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OBJECTIVE: To investigate microRNA (miRNA) expression profiles in the seminal plasma of nonobstructive azoospermia (NOA) patients with different histopathologic patterns and evaluate potential noninvasive diagnostic biomarkers of NOA. DESIGN: Sequencing and validation using quantitative reverse transcription polymerase chain reaction (qRT-PCR). SETTING: Reproductive center and research institute. PATIENT(S): Thirteen patients with NOA (7 Sertoli cell-only syndrome [SCOS] and 6 hypospermatogenesis to spermatogenesis arrest [SA]) and 7 normal fertile controls for sequencing, six samples per group for validation; 54 patients with NOA (27 SCOS and 27 SA) and 19 normal fertile controls for large-sample qRT-PCR analysis. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): MicroRNA expression profiles in the seminal plasma of patients with NOA with different histopathologic patterns were assessed using high-throughput sequencing and validated using qRT-PCR. RESULT(S): There were 78 overexpressed and 132 underexpressed miRNAs in patients with SCOS and 32 up-regulated and 90 down-regulated miRNAs in patients with SA compared with fertile men with normozoospermia. Two down-regulated and one up-regulated miRNA were validated using qRT-PCR, which indicated that the qRT-PCR and sequencing results were basically consistent. Hsa-miR-34c-5p expression was significantly lower in the seminal plasma of patients with NOA than normal fertile controls. The area under the receiver operating characteristic curve(AUC) for hsa-miR-34c-5p was 0.979 and 0.987 in the seminal plasma of patients with SA and patients with SCOS, respectively, compared with normal fertile controls. The AUC was 0.799 for hsa-miR-34c-5p in the seminal plasma between patients with SA and patients with SCOS. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis of differentially expressed miRNA target genes revealed that the Notch signaling pathway was one of the most abundant signaling pathways. The expression of Hes5, an effector of the Notch signaling pathway, was significantly higher in the seminal plasma of patients with NOA than normal fertile controls. CONCLUSION(S): MicroRNA expression profiles in seminal plasma were altered in patients with NOA compared with normal fertile controls. The profiles differed in patients with NOA with different pathologic patterns. We speculate that miR-34c-5p in seminal plasma could be a potential noninvasive biomarker to diagnose patients with NOA and distinguish different pathologic types of NOA. The Notch signaling pathway may be involved in the pathogenesis of NOA.

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BACKGROUND: Infertility is an ever-increasing problem in today's world. It can be due to male or female causes. Azoospermia seen in 5-10% of infertile men is due to obstructive or non-obstructive causes. Traditionally, testicular biopsy is the gold standard for evaluation. Fine-needle aspiration (FNA), however, is minimally invasive, provides qualitative and quantitative information about spermatogenesis, and can aid in assisted reproductive techniques making it a novel technique for the evaluation of male infertility. OBJECTIVE: We aimed to classify different causes of azoospermia into different patterns based upon FNA, and assess the utility of cell indices in classifying cases into different patterns. METHOD: We conducted a prospective and a retrospective study of 42 azoospermic males, confirmed on semen analysis, over a period of 5 years. Patients were subjected to FNA of the testes. Smears were prepared, air-dried, wet-fixed, and then stained with May-Grünwald Giemsa and Papanicolaou stains, respectively. Cells were identified using predetermined morphologic criteria, and various indices were calculated followed by statistical analysis of the observations. RESULTS: The mean age of 40 patients who satisfied the adequacy criteria was 32.75 years (range 22-48 years). Thirty-four patients had primary infertility and 6 had secondary infertility. Of these, 12 had normal spermatogenesis, 8 had hypo-spermatogenesis, 3 had early and 7 had late maturation arrest, 6 had Sertoli cell-only syndrome (SCOS), and there were different results in each testicle in 4 cases. The Sperm Index (SI) was significantly higher in all cases of normal spermatogenesis than in any of the hypo-spermatogenesis cases (p = 0.009). The Sertoli Index (SEI) in cases of hypo-spermatogenesis and maturation arrest was significantly higher than in cases of normal spermatogenesis (p < 0.001). The Sperm-Sertoli Index (SSI) also showed significant differences between cases of hypo-spermatogenesis and normal spermatogenesis (p < 0.001). These indices were useful in categorising patients with azoospermia. CONCLUSION: FNA helps to easily and accurately identify all types of testicular cells without biopsy. SI, SEI, and SSI are powerful cell indices for assessing the extent of spermatogenesis and classifying various causes of azoospermia. Bilateral sampling and multiple aspirations give a better mapping of spermatogenesis within the testes. Testicular FNA can thus play a very important role in the evaluation of male infertility.

