Updates on the relation of weight excess and reproductive function in men： sleep apnea as a new area of interest

Obesity has a negative effect on male reproductive function. It is associated with low testosterone levels and alteration in gonadotropin secretion. Male obesity has been linked to reduced male fertility. Data regarding the relation of obesity to sperm parameters are conflicting in terms of the nature and magnitude of the effect. New areas of interest are emerging that can help explain the variation in study results, such as genetic polymorphism and sleep apnea. Sleep disorders have been linked to altered testosterone production and hypogonadism in men. It was also correlated to erectile dysfunction. The relation of sleep disorders to male fertility and sperm parameters remains to be investigated. Men with hypogonadism and infertility should be screened for sleep apnea. Treatment of obesity and sleep apnea improves testosterone levels and erectile function.

Myo-inositol versus metformin effects on clinical features, endocrine and metabolic profiles in infertile women with polycystic ovary syndrome: A randomized controlled trial

Objective:To compare the effectiveness of inositol and metformin on the clinical characteristics,and endocrine and metabolic profiles of infertile polycystic ovarian syndrome(PCOS)women from Vietnam.Methods:From June 2018 to August 2022,a randomized trial was undertaken at the Hue Center for Endocrinology and Reproduction on infertile women aged 18 to 40 years with polycystic ovarian syndrome.The clinical,endocrine,and metabolic features of these individuals were assessed before and after 3 months of treatment with 2 g of inositol or 1700 mg of metformin per day.Natural pregnancy rates,adverse effects,and tolerance of inositol were recorded.Results:The study included 171 infertile PCOS women who were eligible to participate and took part in the baseline assessment,of whom 132 women participated in data analysis after 3 months.After metformin treatment,42.1%of women with oligomenorrhea experienced regular menstruation.Metformin significantly lowered body mass index(BMI),waist circumference and testosterone levels,but had no effect on other clinical characteristics,endocrine profiles,or metabolic profiles.29.2%Of women reported experiencing side effects.21%Of them attained pregnancy,which resulted in 17.1%of live births.In the inositol group,the rate of regular cycle increased by 18.2%and the total testosterone concentration significantly decreased.In overweight/obese women with PCOS,inositol significantly decreased weight,BMI,waist and hip circumferences(P<0.05).100%Of women tolerated inositol and continued treatment.18.9%Of them became pregnant,leading to 17%of live births.Conclusions:Metformin and inositol can improve weight and waist circumference in overweight/obese infertile women with PCOS.Metformin is associated with a higher rate of regular menstruation,whereas inositol is associated with a lower rate of adverse effects.The spontaneous conception,clinical pregnancy,and live birth rates between two groups are comparable.

Mitophagy links oxidative stress conditions and neurodegenerative diseases

Mitophagy is activated by a number of stimuli, including hypoxia, energy stress, and increased oxidative phosphorylation activity. Mitophagy is associated with oxidative stress conditions and central neurodegenerative diseases. Proper regulation of mitophagy is crucial for maintaining homeostasis; conversely, inadequate removal of mitochondria through mitophagy leads to the generation of oxidative species, including reactive oxygen species and reactive nitrogen species, resulting in various neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. These diseases are most prevalent in older adults whose bodies fail to maintain proper mitophagic functions to combat oxidative species. As mitophagy is essential for normal body function, by targeting mitophagic pathways we can improve these disease conditions. The search for effective remedies to treat these disease conditions is an ongoing process, which is why more studies are needed. Additionally, more relevant studies could help establish therapeutic conditions, which are currently in high demand. In this review, we discuss how mitophagy plays a significant role in homeostasis and how its dysregulation causes neurodegeneration. We also discuss how combating oxidative species and targeting mitophagy can help treat these neurodegenerative diseases.

