Intratesticular Testosterone Levels Research Articles

Breed Differences in Serum Testosterone Levels of Male Pigs Are Highly Correlated with Differences in Testicular mRNA Levels of Enzymes and Proteins Involved in Testosterone Biosynthesis Process.

To clarify the causes of breed differences in serum testosterone levels of male pigs, which affect the mRNA expression of drug metabolizing enzymes and drug transporters in the liver and kidney, we focused on testicular enzymes and proteins involved in testosterone biosynthesis process and comparatively examined their mRNA levels by real time RT-PCR among low serum testosterone-type Landrace pigs and high serum testosterone-type Meishan and Landrace/Meishan-crossbreed (LM and ML) pigs. Testicular mRNA levels of the enzymes (3-hydroxy-3-methylglutaryl-CoA synthase 1 and 3-hydroxy-3-methylglutaryl-CoA reductase) and proteins (low density lipoprotein receptor and scavenger receptor class B member 1) affecting intracellular levels of cholesterol, a precursor of testosterone, were 2-5-fold higher in Meishan, LM and ML pigs than in Landrace pigs. Likewise, the mRNA levels of steroidogenic acute regulatory protein, which imports cholesterol to the inner mitochondrial membrane, and of testosterone biosynthesis enzymes (CYP11A1 and CYP17A1) were over 10-fold and approximately 3-fold higher, respectively, in Meishan, LM and ML pigs than in Landrace pigs. Furthermore, positive correlations between those mRNA levels and serum testosterone levels were observed. Despite large breed differences in testicular mRNA levels described above, no significant breed differences in intratesticular testosterone levels were observed. The present findings strongly suggest that breed differences in serum testosterone levels of male pigs are probably, at least in part, caused by differences in testicular mRNA levels of enzymes and proteins involved in testosterone biosynthesis process and by differences in the levels of testosterone released from testes.

The correlation of intratesticular testosterone with body mass index and smoking

Intratesticular testosterone plays a crucial role in male reproductive function and overall health. Body Mass Index (BMI) and smoking are known lifestyle factors that can influence hormonal balances. Elevated BMI has been associated with alterations in testosterone levels, impacting male fertility and endocrine function. The aim was to examine the concurrent relationships between intratesticular testosterone, BMI, and smoking habits. Biopsies of the testicles were taken from 32 patients with non-obstructive azoospermia. Testicular sperm extraction (TESE) under spinal or general anesthesia was performed after a comprehensive history, physical examination, and investigations. After performing a minced biopsy and centrifuging the fluid, testicular fluid was extracted. The highest intratesticular testosterone levels were in normal patients and lowest levels in over weight patient; on the contrary the highest serum 17-hydroxyprogesterone levels were found in over weight patient and lowest levels in normal weight patients; There were insignificantly higher both intratesticular testosterone and 17- hydroxyprogesterone levels in non-smokers. In conclusion, the statistical analysis revealed that there is an insignificantly low correlation between intratesticular testosterone levels, BMI, and smoking.

Insights from the maternal lineage of the F2 generation after exposure to an environmentally relevant dose of benzo(a)pyrene in the male rats of F0 generation.

Benzo(a)pyrene (BaP) is a substance with the potential to induce endocrine disruption in the F0 generation and cause adverse multigenerational effects (F1 generation) for reproductive parameters in rats. The objective of this study was to investigate the occurrence of transgenerational inheritance in the reproductive aspects of male and female rats belonging to the F2 generation (MF2). This investigation was conducted following the exposure of male rats from the F0 generation to BaP to assess potential effects on subsequent generation from the maternal lineage (F1). For that, juvenile male Wistar rats (F0) were orally exposed to BaP (0.1µg/kg/day) for 31 consecutive days. In adulthood, they were mated with untreated females to obtain female offspring (F1), which later produced the MF2. In the MF2 generation, both males and females exhibited increased body weight on postnatal day (PND) 1. In MF2 males, we observed delayed preputial separation, altered pup weight, reduced levels of follicle-stimulating hormone (FSH), increased intratesticular testosterone levels, decreased type A sperm, epididymal disturbances, reduced 5 α-reductase activity, increased testicular proliferation, and alterations in testicular antioxidant enzymes. In MF2 females, we noted morphological uterine enlargement, reduced sexual activity, and decreased progesterone levels. The findings suggest that the alterations observed in both MF2 males and females can be attributed to modifications in the sperm from F0 generation, which were subsequently transmitted to F1 females and MF2 generation due to BaP exposure.

