The study of varicocele through the use of animal models

The pathophysiology of the varicocele has received considerable study, both in humans and in animal models. Mechanistic information is difficult to obtain from human subjects because study designs must not be invasive and the subject population is variable in the status of the varicocele, patient age, fertility or other health-related issues. Because of these limitations, animal models of varicocele have been developed in several species, the most common being the rat. Surgery to establish the varicocele involves partial obstruction of the left renal vein, causing a varicosity of the left spermatic vein, including the pampiniform plexus. Studies using this model have shown that experimental left varicocele induces bilateral increases in testicular blood flow and temperature contemporaneous with decreases in intratesticular testosterone and testicular sperm output. Spermatic vein reflux is not related to the pathophysiological consequences of experimental varicocele. Many questions remain regarding the mechanism by which varicocele induces testicular dysfunction, chief among them being how the unilateral varicocele causes a bilateral testicular response in the first place.     

The varicocele dilemma

There is probably no subject that is more controversial in the area of male infertility than varicocele. The overwhelming majority of non-urologist infertility specialists in the world are extremely sceptical of the role of varicocele or varicocelectomy in the treatment of male infertility. Directors of most assisted reproductive technologies (ART) programmes view the enthusiasm with which urologists approach varicocelectomy as a potential impediment to the couple that is getting older and do not have much time left to become pregnant using ART. There are many credible, well-controlled studies which show no effect of varicocelectomy on fertility. There are also a few 'controlled' studies that favour varicocelectomy, but all can be criticised on the basis of patient selection bias. Thus the great weight of evidence from controlled studies is against varicocelectomy and the reports supporting varicocelectomy are extremely weak. Finally, the reports that semen parameters are improved by varicocelectomy is flawed by uncontrolled observations and the failure to take into account the variability of semen analysis in infertile men and its regression toward the mean. Many control studies have demonstrated that, because of this variability, men with an initially low sperm count tend later to have higher sperm counts in the absence of any treatment whatsoever.     

Varicocele as a progressive lesion: positive effect of varicocele repair

Varicoceles are the leading correctable cause of infertility in men who present to an infertility clinic for evaluation. Consequently, the surgical correction of a varicocele, known as a varicocelectomy, is the most commonly performed operation for the treatment of male infertility. The current data suggest that an individual with a varicocele, even with a previously normal semen analysis or documentation of previous fertility, is at risk for subsequent loss of testicular function and infertility. Many of these patients will need to be treated because there is convincing evidence that a varicocele may have a progressive toxic effect on the testes that may ultimately result in irreversible infertility if left untreated. Identifying those individuals with varicoceles that will ultimately cause fertility impairment is still beyond our current clinical capabilities. Current investigative modalities, e.g. semen analysis, testicular measurement, serum gonadotrophin determination, gonadotrophin-releasing hormone (GnRH) stimulation test, and testis biopsy analysis, may be employed to detect early changes in testicular physiology produced by a varicocele.     

Varicocele--the most common cause of male factor infertility?

Varicocele is often cited as the most common cause of male factor infertility. Arguments in support of this statement include reports of increased prevalence of varicocele in populations of infertile men compared with fertile or otherwise unselected men, association of varicocele with abnormal semen parameters, and improvements in semen parameters and/or pregnancy rates after varicocele repair. Logically, there would appear to be three possibilities regarding the relationship between varicocele and fertility: (i) varicocele has no association with or effect on male fertility; (ii) varicocele may be associated with, but is not the cause of, male subfertility; and (iii) varicocele is a direct cause of male subfertility. In the following, we review evidence from the literature for and against these three possibilities: at the current time, available evidence appears inadequate to confirm or deny any of these three possibilities. Since the ultimate goal of infertile couples is to conceive, it seem logical that future varicocele research should focus primarily on adequately powered, controlled clinical trials in well-characterized infertile couples, randomized to intervention or appropriate controlled observation, with pregnancy as the primary outcome.     

