The possible role of NF-κB1 Rs28362491 polymorphism in male fertility of Egyptian population.

Male reproductive impairment is responsible for at least 50% of cases of couple infertility. Nuclear factor-kappa B (NF-κB) has been functionally linked to germ cell apoptosis, which may affect human fertility. The aim of this study was to determine the association between the rs28362491 SNP of the NF-κB1 gene and infertility in Egyptian men. In this case-control study, semen and blood samples of 247 infertile men, constituting the case group, and of 113 fertile healthy men as the control group were analysed. All study participants were genotyped for polymorphism of the NF-κB1 gene (rs28362491) by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. Heterozygous I/D genotype of the NF-κB1 rs28362491 polymorphism was associated with a significantly lower risk of poor semen quality, including asthenozoospermia, astheno-teratozoospermia, and oligo-astheno-teratozoospermia, when compared to I/I genotype (odds ratio = 0.25, 0.26, 0.18, p < .0005, <.0005, <.0005) respectively. Overall, the presence of the D allele was associated with a significantly decreased risk of poor sperm quality as compared to the I allele (odds ratio = 0.56, 0.64, 0.49, p = .050, .038, .001). In conclusion, these results suggest that heterozygosity of the NF-κB1 gene may play a protecting role against male infertility in Egyptians.

Replacing HMG/FSH by low-dose HCG to complete corifollitropin alfa stimulation reduces cost per clinical pregnancy: a randomized pragmatic trial.

RESEARCH QUESTION: The cost of IVF treatment remains high, among other factors because of the medication needed for ovarian stimulation. This study investigated the effect of using low-dose human chorionic gonadotrophin (HCG) for the second phase of follicular maturation after corifollitropin alfa induction, to replace the more expensive, either recombinant or human menopausal gonadotrophin (HMG), on the cost of ovarian stimulation. DESIGN: One hundred and five patients were randomly divided into two groups: patients in the HCG group (n = 50) received low-dose HCG from Day 7 until the diameter of at least three follicles reached 17 mm or more, while patients in the FSH group (n = 55) received conventional ovarian stimulation with highly purified HMG injections. RESULTS: The clinical pregnancy rate in the HCG group was 38% higher than in the FSH group (number needed to treat, NNT = 13). The cost per pregnancy needed for ovarian stimulation was reduced from €4902 in the FSH group to €2684 in the HCG group. Hence, the cost of ovarian stimulation medication to obtain 10 pregnancies using the conventional FSH protocol is sufficient to attain 18 pregnancies when applying the low-dose HCG protocol. CONCLUSION: This study provides evidence that using HCG instead of HMG/FSH for ovarian stimulation results in a significant reduction in the cost of IVF with, at least, an equivalent pregnancy rate.

Evaluation of cannabinoid receptors Type 1 and Type 2 mRNA expression in mature versus immature spermatozoa from fertile and infertile males.

The expression of the main cannabinoid receptors (CBR1 and CBR2) was investigated to evaluate the possible association with the sperm maturation from fertile and infertile individuals. One hundred subjects were classified into fertile (n = 50) and infertile groups (n = 50). Fresh semen samples were collected. Computer-assisted semen analysis and acrosin activity test were done. RNA was extracted from mature and immature sperm pellets. Reverse transcriptase reaction and real-time PCR were done to assess the levels of both CBR1 and CBR2 genes expression in all samples. Mature spermatozoa from both groups showed significantly higher levels of both CBR1 and CBR2 compared with the immature spermatozoa (p < .05). This increment was significantly more important in the fertile group (p < .05). In mature spermatozoa, CBR1 expression was significantly related to variation in sperm morphology, and CBR2 was significantly related to both sperm morphology and linearity index. In conclusion, CBR1 and CBR2 mRNA expression may closely direct the sperm maturation at different steps of the reproductive process.

Can the biological mechanisms of ageing be corrected by food supplementation. The concept of health care over sick care.