Switching from high-fat diet to normal diet ameliorate BTB integrity and improve fertility potential in obese male mice

Obesity is a prominent risk factor for male infertility, and a high-fat diet is an important cause of obesity. Therefore, diet control can reduce body weight and regulate blood glucose and lipids, but it remains unclear whether it can improve male fertility and its mechanism. This study explores the effects of switching from a high-fat diet (HFD) to a normal diet (ND) on the fertility potential of obese male mice and its related mechanisms. In our study, male mice were separated into three groups: normal diet group (NN), continuous high-fat diet group (HH), and return to normal diet group (HN). The reproductive potential of mice was tested through cohabitation. Enzymatic methods and ELISA assays were used to measure metabolic indicators, follicle-stimulating hormone (FSH) levels and intratesticular testosterone levels. Transmission electron microscopy and immunofluorescence with biotin tracers assessed the integrity of the blood-testis barrier (BTB). Malondialdehyde (MDA), superoxide dismutase (SOD), and reactive oxygen species (ROS) were inspected for the assessment of oxidative stress. The expression and localization of BTB-related proteins were detected through the immunoblot and immunofluorescence. The mice in the high-fat diet group indicated increased body weight and epididymal fat weight, elevated serum TC, HDL, LDL, and glucose, decreased serum FSH, and dramatic lipid deposition in the testicular interstitium. Analysis of fertility potential revealed that the fertility rate of female mice and the number of pups per litter in the HH group were significantly reduced. After the fat intake was controlled by switching to a normal diet, body weight and epididymal fat weight were significantly reduced, serum glucose and lipid levels were lowered, serum FSH level was elevated and the deposition of interstitial lipids in the testicles was also decreased. Most significantly, the number of offspring of male mice returning to a normal diet was significantly increased. Following further mechanistic analysis, the mice in the sustained high-fat diet group had disrupted testicular BTB integrity, elevated levels of oxidative stress, and abnormal expression of BTB-related proteins, whereas the restoration of the normal diet significantly ameliorated the above indicators in the mice. Our study confirms diet control by switching from a high-fat diet to a normal diet can effectively reduce body weight, ameliorate testicular lipotoxicity and BTB integrity in male mice, and improve fertility potential, providing an effective treatment option for obese male infertility.

Attenuation of doxorubicin-induced hypothalamic-pituitary-testicular axis dysfunction by diphenyl diselenide involves suppression of hormonal deficits, oxido-inflammatory stress and caspase 3 activity in rats

BackgroundDoxorubicin (DOX) is one of the popular anti-cancer drugs in the world and several literatures have implicated it in various toxicities especially cardiotoxicity and reproductive toxicity. Diphenyl diselenide (DPDS) is well acknowledged for its compelling pharmacological effects in numerous disease models and chemically-mediated toxicity. This study was carried out to investigate the effect of DPDS on DOX-induced changes in the reproductive indices of male Wistar rats. MethodsRats were intraperitoneally injected with 7.5 mg/kg body weight of DOX alone once followed by treatment with DPDS at 5 and 10 mg/kg for seven successive days. Excised hypothalamus, testes and epididymis were processed for biochemical and histological analyses. ResultsDPDS treatment significantly (p < 0.05) abated DOX-induced oxidative damage by decreasing the levels of oxidative stress indices such as hydrogen peroxide, reactive oxygen and nitrogen species, and lipid peroxidation with a respective improvement in the level of glutathione in the hypothalamic, testicular and epididymal tissues of DOX-treated rats. The activities of antioxidant enzymes such as catalase, superoxide dismutase, glutathione S-transferase and glutathione peroxidase were upregulated in the DPDS co-treated group. DPDS co-treatment alleviates the burden of DOX-induced inflammation by significant reductions in myeloperoxidase activity, levels of nitric oxide and tumor necrosis factor alpha with concomitant decline in the activity of caspase-3, an apoptotic biomarker. Consequently, significant improvement in the spermiogram, levels of reproductive hormones (follicle stimulating hormone, luteinizing hormone, prolactin, serum testosterone and intra-testicular testosterone) levels in the DPDS co-treatment group in comparison to DOX alone-treated group were observed. Histology results of the testes and epididymis showed that DPDS significantly alleviated pathological lesions induced by DOX in the animals. ConclusionDPDS may modulate reproductive toxicity associated with DOX therapy in male cancer patients.

Effect of anti-estrogen and anti-progesterone on spermatogenesis, testosterone production and expression of steroidogenic enzyme genes in adult male rats.

