Diverse genetic causes of amenorrhea in an ethnically homogeneous cohort and an evolving approach to diagnosis.

RESEARCH QUESTION: Premature ovarian insufficiency (POI) is characterised by amenorrhea associated with elevated follicle stimulating hormone (FSH) under the age of 40 years and affects 1-3.7% women. Genetic factors explain 20-30% of POI cases, but most causes remain unknown despite genomic advancements. DESIGN: We used whole exome sequencing (WES) in four Iranian families, validated variants via Sanger sequencing, and conducted the Acyl-cLIP assay to measure HHAT enzyme activity. RESULTS: Despite ethnic homogeneity, WES revealed diverse genetic causes, including a novel homozygous nonsense variant in SYCP2L, impacting synaptonemal complex (SC) assembly, in the first family. Interestingly, the second family had two independent causes for amenorrhea - the mother had POI due to a novel homozygous loss-of-function variant in FANCM (required for chromosomal stability) and her daughter had primary amenorrhea due to a novel homozygous GNRHR (required for gonadotropic signalling) frameshift variant. WES analysis also provided cytogenetic insights. WES revealed one individual was in fact 46, XY and had a novel homozygous missense variant of uncertain significance in HHAT, potentially responsible for complete sex reversal although functional assays did not support impaired HHAT activity. In the remaining individual, WES indicated likely mosaic Turners with the majority of X chromosome variants having an allelic balance of ∼85% or ∼15%. Microarray validated the individual had 90% 45,XO. CONCLUSIONS: This study demonstrates the diverse causes of amenorrhea in a small, isolated ethnic cohort highlighting how a genetic cause in one individual may not clarify familial cases. We propose that, in time, genomic sequencing may become a single universal test required for the diagnosis of infertility conditions such as POI.

Programmed cell death 4: A novel player in the pathogenesis of polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a pathological condition recognized by menstrual cycle irregularities, androgen excess, and polycystic ovarian morphology, affecting a significant proportion of women of childbearing age and accounting for the most prevalent cause of anovulatory sterility. In addition, PCOS is frequently accompanied by metabolic and endocrine disturbances such as obesity, dyslipidemia, insulin resistance, and hyperinsulinemia, indicating the multiplicity of mechanisms implicated in the progression of PCOS. However, the exact pathogenesis of PCOS is yet to be elucidated. Programmed cell death 4 (PDCD4) is a ubiquitously expressed protein that contributes to the regulation of various cellular processes, including gene expression, cell cycle progression, proliferation, and apoptosis. Despite some disparities concerning its exact cellular effects, PDCD4 is generally characterized as a protein that inhibits cell cycle progression and proliferation and instead drives the cell into apoptosis. The apoptosis of granulosa cells (GCs) is speculated to take a major part in the occurrence and progression of PCOS by ceasing antral follicle development and compromising oocyte competence. Given the possible involvement of GC apoptosis in the progression of PCOS, as well as the contribution of PDCD4 to the regulation of cell apoptosis and the development of metabolic diseases, the current review aimed to discuss whether or how PDCD4 can play a role in the pathogenesis of PCOS by affecting GC apoptosis.

Investigation of Coronavirus disease 2019 virus in vaginal fluid and menses blood and the effect on menstrual cycle duration and sexual desire: A cross-sectional study.

Background: Coronavirus disease 2019 (COVID-19) was detected in the throat, urine, and feces but has little evidence documented of sexual transmission. Objective: Here, we aimed to diagnose the presence of COVID-19 in vaginal fluids and menses blood. Menstrual cycle duration and sexual desire were the other aims. Materials and Methods: In this cross-sectional study, 300 individuals with clinical approval of COVID-19 infection who were referred to the Alzahra hospital of Tabriz University of Medical Sciences, Tabriz, Iran were divided into mild (n = 178, partial pressure of oxygen ≥ 91) and severe (n = 122, partial pressure of oxygen ≤ 91) groups, also based on clinical signs and hospitalization, from January to May 2021. Demographic characteristics, menstruation, and sexual desire of individuals were recorded in the questionnaire blood sampling was done on days 2-4 for menses, and vaginal fluid after menses for polymerase chain reaction by using a Dacron tip swab. Results: Participants were studied in the mild (mean age: 43.32 ± 7.41) and severe (mean age: 47.15 ± 6.9) groups. COVID-19 infection resulted in shortening the menstrual cycle duration in the severe group (30.15 ± 2.9 vs. 25.12 ± 2.1 days, p = 0.01). Polymerase chain reaction test for vaginal fluid and menses blood was negative for all cases. Sexual desire declined in both groups, significantly. Conclusion: This virus was not present in the menses blood and vaginal fluid of women with COVID-19 infection, which proposed a low risk of virus transmission via vaginal tracts. Severe COVID-19 infection may affect the menstrual duration.

