The effect of baicalein on endoplasmic reticulum stress and autophagy on liver damage.

Carbon tetrachloride (CCl4) is a toxic chemical that causes liver injury. CCl4 triggers endoplasmic reticulum (ER) stress and unfolded protein response (UPR). UPR triggers autophagy to deal with the damage. The aim of this study was to investigate the effect of baicalein, derived from Scutellaria baicalensis, on CCl4-induced liver damage concerning ER stress and autophagy. Two groups of Wistar albino rats (n = 7/groups) were treated with 0.2 ml/kg CCl4 for 10 days with and without baicalein. Histological and transmission electron microscopy (TEM) analysis, autophagy, and ER stress markers measurements were carried out to evaluate the effect of baicalein. Histological examinations showed that baicalein reduced liver damage. TEM analysis indicated that baicalein inhibited ER stress and triggered autophagy. CCl4-induced elevation of C/EBP homologous protein (CHOP), glucose-regulating protein 78 (GRP78), activating transcription factor 4 (ATF4), activating transcription factor 6 (ATF6), inositol requiring enzyme 1 (IRE1), pancreatic ER kinase (PERK), and active/spliced form of X-box-binding protein 1 (XBP1s) ER stress markers were decreased by baicalein. Baicalein also increased the autophagy-related 5 (ATG5), Beclin1, and Microtubule-associated protein 1A/1B-light chain 3-phosphatidylethanolamine-conjugated form (LC3-II) autophagy marker levels. In conclusion, baicalein reduced the CCl4-induced liver damage by inhibiting ER stress and the trigger of autophagy.

Genitourinary cancer patients have worse baseline semen parameters than healthy sperm bankers.

BACKGROUND: While the spermatotoxic properties of cancer treatments such as chemotherapy and radiation therapy are widely recognized, the effect of malignancy itself on male fertility is not clearly understood. OBJECTIVES: To determine whether malignancy is associated with diminished semen quality prior to spermatotoxic treatment among sperm bankers. MATERIALS AND METHODS: Retrospective database review of de-identified records was obtained for all episodes of sperm banking performed at a cryobank from January 2004 to May 2017 for one of the following reasons: 'future use' (e.g., military deployment and gender reassignment); infertility; benign disease; and malignancy, further categorized as testicular, other genitourinary (GU), solid non-GU, hematologic, or unspecified. Dependent variables of interest were ejaculatory volume, sperm concentration, % motility, and total motile sperm count (TMSC), as well as post-thaw TMSC. RESULTS: A total of 1558 patients met the inclusion criteria. Multivariable regression analysis on log-transformed data controlling for age demonstrated decreased ejaculatory volume and sperm concentration, % motility, and TMSC in the infertility group as compared to the 'future use' group (p < 0.001). Testicular cancer was associated with decreased sperm concentration, TMSC, and post-thaw TMSC (p < 0.001); other GU malignancy was associated with decreased ejaculatory volume (p < 0.001). Benign disease, solid non-GU malignancy, hematologic malignancy, and unspecified malignancy were not associated with decreased parameters. DISCUSSION: In addition to sperm bankers with known fertility issues, sperm bankers with testicular and other GU malignancy had worse baseline semen parameters as compared to individuals pursuing banking for future use. These findings can inform patient counseling and consent prior to sperm banking and disease treatment. CONCLUSION: Individuals with testicular and other GU malignancy who banked spermatozoa before undergoing spermatotoxic therapy demonstrated worse baseline semen parameters as compared to individuals banking spermatozoa for non-medical reasons.

Semen parameters on the day of oocyte retrieval predict low fertilization during conventional insemination IVF cycles.

PURPOSE: Poor fertilization during conventional IVF is difficult to predict in the absence of abnormal semen parameters; large-scale studies are lacking. The purpose of this study is to evaluate factors associated with low fertilization rates in conventional insemination IVF cycles. METHODS: A retrospective cohort study evaluating demographic, reproductive evaluation, and IVF cycle characteristics to identify predictors of low fertilization (defined as 2PN/MII ≤ 30% per cycle). Participants were included if they were undergoing their first IVF cycle utilizing fresh autologous oocytes and conventional insemination with male partner's sperm (with normal pretreatment semen analysis). They were randomly divided into a training set and a validation set; validation modeling with logistic regression and binary distribution was utilized to identify covariates associated with low fertilization. RESULTS: Postprocessing sperm concentration of less than 40 million/ml and postprocessing sperm motility < 50% on the day of retrieval were the strongest predictors of low fertilization in the training dataset. Next, in the validation set, cycles with either low postprocessing concentration (≤ 40 million/ml) or low postprocessing progressive motility (≤ 50%) were 2.9-times (95% CI 1.4, 6.2) more likely to have low fertilization than cycles without either risk factor. Furthermore, cycles with low postprocessing concentration and progressive motility were 13.4 times (95% CI 4.01, 45.06) more likely to have low fertilization than cycles without either risk factor. CONCLUSIONS: Postprocessing concentration and progressive motility on the day of oocyte retrieval are predictive of low fertilization in conventional IVF cycles with normal pretreatment diagnostic semen analysis parameters.

