Human Reproductive Process Research Articles

Exploring the black box of human reproduction: endometrial organoids and assembloids - generation, implantation modeling, and future clinical perspectives.

One of the critical processes in human reproduction that is still poorly understood is implantation. The implantation of an early human embryo is considered a significant limitation of successful pregnancy. Therefore, researchers are trying to develop an ideal model of endometrium in vitro that can mimic the endometrial micro-environment in vivo as much as possible. The ultimate goal of endometrial modeling is to study the molecular interactions at the embryo-maternal interface and to use this model as an in vitro diagnostic tool for infertility. Significant progress has been made over the years in generating such models. The first experiments of endometrial modeling involved animal models, which are undoubtedly valuable, but at the same time, their dissimilarities with human tissue represent a significant obstacle to further research. This fact led researchers to develop basic monolayer coculture systems using uterine cells obtained from biopsies and, later on, complex and multilayer coculture models. With successful tissue engineering methods and various cultivation systems, it is possible to form endometrial two-dimensional (2D) models to three-dimensional (3D) organoids and novel assembloids that can recapitulate many aspects of endometrial tissue architecture and cell composition. These organoids have already helped to provide new insight into the embryo-endometrium interplay. The main aim of this paper is a comprehensive review of past and current approaches to endometrial model generation, their feasibility, and potential clinical application for infertility treatment.

Demographic Development of Russia within the Boundaries of Human Capital Theory: Problems and Solutions

The article outlines the role of the demographic situation in ensuring the development of the socio-economic system of the country. In the process of empirical research, the dynamics of the list of indicators characterizing the demographic situation in Russia is considered. The calculation of the absolute indicator of the population is presented, which allows to reveal of the numerical losses of human capital. The fact that the reduction of the country’s population was due to the population of rural areas was established. It is also noted that there was a constant increase in the number of population over working age, as well as a decrease in the working-age population. The decrease in the existing volumes of human capital has led to certain economic losses expressed in the form of lost GDP, which the socio-economic system has incurred. In the context of the above trends, the preservation of the existing human capital, which can be assessed on the basis of the dynamics of indicators: life expectancy and the number of marriages and divorces, becomes a priority. The processes of human capital reproduction represent one of the important directions of demographic development in Russia. The authors determined that these processes have a negatively directed tendency to change. This problem is considered from the position of the functioning of the family institution and the dynamics of the divorce process. An analytical study of statistical data allowed us to conclude that the intensity of marriages in Russia during ten years was higher than the intensity of divorces. The calculated value of the coefficient of preservation of family relations indicates an increase in the probability of reproduction of human capital. The authors calculated the numerical value of reserve human capital in the form of the volume of potential labor force, which can provide an additional volume of GDP.

Balancing nutrition for successful reproduction in ruminants

AbstractProper nutrition is essential for sustaining optimal reproductive function in both humans and ruminants. Studies have shown that both undernutrition and overnutrition can negatively impact human reproductive processes. However, the Mediterranean diet, with its balanced and nutrient‐rich composition, is recognised for its positive effects on human reproduction. In the context of ruminants, a well‐balanced and nutrient‐rich diet is equally crucial for achieving peak reproductive performance. Grazing, which allows ruminants to feed on natural pasture in open environments, contrasts with indoor feeding, which is conducted in more controlled settings. A balanced dietary approach is vital for the successful reproduction of ruminant animals, and a combination of grazing and indoor feeding has been identified as an effective strategy to enhance their reproductive success. This review emphasises the impact of nutrition on reproductive outcomes in both human and ruminant populations, advocating for balanced dietary practices to improve reproductive success across species. A thorough understanding of the complex relationship between nutrition and reproductive health can offer valuable insights into enhancing fertility and reproductive efficiency in various contexts.

GPR124 promotes trophoblast proliferation, migration, and invasion and inhibits trophoblast cell apoptosis and inflammation via JNK and P38 MAPK pathways.