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OBJECTIVE: To determine whether the serum anti-Müllerian hormone (AMH) level can be used as a serum marker for the differential diagnosis of obstructive azoospermia (OA) and non-obstructive azoospermia (NOA). METHODS: Using chemiluminescence immunoassay, we detected the levels of serum AMH, inhibin B (IhB) and follicle stimulating hormone (FSH) and measured by scrotal ultrasound the testis volume of 43 normal fertile men and 14 OA and 45 NOA male patients, followed by a comparative analysis of the data obtained among the three groups subjects. RESULTS: Compared with the NOA patients, the men in the normal control and OA groups showed significantly higher levels of AMH (ï¼»5.65 ± 3.13ï¼½ vs ï¼»8.13 ± 3.95ï¼½ and ï¼»8.51 ± 4.77ï¼½ ng/ml, P < 0.05) and InH (ï¼»25.98±16.29ï¼½ vs ï¼»127.38 ± 40.5ï¼½ and ï¼»131.25 ± 52.3ï¼½ pg/ml, P < 0.01), but a lower level of FSH (ï¼»19.87 ± 13.09ï¼½ vs ï¼»4.22 ± 3.23ï¼½ and ï¼»4.54 ± 2.09ï¼½ IU/L, P < 0.01), none with statistically significant difference between the latter two groups (P > 0.05). Pearson correlation analysis exhibited that the level of IhB was correlated positively with that of AMH (r = 0.326, P = 0.01) but negatively with that of FSH (r =－0.662, P < 0.01), the FSH level negatively with the AMH level (r = －0.468, P < 0.01), the testis volume positively with the levels of AMH (r = 0.339, P < 0.01) and IhB (r = 0.733, P < 0.01) but negatively with that of FSH (r = 0.597, P < 0.01), the sperm concentration positively with that of IhB (r = 0.522, P < 0.01) but negatively with that of FSH (r = －0.421, P < 0.01), and the testis volume positively with the sperm concentration (r = 0.605, P < 0.01). CONCLUSIONS: AMH can be used as one of the serum markers for testicular spermatogenesis and employed alone or in combination with IhB and FSH for the differential diagnosis of OA and NOA.

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The objective of this study was to assess genome-wide DNA methylation in testicular tissue from azoospermic patients. A total of 94 azoospermic patients were recruited and classified into three groups: 29 patients presented obstructive azoospermia (OA), 26 displayed non-obstructive azoospermia (NOA) and successful retrieval of spermatozoa by testicular sperm extraction (TESE+) and 39 displayed NOA and failure to retrieve spermatozoa by TESE (TESE-). An Illumina Infinium Human Methylation27 BeadChip DNA methylation array was used to establish a testicular DNA methylation pattern for each type of azoospermic patient. The OA and NOA groups were compared in terms of the relative M-value (the log2 ratio between methylated and non-methylated probe intensities) for each CpG site. We observed significantly different DNA methylation profiles for the NOA and OA groups, with differences at over 9000 of the 27 578 CpG sites; 212 CpG sites had a relative M-value >3. The results highlighted 14 testis-specific genes. Patient clustering with respect to these 212 CpG sites corresponded closely to the clinical classification. The DNA methylation patterns showed that in the NOA group, 78 of the 212 CpG sites were hypomethylated and 134 were hypermethylated (relative to the OA group). On the basis of these DNA methylation profiles, azoospermic patients could be classified as OA or NOA by considering the 212 CpG sites with the greatest methylation differences. Furthermore, we identified genes that may provide insight into the mechanism of idiopathic NOA.

