Clinical and seminal parameters associated with testicular microlithiasis and its severity in males from infertile couples.

STUDY QUESTION: Is there an association of testicular microlithiasis (TM) and its severity with testicular dysfunction in men from infertile couples? SUMMARY ANSWER: The presence of ≥5 testis microcalcifications per sonogram at the scrotal ultrasonography (US) of infertile males was associated with a more severe testicular dysfunction as compared to males with limited, or without, TM. WHAT IS KNOWN ALREADY: TM, representing an incidental finding in the scrotal US, is associated with male infertility and a higher risk for testicular cancer as compared to that in infertile males without TM. Still, there are unresolved questions on the relation between TM severity and testicular dysfunction in infertile men, as well as on the identification of risk factors for TM. STUDY DESIGN, SIZE, DURATION: This study was an observational, retrospective, case-control investigation involving males who underwent clinical evaluation, measurement of reproductive hormones, seminal analysis and scrotal US as part of diagnostic work-up for couple infertility at an andrology clinic, between January 2004 and December 2018. One hundred patients, out of the 2112 scored men, were found to have TM during the US evaluation. One hundred male partners from 100 infertile couples without TM, comprising the control group, were selected through a matched analysis by age and date of evaluation to reduce the confounding effect of both age and technique variability all along the long period of observation. PARTICIPANTS/MATERIALS, SETTING, METHODS: TM was defined as limited TM (LTM) or classical TM (CTM), when the maximum number of hyperecogenic spots per sonogram was <5 or ≥5, respectively. CTM, LTM and control groups were compared for clinical variables, serum levels of FSH, LH, and total testosterone, as well for semen parameters and scrotal US features. MAIN RESULTS AND THE ROLE OF CHANCE: After the exclusion of cases with testicular nodules to eliminate the possible confounding effect of testis cancer on testicular dysfunction, cases with CTM showed a lower mean testis volume (P = 0.03) and a lower sperm concentration (P = 0.03) as compared to the other two groups. A higher FSH level was observed in the CTM group compared to the LTM group (P = 0.02) and in controls (P = 0.009). The multiple logistic regression analysis showed that only a smaller testicle volume exhibited an independent significant association with a higher odds of detecting CTM (odds ratio = 0.84, 95% CI: 0.75-0.94; P = 0.02). No significant differences were observed between groups in the prevalence of risk factors for testicular cancer, or in the prevalence of conditions associated with TM. LIMITATIONS, REASONS FOR CAUTION: The retrospective design of the study did not allow conclusions to be drawn about the possible underlying links in the associations of TM with defective spermatogenesis. WIDER IMPLICATIONS OF THE FINDINGS: Males from infertile couples who exhibit a reduced testicular volume should undergo scrotal US, independent of sperm parameters, to exclude CTM and, eventually, testis cancer, although the association of CTM and current or future testis cancer risk is not yet clear. Evidence is provided here demonstrating that the presence of LTM has no clinical relevance in males from infertile couples. STUDY FUNDING/COMPETING INTEREST(S): Investigation was funded by Ministero dell'Università e della Ricerca, PRIN 2018, Italy. The authors have not declared any competing interests. TRIAL REGISTRATION NUMBER: N/A.

Relationship of Vitamin D status with testosterone levels: a systematic review and meta-analysis.

PURPOSE: Despite a biological plausibility of a direct link between low vitamin D and androgen deficiency, the association remains inconclusive in epidemiological studies. Therefore, this systematic review and meta-analysis of case-control studies aim to assess whether and in what populations such an association can be demonstrated. METHODS: A systematic search was performed in PubMed, EMBASE, Cochrane Library, Web of science, Science Direct, and CINAHL. Standardized mean differences (SMDs) and 95% confidence intervals (CIs) in total testosterone (TT) levels between men with 25-hydroxyvitamin D (25(OH)D) <20 and ≥20 ng/mL were combined using random-effects models. Funnel plot and trim-and-fill analysis were used to assess publication bias. Heterogeneity source was explored by a sub-group analysis according to health-related characteristics of the study populations. RESULTS: Eighteen included studies collectively gave information on 9892 men with vitamin D deficiency and 10,675 controls. The pooled SMD revealed a slight, albeit just significant, positive association between 25(OH)D and TT (pooled SMD: -0.23, 95% CI: -0.45 to -0.01; P = 0.04) with a large between-study heterogeneity (I2 = 98%, Pfor heterogeneity < 0.00001). At the sub-group analysis, a significant positive association, along with noticeable decrease in heterogeneity, could only be demonstrated in studies of patients with frailty states (pooled SMD: -0.19; 95% CI: -0.27, -0.10, P < 0.0001; I2 = 51%, Pfor heterogeneity = 0.06). A sensitivity analysis revealed a high stability of the result and the trim-and-fill adjustment for publication bias did not affect pooled estimate. CONCLUSIONS: Both hypovitaminosis D and androgen deficiency should be regarded as markers of a poor health status, sharing common underlying aetiologies and risk factors.

Clinical features and prognosis of COVID-19 in people with spinal cord injury: a case-control study.