Early-onset preeclampsia, which occurrs before 34 weeks of gestation, is the most dangerous classification of preeclampsia, which is a pregnancy-specific disease that causes 1% of maternal deaths. G protein-coupled receptor 124 (GPR124) is significantly expressed at various stages of the human reproductive process, particularly during embryogenesis and angiogenesis. Our prior investigation demonstrated a notable decrease in GPR124 expression in the placentas of patients with early-onset preeclampsia compared to that in normal pregnancy placentas. However, there is a lack of extensive investigation into the molecular processes that contribute to the role of GPR124 in placenta development. This study aimed to examine the mechanisms by which GPR124 affects the occurrence of early-onset preeclampsia and its function in trophoblast. Proliferative, invasive, migratory, apoptotic, and inflammatory processes were identified in GPR124 knockdown, GPR124 overexpression, and normal HTR8/SVneo cells. The mechanism of GPR124-mediated cell function in GPR124 knockdown HTR8/SVneo cells was examined using inhibitors of the JNK or P38 MAPK pathway. Downregulation of GPR124 was found to significantly inhibit proliferation, invasion and migration, and promote apoptosis of HTR8/SVneo cells when compared to the control and GPR124 overexpression groups. This observation is consistent with the pathological characteristics of preeclampsia. In addition, GPR124 overexpression inhibits the secretion of pro-inflammatory cytokines interleukin (IL)-8 and interferon-γ (IFN-γ) while enhancing the secretion of the anti-inflammatory cytokine interleukin (IL)-4. Furthermore, GPR124 suppresses the activation of P-JNK and P-P38 within the JNK/P38 MAPK pathway. The invasion, apoptosis, and inflammation mediated by GPR124 were partially restored by suppressing the JNK and P38 MAPK pathways in HTR8/SVneo cells. GPR124 plays a crucial role in regulating trophoblast proliferation, invasion, migration, apoptosis, and inflammation via the JNK and P38 MAPK pathways. Furthermore, the effect of GPR124 on trophoblast suggests its involvement in the pathogenesis of early-onset preeclampsia.

Gender features of human capital development in the Republic of Kazakhstan

The basis of this study was the analysis of the human capital reproductive processes in the Republic of Kazakhstan, considering the gender component. The object was the human capital of Kazakhstan’s regions, and the subject was the gender aspect of human capital development. Mincer’s supplemented human capital assessment model was the primary model for calculating human capital. Factors influencing the effective use of human capital in the regions, considering the gender component, were identified, and their indices were calculated. The analysis showed a persistent gender gap in life expectancy, education level, income, and labour market. Based on the results, leader and outsider regions in terms of the accumulated human capital level were identified. The analysis indicates the responsible attitude of the government of the Republic of Kazakhstan towards developing gender equality. Over the past ten years, Kazakhstan has advanced significantly in its efforts to empower women in the socio-political sphere. The Republic of Kazakhstan has assumed obligations under several international agreements, adopted many laws, and developed government measures critical for increasing women’s participation in government activities.

The right to delayed parenthood/maternity – separate issues of legal regulation

The article analyzes the peculiarities of legal relations arising in connection with the cryopreservation of human biological material – embryos and reproductive cells, namely: determining the origin of a child born in this way. It is noted that the birth of children is a component of the demographic policy of the state, and the use of assisted reproductive technologies can change the demographic situation in society for the better. Cryopreservation is relevant not only in cases when a couple who wants to have children have difficulties with conception, but also when such problems do not yet exist, but they may arise with a high probability – this applies to such categories of citizens who are undergoing treatment for oncological diseases with a risk of loss reproductive health, as well as citizens who constantly risk their lives and health due to their activities: military personnel, policemen or workers at factories with harmful working conditions.
 The author notes that medical biotechnologies are becoming more and more diverse and effective, scientific achievements are penetrating deeper and deeper into the natural processes of human reproduction, therefore there is a need to resolve legal issues related to cryopreservation. And the realization of the right to cryopreservation requires legal regulation of so-called delayed parenthood.
 From the point of view of family law, these relations are of interest in terms of the emergence of new family law relations. The author considers several models for determining the origin of a child born with the use of assisted reproductive technologies using cryopreserved reproductive cells or embryos. Separate issues of postmortem reproduction are considered.
 The author concludes that there is a need for legislative regulation of gaps in the field of cryopreservation of reproductive cells and embryos, which will allow to ensure proper consolidation of the guarantee of the right to paternity/maternity and an effective mechanism for their implementation in cases of restriction of vital activity or death of a person.

