Gert R. Dohle

European Association of Urology Guidelines on Male Infertility: The 2012 Update

CONTEXT New data regarding the diagnosis and treatment of male infertility have emerged and led to an update of the European Association of Urology (EAU) guidelines for Male Infertility. OBJECTIVE To review the new EAU guidelines for Male Infertility. EVIDENCE ACQUISITION A comprehensive work-up of the literature obtained from Medline, the Cochrane Central Register of Systematic Reviews, and reference lists in publications and review articles was developed and screened by a group of urologists and andrologists appointed by the EAU Guidelines Committee. Previous recommendations based on the older literature on this subject were taken into account. Levels of evidence and grade of guideline recommendations were added, modified from the Oxford Centre for Evidence-based Medicine Levels of Evidence. EVIDENCE SUMMARY These EAU guidelines are a short comprehensive overview of the updated guidelines of male infertility as recently published by the EAU (http://www.uroweb.org/guidelines/online-guidelines/), and they are also available in the National Guideline Clearinghouse (http://www.guideline.gov/).

Androgens and male fertility

Androgens play a crucial role in the development of male reproductive organs such as the epididymis, vas deferens, seminal vesicle, prostate and the penis. Furthermore, androgens are needed for puberty, male fertility and male sexual function. High levels of intratesticular testosterone, secreted by the leydig cells, are necessary for spermatogenesis. Intratesticular testosterone is mainly bound to androgen binding protein and secreted into the seminiferous tubules. Inside the sertoli cells, testosterone is selectively bound to the androgen receptor and activation of the receptor will result in initiation and maintenance of the spermatogenic process and inhibition of germ cell apoptosis. The androgen receptor is found in all male reproductive organs and can be stimulated by either testosterone or its more potential metabolite dihydrotestosterone. Severe defects of the androgen receptor may result in abnormal male sexual development. More subtle modulations can be a potential cause of male infertility. Treatment of an infertile man with testosterone does improve spermatogenesis, since exogenous administrated testosterone and its metabolite estrogen will suppress both GnRH production by the hypothalamus and Luteinising hormone production by the pituitary gland and subsequently suppress testicular testosterone production. Also, high levels of testosterone are needed inside the testis and this can never be accomplished by oral or parenteral administration of androgens. Suppression of testosterone production by the leydig cells will result in a deficient spermatogenesis, as can be seen in men taking anabolic-androgenic steroids. Suppression of spermatogenesis by testosterone administration is also the basis for the development of a male contraceptive. During cytotoxic treatment or irradiation suppression of intratesticular testosterone production cells may prevent irreversible damage to the spermotogonial stem cells.

Varicocele and male factor infertility treatment: a new meta-analysis and review of the role of varicocele repair.

CONTEXT Varicocele is a common condition, found in many men who present for infertility evaluation. OBJECTIVE To assess the effect of varicocelectomy on male infertility. EVIDENCE ACQUISITION A literature search was performed using Embase and Medline. Literature reviewed included meta-analyses and randomized and nonrandomized prospective (controlled and noncontrolled) studies. In addition, a new meta-analysis was performed. EVIDENCE SYNTHESIS Four randomized controlled trials reporting on pregnancy outcome after repair of clinical varicoceles in oligozoospermic men were identified. Using the random effect model, the combined odds ratio was 2.23 (95% confidence interval [CI], 0.86-5.78; p=0.091), indicating that varicocelectomy is moderately superior to observation, but the effect is not statistically significant. We identified 22, 17, and 5 prospective studies reporting on sperm concentration, total motility, and progressive motility, respectively, before and after repair of clinical varicocele. The random effect model combined improvement in sperm concentration was 12.32 million sperm per milliliter (95% CI, 9.45-15.19; p<0.0001). The random effect model combined improvement in sperm total and progressive motility were 10.86% (95% CI, 7.07-14.65; p<0.0001) and 9.69% (95% CI, 4.86-14.52; p=0.003), respectively. These results indicate that varicocelectomy is associated with a significant increase in sperm concentration as well as total and progressive motility. Prospective studies also show that varicocelectomy reduces seminal oxidative stress and sperm DNA damage as well as improving sperm ultramorphology. Studies indicate that a microsurgical approach to a varicocele repair results in less recurrence and fewer complications than other techniques. CONCLUSIONS Although there is no conclusive evidence that a varicocele repair improves spontaneous pregnancy rates, varicocelectomy improves sperm parameters (count and total and progressive motility), reduces sperm DNA damage and seminal oxidative stress, and improves sperm ultramorphology. The various methods of repair are all viable options, but microsurgical repair seems to be associated with better outcomes.

Diagnostic value of OCT3/4 for pre-invasive and invasive testicular germ cell tumours.