Role of sperm chromatin abnormalities and DNA damage in male infertility

Sperm DNA integrity is essential for the accurate transmission of genetic information. It has a highly compact and complex structure and is capable of decondensation-features that must be present in order for a spermatozoon to be considered fertile. Any form of sperm chromatin abnormalities or DNA damage may result in male infertility. In support of this conclusion, it was reported that in-vivo fecundity decreases progressively when > 30% of the spermatozoa are identified as having DNA damage. Several methods are used to assess sperm chromatin/DNA, which is considered an independent measure of sperm quality that may yield better diagnostic and prognostic approaches than standard sperm parameters (concentration, motility and morphology). The clinical significance of this assessment lies in its association not only with natural conception rates, but also with assisted reproduction success rates. Also, it has a serious impact on the offspring and is highly prognostic in the assessment of fertility in cancer patients. Therefore, screening for sperm DNA damage may provide useful information in cases of male idiopathic infertility and in those men pursuing assisted reproduction. Treatment should include methods for prevention of sperm DNA damage.     

Preserving the reproductive potential of men and boys with cancer: current concepts and future prospects

The introduction of ICSI has totally changed the reproductive prospects for boys and men who are treated for cancer. With post-pubertal boys and adult men, semen cryopreservation should be offered to every patient undergoing a cancer treatment since preservation of fertility cannot be guaranteed for an individual patient and treatment may shift to a more sterilizing regimen. In the ICSI era, all semen samples, even those containing only a few motile sperm, should be accepted for cryopreservation. Patients who are azoospermic at the time cancer is diagnosed may be offered testicular sperm extraction and cryopreservation of testicular tissue. With pre-pubertal boys, no prevention of sterility by sperm banking is possible since no active spermatogenesis is present. However, in the next decade, prevention of sterility in childhood cancer survivors will become a major challenge for reproductive medicine. In theory, testicular stem cell banking is the only way of preserving the future fertility of boys undergoing a sterilizing chemotherapy. In animal models, testicular stem cell transplantation has proved to be effective; however, it remains to be shown that this technique is clinically efficient as well, especially when frozen-thawed cells are to be transplanted. Malignancy recurrence prevention is an important prerequisite for any clinical application of testicular stem cell transplantation. Although still at the experimental stage, cryobanking of testicular tissue from pre-pubertal boys may now be considered an acceptable strategy.     

The pathophysiology of varicoceles in the light of current molecular and genetic information

Varicoceles are a common cause of male infertility, but despite data being obtained from animal models and human studies the pathophysiology remains unclear. Recently, molecular and genetic information has been reported on men with varicoceles which may shed new light onto the causes of decreased semen parameters and poor sperm function. Here, a number of studies are reviewed in an attempt to develop a working hypothesis for the relationship of varicoceles and infertility. New studies on testicular tissue of men with varicoceles have demonstrated increased apoptosis among developing germ cells, which may be the cause of oligospermia. Other studies with semen have shown increased levels of reactive oxygen species (ROS) in association with poor sperm motility. Recent studies of morphologically abnormal spermatozoa have demonstrated disruption of the sperm head actin by cadmium, a cation reported to be present in high concentrations among some men with varicoceles. Finally, microdeletions of the alpha-1 subunit of the sperm calcium channels in a proportion of men with varicoceles suggests a genetic defect leading to abnormal acrosomal function. The intent of this review was to explain the pathophysiology of varicoceles, and the findings seem to support a 'co-factor' hypothesis. In order for varicoceles to be associated with infertility, they exist as 'co-factors' along with other molecular/genetic problems.     