A treatment approach of severe vulvar edema in ovarian hyperstimulation syndrome patient: A case report.

Background: Ovarian hyperstimulation syndrome (OHSS) is a serious life-threatening complication of infertility treatment. Vulvar edema is a disease with various causes and frequent phenomena seen in physiological and pathologic conditions like pregnancy, inflammatory disorders, tumors, idiopathic reasons, and most importantly, in the severe form of OHSS. Case Presentation: Here, we report a 26-yr-old woman with severe OHSS, recombinant follicle-stimulating hormone therapy. 8 days later, we observed a mild and asymmetrical swelling of the vulva with severe edema in the right labia. Due to the worsening of the vulvar edema even after 15 days of conservative treatment, hand massage and compressive bandaging of the vulva were performed, which caused rapid recovery within 20 min of the case. Conclusion: Treatment with a hand massage with lubricant gel followed by compressive bandaging resolved the vulvar edema immediately; it is an easy procedure without any adverse events.

Investigating the efficacy of ultrasound-guided ethanol retention technique for endometrioma sclerotherapy and its effect on pro-inflammatory cytokine levels: A single-arm clinical trial.

BACKGROUND: Endometriosis is a chronic inflammatory disease affecting about 10% of women of reproductive age. Endometrioma is the most common presentation of endometriosis in ovaries. OBJECTIVES: Herein, the authors study the effect of the ultrasound-guided ethanol retention technique for endometrioma sclerotherapy and its effect on the plasma levels of pro-inflammatory cytokines. MATERIALS AND METHODS: Each endometrioma was aspirated and washed with 0.9% saline until clearance and then 2/3 of the cyst volume was filled with ethanol 98%. Patients were followed for 3 months. After that, changes in their cyst diameter, dyspareunia, dysmenorrhea, and antral follicular count were assessed. Also, the sera levels of Interleukin 1ß (IL-ß), IL-6, and IL-8 were assayed before and after the treatment. The primary sera levels were also compared with a control group. RESULTS: In the treatment and control groups, 23 and 25 individuals (respectively) with a matched mean age (p-value = 0.680) were enrolled in the study. Among the laboratory variables, IL-1ß (p-value = 0.035), as well as AMH (p-value = 0.002), were lower, and IL-6 (p-value = 0.011) was higher in the endometriosis group compared to the controls. Following the treatment, dysmenorrhea, dyspareunia, and the mean diameter of all cysts were significantly (p-values < 0.001) decreased in the treatment group. Also, right (p-value = 0.022) and left (p-value = 0.002) ovaries' antral follicular counts were increased following the treatment. No significant change was found among any of the investigated laboratory levels (p-value > 0.05). CONCLUSION: Ethanol retention method is proven to be safe and could improve the clinical status of patients with endometrioma. Although further studies are necessary.

Self-Care Performance of Pregnant Women in Preventing COVID-19 Infection and Its Relationship with Perceived Stress.

