Seminal androgens,oestradiol and progesterone in oligoasthenoteratozoospermic men with varicocele

This study aimed to assess seminal androgens, oestradiol, progesterone levels in oligoasthenoteratozoospermic (OAT) men with varicocele (Vx). In all, 154 men with matched age and body mass index were investigated that were divided into healthy fertile controls (n = 35), OAT men with Vx (n = 55), OAT men without Vx (n = 64). They were subjected to assessment of semen parameters, seminal levels of testosterone (T), androstenedione (A), 5α‐androstane‐3 α,17 β‐diol (3 α‐diol), oestradiol (E₂), 17‐hydroxyprogesterone (17‐OHP) and progesterone (P). Seminal levels of T and A were significantly decreased where seminal levels of 3 α‐diol, E₂, 17‐OHP, P were significantly higher in OAT men with/without Vx compared with fertile controls. Sperm count, sperm motility and sperm normal forms percentage demonstrated significant positive correlation with seminal T and A and significant negative correlation with seminal 3 α‐diol, E₂, P. It is concluded that in fertile men, seminal T and A are significantly increased and seminal 3 α‐diol, E₂, 17‐OHP, P are significantly decreased compared with infertile OAT men with/without Vx. Association of Vx demonstrated a nonsignificant influence on these hormonal levels in OAT cases. Sperm count, sperm motility and sperm normal forms demonstrated significant positive correlation with seminal T, A and significant negative correlation with seminal 3 α‐diol, E₂, P.     

Seminal plasma oxytocin and oxidative stress levels in infertile men with varicocele

This study aimed to assess seminal plasma oxytocin (OT) and oxidative stress (OS) levels in infertile men with varicocele (Vx). A total of 131 men were divided into fertile men (n = 20), fertile men with Vx (n = 17), infertile men without Vx (n = 40) and infertile men with Vx (n = 54). OT, malondialdehyde (MDA) and glutathione peroxidase (GPx) were estimated in seminal plasma. Mean levels of seminal OT, MDA were significantly decreased, and the mean level of GPx was significantly increased in fertile men with/without Vx compared with infertile men with/without Vx. Mean levels of OT, MDA were increased, and mean level of GPx was significantly decreased in Vx grade III cases compared with Vx grades I, II cases and in bilateral Vx cases compared with unilateral Vx. There was significant negative correlation between seminal OT with sperm count, sperm motility, seminal GPx and significant positive correlation with sperm abnormal forms, seminal MDA. It is concluded that seminal OT is significantly decreased in fertile men with/without Vx compared with infertile men with/without Vx. Seminal OT demonstrated significant negative correlation with sperm count, sperm motility, seminal GPx and significant positive correlation with sperm abnormal forms, seminal MDA. Seminal OT is associated with Vx grade and its bilaterality.     

Oestrogen receptor alpha gene polymorphisms relationship with semen variables in infertile men

This study aimed to assess the association of oestrogen receptor alpha (ER‐α) gene polymorphisms and semen variables in infertile oligoasthenoteratozoospermic (OAT) men. In all, 141 men were grouped into fertile men (n = 60) and infertile OAT men (n = 81). They were subjected to assessment of semen analysis, acrosin activity, serum reproductive hormones and genotyping of ER‐α gene. Frequencies of p and x alleles in ER‐α gene PvuII and XbaI polymorphisms were more prevalent among fertile men compared with infertile OAT men. Presence of P and X alleles was associated with increased incidence of male infertility for genotypes PP, XX compared with genotypes pp and xx (OR = 2.8; 95% CI: 2.36–6.97; P = 0.001 and OR = 4.1, 95% CI: 1.49–11.39; P = 0.001, respectively). The mean of semen variables and sperm acrosin activity were significantly higher in cases associated with pp than PP and in xx than XX genotypes of ER‐α gene. Mean levels of all serum reproductive hormones demonstrated nonsignificant differences in different ER‐α genotypes except oestrogen that was elevated in PP and XX ER‐α gene genotypes. It is concluded that as oestrogen is concerned in male gamete maturation, ER‐α gene polymorphisms might play a role in the pathophysiology of male infertility.     