STUDY DESIGN: Observational case-control study. OBJECTIVE: Individuals with spinal cord injury (SCI) develop systemic physiological changes that could increase the risk of severe evolution of coronavirus disease 2019 (COVID-19) and result in atypical clinical features of COVID-19 with possible delay in both diagnosis and treatment. We evaluated differences in clinical features and evolution of COVID-19 between people with SCI and able-bodied individuals. SETTING: The study was conducted in an Italian inpatient rehabilitation referral center for individuals with SCI during the lockdown for the COVID-19 pandemic. METHODS: We compared clinical information between patients with SCI and able-bodied healthcare workers of the same center who tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the nasopharyngeal swab polymerase chain reaction. RESULTS: Overall, 15 out of the 25 SCI patients admitted to the center and 17 out of the 69 healthcare workers tested positive for SARS-CoV-2. Patients with SCI exhibited a significantly more advanced age and a higher prevalence of comorbidities. Nevertheless, no significant differences in clinical expression of COVID-19 and treatment strategies were observed between the two groups. All hospitalized subjects were treated in nonintensive care units and no deaths occurred in either group. CONCLUSIONS: This study does not support the supposed notion that COVID-19 could exhibit atypical clinical features or a worse evolution in the frail population of people with SCI.

Relationship between natural and intrauterine insemination-assisted live births and the degree of sperm autoimmunisation.

STUDY QUESTION: What is the relationship between the degree of sperm autoimmunisation, as assessed by IgG-mixed antiglobulin reaction (MAR) test, and natural and intrauterine insemination (IUI)-assisted live births? SUMMARY ANSWER: Compared with a lower degree of positivity (50-99%), a 100%-positive MAR test was associated with a much lower occurrence of natural live births in infertile couples, who could be successfully treated with IUI, as first-line treatment. WHAT IS KNOWN ALREADY: The World Health Organization (WHO) has recommended screening for antisperm antibodies, through either the IgG-MAR test or an immunobead-binding test, as an integral part of semen analysis, with 50% antibody-coated motile spermatozoa considered to be the clinically relevant threshold. However, the predictive value of the degree of positivity of the MAR test above such a cut-off on the occurrence of natural pregnancies remains largely undetermined. Furthermore, the effectiveness of IUI in cases of strong sperm autoimmunisation is not yet well-established. STUDY DESIGN, SIZE, DURATION: This was a retrospective cohort study on 108 men with a ≥50%-positive MAR test, where the couple had attended a university/hospital andrology/infertility clinic for the management of infertility from March 1994 to September 2017. PARTICIPANTS/MATERIALS, SETTING, METHODS: The IgG-MAR test was carried out as an integral part of semen analysis. The patients were divided into two groups: 100% and 50%-99%-positive MAR test. The post-coital test (PCT) was performed in all the couples, and IUI was offered as the first-line treatment. Laboratory and other clinical data were retrieved from a computerised database. Data on subsequent pregnancies were obtained by contacting patients over the telephone. MAIN RESULTS AND THE ROLE OF CHANGE: A total of 84 men (77.8%) were successfully contacted by telephone, and they agreed to participate. Of these, 44 men belonged to the group with a 100%-positive MAR test, while 40 showed lower MAR test positivity. The couples with a 100%-positive MAR test showed a natural live birth rate per couple (LBR) that was considerably lower than that observed with a lower degree of positivity (4.5% vs. 30.0%; P = 0.00001). Among the clinical variables, a significant difference between the two groups was observed only for the PCT outcome, which was poor in the 100%-positive MAR test group. Better PCT outcomes (categorised as negative, subnormal and good) were positively associated with the occurrence of natural live births (6.3, 21.7 and 46.2%, respectively; P = 0.0005 for trend), for which the sole independent negative predictor was the degree of sperm autoimmunisation. IUI was performed as the first-line treatment in 38 out of 44 couples with a 100%-positive MAR test, yielding 14 live births (36.8%). In couples with lower MAR test positivity, the LBR after IUI (26.9%) was similar to the natural LBR in this group (30.0%). LIMITATIONS, REASONS FOR CAUTION: Given the retrospective nature of the study, we cannot exclude uncontrolled variables that may have affected natural pregnancies during the follow up or a selection bias from the comparison of natural live births with those after IUI. WIDER IMPLICATIONS OF THE FINDINGS: The routine use of the IgG-MAR test in the basic fertility workup is justified as it influences decision making. A 100%-positive IgG-MAR test can represent the sole cause of a couple's infertility, which could be successfully treated with IUI. On the other hand, a lower degree of positivity may only represent a contributing factor to a couple's infertility, and so the decision to treat or wait also depends on the evaluation of conventional prognostic factors including the PCT outcome. STUDY FUNDING, COMPETING INTEREST(S): This study was supported by PRIN 2017, Ministero dell'Università e della Ricerca Scientifica (MIUR), Italy. On behalf of all authors, the corresponding author states that there is no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Endogenous transient doping: physical exercise acutely increases testosterone levels-results from a meta-analysis.