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The misconception that infertility is typically associated with the female is commonly faced in the management of infertile men. It is uncommon for a patient to present for an infertility evaluation with an abnormal semen analysis report before an extensive female partner workup has been performed. Additionally, a man is usually considered fertile based only on seminal parameters without a physical exam. This behavior may lead to a delay in both the exact diagnosis and in possible specific infertility treatment. Moreover, male factor infertility can result from an underlying medical condition that is often treatable but could possibly be life-threatening. The responsibility of male factor in couple's infertility has been exponentially rising in recent years due to a comprehensive evaluation of reproductive male function and improved diagnostic tools. Despite this improvement in diagnosis, azoospermia is always the most challenging topic associated with infertility treatment. Several conditions that interfere with spermatogenesis and reduce sperm production and quality can lead to azoospermia. Azoospermia may also occur because of a reproductive tract obstruction. Optimal management of patients with azoospermia requires a full understanding of the disease etiology. This review will discuss in detail the epidemiology and etiology of azoospermia. A thorough literature survey was performed using the Medline, EMBASE, BIOSIS, and Cochrane databases. We restricted the survey to clinical publications that were relevant to male infertility and azoospermia. Many of the recommendations included are not based on controlled studies.

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Non-obstructive azoospermia is diagnosed in approximately 10% of infertile men. It represents a failure of spermatogenesis within the testis and, from a management standpoint, is due to either a lack of appropriate stimulation by gonadotropins or an intrinsic testicular impairment. The former category of patients has hypogonadotropic hypogonadism and benefits from specific hormonal therapy. These men show a remarkable recovery of spermatogenic function with exogenously administered gonadotropins or gonadotropin-releasing hormone. This category of patients also includes some individuals whose spermatogenic potential has been suppressed by excess androgens or steroids, and they also benefit from medical management. The other, larger category of non-obstructive azoospermia consists of men with an intrinsic testicular impairment where empirical medical therapy yields little benefit. The primary role of medical management in these men is to improve the quantity and quality of sperm retrieved from their testis for in vitro fertilization. Gonadotropins and aromatase inhibitors show promise in achieving this end point.

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We compared pregnancy outcomes following intracytoplasmic sperm injection for the treatment of male infertility according to the type of azoospermia. First, we analyzed our data from 370 couples who underwent intracytoplasmic sperm injection using sperm from men with obstructive azoospermia and nonobstructive azoospermia, and the outcomes were compared to a group of 465 non-azoospermic infertile males. Then, we performed a systematic review of the published data on pregnancy and neonatal outcomes of children born after sperm injection using sperm from men with obstructive and nonobstructive azoospermia. Live birth rates were significantly lower in the nonobstructive azoospermia group (21.4%) compared with the obstructive azoospermia (37.5%) and ejaculated sperm (32.3%) groups. A total of 326 live births resulted in 427 babies born. Differences were not observed between the groups in gestational age, preterm birth, birth weight and low birth weight, although we noted a tendency towards poorer neonatal outcomes in the azoospermia categories. The overall perinatal death and malformation rates were 2.8% and 1.6%, respectively, and the results did not differ between the groups. We identified 20 published studies that directly compared pregnancy outcomes between obstructive azoospermia and nonobstructive azoospermia. Most of these studies were not designed to detect differences in live birth rates and had lower power to detect differences in less frequent outcomes, and the reporting of neonatal outcomes was unusual. The included studies reported either a decrease or no difference in pregnancy outcomes with intracytoplasmic sperm injection in cases of nonobstructive azoospermia and obstructive azoospermia. In general, no major differences were noted in short-term neonatal outcomes and congenital malformation rates between children from fathers with nonobstructive azoospermia and obstructive azoospermia.

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The misconception that infertility is typically associated with the female is commonly faced in the management of infertile men. It is uncommon for a patient to present for an infertility evaluation with an abnormal semen analysis report before an extensive female partner workup has been performed. Additionally, a man is usually considered fertile based only on seminal parameters without a physical exam. This behavior may lead to a delay in both the exact diagnosis and in possible specific infertility treatment. Moreover, male factor infertility can result from an underlying medical condition that is often treatable but could possibly be life-threatening. The responsibility of male factor in couple's infertility has been exponentially rising in recent years due to a comprehensive evaluation of reproductive male function and improved diagnostic tools. Despite this improvement in diagnosis, azoospermia is always the most challenging topic associated with infertility treatment. Several conditions that interfere with spermatogenesis and reduce sperm production and quality can lead to azoospermia. Azoospermia may also occur because of a reproductive tract obstruction. Optimal management of patients with azoospermia requires a full understanding of the disease etiology. This review will discuss in detail the epidemiology and etiology of azoospermia. A thorough literature survey was performed using the Medline, EMBASE, BIOSIS, and Cochrane databases. We restricted the survey to clinical publications that were relevant to male infertility and azoospermia. Many of the recommendations included are not based on controlled studies.