Seminal SIRT1-oxidative stress relationship in infertile oligoasthenoteratozoospermic men with varicocele after its surgical repair

This work assessed seminal SIRT1-oxidative stress (OS) relationship in infertile oligoasthenoteratozoospermic (OAT) men after varicocele repair. Overall, thirty OAT men with varicocele were investigated. Inclusion criteria were infertile males (males who were unable to initiate a pregnancy within 1 year of regular unprotected intercourse), confirmed OAT and normal female factor. These cases were subjected to history taking, clinical checkup and semen analysis. In their semen, seminal SIRT1, malondialdehyde (MDA) and glutathione peroxidase (GPx) levels were assessed. These men were subjected to varicocele surgical repair and were followed up for 3 months. Post-operatively, the mean seminal SIRT1, GPx levels showed significant increases and the mean MDA level showed significant decrease compared to the pre-operative levels linked to improved sperm parameters. The mean seminal SIRT1, GPx, MDA levels showed more significant improvement in grade III varicocele cases compared to grade II cases after surgical repair. Seminal SIRT1 levels showed significant positive correlations with sperm concentration, sperm motility, sperm normal morphology, seminal GPx levels and a significant negative correlation with seminal MDA levels. It could be concluded that seminal SIRT1 is significantly decreased in infertile OAT men with varicocele after its surgical repair linked to improved sperm parameters as well as seminal OS.     

Seminal cyclooxygenase relationship with oxidative stress in infertile oligoasthenoteratozoospermic men with varicocele

This study aimed to assess the relation of seminal cyclooxygenase COX‐1, COX‐2 with oxidative stress in infertile oligoasthenoteratozoospermic (OAT) men with varicocele (Vx). In all, 128 men were allocated into fertile men, fertile men with Vx, infertile OAT men without Vx and infertile OAT men with Vx. They were subjected to history taking, clinical examination and semen analysis. Also, seminal COX‐1, COX‐2, malondialdehyde (MDA) and glutathione peroxidase (GPx) were estimated. Mean levels of seminal COX‐1, COX‐2 were over‐expressed, the mean level of seminal MDA was significantly increased, and the mean level of seminal GPx was significantly decreased in infertile OAT men with Vx compared with other groups. Seminal COX‐1 and COX‐2 were over‐expressed in cases with Vx grade III compared with Vx grades I, II cases and in cases with bilateral Vx compared with unilateral Vx. There was significant negative correlation between seminal COX‐1 and COX‐2 with sperm concentration, sperm motility, sperm normal morphology, seminal GPx and significant positive correlation with seminal MDA. It is concluded that seminal COX‐1 and COX‐2 are over‐expressed in infertile OAT men with Vx compared with fertile men with/without and infertile OAT men without Vx being associated with oxidative stress, Vx grade and Vx laterality.     

Decreased prostate-specific membrane antigen levels in the seminal plasma of oligoasthenoteratozoospermic men

Prostate-specific membrane antigen (PSMA) is a transmembrane glycoprotein with glutamate carboxypeptidase activity. However, its precise function in the prostate, prostasomes and seminal plasma with regard to male fertility remains unknown. This study was conducted to investigate the seminal plasma PSMA levels in fertile men and patients with oligoasthenoteratozoospermia (OAT) and to analyse its association with sperm parameters. Twenty fertile men and twenty patients admitted at the urology clinic of our institution with the diagnosis of OAT were included in the study. Following semen analysis, seminal plasma was isolated from semen ejaculates. PSMA concentrations in the seminal plasma were determined by ELISA. The correlations between seminal PSMA concentrations and semen parameters were statistically analysed. Seminal plasma PSMA concentration was significantly lower in OAT patients compared to fertile controls (p < .01). In fertile men, PSMA concentration was significantly correlated with the sperm concentration (r = −.481, p < .05), whereas in the patient group no statistically significant correlation was found between the sperm parameters and seminal PSMA level. This is the first study in the literature to investigate PSMA levels in the seminal plasma from infertile men. Decreased levels of seminal plasma PSMA might suggest a role for compromised prostasome function in the pathogenesis of OAT syndrome.     