PURPOSE: Although endogenous testosterone levels are demonstrated to be affected by both acute exercise and resistance training, the dynamic regulation of androgen production after physical activity is still a matter of debate. This meta-analysis was designed to assess whether physical exercise acutely affects testosterone levels in men. METHODS: The literature search was conducted to identify longitudinal trials evaluating the acute change of both total testosterone (TT) and free testosterone (fT) after physical activity in adult men. Sensitivity analyses were performed considering the sample collected (blood or saliva), the intensity of the physical exercise and the interval between the end of the exercise and the sample collection. RESULTS: Forty-eight studies were included in the analysis, accounting for 126 trials. A total of 569 patients were enrolled (mean age 29.7 ± 13.1 years). The physical activity increased acutely TT (standardized mean difference 0.74, 95%CI: 0.56, 0.91 nmol/L), considering both serum and saliva samples (p < 0.001). Testosterone increased after moderate (p < 0.001) and high-intensity (p < 0.001) exercises, but not after mild physical activity (p = 0.19). Moreover, the testosterone increase was evident when measured immediately at the end of the exercise and within 30 min (p < 0.001), but not after 30 min (p = 0.930). Similar significant results were obtained considering fT, while SHBG did not change after physical activity (p = 0.090). CONCLUSION: The comprehensive evaluation of the acute physical activity effect on testosterone levels identified a clear increase after exercise, irrespective of the sample collected. The main determinant of this fluctuation was the exercise intensity, with a mechanism that seems to be mostly SHBG independent. In particular, moderate/intense physical activity resulted able to increase endogenous androgenic production, albeit acutely and transitory. TRIAL REGISTRATION NUMBER: PROSPERO registration ID: 157348.

Testosterone, level of the lesion and age are independently associated with prostate volume in men with chronic spinal cord injury.

PURPOSE: Although men with spinal cord injury (SCI) exhibit a prostate volume significantly smaller compared to age-matched able-bodied men, the independent association of lower prostate volume with its putative determinants has never been analyzed in this population. This study was designed to identify variables independently associated with prostate volume in men with chronic SCI. METHODS: In this cross-sectional study, prostate volume of 138 men with chronic (> 1 years) SCI, aged 54.5 (25th-75th percentile: 36.0-66.0) years, was evaluated with trans-rectal ultrasonography. All patients underwent a complete neurological exam, as well as biochemical and hormonal assessment, including total testosterone (TT) levels. Free testosterone levels were calculated (cFT) by the Vermeulen formula. RESULTS: The median prostate volume was 23.4 mL. At the univariate analysis, a larger prostate volume was associated with higher TT (p = 0.00001) and cFT (p = 0.001), SCI level below T12 (p = 0.007), more advanced age (p = 0.04), lower body mass index (p = 0.04), higher functional independence score (p = 0.06), higher values of prostate-specific antigen (p = 0.12) and shorter duration of the injury (p = 0.21). However, at the multiple regression analyses, an independent and positive association only persisted between the prostate volume with either TT or cFT levels, and, to a lesser extent, with age and a level of spinal lesion below T12. A prostate volume below the median value was observed in 91.4% (32/35) of patients with both androgen deficiency (TT < 264 ng/dL) and spinal lesion level ≥ T12, but only in 16.5% (2/12) of patients with both normal androgen levels and spinal lesion level below T12 (p < 0.001). CONCLUSIONS: Our data indicate that lower testosterone levels and, to a lesser extent, a younger age and a spinal lesion level ≥ T12 represent the only variables exhibiting an independent association with a smaller prostate volume in men with SCI.

Metabolic syndrome is the key determinant of impaired vaginal lubrication in women with chronic spinal cord injury.

PURPOSE: Spinal cord injury (SCI) affects sexual health of both male and female, but little attention has been given to sexuality of SCI women. Similar to penile erection, vaginal lubrication represents a neurovascular event and then both denervation and vascular damage might contribute to its impairment. Nevertheless, the relative weight of lesion location/degree and vascular risk factors in determining hypolubrication in women with SCI has not yet been investigated. The aim of this study was to recognize among putative determinants of poor sexual arousal in women with SCI, neurogenic and vascular/metabolic independent predictors of vaginal hypolubrication. METHODS: Twenty-eight consecutive female patients admitted to a rehabilitation program because of chronic SCI (≥ 1 year) underwent clinical and biochemical evaluations, including assessment of vaginal lubrication by the Female Sexual Function Index (FSFI). As, in people with SCI, waist circumference overestimates visceral fat mass due to abdominal muscle paralysis, metabolic syndrome (MetS) was defined according to specific criteria proposed for SCI population: BMI ≥ 22 kg/m2 and two or more of the following: triglycerides ≥ 150 mg/dL (or actual treatment), HDL < 50 mg/dL, hypertension (or actual treatment), fasting glucose ≥ 100 mg/dL or diabetes mellitus type 2. RESULTS: A FSFI lubrication sub-score < 3.6, suggestive for impaired vaginal lubrication, was exhibited by 53.7% of the study population. When compared to the group with normal lubrication, a significantly higher proportion of these women had paraplegia (93.3% vs 38.5%, p = 0.003) and met the SCI-specific criteria for MetS (73.4% vs 7.6%, p = 0.0006), whereas, no significant differences were found between the two groups in the proportion of women exhibiting the single components of MetS. At the multiple logistic regression analysis, only the presence of MetS exhibited a significant independent association with impaired vaginal lubrication (OR = 3.1, 95% CI 1.2, 5.8, p = 0.01). CONCLUSIONS: In women with SCI, a clustering of modifiable vascular/metabolic risk factors, constituting the MetS, could contribute to sexual dysfunctions by affecting the vaginal lubrication, independently of the level of the spinal cord lesion.