Sperm cryopreservation of transgender individuals: trends and findings in the past decade.

OBJECTIVES: Awareness and acceptance of transgenderism have increased in the last two decades. There is limited literature regarding the incidence and semen characteristics of transwomen banking spermatozoa. We sought to assess the incidence of sperm cryopreservation of transgender individuals compared with the cisgender population in the last 10 years. Semen parameters were also compared between the two groups. MATERIALS AND METHODS: We performed a retrospective analysis of sperm cryopreservation performed at a single center from 2006 through 2016. Using available data on indications for banking and prior hormonal therapy status, we isolated healthy transgender and cisgender cohorts for semen parameter comparison. Linear regression was used to compare the incidence trends. Semen parameters were compared using the generalized estimating equations method. The rates of semen parameter abnormality of each group were compared using chi-square test. Semen parameter abnormalities were defined using WHO 2010 reference values. RESULTS: We analyzed 194 transgender samples and 2327 cisgender samples for a total of 84 unique transgender sperm bankers and 1398 unique cisgender sperm bankers. The number of transgender sperm bankers increased relative to cisgender sperm bankers from 2006 to 2016. Following exclusion of cisgender sperm bankers with health issues that might impact semen quality and transgender sperm bankers with known prior hormonal therapy, we compared the semen parameters of 141 healthy cisgender sperm bankers and 78 healthy transgender sperm bankers. The transgender sperm bankers demonstrated lower sperm concentration, total motile sperm count, and post-thaw sperm parameters. The transgender sperm bankers also demonstrated a higher incidence of oligozoospermia. CONCLUSIONS: This is the largest report to date on the incidence of transgender sperm cryopreservation and comparison of semen characteristics with cisgender sperm bankers. The data reveal an increased incidence of transgender sperm banking as well as poorer semen parameters of transgender individuals compared with cisgender controls.

Male caffeine and alcohol intake in relation to semen parameters and in vitro fertilization outcomes among fertility patients.

Much of the literature on the impact of male caffeine and alcohol intake on reproductive outcomes has utilized semen quality as a proxy for male fertility, although semen parameters have a limited predictive value for spontaneous pregnancy. The objective of this study was to investigate whether male caffeine and alcohol intakes are associated with semen parameters and assisted reproductive technology outcome. The Environment and Reproductive Health Study, an ongoing prospective cohort study, enrolls subfertile couples presenting for treatment at an academic fertility center (2007-2012). A total of 171 men with 338 semen analyses and 205 assisted reproductive technology cycles were included in this analysis. Diet was assessed using a 131-item food frequency questionnaire. Mixed models adjusting for potential confounders were used to evaluate the relationships of male caffeine and alcohol intakes with semen parameters and assisted reproductive technology outcomes. There was no association between male caffeine and alcohol intake and semen quality. Male caffeine intake was negatively related to live birth after assisted reproductive technologies (p-trend < 0.01), and male alcohol intake was positively related to live birth after assisted reproductive technologies (p-trend = 0.04). Adjusted live birth rate among couples with a male partner in the highest quartile of caffeine intake (≥272 mg/day) compared to couples with a male partner in the lowest quartile of intake (<99 mg/day) was 19% vs. 55%, respectively, p < 0.01. In terms of alcohol intake, adjusted live birth rate among couples with a male partner in the highest quartile of alcohol intake (≥22 g/day) compared to couples with a male partner in the lowest quartile of intake (<3 g/day) was 61% vs. 28%, respectively, p = 0.05. In conclusion, male pre-treatment caffeine and alcohol intakes were associated with live birth after assisted reproductive technologies, but not with semen parameters, among fertility patients.

Successful sperm extraction and live birth after radiation, androgen deprivation and surgical castration for treatment of metastatic prostate cancer.