The present study was planned to investigate the anti-spermatogenic and anti-steroidogenic effects of Clomiphene Citrate (CC) an anti-estrogen and Mifepristone (MT) an anti-progesterone in the testis of male rats. Following the oral administration of 1.0mg and 5.0mg/kg b.w/day of each for the duration of 30 and 60 days, quantitation of spermatogenesis, RIA for serum and intra-testicular testosterone levels, western blotting and RT-PCR for expression of StAR, 3β-HSD and P450arom enzymes in the testis was done. Clomiphene Citrate at 5.0mg/kg b.w/day for 60 days significantly reduced testosterone (T) levels however the effect was not significant with the lower doses. Reproductive parameters in animals treated by Mifepristone remained mostly unaffected, however, a significant decline in testosterone levels and altered expression of selected genes was observed in 5.0mg for the 30d treatment group. Clomiphene Citrate at higher doses affected the weights of the testis and secondary sex organs. Seminiferous tubules revealed hypo-spermatogenesis with a significant decrease in the number of maturing germ cells and a reduction in tubular diameter. Attenuation in serum testosterone was associated with the downregulation of expression in StAR, 3β-HSD, and P450arom mRNA and protein levels in the testis even after 30 d of CC administration. The results indicate that the anti-estrogen (Clomiphene Citrate) but not anti-progesterone (Mifepristone) induces hypo-spermatogenesis in rats which are associated with a downregulation of expression of two of the steroidogenic enzymes, 3β-HSD and P450arom mRNA and StAR protein.

(253) Comparative Effectiveness in Testosterone Levels and Sperm Parameters of Medical Treatments for Primary Infertility and Testicular Deficiency

Abstract Introduction The goal of treatment for infertile men with testosterone deficiency is to improve intratesticular androgen levels with the aim of increasing the last step of maturation in spermatogenesis. Medical therapy for male factor infertility remains largely empiric and relies on off-label use of medications known to increase intratesticular testosterone levels, such as selective estrogen receptor modulators (clomiphene citrate and enclomiphene citrate) and gonadotropins (human chorionic gonadotropin). There is scarce data of whether the above-mentioned treatment options offer different success rates in improving testosterone levels and sperm parameters. Objective To compare the improvement in total testosterone, intratesticular testosterone, and sperm parameters between patients receiving medical treatment with clomiphene citrate (CC), enclomiphene citrate (ECC), or clomiphene citrate + human chorionic gonadotropin (HCG). Methods We conducted a retrospective study from 2018 to 2022 of men with primary infertility, testicular deficiency, and secondary hypogonadism receiving ECC, CC or CC+HCG for at least 3 months. Among the different treatment groups, we assessed baseline and follow-up total testosterone, 17-hydroxyprogesterone (17-OH), semen parameter(s), and demographics. Semen quality improvement was based on assisted reproduction eligibility according to the total motile sperm count (TMSC) value: in-vitro fertilization ( 9 million). Intratesticular testosterone upgrading was based on 17-OH level, with expected values being ≥55 ng/dL. Variables were compared using paired t-test and ANOVA. Results A total of 18 men received ECC, 19 received CC and 9 received CC+HCG. Mean age was 41.1±2.28 years in the ECC group, 40.62±1.17 in the CC group, and 45±2.75 in the CC+HCG group (p=0.458). Overall, the mean follow-up was 3.64 ±2.14 months (p=0.242). The 3 treatment groups exhibited a statistically significant increase in total testosterone (table 1), but only the CC and CC+HCG groups had a statistically significant improvement in the level of 17-OH (p 9 million. Conclusions Our study showed that ECC, CC and CC+HCG are effective treatment regimens for improving total testosterone without negatively affecting spermatogenesis. Nonetheless, their effects on intratesticular testosterone and sperm parameters varied, suggesting that choosing the best treatment option for improving sperm parameters should be an individualized patient decision. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: Acerus, Boston Scientific, Endo Pharmaceuticals and Coloplast.

Selenized glucose improves rat semen quality by improving the gut microbiota and serum metabolome.