Thyroid autoimmunity and risk of post-partum depression: a systematic review and meta-analysis of longitudinal studies.

PURPOSE: The aim of this study was to systematically investigate whether, and to what extent, the detection of thyroid autoimmunity during pregnancy and in the weeks after childbirth is associated with an increased risk of developing post-partum depression (PPD), a condition associated with possible adverse outcomes for both mother and offspring. We performed a systematic review and meta-analysis of longitudinal studies, assessing the incidence of PPD in women with and without anti-thyroperoxidase antibody (TPOAb) positivity. METHODS: We searched MEDLINE, EMBASE, Web of Science, Cochrane Library, and CINAHL. Methodological quality of the studies was assessed by the Newcastle-Ottawa Scale. In the presence of even modest between-studies heterogeneity, assessed by Cochrane Q and I2 tests, risk ratios (RRs) for PPD were combined using a random effects model. Funnel plot and trim-and-fill analysis were used to assess publication bias. RESULTS: Five included studies provided information on 449 women with TPOAb-positive and 2483 TPOAb-negative women. Pooled RR indicated a significantly increased risk to develop PPD in TPOAb-positive group (RR 1.49, 95% CI 1.11-2.00; P = 0.008; I2 = 47%, Pfor heterogeneity = 0.11). Consistent with a possible publication bias, the trim-and-fill test detected two putative missing studies in the funnel plot. Nevertheless, the adjustment for publication bias produced a negligible effect on the pooled estimate (adjusted RR 1.41, 95% CI 1.18-1.68, P = 0.0002). CONCLUSIONS: Thyroid autoimmunity during pregnancy and in the weeks after childbirth is associated with an increased risk of developing PPD. Further well-designed studies are warranted to confirm this association and elucidate underlying pathophysiological mechanisms. PROSPERO REGISTRATION: CRD42019129643.

Relationship between leukocytospermia, reproductive potential after assisted reproductive technology, and sperm parameters: a systematic review and meta-analysis of case-control studies.

BACKGROUND: The association of leukocytospermia with male fertility is still under debate. OBJECTIVE: To evaluate the impact of leukocytospermia (≥1 × 106  white blood cells/mL of semen, according to the World Health Organization) in men attending a fertility clinic for couple subfertility, on fertility outcomes after assisted reproductive technology (ART) and on semen quality. MATERIALS AND METHODS: A systematic review with meta-analysis of case-control studies reporting mean ± standard deviation for values of different seminal parameters (sperm concentration, progressive motility, sperm morphology, sperm DNA fragmentation, semen volume, and Ph) and fertilization rate (FR), or the odds ratio (OR) for clinical pregnancy rate (PR) per cycle after ART in leukocytospermic and non-leukocytospermic patients was performed. A literature search was carried out in MEDLINE and SCOPUS for English-language studies published till June 2018. RESULTS: Twenty-eight case-controlled retrospective studies met the inclusion criteria, comparing fertility outcomes after ART or semen parameters in men with or without leukocytospermia. FR and PR after ART were not significantly different in the two groups. Leukocytospermic samples showed a lower sperm concentration (pooled SMD = -0.14; 95% CI: -0.28, -0.01, I2  = 71%, pfor heterogeneity  < 0.00001) and a lower progressive motility (pooled SMD = -0.18; 95% CI: -0.29, -0.06; I2  = 59%, pfor heterogeneity  < 0.0001). However, the significant differences disappeared, along with the large inter-study heterogeneity, when analyses were restricted to studies clearly reporting the inclusion of men without clinical evidence of seminal tract infection. DISCUSSION AND CONCLUSION: Leukocytospermia in men seeking consultation for couple subfertility is not associated with a reduced fertility after ART and with altered semen quality in populations asymptomatic for genital tract infection. Therefore, the current clinical criteria for definition of leukocytospermia should be re-assessed in subfertile couples attending a fertility clinic.

Left spermatic vein reflux after varicocele repair predicts pregnancies and live births in subfertile couples.

PURPOSE: Varicocele repair (VR) is proposed to improve fertility in subfertile couples with a poor semen quality. We explored whether the disappearance of a left continuous spermatic venous reflux (SVR) at scrotal colour-Doppler ultrasound (CDUS), an objective evidence for a VR, is predictive for improved fertility outcome in subfertile couples. METHODS: VR was performed by left internal spermatic vein sclero-embolisation in 88 males seeking a consultation for subfertility. Semen analysis and scrotal CDUS were evaluated before and 6 months after VR. Serum levels of FSH and total testosterone (TT) were obtained at baseline. Telephone interview was used to obtain information about fertility outcome. Significant predictors of pregnancy and live births, selected by univariate analyses, were included into multiple logistic regression models to assess independent associations. RESULTS: At the adjusted model, independent significant predictors of pregnancy after VR were a disappeared SVR at CDUS (OR = 5.5, 97.5% CI 2.01-15.4; p = 0.0009) and an improved sperm total motile count (TMC) (OR = 5.5, 97.5% CI 1.4-27.9; p = 0.02). Even live births were independently associated with both disappeared left SVR at CDUS (OR = 4.3, 97.5% CI = 1.6-11.8; p = 0.003) and improved TMC after VR (OR = 4.8, 97.5% CI 1.3-24.2; p = 0.02). CONCLUSION: The still controversial effect of varicocele repair on fertility in subfertile couples may reside on the undefined objective methods to document a successful VR and its effect on couple fertility. The disappearance of a continuous left SVR at CDUS after VR was the objective best predictor for subsequent improved fertility in subfertile couples.