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Non-obstructive azoospermia is diagnosed in approximately 10% of infertile men. It represents a failure of spermatogenesis within the testis and, from a management standpoint, is due to either a lack of appropriate stimulation by gonadotropins or an intrinsic testicular impairment. The former category of patients has hypogonadotropic hypogonadism and benefits from specific hormonal therapy. These men show a remarkable recovery of spermatogenic function with exogenously administered gonadotropins or gonadotropin-releasing hormone. This category of patients also includes some individuals whose spermatogenic potential has been suppressed by excess androgens or steroids, and they also benefit from medical management. The other, larger category of non-obstructive azoospermia consists of men with an intrinsic testicular impairment where empirical medical therapy yields little benefit. The primary role of medical management in these men is to improve the quantity and quality of sperm retrieved from their testis for in vitro fertilization. Gonadotropins and aromatase inhibitors show promise in achieving this end point.

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We compared pregnancy outcomes following intracytoplasmic sperm injection for the treatment of male infertility according to the type of azoospermia. First, we analyzed our data from 370 couples who underwent intracytoplasmic sperm injection using sperm from men with obstructive azoospermia and nonobstructive azoospermia, and the outcomes were compared to a group of 465 non-azoospermic infertile males. Then, we performed a systematic review of the published data on pregnancy and neonatal outcomes of children born after sperm injection using sperm from men with obstructive and nonobstructive azoospermia. Live birth rates were significantly lower in the nonobstructive azoospermia group (21.4%) compared with the obstructive azoospermia (37.5%) and ejaculated sperm (32.3%) groups. A total of 326 live births resulted in 427 babies born. Differences were not observed between the groups in gestational age, preterm birth, birth weight and low birth weight, although we noted a tendency towards poorer neonatal outcomes in the azoospermia categories. The overall perinatal death and malformation rates were 2.8% and 1.6%, respectively, and the results did not differ between the groups. We identified 20 published studies that directly compared pregnancy outcomes between obstructive azoospermia and nonobstructive azoospermia. Most of these studies were not designed to detect differences in live birth rates and had lower power to detect differences in less frequent outcomes, and the reporting of neonatal outcomes was unusual. The included studies reported either a decrease or no difference in pregnancy outcomes with intracytoplasmic sperm injection in cases of nonobstructive azoospermia and obstructive azoospermia. In general, no major differences were noted in short-term neonatal outcomes and congenital malformation rates between children from fathers with nonobstructive azoospermia and obstructive azoospermia.

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Male infertility is directly or indirectly responsible for 60% of cases involving reproductive-age couples with fertility-related issues. Nevertheless, the evaluation of male infertility is often underestimated or postponed. A coordinated evaluation of the infertile male using standardized procedures improves both diagnostic precision and the results of subsequent management in terms of effectiveness, risk and costs. Recent advances in assisted reproductive techniques (ART) have made it possible to identify and overcome previously untreatable causes of male infertility. To properly utilize the available techniques and improve clinical results, it is of the utmost importance that patients are adequately diagnosed and evaluated. Ideally, this initial assessment should also be affordable and accessible. We describe the main aspects of male infertility evaluation in a practical manner to provide information on the judicious use of available diagnostic tools and to better determine the etiology of the most adequate treatment for the existing condition.