Fertility preservation has become an important aspect of cancer treatment given the gonadotoxic effects of oncologic therapies. It is now considered standard of care to offer sperm banking to men undergoing treatment for primaries that affect young individuals. Less is known regarding fertility preservation of patients afflicted with prostate cancer. This cohort has progressively expanded and grown younger in the post-PSA era. Prostatectomy, radiation, chemotherapy and androgen blockade all pose unique challenges to the infertility specialist. Optimum management becomes even more uncertain for those men with metastatic prostate cancer. Most of these individuals will have received multiple forms of therapy, each carrying a distinct insult to the patient's reproductive potential. We describe a case of successful ex vivo sperm extraction and live birth in a patient previously treated with radiation and chronic androgen deprivation for metastatic prostate cancer. The presented case demonstrates that conception after radiation therapy and chronic androgen deprivation is feasible. We propose that fertility counselling and sperm cryopreservation should be considered for all prostate cancer patients. Additionally, for those individuals undergoing external beam radiotherapy, testicular shielding should be routinely offered in the event further family building is desired.

Chronic exposures and male fertility: the impacts of environment, diet, and drug use on spermatogenesis.

Several recent studies have suggested that sperm concentrations and semen quality have been decreasing over the past several decades in many areas of the world. The etiology of these decreases is currently unknown. Acute events can have significant impacts on spermatogenesis and are often readily identified during the male fertility evaluation. The majority of male factor infertility, however, is idiopathic. Chronic, low-dose exposures to chemicals and nutrients are more difficult to identify, but are extremely prevalent. These exposures have been shown to have dramatic effects on both individual and community health and interest in the cumulative and synergistic impacts of such agents on spermatogenesis has been increasing. While our understanding of these potential hazards is evolving, it is clear that they may significantly influence male reproductive potential. This review explores the literature related to effects of chronic exposures from drug use, dietary intake, and the environment on spermatogenesis in humans and animals.

Male soy food intake was not associated with in vitro fertilization outcomes among couples attending a fertility center.

Male factor etiology may be a contributing factor in up to 60% of infertility cases. Dietary intake of phytoestrogens has been related to abnormal semen quality and hormone levels. However, its effect on couple fecundity is still unclear. Intake of soy products was assessed in 184 men from couples undergoing infertility treatment with in vitro fertilization. Couples were recruited between February 2007 and May 2014 and prospectively followed to document treatment outcomes including fertilization, implantation, clinical pregnancy and live birth. Multivariate generalized linear mixed models with random intercepts, binomial distribution and logit link function were used to examine this relation while accounting for repeated treatment cycles and adjusting for potential confounders. Male partner's intake of soy foods and soy isoflavones was unrelated to fertilization rates, the proportions of poor quality embryos, accelerated or slow embryo cleavage rate, and implantation, clinical pregnancy and live birth. The adjusted live birth rates per initiated cycle (95% CI) for partners of men in increasing categories of soy food intake were 0.36 (0.28-0.45), 0.42 (0.29-0.56), 0.36 (0.24-0.51), and 0.37 (0.24-0.52), respectively. Soy food intake in men was not related to clinical outcomes among couples presenting at an infertility clinic. Data on the relation between phytoestrogens and male reproductive potential remain scarce and additional research is required to clarify its role in human reproduction.

Fruit and vegetable intake and their pesticide residues in relation to semen quality among men from a fertility clinic.