Long noncoding RNAs in human reproductive processes and diseases.

Infertility has become a global disease burden. Although assisted reproductive technologies are widely used, the assisted reproduction birth rate is no more than 30% worldwide. Therefore, understanding the mechanisms of reproduction can provide new strategies to improve live birth rates and clinical outcomes of enhanced implantation. Long noncoding RNAs (lncRNAs)have been reported to exert regulatory roles in various biological processes and diseases in many species. In this review, we especially focus on the role of lncRNAs in human reproduction. We summarize the function and mechanisms of lncRNAs in processes vital to reproduction, such as spermatogenesis and maturation, sperm motility and morphology, follicle development and maturation, embryo development and implantation. Then, we highlight the importance and diverse potential of lncRNAs as good diagnostic molecular biomarkers and therapeutic targets for infertility treatment.

Down-regulated Wnt7a and GPR124 in early-onset preeclampsia placentas reduce invasion and migration of trophoblast cells.

Preeclampsia (PE) is a disease specific to pregnancy that causes 9-10 % of maternal deaths. Early-onset PE (<34 weeks' gestation) is the most dangerous category of PE. Wnt7a and GPR124 (G protein-coupled receptor 124) are widely expressed in the human reproductive process. Especially during embryogenesis and tumorigenesis, Wnt7a plays a crucial role. However, few studies have examined the association between Wnt7a-GPR124 and early-onset PE. The aim of this study was to examine the significance of Wnt7a and GPR124 in early-onset PE as well as Wnt7a's role in trophoblast cells. Immunohistochemistry (IHC), real-time PCR, and western blotting (WB) were used to investigate Wnt7a and GPR124 expression in normal and early-onset PE placentas. Additionally, FACS, Transwell, and CCK-8 assays were used to diagnose Wnt7a involvement in migration, invasion, and proliferation. In the early-onset PE group, Wnt7a and GPR124 expression was significantly lower than in the normal group, especially in the area of syncytiotrophoblasts (STBs) and extravillous trophoblasts (EVTs). A negative correlation was found between Wnt7a RNA and GPR124 expression (r=-0.42, p<0.01). However, the Wnt7a RNA expression level was positive correlated with PE severity. In further cellular functional experiments, knockdown of Wnt7a inhibits HTR8/SVeno cells invasion and migration but has little effect on proliferation and apoptosis. Through the Wnt pathway, Wnt7a regulates trophoblast cell invasion and migration, and may contribute to early-onset preeclampsia pathogenesis. A molecular level study of Wnt7a will be needed to find downstream proteins and mechanisms of interaction.

O-304 Whole-exome sequencing in women with reproductive failure is a potentially useful diagnostic test in clinical practice

