The association between hepatitis B virus and semen quality: a systematic review and meta-analysis.

BACKGROUND: Some studies have suggested that hepatitis B virus (HBV) infection had a negative association with semen quality, but the conclusions have been inconsistent. The purpose of our study was to systematically assess the association between HBV infection and semen parameters. METHODS: We searched electronic databases for studies published from January 1980 to August 2023. Eleven studies were included in the analysis. Primary outcomes were semen volume, sperm concentration, sperm morphology, sperm motility and sperm progressive motility. We also conducted a subgroup analysis between China and other countries. RESULT: Compared with the semen quality of HBV-negative men, HBV infection had a negative association with semen volume (MD: -0.20 mL, 95%CI: -0.32 to - 0.09, P = 0.0004), sperm concentration (MD: -4.46 × 106/mL, 95%CI: -7.09 to - 1.84, P = 0.0009), sperm morphology (MD: -2.49%, 95%CI: -4.35 to - 0.64, P = 0.008), sperm motility (MD: -6.85%, 95%CI: -11.53 to - 2.18, P = 0.004), and sperm progressive motility (MD: -6.63%, 95%CI: -10.24 to - 3.02, P = 0.0003). However, HBV infection had no significant association with total sperm count (MD: -31.50 × 106, 95%CI: -74.11 to 11.10, P = 0.15). The association between HBV and semen quality were inconsistent between the subgroups. CONCLUSION: HBV infection had a negative association with sperm concentration, motility, morphology, and semen volume. However, The association between HBV and total sperm count remain unclear. This metaanalysis suggests that we should pay attention to the adverse effect of HBV on sperm quality, and several studies have reported the relevant mechanisms. But due to the significant heterogeneity among studies on some semen parameters, further large and well-designed researches are needed before introducing clinical management recommendations.

The humanin analogue (HNG) alleviates intrauterine adhesions by inhibiting endometrial epithelial cells ferroptosis: a rat model-based study.

STUDY QUESTION: Does a humanin analogue (HNG) have a therapeutic effect on intrauterine adhesions (IUAs) caused by uterine cavity surgery in a rat model? SUMMARY ANSWER: HNG supplementation attenuated the development of endometrial fibrosis and IUAs, improved fertility, and contributed to the regulation of endometrial fibrosis by inhibiting endometrial ferroptosis in rats with IUAs. WHAT IS KNOWN ALREADY: IUAs, which are characterized by endometrial fibrosis, are a common cause of female infertility. Humanin (rattin in rats) is a mitochondrial-derived peptide that is widely expressed in multiple tissues. S14G-humanin (HNG) is an HNG that has been reported to have a protective effect against myocardial fibrosis. STUDY DESIGN, SIZE, DURATION: Endometrial tissues from three patients with IUAs and three controls were tested for humanin expression. Two animal models were used to evaluate the modelling effect of IUAs and the preventive effect of HNG against IUAs. In the first model, 40 rats were equally randomized to control and Day 7, 14, and 21 groups to establish the IUA model. In the second model, 66 rats were equally randomized to the control, IUA, and IUA + humanin analogue (HNG) groups. Erastin was used to induce ferroptosis in the Ishikawa cell line. PARTICIPANTS/MATERIALS, SETTING, METHODS: The endometrium was scraped with a surgical spatula, combined with lipopolysaccharide treatment, to establish the rat model of IUAs. Rats were intraperitoneally injected with 5 mg/kg/day HNG for 21 consecutive days beginning from the day of operation to evaluate the therapeutic effect on IUAs. Haematoxylin-eosin and Masson's trichrome staining were used to assess endometrial morphology and evaluate fibrosis. Ferroptosis-related markers, namely nuclear factor E2-related factor 2 (Nrf2), acyl-CoA synthetase long-chain family member 4 (ACSL4), haeme oxygenase-1 (HO-1), solute carrier family 7 member 11 (SLC7A11), glutathione peroxidase 4 (GPX4), and ferritin, were measured by immunohistochemistry and western blotting to determine whether ferroptosis was involved in the development of IUAs and to assess the attenuative effect of HNG on ferroptosis. Additionally, the female rats were mated with male rats with normal fertility to assess fertility. MAIN RESULTS AND THE ROLE OF CHANCE: Humanin was widely expressed in endometrial cells, including epithelial and stromal cells, in both humans and rats. Humanin expression levels were downregulated in the endometria of patients and rats with IUAs relative to the endometria of controls. Endometrial thickness and the number of glands were significantly decreased on Day 7, 14, and 21 after endometrial scraping when compared with the controls (all P < 0.05), whereas the fibrotic area was significantly increased (P < 0.05). Among the tested ferroptosis markers, the expression levels of Nrf2, SLC7A11, and GPX4 were significantly downregulated and those of ACSL4, HO-1, and ferritin were significantly upregulated after endometrial scraping relative to their expression levels in controls (all P < 0.05). The mating rates in the control, IUA, and IUA + HNG groups were 100% (10/10), 40% (4/10), and 80% (8/10), respectively. The number of embryos in rats with IUAs (mean ± SD: 1.6 ± 2.1) was significantly less than the number in the controls (11.8 ± 1.5). HNG supplementation significantly attenuated this decrease in the number of implanted embryos (6.3 ± 4.5) (P < 0.01). Further results showed that HNG significantly attenuated the altered expression levels of proteins involved in ferroptosis in the endometria of rats with IUAs. Moreover, in vitro experiments showed that HNG significantly attenuated the erastin-induced decrease in the viability of the Ishikawa cell line and also attenuated the increase in reactive oxygen species production and the downregulation of GPX4. LARGE SCALE DATA: None. LIMITATIONS, REASONS FOR CAUTION: The findings of this study showed that HNG inhibited ferroptosis and reduced fibrosis in a rat model of IUAs. However, we could not establish a causal relationship between ferroptosis and the development of IUAs. WIDER IMPLICATIONS OF THE FINDINGS: HNG may be effective at alleviating fibrosis during the development of IUAs, and the inhibition of ferroptosis is a promising new strategy for IUA therapy. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the National Natural Science Foundation of China (No. 82171647); the '1000 Talent Plan' of Yunnan Province (No. RLQN20200001); and the Basic Research Project of the Yunnan Province-Outstanding Youth Foundation (No. 202101AW070018). The authors declare no competing financial interests.

