Infertility in Men: Recent Advances and Continuing Controversies*

Between 1 in 6 and 1 in 10 couples seek medical help for the problem of subfertility. It is important to recognize that, while in 20–25% of cases the problem was due to the male partner and in 30–40% the problem was predominantly female, in approximately 30% of cases, abnormalities were found in both partners, and in 15% no specific factor could be identified (1). It is also important, when dealing with infertile couples, to recognize that the duration of infertility is a critical prognostic factor, and in couples with a history of primary infertility of longer than 3 yr, the possibility of achieving an unassisted pregnancy is low. As is general practice in any branch of medicine, it is essential that the logical clinical approach to diagnosis should be applied in this condition. A detailed history, careful clinical examination, and selected investigations can be used to determine etiological factors that can be classified into pretesticular, testicular and post-testicular (see Table 1). The major frustration for the clinician managing infertile men is the fact that in 40–50% of cases, while the sperm defect can be defined, no specific cause can be found, designating these to the category of idiopathic spermatogenic defects. It is not possible to exhaustively evaluate the approach to each of the specific factors listed in table 1. Consequently this commentary concentrates on major recent advances and areas of continuing controversy. Aetiological factors in male infertility Aetiological factors in male infertility Varicocele treatment for infertility remains enigmatic and controversial. Moderate to large varicoceles are found in about 12–25% of men being examined for infertility, and another 15% have small or subclinical varicoceles (2, 3). Varicoceles are more frequent and larger in taller men and usually first appear at the time of puberty. Most men are unaware of a varicocele. Testes associated with large varicoceles are smaller and may be soft with more severe disturbances of spermatogenesis being commoner on the left side. Men with varicoceles have poorer semen quality than those without varicoceles (3, 4) indicating adverse effects of varicoceles on the testis. Despite this, the association of varicocele with infertility is not clear-cut as varicoceles are frequently found in fertile men, and their size may be a positive prognostic factor for fertility in untreated subfertile couples (2, 4). However the semen patterns are significantly impaired in those men with varicoceles (5, 6). Further varicoceles are more common in men with secondary infertility, but this claim may be due to patient selection bias (7). Unfortunately experimental varicoceles in animals have not revealed the pathophysiology of the condition in man. As varicocele might not be the absolute cause of a couple’s infertility, full evaluation of both male and female partner for other factors is necessary. Treatment of the varicocele involves the venographic obstruction of the incompetent veins or surgery to prevent venous back flow from the abdomen to the pampiniform plexus. Radiographic techniques involve placement of a sclerosant, glue, or coil that promotes clotting in the vein, and they carry a lower morbidity than surgery under general anesthesia, but there are relatively high failure and recurrence rates. A variety of operations can be performed for varicocele, including retroperitoneal ligation and division of the testicular veins with or without preservation of the testicular artery, as well as the more recent new inguinal and scrotal microsurgical approaches with lower failure, recurrence, and hydrocele rates. Successful venous occlusion will relieve pain if present and will reduce the size of large varicoceles (8), but whether semen quality and fertility are improved is not certain. Several large series were published with claims of high success rates for improving semen and fertility (9). Floating numerator pregnancy rates (proportion of men treated who produce a pregnancy without regard to time of follow-up) averaging 35% (range 20–60%) were commonly reported. Regression toward the mean in semen variables, the nature of subfertility, and the need to include time in the denominator of pregnancy rates were ignored (10). While there are reports of successful treatment of azoospermic men by varicocelectomy (11), transient azoospermia may follow a minor illness or occur for unknown reasons, and so such examples do not prove the value of treatment. Most exponents of varicocele treatment regard azoospermia as a bad prognostic sign especially if the FSH level is elevated. Follow-up studies of groups of treated and untreated patients with varicoceles suggest that pregnancies are as frequent without treatment as they are with treatment of the varicocele (2, 12). For example, a follow-up study of 651 subfertile men with grade I-III varicoceles showed no significant difference in pregnancy rate after testicular vein ligations in 283 men, compared with that before ligation or without treatment. None of the factors believed to be important for response to varicocelectomy, including size of varicocele, effectiveness of the prevention of reflux, or degree of reduction in varicocele size were related to the outcome (2). Attempts to conduct randomized controlled clinical trials of varicocele treatment have been difficult because the ideal design incorporating sham operations and blinding, so important in controlling for outcomes affected by psychological factors, have not been possible. Large trials are needed—for example, about 250 pregnancies are required to have a high chance of finding a 25% increase in pregnancy rate after treatment significant at the 5% level (10). So far the trials have produced conflicting results. A small (n = 67) prospective controlled study of percutaneous embolization of the left testicular vein in 17–20-yr-olds showed an increase in testicular volume and sperm concentration in the treated group (13). Others have reported similar beneficial effects of treatment of varicoceles in adolescents in less well controlled studies. A prospective randomized controlled trial comparing spermatic vein occlusion by surgical or angiographic techniques to follow-up counseling alone for 1 yr in couples without other causes of infertility showed no difference in pregnancy