Surgery in Michigan, USA for three months as an observer. She worked as a specialist doctor at Gazi University, Dentistry Faculty, Department of Orthodontics between 2005-2014. She was appointed as associate professor in January, 2014 and as professor in 2021. Dr. Işık Aslan still works as an instructor at the same faculty. She has published a total of 35 articles, 10 book chapters, 39 conference proceedings both internationally and nationally. Also she was the academic editor of the international book 'Current Advances in Orthodontics'. She is a member of the Turkish Orthodontic Society and Turkish Cleft Lip and Palate Society. She is married and has 2 children. Her knowledge of English is at an advanced level.",institutionString:"Gazi University Dentistry Faculty Department of Orthodontics",institution:null},{id:"178412",title:"Associate Prof.",name:"Guhan",middleName:null,surname:"Dergin",slug:"guhan-dergin",fullName:"Guhan Dergin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178412/images/6954_n.jpg",biography:"Assoc. Prof. Dr. Gühan Dergin was born in 1973 in Izmit. He graduated from Marmara University Faculty of Dentistry in 1999. He completed his specialty of OMFS surgery in Marmara University Faculty of Dentistry and obtained his PhD degree in 2006. In 2005, he was invited as a visiting doctor in the Oral and Maxillofacial Surgery Department of the University of North Carolina, USA, where he went on a scholarship. Dr. Dergin still continues his academic career as an associate professor in Marmara University Faculty of Dentistry. He has many articles in international and national scientific journals and chapters in books.",institutionString:null,institution:{name:"Marmara University",country:{name:"Turkey"}}},{id:"178414",title:"Prof.",name:"Yusuf",middleName:null,surname:"Emes",slug:"yusuf-emes",fullName:"Yusuf Emes",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178414/images/6953_n.jpg",biography:"Born in Istanbul in 1974, Dr. Emes graduated from Istanbul University Faculty of Dentistry in 1997 and completed his PhD degree in Istanbul University faculty of Dentistry Department of Oral and Maxillofacial Surgery in 2005. He has papers published in international and national scientific journals, including research articles on implantology, oroantral fistulas, odontogenic cysts, and temporomandibular disorders. Dr. Emes is currently working as a full-time academic staff in Istanbul University faculty of Dentistry Department of Oral and Maxillofacial Surgery.",institutionString:null,institution:{name:"Istanbul University",country:{name:"Turkey"}}},{id:"192229",title:"Ph.D.",name:"Ana Luiza",middleName:null,surname:"De Carvalho Felippini",slug:"ana-luiza-de-carvalho-felippini",fullName:"Ana Luiza De Carvalho Felippini",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/192229/images/system/192229.jpg",biography:null,institutionString:"University of São Paulo",institution:{name:"University of Sao Paulo",country:{name:"Brazil"}}},{id:"256851",title:"Prof.",name:"Ayşe",middleName:null,surname:"Gülşen",slug:"ayse-gulsen",fullName:"Ayşe Gülşen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/256851/images/9696_n.jpg",biography:"Dr. Ayşe Gülşen graduated in 1990 from Faculty of Dentistry, University of Ankara and did a postgraduate program at University of Gazi. \nShe worked as an observer and research assistant in Craniofacial Surgery Departments in New York, Providence Hospital in Michigan and Chang Gung Memorial Hospital in Taiwan. \nShe works as Craniofacial Orthodontist in Department of Aesthetic, Plastic and Reconstructive Surgery, Faculty of Medicine, University of Gazi, Ankara Turkey since 2004.",institutionString:"Univeristy of Gazi",institution:null},{id:"255366",title:"Prof.",name:"Tosun",middleName:null,surname:"Tosun",slug:"tosun-tosun",fullName:"Tosun Tosun",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255366/images/7347_n.jpg",biography:"Graduated at the Faculty of Dentistry, University of Istanbul, Turkey in 1989;\nVisitor Assistant at the University of Padua, Italy and Branemark Osseointegration Center of Treviso, Italy between 1993-94;\nPhD thesis on oral implantology in University of Istanbul and was awarded the academic title “Dr.med.dent.”, 1997;\nHe was awarded the academic title “Doç.Dr.” (Associated Professor) in 2003;\nProficiency in Botulinum Toxin Applications, Reading-UK in 2009;\nMastership, RWTH Certificate in Laser Therapy in Dentistry, AALZ-Aachen University, Germany 2009-11;\nMaster of Science (MSc) in Laser Dentistry, University of Genoa, Italy 2013-14.