Prevalence of anti-sperm antibodies and relationship of degree of sperm auto-immunization to semen parameters and post-coital test outcome: a retrospective analysis of over 10 000 men.

STUDY QUESTION: What is the prevalence and the relationship of anti-sperm antibodies (ASA), screened by means of IgG-mixed anti-globulin reaction (MAR) test, to semen quality and post-coital test (PCT) outcome? SUMMARY ANSWER: A 100% positive IgG-MAR test, detected in 2% of the study population, was associated with lower sperm output and progressive motility, and was the sole determinant of higher prevalence of a negative PCT outcome. WHAT IS KNOWN ALREADY: Although ASA may affect sperm fertilizing ability and the IgG-MAR test is recommended by the World Health Organization (WHO) as an integral part of semen analysis for screening the occurrence of ASA, the prevalence and clinical relevance of positive MAR test results remain controversial. STUDY DESIGN, SIZE, DURATION: A retrospective analysis of 12 296 consecutive men who attended a university/hospital andrology clinic for the evaluation of fertility potential was carried out. PARTICIPANTS/MATERIALS, SETTING, METHODS: Immunological screening with the IgG-MAR test was performed on all ejaculates as an integral part of semen analysis. Positive samples (≥10%) were further tested for IgA-ASA. The prevalence of positive IgG-MAR tests results, along with the relationship of the degree of sperm auto-immunization to semen parameters and PCT outcome, were analyzed. MAIN RESULTS AND THE ROLE OF CHANCE: After excluding semen samples showing azoospermia or severe oligo-asthenozoospermia, the prevalence of a positive IgG-MAR test in the remaining 10 025 men was 4%, 3.4% and 2%, with 10%, 50% and 100% thresholds, respectively. The 100%-positive MAR tests exhibited significantly higher consistency over time, and were significantly associated with higher prevalence of a mixed pattern (i.e. when the majority of sperm exhibited beads attached on both the head and along the tail) of positivity as well as with the concomitant occurrence of IgA-ASA. Additionally, the 100%-positive MAR tests were significantly associated with a lower median value of the total number of spermatozoa and progressive motility, compared to samples with a lower degree of positivity or negative samples. In the PCT performed in 120 couples, where ASA were detected in the male partner, the 100%-positive MAR tests were significantly associated with a higher prevalence of negative PCT outcome, in comparison to the lower degree of positivity, independent of, and without any significant contribution from, other determinants (semen and cervical mucus quality). LIMITATIONS, REASONS FOR CAUTION: Only surrogate infertility-related end-points were analyzed in the present study. However, since the impairment of sperm penetration through the cervical mucus represents the primary mechanism of ASA-interference with fertility, PCT outcome may represent a suitable clinical end-point. WIDER IMPLICATIONS OF THE FINDINGS: The present study, being the largest reported to date, provides a reliable estimate of ASA prevalence. Moreover, it indicates that a 50%-positive MAR test, which is suggested by WHO as the clinically-relevant threshold, also includes patients with a degree of sperm auto-immunization that contributes to couple infertility only in the presence of other causal factors; conversely, the 100%-positive MAR test can represent the sole determinant of couple infertility, as it was the sole significant predictor of the highly prevalent negative PCT outcome. STUDY FUNDING/COMPETING INTEREST(S): The study was supported by the University of L'Aquila, Italy. The authors declare no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Can the positive association of osteocalcin with testosterone be unmasked when the preeminent hypothalamic-pituitary regulation of testosterone production is impaired? The model of spinal cord injury.

PURPOSE: Osteocalcin (OCN), released from the bone matrix during the resorption phase, in its undercarboxylated form, stimulates testosterone (T) biosynthesis in mouse and a loss-of-function mutation of its receptor was associated with hypergonadotropic hypogonadism in humans. Nevertheless, when population-based studies have explored the OCN-T association, conflicting results have been reported. Hypothesizing that the evidence of a positive association between OCN and T could have been hindered by the preeminent role of a well-functioning hypothalamus-pituitary axis in promoting T biosynthesis, we explored this association in men with chronic spinal cord injury (SCI), exhibiting high prevalence of non-hypergonadotropic androgen deficiency. METHODS: Fifty-five consecutive men with chronic SCI underwent clinical/biochemical evaluations, including measurements of total T (TT), OCN and 25(OH)D levels. Free T (FT) levels were calculated by the Vermeulen formula. Comorbidity was scored by Charlson comorbidity index (CCI). RESULTS: A biochemical androgen deficiency (TT < 300 ng/dL) was observed in 15 patients (27.3%). TT was positively correlated with OCN, 25(OH)D and leisure time physical activity and negatively correlated with age, BMI and CCI. OCN was also positively correlated with calculated FT and negatively correlated with BMI and HOMA-IR. At the multiple linear regression analyses, a positive association of OCN with TT and calculated FT persisted after adjustment for confounders. CONCLUSIONS: The positive association here found between OCN and T levels in men with chronic SCI reinforces the notion that a bone-testis axis is also functioning in humans and suggests that it can be unmasked when the preeminent hypothalamic-pituitary regulation of T production is impaired.