Abstract Study question Could whole-exome sequencing (WES) be useful in clinical practice for primary infertile female involving oocyte or embryo defects and unexplained recurrent miscarriage (RM) patients? Summary answer Identifying key genes involved in oocyte and embryo development helps explain approximately 17% cases of reproductive failure. WES results will help optimize clinical therapeutic treatment. What is known already Dozens of genes have been reported to be the genetic causes of human infertility. Variants in these genes have specific effects on certain processes of human early reproduction and result in a spectrum of phenotypes, such as oocyte maturation arrest, fertilization defects, cleavage failure, early embryonic lethality, and recurrent miscarriage. Study design, size, duration This retrospective cohort study was conducted from July 2020 to August 2022. A total of 129 affected females were enrolled. Most of them were primary infertile women who suffered repeated failure of in vitro fertilization (≥2 cycles) due to abnormal development of oocytes or embryos (PI group, n = 125). Our cohort also comprised a small number of unexplained RM subjects without offspring (RM group, n = 4). All patients and their spouses had normal karyotype. Participants/materials, setting, methods The peripheral blood samples from all the participants and all of their available family members were obtained for DNA extraction. Genomic DNA samples from the probands were subjected to WES to identify candidate variants. Subsequently, the variants were validated by Sanger sequencing or qPCR. Familial co-segregation analyses were then carried out within the family members. The relationship between phenotype and genotype by clinical tests and the clinical records of the patients was studied. Main results and the role of chance Firstly, variants that are potentially relevant to the phenotypes of female infertility were identified in 17.05% of cases (n = 22), including TUBB8 in 14 cases, PATL2 in 2 cases, ZP2, ZP3, PANX1, TLE6, NLRP2 and NLRP7 in 1 case for each. A breakdown by phenotype revealed that we identified variants in 16.00% (n = 20) of PI group and 50% (n = 2) of RM group. Secondly, 16 TUBB8 variants were identified in 14 cases, of which 8 were novel, 3 were previously reported, and 5 were novel amino acid change occurring at the same position as another previously reported change. We found 3 TUBB8 variants (p.C211R, p.T232I, p.A342T) in 3 embryonic arrest families and 1 TUBB8 mutation (p.A102V) in a RM family, which were maternally inherited. Thirdly, 75 patients in PI group without phenotypic variant underwent ≥1 cycles of ovulation and/or frozen embryo transfer after WES, and 49.33% had achieved clinical pregnancy (n = 37). Limitations, reasons for caution The genomic DNA of parents were not available in all these 22 families, so we cannot determine whether the variant is de novo or inherited in some cases. Additionally, further functional studies should be performed to prove that these novel mutations affect protein function. Wider implications of the findings The present study expands the kinds of variants and phenotypic spectrum of gene mutations with regard to female reproductive failure. Genetic tests for causative genes involved in oocyte and embryo defects were recommended for primary infertile patients who suffered from these conditions and for unexplained RM patients. Trial registration number not applicable

The Therapeutic Potential of Multipotent Mesenchymal Stromal Cell-Derived Extracellular Vesicles in Endometrial Regeneration.

Disruption of endometrial regeneration, fibrosis formation, and intrauterine adhesions underlie the development of "thin" endometrium and/or Asherman's syndrome (AS) and are a common cause of infertility and a high risk for adverse obstetric outcomes. The methods used (surgical adhesiolysis, anti-adhesive agents, and hormonal therapy) do not allow restoration of the regenerative properties of the endometrium. The experience gained today with cell therapy using multipotent mesenchymal stromal cells (MMSCs) proves their high regenerative and proliferative properties in tissue damage. Their contribution to regenerative processes is still poorly understood. One of these mechanisms is based on the paracrine effects of MMSCs associated with the stimulation of cells of the microenvironment by secreting extracellular vesicles (EVs) into the extracellular space. EVs, whose source is MMSCs, are able to stimulate progenitor cells and stem cells in damaged tissues and exert cytoprotective, antiapoptotic, and angiogenic effects. This review described the regulatory mechanisms of endometrial regeneration, pathological conditions associated with a decrease in endometrial regeneration, and it presented the available data from studies on the effect of MMSCs and their EVs on endometrial repair processes, and the involvement of EVs in human reproductive processes at the level of implantation and embryogenesis.

Incorporando la bioética ambiental a los cuidados materno perinatales para disminuir los riesgos de la Pan-Sindemia en el proceso reproductivo.