Objective: To determine the status of self-care performance of pregnant women in the prevention of COVID-19 disease and its relationship with perceived stress during the epidemic period of this disease. Method : This cross-sectional study was performed on 228 pregnant women who referred to the health centers in Tabriz, Iran, for prenatal care. They were selected by cluster sampling. Data collection tools included questionnaires about Demographic-Social Characteristics, the Self-Care Performance Questionnaire and Cohen's Perceived Stress Scale. Spearman correlation test was used to examine the correlation between self-care performance and perceived stress in bivariate and multivariate analyses. Also, multivariate linear regression was used, with control of demographic-social and obstetric characteristics as possible confounders. Results: The median (25-75 percentiles) self-care performance score of participants was 0.71 (0.65-0.76), from the achievable range of 20-80, and its mean (± SD) perceived stress score was 25.5 (± 5.6), from the achievable range of 0-56. The Spearman's rank correlation test results showed a significant inverse correlation between perceived stress and self-care performance scores (r = -0.13; P = 0.041). According to multivariate linear regression test, the variables of self-care performance, education, spouse's education and number of family members were the predictors of perceived stress in pregnant women during the COVID-19 epidemic. Conclusion: According to the results of the present study, self-care performance of pregnant women in prevention of the COVID-19 disease was good and their stress was moderate. There was a significant inverse correlation between self-care performance and perceived stress that could indicate the high value and importance of the fetus for the mother and her strict adherence to health protocols to prevent COVID-19, which also leads to calming and reduced perceived stress.

Intraovarian Injection of Autologous Platelet-Rich Plasma Improves Therapeutic Approaches in The Patients with Poor Ovarian Response: A before-after Study.

In this article published in Int J Fertil Steril, Vol 16, No 2, April-June 2022, Pages: 90-94, the authors found that this sentence "Also, AMH level was not statistically significantly different after PRP treatment (0.38 ± 0.039) in comparison with before of treatment (0.39 ± 0.04, Fig.1C)" was incorrect. The corrected one is "Also, AMH level was not significantly different before PRP treatment (0.38 ± 0.039) in comparison with after of treatment (0.39 ± 0.04, Fig.1C)" in the first paragraph of the result section.
The authors would like to apologies for any inconvenience caused.

Investigating the efficacy of ultrasound-guided ethanol retention technique for endometrioma sclerotherapy and its effect on pro-inflammatory cytokine levels: A single-arm clinical trial

Abstract Background Endometriosis is a chronic inflammatory disease affecting about 10% of women of reproductive age. Endometrioma is the most common presentation of endometriosis in ovaries. Objectives Herein, the authors study the effect of the ultrasound-guided ethanol retention technique for endometrioma sclerotherapy and its effect on the plasma levels of pro-inflammatory cytokines. Materials and methods Each endometrioma was aspirated and washed with 0.9% saline until clearance and then 2/3 of the cyst volume was filled with ethanol 98%. Patients were followed for 3 months. After that, changes in their cyst diameter, dyspareunia, dysmenorrhea, and antral follicular count were assessed. Also, the sera levels of Interleukin 1β (IL-β), IL-6, and IL-8 were assayed before and after the treatment. The primary sera levels were also compared with a control group. Results In the treatment and control groups, 23 and 25 individuals (respectively) with a matched mean age (p-value = 0.680) were enrolled in the study. Among the laboratory variables, IL-1β (p-value = 0.035), as well as AMH (p-value = 0.002), were lower, and IL-6 (p-value = 0.011) was higher in the endometriosis group compared to the controls. Following the treatment, dysmenorrhea, dyspareunia, and the mean diameter of all cysts were significantly (p-values < 0.001) decreased in the treatment group. Also, right (p-value = 0.022) and left (p-value = 0.002) ovaries' antral follicular counts were increased following the treatment. No significant change was found among any of the investigated laboratory levels (p-value > 0.05). Conclusion Ethanol retention method is proven to be safe and could improve the clinical status of patients with endometrioma. Although further studies are necessary.

Growth Hormone: A Potential Treatment of Patients with Refractory Thin Endometrium: A Clinical Trial Study.