Association of 25-hydroxy-vitamin D levels with semen and hormonal parameters

Vitamin D levels have been linked to various health outcomes including reproductive disorders. The purpose of this study was to explore the association between serum vitamin D level （25-hydroxy-vitamin D, or 250HD） and semen and hormonal parameters. This is a cross-sectional study that included 170 healthy men recruited for the study of spermatogenesis from the general population. Men completed general and reproductive health questionnaires, and donated blood and semen samples. The main measures were hormonal （total and free testosterone, sex hormone-binding globulin, estradiol, follicle-stimulating hormone and luteinizing hormone） and semen parameters, adjusted （n= 147） for age, body mass index （BMI）, season, alcohol intake and smoking, in relation to categories of vitamin D levels, determined apriori. The mean age of the study population was 29.0±8.5 years and mean BMI was 24.3±3.2 kg m-2. The mean 250HD was 34.1± 15.06 ng m1-1. BMI showed a negative association with 250HD. Sperm concentration, sperm progressive motility, sperm morphology, and total progressively motile sperm count were lower in men with ‘250HD ≥ 50 ng ml-1＇ when compared to men with‘20 ng ml-1 ≤ 250H D〈 50 ng ml-1,. Total sperm count and total progressive motile sperm count were lower in men with ‘250HD〈20 ng ml-1＇ when compared to men with‘20 ng ml-1≤250HD〈50 ng ml-1＇. The adjusted means of various hormonal parameters did not show statistical difference in the different categories of 250HD. In conclusion, serum vitamin D levels at high and low levels can be negatively associated with semen parameters.

Recurrent Implantation Failure and Low Molecular Weight Heparin

Implantation of the embryo into the endometrium is the first step in the establishment of pregnancy. This process is complex, and depends on many factors. Recurrent implantation failure is a source of distress to patients and specialists. It is defined as failure to achieve a viable pregnancy, following “>3 embryo transfers with high quality embryos or the transfer of ≥ 10 embryos in multiple transfers”. Thrombophilic conditions that contribute to recurrent implantation failure are the main concern in this review. The mechanism of implantation failure is believed to be due to decreased blood flow to the endometrium and placenta which can hinder normal endometrial receptivity leading to miscarriage. Defects in early placentation resulting in pregnancy failure, have focused attention on the therapeutic potential of low molecular weight heparin in the implantation process. Heparin has a role at all stages of implantation to improve pregnancy outcomes. There are controversies in literature regarding the association between thrombophilia and recurrent implantation failure and available literature regarding this issue is very heterogeneous. Various investigators, have shown that women with RIF are more likely to have a thrombophilia disorder, yet a clear cause cannot be acknowledged from these studies. Heparin treatment has been evaluated in several studies, showing conflicting evidence. However, several studies have pointed out that it may play a role in a subset of patients who presents a thrombophilia mutation, thus the group of patients that might benefit is needed to be identified. This review is dedicated to evaluate the published literature about the role of low molecular weight heparin in case of recurrent implantation failure with or without the presence of thrombophilia.

Association between gamete source, exposure and preeclampsia: A review of literature

Preeclampsia complicates 3%-5% of pregnancies and is one of the major causes of maternal morbidity and mortality. The pathologic mechanisms are well described but despite decades of research, the exact etiology of preeclampsia remains poorly understood. For years it was believed that the etiology of preeclampsia was the result of maternal factors, but recent evidence suggests that preeclampsia may be a couple specific disease where the interplay between both female and male factors plays an important role. Recent studies have suggested a complex etiologic mechanism that includes genetic imprinting, immune maladaptation, placental ischemia and generalized endothelial dysfunction. The immunological hypothesis suggests exaggerated maternal response against fetal antigens. While the role of maternal exposure to new paternal antigens in the development of preeclampsia was the initial focus of research in this area, studies examining pregnancy outcomes in pregnancies from donor oocytes provide intriguingly similar findings. The pregnancies that resulted from male or female donor gametes or donor embryos bring new insight into the role of immune response to new antigens in pathogenesis ofpreeclampsia. The primary goal of the current review is the role of exposure to new gametes on the development of preeclampsia. The objective was therefore to provide a review of current literature on the role of cohabitation length, semen exposure and gamete source in development of preeclampsia.