STUDY QUESTION: Is consumption of fruits and vegetables with high levels of pesticide residues associated with lower semen quality? SUMMARY ANSWER: Consumption of fruits and vegetables with high levels of pesticide residues was associated with a lower total sperm count and a lower percentage of morphologically normal sperm among men presenting to a fertility clinic. WHAT IS KNOWN ALREADY: Occupational and environmental exposure to pesticides is associated with lower semen quality. Whether the same is true for exposure through diet is unknown. STUDY DESIGN, SIZE, DURATION: Men enrolled in the Environment and Reproductive Health (EARTH) Study, an ongoing prospective cohort at an academic medical fertility center. Male partners (n = 155) in subfertile couples provided 338 semen samples during 2007-2012. PARTICIPANTS/MATERIALS, SETTING, METHODS: Semen samples were collected over an 18-month period following diet assessment. Sperm concentration and motility were evaluated by computer-aided semen analysis (CASA). Fruits and vegetables were categorized as containing high or low-to-moderate pesticide residues based on data from the annual United States Department of Agriculture Pesticide Data Program. Linear mixed models were used to analyze the association of fruit and vegetable intake with sperm parameters accounting for within-person correlations across repeat samples while adjusting for potential confounders. MAIN RESULTS AND THE ROLE OF CHANCE: Total fruit and vegetable intake was unrelated to semen quality parameters. High pesticide residue fruit and vegetable intake, however, was associated with poorer semen quality. On average, men in highest quartile of high pesticide residue fruit and vegetable intake (≥1.5 servings/day) had 49% (95% confidence interval (CI): 31%, 63%) lower total sperm count and 32% (95% CI: 7%, 58%) lower percentage of morphologically normal sperm than men in the lowest quartile of intake (<0.5 servings/day) (P, trend = 0.003 and 0.02, respectively). Low-to-moderate pesticide residue fruit and vegetable intake was associated with a higher percentage of morphologically normal sperm (P, trend = 0.04). LIMITATIONS, REASONS FOR CAUTION: Surveillance data, rather than individual pesticide assessment, was used to assess the pesticide residue status of fruits and vegetables. CASA is a useful method for clinical evaluation but may be considered less favorable for accurate semen analysis in the research setting. Owing to the observational nature of the study, confirmation is required by interventional studies as well. WIDER IMPLICATIONS OF THE FINDINGS: To our knowledge, this is the first report on the consumption of fruits and vegetables with high levels of pesticide residue in relation to semen quality. Further confirmation of these findings is warranted. STUDY FUNDING/COMPETING INTERESTS: Supported by National Institutes of Health grants ES009718, ES022955, ES000002, P30 DK046200 and Ruth L. Kirschstein National Research Service Award T32 DK007703-16. None of the authors has any conflicts of interest to declare.

Paternal physical and sedentary activities in relation to semen quality and reproductive outcomes among couples from a fertility center.

STUDY QUESTION: Is paternal physical activity associated with semen quality parameters and with outcomes of infertility treatment? SUMMARY ANSWER: Among men presenting for infertility treatment, weightlifting and outdoor activities were associated with higher sperm concentrations but not with greater reproductive success. WHAT IS ALREADY KNOWN: Higher physical activity is related to better semen quality but no studies to date have investigated whether it predicts greater reproductive success. STUDY DESIGN, SIZE, DURATION: The Environment and Reproductive Health (EARTH) Study is an on-going prospective cohort study which enrolls subfertile couples presenting at Massachusetts General Hospital (2005-2013). In total, 231 men provided 433 semen samples and 163 couples underwent 421 IVF or intrauterine insemination cycles. PARTICIPANTS/MATERIALS, SETTING, METHODS: Leisure time spent in physical and sedentary activities over the past year was self-reported using a validated questionnaire. We used mixed models to analyze the association of physical and sedentary activities with semen quality and with clinical pregnancy and live birth rates. MAIN RESULTS AND THE ROLE OF CHANCE: Men in this cohort engaged in a median of 3.2 h/week of moderate-to-vigorous activities. Men in the highest quartile of moderate-to-vigorous activity had 43% (95% confidence interval (CI) 9, 87%) higher sperm concentrations than men in the lowest quartile (P-trend = 0.04). Men in the highest category of outdoor activity (≥1.5 h/week) and weightlifting (≥2 h/week) had 42% (95% CI 10, 84%) and 25% (95% CI -10, 74%) higher sperm concentrations, respectively, compared with men in the lowest category (0 h/week) (P-trend = 0.04 and 0.02). Conversely, men who reported bicycling ≥1.5 h/week had 34% (95% CI 4, 55%) lower sperm concentrations compared with men who reported no bicycling (P-trend = 0.05). Paternal physical and sedentary activities were not related to clinical pregnancy or live birth rates following infertility treatment. LIMITATIONS, REASONS FOR CAUTION: The generalizability of the findings on live birth rates to populations not undergoing infertility treatment is limited. WIDER IMPLICATIONS OF THE FINDINGS: Certain types of physical activity, specifically weightlifting and outdoor activities, may improve semen quality but may not lead to improved success of infertility treatments. Further research is needed in other non-clinical populations. STUDY FUNDING/COMPETING INTERESTS: The authors are supported by NIH grants R01-ES009718, ES000002, P30-DK046200, T32-DK007703-16 and ES022955 T32-HD060454. None of the authors has any conflicts of interest to declare.

A decision analysis of treatments for obstructive azoospermia.