BACKGROUND: Growth hormone (GH) is a potential treatment in the assisted reproductive technology (ART) to improve endometrial receptivity and thickness. In the current study, we investigated the effect of the intrauterine administration of GH on the endometrial thickness (EMT) and ART outcomes in the patients with refractory thin endometrium. MATERIALS AND METHODS: In this clinical trial study, women with a refractory thin endometrium and a history of one or more frozen embryo transfer (FET) cancellation who were referred to the infertility center of the Tabriz Al-Zahra hospital (Tabriz, Iran) and Milad Infertility Clinic (Tabriz, Iran) received intrauterine injections of GH every other day from day 14 of the menstrual cycle until the EMT reached ≥7 mm in addition to the routine endometrium preparation protocol. EMT was evaluated during the treatment and in the cases with EMT ≥7 mm, biochemical/clinical pregnancy was evaluated after embryo transfer. RESULTS: Thirty-one women aged 35.29 ± 6.21 years were included in this study. The mean amount of EMT was significantly increased following the GH treatment (7.03 ± 1.23 mm) vs. before treatment (5.14 ± 1.1 mm, P<0.001). The EMT reached ≥7 mm in the 65% patients (20/31). Also, the embryo transfer resulted in pregnancy in the patients, biochemical pregnancy: 9/20 (45%) and clinical pregnancy: 7/20 (35%). There was a positive correlation between EMT on the day 13 of cycle (before the treatment) and the maximum EMT (r=0.577 and P=0.001). The EMT was statistically different on the embryo transfer day between clinically pregnant and non-pregnant women (7.18 ± 0.56 vs. 6.21 ± 0.72 mm, P=0.007). CONCLUSION: The intrauterine administration of GH could be an appropriate therapeutic strategy for patients with refractory thin endometrium. This treatment could significantly increase the EMT as well as implantation and pregnancy rates in these patients (registration number: IRCT20210220050429N1).

microRNAs in the blastocoel fluid as accessible indicators of chromosomal normality.

MicroRNAs (miRNAs) derived from the pre-implantation blastocoel fluid (BF) have attracted interest as accessible biomarkers indicative of embryonic health in ongoing IVF cycles. Therefore, we investigated expression levels of some aneuploidy-associated miRNAs and implantation-related mRNAs as predictive markers for embryo chromosomal normality. In this study, the BF of 25 blastocysts that had been checked for aneuploidy (aneuploid=17 and euploid=8) was aspirated and the expression of 10 miRNAs (miR-20a, miR-30c, miR-661, miR-372, miR-142, miR-191, miR-345, miR-339, miR-141, and miR-27b) and four genes (ERBB4, SELL, ITGB3, ITGAV) were evaluated using real time-PCR. Results showed that the levels of miR-661 and miR-20a were significantly higher in the BF of the aneuploid embryos compared to the euploid group (p = 0.0017 and 0.004, respectively). A comparison of the mRNA levels between the aneuploid and euploid groups also demonstrated a significant difference in ITGAV (p = 0.013) and SELL (p = 0.0317) levels. In the euploid group, a negative correlation was found between ITGB3 and miR-30c (r = -0.71, p = 0.08), and in the aneuploid group, a positive correlation was found between ERBB4 and miR-345 (r = 0.71, p = 0.02). It can be suggested that miR-20a, miR-661, and ITGAV levels of BF could be used as less-invasive biomarkers to evaluate embryonic health. Moreover, aneuploidy-related miRNA levels were associated with levels of genes involved in embryo implantation.

Intraovarian Injection of Autologous Platelet-Rich Plasma Improves Therapeutic Approaches in The Patients with Poor Ovarian Response: A Before-After Study.

Background: Advanced age is associated with a decline in the natural oocytes, low oocyte yield, and also increases the assisted reproductive technology (ART) failure rate, and consequently resulted in a pregnancy rate decrease. Platelet-rich plasma (PRP) is one of the proposed therapeutic strategies for women with poor ovarian response (POR). Because of the autologous source of PRP, the lowest risks of disease transmission, immunogenic and allergic reactions have been expected. This study aimed to evaluate the single-dose intraovarian injection of autologous PRP in poor ovarian reserve. Materials and Methods: We conducted a clinical trial study in the Al-Zahra hospital and Milad Infertility Clinic, Tabriz, Iran (April and May, 2021). A total of thirty-five women with a POR and mean age 40.68 ± 0.34 enrolled in this study. After injection of autologous PRP into the ovaries, the number of oocytes, antral follicles, and level of estradiol, anti-Müllerian hormone (AMH), follicle-stimulating hormone (FSH), luteal hormone (LH), FSH/LH ratio also were evaluated while, these parameters were evaluated before PRP administration. Results: At the 2-month follow-up, women treated with PRP showed a significant elevation in the number of oocytes (3.68 ± 0.24, P=0.0043) and embryos (3.17 ± 0.14, P=0.0001), as well as in the estradiol levels (404.1 ± 16.76 vs. 237.7 ± 13.14, P=0.0003). Conclusion: Single PRP injection is effective and might be a promising therapeutic approach in the patients with POR to conceive with their own oocytes, although further evidence is required to assess the influence of PRP on the live birth rate.

