Functional and Taxonomic Dysbiosis of the Gut, Urine, and Semen Microbiomes in Male Infertility.

BACKGROUND: Little is known about the role of the genitourinary and gastrointestinal microbiota in the pathogenesis of male infertility. OBJECTIVE: To compare the taxonomic and functional profiles of the gut, semen, and urine microbiomes of infertile and fertile men. DESIGN, SETTING, AND PARTICIPANTS: We prospectively enrolled 25 men with primary idiopathic infertility and 12 healthy men with proven paternity, and we collected rectal swabs, semen samples, midstream urine specimens, and experimental controls. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We performed comprehensive semen analysis, 16S rRNA sequencing for quantitative high-resolution taxonomy, and shotgun metagenomics with a median of 140 million reads per sample for functional metabolic pathway profiling. RESULTS AND LIMITATIONS: We identified a diverse semen microbiome with modest similarity to the urinary microbiome. Infertile men harbored increased seminal α-diversity and distinct ß-diversity, increased seminal Aerococcus, and decreased rectal Anaerococcus. Prevotella abundance was inversely associated with sperm concentration, and Pseudomonas was directly associated with total motile sperm count. Vasectomy appeared to alter the seminal microbiome, suggesting a testicular or epididymal contribution. Anaerobes were highly over-represented in the semen of infertile men with a varicocele, but oxidative stress and leukocytospermia were associated with only subtle differences. Metagenomics data identified significant alterations in the S-adenosyl-L-methionine cycle, which may play a multifaceted role in the pathogenesis of infertility via DNA methylation, oxidative stress, and/or polyamine synthesis. CONCLUSIONS: This pilot study represents the first comprehensive investigation into the microbiome in male infertility. These findings provide the foundation for future investigations to explore causality and identify novel microbiome-based diagnostics and therapeutics for men with this complex and emotionally devastating disease. PATIENT SUMMARY: We explored the resident populations of bacteria living in the gut, semen, and urine of infertile and fertile men. We found several important bacterial and metabolic pathway differences with the potential to aid in diagnosing and treating male infertility in the future.

Empirical medical therapy for idiopathic male infertility.

OBJECTIVE: To determine if there has been a change in empirical medical therapy (EMT) practices since a 2010 American Urological Association survey reported that 25% of urologists treated infertile men who were pursuing a pregnancy with testosterone (T). DESIGN: Survey-based cohort study of AUA members. SETTING: Practice patterns were evaluated of urologists in academic and nonacademic hospital centers. PATIENTS: Practice patterns were evaluated in the treatment of men with idiopathic infertility. INTERVENTIONSS: None. MAIN OUTCOME MEASURES: Subgroup analysis by means of univariate analysis between means (Fisher exact test) and descriptive proportions was used to compare male infertility fellowship-trained urologists (RUs) to general urologists (non-RUs). RESULTS: A total of 191 urologists responded (4.7%). Excluding trainees, 164 responses (85.9%) were analyzed: 134 (82.3%) were from non-RUs and 29 from (17.7%) RUs. Over all, 65.9% treated male infertility with a combination of EMT and surgery (93.1% of RU vs. 60.4% of non-RUs). The most common medications used by RUs were clomiphene (100%), anastrozole (85.7%), and hCG/LH (82.1%). Non-RUs used these less frequently. Overall, 24.4% of the urologists reported that they would use T to treat male infertility: 14.4% (n = 4) of RUs and 24.4% (n = 30) of non-RUs. CONCLUSIONS: A total of 65.9% of urologists would treat male infertility with the use of EMT and surgery. The most common EMTs were clomiphene, anastrozole, and hCG/LH. Of concern, 24.4% of urologists considered T to treat male infertility, a medication with known contraceptive potential. This is unchanged from the 2010 survey, and confirms the need for reproductive medicine guidelines that include the topic of EMT use in infertile men.

Varicocele management for infertility and pain: A systematic review.

Despite being first described two thousand years ago, the varicocele remains a controversial multifaceted disease process with numerous biological consequences including infertility, hypogonadism, and chronic orchidalgia. The underlying mechanisms remain poorly understood and likely include hypoxia, oxidative stress, hyperthermia, anatomical aberrations, and genetics as primary components. Despite a high prevalence amongst asymptomatic fertile men, varicoceles paradoxically also represent the most common correctable cause for male infertility. In this systematic review we discuss the rich historical aspects of the varicocele and the contemporary data regarding its clinical manifestations. We performed a systematic literature review with the goal of comparing outcomes and complication rates of each of the major surgical approaches as they relate to infertility and pain. We performed a Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA)-compliant systematic literature review for manuscripts focused on varicocele and its biological consequences. We identified 112 studies suitable for qualitative analysis and included 56 of these for quantitative analysis, with an emphasis on infertility and chronic pain outcomes. Taken together, the clinical work to date suggests that the highest fertility rates and the lowest complication rates are associated with the microsurgical subinguinal surgical approach to varicocelectomy. In all, 26-40% of patients undergoing varicocelectomy will successfully achieve short-term spontaneous pregnancy, and up to 90% of all patients undergoing varicocelectomy for pain will have improvement and/or resolution of their symptoms. Taken together, the data support an ongoing role for varicocelectomy in both of these clinical arenas.