The micronutrient supplements,zinc sulphate and folic acid,did not ameliorate sperm functional parameters in oligoasthenoteratozoospermic men

We investigated the effects of folic acid and zinc sulphate supplementation on the improvement of sperm function in subfertile oligoasthenoteratozoospermic (OAT) men. Eighty‐three OAT men participated in a 16‐week intervention randomised, double‐blind clinical trial with daily treatment of folic acid (5 mg day^?1) and zinc sulphate (220 mg day^?1), or placebo. Before and after treatment, semen and blood samples were obtained for determining sperm concentration, motility, and morphology, sperm viability, sperm mitochondrial function, sperm chromatin status using toluidine blue, aniline blue, acridine orange and chromomycin A₃ staining; and semen and blood folate, zinc, B₁₂, total antioxidant capacity ( TAC) and malondialdehyde (MDA) concentrations. Sperm concentration (×10⁶ ml^?1) increased in subfertile men receiving the combined treatment of folic acid and zinc sulphate and also in the group receiving only folic acid treatment; however, it was not statistically significant (P = 0.056 and P = 0.05, respectively). Sperm chromatin integrity (%) increased significantly in subfertile men receiving only zinc sulphate treatment (P = 0.048). However, this improvement in sperm quality was not significant after adjusting placebo effect. This study showed that zinc sulphate and folic acid supplementation did not ameliorate sperm quality in infertile men with severely compromised sperm parameters, OAT. Male infertility is a multifactorial disorder, and also nutritional factors play an important role in results of administration of supplementation on sperm parameters. However, these results should be confirmed by multiple studies in larger populations of OAT men.     

Oxidative stress status and sperm DNA fragmentation in fertile and infertile men

Evidence suggests that disturbing the balance between reactive oxygen species levels and antioxidant contents in seminal plasma leads to oxidative stress resulting in male infertility. This study was carried out to identifying clinical significance of seminal oxidative stress and sperm DNA fragmentation in treatment strategies of male infertility in southwest Iran. Sperm parameters, lipid peroxidation and activity of antioxidant enzymes were assessed in fertile (n = 105) and infertile (n = 112) men. Malondialdehyde (MDA) levels in seminal plasma were found to be higher significantly (p < .001) in patients. Superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities in seminal plasma were significantly (p < .001) lower in infertile men. Significant negative correlations were observed between MDA levels and sperm motility and normal morphology. Spermatozoa with fragmented DNA were higher (p < .001) in infertile men and significantly correlated with MDA levels and SOD and GPx activities. MDA of 4.2 nmol/ml, SOD of 4.89 U/ml and GPx of 329.6 mU/ml were optimum cut‐off limits to discriminate infertile patients from fertile men. The results show the leading role of oxidative stress in aetiology of male infertility in southwest Iran and indicate that evaluation of seminal antioxidant status and DNA integrity can be helpful in men attending infertility clinics during fertility assessment.     

The impact of genetic polymorphisms,diltiazem, and demographic variables on everolimus trough concentrations in lung transplant recipients

