Effects of leukocytospermia on the outcomes of assisted reproductive technology.

Leukocytospermia is one of the common causes of male infertility, and its effects on the clinical outcomes of assisted reproduction are controversial. There are no recommendations for the management of leukocytospermia in cases of assisted reproductive technology (ART). To investigate the impact of leukocytospermia on ART, we retrospectively compared the clinical outcomes in ART couples with or without leukocytospermia and further analysed the impact of the insemination method itself by split insemination treatment in ART couples with leukocytospermia. In this study, leukocytospermia was detected in 133 patients, namely 63 in the conventional in vitro fertilization (IVF) group, 38 in the intracytoplasmic sperm injection (ICSI) group and 32 in the split insemination group. Leukocytospermia has a negative influence on the parameters of semen samples; however, leukocytospermia did not affect the clinical outcomes of IVF or ICSI. Different insemination methods did not affect the fertilization, clinical pregnancy or live birth rates. In the split insemination study, no significant differences in clinical pregnancy and live birth rates between the IVF and ICSI groups were found; however, the numbers of two pronuclei (2PN), available embryos and good-quality embryos in the ICSI group were higher than those in the IVF group. Leukocytospermia may be a risk factor affecting semen parameters, and more attention should be given to IVF insemination. Leukocytospermia has no significant negative effect on the outcomes of ART. ICSI may obtain better embryos than IVF, but it cannot improve the clinical pregnancy and live birth rates.

Irisin deletion induces a decrease in growth and fertility in mice.

BACKGROUND: Irisin, which is cleaved from fibronectin type III domain-containing protein 5 (Fndc5), plays an important role in energy homeostasis. The link between energy metabolism and reproduction is well known. However, the biological actions of irisin in reproduction remain largely unexplored. METHODS: In this study, we generated Fndc5 gene mutation to create irisin deficient mice. Female wild-type (WT) and Fndc5 mutant mice were fed with standard chow for 48 weeks. Firstly, the survival rate, body weight and fertility were described in mice. Secondly, the levels of steroid hormones in serum were measured by ELISA, and the estrus cycle and the appearance of follicles were determined by vaginal smears and ovarian continuous sections. Thirdly, mRNA-sequencing analysis was used to compare gene expression between the ovaries of Fndc5 mutant mice and those of WT mice. Finally, the effects of exogenous irisin on steroid hormone production was investigated in KGN cells. RESULTS: The mice lacking irisin presented increased mortality, reduced body weight and poor fertility. Analysis of sex hormones showed decreased levels of estradiol, follicle-stimulating hormone and luteinizing hormone, and elevated progesterone levels in Fndc5 mutant mice. Irisin deficiency in mice was associated with irregular estrus, reduced ratio of antral follicles. The expressions of Akr1c18, Mamld1, and Cyp19a1, which are involved in the synthesis of steroid hormones, were reduced in the ovaries of mutant mice. Exogenous irisin could promote the expression of Akr1c18, Mamld1, and Cyp19a1 in KGN cells, stimulating estradiol production and inhibiting progesterone secretion. CONCLUSIONS: Irisin deficiency was related to disordered endocrinology metabolism in mice. The irisin deficient mice showed poor growth and development, and decreased fertility. Irisin likely have effects on the expressions of Akr1c18, Mamld1 and Cyp19a1 in ovary, regulating the steroid hormone production. This study provides novel insights into the potential role of irisin in mammalian growth and reproduction.

Loss-of-function mutation in DNAH8 induces asthenoteratospermia associated with multiple morphological abnormalities of the sperm flagella.

Asthenozoospermia is a common cause of male infertility associated with the reduced motility and/or abnormal morphology of spermatozoa, although its etiology remains incompletely understood. Multiple morphological abnormalities of the sperm flagella (MMAF) is one of the main causes of asthenozoospermia. However, the MMAF-associated genes identified to date cannot explain all the human MMAF cases. Herein, a loss-of-function mutation of DNAH8 was identified in an asthenozoospermia patient with MMAF. Moreover, the negative effect of this mutation on DNAH8 expression was confirmed by immunofluorescence staining and western blotting. Remarkably, it is the first time that DNAH8 is suggested to be associated with human MMAF. Our findings provide strong evidence that a loss-of-function mutation in DNAH8 can cause male infertility with MMAF and that DNAH8 is essential for sperm flagellar formation.

Irisin promotes proliferation but inhibits differentiation in osteoclast precursor cells.