Selenium (Se), a well-known antioxidant, is important for male fertility and sperm quality. The gut microbiota is involved in vital activities and cross-talk between reproduction and the gut axis. It is still unclear whether the gut microbiota mediates the impact of selenium on semen quality, and what the underlying mechanisms may be. A selenized glucose (SeGlu) derivative is a novel organic Se compound. After 7 days of acclimation, the Sprague-Dawley (SD) male rats (230 g, 6 weeks) were divided into three drinking groups: deionized water group (CK), SeGlu 0.15 group (0.15 mg Se per L), and SeGlu 0.4 group (0.4 mg Se per L). All animals were euthanized 30 days post-treatment. Serum and intratesticular testosterone and semen parameters were measured. Metagenomic and non-targeted metabolomic approaches were used to study the effects of SeGlu on the gut microbiota and serum metabolites of rats. In both the SeGlu 0.15 Group and the SeGlu 0.4 Group, we found a significant increase in seminiferous epithelium thickness. While the SeGlu 0.4 Group had a tendency to increase with insignificant difference, the SeGlu 0.15 Group significantly improved the sperm viability, survival rate, and seminal plasma fructose. SeGlu had no effect on intratesticular testosterone levels, or abnormal sperm counts. Measured serum testosterone levels using ELISA and LC-MS, which showed a decreasing trend. ELISA did not reveal significant differences, but LC-MS indicated a significant decrease in SeGlu 0.4 group. Meanwhile, the SeGlu 0.15 Group reduced the abundance of harmful bacteria such as Rikenella, Barnesiella, Tenacibaculum, and Aeromonas while increasing the abundance of beneficial microbiota such as Intestinimonas, Christensenella, Coprococcus, and Butyrivibrio. Linear discriminant analysis Effect Size (LEfSe) identified the SeGlu 0.15 group's feature genera as Roseburia, Clostridium, Ruminococcus, and Eubacterium. Serum metabolites showed that the SeGlu 0.15 Group increased 5 beta-androstane-3,17-dione while decreasing estrone and 2-methoxyestradiol (2-MeOE2). In conclusion, the SeGlu 0.15 Group can significantly alter the levels of several sex hormones in serum, improve the quality of rats' sperm, and reduce harmful bacterial colonization. SeGlu 0.15 may be used as an effective dietary supplement.

The role of steroidogenic factor 1 (SF-1) in steroidogenic cell function of the testes and ovaries of mature mice.

The nuclear receptor steroidogenic factor 1 (SF-1) is essential for mature mouse gonad steroidogenic gene expression, for Leydig and Sertoli cell function, and depletion of SF-1 in steroidogenic cells of the testis compromises steroidogenesis, spermatogenesis and male fertility. Steroidogenic factor 1 (SF-1 or NR5A1) plays an essential role in the development of fetal gonads and regulates genes involved in steroid biosynthesis. Since SF-1 is expressed in multiple cell types in mouse gonads, we developed three novel conditional knockout (cKO) mouse models employing Cre-recombinase and floxed alleles of SF-1 (Nr5a1f/f) to identify its role in testes and ovaries of mature mice: Cytochrome P450 17α-hydroxylase (Cyp17Cre/+;Nr5a1f/f, Leydig and theca cell-specific), aromatase (Cyp19Cre/+;Nr5a1f/f, Sertoli and granulosa cell-specific), as well as a combination of both (Cyp17+Cyp19-Cre;Nr5a1f/f). Compared to control animals, Cyp19-Cre;Nr5a1f/f cKO males showed normal fertility and testicular function. The Cyp17Cre/+;Nr5a1f/f cKO males had smaller testis, with drastically reduced Leydig cell volumes and impaired steroidogenesis, though their reproductive performance remained comparable to controls. Some 50% of Cyp17Cre/++Cyp19Cre/+;Nr5a1f/f double-cKO (dKO) males were infertile, while the remaining 50% showed significantly reduced fertility. These dKO males also had smaller testis with degenerative seminiferous tubules, abnormal Leydig cell morphology and lower levels of intra-testicular testosterone. Abnormal Sertoli cell localization was noted in dKO testes, with increased Sox9, p27 and inhibin subunit ßb and decreased androgen receptor expression. Female mice from all genotypes showed normal reproductive capacity, though steroidogenic gene expression levels were significantly decreased in both Cyp17Cre/+;Nr5a1f/f cKO and dKO females. These results show the essential role of SF-1 in mature mouse gonad steroidogenic gene expression, for Leydig and Sertoli cell function, and that depletion SF-1 in all steroidogenic cells of the testis compromises steroidogenesis, spermatogenesis and male fertility.