Role of miRNAs in preimplantation embryo development and their potential as embryo selection biomarkers.

CONTEXT: MicroRNAs (miRNAs) play different roles in oocyte fertilisation, degradation of maternal transcripts, embryo development, and implantation. During in vitro fertilisation (IVF), different miRNAs are released from embryos into the spent culture media (SCM) that can potentially reflect the status of the embryo. AIMS: This study is the assessment of miRNAs, which secreted in SCM during the IVF cycles can be used as noninvasive biomarkers to predict an embryo's ability to form a blastocyst, implant, and give live birth. METHODS: Systematic literature search was conducted to review all recent studies about miRNAs as potential non-invasive biomarkers for selecting the best embryos in the assisted reproductive technology (ART) cycle. KEY RESULTS: Studies have shown that levels of some miRNAs in the SCM have an association with the implantation potential and pregnancy outcome of the embryo. CONCLUSIONS: Embryo-secreted miRNAs can be used as potential non-invasive biomarkers for selecting the best embryos in the ART cycle. Unfortunately, few human studies evaluated the association between ART outcomes and miRNAs in SCM. IMPLICATIONS: This review can pave the way for further miRNAs transcriptomic studies on human embryo culture media and introducing a specific miRNA profile as a multivariable prediction model for embryo selection in IVF cycles.

Novel bone morphogenetic protein 15 (BMP15) gene variants implicated in premature ovarian insufficiency.

BACKGROUND: Bone morphogenetic protein 15 (BMP15) is expressed in oocytes and plays a crucial role in the reproduction of mono-ovulating species. In humans, BMP15 gene mutations lead to imperfect protein function and premature ovarian insufficiency. Here we investigated the BMP15 gene variants in a population of Iranian women with premature ovarian insufficiency. We conducted predictive bioinformatics analysis to further study the outcomes of BMP15 gene alterations. METHODS: Twenty-four well-diagnosed premature ovarian insufficiency cases with normal karyotype participated in this study. The entire coding sequence and exon-intron junctions of the BMP15 gene were analyzed by direct sequencing. In-silico analysis was applied using various pipelines integrated into the Ensembl Variant Effect Predictor online tool. The clinical interpretation was performed based on the approved guidelines. RESULTS: By gene screening of BMP15, we discovered p.N103K, p.A180T, and p.M184T heterozygous variants in 3 unrelated patients. The p.N103K and p.M184T were not annotated on gnomAD, 1000 Genome and/or dbSNP. These mutations were not identified in 800 Iranians whole-exome sequencing that is recorded on Iranom database. We identified the p.N103K variant in a patient with secondary amenorrhea at the age of 17, elevated FSH and atrophic ovaries. The p.M184T was detected in a sporadic case with atrophic ovaries and very high FSH who developed secondary amenorrhea at the age of 31. CONCLUSIONS: Here we newly identified p.N103K and p.M184T mutation in the BMP15 gene associated with idiopathic premature ovarian insufficiency. Both mutations have occurred in the prodomain region of protein. Despite prodomain cleavage through dimerization, it is actively involved in the mature protein function. Further studies elucidating the roles of prodomain would lead to a better understanding of the disease pathogenesis.

Combination of Estradiol with Leukemia Inhibitory Factor Stimulates Granulosa Cells Differentiation into Oocyte-Like Cells.