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Male infertility is directly or indirectly responsible for 60 percent of cases involving reproductive-age couples with fertility-related issues. Nevertheless, the evaluation of male infertility is often underestimated or postponed. A coordinated evaluation of the infertile male using standardized procedures improves both diagnostic precision and the results of subsequent management in terms of effectiveness, risk and costs. Recent advances in assisted reproductive techniques (ART) have made it possible to identify and overcome previously untreatable causes of male infertility. To properly utilize the available techniques and improve clinical results, it is of the utmost importance that patients are adequately diagnosed and evaluated. Ideally, this initial assessment should also be affordable and accessible. We describe the main aspects of male infertility evaluation in a practical manner to provide information on the judicious use of available diagnostic tools and to better determine the etiology of the most adequate treatment for the existing condition.

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PURPOSE: To evaluate the usefulness of scrotal and transrectal ultrasonography (US) in the differential diagnosis of azoospermia and the etiologic classification of obstructive azoospermia. MATERIALS AND METHODS: This study was approved by the institutional ethics committee, and all patients provided written informed consent. Between April 2006 and November 2008, 100 infertile men (mean age, 32 years; range, 22-51 years) with azoospermia were evaluated at scrotal and transrectal US, with an emphasis on abnormal US findings of the seminal tract and measurement of testicular volume. On the basis of the results of percutaneous epididymal sperm aspiration, testicular fine-needle aspiration cytology, or testicular biopsy, 97 patients with azoospermia were divided into obstructive or nonobstructive groups. The remaining three patients had Klinefelter syndrome and did not undergo testicular biopsy. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the diagnostic performance of different indexes for discrimination between obstructive and nonobstructive azoospermia. Cases of obstructive azoospermia were further classified according to obstructive causes. RESULTS: Seminal tract abnormalities were more common in obstructive (92.2% [59 of 64 patients]) than in nonobstructive (2.8% [one of 36 patients]; P < .001) azoospermia. Testicular volume was significantly larger for obstructive (median, 16.0 mL; range, 8.4-27.5 mL) than for nonobstructive (median, 8.6 mL; range, 0.9-21.0 mL; P < .001) azoospermia. The area under the ROC curve for discrimination between the groups through combined assessment of the seminal tract and testicular volume at scrotal and transrectal US was 0.96. Sensitivity, specificity, and accuracy for combined assessment in discriminating between obstructive and nonobstructive azoospermia were 95.3% (61 of 64 patients), 97.2% (35 of 36), and 96.0% (96 of 100), respectively. CONCLUSION: Scrotal US and transrectal US are effective imaging modalities for distinguishing obstructive from nonobstructive azoospermia and can provide meaningful diagnostic information for determining the etiologic classification of obstructive azoospermia.

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For men presenting azoospermia, the development of ICSI with epidydimal (MESA) or testicular (TESE) sperm, allowed them to father their own progeny. Little is known about the issue of these ICSI, in terms of efficiency and quality of the conceptus, and many controversies remain. Some studies emphasized that children born after Assisted Reproductive Technology (ART) with surgically sperm retrieved were at increased risk of birth defects. In this context, we proposed a retrospective analysis of pregnancy issues with non-ejaculated sperm.

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OBJECTIVES: To report fertility for men with obstructive (OA) and nonobstructive (NOA) azoospermia after frozen and thawed spermatozoa recovered from the seminiferous tubules and intracytoplasmic sperm injection (ICSI) and to evaluate the factors other than spermatozoa. DESIGN: Retrospective clinical analysis. SETTING: Male infertility clinic for testicular sperm extraction and freezing/thawing (cryoTESE) and assisted reproductive technologies clinic for ICSI. PATIENT(S): Seventy-four men with OA and 140 men with NOA undergoing attempted cryoTESE-ICSI. INTERVENTION(S): Seventy-three couples with OA underwent a total of 184 cryoTESE-ICSI cycles, and 46 couples with NOA underwent a total of 75 cryoTESE-ICSI cycles. MAIN OUTCOME MEASURE(S): The numbers of eggs at metaphase II injected, two-pronuclei oocytes, normal cleaved embryos, embryos transferred, transfer cycles, biochemical pregnancies, and clinical pregnancies, as well as the implantation and delivery rates, were examined. RESULT(S): Fertilization rate in NOA was significantly lower than in OA. Neither the pathology, the source, nor the quantity of spermatozoa had any effect on fertilization or pregnancy rates. Maternal age had no effect on fertilization or embryo cleavage, but did dramatically affect the implantation, pregnancy, and delivery rates in NOA and OA. CONCLUSION(S): Good pregnancy rates were achieved without significant differences among the sperm sources. The pregnancy and the delivery rate were dependent strictly on the age of the female partner but not on her ovarian reserve.