Erkek İnfertilitesine Alternatif Farmakolojik Yaklaşım: Anti-Aromataz Bileşikler: Sistematik Derleme

Infertility is a reproductive system disease in which pregnancy does not occur despite long-term, regular and unprotected sexual intercourse. In the near future, it is estimated that approximately 15% of the world population will be affected by infertility and the majority of this will be male-induced infertility. In male infertility, 90% defective sperm production is effective and it is known that in infertile men, as a result of the increase in estrogen levels due to aromatase activity, the testosterone/estradiol ratio may decrease and spermatogenesis is impaired. Therefore, research on increasing intratesticular testosterone levels and improving impaired spermatogenesis has focused on aromatase inhibitors. However, since the efficacy and safety of aromatase inhibitors have not been clarified, it has been thought that anti-aromatase compounds with fewer side effects and stronger efficacy can be used as alternative therapeutic agents in the treatment of infertility. Phytoestrogens are estrogenic plant-derived compounds. Many have been shown to have aromatase inhibition, thereby increasing testosterone levels. In addition, it is known that there are different mechanisms that affect spermatogenesis apart from binding to estrogen receptors in their effects on the male reproductive system. Therefore, our aim is to review the latest developments and treatment approaches to natural polyphenolic compounds with anti-aromatase activity in male infertility. According to the literature, the most commonly used anti-aromatase compounds include resveratrol, quercetin, apigenin, and naringenin. All the compounds in this review were found to have positive effects on male infertility.

Linagliptin and Vitamin D3 Synergistically Rescue Testicular Steroidogenesis and Spermatogenesis in Cisplatin-Exposed Rats: The Crosstalk of Endoplasmic Reticulum Stress with NF-κB/iNOS Activation.

This study investigated the therapeutic effect of linagliptin and/or vitamin D3 on testicular steroidogenesis and spermatogenesis in cisplatin-exposed rats including their impact on endoplasmic reticulum (ER) stress and NF-κB/iNOS crosstalk. Cisplatin (7 mg/kg, IP) was injected into adult male albino rats which then were orally treated with drug vehicle, linagliptin (3 mg/kg/day), vitamin D3 (10 μg/kg/day) or both drugs for four weeks. Age-matched rats were used as the control group. Serum samples and testes were collected for further analyses. Cisplatin induced testicular weight loss, deteriorated testicular architecture, loss of germ cells and declined serum and intra-testicular testosterone levels, compared to the control group. There was down-regulation of steroidogenic markers including StAR, CYP11A1, HSD3b and HSD17b in cisplatin-exposed rats, compared with controls. Cisplatin-exposed rats showed up-regulation of ER stress markers in testicular tissue along with increased expression of NF-κB and iNOS in spermatogenic and Leydig cells. These perturbations were almost reversed by vitamin D3 or linagliptin. The combined therapy exerted a more remarkable effect on testicular dysfunction than either monotherapy. These findings suggest a novel therapeutic application for linagliptin combined with vitamin D3 to restore testicular architecture, aberrant steroidogenesis and spermatogenesis after cisplatin exposure. These effects may be attributed to suppression of ER stress and NF-kB/iNOS.

The predictive factors of successful sperm retrieval for men with Y chromosome AZFc microdeletion.

To identify key predictors for successful sperm retrieval in men with AZFc microdeletion. Totally, 71 infertile men with confirmed AZFc microdeletion were studied. For each patient, the endocrine profile including serum follicle stimulating hormone (FSH), luteinizing hormone, total testosterone, prolactin, and estradiol was recorded, along with intratesticular testosterone levels (ITT), age, and testicular size. The factors were further analyzed to determine the key predictors for successful sperm retrieval. Of the 71 men with AZFc microdeletion, 52 (73.2%) were classified as having non-obstructive azoospermia (NOA), 7 (9.9%) as having cryptozoospermia, and 12 (15.8%) as having severe oligoasthenoteratozoospermia. Of the 52 men with azoospermia, 47 received microdissection testicular sperm retrieval, and sperm retrieval was successful in 35 of those cases (74.5%). A significantly lower serum FSH (p = 0.03) was found in those patients from whom sperm could be successfully retrieved. The area under the receiving operating characteristic curve for FSH was determined to be 0.721. Using an FSH cutoff point of 12.95 mIU/mL, the model for predicting successful sperm retrieval was found to have 51.4% sensitivity, 83.3% specificity, 90.0% positive predictive value, and 37.0% negative predictive value. ITT levels were obtained from 7 NOA patients, the mean ITT and the mean ITT/serum testosterone ratio was 1932.8ng/ml and 567.2 in 6 men with successful sperm retrieval, whereas, in a patient with fail sperm retrieval, the levels were 2370ng/ml and 393.0. Men exhibiting AZFc microdeletion with discernible spermatogenesis from whom sperm was successfully retrieved by mTESE generally presented with relatively lower FSH levels.