Everolimus (EVR) has inter‐individual pharmacokinetic (PK) variability and a narrow therapeutic index. The study objective was to determine whether genetic polymorphisms, co‐medications, and/or demographic variables accounted for inter‐individual variability in EVR PK in lung transplant recipients (LTxR). LTxR were genotyped for ABCB1 c.1236C>T, ABCB1 c.2677G>T/A, ABCB1 c.3435C>T, CYP3A4*1B, CYP3A5*3, CYP2C8*2/*3/*4, and pregnane X receptor (NR1I2) c.44477T>C, c.63396C>T, c.69789A>G polymorphisms. The primary outcome was the difference in dose‐adjusted EVR levels (EVR L/D) between ABCB1 diplotype groups (2 vs. 1 vs. 0 copies of the 1236C/2677G/3435C haplotype). Sixty‐five LTxR were included. There was no significant difference in EVR L/D between ABCB1 CGC diplotype groups (CGC/CGC = 2.4 ± 1.1 [n = 9] vs. CGC/XXX = 2.5 ± 1.7 [n = 36] vs. XXX/XXX = 2.7 ± 1.7 ng/mL per mg/d [n = 20]; p = 0.9). CYP3A5*3, CYP3A4*1B, CYP2C8*3/*4, and NR1I2 polymorphisms were not associated with EVR L/D. EVR L/D was 3.4 ± 1.7 in LTxR receiving diltiazem (DILT) vs. 1.8 ± 1.1 ng/mL per mg/d in LTxR not receiving DILT (p <0.001). Demographic variables, including cystic fibrosis, were not associated with EVR PK. DILT use increased EVR L/D, but selected polymorphisms in ABCB1, CYP3A5, CYP3A4, CYP2C8, and NR1I2 did not affect EVR L/D in LTxR. Genotyping LTxR for these polymorphisms is unlikely to aid clinicians in optimizing EVR therapy.     

Effect of omega-3 polyunsaturated fatty acid supplementation on semen profile and enzymatic anti-oxidant capacity of seminal plasma in infertile men with idiopathic oligoasthenoteratospermia: a double-blind, placebo-controlled, randomised study

Effective medical treatments of infertile men with idiopathic oligoasthenoteratospermia (OAT) have yet to be determined. This study considered two major aims: (i) to measure the changes in semen parameters, omega‐3 fatty acids (FA) compositions and anti‐oxidant activity; (ii) to determine if the administration of omega‐3 FA affect semen quality in infertile men with OAT. Two hundred thirty‐eight infertile men with idiopathic OAT were randomised to eicosapentaenoic (EPA) and docosahexaenoic acids (DHA), 1.84 g per day (EPAX 5500TG; Lysaker, Norway), or placebo for 32 weeks. The semen parameters were assessed according to WHO criteria, and the EPA and DHA concentrations were determined in red blood cells (RBCs), seminal plasma and sperm cells at baseline and 32‐week treatment period. Of randomised subjects, 211 (88.7%) completed the full 32‐week randomisation period. The anti‐oxidant status of seminal plasma was also evaluated by measuring the superoxide dismutase (SOD) and catalase‐like activity. In the total group of participants, all EPA and DHA levels in RBC, and seminal plasma, were statistically significantly correlated with those in spermatozoa (both P = 0.001). A significant improvement of sperm cell total count (from 38.7 ± 8.7 ′ 10⁶ to 61.7 ± 11.2 ′ 10⁶, P = 0.001) and sperm cell concentration (from 15.6 ± 4.1 ′ 10⁶ per ml to 28.7 ± 4.4 ′ 10⁶ per ml, P = 0.001) was observed in the omega‐3 group. A significant positive correlation was found between the EPA and DHA in seminal plasma and the semen parameters. Seminal plasma EPA and DHA concentrations were positively correlated with seminal plasma SOD‐like and catalase‐like activity (both P = 0.001). In seminal plasma, both SOD‐like and catalase‐like activity were positively correlated with sperm count, sperm motility, and sperm morphology. Oligoasthenoteratospermic men with low levels of EPA and DHA may benefit from omega‐3 FA supplementation. Further studies are warranted to shed more light on this important issue.     

Relationship of semen hyperviscosity with IL‐6, TNF‐α, IL‐10 and ROS production in seminal plasma of infertile patients with prostatitis and prostato‐vesiculitis

