Advances in the evaluation and treatment of the infertile man

Numerous advances in technology have been made in the last several years in the diagnosis and treatment of the infertile man. Using case presentations, this article highlights these important new developments and reviews the basics of a comprehensive male infertility evaluation. The use of ultrasound as a critical, indispensable, yet noninvasive tool in the evaluation of possible male reproductive tract obstruction is discussed. Since assisted reproductive techniques (ARTs) have be come increasingly important in the management of the otherwise untreatable infertile man, specialized testing of sperm function, e.g., the sperm penetration assay (SPA), and strict morphology assessment are often useful prior to the initiation of some of these assisted reproductive procedures such as intrauterine insemination (IUI) or in vitro fertilization (IVF). Testicular touch preparation cytology and image analysis are also important additions to routine testicular biopsy for quantifying the extent of spermatogenesis. Finally, the revolutionary micromanipulation procedure of intracytoplasmic sperm injection (ICSI) has forever changed the practice of andrology by enabling men previously thought to be irreversibly infertile the chance to initiate their own biologic pregnancy.     

Detection of chromosomes and estimation of aneuploidy in human spermatozoa using fluorescence in-situ hybridization

The development and application of fluorescence in-situ hybridization (FISH) has opened the way for comprehensive studies on numerical chromosome abnormalities in human spermatozoa. FISH can be rapidly applied to large numbers of spermatozoa and thus overcomes the major limitation of karyotyping spermatozoa after penetration of zona-free hamster oocytes. The simultaneous hybridization of two or more chromosome-specific probes to spermatozoa and subsequent detection of the bound probes using different fluorescent detection systems enables two or more chromosomes to be localized simultaneously in the same spermatozoon and provides a technique for undertaking reasonable estimates of aneuploidy. The most commonly used probes are those which bind to the centromeric region of specific chromosomes. Most studies to date have concentrated on estimating aneuploidy in spermatozoa from normospermic men, although reports are beginning to appear on aneuploidy in spermatozoa from subfertile and infertile men. Multi- probe FISH studies have generally reported disomy (hyperhaploidy) estimates of 0.05-0.2% per chromosome. There is preliminary evidence that some chromosomes such as X, Y and 21 are predisposed towards higher rates of non-disjunction during spermatogenesis. There are also suggestions of inter-donor variability in aneuploidy frequencies for specific chromosomes, although this requires confirmation in larger studies. While FISH is clearly a powerful technique that has many applications in reproductive medicine, it must also be realized that it does have limitations and the technology itself is still evolving and has yet to be fully validated on spermatozoa.      

Testicular function after orchiopexy for unilaterally undescended testis.

Testicular function was determined in 29 men, 21 to 35 years old, who had undergone orchiopexy for unilaterally undescended testis at four to 12 years of age. Serum testosterone and dialyzable testosterone concentrations of these men were not significantly different from those of a control group of 30 normal men, and their basal serum luteinizing hormone concentrations and serum luteinizing hormone responses to synthetic gonadotropin-releasing hormone were only slightly higher than those of the normal men. The mean sperm density of the patients, however, was only one third of that of the normal men (p less than 0.001). The mean serum follicle stimulating hormone response ro gonadotropin-releasing hormone of the patients was doubled that of the normal men (p less than 0.001). The data indicate that spermatogenesis may be abnormal after orchipexy, and suggest that men with unilaterally undescended testis may have bilateral testicular abnormality.     

Identification of MEN1 gene mutations in sporadic carcinoid tumors of the lung

Lung carcinoids occur sporadically and rarely in association with multiple endocrine neoplasia type 1 (MEN1). There are no well defined genetic abnormalities known to occur in these tumors. We studied 11 sporadic lung carcinoids for loss of heterozygosity (LOH) at the locus of the MEN1 gene on chromosome 11q13, and for mutations of the MEN1 gene using dideoxy fingerprinting. Additionally, a lung carcinoid from a MEN1 patient was studied. In four of 11 (36%) sporadic tumors, both copies of the MEN1 gene were inactivated. All four tumors showed the presence of a MEN1 gene mutation and loss of the other allele. Observed mutations included a 1 bp insertion, a 1 bp deletion, a 13 bp deletion and a single nucleotide substitution affecting a donor splice site. Each mutation predicts truncation or potentially complete loss of menin. The remaining seven tumors showed neither the presence of a MEN1 gene mutation nor 11q13 LOH. The tumor from the MEN1 patient showed LOH at chromosome 11q13 and a complex germline MEN1 gene mutation. The data implicate the MEN1 gene in the pathogenesis of sporadic lung carcinoids, representing the first defined genetic alteration in these tumors.      