"From care for the sick to care for health" implies that age-related diseases and discomforts, which impair the quality of life, should be prevented rather than treated. Healthy lifestyle and nutrition, and hormone supplementation - when needed - are of crucial importance. Food supplementation with nutraceuticals composed of vitamins, oligo-minerals, plant extracts and essential amino- and fatty acids should reduce age-related oxidative and epigenetic damage to DNA, and inhibit inflammatory and metabolic impairment. This study of the potential beneficial effects of novel nutraceuticals on the biological mechanisms of physical and mental ageing suggests these supplements may be scientifically justified. In the absence of adverse side effects and the expected favourable effect on the quality-adjusted life years, the benefit over risk ratio of nutraceutical supplementation should be positive.

Lowered Plasma Steady-State Levels of Progesterone Combined With Declining Progesterone Levels During the Luteal Phase Predict Peri-Menstrual Syndrome and Its Major Subdomains.

BACKGROUND: It is unknown whether lowered steady state levels of sex hormones coupled with changes in those hormones during the menstrual cycle are associated with premenstrual syndrome (PMS). OBJECTIVE: To examine associations between levels of progesterone and oestradiol during the menstrual cycle and PMS considering different diagnostic criteria for PMS. METHODS: Forty-one women aged 18-45 years with a regular menstrual cycle completed the Daily Record of Severity of Problems (DRSP) for all 28 consecutive days of the menstrual cycle. Blood was sampled at days 7, 14, 21, and 28 to assay oestradiol and progesterone. RESULTS: We developed a new diagnosis of peri-menstrual syndrome, which is characterized by increased DRSP severity in pre and post-menstrual periods and increased scores on the major DRSP dimensions, i.e., depression, physio-somatic symptoms, breast tenderness and appetite, and anxiety. This new diagnosis performed better than classical diagnoses of PMS, including that of the American College of Obstetricians and Gynecologists (ACOG). Lowered steady state levels of progesterone, when averaged over the menstrual cycle, together with declining progesterone levels during the luteal phase predict severity of peri-menstrual symptoms. Steady state levels of oestradiol and declining oestradiol levels during the cycle are also related to DRSP severity although most of these effects appeared to be mediated by progesterone. CONCLUSION: A significant increase in menstrual-cycle related symptoms can best be conceptualized as "peri-menstrual syndrome" and may result from insufficient progesterone production (relative corpus luteum insufficiency), which, in part may result from lowered oestradiol production indicating suboptimal pre-ovulatory follicular development.

Relating the Diers formetric measurements with the subjective severity of acute and chronic low back pain.

BACKGROUND CONTEXT: Nonspecific low back pain (LBP) is a common disorder with a high economic, social and psychological burden. Many systems have been developed for evaluating the severity of LBP, though these are mainly based on scoring questionnaires for the functional status of the patients. Objective quantifiable methods relating LBP with anthropometric factors are scarce. PURPOSE: To find the correlates of nonspecific LBP with spine shape variables and demographic characteristics. To investigate the possible relationship between the latter and the result of a questionnaire subjectively quantifying the severity of LBP. STUDY DESIGN/SETTING: This is a pragmatic observational prospective cohort study. PATIENT SAMPLE: 218 subjects participated in this study. A first group of participants were 160 patients consulting at an osteopathic outpatient clinic for back pain complaints. The second group consisted of 58 healthy pain-free volunteers. OUTCOME MEASURES: The Oswestry Disability Index (ODI) was used to quantify the degree of functional impairment due to low back pain. The surface topography of the back was registered statically with the Diers-4D formetric® system. METHODS: Multivariate analyses of the DIERS 4D formetric system recordings in the subjects with or without nonspecific, acute or chronic LBP. RESULTS: Different patterns between female and male subjects were found. Age, coronal and sagittal imbalance correlated with LBP in female subjects, whereas pelvic inclination, the trunk torsion and apical deviation correlated with LBP in male. Multivariate analyses allowed creating an algorithm to predict the functional disability (predicted LBP-score, PLBP), based on the above variables for females and males. Logistic stepwise regression analysis indicated the probability of a patient having a LBP-score above or below ODI 20 (P= <0.0001), which is considered the clinically relevant threshold value for justifying absence from work. CONCLUSIONS: In this study LBP was correlated with spine shape variables leading to an algorithm predicting the functional disability of a patient due to LBP. Discrepancies between the model and the ODI result may suggest elements that are clinically relevant.