The receptor activator of NF-κB ligand-induced osteoclast differentiation has a critical role in the process of bone metabolism. Overactivation of osteoclastogenesis may result in a series of diseases. Irisin, a novel myokine, which was first reported in 2012, has been proposed to mediate the beneficial metabolic effects of exercise. Studies have demonstrated that irisin targets osteoblasts by promoting osteoblast proliferation and differentiation; however, the underlying mechanism regarding the effect of irisin on osteoclasts remains elusive. Using 2 types of osteoclast precursor cells, RAW264.7 cells and mouse bone marrow monocytes, we showed that irisin promoted osteoclast precursor cell proliferation but inhibited osteoclast differentiation. Irisin down-regulated the expression of osteoclast differentiation marker genes, including receptor activators of NF-κB, nuclear factor of activated T cells, cytoplasmic 1, cathepsin K, and tartrate-resistant acid phosphatase (TRAP), as well as decreasing the number of TRAP-positive multinucleated cells and hydroxyapatite resorption pits. Furthermore, we showed that irisin suppressed the NF-κB signaling pathway, but activated the p38 and JNK signaling pathways. In the presence of an inhibitor of p38 and JNK, irisin-induced promotion of RAW264.7 cell proliferation was attenuated. However, irisin-induced inhibition of osteoclast differentiation was not affected by either the p38 or JNK signaling pathway. Our study suggested the direct effect of irisin on osteoclastogenesis and revealed the mechanism responsible for the therapeutic potential of irisin in bone metabolism disease.-Ma, Y., Qiao, X., Zeng, R., Cheng, R., Zhang, J., Luo, Y., Nie, Y., Hu, Y., Yang, Z., Zhang, J., Liu, L., Xu, W., Xu, C. C., Xu, L. Irisin promotes proliferation but inhibits differentiation in osteoclast precursor cells.

Association of gene polymorphisms in the anti-Müllerian hormone signalling pathway with ovarian function: a systematic review and meta-analysis.

This systematic review evaluated whether single nucleotide polymorphisms of AMH and AMHRII genes are associated with ovarian function. A literature search of PubMed and Embase was complemented by hand searches in the reference lists. Eight studies involving 3155 participants were included in a meta-analysis and 10 studies included for description. For AMH c.146T>G polymorphism, no significant difference in serum anti-Müllerian hormone (AMH) levels was found between participants with different genotypes (weighted mean difference [WMD] 0.42, 95% confidence interval [CI] -0.16 to 0.99). Subgroup analyses showed similar results for the European region and in healthy and infertile populations. Regarding AMHRII -482 A>G, there was no significant difference in serum AMH levels between participants with A/A genotype and G/A or G/G genotype carriers (WMD -0.04, 95% CI -0.31 to 0.23). In subgroup analysis, an interesting trend was confirmed in healthy women and polycystic ovary syndrome (PCOS) patients (WMD -0.36, 95% CI -0.63 to -0.09, P = 0.009; WMD 0.46, 95% CI 0.15 to 0.77, P = 0.004). The review suggests that AMH c.146T>G is not associated with AMH levels, while AMHRII -482 A>G may be related to AMH levels in PCOS and healthy subgroups. However, the impact of polymorphisms in the AMH signalling pathway on ovarian function still requires further investigation.

Chromosomal polymorphisms are associated with female infertility and adverse reproductive outcomes after infertility treatment: a 7-year retrospective study.

Data from 19,950 women were retrospectively analysed to determine the effect of chromosomal polymorphisms on female infertility and pregnancy outcome; fertile women were used as controls. Frequency of chromosomal polymorphisms and adverse pregnancy outcomes were compared between groups. A significantly higher incidence of chromosomal polymorphisms was found in total infertile patients, and patients with tubal infertility, ovulatory dysfunction, cervical and uterine abnormalities, and unexplained infertility compared with controls (5.53% [P < 0.001], 4.86% [P = 0.012] 5.40% [P < 0.001], 5.75% [P < 0.001] and 8.51% [P < 0.001], versus 3.74%, respectively). Infertile women had a higher incidence of 9qh+ and inv(9) compared with controls (P < 0.001 and P = 0.027). Logistic regression analysis showed an effect of chromosomal polymorphisms on female infertility (adjusted OR 1.662, 95% CI 1.551 to 1.796, P < 0.001). All couples reported a phenotypically normal baby. In control and tubal infertility groups, miscarriage rates were higher in women with chromosomal polymorphisms than in women with normal chromosomes (4.95% versus 0.96%, P = 0.001 and 6.17% versus 1.08%, P < 0.001). Preterm birth rate showed a similar trend. Chromosomal polymorphisms adversely affected spontaneous miscarriage rates (adjusted OR 1.625, 95% CI 1.514 to 1.769, P = 0.005).

