Sandro C. Esteves

An update on the clinical assessment of the infertile male

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.

Critical Appraisal of World Health Organization's New Reference Values for Human Semen Characteristics and Effect on Diagnosis and Treatment of Subfertile Men

In 2010, the World Health Organization established new reference values for human semen characteristics that are markedly lower than those previously reported. Despite using controlled studies involving couples with a known time to pregnancy to establish the new limits, the reference studies are limited with regard to the population analyzed and the methods used for semen evaluation. The present review discusses concerns related to the new reference values for semen characteristics, including the effect on patient referral, diagnosis, and treatment of recognized conditions, such as varicocele, and on the indications for assisted reproductive technologies.

Insight into oxidative stress in varicocele-associated male infertility: part 2

Varicocele, the leading cause of male infertility, can impair spermatogenesis through several pathophysiological mechanisms. Of these, current evidence suggests that oxidative stress is the central element contributing to infertility in men with varicocele, to which the testis responds by way of heat stress, ischaemia or production of vasodilators, such as nitric oxide. Surgical varicocele repair (varicocelectomy) is beneficial not only for alleviating oxidative stress-associated infertility, but also for preventing and protecting against the progressive character of varicocele and its consequent upregulations of systemic oxidative stress. However, antioxidant therapy in infertile men with surgically treated and those with untreated varicocele is poorly studied, and well-designed trials are needed.

Unexplained Male infertility: diagnosis and Management

Unexplained male infertility is a diagnosis reserved for men in whom routine semen analyses results are within normal values and physical as well as endocrine abnormalities were ruled out. In addition to erectile problems and coital factors, immunologic causes and sperm dysfunction may contribute to such condition. New etiologies of unexplained male infertility include low level leukocytospermia and mitochondrial DNA polymerase gene polymorphism. Contemporary andrology may reveal cellular and sub-cellular sperm dysfunctions which may explain subfertility in such cases, thus aiding the clinician to direct the further work-up, diagnosis and counseling of the infertile male. The objective of this article is to highlight the concept of unexplained male infertility and focuses on the diagnosis and treatment of this condition in the era of modern andrology and assisted reproductive techniques. Extensive literature review was performed using the search engines: Pubmed, Science-direct, Ovid and Scopus.

Ureteroscopic stone removal in the distal ureter. Why change

PURPOSE We compared our experience with ureteroscopic stone basket manipulation under fluoroscopic guidance to ultrasound ureterolithotripsy for distal ureteral stone removal. MATERIALS AND METHODS Retrospectively, we analyzed the medical records of 981 patients with ureteral calculi between January 1994 and December 1995, of whom 483 (49%) were treated for stones in the lower ureter and constituted our study group. The decision of when to perform lithotripsy (group 2) versus a basket procedure (group 1) was based on a prospective nonrandomized study and both groups were compared historically. All 322 patients in group 1 (mean age 49 years, range 14 to 86) primarily underwent ureteroscopic stone basket manipulation using the 4-wire Segura* basket. If the calculus could not be removed with the basket and another procedure was necessary, the case was considered a failure. The 161 patients in group 2 (mean age 37 years, range 14 to 74) underwent initially ultrasound ureterolithotripsy for stone fragmentation followed or not by removal of the fragments with the basket. Stone size did not differ significantly between groups 1 (mean 0.9 cm., range 0.6 to 1.7) and 2 (mean 0.8 cm., range 0.7 to 2.0). Ureteroscopy was performed in both groups with epidural anesthesia and on an outpatient basis in the majority of cases. RESULTS The stone-free rate after 1 procedure was 98.1 and 95.6% in group 1 and 2, respectively. For group 2 versus group 1 the operative time was longer (mean 50, range 25 to 90 versus mean 19 minutes, range 11 to 40, respectively, p < 0.001), the complication rate was greater (16.1 versus 4.3%, respectively, p < 0.001) and average hospital stay was longer (2.1 versus 0.15 day, respectively, p < 0.001). CONCLUSIONS Ureteroscopic stone treatment with basket manipulation under fluoroscopic guidance or ultrasound ureterolithotripsy provided a high stone-free rate. However, stone removal with the basket manipulation technique should be considered the first choice for treatment of small distal ureteral calculi based on the minimal morbidity, and short operative and recovery times.