rate: 29% and 25% respectively at 12 months (14). In a multicenter controlled trial, sponsored by the World Health Organization (WHO), of Palomo ligation in men with infertility of greater than 1 yr duration, abnormal semen analyses, a moderate to large left varicocele, and potentially fertile female partner, volunteers were randomized to immediate operation or operation delayed for 12 months to provide an untreated control group. One of the participating centers reported their results separately and showed a significant improvement in couples after operation compared to controls (15). Semen analysis results also improved after the operation. In the other centers there was a less marked but significant improvement, with life table pregnancy rates at 1 yr being 35% for the operated group and 17% for the unoperated group (relative pregnancy rate 2.7; 95% confidence limits 1.6–4.4). Semen analysis results also improved over the first year in the operated group. In the control patients having the delayed operation, the life table pregnancy rate at 1 yr after the operation was 21% (16). However, there were problems with the WHO trial, particularly with irregular randomization and drop-out rates, and the results have not yet been published in detail. Surprisingly, the pregnancy rates in the control groups were lower than expected for untreated subfertile men with varicoceles, wherein approximately 30% produced a pregnancy in 12 months (2, 15). After a recent meta-analysis by Evers (17), the Royal College of Obstetricians and Gynaecologists concluded that there was insufficient evidence to recommend occlusion of the left internal spermatic vein in subfertile or oligosoospermic men with a varicocele. It is difficult to resolve the differing results emerging from a variety of trials, some of which have been carefully designed and executed. Patient populations may differ based on the thoroughness of the exclusion of other causes of male infertility, as varicoceles may co-exist with other abnormalities, for example Y chromosome deletions. Further, with the use of pregnancy as an outcome of varicocele treatment, the fertility of the female partner enters into the analysis. The degree to which the female partner is investigated before confirming normality can vary, and adjustments are not made for the age of the female partner. These issues are raised to provide the reader with some insight into the difficulties of performing such trials. The possibility that there may be some manner of identifying responders has been raised. Hudson (18) showed that patients who respond to treatment of varicocele had significantly greater GnRH-stimulated rises in FSH than did nonresponders, an observation confirmed by others (19). The mechanism of this intriguing observation remains obscure. Androgen deficiency with increased estradiol and SHBG levels may also be attributes of responders (20). The possibilities that responders can be predicted from hormone profiles or age and that the beneficial effect may be greater in younger men deserve study with objective methods of semen analysis and varicocele detection and simpler methods of treatment such as antegrade sclerotherapy (16). Certainly further trials are necessary to meet the demands of evidence based medicine. Thus while some people remain convinced of the value of treating varicoceles for infertility, it is not easy to demonstrate this unequivocally. The apparent improvements in semen quality and fertility may result from random fluctuations and regression toward the mean (10). It is clear that normal fertility is not achieved in a high proportion of patients treated for varicocele. Assisted reproductive technology is a realistic alternative for most couples who have not conceived after a reasonable time. Our current clinical approach to patients with varicocele and infertility is to advise the patient of the uncertainty of the effectiveness of treatment of the varicocele, and most patients choose alternative managements for the infertility. A few may have the varicocele treated because they do not want to use assisted reproductive technologies (ART) or, as a last resort, after ART has been unsuccessful. Using oocytes that have failed to fertilize in vitro to test sperm function has improved understanding of abnormalities of the human fertilization process (21). Studies with computer image analysis show that particular defects of sperm shape impair sperm-zona pellucida binding (22). The shape of the acrosome area of the sperm head appears to be particularly important. Although some workers have reported patients that appear to have isolated defects of the sperm zona receptors, these appear to be very rare, as poor sperm-zona binding is very uncommon in the absence of an obvious defect of sperm morphology (21, 23). A group of patients with unexpected failure of standard in vitro fertilization has been discovered that have disordered zona pellucida-induced acrosome reactions, which prevent sperm-zona penetration (24). The patients have morphologically normal sperm that bind to the surface of the zona pellucida, but very few undergo the acrosome reaction. They can be successfully treated by intracytoplasmic injection (ICSI), a process in which a single sperm is introduced into the cytoplasm of the oocyte. This condition may be present in 15–30% of couples with idiopathic infertility. Defective sperm-oolemma binding appears to be uncommon. Abnormalities of intravitelline sperm processing also rarely results from a sperm defect. Only globozoospermic and immotile sperm have been found to produce low fertilization rates with ICSI (25). These sperm may not decondense after intracytoplasmic sperm injection. Other than these cases, failure of the sperm head to decondense in the oocyte cytoplasm appears to be an infrequent cause of infertility. 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Several causes of male infertility, such as and have been for some time However, the possibility that could for a proportion of men classified as from the studies of and Several disordered have been to to male infertility and these are Y chromosome deletions. 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Further studies are required to these issues The use of ICSI has also the of achieving fertilization from sperm from the or from the testis. 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