Rural and urban differences in prenatal exposure to essential and toxic elements.

Excess or inadequate levels of inorganic ions may induce significant acute and long-term irreversible dysfunction in humans. The fetus and placenta are particularly vulnerable to toxins due to the immaturity of the blood-brain barrier and diminished biotransformation enzymatic activity. A comparative cross-sectional study was conducted on 172 pregnant women, 79 rural, and 93 urban. Umbilical cord blood was collected at the time of delivery and analyzed for 20 inorganic elements. Significant differences were found between urban and rural samples for two elements where copper (Cu) and molybdenum (Mo) were higher in urban samples. No marked differences between groups occurred for: arsenic, barium, cadmium, calcium, cobalt, lead, lithium, magnesium, manganese, mercury, selenium, strontium, or zinc. All samples were devoid of platinum, silver, thallium or uranium. Data demonstrated significant differences in urban and rural prenatal exposure to Cu and Mo. Further study is needed to determine if there is a causal link between neonatal outcomes and prenatal exposure to these elements.

Determination of spermatic vein reflux after varicocele repair helps to define the efficacy of treatment in improving sperm parameters of subfertile men.

PURPOSE: A continuous spermatic venous reflux (SVR) at colour Doppler ultrasound (CDU) is an evidence for varicocele, a frequent correlate for male subfertility. We explored whether SVR after left varicocele repair is predictive for changes in semen quality in subfertile men. METHODS: Blood hormones (FSH, LH, and total testosterone) and scrotal CDU were obtained in subfertile patients with left grade II or grade III varicocele on physical evaluation and a poor sperm quality. Semen analysis and CDU were re-evaluated 6 months after a retrograde internal spermatic vein scleroembolisation. RESULTS: The retrospective study included 100 men with a baseline SVR >3 cm/s; 60 men showed a disappearance (group 1) and 40 men (group 2) showed a reduced SVR after varicocele repair. Total motile sperm count (TMC) was markedly increased after treatment (p < 0.0001; F = 35.79) and the increase was more relevant in group 1 compared to group 2 (p = 0.04; F = 4.20). TMC and left SVR values after varicocele repair were negatively correlated (R = -0.218; p = 0.035). Multivariate analysis showed that adjusted SVR after repair negatively predicted TMC change (TMC after repair minus baseline TMC) (ß = -2.56; p = 0.022). Disappearance of a continuous left SVR at CDU after varicocele repair was associated to a better improvement of semen parameters in subfertile men. CONCLUSION: Recording of a continuous left spermatic vein reflux is an objective method to assess a successful varicocele repair aimed to improve sperm parameters in subfertile men.

Semen leukocytes and oxidative-dependent DNA damage of spermatozoa in male partners of subfertile couples with no symptoms of genital tract infection.

The influence of seminal leukocytes on generation of oxidative damage to sperm DNA was here investigated on male partners of subfertile couples asymptomatic for a genital tract infection. The study included 111 ejaculates from men attending the Andrology Centre at University of L'Aquila. Semen leukocytes subset included round cells expressing pan-leukocyte CD45 antigen, monocyte/macrophage lineage antigen CD14, and activated macrophages HLA-DR antigen. The 8-hydroxy-2'-deoxyguanosine (8-OHdG) expression identified spermatozoa with DNA oxidative adducts while terminal deoxynucleotidyl transferase (TdT)-mediated fluorescein-dUTP nick end labeling (TUNEL) assay detected spermatozoa with DNA fragmentation. Flow cytometry and immunocytochemistry was used for determinations. Main outcome measure was the association of semen leukocyte subpopulations with spermatozoa showing oxidative-related DNA damage and with routine semen parameters. Leukocyte subpopulations were strictly correlated (p < 0.0001), but no association was found between the concentration of leukocytes, semen parameters, the percentage of TUNEL-positive and of 8-OHdG-positive spermatozoa. The percentage of 8-OHdG-positive spermatozoa was positively correlated with the percentage of TUNEL-positive spermatozoa (r = 0.48; p < 0.0001) and negatively correlated with sperm concentration (r = -0.44; p < 0.0001). Sperm concentration and the percentage of TUNEL-positive spermatozoa independently contributed (ß = -0.25, p = 0.008; ß = 0.23, p = 0.05, respectively) to the variation in percentage of 8-OHdG-positive spermatozoa after adjusting for age, abstinence time, and smoking. In conclusion, oxidative-dependent DNA damage in spermatozoa was associated to poor semen quality but not to different leukocyte subpopulations in ejaculates of men asymptomatic for a genital tract infection.

Radiotherapy-induced miR-223 prevents relapse of breast cancer by targeting the EGF pathway.