Effect of mobile telephones on sperm quality: A systematic review and meta-analysis☆

Mobile phones are owned by most of the adult population worldwide. Radio-frequency electromagnetic radiation (RF-EMR) from these devices could potentially affect sperm development and function. Around 14% of couples in high- and middle-income countries have difficulty conceiving, and there are unexplained declines in semen quality reported in several countries. Given the ubiquity of mobile phone use, the potential role of this environmental exposure needs to be clarified. A systematic review was therefore conducted, followed by meta-analysis using random effects models, to determine whether exposure to RF-EMR emitted from mobile phones affects human sperm quality. Participants were from fertility clinic and research centres. The sperm quality outcome measures were motility, viability and concentration, which are the parameters most frequently used in clinical settings to assess fertility. We used ten studies in the meta-analysis, including 1492 samples. Exposure to mobile phones was associated with reduced sperm motility (mean difference -8.1% (95% CI -13.1, -3.2)) and viability (mean difference -9.1% (95% CI -18.4, 0.2)), but the effects on concentration were more equivocal. The results were consistent across experimental in vitro and observational in vivo studies. We conclude that pooled results from in vitro and in vivo studies suggest that mobile phone exposure negatively affects sperm quality. Further study is required to determine the full clinical implications for both sub-fertile men and the general population.

A comprehensive review of genetics and genetic testing in azoospermia

Azoospermia due to obstructive and non-obstructive mechanisms is a common manifestation of male infertility accounting for 10-15% of such cases. Known genetic factors are responsible for approximately 1/3 of cases of azoospermia. Nonetheless, at least 40% of cases are currently categorized as idiopathic and may be linked to unknown genetic abnormalities. It is recommended that various genetic screening tests are performed in azoospermic men, given that their results may play vital role in not only identifying the etiology but also in preventing the iatrogenic transmission of genetic defects to offspring via advanced assisted conception techniques. In the present review, we examine the current genetic information associated with azoospermia based on results from search engines, such as PUBMED, OVID, SCIENCE DIRECT and SCOPUS. We also present a critical appraisal of use of genetic testing in this subset of infertile patients.

Cigarette Smoking and Semen Quality: A New Meta-analysis Examining the Effect of the 2010 World Health Organization Laboratory Methods for the Examination of Human Semen

OBJECTIVE Approximately 37% of men of reproductive age smoke cigarettes, with Europe having the highest tobacco use among all the World Health Organization (WHO) regions. Toxins from tobacco smoking can potentially affect sperm development and function, with a negative effect on semen parameters. Given the high prevalence of smoking and recent changes in the WHO laboratory methods for the examination of human semen, the role of this exposure in face of new WHO methods needs to be clarified. EVIDENCE ACQUISITION We conducted a systematic review, followed by a meta-analysis, to determine whether cigarette smoking affects human semen parameters. PubMed, Saint Josephs University Discover, and Google Scholar were used to identify relevant studies published after release of the latest WHO methods for laboratory evaluation of human semen. Participants were from fertility/urologic clinics and andrology laboratories. The outcome measures were semen volume, sperm concentration, motility, and morphology, the parameters usually used in clinical settings to assess fertility. EVIDENCE SYNTHESIS Twenty studies with 5865 participants were included in the meta-analysis. Exposure to cigarette smoking was associated with reduced sperm count (mean difference [MD]: -9.72×106/ml; 95% confidence interval [CI], -13.32 to -6.12), motility (MD: -3.48%; 95% CI, -5.53 to -1.44), and morphology (MD: -1.37%; 95% CI, -2.63 to -0.11). Subgroup analyses indicated that effect size was higher in infertile men than in the general population and in moderate/heavy smokers than in mild smokers. The overall effect size on semen volume, sperm count, and motility remained similar when 2010 and earlier WHO manuals were used for semen analysis but was lower with regard to sperm morphology. CONCLUSIONS Our results suggest that cigarette smoking has an overall negative effect on semen parameters. The latest WHO laboratory methods for the examination of human semen had a minimal impact on the magnitude of effect size, thus confirming the observed negative effect of smoking on conventional semen parameters. PATIENT SUMMARY A new systematic review and meta-analysis comprising 5865 men shows that cigarette smoking is associated with reduced sperm count and motility. Deterioration of semen quality is more pronounced in moderate and heavy smokers.