Reduction in Opioid Prescribing Using a Postoperative Pain Management Protocol following Scrotal and Subinguinal Surgery.

INTRODUCTION: Excess prescribing of opioid pain medication increases medical costs and the potential for abuse by patients and others. We sought to improve our understanding of postoperative pain and opioid use after scrotal and subinguinal urological surgery to develop a protocol for pain management. METHODS: We retrospectively analyzed opioid prescribing and usage in 20 patients undergoing scrotal or subinguinal surgery. Collected data were used to develop a standardized postoperative protocol. This protocol included enhanced pain management education and limiting outpatient opioid prescriptions. Outcomes analysis was then performed for 60 consecutive patients via questionnaire. Statistical analysis was performed using the Wilcoxon rank sum test and ANOVA. Linear regression was performed comparing age and narcotic use. RESULTS: Comparison of preprotocol and postprotocol implementation opioid prescriptions and consumption showed a statistically significant decrease in the number of tablets prescribed but no difference in opioid usage. Preprotocol and postprotocol opioid prescription usage was 20 and 10 tablets, respectively, while median usage was 3.5 and 3 tablets, respectively. CONCLUSIONS: Evaluation of postoperative pain management revealed excessive prescribing of opioid medications compared to actual usage. Our protocol resulted in a significant decrease in opioid prescribing without compromising management of postoperative pain. Adjunct treatments for pain, including scrotal support, ice packs, elevation and nonsteroidal anti-inflammatory drugs, may improve postoperative pain control without increasing opioid usage. The combination of enhanced patient education and reduced opioid prescribing may result in decreased opioid use, opioid abuse and medication costs.

Empiric medical therapy with hormonal agents for idiopathic male infertility.

INTRODUCTION: Infertility affects approximately 15% of all couples, and male factor contribute to up to 50% of cases. Unfortunately, the cause of male infertility is unknown in about 30% of these cases. Infertility of unknown origin is classified as idiopathic male infertility when abnormal semen parameters are present. Despite not having a definable cause, these men may respond to treatment. This review focuses on the use of empiric hormonal therapies for idiopathic male infertility. METHODS: A detailed PubMed/MEDLINE search was conducted to identify all publications pertaining to empiric use of hormonal therapies in the treatment of idiopathic male infertility using the keywords "idiopathic," "male infertility," "empiric treatment," "clomiphene," "SERM," "gonadotropin," "aromatase inhibitor," and "androgen." These manuscripts were reviewed to identify treatment modalities and results. RESULTS: Gonadotropins, androgens, aromatase inhibitors, and selective estrogen receptor modulators (SERMs) have all been used with varying results. The studies on these treatments are of variable quality. The most well-studied agents are the SERMs which show a modest increase in semen parameters and pregnancy rates. Aromatase inhibitors are most effective in non-idiopathic patients. Gonadotropin treatment is limited by their inconvenience and relative ineffectiveness in this population. Testosterone suppresses spermatogenesis and should not be used to treat infertility. CONCLUSION: Gonadotropins, SERMs, and aromatase inhibitors may improve semen parameters and hormone levels in men with idiopathic infertility with the best results from SERMs. Testosterone should never be used to treat infertility. Large multicenter randomized controlled studies are needed to better determine the success of empiric use of hormonal therapy on pregnancy rates.

Adenomatoid Tumor of the Testis Arising From the Tunica Albuginea.

Adenomatoid tumors are the most common paratesticular tumor. Although they primarily arise from the epididymis, they can rarely occur as an isolated intratesticular mass. These tumors are benign and surgical excision is curative. We present a case of a 36-year-old man diagnosed with an intratesticular adenomatoid tumor.

A novel nomogram for prediction of spermatogenic improvement following empiric medical therapy for moderate-severe oligospermia.