Characterization of a GH10 extremely thermophilic xylanase from the metagenome of hot spring for prebiotic production.

A xylanase gene (named xyngmqa) was identified from the metagenomic data of the Gumingquan hot spring (92.5 °C, pH 9.2) in Tengchong City, Yunnan Province, southwest China. It showed the highest amino acid sequence identity (82.70%) to endo-1,4-beta-xylanase from Thermotoga caldifontis. A constitutive expression plasmid (denominated pSHY211) and double-layer plate (DLP) method were constructed for cloning, expression, and identification of the XynGMQA gene. The XynGMQA gene was synthesized and successfully expressed in Escherichia coli DH5α. XynGMQA exhibited optimal activity at 90 °C and pH 4.6, being thermostable by maintaining 100% of its activity after 2 h incubated at 80 °C. Interestingly, its enzyme activity was enhanced by high temperatures (70 and 80 °C) and low pH (3.0-6.0). About 150% enzyme activity was detected after incubation at 70 °C for 20 to 60 min or 80 °C for 10 to 40 min, and more than 140% enzyme activity after incubation at pH 3.0 to 6.0 for 12 h. Hydrolytic products of beechwood xylan with XynGMQA were xylooligosaccharides, including xylobiose (X2), xylotriose (X3), and xylotetraose (X4). These properties suggest that XynGMQA as an extremely thermophilic xylanase, may be exploited for biofuel and prebiotic production from lignocellulosic biomass.

Thyroid Autoimmunity Is Not Associated with Embryo Quality or Pregnancy Outcomes in Euthyroid Women Undergoing Assisted Reproductive Technology in China.

Background: Studies have shown that thyroid autoimmunity (TAI) is associated with increased risks of adverse pregnancy outcomes. The aim of this study was to investigate the associations between TAI and embryo quality in euthyroid women undergoing in vitro fertilization or intracytoplasmic sperm injection (IVF/ICSI). Methods: This retrospective cohort study included euthyroid infertile women with and without TAI (defined as a serum thyroperoxidase concentration ≥34 IU/mL or a thyroglobulin concentration ≥115.0 IU/mL) who underwent their first complete IVF/ICSI treatment cycles at a tertiary referral center between April 2016 and February 2022. Embryo quality measurements and clinical outcomes were compared between women with (TAI positive) and without TAI (TAI negative). The high-quality cleavage embryo rate and cumulative live birth rate (cLBR) were the primary outcomes. Results: A total of 499 TAI-positive and 2945 TAI-negative women were included in this study, and their mean (standard deviation) ages were 31.6 (4.5) and 30.9 (4.4) years, respectively (p = 0.001). The overall analysis showed no significant differences between TAI-negative and TAI-positive women in the high-quality cleavage embryo rate (n/N: 11,139/22,553 vs. 1971/3820; adjusted rate: 52.8% vs. 53.4%, p = 0.66) and cLBR (1917/2945 vs. 327/499; 53.4% vs. 56.2%, p = 0.31). Moreover, no significant differences were observed between TAI-negative and TAI-positive women in the rates of oocyte retrieval (35,078/51,978 vs. 5853/8628; 69.1% vs. 69.4%; p = 0.65), fertilization (23,067/34,197 vs. 3902/5728; 61.1% vs. 62.2%, p = 0.34), embryo utilization (18,233/22,553 vs. 3156/3820; 80.2% vs. 80.8%, p = 0.61), blastocyst formation (7051/13,721 vs. 1192/2330; 48.5% vs. 48.4%, p = 0.97), and high-quality blastocysts (4819/13,721 vs. 799/2330; 29.9% vs. 29.4%, p = 0.73). Furthermore, no significant differences were observed between TAI-negative and TAI-positive women in the clinical pregnancy rate (1524/2808 vs. 248/482; 46.7% vs. 44.6%, p = 0.40), early pregnancy loss rate (156/1524 vs. 23/248; 13.5% vs. 11.5%, p = 0.44), and LBR (1338/2808 vs. 218/482; 37.4% vs. 36.0%, p = 0.55) of the first transfer cycle. Conclusions: This study demonstrated that TAI in women was not associated with embryo quality or the cLBR following IVF/ICSI. Future large studies are warranted to confirm these findings.

Subclinical Hypothyroidism and Sperm DNA Fragmentation: A Cross-sectional Study of 5401 Men Seeking Infertility Care.