Human testicular germ cell tumours of adolescents and adults (TGCTs), the seminomatous and non‐seminomatous germ cell tumours, show morphological and biological similarities to normal embryonic development, presumably determined by their supposed cell of origin, the primordial germ cell/gonocyte. Based on this knowledge, OCT3/4, also known as POU5F1, was recently defined as a diagnostic marker for these tumour types. In the adult testis, positive immunohistochemistry for OCT3/4 is an absolute indicator for the presence of the TGCT precursor carcinoma in situ/intratubular germ cell neoplasia undifferentiated (CIS/ITGCNU), seminoma, and/or embryonal carcinoma. Several studies have confirmed this observation, using the same polyclonal antibody. The present study demonstrates the usefulness of OCT3/4 immunohistochemistry in a diagnostic setting of a consecutively collected series of more than 200 testicular tumours and over 80 testicular biopsies. Moreover, it is shown that a monoclonal antibody directed against OCT3/4 is as informative as the polyclonal antibody, both in immunohistochemistry and in western blot analysis. The antibodies are robust and applicable with different methods of pretreatment and storage of tissue. This allows routine application of this diagnostic marker. Copyright

Male infertility in cancer patients: Review of the literature

The number of men surviving cancer at a young age has increased dramatically in the past 20 years as a result of early detection and improved cancer treatment protocols; more than 75% of young cancer patients nowadays are long‐term survivors. Quality of life has become an important issue in childhood and adult cancer patients. The commonest cancers in patients of reproductive age are leukaemia, Hodgkins lymphomas and testicular germ cell tumors. Fertility is often impaired after chemotherapy and radiation therapy. Cryopreservation of semen before cancer treatment starts is currently the only method to preserve future male fertility. In some malignancies, especially in germ cell tumors, sperm quality is already abnormal at the time of diagnosis. In approximately 12% of men, no viable spermatozoa are present for cryopreservation before the start of chemotherapy. Cytotoxic therapy influences spermatogenesis at least temporarily and in some cases permanently. The amount of damage inflicted by chemotherapy on spermatogenesis depends on the combination of drugs used and on the cumulative dose given for cancer treatment. Alkylating agents, such as cyclophosphamide and procarbazine, are most detrimental to germ cells. Radiation therapy, especially whole‐body irradiation, is also associated with the risk of permanent sterility. Besides the cancer treatment, tumor type and pretreatment fertility are of prognostic value for future fertility in male cancer survivors. After cancer treatment, many men need artificial reproductive techniques to achieve fatherhood; usually in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) is indicated for successful treatment. About 15% of men will use their cryopreserved semen because of persistent azoospermia after cancer treatment. Treatment results with cryopreserved semen are generally good and comparable to general IVF and ICSI results. So far, no studies have reported an increased rate of congenital abnormalities or malignancies in children born from fathers who had cancer treatment is the past, but close follow up is warranted, especially in children born after IVF/ICSI.

Erectile dysfunction prospectively associated with cardiovascular disease in the Dutch general population: results from the Krimpen Study

The possible relationship between erectile dysfunction and the later occurrence of cardiovascular disease while biologically plausible has been evaluated in only a few studies. Our objective is to determine the relation between ED as defined by a single question on erectile rigidity and the later occurrence of myocardial infarction, stroke and sudden death in a population-based cohort study. In Krimpen aan den IJssel, a municipality near Rotterdam, all men aged 50–75 years, without cancer of the prostate or the bladder, without a history of radical prostectomy, neurogenic bladder disease, were invited to participate for a response rate of 50%. The answer to a single question on erectile rigidity included in the International Continence Society male sex questionnaire was used to define the severity of erectile dysfunction at baseline. Data on cardiovascular risk factors at baseline (age smoking, blood pressure, total- and high-density lipoprotein cholesterol, diabetes) were used to calculate Framingham risk scores. During an average of 6.3 years of follow-up, cardiovascular end points including acute myocardial infarction, stroke and sudden death were determined. Of the 1248 men free of CVD at baseline, 258 (22.8%) had reduced erectile rigidity and 108 (8.7%) had severely reduced erectile rigidity. In 7945 person-years of follow-up, 58 cardiovascular events occurred. In multiple variable Cox proportional hazards model adjusting for age and CVD risk score, hazard ratio was 1.6 (95% confidence interval (CI): 1.2–2.3) for reduced erectile rigidity and 2.6 (95% CI: 1.3–5.2) for severely reduced erectile rigidity. The population attributable risk fraction for reduced and severely reduced erectile rigidity was 11.7%. In this population-based study, a single question on erectile rigidity proved to be a predictor for the combined outcome of acute myocardial infarction, stroke and sudden death, independent of the risk factors used in the Framingham risk profile.