Why do some ME/CFS patients benefit from treatment with sodium dichloroacetate, but others do not?

Myalgic Encephalopathy/Chronic Fatigue Syndrome (ME/CFS) is an enigmatic disease the pathogenesis of which remains elusive. Pragmatic proof-of-principle of the hypothetical mechanisms causing the clinical symptoms has been delivered, but it is hard to explain why some patients do respond favourably to treatment with sodium dichloroacetate (DCA), which enhances the activity of the mitochondrial enzyme pyruvate dehydrogenase, but other patients experience no benefit from this substance. In a prospective trial including 35 ME/CFS patients, logistic regression analysis with stepwise elimination has identified 6 pre-treatment characteristics allowing for the differentiation between responders (n = 13) and non-reponders (n = 22) with high accuracy (P < 0.0001; area under the ROC-curve = 0.92). A formula was derived generating the probability of belonging to the group of responders. This finding may assist in selecting ME/CFS patients suitable for treatment with DCA, but requires further studies as to the predictive capacity of the derived formula.

Treating patients suffering from myalgic encephalopathy/chronic fatigue syndrome (ME/CFS) with sodium dichloroacetate: An open-label, proof-of-principle pilot trial.

Twenty-two consecutive patients suffering from refractory myalgic encephalitis/chronic fatigue syndrome (ME/CFS) were treated with an innovative nutriceutical containing sodium dichloroacetate in a proof-of-principle, pilot, open-label prospective cohort trial. Ten patients experienced significant improvement of their health condition with reduction to almost half of their score in the fatigue severity scale. In twelve patients treatment failed to exert any beneficial effect. In the latter patients several other diseases have commonly been revealed by extensive biological and imaging investigations. These preliminary findings sustain the hypothetical role of mitochondrial hypo-metabolism due to inhibition of the activity of the pyruvate dehydrogenase in the pathogenesis of primary ME/CFS, and suggest a possible benefit of nutriceutical treatment by sodium dichloroacetate.

Herbal preparations for the menopause: beyond isoflavones and black cohosh.

Complementary and alternative medicines (CAM) such as isoflavones and black cohosh are commonly used to deal with menopausal symptoms, but benefit a limited proportion of women. The aim of this minireview is to summarize the evidence of the efficacy and safety of other herbal preparations. Randomized controlled trials (RCTs) find that the extracts of Mediterranean pine bark (Pycnogenol(®)), linseed, and Lepididium meyenii (Maca) reduce vasomotor symptoms. The results of RCTs of the hop flavonoid 8-prenylnaringenin are conflicting. Animal and human studies suggest that Dioscorea villosa (Wild yam),and Broccoli may protect against osteoporosis and breast and gynecological cancers but further evidence is required. Linseed may protect against breast cancer but the results are conflicting.

Quantifying the effectiveness and cost-efficiency of food supplementation with antioxidants for male infertility.

In male infertility, complementary treatment with antioxidant-containing food supplements quadruples the spontaneous pregnancy rate and reduces the cost per pregnancy by 60%.

The role of food supplementation in the treatment of the infertile couple and for assisted reproduction.

Couple infertility commonly results from the synergistic negative influence of several factors. External factors, related to life-style and environmental exposure, reinforce the effects of congenital or acquired damage through direct toxicity, hormone disruption and overload of reactive oxygen species. Combating obesity, correcting inappropriate diet, and banning the abuse of tobacco and alcohol are part of the integrated approach of the infertile couple. Nutraceuticals are judiciously formulated food supplements containing particular vitamins, antioxidants, minerals and plant extracts. There is strong evidence that complementary treatment with an appropriate nutraceutical improves the natural conception rate of infertile couples and increases the success rate of assisted reproductive techniques.

Precision, reproducibility, and clinical usefulness of measuring the Norberg angle by means of computerized image analysis.