Changes in levels of oxidative damage products in semen and their relationship to seminal fluid viscosity (SFV) have recently received increasing research interest. We analysed whether SFV was associated with ROS generation, levels of cytokines TNF‐alpha (TNF‐α), IL‐6 and IL‐10 and seminal leucocyte concentration, and whether ROS production was related to the extent of infections/inflammations at one (prostatitis) or two (prostato‐vesiculitis) male accessory glands. We studied 169 infertile patients, with chronic bacterial prostatitis (PR, n = 74) and/or bilateral prostato‐vesiculitis (PV, n = 95), as diagnosed by the ultrasound (US) criteria. Healthy fertile men (n = 42) served as controls. In the PV patient group, SFV, semen characteristics and ROS production had median values that were significantly higher than those found in PR patients and controls, although other sperm variables had values significantly lower than those found in PR patients or controls. In PV infertile patients, ROS generation and pro‐inflammatory cytokines levels were higher than those found in PR infertile patients and controls, although seminal IL‐10 levels in PV and PR patients were lower than those found in the controls. In PR patients, the levels of SFV were positively related to TNF‐α (r = 0.67; P < 0.01), fMLP‐stimulated ROS production in the 45% Percoll fraction (r = 0.687, P < 0.01) and the 90% Percoll fraction in basal condition (r = 0.695, P < 0.01), and after fMLP‐stimulation (r = 0.688, P < 0.01). Thus, our data indicated that seminal hyperviscosity is associated with increased oxidative stress in infertile men and increased pro‐inflammatory interleukins in patients with male accessory gland infection, more when the infection was extended to the seminal vesicles.     

The recipient CYP2D6 allele 4‐associated poor metabolizer status correlates with an early fibrosis development after liver transplantation

CYP2D6 is part of the cytochrome P450 system, which catalyzes biotransformation of endogenous substrates and xenobiotics. Approximately 10% of the Caucasian population has two null alleles, resulting in a poor metabolizer (PM) status. Mostly, allele four (CYP2D6*4) is responsible for the PM status, which is suspected to be associated with an accelerated fibrosis progression (FP). The aim of the present study was to analyze the role of the CYP2D6*4 genotype for FP after liver transplantation (LT). Genotypes were determined in liver biopsies (donor) and peripheral blood (recipient) by fluorescence resonance energy transfer. Data were correlated with clinical variables and risk factors for fibrosis. We analyzed 517 LTs performed between 1997 and 2009. Overall donor and recipient allele frequencies were comparable (18.0%, 20.5%; P = 0.43). The donor genotype did not correlate with FP. In contrast, recipients carrying CYP2D6*4, showed a significant higher risk for an accelerated FP (P = 0.011) in HCV positive (P = 0.038) and HCV negative patients (P = 0.033). Results were confirmed by multivariate analysis (Hazard ratio 1.65; P = 0.001). The CYP2D6*4‐associated PM status of the donor liver seems to have no influence on FP after LT. Recipients, carrying the allele, have an elevated risk for an accelerated FP.     

Effect of Coenzyme Q10 supplementation on antioxidant enzymes activity and oxidative stress of seminal plasma: a double‐blind randomised clinical trial

Low seminal plasma concentrations of coenzyme Q10 (CoQ10) have been correlated with impaired sperm parameters, but the exact mechanism remains of dominating interest. This randomised, placebo‐controlled study examined the effect of CoQ10 on catalase, superoxide dismutase (SOD) and F₂‐isoprostanes in seminal plasma in infertile men and their relation with CoQ10 concentration. Sixty infertile men with idiopathic oligoasthenoteratozoospermia (OAT) were randomised to receive 200 mg d^?1 of CoQ10 or placebo for 3 months. 47 persons of them completed the study. Semen analysis, anthropometric measurements, diet and physical activity assessment were performed for subjects before and after treatment. Independent and paired t‐test, chi‐square test and ancova were compared outcomes of supplementation between two groups. CoQ10 levels increased from 44.74 ± 36.47 to 68.17 ± 42.41 ng ml^?1 following supplementation in CoQ10 (P < 0.001). CoQ10 group had higher catalase and SOD activity than the placebo group. There was a significant positive correlation between CoQ10 concentration and normal sperm morphology (P = 0.037), catalase (P = 0.041) and SOD (P < 0.001). Significant difference was shown between the mean of changes in seminal plasma 8‐isoprostane in two groups (P = 0.003) after supplementation. Three‐month supplementation with CoQ10 in OAT infertile men can attenuate oxidative stress in seminal plasma and improve semen parameters and antioxidant enzymes activity.     