Associations between isoflavone exposure and reproductive damage in adult males: evidence from human and model system studies†.

It is controversial whether exposure to isoflavones exerts male reproductive toxicity. The aim of this study was to investigate whether isoflavone exposure during adulthood could have deleterious impacts on male reproductive health by the cross-sectional study, animal experiments, and in vitro tests. In the cross-sectional study, we observed that urinary isoflavones were not significantly associated with semen quality including sperm concentrations, sperm count, progressive motility, and total motility, respectively. However, negative associations were found between plasma testosterone and urinary Σisoflavones, genistein, glycitein, and dihydrodaidzein. In the animal experiments, serum and intratesticular testosterone levels were decreased in mice exposed to several dosages of genistein. Genistein administration caused upregulation of estrogen receptor alpha and downregulation of cytochrome P45017A1 protein levels in testes of mice. In vitro tests showed that genistein caused a concentration-dependent inhibition of testosterone production by TM3 Leydig cells. Elevated protein expression of estrogen receptor alpha and decreased messenger RNA/protein level of cytochrome P45017A1 were also observed in genistein-treated cells. Protein level of cytochrome P45017A1 and testosterone concentration were significantly restored in the estrogen receptor alpha small interferring RNA-transfected cells, compared to cells that treated with genistein alone. The results demonstrate that exposure to isoflavones during adulthood may be associated with alterations of reproductive hormones. Particularly, genistein, which inhibits testosterone biosynthesis through upregulation of estrogen receptor alpha in Leydig cells of mice, might induce the disruption of testosterone production in human. The present study provides novel perspective into potential targets for male reproductive compromise induced by isoflavone exposure.

O-132 Is there an association between sDF index and serum testosterone in human follicle stimulating hormone alfa (r-hFSH alfa) treated males with idiopathic infertility?

Abstract Study question Is there correlation between testosterone serum levels and sperm DNA fragmentation (sDF) index before and after follicle-stimulating hormone (FSH) administration in male idiopathic infertility? Summary answer Correlation between testosterone and sDF was highlighted for the first time in FSH-treated men. Significant amelioration of conventional semen parameters and sDF index were confirmed. What is known already Testicular overstimulation is the yearned therapeutic goal when exogenous FSH is empirically administered in male idiopathic infertility. Although a robust physiological rationale theoretically supports the FSH use in male idiopathic infertility, useful markers to evaluate its efficacy are still far to be identified. Whether pregnancy outcomes remain the expected valuable endpoint for couple infertility treatment, the identification of reliable, and possibly early, markers of therapeutic response to FSH in males is mandatory. Randomized controlled clinical trials (RCTs) on this topic focused, as main outcomes of FSH treatment effectiveness, on testicular seminiferous component, not considering involvement of testosterone-secreting compartment. Study design, size, duration A retrospective post-hoc analysis of raw data extracted from two RCTs in which 148 idiopathic infertile men were treated with FSH. Participants/materials, setting, methods A retrospective post-hoc re-analysis was performed on raw data of RCTs in which idiopathic infertile men were treated with FSH and both testosterone serum levels and sDF were reported among primary and/or secondary endpoints. Additional data regarding couple infertility history, age, anthropometric variables, FSH treatment scheme and semen variables were included in a single dataset. Data were evaluated by logistic regression analyses. Main results and the role of chance Two RCTs were included accounting for 148 patients (median age 37, 25-52 years). After three months of FSH administration, a significant increase was observed in FSH levels (p &amp;lt; 0.001), inhibin B (p = 0.012), sperm concentration (p = 0.003), total sperm number (p = 0.021), progressive motility (p &amp;lt; 0.001) and normal sperm morphology (p &amp;lt; 0.001). Moreover, an overall sDF index reduction was confirmed after treatment (19.3±9.4 versus 16.4±6.8, p = 0.002). SDF was found significantly inversely related to sperm concentration both at baseline and after FSH treatment (Rho -0.325, p &amp;lt; 0.001 and Rho -0.316, p = 0.001, respectively). Interestingly, sDF index after treatment showed a significant inverse correlation with testosterone serum levels (Rho -0.327, p = 0.002). Multivariate stepwise linear regression analyses using sDF index as dependent variable identified testosterone as a predictor for sDF index change (p = 0.005). Similarly, logistic regression analysis highlighted testosterone and SHBG levels as predictive of sDF reduction after FSH administration (p = 0.043 and p = 0.005, respectively). Combining raw data of published RCTs investigating FSH administration to idiopathic infertile men, a significant amelioration of conventional semen parameters together with a reduction in sDF were confirmed. Intriguingly, a potential correlation between serum testosterone and sDF was highlighted for the first time. Limitations, reasons for caution Since the analysis was performed on raw data obtained in previous RCTs, heterogeneity among patients enrolled and evaluated should be considered interpreting these results. Moreover, a real and accurate evaluation of intratesticular testosterone levels, rather than serum levels should be more informative to the objective of the study. Wider implications of the findings The highlighted significant correlation between testosterone serum levels and sDF is opening a completely unexplored field in the possibility to identify early predictors of FSH therapy response in male idiopathic infertility. Trial registration number Not applicable