INTRODUCTION: To identify pre-treatment clinical variables and hormonal responses predictive of successful spermatogenic response to empiric medical therapy (EMT), then to create a nomogram to guide clinical therapy. MATERIALS AND METHODS: All men who had been treated at our institution with EMT for moderate-severe oligospermia (≤ 10 million sperm/mL) from 2003 to 2014 were included in our study. Men with hypogonadotropic hypogonadism, azoospermia, or those who had varicocelectomy or had received fertility altering medications within 6 months of initiating EMT were excluded, as well as those who did not obtain a follow up semen analysis. Pre-treatment clinical variables, hormonal responses, and spermatogenic responses were assessed. Success was defined by improvements in baseline sperm concentrations as follows: (1) cryptospermia to ≥ 0.3 million/mL, (2) > 100% increase in sperm concentration for men with baseline concentration < 1 million/mL, or (3) a 30% increase in sperm concentration for men with a baseline concentration between 1-10 million/mL. We performed univariate analysis to evaluate for predictors of success. The Wilcoxon rank sum test was used for continuous variables and the Fisher's exact test was used for categorical variables. Multivariable logistic regression was then used to build a nomogram. RESULTS: We identified 107 men who were treated with EMT for oligospermia (≤ 10 million sperm/mL) who met our inclusion criteria. Forty-five men (42%) exhibited a poor spermatogenic response to EMT and 62 men (58%) exhibited a good response. Univariate analysis did not identify significant differences in any variable between the two groups. Multivariate analysis did identify predictive combinations which allowed the development of a nomogram with a high concordance index (0.78) for predicting spermatogenic response to EMT. CONCLUSIONS: While none of the individual pre-treatment clinical variables or hormonal responses were predictive of success following EMT, analysis of multiple factors in concert yielded a clinically useful nomogram with a high concordance index.

Anatomical Targeting Improves Delivery of Unconjugated Nanoparticles to the Testicle.

PURPOSE: Nanoparticles, which are submicroscopic particles typically ranging from 100 to 300 nm, are interesting as potential treatment of testicular disorders because they can be engineered to allow delivery to privileged tissues, such as across the blood-brain barrier or theoretically the blood-testis barrier. We compared the effects of anatomical and/or ligand targeting on testicular nanoparticle uptake in a rat model. MATERIALS AND METHODS: A total of 48 rats were divided into 6 groups, including a control group and groups that received intra-arterial injection of unconjugated nanoparticles with and without saline flush, intravenous injection of unconjugated nanoparticles, intra-arterial injection of follicle stimulating hormone conjugated nanoparticles, intravenous injection of follicle stimulating hormone conjugated nanoparticles and intra-arterial injection of transactivating transcriptor conjugated nanoparticles. A dose response curve was assessed for intra-arterially injected unconjugated nanoparticles. Using high performance liquid chromatography and histological analysis we determined nanoparticle uptake by the testicle at 4 hours. RESULTS: Intra-arterial injection resulted in a 5.8-fold increase in uptake compared to intravenous injection at 35 mg/kg of unconjugated nanoparticles (3.7 vs 0.6 µg nanoparticles per gm testicle, p = 0.04). Anatomical targeting failed to improve testicular uptake in FSH conjugated nanoparticles (intra-arterial vs intravenous injection 0.33 vs 0.38 µg FSH nanoparticles per gm testicular tissue, p = 0.73). On fluorescence microscopy nanoparticles were noted in the testicular interstitium and seminiferous tubules, and absent from the testicular vasculature. CONCLUSIONS: Arterial injection for anatomical targeting of nanoparticles to the testis is feasible, improves unconjugated nanoparticle delivery to testicular tissue and enables nanoparticles to cross the gonadal vascular endothelium and the blood-testis barrier.

Male infertility testing: reactive oxygen species and antioxidant capacity.

Reactive oxygen species (ROS) are an integral component of sperm developmental physiology, capacitation, and function. Elevated ROS levels, from processes such as infection or inflammation, can be associated with aberrations of sperm development, function, and fertilizing capacity. We review the impact of ROS on sperm physiology, its place in infertility evaluation, the implications for reproductive outcomes, and antioxidant therapy. Our systematic review of PubMed literature from the last 3 decades focuses on the physiology and etiology of ROS and oxidative stress (OS), evaluation of ROS, and antioxidants. ROS is normally produced physiologically and is used to maintain cellular processes such as sperm maturation, capacitation, and sperm-oocyte interaction. When ROS production exceeds the buffering capacity of antioxidants, OS occurs and can have a negative impact on sperm and fertility. ROS and antioxidant capacity testing can potentially add additional prognostic information to standard laboratory testing for the infertile male, although its role as standard part of an evaluation has yet to be determined. Elevated ROS levels have been implicated with abnormal semen parameters and male infertility, but the impact of ROS on fertilization rates and pregnancy is controversial. This is partly because of the lack of consensus on what type of patients may be suitable for ROS testing and assay standardization. Routine ROS testing for the infertile male is not currently recommended.