CONTEXT: Our previous study showed that paternal subclinical hypothyroidism (SCH) had a detrimental effect on the clinical outcomes of assisted reproductive technologies. However, it remains to be determined whether paternal SCH affects sperm DNA integrity. OBJECTIVE: To investigate the association between SCH and sperm DNA fragmentation in men seeking infertility care. METHODS: This cross-sectional study included 4983 men with euthyroidism and 418 men with SCH seeking infertility treatment in a tertiary care academic medical center between January 2017 and December 2021. The outcome measures were the absolute DNA fragmentation index (DFI) and the risk of abnormal DFI (defined as DFI ≥ 25% or ≥ 30%). RESULTS: The mean (SD) age of men with euthyroidism and men with SCH was 34.20 (5.97) and 35.35 (6.48) years, respectively (P < 0.001). The difference in DFI was not statistically significant (adjusted mean: 19.7% vs 18.9% in the SCH and euthyroidism groups, respectively; P = 0.07) after confounder adjustment. A DFI ≥25% was significantly more frequent in men with SCH (20.57%) than in men with euthyroidism (14.49%) after confounder adjustment [odds ratio (OR) 1.43 (95% CI 1.09-1.88)]. DFI ≥ 30% was also significantly more common in men with SCH (11.72%) than in men with euthyroidism [6.74%; OR 1.84 (95% CI 1.34-2.52)]. In addition, thyroid-stimulating hormone concentration was significantly associated with an increased risk of having a DFI ≥25% (P < 0.001) or ≥30% (P = 0.011). CONCLUSION: SCH was significantly associated with an increased risk of an abnormal DFI.

Cumulative live birth rates after IVF/ICSI cycles with sperm prepared by density gradient centrifugation vs. swim-up: a retrospective study using a propensity score-matching analysis.

BACKGROUND: Density gradient centrifugation (DGC) and swim-up (SU) are the two most widely used sperm preparation methods for in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI). However, existing comparisons of IVF/ICSI outcomes following these sperm preparation methods are insufficient and controversial. METHODS: This retrospective study included all first autologous IVF and ICSI cycles performed between March 1, 2016, and December 31, 2020 in a single university-based center. A total of 3608 cycles were matched between DGC and SU using propensity score (PS) matching for potential confounding factors at a ratio of 1:1. The primary outcome was the cumulative live birth rate (cLBR) per aspiration. RESULTS: PS matching provided 719 cycles after DGC and 719 cycles after SU. After adjusting for confounders, the recovery rate, progressive motility rate after sperm preparation, fertilization rate, good-quality embryo rate, and blastocyst formation rate were similar between the DGC and SU groups. The cLBR (odds ratio [OR] = 1.143, 95% confidence interval [CI]: 0.893-1.461) and LBR per transfer (OR = 1.082, 95% CI: 0.896-1.307) were also not significantly different between the groups. Furthermore, no significant differences were found in all of the laboratory and clinical outcomes following conventional IVF or ICSI cycles between the two groups. However, a significantly higher fertilization rate (ß = 0.074, 95% CI: 0.008-0.140) was observed when using poor-quality sperm in the DGC group than in the SU group. CONCLUSIONS: Sperm preparation using DGC and SU separately resulted in similar IVF/ICSI outcomes. Further studies are warranted to compare the effects of these methods on IVF/ICSI outcomes when using sperm from subgroups of different quality.

Normal-Range Paternal Serum-Free Thyroxine Concentrations and Outcomes of Assisted Reproductive Technologies.

Background: A recent study showed that paternal subclinical hypothyroidism adversely affects the clinical outcomes of assisted reproductive technologies (ARTs). The aim of this study was to determine whether paternal serum-free thyroxine (fT4) concentrations within the reference range are associated with ART outcomes. Methods: This retrospective cohort study included 4066 couples who received 4894 ART treatment cycles in our clinic between April 1, 2016 and August 31, 2021. The differences in sperm parameters and ART outcomes across the paternal fT4 concentration tertiles were compared by using generalized linear models or generalized estimation equation models. The primary outcomes were clinical pregnancy rate (CPR) and live birth rate (LBR) per oocyte retrieval after the first embryo transfer cycle. Results: The mean ages of the males and their female partners were 32.8 (standard deviation, 5.0) and 30.7 (standard deviation, 4.1) years, respectively. No significant differences were observed in the sperm parameters or ART outcomes between the paternal fT4 concentration tertiles of the overall population. However, a stratified analysis of men aged ≥35 showed an adjusted CPR of 0.36 [confidence interval, CI: 0.27-0.45] for the lower paternal fT4 concentration tertile relative to the middle (adjusted rate: 0.45, CI: 0.38-0.53) and upper (adjusted rate: 0.43, CI: 0.36-0.51) tertiles (p for trend >0.05). The adjusted LBRs were 0.21 [CI: 0.15-0.30] for men aged ≥35 in the lower fT4 concentration tertile (p = 0.024, with reference to the upper tertile), 0.27 [CI: 0.21-0.35] for those in the middle tertile, and 0.30 [CI: 0.23-0.38] for those in the upper tertile. No differences in these outcomes were observed in men aged <35. The nonlinear smoothing curve obtained by using fT4 concentration as a continuous variable further supported these findings. Conclusions: Men of older reproductive age (≥35 years old) with low-normal fT4 concentrations within the reference range are associated with a decreased LBR. Future prospective studies are warranted to confirm the detrimental effects of low-normal paternal fT4 concentrations on ART outcomes.