Evolving ethical issues in third party reproduction:Local and global considerations

There continues to be an increase in utilization of assisted reproductive technology(ART), including the use of third party gametes. Specifically, the use of third party oocytes, most recently reported in 2010 by the United States(US) Center for Disease Control and Society of Reproductive Medicine, accounted for 15 504 cycles and 7334 live births. This translates into approximately 11% of all the in vitro fertilization cases performed in the US. As utilization increases and the technological tools advance, they have created underappreciated and unforeseen ethical quandaries. As such, many practitioners think they "have heard it all". However, each ART scenario is novel with the potential to pose complex unforeseen issues, potentially creating global challenges that could impact broad social and legal questions and test the moral consciousness' of practitioners, policymakers and patients. While there are published US national guidelines to assist practitioners, we have identified new complex issues in assisted reproduction that present unique challenges, and we give a perspective from oureyes in the Western Hemisphere looking out to a global level. Specifically, this review focuses on some of the more recent and evolving issues that currently are and will be confronting us in the upcoming years. Particular attention focuses on discrepancies between third party legal contracts and ART consents regarding level of information sharing, and oocyte and embryo directives and management; dilemmas and obligations surrounding disclosure of medical outcomes especially in the context of growing access to Direct to Consumer genetic testing and Reproductive Tourism-Exile. Given the complexity of these and other ethical questions, finding answers may be achieved by ending the isolation of reproductive professionals and instead promoting increased and consistent communication among physicians, embryologists, therapists and reproductive attorneys to confront these evolving ethical quandaries.

First experience with intracytoplasmic sperm injection for extreme oligozoospermia associated with Crohn's disease and 6-mercaptopurine chemotherapy

<abstract>Aim: To describe the reproductive outcome following intracytoplasmic sperm injection (ICSI) for male factor infertility associated with Crohn's disease and 6-mercap-topurine (6-MP) chemotherapy. Methods: The male partner of a couple suffered from severe Crohn's disease and received a 3-month course of 6-MP for this condition. Two spontaneous conceptions were established before 6-MP, although post-chemotherapy semen analysis found the sperm concentration to be 8,000/mL. In vitro fertilization (IVF) with ICSI and embryo transfer was performed. Results: The woman underwent an uncomplicated controlled ovarian hyperstimulation sequence using a combined rec-FSH+hMG protocol, following late luteal phase pituitary downregulation. This culminated in the retrieval of 18 oocytes, 11 of which were fertilized with ICSI. She later delivered a normal male infant without urogenital anomaly. Four nontransferred blastocysts were cryopreserved. Conclusion: This report describes the first successful birth after ICSI for severe oligozoospermia associated with Crohn's disease and 6-MP therapy. We outline salient features of Crohn's disease, 6-MP pharmacology, and their relevance to human fertility.

Ovarian hyperstimulation syndrome following the use of GnRH agonist trigger of final oocyte maturation and freeze-all strategy: A case report and review of the literature

Rationale:The current literature has a surprising controversy regarding the use of low-dose human chorionic gonadotropin(hCG)for luteal support as an explanation for the development of ovarian hyperstimulation syndrome,and this is because of the gap in the listing of the predisposing factors that put women at an increased risk of ovarian hyperstimulation syndrome.Patient concerns:A case of 25-year-old woman presented with abdominal pain,distention,dyspnea,and nausea with a 6.5 kg increase in weight from baseline.Ultrasonographic examination showed bilaterally enlarged multicystic ovaries after gonadotropin-releasing hormone(GnRH)agonist triggering and cycle segmentation with no hCG rescue administration.Diagnosis:Moderate/severe ovarian hyperstimulation syndrome.Interventions:The woman was admitted to the hospital for medical management of moderate/severe ovarian hyperstimulation syndrome,and pain management was advanced to patient-controlled anesthesia with the start of low molecular weight heparin.On day 2,albumin therapy followed by a furosemide chase was started due to an increase in abdominal girth.On day 1,Cabergoline was maintained,and on day 2 the GnRH antagonist Cetrorelix was started.Outcomes:The woman’s clinical condition improved,and a clinical pregnancy was eventually achieved during the first cryo-warmed blastocyst cycle.Lessons:Ovarian hyperstimulation syndrome can still happen even after the use of GnRH agonist and avoidance of hCG support.Segmentation of in vitro fertilization with complete avoidance of hCG for luteal support remains the best approach.