\n\nDr.Tosun worked as Research Assistant in the Department of Oral Implantology, Faculty of Dentistry, University of Istanbul between 1990-2002. \nHe worked part-time as Consultant surgeon in Harvard Medical International Hospitals and John Hopkins Medicine, Istanbul between years 2007-09.\u2028He was contract Professor in the Department of Surgical and Diagnostic Sciences (DI.S.C.), Medical School, University of Genova, Italy between years 2011-16. \nSince 2015 he is visiting Professor at Medical School, University of Plovdiv, Bulgaria. \nCurrently he is Associated Prof.Dr. at the Dental School, Oral Surgery Dept., Istanbul Aydin University and since 2003 he works in his own private clinic in Istanbul, Turkey.\u2028\nDr.Tosun is reviewer in journal ‘Laser in Medical Sciences’, reviewer in journal ‘Folia Medica\\', a Fellow of the International Team for Implantology, Clinical Lecturer of DGZI German Association of Oral Implantology, Expert Lecturer of Laser&Health Academy, Country Representative of World Federation for Laser Dentistry, member of European Federation of Periodontology, member of Academy of Laser Dentistry. Dr.Tosun presents papers in international and national congresses and has scientific publications in international and national journals. He speaks english, spanish, italian and french.",institutionString:null,institution:{name:"Istanbul Aydın University",country:{name:"Turkey"}}},{id:"171887",title:"Prof.",name:"Zühre",middleName:null,surname:"Akarslan",slug:"zuhre-akarslan",fullName:"Zühre Akarslan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/171887/images/system/171887.jpg",biography:"Zühre Akarslan was born in 1977 in Cyprus. She graduated from Gazi University Faculty of Dentistry, Ankara, Turkey in 2000. \r\nLater she received her Ph.D. degree from the Oral Diagnosis and Radiology Department; which was recently renamed as Oral and Dentomaxillofacial Radiology, from the same university. \r\nShe is working as a full-time Associate Professor and is a lecturer and an academic researcher. \r\nHer expertise areas are dental caries, cancer, dental fear and anxiety, gag reflex in dentistry, oral medicine, and dentomaxillofacial radiology.",institutionString:"Gazi University",institution:{name:"Gazi University",country:{name:"Turkey"}}},{id:"256417",title:"Associate Prof.",name:"Sanaz",middleName:null,surname:"Sadry",slug:"sanaz-sadry",fullName:"Sanaz Sadry",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/256417/images/8106_n.jpg",biography:null,institutionString:null,institution:null},{id:"272237",title:"Dr.",name:"Pinar",middleName:"Kiymet",surname:"Karataban",slug:"pinar-karataban",fullName:"Pinar Karataban",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/272237/images/8911_n.png",biography:"Assist.Prof.Dr.Pınar Kıymet Karataban, DDS PhD \n\nDr.Pınar Kıymet Karataban was born in Istanbul in 1975. After her graduation from Marmara University Faculty of Dentistry in 1998 she started her PhD in Paediatric Dentistry focused on children with special needs; mainly children with Cerebral Palsy. She finished her pHD thesis entitled \\'Investigation of occlusion via cast analysis and evaluation of dental caries prevalance, periodontal status and muscle dysfunctions in children with cerebral palsy” in 2008. She got her Assist. Proffessor degree in Istanbul Aydın University Paediatric Dentistry Department in 2015-2018. ın 2019 she started her new career in Bahcesehir University, Istanbul as Head of Department of Pediatric Dentistry. In 2020 she was accepted to BAU International University, Batumi as Professor of Pediatric Dentistry. She’s a lecturer in the same university meanwhile working part-time in private practice in Ege Dental Studio (https://www.egedisklinigi.com/) a multidisciplinary dental clinic in Istanbul. Her main interests are paleodontology, ancient