Recombinant gonadotropin therapy to improve spermatogenesis in nonobstructive azoospermic patients – A proof of concept study

ABSTRACTPurpose:Nonobstructive azoospermia (NOA) associated with primary spermatogenic failure is a common cause of male infertility usually considered untreatable; however, some reports have suggested that hormonal stimulation to boost the intra-testicular testosterone level and spermatogenesis might increase the chance of achieving pregnancy using homologous sperm.Materials and Methods:We report a series of eight NOA males who received long-term treatment with recombinant human chorionic gonadotropin twice a week for spermatogenesis stimulation. Six males received additional recombinant follicle-stimulating hormone (FSH) supplementation 150-225 IU twice weekly.Results:After recombinant gonadotropin therapy, viable spermatozoa were retrieved from the ejaculate in two patients and by testicular sperm aspiration (TESA) in another two subjects. Singleton spermatozoon retrieved from testes were frozen by vitrification on Cell-Sleeper devices. Two live births were obtained after intracytoplasmic sperm injection with ejaculated spermatozoa and one live birth and an ongoing pregnancy using thawed spermatozoa from TESA.Conclusion:Our proof-of-concept study indicates that hormonal therapy with recombinant gonadotropins could be considered in infertile men with NOA as an alternative to sperm donation. Large-scale studies are needed to substantiate hormone stimulation therapy with recombinant gonadotropins in routine clinical practice for this severe form of male infertility.

Clinical utility of serum 17-hydroxyprogesterone as a marker for medical therapy for male infertility: recommendations based on clinical scenarios.

Traditional serum hormone testing in the evaluation of male infertility consists of testosterone, follicle-stimulating hormone, luteinizing hormone, and estradiol. Based on these values, medical therapy is often initiated in an attempt to increase intratesticular testosterone levels and, in turn, promote spermatogenesis. While this hormone panel provides serum testosterone levels, it does not evaluate intratesticular testosterone, obviously an important factor that is critical for spermatogenesis. 17-hydroxyprogesterone (17-OHP) is an intermediate in the steroidal pathway of cholesterol to testosterone conversion that has recently demonstrated promise as an accurate serum biomarker for intratesticular testosterone. At present, 17-OHP has not been widely adopted as a clinical tool in the evaluation of male infertility, which likely stems, in part, from a lack of concrete indications for its use. In this review, we present five commonly encountered scenarios of male infertility where the utilization of 17-OHP has aided in the management and provided a more personalized approach to treatment.

Recombinant gonadotropin therapy to improve spermatogenesis in nonobstructive azoospermic patients - A proof of concept study.

Nonobstructive azoospermia (NOA) associated with primary spermatogenic failure is a common cause of male infertility usually considered untreatable; however, some reports have suggested that hormonal stimulation to boost the intra-testicular testosterone level and spermatogenesis might increase the chance of achieving pregnancy using homologous sperm. We report a series of eight NOA males who received long-term treatment with recombinant human chorionic gonadotropin twice a week for spermatogenesis stimulation. Six males received additional recombinant follicle-stimulating hormone (FSH) supplementation 150-225 IU twice weekly. After recombinant gonadotropin therapy, viable spermatozoa were retrieved from the ejaculate in two patients and by testicular sperm aspiration (TESA) in another two subjects. Singleton spermatozoon retrieved from testes were frozen by vitrification on Cell-Sleeper devices. Two live births were obtained after intracytoplasmic sperm injection with ejaculated spermatozoa and one live birth and an ongoing pregnancy using thawed spermatozoa from TESA. Our proof-of-concept study indicates that hormonal therapy with recombinant gonadotropins could be considered in infertile men with NOA as an alternative to sperm donation. Large-scale studies are needed to substantiate hormone stimulation therapy with recombinant gonadotropins in routine clinical practice for this severe form of male infertility.