In breast cancer (BC) patients, local recurrences often arise in proximity of the surgical scar, suggesting that response to surgery may have a causative role. Radiotherapy (RT) after lumpectomy significantly reduces the risk of recurrence. We investigated the direct effects of surgery and of RT delivered intraoperatively (IORT), by collecting irradiated and non-irradiated breast tissues from BC patients, after tumor removal. These breast tissue specimens have been profiled for their microRNA (miR) expression, in search of differentially expressed miR among patients treated or not with IORT. Our results demonstrate that IORT elicits effects that go beyond the direct killing of residual tumor cells. IORT altered the wound response, inducing the expression of miR-223 in the peri-tumoral breast tissue. miR-223 downregulated the local expression of epidermal growth factor (EGF), leading to decreased activation of EGF receptor (EGFR) on target cells and, eventually, dampening a positive EGF-EGFR autocrine/paracrine stimulation loop induced by the post-surgical wound-healing response. Accordingly, both RT-induced miR-223 and peri-operative inhibition of EGFR efficiently prevented BC cell growth and reduced recurrence formation in mouse models of BC. Our study uncovers unknown effects of RT delivered on a wounded tissue and prompts to the use of anti-EGFR treatments, in a peri-operative treatment schedule, aimed to timely treat BC patients and restrain recurrence formation.

Vitamin D supplementation improves pathophysiology in a rat model of preeclampsia.

Deficiency of vitamin D (VD) is associated with preeclampsia (PE), a hypertensive disorder of pregnancy characterized by proinflammatory immune activation. We sought to determine whether VD supplementation would reduce the pathophysiology and hypertension associated with the reduced uterine perfusion pressure (RUPP) rat model of PE. Normal pregnant (NP) and RUPP rats were supplemented with VD2 or VD3 (270 IU and 15 IU/day, respectively) on gestation days 14-18 and mean arterial pressures (MAPs) measured on day 19. MAP increased in RUPP to 123 ± 2 mmHg compared with 102 ± 3 mmHg in NP and decreased to 113 ± 3 mmHg with VD2 and 115 ± 3 mmHg with VD3 in RUPP rats. Circulating CD4+ T cells increased in RUPP to 7.90 ± 1.36% lymphocytes compared with 2.04 ± 0.67% in NP but was lowered to 0.90 ± 0.19% with VD2 and 4.26 ± 1.55% with VD3 in RUPP rats. AT1-AA, measured by chronotropic assay, decreased from 19.5 ± 0.4 bpm in RUPPs to 8.3 ± 0.5 bpm with VD2 and to 15.4 ± 0.7 bpm with VD3. Renal cortex endothelin-1 (ET-1) expression was increased in RUPP rats (11.6 ± 2.1-fold change from NP) and decreased with both VD2 (3.3 ± 1.1-fold) and VD3 (3.1 ± 0.6-fold) supplementation in RUPP rats. Plasma-soluble FMS-like tyrosine kinase-1 (sFlt-1) was also reduced to 74.2 ± 6.6 pg/ml in VD2-treated and 91.0 ± 16.1 pg/ml in VD3-treated RUPP rats compared with 132.7 ± 19.9 pg/ml in RUPP rats. VD treatment reduced CD4+ T cells, AT1-AA, ET-1, sFlt-1, and blood pressure in the RUPP rat model of PE and could be an avenue to improve treatment of hypertension in response to placental ischemia.

Embolization of left spermatic vein in non-obstructive azoospermic men with varicocele: role of FSH to predict the appearance of ejaculated spermatozoa after treatment.

PURPOSE: Varicocele repair in non-obstructive azoospermia (NOA) was occasionally associated to ejaculated spermatozoa independently from clinical and laboratory measures. We performed a prospective study in infertile men affected by NOA and left side varicocele to find whether or not the appearance of ejaculated spermatozoa after varicocele repair is predicted by baseline measures. METHODS: Patients with NOA and grade II, or grade III left side varicocele were submitted to hormone analysis and to scrotal color Doppler ultrasound (CDU). Azoospermia was confirmed in 23 patients aged 25-47 years who were than submitted to varicocele repair through a retrograde internal spermatic vein embolization. Patients were re-evaluated after 6 months. RESULTS: Six months after varicocele repair 12 patients (52.2 %) were still azoospermic (Group 1) while 11 patients (47.8 %) reported ejaculated spermatozoa (Group 2) [sperm count: 1.3 × 10(6)/mL; 0.5 × 10(6)/mL-1.6 × 10(6)/mL (median 25th-75th centiles)]. Serum baseline FSH was lower in Group 2 compared to Group 1 (p = 0.012), while no differences between groups were revealed for all other clinical and laboratory parameters. ROC analysis indicated that baseline FSH level predicted the appearance of ejaculated spermatozoa after treatment [AUC = 0.811; 95 % Confidence Interval (CI) 0.6-0.9; p = 0.0029]. A cut-off level of FSH <10.06 mIU/mL identified 82.0 % of cases with ejaculated spermatozoa with a specificity of 81.8 % and a sensitivity of 83.3 %. CONCLUSION: Selected patients with NOA may show ejaculated spermatozoa after a non-invasive repair of a left side varicocele, therefore avoiding testicular sperm extraction. Baseline serum FSH was a valuable predictor for ejaculated spermatozoa after treatment.