Reproductive functions of the ageing male

Delayed childbearing is a common phenomenon in industrialized countries. This review focuses on age-associated alterations of male fertility and genetic risks. Semen volume, sperm motility and sperm morphology decrease with age, whereas the data concerning sperm concentration are conflicting. The age-related changes of semen parameters reflect the histological modifications which are found to varying degrees in individual testes. Men aged >40 years contribute to reduced fertility and fecundity of a couple, especially when the female partner is also of advanced age. Because relatively few children are born to older fathers and genetic diseases are rare, there is little statistical power supporting an association of genetic diseases in the offspring with advancing paternal age. Nevertheless, autosomal dominant diseases and some diseases of complex aetiology, such as schizophrenia, are associated with advancing paternal age. The single point mutations in sperm which are responsible for achondroplasia and Apert's syndrome, two autosomal dominant diseases, increase with the man's age. In case of Apert's syndrome this increase is believed to be due to a pre-meiotic selection of mutant spermatogonia. Although structural chromosome anomalies and disomies of certain chromosomes increase in sperm with the man's age, paternal age is, with the exception of trisomy 21, not associated with numerical or de novo structural chromosomal aberrations in newborns. However, even if the genetic risk for progeny from older fathers is slightly increased, the risk to the individual is low.     

Prostasomes--their effects on human male reproduction and fertility

The prostate is a glandular male accessory sex organ vital fornormal fertility. It provides the prostatic component of seminalplasma which nourishes and protects sperm following ejaculation.Prostasomes are small (40–500 nm) membrane-bound vesiclesproduced by epithelial cells lining the prostate acini and area component of prostatic secretions. Although the existenceof these particles has been known for many years, their fullfunction and relevance to reproductive health are largely unknown.Proteomic studies have shown a wide range of proteins (enzymes,structural proteins and novel, unannotated proteins) presentin or on the surface of prostasomes providing them with a diversenature. Interestingly prostasomes are able to fuse with sperm,this event and the associated transfer of proteins lies at theheart of many of their proposed functions. Sperm motility isincreased by the presence of prostasomes and their fusion preventspremature acrosome reactions. Prostasomes have been shown toaid protection of sperm within the female reproductive tractbecause of immunosuppressive, antioxidant and antibacterialproperties. Clinically these functions imply a role for prostasomesin male factor infertility. However, the very functions thatpromote fertility may have negative connotations in later life;recent work has suggested that prostasomes are involved in prostatecancer. Clearly more work is needed to clarify the role of thesenovel particles and their impact on men’s health.     

Male hormonal contraception: concept proven, product in sight?

Current male hormonal contraceptive (MHC) regimens act at various levels within the hypothalamic pituitary testicular axis, principally to induce the withdrawal of the pituitary gonadotrophins and in turn intratesticular androgen production and spermatogenesis. Azoospermia or severe oligozoospermia result from the inhibition of spermatogonial maturation and sperm release (spermiation). All regimens include an androgen to maintain virilization, while in many the suppression of gonadotrophins/spermatogenesis is augmented by the addition of another anti-gonadotrophic agent (progestin, GnRH antagonist). The suppression of sperm concentration to 1 x 10(6)/ml appears to provide comparable contraceptive efficacy to female hormonal methods, but the confidence intervals around these estimates remain relatively large, reflecting the limited number of exposure years reported. Also, inconsistencies in the rapidity and depth of spermatogenic suppression, potential for secondary escape of sperm into the ejaculate and onset of fertility return not readily explainable by analysis of subject serum hormone levels, germ cell number or intratesticular steroidogenesis, are apparent. As such, a better understanding of the endocrine and genetic regulation of spermatogenesis is necessary and may allow for new treatment paradigms. The development of an effective, consumer-friendly male contraceptive remains challenging, as it requires strong translational cooperation not only between basic scientists and clinicians but also between public and private sectors. At present, a prototype MHC product using a long-acting injectable testosterone and depot progestin is well advanced.     

Sperm banking and assisted reproduction treatment for couples following cancer treatment of the male partner

In recent years, the survival of young males suffering from cancer has been improved. Development of new techniques such as IVF and intracytoplasmic sperm injection enables even low quality spermatozoa to be used successfully. It is possible therefore to preserve fertility potential of cancer patients before embarking on adjuvant chemotherapy and radiotherapy. Recognizing the importance of protecting the fertility potential of these young males, we present our recommendations for sperm cryopreservation based on the 11 year experience of Bourn Hall and the British Joint Council for Clinical Oncology consultation report. This paper discusses the options available for patients who recover from cancer to become fathers. In many cases patients are concerned about possible abnormalities and teratogenic risks to their future children who have been conceived naturally or by fertility treatment. The data available in the literature may reassure the medical community that there is no such increased risk. However, due to the relatively small number of children born after such treatment, a long-term follow-up is required. There is an ongoing debate regarding the justification for the programme due to the small number of patients who make use of their banked spermatozoa. The authors believe in the importance of protecting the fertility potential of cancer patients, enabling them to father their genetic children in the future while fighting their illness.     