The role of humanin in the regulation of reproduction.

Humanin, a mitochondria-derived peptide, has been found to exert variously protective function in many tissues, especially in the nervous tissues. However, relatively limited studies have focused on the role of humanin in the regulation of reproduction. Current observations indicate that humanin plays an important role in regulating the response of the cell to oxidative stress and apoptosis in ovaries and testes via the modulation of several signaling pathways, especially when the body is in an abnormal state. Even so, the detailed mechanism of humanin function needs to be explored urgently. In this passage, we demonstrate how humanin exerts its protective role in female and male reproduction and raise several questions that need further investigations. Given humanin's new frontier for the design of novel therapeutic approaches for male infertility, male contraception, female infertility, and glucose metabolism in polycystic ovary syndrome, it is worthy of further study on its protective effects and clinical applications in reproductive function.

Obstetric and neonatal outcomes of pregnancies resulting from preimplantation genetic testing: a systematic review and meta-analysis.

BACKGROUND: Preimplantation genetic testing (PGT) includes methods that allow embryos to be tested for severe inherited diseases or chromosomal abnormalities. In addition to IVF/ICSI and repeated freezing and thawing of the embryos, PGT requires a biopsy to obtain embryonic genetic material for analysis. However, the potential effects of PGT on obstetric and neonatal outcomes are currently uncertain. OBJECTIVE AND RATIONALE: This study aimed to investigate whether pregnancies conceived after PGT were associated with a higher risk of adverse obstetric and neonatal outcomes compared with spontaneously conceived (SC) pregnancies or pregnancies conceived after IVF/ICSI. SEARCH METHODS: PubMed, EMBASE, MEDLINE, Web of Science and The Cochrane Library entries from January 1990 to January 2021 were searched. The primary outcomes in this study were low birth weight (LBW) and congenital malformations (CMs), and the secondary outcomes included gestational age, preterm delivery (PTD), very preterm delivery (VPTD), birth weight (BW), very low birth weight (VLBW), neonatal intensive care unit (NICU) admission, hypertensive disorders of pregnancy (HDP), gestational diabetes, placenta previa and preterm premature rupture of membranes (PROM). We further pooled the results of PGT singleton pregnancies. Subgroup analyses included preimplantation genetic diagnosis (PGD), preimplantation genetic screening (PGS), cleavage-stage biopsy combined with fresh embryo transfer (CB-ET) and blastocyst biopsy combined with frozen-thawed embryo transfer (BB-FET). OUTCOMES: This meta-analysis included 15 studies involving 3682 babies born from PGT pregnancies, 127 719 babies born from IVF/ICSI pregnancies and 915 222 babies born from SC pregnancies. The relative risk (RR) of LBW was higher in PGT pregnancies compared with SC pregnancies (RR = 3.95, 95% confidence interval [CI]: 2.32-6.72), but the risk of CMs was not different between the two groups. The pooled results for the risks of LBW and CMs were similar in PGT and IVF/ICSI pregnancies. The risks of PTD (RR = 3.12, 95% CI: 2.67-3.64) and HDP (RR = 3.12, 95% CI: 2.18-4.47) were significantly higher in PGT pregnancies compared with SC pregnancies. Lower gestational age (mean difference [MD] = -0.76 weeks, 95% CI -1.17 to -0.34) and BW (MD = -163.80 g, 95% CI: -299.35 to -28.24) were also noted for PGT pregnancies compared with SC pregnancies. Nevertheless, compared with IVF/ICSI pregnancies, the risks of VPTD and VLBW in PGT pregnancies were significantly decreased by 41% and 30%, respectively, although the risk of HDP was still significantly increased by 50% in PGT pregnancies compared with IVF/ICSI pregnancies. The combined results of obstetric and neonatal outcomes of PGT and IVF/ICSI singleton pregnancies were consistent with the overall results. Further subgroup analyses indicated that both PGD and PGS pregnancies were associated with a higher risk of PTD and a lower gestational age compared with SC pregnancies. WIDER IMPLICATIONS: This meta-analysis showed that PGT pregnancies may be associated with increased risks of LBW, PTD and HDP compared with SC pregnancies. The overall obstetric and neonatal outcomes of PGT pregnancies are favourable compared with those of IVF/ICSI pregnancies, although PGT pregnancies were associated with a higher risk of HDP. However, because the number of studies that could be included was limited, more randomised controlled trials and prospective cohort studies are needed to confirm these conclusions.

Humanin Alleviates Insulin Resistance in Polycystic Ovary Syndrome: A Human and Rat Model-Based Study.