Irisin: circulating levels in serum and its relation to gonadal axis.

Irisin is an exercise-induced myokine/adipokine in mice and humans that plays an important role in 'browning' of white adipose tissue and has shown great potential as a treatment for some metabolic diseases, such as obesity, insulin resistance, and inflammation. The circulating irisin level is reported to be associated with exercise, obesity, diet, diseases, and exposure to different pharmacological agents. Several studies have attempted to characterize the role of irisin in PCOS and other reproductive diseases, but contradictory results have been reported. Our previous study showed that irisin may serve further functions in folliculogenesis and fertility. In this review, we present the current knowledge on the physiology of irisin and its role in gonadal axis. Firstly, we describe irisin circulating levels and speculate on the potential mechanisms involved in irisin secretion and regulation. Then, we focus on the irisin levels in PCOS, and explore the relationships between, BMI, insulin resistance, and hyperandrogenism. Finally, we present the results from animal interventional studies and in vitro experiments to investigate the relationship between irisin and gonadal axis, indicating its novel effects on reproduction and fertility.

Dichorionic quadruplet pregnancy comprising monozygotic triplets and singleton after intracytoplasmic sperm injection and transfer of two fresh embryos: a case report.

Monozygotic triplet pregnancies are very rare in assisted reproductive technology, and the relationship between monozygotic multiple pregnancies and several assisted reproductive techniques, including blastocyst transfer, remains unclear. Here, the case of a 28-year-old female patient with dichorionic quadruplet pregnancy following intracytoplasmic sperm injection and transfer of two day-3 fresh embryos, without assisted hatching, is reported. At 7 weeks following embryo transfer, the dichorionic quadruplet pregnancy, comprising monozygotic monochorionic triamniotic (MCTA) triplets plus a singleton, was detected by a transabdominal ultrasound scan. After counselling, the patient underwent selective reduction of the MCTA triplet pregnancy at 7 weeks after embryo transfer. The remaining singleton pregnancy was uneventful, resulting in a live birth at 38+ weeks. As the predictors of monozygotic multiple gestations remain poorly characterized, clinicians and patients should give great consideration to the risks associated with monozygotic multiple pregnancies, even if the patient has not undergone blastocyst transfer.

Different regimens of menopausal hormone therapy for improving sleep quality: a systematic review and meta-analysis.

IMPORTANCE: Long-term sleep disturbances in menopausal women are closely related to cardiovascular disorders, metabolic disorders, and cognitive impairment. At present, hormone therapy (HT) is a standard treatment for menopausal symptoms. However, it remains unclear whether HT can improve sleep quality. OBJECTIVE: We did a systematic review and meta-analysis to assess the effects of different HT regimens on menopausal sleep quality. EVIDENCE REVIEW: We systematically searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, PsycINFO, CINAHL, and Web of Science for randomized controlled trials of menopausal HT on sleep disturbances up to June 14,2021. Information about ongoing and unpublished trials was collected by searching WHOICTRP and ClinicalTrials.gov. Our primary outcome was sleep quality with objective measurements. We estimated the standardized mean difference (SMD) using random-effects models. FINDINGS: We identified a total of 3,059 studies and finally included 15 studies in the meta-analysis. Compared with placebo, HT improved self-reported sleep outcomes (SMD = -0.13; 95% CI, -0.18 to -0.08, P  < 0.00001 and I2 = 41%), but not sleep parameters measured by polysomnography. Subgroup analyses according to the regimen of HT showed that 17ß-estradiol (17ß-E2) (SMD = -0.34; 95% CI, -0.51 to -0.17, P  < 0.0001, and I2 = 0%) and conjugated equine estrogens (SMD = -0.10; 95% CI, -0.12 to -0.07, P  < 0.00001, and I2 = 0%) improved sleep quality. Moreover, transdermal administration (SMD = -0.35; 95% CI, -0.64 to -0.06, and P  = 0.02) was more beneficial than oral (SMD = -0.10; 95% CI, -0.14 to -0.07, and P  < 0.00001). In addition, the combination of estrogen and progesterone had a positive effect on sleep disturbance (SMD = -0.10; 95% CI, -0.13 to -0.07, P  < 0.00001, and I2 = 0%), while estrogen monotherapy did not. The results showed that estrogen/micronized progesterone (SMD = -0.22; 95% CI, -0.37 to -0.06, P = 0.007, and I2 = 0%) and estrogen/medroxyprogesterone acetate (SMD = -0.10; 95% CI, -0.13 to -0.07, P  < 0.00001, and I2 = 0%) could alleviate sleep disturbance. CONCLUSIONS AND RELEVANCE: HT has a beneficial effect on sleep disturbance to some extent, and the formulations and routes of administration of hormonal agents influence the effect size.