Functional sperm testing and the role of proteomics in the evaluation of male infertility.

The limitations of conventional semen analysis testing in the diagnosis and management of male factor infertility have been well documented. A number of more sophisticated assays including measurements of sperm deoxyribonucleic acid (DNA) fragmentation rates, seminal oxidative stress, and antioxidant capacity have been increasingly used in the evaluation of male infertility. Moreover, in the past few years, tremendous advancements in the burgeoning field of sperm proteomics promise to revolutionize the andrologist's diagnostic armamentarium, as will be discussed in this review.

Robotic intra-abdominal vasectomy reversal: A new approach to a difficult problem.

The management of obstructive azoospermia resulting from intra-abdominal vasal obstruction poses a formidable surgical challenge. A number of surgical methods have been described to address this problem, including both open and laparoscopic approaches to mobilize and sometimes even re-route the abdominal vas deferens prior to performing a re-anastamosis. We present the first report, to our knowledge, of robotic intra-abdominal vasectomy reversal used to repair obstructive azoospermia resulting from prior laparoscopic vasectomy. In doing so, we summarize the techniques described previously in the literature and build upon this body of surgical experience by combining robotic-assisted laparoscopic mobilization of the vas with robotic vasovasostomy. We believe this novel approach for repairing intra-abdominal vasal defects minimizes morbidity, while at the same time obviating the need for the operating microscope, and thus represents a practical alternative to existing techniques.

The economic burden of genetic tests for the infertile male: a pilot algorithm to improve test predictive value.

PURPOSE: We developed a model to optimize genetic testing in infertile men with nonobstructive azoospermia and severe oligospermia. We also assessed the optimal cutoff value of the predicted probability of advising genetic testing and evaluated the direct cost saving of using the model. MATERIALS AND METHODS: We retrospectively reviewed the records of infertile men who underwent Y microdeletion and karyotype testing at our fertility center from 2006 to 2012. Semen parameters, testicular volume, testosterone, luteinizing hormone, follicular stimulating hormone and varicocele were assessed as potential predictors of genetic disorders. We fitted logistic regression to all predictors and selected a nomogram based on the concordance index and calibration. We calculated the cost saving of using the model. RESULTS: Of 325 patients 278 fulfilled study inclusion criteria, including 27 with an abnormal karyotype, 11 with a Y microdeletion and 1 with each condition. We developed a nomogram using sperm concentration and motility, testicular volume and serum testosterone level. The nomogram concordance index was 0.738. The optimal cutoff value was 13.8% with 0.788 sensitivity, 0.590 specificity, 0.245 positive predictive value and 0.943 negative predictive value. Testing men above the 13.8% cutoff resulted in a direct 45% cost saving. However, 15.4% of genetic anomalies were missed, including 2 Y microdeletions. CONCLUSIONS: Using common clinical and laboratory parameters our nomogram detects 84.6% of genetic anomalies. Nomogram use resulted in a 45% direct cost saving but carries the risk of missing pertinent genetic abnormalities.

The role of nutraceuticals in male fertility.

Nutraceuticals are food products that that can provide medical or health benefits by preventing or treating disease processes. The high costs associated with assisted reproductive techniques for male infertility have led consumers to find less expensive alternatives for potential treatment. Nutraceuticals are widely available and have many antioxidant properties. This articles reviews the current English literature regarding readily available nutraceuticals and their potential effects on male infertility and potential side effects with excess intake.

Superoxide dismutase-loaded biodegradable nanoparticles targeted with a follicle-stimulating hormone peptide protect Sertoli cells from oxidative stress.

OBJECTIVE: To evaluate targeted superoxide dismutase (SOD)-loaded biodegradable nanoparticles' (NPs) ability to protect Sertoli cells from hydrogen peroxide (H2O2)-induced oxidative stress. DESIGN: Cell culture controlled experimental study. SETTING: Research laboratory. CELLS: Mouse testis Sertoli cells (TM4). INTERVENTIONS: Sertoli cells were exposed to 0-200 µg/mL plain media, unconjugated NPs, or FSH peptide-conjugated NPs for 2 or 24 hours to assess uptake. Next, Sertoli cells were exposed to 0-50 mmol H2O2 with 0-1 mg/mL unconjugated SOD-loaded NPs, FSH-conjugated SOD-loaded NPs, or equivalent units of SOD in solution as a control for 2-6 hours to assess influence on cell survival after oxidative stress. MAIN OUTCOME MEASURE(S): Cell viability, flow cytometry, and microscopy. RESULT(S): FSH peptide targeting improved uptake of NPs by Sertoli cells. FSH-conjugated SOD-NPs significantly protected Sertoli cells at 6 hours of H2O2--induced oxidative stress, with 100% survival with FSH-conjugated SOD-NPs compared with unconjugated SOD-NPs (45%) or SOD in solution (36%). CONCLUSION(S): Conjugation of NPs with FSH peptide improves cellular uptake and survival when SOD-loaded NPs are coincubated with Sertoli cells undergoing oxidative stress. This study represents a step toward developing NPs for the targeted treatment of testicular oxidative stress.