Validation of the Killip-Kimball Classification and Late Mortality after Acute Myocardial Infarction / Validação da Classificação de Killip e Kimball e Mortalidade Tardia Após Infarto Agudo do Miocárdio

Background: The classification or index of heart failure severity in patients with acute myocardial infarction (AMI) was proposed by Killip and Kimball aiming at assessing the risk of in-hospital death and the potential benefit of specific management of care provided in Coronary Care Units (CCU) during the decade of 60. Objective: To validate the risk stratification of Killip classification in the long-term mortality and compare the prognostic value in patients with non-ST-segment elevation MI (NSTEMI) relative to patients with ST-segment elevation MI (STEMI), in the era of reperfusion and modern antithrombotic therapies. Methods: We evaluated 1906 patients with documented AMI and admitted to the CCU, from 1995 to 2011, with a mean follow-up of 05 years to assess total mortality. Kaplan-Meier (KM) curves were developed for comparison between survival distributions according to Killip class and NSTEMI versus STEMI. Cox proportional regression models were developed to determine the independent association between Killip class and mortality, with sensitivity analyses based on type of AMI. Results: The proportions of deaths and the KM survival distributions were significantly different across Killip class >1 (p <0.001) and with a similar pattern between patients with NSTEMI and STEMI. Cox models identified the Killip classification as a significant, sustained, consistent predictor and independent of relevant covariables (Wald χ2 16.5 [p = 0.001], NSTEMI) and (Wald χ2 11.9 [p = 0.008], STEMI). Conclusion: The Killip and Kimball classification performs relevant prognostic role in mortality at mean follow-up of 05 years post-AMI, with a similar pattern between NSTEMI and STEMI patients. .

Fundamento: A classificação ou índice de gravidade de insuficiência cardíaca em pacientes com infarto agudo do miocárdio (IAM) foi proposta por Killip e Kimball com o objetivo de avaliar o risco de mortalidade hospitalar e o potencial benefício do tratamento especializado em unidades coronárias (UCO) na década de 1960. Objetivos: Validar a classificação de Killip para mortalidade total em longo prazo e comparar o valor prognóstico em pacientes com IAM sem elevação do segmento ST (IAMSEST) em relação àqueles com elevação do segmento ST (IAMCEST), na era pós-reperfusão e de terapia antitrombótica moderna. Métodos: Foram avaliados 1906 pacientes com IAM confirmado, admitidos em UCO entre 1995 e 2011, com seguimento médio de cinco anos, para avaliação da mortalidade total. Curvas de Kaplan-Meier foram construídas para comparação da sobrevida por classe Killip e IAMSEST versus IAMCEST. Modelos de regressão de risco proporcional de Cox foram construídos para determinar a associação independente entre a classe Killip e a mortalidade, com análises de sensibilidade por tipo de IAM. Resultados: As proporções de óbitos e as distribuições das curvas de sobrevida foram diferentes conforme a classe Killip >1 (p <0,001) e similares entre IAMSEST e IAMCEST. Os modelos de risco identificaram a classificação de Killip como preditor significante, sustentado, consistente e independente de covariáveis relevantes (Wald χ2 16,5 [p = 0,001], IAMSEST) e (Wald χ2 11,9 [p = 0,008], IAMCEST). Conclusão: A classificação de Killip e Kimball desempenha papel prognóstico relevante na mortalidade em seguimento médio de cinco anos pós-IAM e, de modo similar, entre pacientes com IAMSEST e IAMCEST. .

Validation of the Killip-Kimball classification and late mortality after acute myocardial infarction.

BACKGROUND: The classification or index of heart failure severity in patients with acute myocardial infarction (AMI) was proposed by Killip and Kimball aiming at assessing the risk of in-hospital death and the potential benefit of specific management of care provided in Coronary Care Units (CCU) during the decade of 60. OBJECTIVE: To validate the risk stratification of Killip classification in the long-term mortality and compare the prognostic value in patients with non-ST-segment elevation MI (NSTEMI) relative to patients with ST-segment elevation MI (STEMI), in the era of reperfusion and modern antithrombotic therapies. METHODS: We evaluated 1906 patients with documented AMI and admitted to the CCU, from 1995 to 2011, with a mean follow-up of 05 years to assess total mortality. Kaplan-Meier (KM) curves were developed for comparison between survival distributions according to Killip class and NSTEMI versus STEMI. Cox proportional regression models were developed to determine the independent association between Killip class and mortality, with sensitivity analyses based on type of AMI. RESULTS: The proportions of deaths and the KM survival distributions were significantly different across Killip class >1 (p <0.001) and with a similar pattern between patients with NSTEMI and STEMI. Cox models identified the Killip classification as a significant, sustained, consistent predictor and independent of relevant covariables (Wald χ2 16.5 [p = 0.001], NSTEMI) and (Wald χ2 11.9 [p = 0.008], STEMI). CONCLUSION: The Killip and Kimball classification performs relevant prognostic role in mortality at mean follow-up of 05 years post-AMI, with a similar pattern between NSTEMI and STEMI patients.