Until now, the bioethical approach to maternal perinatal care is projected from the integral vision of bio-psycho-social health, the perspective of Human Rights and the gender perspective. In general, the ecological bioethics that arises from the perspective of environmental health has not been incorporated into maternal-perinatal care with regard to “global ethics”, environmental bioethics, the perspective of “consilience” and the importance of the healthy environment as a human right. The current global crisis situation due to the combination of the COVID 19 Pandemic and the Global Syndemic, characterized as Pan Syndemic, increases the risks and damages in the reproductive process, especially in populations violated in their rights. JUSTIFICATION It is necessary to minimize the effect of the Pan Syndemic on the human reproductive process. On the global agenda, humanity must reverse the causes of the Pan Syndemic. Meanwhile, health professionals and teams must reformulate their role when it comes to maternal-perinatal care, incorporating into the clinic the right to a healthy environment for reproduction. PERSPECTIVES Modifications in the clinical practice of sexual and reproductive health teams should be aimed at: incorporate ecological bioethics into maternal perinatal care from training to clinical practice; develop a comprehensive approach to major perinatal obstetric syndromes, prematurity and fetal growth restriction, to minimize the impact of the Pan Syndemic on the human reproductive process.

Corrigendum to: Direct action of leptin, obestatin and ginkgo on hormone release by luteinised human ovarian granulosa cells.

The role of metabolic hormones, medicinal plants and their interrelationships in the control of human reproductive processes are poorly understood. To examine how leptin, obestatin and ginkgo (Ginkgo biloba L.) affect human ovarian hormone release. We analysed the influence of leptin and obestatin alone and in combination with ginkgo extract on cultured human ovarian granulosa cells. The release of progesterone (P), insulin-like growth factor I (IGF-I), oxytocin (OT) and prostaglandin F (PGF) were analysed by enzyme immunoassay and enzyme-linked immunosorbent assay. Leptin addition promoted the release of all the measured hormones. Obestatin stimulated the release of P, IGF-I and OT and inhibited PGF output. Ginkgo suppressed P, IGF-I and OT and promoted PGF release. Furthermore, ginkgo changed the stimulatory action of leptin on PGF to an inhibitory one. Leptin and obestatin are involved in the control of human ovarian hormone release and ginkgo influences their function. Leptin and obestatin could be useful as stimulators of human ovarian cell functions. The suppressive influence of ginkgo on ovarian function should lead to the development of ginkgo-containing drugs.

Direct action of leptin, obestatin and ginkgo on hormone release by luteinised human ovarian granulosa cells.

The role of metabolic hormones, medicinal plants and their interrelationships in the control of human reproductive processes are poorly understood. To examine how leptin, obestatin and ginkgo (Ginkgo biloba L.) affect human ovarian hormone release. We analysed the influence of leptin and obestatin alone and in combination with ginkgo extract on cultured human ovarian granulosa cells. The release of progesterone (P), insulin-like growth factor I (IGF-I), oxytocin (OT) and prostaglandin F (PGF) were analysed by enzyme immunoassay and enzyme-linked immunosorbent assay. Leptin addition promoted the release of all the measured hormones. Obestatin stimulated the release of P, IGF-I and OT and inhibited PGF output. Ginkgo suppressed P, IGF-I and OT and promoted PGF release. Furthermore, ginkgo changed the stimulatory action of leptin on PGF to an inhibitory one. Leptin and obestatin are involved in the control of human ovarian hormone release and ginkgo influences their function. Leptin and obestatin could be useful as stimulators of human ovarian cell functions. The suppressive influence of ginkgo on ovarian function should lead to the development of ginkgo-containing drugs.

The mitochondrial protease LONP1 maintains oocyte development and survival by suppressing nuclear translocation of AIFM1 in mammals.