Function of aquaporins in female and male reproductive systems

The flow of water and some other small molecules across cell membranes is important in many of the processes underlying reproduction. The fluid movement is strongly associated with the presence of aquaporins (AQPs) in the female and male reproductive systems. It has been suggested that AQPs mediate water movement into the antral follicle and play important roles in follicle development. AQPs are known to be involved in the early stage of spermatogenesis, in the secretion of tubule liquid and in the concentration and storage of spermatozoa. Fluid reabsorption in some regions of the male reproductive tract is under steroid hormone control and could be mediated by various AQPs. Also AQPs take part in the processes of fertilization, blastocyst formation (as the pathway for transtrophoectodermal water movement during cavitation) and implantation. Alterations in the expression and function or regulation of AQPs have already been demonstrated in disorders of the male reproductive system, such as abnormal sperm motility, the abnormal epididymis and infertility seen in cystic fibrosis, and varicocele. This article extensively reviews the distribution of AQPs in mammalian reproductive tissues and discusses their possible physiological and pathophysiological roles.     

Mood disorders and fertility in women: a critical review of the literature and implications for future research

A medline literature review of fertility and mood disorder articles published since 1980 was performed in order to critically review the literature regarding a relationship between mood disorders, fertility and infertility treatment. Previous studies suggests that mood disorders, both in the bipolar and unipolar spectrum, may be associated with decreased fertility rates. Most studies report that women seeking treatment for infertility have an increased rate of depressive symptoms and possibly major depression (none showed evaluated mood elevations). Many, but not all, studies found that depressive symptoms may decrease the success rate of fertility treatment. Treatments for infertility may independently influence mood through their effects on estrogen and progesterone, which have been shown to influence mood through their actions on serotonin. Studies are limited in scope and confounding variables are many, limiting the strength of the results. In conclusion, a range of existing studies suggests that fertility and mood disorders are related in a complex way. Future studies should use clinical interviews and standardized and validated measures to confirm the diagnosis of mood disorders and control for the variables of medication treatment, desire for children, frequency of sexual intercourse, age, FSH levels, menstrual cycle regularity in assessing an interrelationship between mood disorders and fertility.     

Predictive value of normal sperm morphology in intrauterine insemination (IUI): a structured literature review

The aim of the study was to conduct a structured review of the literature published on the use of normal sperm morphology, as an indicator of male fertility potential in intrauterine insemination (IUI) programmes. Published literature in which normal sperm morphology was used to predict pregnancy outcome in IUI during the period 1984-1998 was reviewed. In total, 421 articles were identified via Medline searches. Eighteen provided data that could be tabulated and analysed. Eight of the analysed studies provided sufficient data for statistical analysis, six studies used the Tygerberg 'strict' criteria, and two the WHO guidelines (1987, 1992). A meta-analysis of the six studies in the strict morphology group yielded a risk difference (RD) between the pregnancy rates achieved in the patients below and above the 4% strict criteria threshold of -0.07 (95% CI: -0.11 to 4.03; P<0.001). The WHO criteria group (1987, 1992) had insufficient data to be analysed. Meta-analysis showed a significant improvement in pregnancy rate above 4% threshold for strict criteria. Accurate evaluation of normal sperm morphology results should be an integral part of evaluating the male factor.     

