Mark Sigman

Best practice policies for male infertility

University of California, San Francisco, San Francisco, California; Johns Hopkins University School of Medicine, Baltimore, Maryland; University of Louisville School of Medicine, Louisville, Kentucky; Baylor College of Medicine, Houston, Texas; Brown University, Providence, Rhode Island; Cleveland Clinic Foundation, Cleveland, Ohio; New York Presbyterian Hospital-Cornell, New York, New York; University of Virginia School of Medicine, Charlottesville, Virginia; Mayo Medical School, Rochester, Minnesota; University of Pennsylvania School of Medicine, York, Pennsylvania; University of California, Davis, Davis, California; and SUNY Health Science Center at Brooklyn, Brooklyn, New York

Are Tests of Sperm DNA Damage Clinically Useful? Pros and Cons

The advent of assisted reproductive technologies, particularly intracytoplasmic sperm injection (ICSI), has revolutionized the treatment of male-factor infertility. However, there are many unanswered questions regarding the safety of these techniques. These safety concerns are relevant because 1) these technologies often bypass the barriers to natural selection; 2) infertile men, particularly those with severe male-factor infertility, possess substantially more sperm DNA damage than do fertile men; and 3) experimentally, sperm DNA damage has been shown to adversely affect the developing embryo. This review discusses the etiology of sperm DNA damage, describes the individual tests of sperm DNA damage, and explores the relationship between sperm DNA damage and pregnancy outcomes. Based on a systematic review of the literature, sperm DNA damage is associated with lower natural, intrauterine insemination (IUI), and in vitro fertilization (IVF) pregnancy rates, but not with ICSI pregnancy rates. The literature also suggests that that sperm DNA damage is associated with an increased risk of pregnancy loss in those couples undergoing IVF or ICSI. Nonetheless, the true clinical utility of sperm DNA damage tests remains to be established, because the available studies are small and few in number and the study characteristics are heterogeneous. Although current data suggest that impaired sperm DNA integrity may have the greatest effect on IUI pregnancy rates and pregnancy loss by IVF and ICSI, further prospective studies are needed before testing should become a routine part of patient management.

Sperm DNA damage in male infertility: etiologies, assays, and outcomes

Male factor infertility is the sole cause of infertility in approximately 20% of infertile couples, with an additional 30% to 40% secondary to both male and female factors. Current means of evaluation of male factor infertility remains routine semen analysis including seminal volume, pH, sperm concentration, motility, and morphology. However, approximately 15% of patients with male factor infertility have a normal semen analysis and a definitive diagnosis of male infertility often cannot be made as a result of routine semen analysis. Attention has focused on the role of sperm nuclear DNA integrity in male factor infertility. Here we review the structure of human sperm chromatin, the etiology and mechanisms of sperm DNA damage, current tests available to assess sperm DNA integrity, and effect of sperm DNA integrity on reproductive outcomes.

Incidence of varicoceles in men with primary and secondary infertility

OBJECTIVES To determine whether varicoceles are more prevalent in men with secondary infertility than in men with primary infertility. METHODS The records of 2188 consecutive men attending three infertility centers were reviewed to determine the incidence of varicoceles in men with primary and secondary infertility. In addition, other factors affecting both male and female infertility were assessed in these patients. RESULTS The incidence of varicoceles was not significantly different between the 1447 men with primary infertility versus the 741 men with secondary infertility: 44% and 45%, respectively. The incidence of vasal agenesis was significantly greater in men with primary infertility (P < 0.001). In addition, the female partner was significantly older in couples with secondary infertility (P < 0.001). CONCLUSIONS These findings do not support the conclusion that varicoceles have a progressive adverse effect on fertility over time and suggest that further study is needed to determine whether varicocele repair is indicated in patients with normal semen parameters.

Endocrine evaluation of infertile men

OBJECTIVES To determine the incidence and type of endocrinologic abnormalities in men undergoing infertility evaluations and the most appropriate testing to detect them. METHODS A retrospective review of consecutive patients attending two infertility centers was performed. Results of endocrine testing were compared to medical history and physical and laboratory findings to determine whether endocrinologic screening could be limited to a specific subpopulation. RESULTS Only 99 of the 1035 patients (9.6%) had abnormal endocrine studies upon repetitive testing. The majority of these patients had an isolated elevation of serum follicle stimulating hormone (FSH) levels. Only 1.7% had a clinically significant endocrinopathy that would have had an effect upon disease management. Screening with serum testosterone and FSH levels alone was just as effective as a complete hormonal panel of testosterone, FSH, luteinizing hormone, and prolactin for the detection of clinically significant endocrinopathy. Only 1 patient with a clinically significant endocrinopathy would not have been identified if hormonal screening was limited to only those patients with a sperm density of less than 10 x 10(6)/mL. CONCLUSIONS Endocrinopathies are a rare cause of male infertility. Endocrine screening of men with sperm counts of less than 10 million/mL with serum testosterone and FSH levels alone will detect the vast majority of clinically significant endocrinopathies.