OBJECTIVE: To evaluate the precision, reproducibility, and clinical usefulness of measuring the Norberg angle (NA) by means of a computerized system of image analysis. SAMPLE POPULATION: 1,182 consecutive radiographs of hip joints of various breeds of dogs assessed for hip dysplasia and 72 radiographs of hip joints of German Shepherd Dogs. PROCEDURES: Radiographs were assessed by a panel of 4 experts in consensus, and NAs were measured by means of a computerized system. Results of classification of hip dysplasia according to the Fédération Cynologique Internationale (FCI) and NAs were compared within dogs and among breeds. RESULTS: Measurement of the NA by means of image analysis was twice as reproducible as that via calipers. Mean NA of left hip joints was 0.38 degrees higher than that of right hip joints. The NA values accurately discriminated between hip joints of dogs without or with hip dysplasia, provided the values were also expressed as percentile rank based on the cumulative frequency distribution of NAs within the breed, and had good power to discriminate among various FCI classifications of hip joints. Mean NA for each dog breed as calculated by use of the lower of 2 NAs for each dog was highly variable and was moderately correlated with the existence of hip dysplasia (r = 0.5). CONCLUSIONS AND CLINICAL RELEVANCE: Computer-assisted measurement of the NA was useful in assessing hip joint quality and can be implemented for quality control and standardization of the FCI classification and for international comparisons.

Comparison of two canine registry databases on the prevalence of hip dysplasia by breed and the relationship of dysplasia with body weight and height.

OBJECTIVE: To compare the results of 2 canine registries for classification of the hip joints for dysplasia by breed, and to relate the percentage of dysplastic dogs with body metric characteristics. SAMPLE POPULATION: Data on the ranking order of hip dysplasia by breed from 2 registries for 156 dog breeds. PROCEDURES: The prevalence of hip dysplasia listed by the Orthopedic Foundation for Animals (OFA) and the breed mean score according to the list of the British Veterinary Association (BVA) Kennel Club Hip Dysplasia scheme were related to weight and height as well as the body mass index (BMI; kg/m(2)) by breed. RESULTS: The OFA ranking order and the percentage of dysplastic dogs were highly correlated with the BVA mean score (rho = 0.74). A significant correlation was found between the prevalence of hip dysplasia and the BMI (r = 0.63). Receiver operating characteristic curve analysis revealed that the highest area under the curve, corresponding to the best discrimination, was at a BMI of 110 kg/m(2) with a criterion value of 15% dysplastic dogs (area under the curve, 0.89). Because the ratio of dogs in the positive and negative groups reflected the prevalence of the condition among breeds in the OFA database, the positive likelihood ratio was 9.32 and the negative likelihood ratio was 0.24. CONCLUSION AND CLINICAL RELEVANCE: The OFA statistics and the BVA mean scores reflected the prevalence of hip dysplasia among dog breeds. Body mass index accurately discriminated between breeds with high or low prevalence of hip dysplasia.

Reproductive parameters of community-dwelling men from 2 regions in flanders are associated with the consumption of self-grown vegetables.

Although regional differences in semen parameters have been described, little is known about the etiologic factors underlying these variations in male fertility status. We previously reported people from a rural area (Peer) in Flanders to have lower sperm parameters and free testosterone than men from the city of Antwerp. In the present study, our objectives were to investigate to what extent these differences were associated with lifestyle or environmental factors. People in Peer were slightly older and had a higher body mass index, factors known to affect testosterone concentrations but not sperm parameters. People consuming locally produced vegetables (n = 37 of 94) but not fruit had significantly lower serum free testosterone and luteinizing hormone (LH) (both P = .04) and nonsignificantly lower follicle-stimulating hormone (FSH) (P = .05). Per unit increase of monthly intake of locally produced vegetables, free testosterone declined by 0.7% (P = .01) and sperm concentration by 2.3% (P = .04) over the whole range of the explanatory variable, whereas LH declined by 3.6% (P = .02), FSH declined by 3.5% (P = .08), and sperm morphology by 7% (P = .002) in the range of 0-10 consumptions per month. No relationship was found with lifelong exposure to cadmium. These results support a hypothesis of impaired gonadotropic signaling causing the regional difference in reproductive parameters. The surprising strong impact of self-grown vegetable consumption did not seem to be related to soil contamination by cadmium. We could not exclude pesticide exposure by inappropriate application or other factors such as nutritional deficiency, physical activity, or stress as contributors to the observed regional differences.

Estrogen receptor signaling is an unstable feature of the gonadotropic LbetaT2 cell line.