3-Monochloropropane-1,2-diol causes spermatogenesis failure in male rats via Sertoli cell dysfunction but not testosterone reduction

3-Monochloropane-1,2-diol (3-MCPD), a common food contaminant, has been confirmed to impair male fertility, but the mechanism has not been fully clarified. This study systematically explored the spermatogenesis impairment induced by 3-MCPD in vivo and in vitro with a focus on Sertoli cells (SCs) and spermatogonial stem cells (SSCs). After adult male Sprague–Dawley rats were administered 36 and 72 mg/kg b.w./day 3-MCPD daily for 4 weeks, the total sperm concentration dramatically decreased by 28.9 % and 57.7 %, respectively, and obvious testicular seminiferous tubule atrophy was observed. 3-MPCD exposure decreased serum testosterone levels but not intratesticular testosterone levels and upregulated the expression of steroidogenesis enzymes in both rat testes and primary Leydig cells. 3-MCPD did not reduce the number and self-renewal marker PLZF+ of SSCs; however, it downregulated the key meiotic genes Stra8 and Rec8 in the rat testis but not in primary germ cells. Although SC counts were not affected, 3-MCPD downregulated androgen receptor (AR) in rat testes and primary SCs. In addition, 3-MCPD downregulated p-CREB (transcription factor of AR), paracrine meiosis regulators Nrg1 and Nrg3 and retinoic acid synthetase Aldh1a1 in primary SCs. In summary, 3-MCPD caused impairment of spermatogenesis by inhibiting secretion of meiosis regulators and disturbing testosterone signalling in SCs.

An update on male infertility and intratesticular testosterone-insight into novel serum biomarkers.

Intratesticular testosterone is vital for spermatogenesis, male fertility, and virility. Currently the only method to assess levels of intratesticular testosterone is to perform testicular biopsy which is invasive and can lead to several complications. Approaches to assess intratesticular testosterone have been understudied but hold promise as future male contraceptive agents and maygrant the ability to monitor patients undergoing hormonal changes from therapeutic and diagnostic perspectives. Previous studies have sought to assess the utility of 17-hydroxyprogesterone (17-OHP) and insulin-like factor 3 (INSL3) as accurate surrogate biomarkers of intratesticular testosterone. The aim of this review is thus to highlight the importance of intratesticular testosterone and the consequent advances that have been made to elucidate the potential of biomarkers for intratesticular testosterone in the context of male infertility.

Venlafaxine-induced adrenergic signaling stimulates Leydig cells steroidogenesis via Nur77 overexpression: A possible role of EGF

Venlafaxine, a norepinephrine and serotonin reuptake inhibitor, impairs rat sperm parameters, spermatogenesis and causes high intratesticular estrogen and testosterone levels, indicating that Leydig cells (LCs) may be a venlafaxine target. We evaluated the effect of venlafaxine treatment on rat LCs, focusing on adrenergic signaling, EGF immunoexpression and steroidogenesis. Germ cells mitotic/meiotic activity and UCHL1 levels were also evaluated in the seminiferous epithelium. Eighteen adult male rats received 30 mg/kg of venlafaxine (n = 9) or distilled water (n = 9). The seminiferous tubules, epithelium and LCs nuclear areas were measured, and the immunoexpression of Ki-67, UCHL1, StAR, EGF, c-Kit and 17β-HSD was evaluated. UCHL1, StAR and EGF protein levels and Adra1a, Nur77 and Ndrg2 expression were analyzed. Malondialdehyde (MDA) and nitrite testicular levels, and serum estrogen and testosterone levels were measured. Venlafaxine induced LCs hypertrophy and Ndrg2 upregulation in parallel to increased number of Ki-67, c-Kit- and 17β-HSD-positive interstitial cells, indicating that this antidepressant stimulates LCs lineage proliferation and differentiation. Upregulation of Adra1a and Nur77 could explain the high levels of StAR and testosterone levels, as well as aromatization. Enhanced EGF immunoexpression in LCs suggests that this growth fact is involved in adrenergically-induced steroidogenesis, likely via upregulation of Nur77. Slight tubular atrophy and weak Ki-67 immunoexpression in germ cells, in association with high UCHL1 levels, indicate that spermatogenesis is likely impaired by this enzyme under supraphysiological estrogen levels. These data corroborate the unchanged MDA and nitrite levels. Therefore, venlafaxine stimulates LCs steroidogenesis via adrenergic signaling, and EGF may be involved in this process.