Polycystic ovary syndrome (PCOS), the most common endocrine disorder in women of reproductive age, is characterized by hyperandrogenism and insulin resistance (IR); however, the pathogenesis of local ovarian IR in PCOS remains largely unclear. Humanin, a mitochondria-derived peptide, has been reported to be associated with IR. Our previous study confirmed that humanin is expressed in multiple cell types in the ovary and is present in follicular fluid. However, it remains unknown whether humanin participates in the pathogenesis of local ovarian IR or whether humanin supplementation can improve IR in PCOS patients. In this study, we compared humanin concentrations in follicular fluid from PCOS patients with and without IR. We further investigated the effect of humanin analogue (HNG) supplementation on IR in a rat model of dehydroepiandrosterone-induced PCOS. Humanin concentrations in the follicular fluid were found to be significantly lower in PCOS patients with IR than in those without IR. HNG supplementation attenuated both the increases in the levels of fasting plasma glucose and fasting insulin in rats with PCOS and the decreases in phosphorylation of IRS1, PI3K, AKT, and GLUT4 proteins in the granulosa cells of these rats. Combined supplementation with HNG and insulin significantly improved glucose consumption in normal and humanin-siRNA-transfected COV434 cells. In conclusion, downregulated humanin in the ovaries may be involved in the pathogenesis of IR in PCOS, and exogenous supplementation with HNG improved local ovarian IR through modulation of the IRS1/PI3K/Akt signaling pathway in a rat model. This finding supports the potential future use of HNG as a therapeutic drug for PCOS.

Humanin regulates oxidative stress in the ovaries of polycystic ovary syndrome patients via the Keap1/Nrf2 pathway.

Polycystic ovary syndrome (PCOS) is the most common endocrinological pathology among women of reproductive age, whereas the pathogenesis is still not fully understood. Systemic and ovarian oxidative stress (OS) imbalance is a pivotal feature of PCOS. Humanin, a mitochondria-derived peptide, has been reported to function as an antioxidant in cardiomyocytes, pancreatic beta cells and other cells, but how this function is regulated remains unclear. In this study, we investigated whether humanin expression differs in the granulosa cells (GCs) of PCOS patients versus controls, and whether humanin alleviates OS in PCOS ovaries. Sixteen PCOS patients and 28 age- and BMI-matched controls undergoing IVF were recruited, and their serum, follicular fluid and GCs were collected for humanin analysis. Dehydroepiandrosterone-induced rat PCOS models, and vitamin K3-induced OS COV434 cell lines were applied to investigate the mechanism. Humanin expression was significantly down-regulated in the ovaries of PCOS patients relative to those of non-PCOS patients. Exogenous humanin supplementation significantly attenuated body weight gain, ovarian morphological abnormalities, endocrinological disorders and ovarian and systemic OS in PCOS rat models. Our study further demonstrated that this attenuation effect was involved in the modulation of the Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor-erythroid 2-related factor 2 (Nrf2) signalling pathway. In summary, this study reported for the first time that decreased expression of humanin in the GCs was associated with oxidative imbalance in PCOS. Humanin alleviates OS in ovarian GCs of PCOS patients via modulation of the Keap1/Nrf2 signalling pathway.

Paternal Subclinical Hypothyroidism Affects the Clinical Outcomes of In Vitro Fertilization/Intracytoplasmic Sperm Injection.

Background: Maternal subclinical hypothyroidism (SCH) is a risk factor for adverse pregnancy outcomes. However, it is still unclear whether SCH affects male fertility. The aim of this study was to determine the association between paternal SCH and clinical outcomes after in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI). Methods: This retrospective study included 2511 couples with paternal euthyroidism (n = 2282) or SCH (n = 229) who visited our clinic for infertility treatment between April 1, 2017, and September 30, 2019. The primary outcomes were the fertilization rate and clinical pregnancy rate; the secondary outcomes were the good-quality embryo rate, blastocyst formation rate, implantation rate, and early miscarriage rate. These outcomes were compared between the euthyroid and the SCH groups after adjusting for various potential confounders. Results: The mean paternal ages in the euthyroid and SCH groups were 34.5 and 36.0 years, respectively (p = 0.002). Semen parameters and sperm DNA fragmentation index were similar between the two groups (all p > 0.05). The adjusted fertilization (0.69 vs. 0.71, p = 0.30), good-quality embryo (0.49 vs. 0.52, p = 0.31), blastocyst formation (0.51 vs. 0.53, p = 0.57), and early miscarriage (0.11 vs. 0.10, p = 0.81) rates were also similar between the two groups. There was a significantly decreased adjusted clinical pregnancy rate [confidence interval, CI] and implantation rate [CI] in the paternal SCH group compared with the euthyroid group (0.32 [0.26-0.40] vs. 0.42 [0.40-0.45], p = 0.009 for the clinical pregnancy rate; 0.24 [0.19-0.29] vs. 0.29 [0.27-0.31], p = 0.037 for the implantation rate). Stratified analysis indicated that these differences were only significant in men aged ≥35 years (p = 0.009 and 0.022, respectively) and not in men <35 years (p = 0.39 and 0.45, respectively). Conclusions: Paternal SCH was associated with worse clinical outcomes after IVF/ICSI, whereas this detrimental impact was only present in males ≥35 years old. Prospective studies and basic research are warranted to confirm these results and to clarify the mechanisms underlying these associations, respectively.

Predictive value of the sperm DNA fragmentation index for low or failed IVF fertilization in men with mild-to-moderate asthenozoospermia.