The present and future state of hormonal treatment for male infertility

Although male factors contribute to over half of all cases of infertility, most infertile men are described as 'idiopathic oligo/asthenozoospermic' rather than diagnosed precisely; hence, specific medical treatment is not possible. One uncommon but treatable cause of male infertility is gonadotrophin deficiency in which gonadotrophin replacement therapy is highly effective at inducing spermatogenesis and fertility. Hormonal therapy is a logical approach for empirical drug therapy given the fundamental role of hormonal regulation in spermatogenesis. However, treatment with GnRH analogues, gonadotrophins, androgens, anti-estrogens, aromatase inhibitors, growth hormone- and prolactin-suppressing drugs is ineffective in unselected infertile men. Prolonged high-dose glucocorticoid therapy for sperm autoimmunity may improve pregnancy rates modestly, but the risks are generally unacceptable compared with IVF or ICSI. For these reasons, modern reproductive technologies, notably ICSI/IVF, have become the de-facto standard empirical treatment of male infertility, despite involving significant though infrequent risks to the fetus and mother. There remains a potential for hormonal methods to improve sperm quality or ultrastructure in subgroups of infertile men more responsive to hormonal manipulation or using novel protein or gene-targeted therapies or biochemical approaches based on post-hormonal receptor mechanisms that stimulate spermatogenesis. How such novel hormonal methods will develop in conjunction with improved ICSI/IVF or cloning technologies, and the potential role of adjunctive hormonal therapy remains to be clarified.     

Impact of genetic engineering on the understanding of spermatogenesis

To date, about 100 genes have been found, by genetic engineering, to be implicated in spermatogenesis. Primordial germ cells, spermatogonia, spermatocytes I and elongating spermatids are particularly sensitive. Transgenic and knockout mice permit an approach to be made to the question of genetic factors involved in DNA damage repair, thermal injury, sperm chromatin compaction and sex-specific recombination. Knockout mice reveal unexpected functional redundancies of testis-specific genes. This review considers how functional divergences can exist among homologous genes from different species, and to what extent the phenotypes of knockout mice can be similar to those from spontaneous mutations. Additional anomalies in reproductive function have frequently been found in these mice, as were found factors leading to tumour susceptibility and/or various diseases. Finally, knockout mice remind us that, in nearly all cases, hemizygous individuals retain a fertility and a wild-type sperm phenotype, although half of the spermatozoa share a genetic defect. The findings strongly emphasize the importance of understanding epidemiology in male infertility, to identify hereditary forms of impaired spermatogenesis, and to create DNA and pathological germ cell banks.     

The role of circadian rhythmicity in reproduction

Circadian rhythmicity is evident in a wide range of physiological systems including the reproductive axis. The recent discoveries of rhythmic clock gene expression in peripheral tissues, including reproductive tissue, suggests that they may play an important role in optimizing fertility. The evidence for rhythmic control of reproduction from studies in laboratory animals is reviewed and where possible this includes evidence from human studies. Clock genes are highly conserved across species including humans and there is no reason to suggest that they are functionless in humans. The challenge issued here is for researchers to probe their function and the consequences of their disruption in both animal and human reproduction.     

Transmission of male infertility to future generations: lessons from the Y chromosome

The introduction of ICSI and testicular sperm extraction (TESE) has allowed many infertile men to father children. The biggest concern about the wide use of these techniques is the health of the resulting offspring, in particular their fertility status. If the spermatogenic defect is genetic in origin, there is potential risk of transmitting this defect to future offspring. The most frequently documented genetic cause of male infertility is a Y chromosome deletion. The Y chromosome has acquired a large number of testis-specific genes during recent evolution, and deletions causing infertility take out a number of these genes. These deletions have been shown to be transmitted to 100% of male offspring. Also, absence of an aberration on the Y chromosome does not rule out a genetic cause of the infertility phenotype, as there are many other genes involved in spermatogenesis elsewhere in the genome, and current mapping techniques--especially on the Y chromosome--can miss many aberrations. More detailed studies of these spermatogenesis genes, which are now possible because of more precise sequence-based mapping, will lead to improved understanding of the genetic basis of male infertility and enable proper counselling of patients undergoing ICSI in the future.