SummaryBackgroundOogenesis is a fundamental process of human reproduction, and mitochondria play crucial roles in oocyte competence. Mitochondrial ATP-dependent Lon protease 1 (LONP1) functions as a critical protein in maintaining mitochondrial and cellular homeostasis in somatic cells. However, the essential role of LONP1 in maintaining mammalian oogenesis is far from elucidated.MethodsUsing conditional oocyte Lonp1-knockout mice, RNA sequencing (RNA-seq) and coimmunoprecipitation/liquid chromatography–mass spectrometry (Co-IP/LC–MS) technology, we analysed the functions of LONP1 in mammalian oogenesis.FindingsConditional knockout of Lonp1 in mouse oocytes in both the primordial and growing follicle stages impairs follicular development and causes progressive oocyte death, ovarian reserve loss, and infertility. LONP1 directly interacts with apoptosis inducing factor mitochondria-associated 1 (AIFM1), and LONP1 ablation leads to the translocation of AIFM1 from the cytoplasm to the nucleus, causing apoptosis in mouse oocytes. In addition, women with pathogenic variants of LONP1 lack large antral follicles (>10 mm) in the ovaries, are infertile and present premature ovarian insufficiency.InterpretationWe demonstrated the function of LONP1 in regulating oocyte development and survival, and in-depth analysis of LONP1 will be crucial for elucidating the mechanisms underlying premature ovarian insufficiency.FundingThis work was supported by grants from the National Key Research and Development Program of China (2018YFC1004701), the National Nature Science Foundation of China (82001629, 81871128, 81571391, 81401166, 82030040), the Jiangsu Province Social Development Project (BE2018602), the Jiangsu Provincial Medical Youth Talent (QNRC2016006), the Youth Program of the Natural Science Foundation of Jiangsu Province (BK20200116) and Jiangsu Province Postdoctoral Research Funding (2021K277B).

Genetic factors as potential molecular markers of human oocyte and embryo quality.

Successful human reproduction requires gamete maturation, fertilization, and early embryonic development. Human oocyte maturation includes nuclear and cytoplasmic maturation, and abnormalities in the process will lead to infertility and recurrent failure of IVF/ICSI attempts. In addition, the quality of oocytes/embryos in the clinic can only be determined by morphological markers, and there is currently a lack of molecular markers for determining oocyte quality. As the number of patients undergoing IVF/ICSI has increased, many patients have been identified with recurrent IVF/ICSI failure. However, the genetic basis behind this phenotype remains largely unknown. In recent years, a few mutant genes have been identified by us and others, which provide potential molecular markers for determining the quality of oocytes/embryos. In this review, we outline the genetic determinants of abnormalities in the processes of oocyte maturation, fertilization, and early embryonic development. Currently, 16 genes (PATL2, TUBB8, TRIP13, ZP1, ZP2, ZP3, PANX1, TLE6, WEE2, CDC20, BTG4, PADI6, NLRP2, NLRP5, KHDC3L, and REC114) have been reported to be the causes of oocyte maturation arrest, fertilization failure, embryonic arrest, and preimplantation embryonic lethality. These abnormalities mainly have Mendelian inheritance patterns, including both dominant inheritance and recessive inheritance, although in some cases de novo mutations have also appeared. In this review, we will introduce the effects of each gene in the specific processes of human early reproduction and will summarize all known variants in these genes and their corresponding phenotypes. Variants in some genes have specific effects on certain steps in the early human reproductive processes, while other variants result in a spectrum of phenotypes. These variants and genetic markers will lay the foundation for individualized genetic counseling and potential treatments for patients and will be the target for precision treatments in reproductive medicine.