The murine, gonadotropic LbetaT2 cell line was assessed as a potential in vitro model to analyze estrogen receptor (ER)-mediated regulation of luteinizing hormone (LH) synthesis and secretion. In agreement with limited literature data, repeated exposure to (sub) physiological concentrations of gonadotropin-releasing hormone enhanced LHbeta-subunit gene expression, being the rate-limiting step of LH synthesis, and the corresponding LH secretory response. However, in the same subclone of the LbetaT2 cell line, we observed that LH production was not affected following exposure to E(2), which is in contrast to previously reported weak or modest effects. One explanation may be the absence of measurable ERalpha protein expression on the one hand and impaired ER signal transduction on the other. Furthermore, an alternative ERalpha mRNA splicing variant was detected in the LbetaT2 cell line, which (theoretically) encodes for a protein that may alter ERalpha transcriptional activity, depending on the cellular context. The studied LbetaT2 subclone did not show a generalized impairment of nuclear receptor function, as we observed androgen- and glucocorticoid-induced gene transcription, together with enhanced LH secretory response following dexamethasone treatment. Since its development, the gonadotropic LbetaT2 cell line served as a reference model to study gonadotroph-specific effects because of its mature properties. Nevertheless, this cell line does not seem to be a suitable in vitro model for the study of estrogenic regulatory effects at the level of the pituitary gonadotrophs in view of the unstable nature of ER signaling in LbetaT2 cells.

Estrogen receptor alpha (ERalpha) and insulin-like growth factor I receptor (IGF-IR) cross-talk in the gonadotropic alphaT3-1 cell line.

In reproductive tissues such as the breast and the uterus, cell proliferation and differentiation is strongly regulated by complex interactions between estrogen receptor alpha (ERalpha) and growth factor receptors. In the present study, we investigated the potential occurrence of such cross-talk in the murine, gonadotropic alphaT3-1 cell line, which expresses ERalpha and the IGF-I receptor (IGF-IR). Under estrogen-free conditions, basal cell proliferation and ER-mediated gene transcription was strongly inhibited by the selective estrogen receptor modulator (SERM) 4-hydroxy-tamoxifen (4-OH-Tam) and by the pure anti-estrogen ICI 182,780 (ICI). These effects can be reversed by either 17-beta-estradiol (E(2)) or insulin-like growth factor I (IGF-I), both exerting modest mitogenic effects in the alphaT3-1 cell line. Furthermore, IGF-I enhanced both basal and E(2)-induced ER-driven gene transcription. This may be explained, at least in part, by enhanced phosphorylation of ERalpha at serine 118, a prerequisite for the transactivation capacity of the receptor. Finally, the IGF-I-induced response on cell growth and ER-mediated transactivation can be inhibited with either ICI or 4-OH-Tam. In conclusion, our data indicate IGF-IR and ER interactions in the alphaT3-1 cell line, an in vitro model for the pituitary gonadotrophs, hereby suggesting a role of IGF-I in the regulation of gonadotropin synthesis and secretion.

Sperm quality, birth rates and the environment in Flanders (Belgium).

The relationship between fertility and pollution is unclear. We evaluated sperm quality of 562 candidate donors (years 1977-2004), births rates (births), pollutants, and the number of females in reproductive age (NFRA, 20-39 years) in Flanders. Total sperm count did not change significantly with time. Births correlated with sperm morphology (r=0.60, P=0.0027). Continuing decline in sperm morphology with time is confirmed, statistically unrelated to pollutants. Grade A sperm motility declined (1977-1992) with gradual incomplete recovery thereafter. Multiple regression analysis (1995-2002) indicated dioxin (negative association) as the only independent variable for grade A motility (r-adjusted co-efficient of determination "r-adjusted"=0.76, P=0.008). Births and pollution were positively associated but births were only dependent on NFRA (r-adjusted=0.91, P<0.001). Our results suggest a relation between dioxin and sperm motility, partially reversible upon reduction of environmental dioxin. Though significantly correlated with sperm morphology, births are primarily associated with demographic factors.

Regional variations in semen quality of community-dwelling young men from Flanders are not paralleled by hormonal indices of testicular function.