Purpose: Previous studies have documented that cumulus granulosa cells (GCs) can trans-differentiation into different non-ovarian cells, showing their multipotentiality to repopulate the injured cells in ovarian tissue. The current experiment is aimed to assess the differentiation capacity of human cumulus GCs toward the oocyte-like phenotype in vitro. Methods: GCs were isolated from healthy female volunteers subjected to in vitro fertilization or intra-cytoplasmic sperm injection (IVF-ICSI). The effect of different media supplemented with leukemia inhibitory factors (LIFs), 5 ng/mL estradiol, and 0.005 IU/mL follicle-stimulating hormone (FSH) were investigated to the differentiation of GCs toward oocyte-like phenotype via monitoring the expression of Oct3/4 and GATA-4 using flow cytometry analysis. The expression of genes such as FIGLA, NOBOX, and SYCP3 was measured by real-time polymerase chain reaction (PCR) assay. We also assess morphological adaptation by using bright-field microscopic imaging. Results: Exposure of GCs to LIFs increased the number of cells expressing stemness factor Oct3/4 coincided with the suppression of GATA-4 after 7 days (P < 0.05). We found that the transcript level of all genes FIGLA, Nobox, and SYCP-3 decreased in cells after treatment with a FSH (P < 0.05). According to our data, the incubation of GCs with estradiol increased the expression of genes related to the oocyte-like phenotype. Conclusion: Our finding revealed that the combination of LIFs and estradiol could induce the GCs' oogenesis capacity and thereby is possibly suggested as a therapeutic strategy during the occurrence of gynecological disorders.

A human chorionic gonadotropin (hCG) delivery platform using engineered uterine exosomes to improve endometrial receptivity.

AIM: Endometrial exosomes carry bioactive agents to uterine epithelial cells and trophectoderm to promote implantation. On the other hand, intrauterine administration of human chorionic gonadotropin (hCG) could improve endometrial receptivity. Therefore, we investigated the delivery of hCG to the endometrial cells by uterine exosomes to increase endometrial receptivity. MAIN METHODS: Exosomes were isolated from uterine fluid and characterized by dynamic light scattering, transmission electron microscopy, and western blotting. The freeze-thaw cycle and sonication methods were used to load hCG into the exosomes. The drug release pattern and uptake of exosomes into the endometrial cells were evaluated. Finally, the influence of hCG loaded-exosomes on the expression of several endometrial receptivity markers was evaluated. KEY FINDINGS: The isolated uterine fluid exosomes had a cup-shaped or spherical morphology with a mean size of 91.8 nm and zeta potential of -9.75 mV. The average loading capacity of exosomes for hCG was 710.05 ± 73.74 and 245.06 ± 95.66 IU/mg using the sonication and freeze-thaw cycle methods, respectively. The effect of hCG loaded-exosomes on the endometrial receptivity was greater than the hCG or exosomes alone. We found that hCG upregulated LIF and Trophinin and downregulated Muc-16 and IGFBP1 genes. Interestingly, the effect of hCG on the expression of LIF and Muc-16 was significantly intensified when used in the form of hCG loaded-exosomes. SIGNIFICANCE: These findings strengthen our hope in using uterine fluid-derived exosome as an effective carrier for proteins or other therapeutic agents to effective delivery into endometrial cells.

An update on platelet-rich plasma (PRP) therapy in endometrium and ovary related infertilities: clinical and molecular aspects.