Changes in clinical measures of autonomic nervous system function related to cancer chemotherapy-induced nausea

Individual cancer patients differ in their nausea/vomiting response to chemotherapy. It is not known why patients receiving the same chemotherapy have different severity of side effects. Several lines of research implicate the autonomic nervous system (ANS) in the development of chemotherapy-induced nausea. We examined the association between autonomic reactivity and the level of nausea experienced following chemotherapy in 20 patients with ovarian cancer treated with cisplatin or carboplatin who received the same antiemetic. We applied eight common non-invasive clinical tests of autonomic function prior to inpatient chemotherapy treatment, 2 h after treatment and again 24 h following treatment. Two hours after chemotherapy and before any nausea was reported by the patients, the nine patients who subsequently experienced high levels of nausea had a greater overall percentage of abnormal clinical ANS tests than the 11 patients who subsequently developed low levels of nausea (P < 0.01). Twenty-four hours after treatment, the overall number of abnormal autonomic tests remained non-significantly higher than at the pretreatment baseline for the high nausea group. Demographic and clinical characteristics were not related to chemotherapy-induced nausea in this sample. Autonomic reactivity appears to be related to the development of nausea following chemotherapy. Further investigation of ANS involvement in chemotherapy-induced nausea could increase understanding of nausea etiology and potentially lead to the prediction of susceptible patients.     

Semen Parameters Before and After Transurethral Surgery for Ejaculatory Duct Obstruction

Purpose

We examined how transurethral resection of the ejaculatory ducts, performed for infertility, affects semen quality in patients with azoospermia and oligo-asthenospermia.

Materials and Methods

A retrospective review was done of 46 cases of transurethral resection of the ejaculatory ducts for ejaculatory duct obstruction, confirmed by transrectal ultrasound. Clinical course and semen quality were assessed by semen parameter indications.

Results

In 65 percent of the patients transurethral resection of the ejaculatory ducts improved semen quality (greater than a 50 percent increase in total motile sperm count) and 20 percent initiated a pregnancy an average of 6.1 months postoperatively. Statistically significant increases in total motile sperm count were achieved in men with azoospermia and those treated for oligo-asthenospermic indications; the improvement also was shown to be sustainable. Complications occurred in 20 percent of the men.

Conclusions

Significant and durable semen quality improvement can be achieved after transurethral resection of the ejaculatory ducts for all surgical indications. In most unsuccessful cases the reason for failure is unclear.     

Dibromochloropropane and its effect on testicular function in man

This study represents the largest series to date documenting the gonadotoxic effect in humans of dibromochloropropane, a widely used pesticide. Three semen analyses, serum hormonal determinations (luteinizing hormone, follicle-stimulating hormone and testosterone) as well as genital examinations were completed for 228 workers at 2 chemical production sites and consisting of a dibromochloropropane-exposed and non-exposed cohort. Parameteric and non-parametric statistical analyses of the data sets of the sperm densities from the 2 subpopulations demonstrated statistical significance (p less than 0.10) at the short-term (1.5 years) manufacturing plant. Log transformation of the sperm count and hourly exposure data were necessary to develop meaningful statistical conclusions. The serum concentration of follicle-stimulating hormone as a group mean was significantly greater at both production sites for the exposed cohort when compared to the non-exposed participants but decreased by 10 levels of magnitude when the group demonstraing shorter but more recent exposure was compared to those from the plant with longer chemical production. Finally, a dose-response model suggested significant changes in sperm density at the short-term but more recently operated production site when more than 100 adjusted hours of exposure were exceeded, while the longer operated but longer closed facility demonstrated a significant impairment only when more than 1,000 adjusted hours of dibromochloropropane exposure were surpassed. This difference in exposure data may reflect regenerative changes in the tests once the gonadotoxic substance had been removed but exact nature of the dibromochloropropane effect and the possibility of a "no effect" concentration remain to be defined clearly.     

A prospective study of methylenetetrahydrofolate reductase and methionine synthase gene polymorphisms, and risk of colorectal adenoma

We examined the relationship between a functional polymorphism (667C-- >T, ala-->val) of the methylenetetrahydrofolate reductase gene (MTHFR) and the risk of colorectal adenomas in the prospective Nurses' Health Study. Among 257 incident polyp cases and 713 controls, the MTHFR val/val polymorphism [relative risk (RR) = 1.35, 95% confidence interval (CI) 0.84-2.17] was not significantly associated with risk of adenomas. This lack of association was observed for both small (RR = 1.36, 95% CI 0.76-2.45) and large (RR = 1.32, 95% CI 0.66-2.66) adenomas. Furthermore, there was no significant interaction between this polymorphism and consumption of either folate, methionine or alcohol. We also examined the relationship of a newly identified polymorphism (asp919gly) of the methionine synthase gene (MS) with the risk of colorectal adenomas in the same population. The MS gly/gly polymorphism was also not significantly associated with risk of colorectal adenomas (RR = 0.66, 95% CI 0.26-1.70). These results, which need to be confirmed in other studies, suggest that the MTHFR val/val polymorphism, which has been previously inversely associated with risk of colorectal cancer, plays a role only in a late stage (adenoma-- >carcinoma) of colorectal tumorigenesis, and/or may protect against malignant transformation in the subset of benign adenomas, which may progress to malignancy.