Prolonged post-thaw culture of embryos does not improve outcomes of frozen human embryo transfer cycles: A prospective randomized study

Objective:To evaluate the impact of prolonged post-thaw embryos culture on pregnancy outcome during frozen embryo transfer cycles.Methods:This prospective cohort study evaluated 324 thaw transfer cycles with 819 embryos from 269 patients at the Center for Reproductive Endocrinology and Infertility of Hue University Hospital in Vietnam.These frozen embryo transfer cycles were divided into two groups at the time of thawing:the short culture group(2-hour post-thaw culture)and the overnight culture group(overnight culture for 18 h)before the embryo was transferred into the uterus.The rates of embryo intact,grade A embryo at frozen and transfer time and continuing cleavage were recorded.The clinical outcomes including serum beta-human chorionic gonadotropin,clinical pregnancy and implantation rate were evaluated after 14 days,4 weeks,6 weeks,respectively,after embryo transfer.Results:Human chorionic gonadotropin positive occurred in 39.5%of patients in the short culture group compared to 25.9%in the overnight culture group with risk difference(RD)=13.6%,relative risk(RR)=1.343,95%confidence interval(CI)1.085-1.663,P<0.01.Clinical pregnancy rate of the short culture group and overnight culture group was 33.3%and 24.1%,respectively(RD=9.2%,RR=1.242,95%CI 0.996-1.549,P=0.06)and the implantation rate in the short culture group and overnight culture group was 16.5%and 11.0%,respectively(RD=5.5%,RR=1.244,95%CI 1.046-1.479,P=0.01).In women of advanced age(≥35 years)and women who received 3 embryos,pregnancy outcomes were found to be significantly(P<0.05)higher in the short culture than in the overnight culture group.Conclusions:The prolonged post-thaw culture period does not increase pregnancy outcome in comparison with the short culture.

Impacts of assisted reproductive technology on perinatal outcomes and offspring health

Assisted reproductive technology(ART)has evolved rapidly over the last 40 years,offering hope to individuals and couples struggling with infertility.As technology continues to evolve,simulating a realistic female reproductive system environment has become a common goal for all types of ARTs,thereby reducing the impact of the artificial microenvironment on perinatal and offspring health.In this review,we provide a brief history of the development of each major ART and discuss the impact of ART on perinatal and offspring health.We also explore how the negative consequences of ART may be overcome and how its benefits can be maximized.

Pregnancy outcome of day 3versus day 5 embryo transfer: A retrospective analysis

Objective:To compare the pregnancy rate between day 3 and day 5 transfer regardless grades of embryos and number of transferred embryo.Methods: Retrospective cohort, a total of seven hundred and four patients met our inclusion criteria, with 411 had day 3 embryo transfer and 293 had day 5 embryo transfer. The patients who were older than 40 years old were excluded. Embryo transfer was carried out in all patients in both transfer groups.Results:Both clinical pregnancy rate and implantation rate did not show any statistically significant difference between the day 3 and day five transfer groups. These were 44%vs. 45% withP=0.82 and 19%vs. 19% withP=0.99 respectively. An increase of miscarriage rate with day 5 embryo transferred compare with day 3 (12.0%vs. 4.4%,P=0.01), but no significant difference was found about biochemical pregnancy rate (P=0.52).Conclusions:Transferring embryo at day 5 may not provide any additional benefit over day 3 transfers to patients. In addition, it increases the risk of miscarriage. Further studies of this issue needed for confirming our findings.

Anatomical distributional defects in mutant genes associated with dominant intermediate Charcot-Marie-Tooth disease type C in an adenovirus-mediated mouse model

Dominant intermediate Charcot-Marie-Tooth disease type C（DI-CMTC） is a dominantly inherited neuropathy that has been classified primarily based on motor conduction velocity tests but is now known to involve axonal and demyelination features.DI-CMTC is linked to tyrosyl-t RNA synthetase（YARS）-associated neuropathies,which are caused by E196 K and G41 R missense mutations and a single de novo deletion（153-156 del VKQV）.It is well-established that these YARS mutations induce neuronal dysfunction,morphological symptoms involving axonal degeneration,and impaired motor performance.The present study is the first to describe a novel mouse model of YARS-mutation-induced neuropathy involving a neuron-specific promoter with a deleted mitochondrial targeting sequence that inhibits the expression of YARS protein in the mitochondria.An adenovirus vector system and in vivo techniques were utilized to express YARS fusion proteins with a Flag-tag in the spinal cord,peripheral axons,and dorsal root ganglia.Following transfection of YARS-expressing viruses,the distributions of wild-type（WT） YARS and E196 K mutant proteins were compared in all expressed regions; G41 R was not expressed.The proportion of Flag/green fluorescent protein（GFP） double-positive signaling in the E196 K mutant-type mice did not significantly differ from that of WT mice in dorsal root ganglion neurons.All adenovirus genes,and even the empty vector without the YARS gene,exhibited GFP-positive signaling in the ventral horn of the spinal cord because GFP in an adenovirus vector is driven by a cytomegalovirus promoter.The present study demonstrated that anatomical differences in tissue can lead to dissimilar expressions of YARS genes.Thus,use of this novel animal model will provide data regarding distributional defects between mutant and WT genes in neurons,the DICMTC phenotype,and potential treatment approaches for this disease.