and contemporary dentistry, oral microbiology, cerebral palsy and special care dentistry. She has national and international publications, scientific reports and is a member of IAPO (International Association for Paleodontology), IADH (International Association of Disability and Oral Health) and EAPD (European Association of Pediatric Dentistry).",institutionString:null,institution:null},{id:"202198",title:"Dr.",name:"Buket",middleName:null,surname:"Aybar",slug:"buket-aybar",fullName:"Buket Aybar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/202198/images/6955_n.jpg",biography:"Buket Aybar, DDS, PhD, was born in 1971. She graduated from Istanbul University, Faculty of Dentistry, in 1992 and completed her PhD degree on Oral and Maxillofacial Surgery in Istanbul University in 1997.\nDr. Aybar is currently a full-time professor in Istanbul University, Faculty of Dentistry Department of Oral and Maxillofacial Surgery. She has teaching responsibilities in graduate and postgraduate programs. Her clinical practice includes mainly dentoalveolar surgery.\nHer topics of interest are biomaterials science and cell culture studies. She has many articles in international and national scientific journals and chapters in books; she also has participated in several scientific projects supported by Istanbul University Research fund.",institutionString:null,institution:null},{id:"260116",title:"Dr.",name:"Mehmet",middleName:null,surname:"Yaltirik",slug:"mehmet-yaltirik",fullName:"Mehmet Yaltirik",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/260116/images/7413_n.jpg",biography:"Birth Date 25.09.1965\r\nBirth Place Adana- Turkey\r\nSex Male\r\nMarrial Status Bachelor\r\nDriving License Acquired\r\nMother Tongue Turkish\r\n\r\nAddress:\r\nWork:University of Istanbul,Faculty of Dentistry, Department of Oral Surgery and Oral Medicine 34093 Capa,Istanbul- TURKIYE",institutionString:null,institution:null},{id:"172009",title:"Dr.",name:"Fatma Deniz",middleName:null,surname:"Uzuner",slug:"fatma-deniz-uzuner",fullName:"Fatma Deniz Uzuner",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/172009/images/7122_n.jpg",biography:"Dr. Deniz Uzuner was born in 1969 in Kocaeli-TURKEY. After graduating from TED Ankara College in 1986, she attended the Hacettepe University, Faculty of Dentistry in Ankara. \nIn 1993 she attended the Gazi University, Faculty of Dentistry, Department of Orthodontics for her PhD education. After finishing the PhD education, she worked as orthodontist in Ankara Dental Hospital under the Turkish Government, Ministry of Health and in a special Orthodontic Clinic till 2011. Between 2011 and 2016, Dr. Deniz Uzuner worked as a specialist in the Department of Orthodontics, Faculty of Dentistry, Gazi University in Ankara/Turkey. In 2016, she was appointed associate professor. Dr. Deniz Uzuner has authored 23 Journal Papers, 3 Book Chapters and has had 39 oral/poster presentations. She is a member of the Turkish Orthodontic Society. Her knowledge of English is at an advanced level.",institutionString:null,institution:null},{id:"332914",title:"Dr.",name:"Muhammad Saad",middleName:null,surname:"Shaikh",slug:"muhammad-saad-shaikh",fullName:"Muhammad Saad Shaikh",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Jinnah Sindh Medical University",country:{name:"Pakistan"}}},{id:"315775",title:"Dr.",name:"Feng",middleName:null,surname:"Luo",slug:"feng-luo",fullName:"Feng Luo",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Sichuan University",country:{name:"China"}}},{id:"423519",title:"Dr.",name:"Sizakele",middleName:null,surname:"Ngwenya",slug:"sizakele-ngwenya",fullName:"Sizakele Ngwenya",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of the Witwatersrand",country:{name:"South Africa"}}},{id:"419270",title:"Dr.",name:"Ann",middleName:null,surname:"Chianchitlert",slug:"ann-chianchitlert",fullName:"Ann Chianchitlert",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Walailak University",country:{name:"Thailand"}}},{id:"419271",title:"Dr.",name:"Diane",middleName:null,surname:"Selvido",slug:"diane-selvido",fullName:"Diane Selvido",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Walailak