Decreased Sperm DNA Fragmentation After Surgical Varicocelectomy is Associated With Increased Pregnancy Rate

PURPOSE We prospectively evaluated changes in sperm chromatin structure in infertile patients before and after surgical repair of varicocele, and the impact on the pregnancy rate. MATERIALS AND METHODS Included in the study were 49 men with at least a 1-year history of infertility, a palpable varicocele and oligospermia. World Health Organization semen analysis and sperm DNA damage expressed as the DNA fragmentation index using the sperm chromatin structure assay were assessed preoperatively and postoperatively. Pregnancy (spontaneous and after assisted reproductive technique) was recorded 2 years after surgery. RESULTS Mean sperm count, sperm concentration and sperm progressive motility improved significantly after varicocelectomy from 18.3 x 10(6) to 44.4 x 10(6), 4.8 x 10(6)/ml to 14.3 x 10(6)/ml and 16.7% to 26.6%, respectively (p <0.001). The DNA fragmentation index decreased significantly after surgery from 35.2% to 30.2% (p = 0.019). When the definition of greater than 50% improvement in sperm concentration after varicocelectomy was applied, 31 of 49 patients (63%) responded to varicocelectomy. After varicocelectomy 37% of the couples conceived spontaneously and 24% achieved pregnancy with assisted reproductive technique. The mean postoperative DNA fragmentation index was significantly higher in couples who did not conceive spontaneously or with assisted reproductive technique (p = 0.033). CONCLUSIONS After varicocelectomy sperm parameters significantly improved and sperm DNA fragmentation was significantly decreased. Low DNA fragmentation index values are associated with a higher pregnancy rate (spontaneous and with assisted reproductive technique). We suggest that varicocelectomy should be considered in infertile men with palpable varicocele, abnormal semen analysis and no major female factors.

IS ROUTINE SCROTAL ULTRASOUND ADVANTAGEOUS IN INFERTILE MEN

PURPOSE We determine the value of routine scrotal ultrasonography in the evaluation of male infertility. MATERIALS AND METHODS Scrotal color Doppler ultrasonography reports of 1,372 infertile men were reviewed to assess the prevalence of scrotal abnormalities and compared to clinical findings. RESULTS The prevalence of scrotal abnormalities was 38%. Testicular tumor was found in 0.5%, varicocele in 29.7%, testicular cyst in 0.7%, testicular microlithiasis in 0.9%, epididymal cyst in 7.6% and hydrocele in 3.2% of the cases. Overall, 67% of sonography findings were not evident on palpation, and only 1 of 7 testicular tumors was suspected. Of the varicoceles 60% were not found on physical examination. The rate of testicular tumors (1/200) was higher than that reported for the general European population (1/20,000). CONCLUSIONS Routine scrotal ultrasound provides valuable information in the diagnostic evaluation of infertile men and substantially more pathological conditions are detected compared to clinical palpation. The high prevalence of testicular malignancies underlines the clinical relevance of routine scrotal ultrasonography in infertile men.

Use rate and assisted reproduction technologies outcome of cryopreserved semen from 629 cancer patients

OBJECTIVE To assess the use rate and assisted reproductive technologies (ART) outcome of the cryopreserved semen of cancer patients with an average follow-up of 7 years (range, 2-23 years). DESIGN Retrospective data analysis. SETTING University-affiliated andrology and reproduction center. PATIENT(S) Six hundred twenty-nine male cancer patients who were referred for semen cryopreservation between 1983 and 2004. INTERVENTION(S) Review of patient characteristics and ART outcome. MAIN OUTCOME MEASURE(S) Use rate and live births using cryopreserved semen. RESULT(S) A total of 749 semen samples from 557 men were preserved. Ninety-one patients died during follow-up, and another 29 requested disposal. Forty-two patients requested the use of their banked semen. ART data were available for 37 patients. A total of 101 ART cycles (32 IVF, 53 intracytoplasmic sperm injection [ICSIs], nine cryo-ET, and seven intrauterine inseminations [IUIs]) were performed, resulting in, respectively, 8, 16, 2, and 1 pregnancies. Pregnancies rates for IVF and ICSI were significantly higher than those for IUI. CONCLUSION(S) So far, 7.5% of the cancer survivors have used their banked semen, which led to live births in 49% of the couples. Semen cryopreservation is a reliable method to preserve fertility potential and gives couples a reasonable chance of achieving parenthood.

Effect of childhood cancer treatment on fertility markers in adult male long-term survivors

Although it is accepted that pediatric cancer treatment harbors a risk of gonadal damage, large cohort studies using up‐to‐date fertility markers are lacking.