INTRODUCTION: It has been observed that there is an increased incidence of total fertilization failure (TFF) and a low fertilization rate (LFR, <25 %) during conventional in vitro fertilization (IVF) treatments involving men with poor sperm motility. These men also exhibit a high sperm DNA fragmentation index (DFI), which has adverse effects on various IVF outcomes. However, the relationship between a high DFI and an increased TFF or LFR during IVF cycles has not been elucidated. Here, we aimed to investigate the association between the sperm DFI and TFF or LFR in IVF cycles involving men with mild-to-moderate asthenozoospermia and normozoospermia. MATERIALS AND METHODS: This retrospective study included 116 men diagnosed as mild-to-moderate asthenozoospermia, and 407 men with normozoospermia. The sperm DFI was assessed using the sperm chromatin dispersion (SCD) test. RESULTS: Men in the asthenozoospermia group had a significantly higher incidence of cycles with a TFF or LFR (9.5 % vs 2.7 %, P = 0.01), and these were associated significantly with an increased DFI (P < 0.01). After adjustment for confounding factors, a TFF or LFR was to correlate significantly with the DFI (odds ratio: 1.188; 95 % confidence interval, 1.035-1.363; P = 0.014). Area under the receiver operating characteristic curve was 0.772. No similar relationships between the DFI and IVF outcomes were observed in the normozoospermia group. CONCLUSIONS: For men with mild-to-moderate asthenozoospermia, a high sperm DFI is associated with a decreased fertilization rate and an increased risk of a TFF or LFR. Additional prospectively-designed studies are warranted to confirm our results.

Effect of transient scrotal hyperthermia on human sperm: an iTRAQ-based proteomic analysis.

BACKGROUND: Through this prospective study, we aimed to explore the change of molecular modification after the transient scrotal hyperthermia on human sperm. METHODS: Ten healthy subjects selected with strict screening criteria underwent testicular warming in a 43 °C water bath for 30 min a day for 10 consecutive days. Semen samples were collected 2 weeks before the first heat treatment and 6 weeks after the first heat treatment. Proteins from the samples were labeled with isobaric tags for relative and absolute quantitation and analyzed by two-dimensional liquid chromatography-tandem mass spectrometry. RESULTS: In contrast to the control, of the 3446 proteins identified, 61 proteins were deregulated: 28 were up-regulated and 33 were down-regulated. Approximately 95% of the differentially expressed proteins were found to participate in spermatogenesis, fertilization, or other aspects of reproduction. In particular, the expression of sperm motility and energy metabolism-related proteins AKAP4, SPESP1, ODF1, ODF2, GAPDHS, and ACTRT2, validated by western blotting of the proteins obtained from human and mouse samples, tended to be reduced under scrotal hyperthermia. CONCLUSIONS: The results indicated that the proteins AKAP4, ODF1, ODF2, GAPDHS, SPESP1, and ACTRT2, play an important role in the heat-induced reversible reduction in sperm concentration and motility and have the potential to be the biomarkers and clinical targets for scrotal heat treatment induced male infertility.

Cross-talk between autophagy and apoptosis regulates testicular injury/recovery induced by cadmium via PI3K with mTOR-independent pathway.

Autophagy and apoptosis are two major modes of cell death. A balanced interplay between both is vital for phagocytic clearance of apoptotic testicular cells. Here, generating a SD rats model-treated with cadmium (Cd) to mimic environmental exposure on human, we show that autophagy and apoptosis present synchronous change trends in Cd-induced testicular injury/self-recovery. Further, the cross-talk of autophagy and apoptosis is investigated in four testicular cell lines (GC-1/GC-2/TM3/TM4 cells) respectively. Results reveal that Cd-exposure for five consecutive weeks induces reproductive toxicity in male rats. After one cycle of spermatogenesis within 8 weeks without Cd, toxic effects are ameliorated significantly. In vitro, we find that PI3K inhibitor 3-MA regulates apoptosis by inhibiting autophagy with mTOR-independent pathway in Cd-treated testicular cells. Conclusively, cross-talk between autophagy and apoptosis regulates testicular injury/recovery induced by Cd via PI3K with mTOR-independent pathway.

Subclinical Hypothyroidism Is Associated with Lower Ovarian Reserve in Women Aged 35 Years or Older.

Background: Overt thyroid diseases have been identified as risk factors for female infertility. However, it remains largely unclear whether subclinical hypothyroidism (SCH), a very common thyroid disorder, is associated with female infertility. This study aimed to investigate the potential association between SCH and the ovarian reserve in women seeking infertility treatment. Methods: This retrospective study included 2568 women with normal thyroid function (n = 2279) or SCH (n = 289) who visited our clinic for infertility treatment. Ovarian reserve markers, including follicle-stimulating hormone (FSH) concentrations on days 2-4, the antral follicle count (AFC), and anti-Müllerian hormone (AMH) concentration, were compared between euthyroid women and those with SCH. Multiple linear and Poisson regression analyses were used to estimate the associations of SCH with ovarian reserve markers. These analyses were repeated separately in women aged <35 (n = 1349) and ≥35 years (n = 1219). Results: In the total study population, women with SCH had significantly lower AMH concentrations (median: 2.05 vs. 2.51 ng/mL, p = 0.015) and AFCs (median: 10.0 vs. 11.0, p = 0.013), compared with euthyroid women. In linear and Poisson regression analyses, SCH was significantly associated with a higher basal FSH concentration (mean difference = 1.13 mIU/mL [95% confidence interval (CI) 0.97 to 1.29 mIU/mL], p < 0.001), lower AMH concentration (mean difference = -0.27 ng/mL [CI -0.43 to -0.12 ng/mL], p = 0.001), and lower AFC (mean difference = -0.7 [CI -1.3 to -0.2], p = 0.005). In women aged ≥35 years, SCH was significantly associated with FSH (mean difference = 1.74 mIU/mL, p < 0.001) and AMH concentrations (mean difference = -0.40 mg/mL, p < 0.001) and AFC (mean difference = -0.8, p < 0.001). In women <35 years old, SCH was significantly associated with a higher FSH concentration (mean difference = 0.30 mIU/mL, p < 0.001), but not with AMH or AFC concentrations (p = 0.84 and 0.06, respectively). Thyroperoxidase antibody (TPOAb) positivity was not associated with measures of ovarian reserve. Conclusions: The data suggest that SCH is associated with decreased ovarian reserve during later reproductive age. TPOAb positivity was not associated with ovarian reserve. Future research is necessary to investigate the underlying molecular mechanisms regulating the diminished ovarian reserve in women with SCH and to evaluate whether levothyroxine supplementation may improve the ovarian function of women with SCH.