University",country:{name:"Thailand"}}},{id:"419272",title:"Dr.",name:"Irin",middleName:null,surname:"Sirisoontorn",slug:"irin-sirisoontorn",fullName:"Irin Sirisoontorn",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Walailak University",country:{name:"Thailand"}}},{id:"355660",title:"Dr.",name:"Anitha",middleName:null,surname:"Mani",slug:"anitha-mani",fullName:"Anitha Mani",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"355612",title:"Dr.",name:"Janani",middleName:null,surname:"Karthikeyan",slug:"janani-karthikeyan",fullName:"Janani Karthikeyan",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"334400",title:"Dr.",name:"Suvetha",middleName:null,surname:"Siva",slug:"suvetha-siva",fullName:"Suvetha Siva",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}}]}},subseries:{item:{id:"6",type:"subseries",title:"Viral Infectious Diseases",keywords:"Novel Viruses, Virus Transmission, Virus Evolution, Molecular Virology, Control and Prevention, Virus-host Interaction",scope:"The Viral Infectious Diseases Book Series aims to provide a comprehensive overview of recent research trends and discoveries in various viral infectious diseases emerging around the globe. The emergence of any viral disease is hard to anticipate, which often contributes to death. A viral disease can be defined as an infectious disease that has recently appeared within a population or exists in nature with the rapid expansion of incident or geographic range. This series will focus on various crucial factors related to emerging viral infectious diseases, including epidemiology, pathogenesis, host immune response, clinical manifestations, diagnosis, treatment, and clinical recommendations for managing viral infectious diseases, highlighting the recent issues with future directions for effective therapeutic strategies.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/6.jpg",hasOnlineFirst:!0,hasPublishedBooks:!0,annualVolume:11402,editor:{id:"158026",title:"Prof.",name:"Shailendra K.",middleName:null,surname:"Saxena",slug:"shailendra-k.-saxena",fullName:"Shailendra K. Saxena",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRET3QAO/Profile_Picture_2022-05-10T10:10:26.jpeg",biography:"Professor Dr. Shailendra K. Saxena is a vice dean and professor at King George's Medical University, Lucknow, India. His research interests involve understanding the molecular mechanisms of host defense during human viral infections and developing new predictive, preventive, and therapeutic strategies for them using Japanese encephalitis virus (JEV), HIV, and emerging viruses as a model via stem cell and cell culture technologies. His research work has been published in various high-impact factor journals (Science, PNAS, Nature Medicine) with a high number of citations. He has received many awards and honors in India and abroad including various Young Scientist Awards, BBSRC India Partnering Award, and Dr. JC Bose National Award of Department of Biotechnology, Min. of Science and Technology, Govt. of India. Dr. Saxena is a fellow of various international societies/academies including the Royal College of Pathologists, United Kingdom; Royal Society of Medicine, London; Royal Society of Biology, United Kingdom; Royal Society of Chemistry, London; and Academy of Translational Medicine Professionals, Austria. He was named a Global Leader in Science by The Scientist. He is also an international opinion leader/expert in vaccination for Japanese encephalitis by IPIC (UK).",institutionString:"King George's Medical University",institution:{name:"King George's Medical University",institutionURL:null,country:{name:"India"}}},editorTwo:null,editorThree:null,series:{id:"6",title:"Infectious Diseases",doi:"10.5772/intechopen.71852",issn:"2631-6188"},editorialBoard:[{id:"188773",title:"Prof.",name:"Emmanuel",middleName:null,surname:"Drouet",slug:"emmanuel-drouet",fullName:"Emmanuel Drouet",profilePictureURL:"https://mts.intechopen.com/storage/users/188773/images/system/188773.png",institutionString:null,institution:{name:"Grenoble Alpes University",institutionURL:null,country:{name:"France"}}},{id:"188219",title:"Prof.",name:"Imran",middleName:null,surname:"Shahid",slug:"imran-shahid",fullName:"Imran