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Infertility affects about one in six couples attempting pregnancy, with the man responsible in approximately half of the cases. Because the pathophysiology underlying azoospermia is not elucidated, most male infertility is diagnosed as idiopathic. Genome-wide gene expression analyses with microarray on testis specimens from 47 non-obstructive azoospermia (NOA) and 11 obstructive azoospermia (OA) patients were performed, and 2,611 transcripts that preferentially included genes relevant to gametogenesis and reproduction according to Gene Ontology classification were found to be differentially expressed. Using a set of 945 of the 2,611 transcripts without missing data, NOA was further categorized into three classes using the non-negative matrix factorization method. Two of the three subclasses were different from the OA group in Johnsen's score, FSH level, and/or LH level, while there were no significant differences between the other subclass and the OA group. In addition, the 52 genes showing high statistical difference between NOA subclasses (p < 0.01 with Tukey's post hoc test) were subjected to allelic association analyses to identify genetic susceptibilities. After two rounds of screening, SNPs of the ADP-ribosyltransferase 3 gene (ART3) were associated with NOA with highest significance with ART3-SNP25 (rs6836703; p = 0.0025) in 442 NOA patients and 475 fertile men. Haplotypes with five SNPs were constructed, and the most common haplotype was found to be under-represented in patients (NOA 26.6% versus control 35.3%, p = 0.000073). Individuals having the most common haplotype showed an elevated level of testosterone, suggesting a protective effect of the haplotype on spermatogenesis. Thus, genome-wide gene expression analyses were used to identify genes involved in the pathogenesis of NOA, and ART3 was subsequently identified as a susceptibility gene for NOA. These findings clarify the molecular pathophysiology of NOA and suggest a novel therapeutic target in the treatment of NOA.

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OBJECTIVE: This case series study aimed to find the relation of testicular volume with fine- needle aspiration cytology results in azoospermic infertile males to indicate the probable reason for azoospermia. PATIENTS AND METHODS: After clinical examination and two basic semen analyses, fine- needle aspiration and cytology study was performed on 221 testicles of 112 men. RESULTS: primary infertility was 87% and about 88% were town dwellers. The mean age and duration of infertility was 35 and 6 years respectively. History of scrotal swelling and/or sexually transmitted infection was present in 37% and two-third of the other medical problems was tuberculosis. Bilateral scrotal testicles and epididymis were palpated in 109 males, of which 92% had symmetrical testicles and 35% abnormal epididymis. Among the normal consistent testicles, 64% and 25% were normal and small in size respectively. Normal size with soft consistency was 5% and others make 4%. Mature sperm cells were identified in 51% of the fine needle-aspiration cytology report, and in 93% of the normal size testicles. The rest were spermatogenic arrest 38%, sertoli cell-only 7%, and spermatocele 2%. Early maturation arrest was observed in 65% of the small and 10% of the normal testicles (p = 0.000001). Sertoli cell only syndrome were also significantly higher in small testicles compared to the normal (P < 000001) DISCUSSION: Complete spermatogenesis was more associated with normal size testicles while spermatogenic arrest was mostly in the small size testicles. Azoosperrmic males with normal size testicles and complete spermatogenesit most likely have duct obstruction while those with small testicles were likely to suffer from incomplete spermatogenesis. Small testicles and atrophic testis may have destructive form (3%). CONCLUSION: The size of the testicle assessed by the Prader orchidometer allows a rough evaluation of the underlying cause of infertility. In two-thirds of the normal sized testicles, complete spermatogenesis was detected while 51% and 19% of the small testicles exhibited maturation arrest and Sertoli cell-only syndrome respectively.

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The Greek-based terms used to describe semen-analysis abnormalities (e.g., "oligozoospermia" and "azoospermia") are unscientific, have overlapping definitions, and are often misinterpreted. The best course is to abandon these vague and difficult labels and simply report semen analyses quantitatively.

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