Effect of levothyroxine supplementation on pregnancy loss and preterm birth in women with subclinical hypothyroidism and thyroid autoimmunity: a systematic review and meta-analysis.

BACKGROUND: Subclinical hypothyroidism (SCH) and thyroid autoimmunity (TAI) are associated with adverse pregnancy outcomes such as pregnancy loss and preterm birth. However, the ability of levothyroxine (LT4) supplementation to attenuate the risks of these outcomes remains controversial. OBJECTIVE AND RATIONALE: This systematic review and meta-analysis was conducted to determine the effect of LT4 supplementation on pregnancy loss rate (PLR) and preterm birth rate (PBR) among pregnant women with SCH and TAI. SEARCH METHODS: A systematic literature search of the PubMed, EMBASE, Web of Science and Cochrane Controlled Trials Register databases and Clinicaltrials.gov was performed to identify all relevant English studies published up to April 2018. The following terms were used for the search: [subclinical hypothyroidism OR thyroid autoimmunity OR thyroperoxidase antibody (TPO-Ab) OR thyroglobulin antibodies (Tg-Ab)] AND (levothyroxine OR euthyrox) AND [pregnancy outcome OR miscarriage OR abortion OR pregnancy loss OR preterm birth OR premature delivery OR early labo(u)r]. The reference lists of the relevant publications were also manually searched for related studies. Published manuscripts were included if they reported data on pregnancy loss, preterm birth or both. We separately analysed the pooled effects of LT4 supplementation on PLR and PBR in women with SCH and TAI. OUTCOMES: Overall, 13 eligible studies including 7970 women were included in the meta-analysis. Eight and five of these studies were randomized controlled trials (RCTs) and retrospective studies, respectively. The pooled results indicated that LT4 supplementation significantly decreased the PLR [relative risk (RR) = 0.56, 95% confidence interval (CI): 0.42-0.75, I2 = 1%, 12 studies] and PBR (RR = 0.68, 95% CI: 0.51-0.91, I2 = 21%, eight studies) in women with SCH and/or TAI. We further found that LT4 supplementation significantly decreased the risk of pregnancy loss (RR = 0.43, 95% CI: 0.26-0.72, P = 0.001, I2 = 0%) but not of preterm birth (RR = 0.67, 95% CI: 0.41-1.12, P = 0.13, I2 = 0%) in women with SCH. Furthermore, LT4 supplementation significantly decreased the risks of both pregnancy loss (RR = 0.63, 95% CI: 0.45-0.89, P = 0.009, I2 = 0%) and preterm birth (RR = 0.68 95% CI: 0.48-0.98, P = 0.04, I2 = 46%) in women with TAI. These results were consistent when only RCTs were included in the analysis. Further, in women with SCH, LT4 supplementation reduced the risk of pregnancy loss in pregnancies achieved by assisted reproduction (RR = 0.27, 95% CI: 0.14-0.52, P < 0.001, I2 = 14%) but not in naturally conceived pregnancies (RR = 0.60, 95% CI: 0.28-1.30, P = 0.13, I2 = 0%). By contrast, in women with TAI, LT4 supplementation reduced the risks of both pregnancy loss (RR = 0.61, 95% CI: 0.39-0.96, P = 0.03, I2 = 0%) and preterm birth (RR = 0.49, 95% CI: 0.30-0.79, P = 0.003, I2 = 0%) in naturally conceived pregnancies but not in pregnancies achieved by assisted reproduction (RR = 0.68, 95% CI: 0.40-1.15, P = 0.15, I2 = 0% for pregnancy loss and RR = 1.20, 95% CI: 0.68-2.13, P = 0.53, I2 not applicable for preterm birth). WIDER IMPLICATIONS: This meta-analysis confirmed the beneficial effects of LT4 supplementation, namely the reduced risks of pregnancy loss and preterm birth, among pregnant women with SCH and/or TAI. The different effects of LT4 supplementation on naturally conceived pregnancies and pregnancies achieved by assisted reproduction in women with SCH and/or TAI suggest that these women should be managed separately. Due to the limited number of studies included in this meta-analysis, especially in the subgroup analysis, further large RCTs and fundamental studies are warranted to confirm the conclusions and better clarify the molecular mechanism underlying these associations.

Antifertility effectiveness of a novel polymer matrix composite and its influence on the endometrium in rhesus macaques (Macaca mulatta).