Administration of platelet-rich plasma (PRP) is one of the well-recommended strategies for the treatment of endometrium- and ovary-associated infertility. Due to the autologous source of PRP, minimal risks for disease transmission and immunogenic and allergic responses are expected in this method. Despite the extensive use of PRP in medicine, its precise mechanism of action in endometrial and ovarian tissues is still unknown. Nevertheless, the induction of cell proliferation, chemotaxis, regeneration, extracellular matrix synthesis, remodeling, angiogenesis, and epithelialization are the main pathways for PRP to affect female reproductive organs. Given the promising results of previous studies, it is necessary to standardize PRP preparation protocols for different therapeutic purposes and also clearly determine appropriate inclusion and exclusion criteria for recruiting patients. In the current review, we presented a summary of studies on PRP therapy for endometrium- and ovary-associated infertility with a focus on the possible mechanisms by which PRP enhances endometrial receptivity and regenerates ovarian function.Abbreviations: PRP: platelet-rich plasma; ART: assisted reproductive technology; POF: premature ovarian failure; TGF: transforming growth factors; PDGF: platelet-derived growth factors; IGF-I: insulin-like growth factor-1; HGF: hepatocyte growth factor; EGF: epidermal growth factor; FGF: fibroblast growth factor; VEGF: vascular endothelial growth factor; ADP: adenosine diphosphate, ATP: adenosine triphosphate; PDGF: platelet-derived growth factor; COX2: cyclooxygenase-2; TP53: tumor protein 53; ER-α: estrogen receptors alpha; ER-ß: estrogen receptors beta; PR: progesterone receptor; RIF: recurrent implantation failure; G-CSF: granulocyte colony-stimulating factor; iNOS: inducible nitric oxide synthase; NF-kß: nuclear factor kappa beta; MMPs: matrix metalloproteinases; Col1a1: collagen type I alpha 1; IL: interleukin; FSH: follicle-stimulating hormone; AMH: anti-Mullerian hormone; GDF-9: growth differentiation factor 9.

Synbiotic Supplementation Improves Metabolic Factors and Obesity Values in Women with Polycystic Ovary Syndrome Independent of Affecting Apelin Levels: A Randomized Double-Blind Placebo - Controlled Clinical Trial.

BACKGROUND: This research investigated the symbiotic supplement influences on serum glycemic indices and lipids as well as apelin rates and obesity values in polycystic ovary syndrome (PCOS) patients. MATERIALS AND METHODS: A total of 68 obese or overweight patients (20-44 years old) with PCOS were enrolled to conduct a randomized double-blinded placebo-controlled clinical trial. A total of 34 people in the synbiotic group received a synbiotic supplement and 34 people in the placebo group received placebo, daily for 8 weeks. Fasting blood specimens, anthropometric measurements and dietary intake data were gathered three times during the study. The information was analyzed by independent t test, paired t test, analysis of covariance and chi-square test. RESULTS: Synbiotic supplementation significantly decreased serum fasting glucose (P=0.02), insulin (P=0.001), homeostatic model assessment for insulin resistance (IR, P=0.001), weight (P=0.02), body mass index (BMI, P=0.02), waist circumference (WC, P=0.01), hip circumference (HC, P=0.02), and waist-to-height ratio (WHtR, P=0.02) but significantly increased high-density lipoprotein (HDL) cholesterol (P=0.02) compared to the placebo. At the end of the trial, no significant differences were seen in serum total cholesterol, triglyceride (TG), low-density lipoprotein (LDL) cholesterol, or apelin levels as well as waist-to-hip ratio (WHR) between the two groups. CONCLUSION: Synbiotic supplementation improved glycemic indices, lipid profile and obesity values in women with PCOS. These beneficial effects were not related with alterations in serum apelin levels (Registration number: IRCT20100408003664N19).

Cytokines in embryonic secretome as potential markers for embryo selection.

Despite performing certain morphological assessments for selecting the best embryo for transfer, the results have not been satisfactory. Given the global tendency for performing quick and noninvasive tests for embryo selection, great efforts have been made to discover the predictive biomarkers of embryo implantation potential. In recent years, many factors have been detected in embryo culture media as a major source of embryo secretions. Previous studies have evaluated cytokines, miRNAs, extracellular vesicles, and other factors such as leukemia inhibitory factor, colony-stimulating factor, reactive oxygen species, soluble human leukocyte antigen G, amino acids, and apolipoproteins in these media. Given the key role of cytokines in embryo implantation, these factors can be considered promising molecules for predicting the implantation success of assisted reproductive technology (ART). The present study was conducted to review embryo-secreted molecules as potential biomarkers for embryo selection in ART.

The effect of clomiphene citrate, herbal mixture, and herbal mixture along with clomiphene citrate on clinical and para-clinical parameters in infertile women with polycystic ovary syndrome: a randomized controlled clinical trial.