Total antioxidant status and lipid peroxidation with and without in vitro zinc supplementation in infertile men

The aim of this study was to assess the total antioxidant capacity (TAC) and malondialdehyde (MDA) level in infertile men with asthenozoospermia and asthenoteratozoospermia compared to fertile donors, and to examine the effect of zinc on sperm lipid peroxidation and antioxidant status in infertile and fertile men. Semen samples provided by infertile men (n = 38) and fertile donors (controls; n = 12) were exposed to 6 mmol/L of zinc for 2 hr at 37°C. After semen analysis, lipid peroxidation was detected by MDA assay and seminal TAC was assessed by colorimetric method using TAS (total antioxidant status) Kit. TAC was significantly lower in infertile group compared to controls (p = .037). However, lipid peroxidation did not alter in infertile patients compared to controls (p > .05). After in vitro incubation of samples with zinc, a significant increase in TAC level was found only in infertile men (p < .001). Meanwhile, zinc had no effect on sperm lipid peroxidation in both fertile and infertile men (p > .05). Our data indicate that antioxidant treatment based on zinc in vitro supplementation may be helpful to enhance the rate of seminal antioxidant status in infertile men; however, it does not prevent sperm lipid peroxidation.     

Heme oxygenase enzyme activity in seminal plasma of oligoasthenoteratozoospermic males with varicocele

This work aimed to assess seminal plasma heme oxygenase (HO) enzyme activity in oligoasthenoteratozoospermia (OAT) males with varicocele. Ninety‐three men were divided according to their sperm count and clinical examination into: healthy fertile controls (n = 34), OAT without varicocele (n = 37) and OAT associated with varicocele (n = 22). They were subjected to semen analysis and estimation of seminal plasma HO enzyme activity in the form of bilirubin concentration. Seminal plasma HO enzyme activity decreased significantly in OAT cases compared with controls. Seminal plasma HO in OAT cases associated with varicocele decreased significantly compared with OAT cases without varicocele and healthy controls (mean ± SD; 109.2 ± 29.5, 283.6 ± 88.4, 669.5 ± 236.1 nMol bilirubin/mg ptn/min, P < 0.001). There was positive correlation between seminal plasma HO enzyme activity and sperm concentration, per cent of motile spermatozoa, number of motile spermatozoas ml^?1 and significant negative correlation with sperm abnormal forms per cent. It is concluded that varicocele has a negative impact on seminal HO enzyme activity. Therefore, improved seminal picture after correcting varicocele repair might be related, in part, to improved HO action(s).     

Assessment of seminal mast cells in infertile men with varicocele after surgical repair

This study aimed to assess seminal mast cells in infertile men associated with varicocele (Vx) pre‐ and post‐surgical repair. Forty‐five infertile men associated with Vx were subjected to history taking and clinical examination. In addition, semen parameters and seminal mast cells stained with 1% toluidine blue were estimated pre‐varicocelectomy and three months post‐varicocelectomy. Vx surgical repair revealed a significant improvement in the mean sperm concentration, progressive sperm motility, total sperm motility and sperm abnormal morphology and a significant decrement in seminal mast cells (mean ± SD, 3.56 ± 2.23 cells per high‐power field (HPF) vs. 2.22 ± 1.06 cells per HPF, p = .01). The pre‐operative mean mast cell count demonstrated significant increases in cases with Vx grade III compared with other Vx grades and in cases with bilateral Vx compared with unilateral Vx cases. Seminal mast cells demonstrated a significant correlation with sperm concentration, progressive sperm motility and total sperm motility and a nonsignificant correlation with age and sperm abnormal morphology. It is concluded that seminal mast cells decrease significantly in infertile men with Vx after surgical repair showing a significant negative correlation with sperm concentration, progressive sperm motility and total sperm motility.     