Office-based sperm retrieval for treatment of infertility.

This article describes sperm retrieval procedures that may be performed in an office setting. Indications for sperm retrieval, preprocedural preparation, and anesthetic considerations are discussed. Vasal sperm aspiration, percutaneous epididymal sperm aspiration, microsurgical epididymal sperm aspiration, testicular sperm aspiration, conventional, and microdissection testicular sperm extraction are reviewed. Success and complication rates as well as factors that may influence success (histopathology, cancerous cause, Klinefelter syndrome, Y microdeletions, varicocele, and hormone administration) are reviewed.

Spermaturia after radical prostatectomy: is surgical preservation of fertility possible?

Ease of sperm retrieval has not been previously described as a goal for patients undergoing radical prostatectomy for prostate cancer; however preservation of fertility is a known concern for some younger prostate cancer patients. We present the first known case of a patient with postejaculatory spermaturia following robotic assisted radical prostatectomy. We hypothesize that this is due to fistula formation between the vas deferens and the urinary tract.

47,XYY Syndrome and Male Infertility.

Men with 47,XYY syndrome present with varying physical attributes and degrees of infertility. A retrospective chart review was performed on a male infertility and genetic anomaly database. Three patients with 47,XYY were found. Each presented with > 2 years of infertility. All were tall with elevated body mass indices. Scrotal findings ranged from normal to atrophic testicles. Semen analyses demonstrated oligospermia and varying endocrine profiles. Because of the diverse phenotype and potential lack of symptoms, identification and diagnosis of men with 47,XYY syndrome may be difficult. We recommend careful screening of 47,XYY patients and referral to primary physicians for long-term follow-up for increased incidence of health-related comorbidities.

Androgen deficiency in older men: indications, advantages, and pitfalls of testosterone replacement therapy.

The decline in testosterone with age has been associated with specific physical changes that affect quality of life and life expectancy, although a cause-and-effect relationship is yet to be established. While female menopause is rapid and well described, "male menopause" or androgen decline in older men is gradual and marked by nonspecific symptoms. This makes diagnosis of true testosterone deficiency and prediction of response to testosterone replacement therapy (TRT) challenging. This article reviews androgen decline in men, focusing on those over age 40, and covers symptoms, indications, contraindications,diagnosis, treatments, and the risks and benefits of treatment [corrected].

Empirical medical therapy for idiopathic male infertility: a survey of the American Urological Association.

PURPOSE: We determined empirical medical therapy practice patterns for idiopathic infertility. MATERIALS AND METHODS: We performed a survey of 7,745 practicing American Urological Association members from July to November 2010. Respondents were questioned on empirical medical therapy use, patient evaluation and selection, and preferred medications. RESULTS: A total of 387 urologists (5%) participated in the survey, of whom 16% had infertility fellowship training, two-thirds used empirical medical therapy and 78% treated with empirical medical therapy and surgery. Laboratory values important for identifying ideal candidates include sperm concentration, serum follicle-stimulating hormone and serum testosterone. The most common medications used were clomiphene citrate, human chorionic gonadotropin and anastrozole. Of respondents 25% would treat infertile males with testosterone while the patient actively pursued pregnancy. Overall 60.5% of respondents would treat with empirical therapy for 3 to 6 months. Of fellowship trained and general urologist respondents 70% and 47%, respectively, counseled patients that empirical medical therapy has unknown effects on pregnancy and sperm count. CONCLUSIONS: Empirical medical therapy is used by two-thirds of survey respondents for idiopathic male infertility. There is no clear, universal pattern to the evaluation or identification of the ideal patient for such therapy among those surveyed. There is no consensus on the optimal medication and considerable ambiguity exists as to perceived effects on fertility. Of concern is that 25% of respondents use exogenous testosterone, a medication known for its contraceptive potential, for male infertility treatment. These findings confirm the need for additional studies to establish recommendations on the empirical use of medical therapy in the setting of male infertility.