针灸对于体外受精和卵母细胞单精子显微注射结局的影响:一项前瞻性的随机对照临床研究

Objective: To determine the effect of luteal-phase acupuncture on the outcome of IVF/intracytoplasmic sperm injection (ICSI). Design: Randomized, prospective, controlled clinical study. Setting: University IVF center. Patient(s): Two hundred twenty-five infertile patients undergoing IVF/ICSI. Intervention( s): In group I, 116 patients received luteal-phase acupuncture according to the principles of traditional Chinese medicine. In group II, 109 patients received placebo acupuncture. Main Outcome Measure(s): Clinical and ongoing pregnancy rates. Result(s): In group I, the clinical pregnancy rate and ongoing pregnancy rate (33.6% and 28.4% , respectively) were significantly higher than in group II (15.6% and 13.8% ). Conclusion(s): Luteal-phase acupuncture has a positive effect on the outcome of 5 IVF/ICSI. .

在大规模非转诊城内人群中精子缺乏的病因学

A higher proportion of nonobstructive than obstructive azoospermia, as well as an increased prevalence of hypogonadotropic hypogonadism were documented in a retrospective study characterizing azoospermia in a population of predominantly Latino, inner-city male partners of infertile couples, as compared to previous reports from relatively affluent socioeconomic status male populations.

Glycodelin对卵丘细胞血管内皮生长因子产生的影响

Glycodelin modulates vascular endothelial growth factor (VEGF) production in cumulus cells in vitro. Patients with normal gonadotropin responses who were undergoing IVF demonstrated increased VEGF production to glycodelin, whereas poor responders had a decreased response to glycodelin.

Fertility Preservation in Premature Ovarian Insufficiency (POI) Secondary to FSH Receptor Gene (FSHR) Mutation: Is There a New Hope?

A 19 years old patient with primary amenorrhea was referred to our center. Based on discrepancy between high follicle stimulating hormone (FSH) level and normal ovarian reserve parameters, follicle stimulating hormone receptor (FSHR) mutation was screened. The patient was homozygous in exon 6 of the FSHR gene for the new variant c.479T > C and predicted to result in an aminoacid substitution p.Ile160Thr. One year later, her anti-müllerian hormone (AMH) level inexplicably decreased. Oocyte vitrification was thus offered for fertility preservation. After 17 days of recombinant follicle stimulating hormone (recFSH) (900 IU daily), no follicular growth was seen and estradiol levels remained low. In vitro maturation (IVM) was then suggested. Ten oocytes were successfully vitrified.

进行体外受精的卵巢反应不良患者应用3种不同降调方案的比较

Objective: To assess the efficacy of three different GnRH agonist (GnRH-a) stimulation regimens to improve ovarian response in poor responders undergoing IVF. Design: Retrospective cohort study. Setting: Center for Reproductive Health at the University of Cincinnati Medical Center. Patient(s): Women diagnosed as poor responders who presented consecutively from January 1999 to January 2004. Intervention(s): Patients underwent three different stimulation regimens during IVF cycles: 1 stop protocol: GnRH-a 500 μg/d administered from the midluteal phase to the start of menses, then gonadotropins from day 2 of cycle, 2 microdose flare: GnRH-a 20 μg administered twice daily with gonadotropins from day 2 to the day of hCG administration, or 3 regular dose flare: gonadotropins beginning with GnRH-a on day 2 at 1 mg/d for 3 days, followed by 250 μg/d until the day of hCGadministration. Main Outcome Measure(s): Ovarian response, implantation rates, clinical pregnancy and delivery rates. Result(s): Sixty-one IVF cycles were included in the study. None of the comparisons reached statistical significance; however, the microdose group demonstrated a trend toward a higher completed pregnancy rate. Conclusion(s): The microdose flare protocol for poor responders demonstrated a trend toward higher delivery rates. A larger prospective study would need to be performed to determine whether this trend leads to a significant finding in this patient population.