The Influence of Plant Isoflavones Daidzein and Equol on Female Reproductive Processes

In this review, we explore the current literature on the influence of the plant isoflavone daidzein and its metabolite equol on animal and human physiological processes, with an emphasis on female reproduction including ovarian functions (the ovarian cycle; follicullo- and oogenesis), fundamental ovarian-cell functions (viability, proliferation, and apoptosis), the pituitary and ovarian endocrine regulators of these functions, and the possible intracellular mechanisms of daidzein action. Furthermore, we discuss the applicability of daidzein for the control of animal and human female reproductive processes, and how to make this application more efficient. The existing literature demonstrates the influence of daidzein and its metabolite equol on various nonreproductive and reproductive processes and their disorders. Daidzein and equol can both up- and downregulate the ovarian reception of gonadotropins, healthy and cancerous ovarian-cell proliferation, apoptosis, viability, ovarian growth, follicullo- and oogenesis, and follicular atresia. These effects could be mediated by daidzein and equol on hormone production and reception, reactive oxygen species, and intracellular regulators of proliferation and apoptosis. Both the stimulatory and the inhibitory effects of daidzein and equol could be useful for reproductive stimulation, the prevention and mitigation of cancer development, and the adverse effects of environmental stressors in reproductive biology and medicine.

The Role of Arachidonic and Linoleic Acid Derivatives in Pathological Pregnancies and the Human Reproduction Process.

The aim of the available literature review was to focus on the role of the proinflammatory mediators of AA and LA derivatives in pathological conditions related to reproduction and pregnancy. Arachidonic (AA) and linoleic acid (LA) derivatives play important roles in human fertility and the course of pathological pregnancies. Recent studies have demonstrated that uncontrolled inflammation has a significant impact on reproduction, spermatogenesis, endometriosis, polycystic ovary syndrome (PCOS) genesis, implantation, pregnancy and labor. In addition, cyclooxygenase-mediated prostaglandins and AA metabolite levels are higher in women’s ovarian tissue when suffering from PCOS. It has been demonstrated that abnormal cyclooxygenase-2 (COX-2) levels are associated with ovulation failure, infertility, and implantation disorders and the increase in 9-HODE/13-HODE was a feature recognized in PCOS patients. Maintaining inflammation without neutrophil participation allows pregnant women to tolerate the fetus, while excessive inflammatory activation may lead to miscarriages and other pathological complications in pregnancies. Additionally AA and LA derivatives play an important role in pregnancy pathologies, e.g., gestational diabetes mellitus, preeclampsia (PE), and fetal growth, among others. The pathogenesis of PE and other pathological states in pregnancy involving eicosanoids have not been fully identified. A significant expression of 15-LOX-1,2 was found in women with PE, leading to an increase in the synthesis of AA and LA derivatives, such as hydroxyeicozatetraenoic acids (HETE) and hydroxyoctadecadiene acids (HODE). Synthesis of the metabolites 5-, 8-, 12-, and 15-HETE increased in the placenta, while 20-HETE increased only in umbilical cord blood in women with preeclampsia compared to normal pregnancies. In obese women with gestational diabetes mellitus (GDM) an increase in epoxygenase products in the cytochrome P450 (CYP) and the level of 20-HETE associated with the occurrence of insulin resistance (IR) were found. In addition, 12- and 20-HETE levels were associated with arterial vasoconstriction and epoxyeicosatrienoic acids (EETs) with arterial vasodilatation and uterine relaxation. Furthermore, higher levels of 5- and 15-HETE were associated with premature labor. By analyzing the influence of free fatty acids (FFA) and their derivatives on male reproduction, it was found that an increase in the AA in semen reduces its amount and the ratio of omega-6 to omega-3 fatty acids showed higher values in infertile men compared to the fertile control group. There are several studies on the role of HETE/HODE in relation to male fertility. 15-Hydroperoxyeicosatetraenoic acid may affect the integrity of the membrane and sperm function. Moreover, the incubation of sperm with physiologically low levels of prostaglandins (PGE2/PGF2α) improves the functionality of human sperm. Undoubtedly, these problems are still insufficiently understood and require further research. However, HETE and HODE could serve as predictive and diagnostic biomarkers for pregnancy pathologies (especially in women with risk factors for overweight and obesity). Such knowledge may be helpful in finding new treatment strategies for infertility and the course of high-risk pregnancies.