OBJECTIVE(S): To explored the antifertility effectiveness and influence on the endometrium of a micro-copper/low-density polyethylene/methyl vinyl silicone rubber (Cu/LDPE/MVQ) composite in rhesus macaques. STUDY DESIGN: Healthy reproductive aged female rhesus macaques underwent abdominal hysterotomy for surgical placement of either the experimental Cu/LDPE/MVQ composite (Cu/LDPE/MVQ, n=5), bare copper wire (Cu, n=5), or hysterotomy only sham-operation group [(SOI, n=4), (SOII, n=6)]. Females in the Cu/LPDE/MVQ, Cu, and SOI groups were housed with fertile males for approximately three menstrual cycles. We assessed pregnancy by hysterectomy. Females in the Cu/LDPE/MVQ, Cu, and SOII groups underwent hysterectomy at about 4 months post-insertion for histologic assessment of morphologic changes of the endometrium, evaluation of materials using scanning electron microscopy (SEM), and evaluation of the inflammatory markers, including substance P receptor (SPR), associated with endometrial bleeding using enzyme linked immunosorbent assay, quantitative RT-PCR, and Western blot analyses. RESULTS: All of the SOI group females became pregnant (4/4, 100%). In contrast, no pregnancies occurred in either the Cu/LDPE/MVQ (0/5, 0%) or Cu (0/5, 0%) groups. We observed histologic features consistent with chronic endometrial inflammation in all females of the Cu group, but none of the SOII or Cu/LDPE/MVQ animals. Levels of inflammatory markers were significantly increased in the Cu group, compared with SOII or Cu/LDPE/MVQ groups (p<.05). SEM showed evidence of corrosion in the Cu wire not seen in the Cu/LDPE/MVQ group. CONCLUSION(S): Cu/LDPE/MVQ material provided a contraceptive effect similar to Cu in macaques, with a lower impact on inflammation and inflammatory markers of the endometrium. IMPLICATIONS: This study demonstrates the possibility of a Cu/LDPE/MVQ composite as an alternative to conventional copper device materials.

Polymorphism of MTHFR 1298A>C in relation to adverse pregnancy outcomes in Chinese populations.

BACKGROUND: Adverse pregnancy outcomes (APOs) are involved in a series of abnormal pregnancies like embryo growth arrest, spontaneous abortion, premature birth, stillbirth, fetal malformation, birth defects and other pathological pregnancy, and childbirth complications. Polymorphism of methylenetetrahydrofolate reductase gene (MTHFR, 607093) is one of the main genetic causes of APO. However, there is still debate on whether MTHFR 1298A>C, rs1801131, polymorphism is related to APO. For the lack of extensive research in the Chinese population at present, the study aim to investigate the relationship between MTHFR 1298A>C polymorphism with APO through a large number of data. METHODS: A total of 241 samples from patients with APO and 117 healthy controls in Yunnan province were used for MTHFR gene polymorphism analysis, with double fluorescence quantitative polymerase chain reaction (PCR). In consideration of the low frequency of MTHFR 1298C/C genotype, which might affect the statistic results, further datasets of MTHFR 1298A>C polymorphism were collected from literature and analyzed. RESULTS: No statistical difference was detected in the frequency of MTHFR1298A>C polymorphism between two groups in Yunnan. Our data showed that the frequency of MTHFR 1298A/A genotype had the decreasing tendency among Chinese population from northern to southern, as well as eastern to western of China. The frequency of MTHFR 1298A/C and 1298C/C genotypes had the adverse tendency. The frequency of MTHFR 1298C/C genotype was significantly different between two groups in Chinese populations. The significant difference was also observed in the frequency of MTHFR 1298C/C polymorphism between two groups from central China and southern China. CONCLUSION: In summary, our data showed that MTHFR 1298C/C genotype was one of the important genetic factors of APO in China.

Sex Differences Associated With Circulating PCSK9 in Patients Presenting With Acute Myocardial Infarction.

A limited number of studies have explored whether the role of circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) in the pathogenesis of acute myocardial infarction (AMI) is sex specific. The purpose of the present study was to examine sex differences in plasma PCSK9 in Chinese patients with AMI. In this study, a total of 281 records from patients presenting with AMI were analyzed.We compared hospital data and plasma PCSK9 levels by sex difference for inpatients presenting with AMI. After 1 year of follow-up, major adverse cardiac events(MACE) were recorded. A Cox proportional hazards model was used to calculate hazard ratios with 95% confidence intervals. We found that, compared with male groups, PCSK9 levels were higher in female patients not only for overall patients with AMI but also for patients with ST-elevation myocardial infarction (STEMI) (median: 273.6 [215.6-366.8] vs. 325.1 [247.5-445.3] ng/ml, P = 0.0136; 273.4 [215.6-369.7] vs. 317.1 [249.6-450.1], P = 0.0275, respectively). The cumulative incidence of cardiac death and 1-year MACE were significantly higher in the female group compared with male group (10% vs. 2.74%, P = 0.025; 15% vs. 4.11%, P = 0.0054, respectively). On multivariate Cox regression analysis, female sex, total triglyceride, glycosylated hemoglobin A, and homocysteic acid were independent risk factors of 1-year MACE. There was no significant correlation between PCSK9 and 1-year MACE in total AMI patients. In conclusion, PCSK9 levels and 1-year MACE were higher in women with AMI than in men with AMI, however, female sex but not PCSK9 were significant correlated with the 1-year MACE. The clinical implications of this finding are worthy of further investigations and must be confirmed in larger cohorts.