Irisin level and neonatal birthweight: A systematic review and meta-analysis.

Irisin is an important crosstalk myokine between adipose and muscle tissue. Disorders in irisin secretion can lead to fetal growth abnormalities and even lead to metabolic syndromes in adult life. This study aimed to evaluate the association between irisin level in umbilical cord blood and maternal serum with neonatal birthweight. The Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) statement and the Meta-analysis of Observational Studies in Epidemiology (MOOSE) guideline were followed. A comprehensive search of eight databases (PubMed, Embase, Web of Science, Cochrane Central Register of Controlled Trials, CBM, CNKI, WANFANG and VIP) was performed from inception to November 2019. Studies with original date reporting irisin levels in newborns of small for gestational age (SGA) and newborns of large for gestational age (LGA) were included. Additionally, studies reporting correlation coefficients of irisin with birthweight were analyzed. Newcastle-Ottawa score system and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach were applied. Seventeen studies with 1866 participants were included. Pooled analysis indicated decreased cord irisin levels in SGA newborns (MD -10.57, 95 % CI -13.41 to -7.73) and increased irisin levels in LGA newborns (MD 3.80, 95 % CI 1.91-5.70). Umbilical cord irisin level was positively correlated with neonatal birthweight (r = 0.41 95 %CI 0.04 to 0.68). The pooled correlation coefficient of maternal serum irisin with birthweight has no statistical significance. This meta-analysis suggested that the umbilical cord irisin levels were impaired in fetal growth abnormalities. Umbilical cord blood irisin level was positively correlated with birthweight.

Disordered metabolism in mice lacking irisin.

Irisin is a product of fibronectin type III domain-containing protein (Fndc5) and is involved in the regulation of adipokine secretion and the differentiation of osteoblasts and osteoclasts. In this study, we aimed to determine whether irisin lacking affects glucose/lipid and bone metabolism. We knocked out the Fndc5 gene to generate irisin-lacking mice. Remarkable, irisin lacking was related to poor 'browning response', with a bigger size of the intraperitoneal white adipose cell and decreased a number of brown adipose cells in brown adipose of interscapular tissue. The irisin lacking mice had hyperlipidemia and insulin resistance, reduced HDL-cholesterol level, increased LDL-cholesterol level, and decreased insulin sensitivity. The lacking of irisin was associated with reduced bone strength and bone mass in mice. The increased number of osteoclasts and higher expression of RANKL indicated increased bone resorption in irisin lacking mice. The level of IL-6 and TNF-α also increased in irisin lacking mice. The results showed that irisin lacking was related to decreased 'browning response', glucose/lipid metabolic derangement, and reduced bone mass with increased bone resorption. Further studies are needed to confirm these initial observations and explore the mechanisms underlying the effects of irisin on glucose/lipid and bone metabolism.

Lower circulating irisin in middle-aged and older adults with osteoporosis: a systematic review and meta-analysis.

OBJECTIVE: Osteoporosis has imposed a heavy socioeconomic burden worldwide, especially in postmenopausal women. As a newly found protein, irisin has an important physiological role in bone metabolism. This meta-analysis intends to identify the association between circulating irisin levels and osteoporosis. METHODS: This meta-analysis was conducted following the Meta-analysis of Observational Studies in Epidemiology (MOOSE) guideline. A comprehensive search of five databases was performed from inception to January 2019. Studies with original date on middle-aged and older participants were included. Data were analyzed according to study characteristics and heterogeneity between studies. The quality of each study and the presence of publication bias were assessed by Newcastle-Ottawa score (NOS) and normal quantile plot. RESULTS: Seven studies, with a total of 1,018 participants, conducted in four countries, were included. Six of them were identified as high-quality research. Five studies included postmenopausal women, and two studies included both men and women. Possible publication bias was found in the analysis of irisin and osteoporosis. Pooled analysis indicated decreased irisin levels in osteoporotic participants (mean difference -87.91, 95% CI, -92.56 to -83.25). Subgroup analysis revealed an even lower level of irisin in postmenopausal women and in participants with a history of fractures. Analysis on associations between irisin and femoral neck or lumbar spine bone mineral density showed a weak positive correlation. CONCLUSIONS: The findings of this analysis suggested that circulating irisin levels were decreased in middle-aged and older participants with osteoporosis. Irisin was positively correlated with bone mineral density.