INTRODUCTION: To evaluate the effect of a herbal mixture (i.e., Mentha spicata, Zingiber officinale, Cinnamomum zeylanicum, and Citrus sinensis) alone and in combination with clomiphene citrate (CC) compared to CC on the treatment of polycystic ovary syndrome (PCOS). MATERIAL AND METHODS: This single-blind randomized clinical trial was conducted on 60 infertile participants with PCOS who were randomly divided into three groups. After spontaneous or progestin-induced withdrawal bleeding, group 1 (n = 20) received routine treatment with CC (50-150 mg) for three menstrual cycles from the 3rd to 5th day of menstruation for 5 days while group 2 (n = 20) and group 3 (n = 20) received herbal mixture capsules 700 mg/day and the herbal mixture along with CC for 3 months, respectively. Finally, several related parameters were measured, including the level of sex steroids, homeostatic model assessment for insulin resistance (HOMA-IR), lipid profile (primary outcomes), thyroid hormones, and clinical features. The analysis was based on intention-to-treat analysis. RESULTS: No statistically significant differences were observed between the groups in terms of socio-demographic characteristics. However, after adjustment for baseline, luteinizing hormone (aMD = 4.9; 95% CI: 3.7-6.2), luteinizing hormone/follicle-stimulating hormone (aMD = 0.9; 95% CI: 0.7-1.2), total testosterone (aMD = -0.12; 95% CI: -0.2 to -0.01) in group 2 and free testosterone (aMD = -6.0; 95% CI: -9.7 to -2.3) in group 3 revealed a significant difference compared to group 1. In addition, HOMA-IR in group 2 (aMD = -1.3; 95% CI: -2.4 to -0.2) decreased significantly compared to group 1. Further, total cholesterol, triglycerides, low-density lipoprotein cholesterol, and very low-density lipoprotein cholesterol decreased significantly in group 2 (aMD = -21.8; 95% CI: -31.5 to -12.1; aMD = -29.9; 95% CI: -47.9 to -12.0; aMD = -21.2; 95% CI: -31.3 to -11.1; aMD = -5.1; 95% CI: -7.5 to -2.7) and group 3 (aMD = -18.3; 95% CI: -27.4 to -9.2; aMD = -26.9; 95% CI: -43.8 to -9.9; aMD = -21.4; 95% CI: -31.1 to -11.7; aMD = -5.9; 95% CI: -8.3 to -3.6) compared to group 1, respectively. However, high-density lipoproteins cholesterol in group 2 (aMD = 6.8; 95% CI: 2.9-10.7) and group 3 (aMD = 10.7; 95% CI: 7.2-14.7) increased remarkably compared to group 1. Overall, clinical outcomes improved significantly in all groups (p < 0.05). CONCLUSIONS: In general, the herbal mixture along with CC was found to improve free testosterone, HOMA-IR, lipid profile, and clinical features of PCOS women.

Tacrolimus Improves the Implantation Rate in Patients with Elevated Th1/2 Helper Cell Ratio and Repeated Implantation Failure (RIF).

Introduction An abnormal endometrial immune response is involved in the pathogenesis of repeated implantation failure (RIF), so we investigated the effectiveness of tacrolimus treatment on the endometrium of RIF patients. Materials and Methods Ten RIF patients with elevated T-helper 1/T-helper 2 (Th1/Th2) cell ratios were recruited into a clinical study. The expression of p53, leukemia inhibitory factor (LIF), interleukin (IL)-4, IL-10, IL-17, and interferon gamma (IFN-γ) in the endometrium of patients with and without tacrolimus treatment and the association of these factors with assisted reproductive technology (ART) outcomes were investigated. Results Tacrolimus significantly increased the expression of LIF, IL-10, and IL-17 and decreased the expression of IL-4, IFN-γ, and the IFN-γ/IL-10 ratio in RIF patients. Tacrolimus treatment resulted in an implantation rate of 40%, a clinical pregnancy rate of 50%, and a live birth rate of 35% in RIF patients with elevated Th1/Th2 ratios who had previously failed to become pregnant despite at least three transfers of embryos. We also found a significant positive correlation between IL-10 levels and the implantation rate. Conclusions Our findings suggest that RIF patients with a higher Th1/Th2 ratio could be candidates for tacrolimus therapy and that this immunosuppressive drug could be acting through upregulation of LIF, IL-10, and IL-17.