BACKGROUND: Treatments for post-vasectomy obstructive azoospermia include vasectomy reversal, microsurgical epididymal sperm aspiration (MESA) or percutaneous testicular sperm extraction (TESE) with IVF/ICSI. We examined the cost-effectiveness of these treatments. METHODS: A decision analytic model was created to simulate treatment. Outcome probabilities were derived from peer-reviewed literature and the Society for Assisted Reproductive Technologies database. Procedural costs were derived from a sampling of high-volume IVF centers and the Medicare Resource Based Relative Value Scale. Indirect costs of complications, lost productivity and multiple gestation pregnancies were considered. Sensitivity analyses were performed. RESULTS: Vasectomy reversal was more cost-effective than either MESA or TESE under all probability conditions. In 1999, vasectomy reversal demonstrated superior cost-effectiveness to TESE and MESA ($19,633 versus $45,637 and $48,055, respectively, equivalent to $25,321 versus $58,858 and $61,977 in 2005 dollars). In 2005, vasectomy reversal ($20,903) remained the most cost-effective treatment over TESE ($54,797) and MESA ($56,861). The cost-effectiveness of all treatments improved over projections by inflation. The relative cost-effectiveness of the therapies was unchanged over time. CONCLUSIONS: Vasectomy reversal appears more cost-effective than percutaneous TESE and MESA for treatment of obstructive azoospermia when the impact of indirect costs is considered. The absolute cost-effectiveness of all therapies improved over time. These results may be tailored with institution-specific data to allow more individualized results.

Three-dimensional cortical morphometry of the planum temporale in childhood-onset schizophrenia.

OBJECTIVE: Anomalous planum temporale asymmetry has been linked to both schizophrenia and dyslexia. The authors examined the planum temporale of adolescents with childhood-onset schizophrenia who had a high rate of prepsychotic language disorders. METHOD: Planum temporale area and asymmetry were measured in 16 right-handed adolescent patients with schizophrenia who had experienced onset of psychosis by age 12. The same measures were made in 16 healthy adolescents matched for age, sex, and handedness. RESULTS: No differences between the healthy adolescents and those with schizophrenia in planum temporale area or asymmetry were observed. Prepsychotic language disorder predicted abnormal planum temporale asymmetry in the adolescents with schizophrenia. CONCLUSIONS: These findings do not support anomalous planum temporale asymmetry as a basis for psychopathology in childhood-onset schizophrenia.

d-fenfluramine treatment of binge eating disorder.

OBJECTIVE: The purpose of this study was to assess the efficacy of the appetite suppressant d-fenfluramine in the treatment of binge eating disorder. METHOD: The authors conducted an 8-week double-blind, placebo-controlled clinical trial of the drug with 28 severely obese female patients meeting full criteria for binge eating disorder. The primary outcome measure was number of binges per week, as recorded in binge diaries and reviewed weekly with the principal investigators. RESULTS: Random effects linear regression analysis showed that the rate of binge eating in the d-fenfluramine group fell three times more rapidly than that in the placebo group, a result that was both clinically and statistically significant. At 4-month follow-up the binge frequency of the d-fenfluramine group had increased to pretreatment levels and no longer differed from that of the placebo group. CONCLUSIONS: d-Fenfluramine reduced the frequency of binge eating by obese women with binge eating disorder.

Binge eating disorder and the night-eating syndrome.

OBJECTIVE: To determine in three samples of obese women the prevalence of two eating disorders--binge eating disorder and the night-eating syndrome. METHOD: Interviews utilizing standard criteria. For binge eating disorder: the consumption of large amounts of food in a discrete period of time together with a subjective sense of loss of control and no vomiting or laxative abuse. For the night-eating syndrome: morning anorexia, evening hyperphagia and insomnia. Determining the rate of binging among patients receiving a placebo. SUBJECTS: (1) 102 viewers of a television show describing binge eating disorder; (2) 50 participants in a trial of medication for this disorder and (3) 79 participants in a weight reduction program. RESULTS: In the television sample 19.6% of respondents and in the weight reduction sample 7.6% met criteria for binge eating disorder; all subjects in the medication sample met criteria. During a 4-week placebo period average binge frequency fell from 6.0 to 1.7 binges per week. The night-eating syndrome was manifested by 13.7% of the television sample, 8.9% of the weight reduction sample and 15.0% in the medication trial sample. There was little overlap between the two disorders. CONCLUSIONS: Binge eating disorder is far less frequent than has been believed on the basis of questionnaire studies and it is highly responsive to placebos. Frequency of the night-eating syndrome is comparable to that of binge eating disorder. Future studies should assess binge eating disorder by interview rather than by self-administered questionnaire.