多囊卵巢综合征妇女应用2周二甲双胍改善克罗米芬诱导排卵作用及其代谢特征

Objective: To determine if short courses of metformin (MET)- administration in patients with polycystic ovary syndrome (PCOS) would reduce fasting insulin and improve the efficacy of clomiphene citrate (CC) to induce ovulation. Design: A randomized prospective trial involving 31 subjects with PCOS and infertility. Setting: University- based medical center. Patient(s): Obese patients (body mass index > 29 kg/m2) with PCOS. Intervention(s): Patients with PCOS were treated either with CC or CC+ MET for 2 weeks. Main Outcome Measure(s): Ovulation as determined by serum P, serum insulin, and total and free T. Result(s): In the CC/MET group, a significant increase in sex hormone-binding globulin (SHBG) levels, a decrease in fasting insulin, and an increase in fasting glucose/fasting insulin was detected on day 21 of the cycle. Of these parameters, only SHBG levels increased significantly in the CC group. In the CC/MET group, a significant increase in day 21 progesterone occurred, with 44% of subjects ovulating in the CC+ MET group as compared with 6.7% in the CC group. Five subjects in the CC+ MET group and none in the CC group conceived. Total and free testosterone levels did not change significantly for either group. Conclusion(s): In obese PCOS patients, 2 weeks of MET significantly reduces serum insulin and insulin resistance and increases SHBG levels, resulting in an improved response to CC. This regimen may be beneficial in noncompliant patients or those with intolerance to the side effects of MET.

体外受精胚胎移植过程中应用促性腺激素释放激素拮抗剂后,增加重组卵泡刺激素的随机对照试验

Objective: Pituitary suppression with a GnRH antagonist before IVF may result in a plateau or decrease in estradiol levels. We sought to investigate the effect of increasing recombinant FSH (rFSH) after starting a GnRH antagonist on estradiol levels, implantation rates, and pregnancy rates. Design: Prospective, randomized multicenter study. Setting: Military medical center and private practice. Patient(s): Sixty infertile women undergoing IVF who met the appropriate inclusion criteria. Intervention(s): Participants were pretreated with combined oral contraceptives (COCs) and received a dose 150-300 IU of rFSH 5 days after taking their last COC. They were randomly assigned to receive their current dose of rFSH (control group) or an additional 75 IU of rFSH (step-up group) after starting a GnRH antagonist. Daily GnRH antagonist injections were started when the lead follicles were 13- 14 mm in diameter and continued until hCG was given when two follicles were ≥ 18 mm. One to three embryos were transferred 3 or 5 days following oocyte retrieval. Women with PCOS, a body mass index > 33, a day 3 FSH > 14.1 mIU/mL, or prior poor stimulation were excluded. Main Outcome Measure(s): The primary endpoints of this pilot study were embryo implantation, pregnancy, and livebirth rates. Secondary endpoints included the amount and days of rFSH; number of days of GnRH antagonist use; estradiol levels on the day of GnRH antagonist initiation, day 1 and day 2 after initiation, and on the day of hCG; endometrial stripe thickness; number of follicles; and number of oocytes. Result(s): No differences were reported within the groups with respect to age, BMI, baseline FSH, use of intracytoplasmic sperm injection, vials of rFSH, number of GnRH antagonist injections, changes in estradiol patterns, or peak estradiol level. The control and step-up groups had similar pregnancies (73.3% vs. 63.3% , P = .41), clinical pregnancies (70.0% vs. 60.0% , P = .42), live births (56.7% vs. 60.0% , P = .8), and implantation rates (50.0% and 39.1% , P = .22). Conclusion(s): The use of rFSH and a GnRH antagonist in good candidates for IVF resulted in outstanding implantation and pregnancy rates. Increasing the dose of rFSH after starting a GnRH antagonist does not alter the estradiol response or improve the implantation and pregnancy rates.