New insights into the processes of biological evolution and human reproduction provided through a dialogue between science and Qur’an

In this paper I present new insights into the processes of biological evolution and human reproduction in the light of a dialogue between the current scientific knowledge and Qur‟an verses. I demonstrate how this dialogue could provide new complementary information and a more comprehensive state of each of these two processes. After clearing up some confusions and uncertainties related to the biological evolution process I propose a new vision for this process considering that the Creator (Allah) of the entire Universe had organized and supervised the emergence of living beings depending on a wonderful evolutionary plan. As this vision is hopefully in agreement with my interpretations of related Qur‟an verses, I concretize it from them. One of scientific paintings deduced from these verses shows how our humankind emerged at the top of a complex network of evolutionary stages evolved from the earth like the emergence of the upper part of the top of a tree. To the second biological process „Human Reproduction‟ Allah gives a more accurate designation „Human Picturing Creation‟ insisting on the fact that the major acts of this process do not happen randomly but under His supervision. Moreover Allah given to the major elements of this process, wonderful designations including some unnoticed details through superb rhetoric formats peculiar to Qur‟an. At the end of this paper I point out that my interpretations of Qur‟an verses, based on new rigorous methodology, are generally different from the existing ones showing how the latter include errors and distortions making them incompatible with science. More bad consequences, such as terrorism, have been the result of erroneous interpretations of some verses on socio-political issues. To solve this problem of erroneous interpretations and related false considerations that have accumulated through the ages and were merged into cultures of Muslim societies, I call for a “First International Real Renewal of Islam”&#x0D; Key words: Qur‟an interpretation, Biological evolution, Supernatural Creator, Limits of science, Human reproduction, Picturing creation, Human gametes, Human zygote, Human embryogenesis, Real Renewal of Islam.

Prokineticin receptor 2 affects GnRH3 neuron ontogeny but not fertility in zebrafish

Prokineticin receptors (PROKR1 and PROKR2) are G protein-coupled receptors which control human central and peripheral reproductive processes. Importantly, allelic variants of PROKR2 in humans are associated with altered migration of GnRH neurons, resulting in congenital hypogonadotropic hypogonadism (CHH), a heterogeneous disease characterized by delayed/absent puberty and/or infertility. Although this association is established in humans, murine models failed to fully recapitulate the reproductive and olfactory phenotypes observed in patients harboring PROKR2 mutations. Here, taking advantage of zebrafish model we investigated the role of prokr1b (ortholog of human PROKR2) during early stages of GnRH neuronal migration. Real-Time PCR and whole mount in situ hybridization assays indicate that prokr1b spatial-temporal expression is consistent with gnrh3. Moreover, knockdown and knockout of prokr1b altered the correct development of GnRH3 fibers, a phenotype that is rescued by injection of prokr1b mRNA. These results suggest that prokr1b regulates the development of the GnRH3 system in zebrafish. Analysis of gonads development and mating experiments indicate that prokr1b is not required for fertility in zebrafish, although its loss determine changes also at the testis level. Altogether, our results support the thesis of a divergent evolution in the control of vertebrate reproduction and provide a useful in vivo model for deciphering the mechanisms underlying the effect of PROKR2 allelic variants on CHH.

Design of stochastic model for the distribution interval between fetal development stage and post-partum amenorrhoea

Abstract In human reproduction process, analysing the birth interval is a crucial and important aspect. Normally, the distribution of fetal development stage interval of any exact order may be the same as the distribution of Post-partum Amenorrhoea interval of the same order but it cannot be same. Here the interval between the distribution of a specific order of fetal development stage interval and Post-partum Amenorrhoea interval of the same order is analysed. In this context, it is demonstrated the distinction between the Post-partum Amenorrhoea interval and fetal development stage interval empirically by allowing for a actual data set. Further, the distinction between these distributions is demonstrated theoretically, by taking certain proposed values of fertility factors involved in the stochastic model proposed for the purpose.