Epidemiological studies of sperm quality are hampered by problems such as low participation rates and poor comparability of results due to methodological differences in semen analysis. More objective sperm quality-related serum markers would facilitate worldwide comparisons of male reproductive status. Our objectives were to investigate to what extent a set of hormonal indices of testicular function, previously established in a clinical setting, could predict regional variations in seminal parameters in men from the general population. We recruited 101 men aged 20-40 years from two regions in Flanders, and assessed their sperm parameters and levels of serum reproductive hormones. In one region compared to another, the participants had lower sperm counts (by 34%; P=.06), lower total sperm counts (by 41%; P=.02) and poorer sperm morphology (by 32%; P<.001), which were paralleled by significantly lower levels of free testosterone (by 11%; P=.03), while for total testosterone (T) and follicle-stimulating hormone (FSH), the differences were not significant (both P=.09) at 10% and 17%, respectively. There were no differences in inhibin B and the T to luteinizing hormone (LH) ratio, which are markers of testicular function. Receiver operating characteristic curve analysis revealed that T:LH, inhibin B, and the inhibin B/FSH ratio had significant discriminatory power between men with sperm concentrations below or above 13.5x10(6)/mL. Regional variations in the semen quality of community-dwelling individuals are not necessarily reflected in altered hormonal indices of testicular function and thus, these markers, validated in clinical settings, are not valid substitutes for the traditional semen quality assessment used in epidemiological population studies.

Subtle side-chain modifications of the hop phytoestrogen 8-prenylnaringenin result in distinct agonist/antagonist activity profiles for estrogen receptors alpha and beta.

In search of therapeutic agents for estrogen-related pathologies, phytoestrogens are being extensively explored. In contrast to naringenin, 8-prenylnaringenin is a potent hop-derived estrogenic compound, highlighting the importance of the prenyl group for hormonal activity. We investigated the effects of substituting the prenyl group at C(8) with alkyl chains of varying lengths and branching patterns on estrogen receptor (ER) subtype ERalpha- and ERbeta-binding affinities and transcriptional activities. In addition, features of the ligand-induced receptor conformations were explored using a set of specific ER-binding peptides. The new 8-alkylnaringenins were found to span an activity spectrum ranging from full agonism to partial agonism to antagonism. Most strikingly, 8-(2,2-dimethylpropyl)naringenin exhibited full agonist character on ERalpha, but pronounced antagonist character on ERbeta. Knowledge on how ER-subtype-selective activities can be designed provides valuable information for future drug or tool compound discovery.

Serum dioxin-like activity is associated with reproductive parameters in young men from the general Flemish population.

BACKGROUND: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and some related environmental contaminants are aryl hydrocarbon receptor (AhR) ligands that exert reproductive and developmental toxicity in laboratory animals. In humans, fertility-related effects are less documented. OBJECTIVE: The aim of this study was to investigate the relationship between dioxin-like biological activity in serum and parameters of reproductive status in men from the general population 5 months after a polychlorinated biphenyl and dioxin food-contamination episode in Belgium. DESIGN: In the framework of the cross-sectional Flemish Environment and Health Study (FLEHS), we recruited 101 men 20-40 years of age and evaluated sperm parameters, measured sex hormones, and gathered information on a number of lifestyle factors. In addition, we determined the AhR-mediated enzymatic response elicited by individual serum samples and expressed it as TCDD equivalent concentrations (CALUX-TEQs) using an established transactivation assay. RESULTS: Age (p = 0.04) and the frequency of fish (p = 0.02) and egg (p = 0.001) consumption were independent positive determinants of serum dioxin-like activity. After correcting for possible confounders, we found that a 2-fold increase in CALUX-TEQ > 16 pg/L was associated with a 7.1% and 6.8% (both p = 0.04) decrease in total and free testosterone, respectively. We also observed a more pronounced drop in semen volume of 16.0% (p = 0.03), whereas sperm concentration rose by 25.2% (p = 0.07). No relationship was found with total sperm count or sperm morphology. CONCLUSIONS: These data suggest an interaction of dioxin-like compounds with the secretory function of the seminal vesicles or prostate, possibly indirectly through an effect on testosterone secretion, at levels not affecting spermatogenesis as such.