Integrative DNA Methylation and Gene Expression Analyses Identify DNA Packaging and Epigenetic Regulatory Genes Associated with Low Motility Sperm

Background In previous studies using candidate gene approaches, low sperm count (oligospermia) has been associated with altered sperm mRNA content and DNA methylation in both imprinted and non-imprinted genes. We performed a genome-wide analysis of sperm DNA methylation and mRNA content to test for associations with sperm function. Methods and Results Sperm DNA and mRNA were isolated from 21 men with a range of semen parameters presenting to a tertiary male reproductive health clinic. DNA methylation was measured with the Illumina Infinium array at 27,578 CpG loci. Unsupervised clustering of methylation data differentiated the 21 sperm samples by their motility values. Recursively partitioned mixture modeling (RPMM) of methylation data resulted in four distinct methylation profiles that were significantly associated with sperm motility (P = 0.01). Linear models of microarray analysis (LIMMA) was performed based on motility and identified 9,189 CpG loci with significantly altered methylation (Q<0.05) in the low motility samples. In addition, the majority of these disrupted CpG loci (80%) were hypomethylated. Of the aberrantly methylated CpGs, 194 were associated with imprinted genes and were almost equally distributed into hypermethylated (predominantly paternally expressed) and hypomethylated (predominantly maternally expressed) groups. Sperm mRNA was measured with the Human Gene 1.0 ST Affymetrix GeneChip Array. LIMMA analysis identified 20 candidate transcripts as differentially present in low motility sperm, including HDAC1 (NCBI 3065), SIRT3 (NCBI 23410), and DNMT3A (NCBI 1788). There was a trend among altered expression of these epigenetic regulatory genes and RPMM DNA methylation class. Conclusions Using integrative genome-wide approaches we identified CpG methylation profiles and mRNA alterations associated with low sperm motility.

Initial Experience with Extracorporeal Shock Wave Lithotripsy in Children

The clinical experience is presented of 4 United States centers at which extracorporeal shock wave lithotripsy was used for the treatment of renal calculi in 38 children 12 months to 16 years old. Patient characteristics, treatment specifics and followup data are detailed. Complete fragmentation of calculi was obtained in 97 per cent of those treated, with a 5 per cent complication rate. This experience demonstrates that with proper safeguards, extracorporeal shock wave lithotripsy can be performed safely and effectively in the pediatric population.

Prognostic utility of erectile dysfunction for cardiovascular disease in younger men and those with diabetes.

Multiple published studies have established erectile dysfunction (ED) as an independent risk marker for cardiovascular disease (CVD). In fact, incident ED has a similar or greater predictive value for cardiovascular events than traditional risk factors including smoking, hyperlipidemia, and family history of myocardial infarction. Here, we review evidence that supports ED as a particularly significant harbinger of CVD in 2 populations: men <60 years of age and those with diabetes. Although addition of ED to the Framingham Risk Score only modestly improved the 10-year predictive capacity of the Framingham Risk Score for myocardial infarction or coronary death data in men enrolled in the Massachusetts Male Aging Study, other epidemiologic studies suggest that the predictive value of ED is quite strong in younger men. Indeed, in the Olmstead County Study, men 40 to 49 years of age with ED had a 50-fold higher incidence of new-incident coronary artery disease than those without ED. However, ED had less predictive value (5-fold increased risk) for coronary artery disease in men 70 years and older. Several studies, including a large analysis of more than 6300 men enrolled in the ADVANCE study, suggest that ED is a particularly powerful predictor of CVD in diabetic men as well. Based on the literature reviewed here, we encourage physicians to inquire about ED symptoms in all men more than 30 years of age with cardiovascular risk factors. Identification of ED, particularly in men <60 years old and those with diabetes, represents an important first step toward CVD risk detection and reduction.

Laparoscopic versus subinguinal varicocelectomy: a comparative study

OBJECTIVE To determine the relative advantages of the laparoscopic approach to varicocelectomy, postoperative morbidity and pain in patients undergoing subinguinal varicocelectomies were compared with that of patients undergoing laparoscopic varicocele repairs. DESIGN Retrospective study of concurrent groups of patients undergoing laparoscopic or open subinguinal varicocele repairs. SETTING Tertiary teaching hospital. PATIENTS Forty-seven patients with primary or secondary infertility. INTERVENTIONS Patients were offered a choice between a laparoscopic or open subinguinal varicocele repair. MAIN OUTCOME MEASURES The total number of pain pills used, the number of days of analgesics, and the number of days off from work after surgery were recorded. RESULTS Fourteen patients underwent laparoscopic varicocelectomies, and 33 patients underwent subinguinal varicocelectomies. Analgesic use by the laparoscopic patients was no different from that of the subinguinal patients. The length of time off from work was significantly longer for the laparoscopic patients (6.4 days) as compared with the time off from work for the patients who underwent subinguinal varicocele repairs (2.6 days). CONCLUSION The subinguinal varicocele repair performed with local anesthesia is a safe, low morbid technique offering a quicker recovery period than laparoscopic approaches. Although laparoscopic repairs may offer a shorter recovery period when compared with standard inguinal varicocelectomies, this is not the case when compared with subinguinal approaches.

Semen Analysis and Sperm Function Assays: What Do They Mean?

Appropriate laboratory testing is an integral component of the proper evaluation of the male presenting with infertility. This article reviews the semen analysis and sperm function assays. Sperm function testing is used to determine if the sperm have the biologic capacity to perform the tasks necessary to reach and fertilize ova and ultimately result in live births. For a sperm to be fertile in vivo, it must be able to traverse the cervical mucus and reach the ova. The sperm must undergo capacitation and the acrosome reaction, fuse with the oolemma, and incorporate into the ooplasm. Proper embryo development requires that functional DNA be delivered to the ooplasm. Defects in any of these steps may result in infertility. A variety of tests are available to evaluate different aspects of these functions. To accurately use these functional assays, the clinician must understand what the tests measure, what the indications are for the assays, and how to interpret the results to direct further testing or patient management.