Clinical outcome of intracytoplasmic sperm injection in infertile men with treated and untreated clinical varicocele.

PURPOSE We evaluated the impact of varicocelectomy on intracytoplasmic sperm injection outcomes in infertile men with clinical varicocele. MATERIALS AND METHODS We studied 242 infertile men with a history of clinical varicocele who underwent intracytoplasmic sperm injection. Of the men 80 underwent prior subinguinal microsurgical varicocelectomy (treated group 1) and 162 had any grade of clinical varicocele (untreated group 2) at sperm injection. We compared semen analysis results before and after varicocelectomy, and the sperm injection procedure outcomes. Mean time from surgery to sperm injection was 6.2 months. Logistic regression was done to verify whether varicocelectomy influenced the odds of clinical pregnancy, live birth and miscarriage. RESULTS We noted an improved total number of motile sperm (6.7 × 10(6) vs 15.4 × 10(6), p <0.01) and a decreased sperm defect score (2.2 vs 1.9, p = 0.01) after vs before varicocele repair. The clinical pregnancy (60.0% vs 45.0%, p = 0.04) and live birth (46.2% vs 31.4%, p = 0.03) rates after the sperm injection procedure were higher in the treated than in the untreated group. The chance of achieving clinical pregnancy (OR 1.82; 95% CI 1.06-3.15) and live birth (OR 1.87, 95% CI 1.08-3.25) by the sperm injection procedure were significantly increased while the chance of miscarriage was decreased (OR 0.433, 95% CI 0.22-0.84) after varicocele was treated. CONCLUSIONS Results suggest that varicocelectomy improves clinical pregnancy and live birth rates by intracytoplasmic sperm injection in infertile couples in which the male partner has clinical varicocele. The chance of miscarriage may be decreased if varicocele is treated before assisted reproduction.

Hypogonadotropic Hypogonadism Revisited

Impaired testicular function, i.e., hypogonadism, can result from a primary testicular disorder (hypergonadotropic) or occur secondary to hypothalamic-pituitary dysfunction (hypogonadotropic). Hypogonadotropic hypogonadism can be congenital or acquired. Congenital hypogonadotropic hypogonadism is divided into anosmic hypogonadotropic hypogonadism (Kallmann syndrome) and congenital normosmic isolated hypogonadotropic hypogonadism (idiopathic hypogonadotropic hypogonadism). The incidence of congenital hypogonadotropic hypogonadism is approximately 1-10:100,000 live births, and approximately 2/3 and 1/3 of cases are caused by Kallmann syndrome (KS) and idiopathic hypogonadotropic hypogonadism, respectively. Acquired hypogonadotropic hypogonadism can be caused by drugs, infiltrative or infectious pituitary lesions, hyperprolactinemia, encephalic trauma, pituitary/brain radiation, exhausting exercise, abusive alcohol or illicit drug intake, and systemic diseases such as hemochromatosis, sarcoidosis and histiocytosis X. The clinical characteristics of hypogonadotropic hypogonadism are androgen deficiency and a lack/delay/stop of pubertal sexual maturation. Low blood testosterone levels and low pituitary hormone levels confirm the hypogonadotropic hypogonadism diagnosis. A prolonged stimulated intravenous GnRH test can be useful. In Kallmann syndrome, cerebral MRI can show an anomalous morphology or even absence of the olfactory bulb. Therapy for hypogonadotropic hypogonadism depends on the patients desire for future fertility. Hormone replacement with testosterone is the classic treatment for hypogonadism. Androgen replacement is indicated for men who already have children or have no desire to induce pregnancy, and testosterone therapy is used to reverse the symptoms and signs of hypogonadism. Conversely, GnRH or gonadotropin therapies are the best options for men wishing to have children. Hypogonadotropic hypogonadism is one of the rare conditions in which specific medical treatment can reverse infertility. When an unassisted pregnancy is not achieved, assisted reproductive techniques ranging from intrauterine insemination to in vitro fertilization to the acquisition of viable sperm from the ejaculate or directly from the testes through testicular sperm extraction or testicular microdissection can also be used, depending on the womans potential for pregnancy and the quality and quantity of the sperm.