Shahid",profilePictureURL:"https://mts.intechopen.com/storage/users/188219/images/system/188219.jpeg",institutionString:null,institution:{name:"Umm al-Qura University",institutionURL:null,country:{name:"Saudi Arabia"}}},{id:"214235",title:"Dr.",name:"Lynn",middleName:"S.",surname:"Zijenah",slug:"lynn-zijenah",fullName:"Lynn Zijenah",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSEJGQA4/Profile_Picture_1636699126852",institutionString:null,institution:{name:"University of Zimbabwe",institutionURL:null,country:{name:"Zimbabwe"}}},{id:"178641",title:"Dr.",name:"Samuel Ikwaras",middleName:null,surname:"Okware",slug:"samuel-ikwaras-okware",fullName:"Samuel Ikwaras Okware",profilePictureURL:"https://mts.intechopen.com/storage/users/178641/images/system/178641.jpg",institutionString:null,institution:{name:"Uganda Christian University",institutionURL:null,country:{name:"Uganda"}}}]},onlineFirstChapters:{paginationCount:15,paginationItems:[{id:"82195",title:"Endoplasmic Reticulum: A Hub in Lipid Homeostasis",doi:"10.5772/intechopen.105450",signatures:"Raúl Ventura and María Isabel Hernández-Alvarez",slug:"endoplasmic-reticulum-a-hub-in-lipid-homeostasis",totalDownloads:4,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Updates on Endoplasmic Reticulum",coverURL:"https://cdn.intechopen.com/books/images_new/11674.jpg",subseries:{id:"14",title:"Cell and Molecular Biology"}}},{id:"82103",title:"The Role of Endoplasmic Reticulum Stress and Its Regulation in the Progression of Neurological and Infectious Diseases",doi:"10.5772/intechopen.105543",signatures:"Mary Dover, Michael Kishek, Miranda Eddins, Naneeta Desar, Ketema Paul and Milan Fiala",slug:"the-role-of-endoplasmic-reticulum-stress-and-its-regulation-in-the-progression-of-neurological-and-i",totalDownloads:6,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Updates on Endoplasmic Reticulum",coverURL:"https://cdn.intechopen.com/books/images_new/11674.jpg",subseries:{id:"14",title:"Cell and Molecular Biology"}}},{id:"80954",title:"Ion Channels and Neurodegenerative Disease Aging Related",doi:"10.5772/intechopen.103074",signatures:"Marika Cordaro, Salvatore Cuzzocrea and Rosanna Di Paola",slug:"ion-channels-and-neurodegenerative-disease-aging-related",totalDownloads:7,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Ion Channels - From Basic Properties to Medical Treatment",coverURL:"https://cdn.intechopen.com/books/images_new/10838.jpg",subseries:{id:"14",title:"Cell and Molecular Biology"}}},{id:"81647",title:"Diabetes and Epigenetics",doi:"10.5772/intechopen.104653",signatures:"Rasha A. 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Behind these definitions are hidden all the aspects of normal and pathological functioning of all processes that the topic ‘Metabolism’ will cover within the Biochemistry Series. 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Thus proteomics, an area of research that detects all protein forms expressed in an organism, including splice isoforms and post-translational modifications, is more suitable than genomics for a comprehensive understanding of the biochemical processes that govern life. The most common proteomics applications are currently in the clinical field for the identification, in a variety of biological matrices, of biomarkers for diagnosis and therapeutic intervention of disorders. From the comparison of proteomic profiles of control and disease or different physiological states, which may emerge, changes in protein expression can provide new insights into the roles played by some proteins in human pathologies. Understanding how proteins function and interact with each other is another goal of proteomics that makes this approach even more intriguing. Specialized technology and expertise are required to assess the proteome of any biological sample. Currently, proteomics relies mainly on mass spectrometry (MS) combined with electrophoretic (1 or 2-DE-MS) and/or chromatographic techniques (LC-MS/MS). MS is an excellent tool that has gained popularity in proteomics because of its ability to gather a complex body of information such as cataloging protein expression, identifying protein modification sites, and defining protein interactions. 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