Anti-interleukin-6 antibody clazakizumab in late antibody-mediated kidney transplant rejection: effect on cytochrome P450 drug metabolism

Targeting interleukin-6 (IL-6) is a promising strategy to counteract antibody-mediated rejection (ABMR). In inflammatory states, IL-6 antagonism was shown to modulate cytochrome P450 (CYP), but its impact on drug metabolism in ABMR treatment was not addressed so far. We report a sub-study of a phase 2 trial of anti-IL-6 antibody clazakizumab in late ABMR (ClinicalTrials.gov, NCT03444103). Twenty kidney transplant recipients were randomized to clazakizumab versus placebo (4-weekly doses; 12 weeks), followed by a 9-month extension where all recipients received clazakizumab. To study CYP2C19/CYP3A4 metabolism, we administered pantoprazole (20 mg intravenously) at prespecified time points. Dose-adjusted C₀ levels (C₀/D ratio) of tacrolimus (n = 13) and cyclosporin A (CyA, n = 6) were monitored at 4-weekly intervals. IL-6 and C-reactive protein were not elevated at baseline, the latter was then suppressed to undetectable levels under clazakizumab. IL-6 blockade had no clinically meaningful impact on pantoprazole pharmacokinetics (area under the curve; baseline versus week 52: 3.16 [2.21–7.84] versus 4.22 [1.99–8.18] μg/ml*h, P = 0.36) or calcineurin inhibitor C₀/D ratios (tacrolimus: 1.49 [1.17–3.20] versus 1.37 [0.98–2.42] ng/ml/mg, P = 0.21; CyA: 0.69 [0.57–0.85] versus 1.08 [0.52–1.38] ng/ml/mg, P = 0.47). We conclude that IL-6 blockade in ABMR – in absence of systemic inflammation – may have no meaningful effect on CYP metabolism.     

Determinants of the Magnitude of Interaction Between Tacrolimus and Voriconazole/Posaconazole in Solid Organ Recipients

Administration of azole antifungals to tacrolimus‐treated solid organ recipients results in a major drug–drug interaction characterized by increased exposure to tacrolimus. The magnitude of this interaction is highly variable but cannot currently be predicted. We performed a retrospective analysis of 126 solid organ recipients (95 lung, 31 kidney) co‐treated with tacrolimus and voriconazole (n = 100) or posaconazole (n = 26). Predictors of the change in tacrolimus dose‐corrected trough concentrations (C/D) between baseline and tacrolimus–azole co‐therapy were assessed using linear mixed modeling. Patients were genotyped for relevant polymorphisms in CYP3A4, CYP3A5, MDR1, CYP2C19, POR, and UGT1A4. Tacrolimus C/D increased by a factor 5.0 ± 2.7 (range 1.0–20.2) for voriconazole and 4.4 ± 2.6 (range 0.9–18.0) for posaconazole, suggesting that a 66% dose reduction is insufficient for the majority of patients. Change in C/D was blunted in CYP3A5 expressors (estimated effect: ‐43%, p = 0.017) and affected by hematocrit (+8% per %, p = 0.004), baseline C/D (‐14% per 100% increase, p < 0.001), and age (+1%, p = 0.008). However, the final model explained only 22% of interindividual variability in C/D change. In conclusion, CYP3A5 genotype and several clinical variables were identified as modulators of the tacrolimus–azole interaction, but these did not permit accurate predictions in individual patients.     

Assessment of seminal granulysin in infertile men with varicocele

Varicocele has a common association with male infertility, but its exact role is still debated. Apoptosis has been suggested as one of the mechanisms of varicocele‐associated infertility. Granulysin is a molecule that plays a role in apoptosis with no previous study about its role in male infertility. This case‐controlled study aimed to assess seminal plasma granulysin level in infertile patients with varicocele. This study involved 90 men that were allocated into fertile normozoospermic men (n = 20), infertile men without varicocele (n = 30) and infertile men with varicocele (n = 40). These men were subjected to history taking, clinical examination, semen analysis and estimation of seminal granulysin. In general, seminal granulysin level was significantly elevated in infertile men compared with fertile men. Infertile men with varicocele showed significantly higher seminal granulysin compared with infertile men without varicocele, in bilateral varicocele cases and in grade III varicocele. Seminal granulysin level was negatively correlated with sperm concentration, sperm motility, sperm normal forms percentage and testicular volumes. It is concluded that increased seminal granulysin has a negative impact on spermatogenesis in infertile men in general and in infertile men associated with varicocele in particular.