Effects of the Dibutyl Phthalate (DBP) on the Expression and Activity of Aromatase in Human Granulosa Cell Line KGN.

In recent years, environmental endocrine disruptors (EEDs) have received extensive attention because of their hormone-like or anti-hormone effects. Dibutyl phthalate (DBP) is not only one of the most widely-used phthalates but also a member of EEDs with the estrogenic property. Although some studies have revealed the negative effect of DBP on the reproductive system, the underlying mechanisms are still elusive. Here the effect of DBP on P450 aromatase, a rate-limiting enzyme stimulated by FSH in the estradiol synthesis, was investigated in human granulosa cell line KGN. Cultured cells were treated with FSH and various doses of DBP (0.1µM, 1µM, 10µM, 50µM, or 100µM) for 24hr. Then the expression of aromatase was assessed, and the synthesis of estradiol was detected to reflect aromatase activity. As shown by the results, all concentrations of DBP could up-regulate the mRNA as well as protein levels of aromatase, and 0.1µM DBP increased the production of estradiol significantly. Furthermore, the ovary-specific promoter of aromatase, promoter II, was activated by 0.1µM DBP, and the expression of FSH receptor (FSHR) was increased by DBP from 0.1µM to 100µM. The study results show that DBP can affect aromatase from both quantitative and functional aspects, and this process may involve the activation of aromatase promoter II and upregulation of FSHR in KGN. Additionally, low-concentration DBP, near human serum concentration, has a more robust effect. This study suggests that DBP may affect the steroidogenic capacity in human ovaries and contributes to our understanding of the effects of DBP on the female reproductive system.

[Efficacy and metabolic safety of long-term treatment with ethinyl oestradiol/cyproterone and desogestrel/ethinyl oestradiol tablets in women with polycystic ovary syndrome].

OBJECTIVE: To evaluate the efficacy and metabolic safety of long-term treatment with ethinyl oestradiol/cyproteroneand desogestrel/ethinyl oestradiol tablets in women with polycystic ovary syndrome (PCOS). METHODS: Women with PCOSfrom West China Second Hospital of Sichuan University enrolled between September, 2011 and August, 2013 were randomlyallocated to receive either ethinyl oestradiol/cyproterone tablets (Group A, n=355) or desogestrel/ethinyl oestradiol tablets(Group B, n=357) for a prospective observation period of 6 months. Women with insulin resistance also received metformin. Atbaseline, 3 months, and 6 months, the patients were evaluated for menstruation, acne score, body mass index (BMI), waist-tohip ratio (WHR), plasma levels of sex hormones, fasting blood glucose (FPG), HOMA-insulin resistance index (HOMA-IR), serum lipid, ovarian volume, and the number of ovarian follicles. RESULTS: All the patients had a regular menstrual cycle aftertreatments. Testosterone level, acne score, LH/FSH, ovarian volume, and the number of follicles decreased significantly afterthe treatments without significant differences between the two groups. Significant increases were noted in TG, TCh, LDL, HDL, and AIP, and HDL level in group A as compared with group B (P < 0.001). FPG decreased in both groups, and wassignificantly lower in group B at 6 months (P < 0.05). BMI and WHR decreased in all the patients with insulin resistance aftercombination treatment with metformin (P < 0.05), but increased significantly in patients without insulin resistance (P < 0.05). Ingroup A, HOMA- IR significantly increased in patientswithout insulin resistance at 3 months (P < 0.05), whereas asignificant increase was not observed until 6 months ingroup B (P < 0.05). CONCLUSIONS: Both ethinyl oestradiol/cyproterone tablets and desogestrel/ethinyl oestradioltablets can relieve the symptoms of PCOS, but it isadvisable to assess the risk of cardiovascular diseasebefore the treatments.