Developmental Disorders

1.3.4.3 Congenital malformations of the male genital organs 1.3.4.3.1 Cryptorchidism

Clinical signs: • • •

undescended testis in a mature newborn, unilaterally or bilaterally very frequent defect in healthy newborns (3 – 5% of full-term boys) sometimes part of syndromes and somatosexual disorders

1.3.4.3.2 Congenital malformations of penis and scrotum

Clinical signs: •

•

•

Hypospadia: o deficient closure of urethral sulcus in 11th – 12th week of gestation o urethra leads into any place on the lower side (ventral surface) of the penis from glans penis to perineum o ventral penis flexion is caused by fibrous band (chorda urethrae) o incidence is 1 : 350 o more serious hypospadia (urethra leads to the scrotum, perineum) is a symptom of feminization and has to be differentiated from intersex Epispadia: o congenital malformations of genital tubercle o urethra leads to the dorsum of the penis o see urinary bladder extrophy Complete penoscrotal transposition (synonyms: prepenile scrotum, transposition of the penis) o abnormal development of indifferent external genitalia in 4th – 5th week of gestation o very rare defect, occurs sporadically o sometimes part of syndromes, e.g. Smith-Lemli-Opitz

Scientific interest in morbidity in children born small for gestational age (SGA) has increased considerably over the last few decades. The elevated risk of cardiovascular and metabolic diseases in adulthood in individuals born SGA has been well documented, whereas data on gonadal development are limited. Prospective studies, case-control investigations and registry surveys show that impaired intrauterine growth increases the risks of congenital hypospadias, cryptorchidism and testicular cancer approximately two- to threefold. Although few studies focus on the effect of intrauterine growth on male pubertal development, testicular hormone production or sperm quality, available evidence points towards a subtle impairment of both Sertoli cell and

Leydig cell function. Animal studies support the hypothesis that impaired perinatal growth restriction, depending on the timing, can affect postnatal testis size and function into adulthood. Current human data, however, are often based on highly selected hospital populations and lack precise distinctions between low birth weight, SGA, timing of growth restriction and a differentiation of catch-up growth patterns. Despite the methodological inadequacies of individual study results, the combined evidence from all data leaves little doubt that fetal growth restriction is associated with increased risk of male reproductive health problems, including hypospadias, cryptorchidism and testicular cancer.

Developmental disorders Hypospadias is a developmental disorder where the meatus is positioned wrongly at birth. Hypospadias can also occur iatrogenically by the downward pressure of an indwelling urethral catheter.[7] It is usually corrected by surgery. The Intersex Society of North America classifies hypospadias as an intersex condition. They believe in halting all medically unnecessary surgeries, including many of those done on people with hypospadias. A micropenis is a very small penis caused by developmental or congenital problems. Diphallia, or penile duplication (PD), is the condition of having two penises. However, this disorder is exceedingly rare.

Testicular disease From Wikipedia, the free encyclopedia

Jump to: navigation, search Testicular diseases can be classified as endocrine disorders or as a disorders of the reproductive system. The testicles are well-known to be very sensitive to impact and injury. Blue balls is a slang term for a temporary fluid congestion in the testicles and prostate region caused by prolonged sexual arousal. The most prominent diseases of testicles are: • • • • • •

testicular cancer and other neoplasms swelling of a testicle, caused by hydrocele testis inflammation of the testicles, called orchitis inflammation of the epididymis, called epididymitis retention cyst of a tubule of the rete testis or the head of the epididymis, called spermatocele spermatic cord torsion also called testicular torsion

• • •

varicocele — swollen vein from the testes, usually affecting the left testicle[1] Hydrocele testis - Collection of fluid around the testicle, like a water balloon. Completely harmless. anorchidism is the absence of one or both testicles.

The removal of one or both testicles is termed: • • •

Inguinal orchiectomy, in medicine (where orchiectomy and orchectomy are synonymous), and castration in general use, especially when done as punishment or torture, or as a catch-all term for orchidectomy in a veterinary context. Gelding in the specifically equine sense.

Testicular prostheses are available to mimic the appearance and feel of one or both testicles, when absent as from injury or as treatment for gender identity disorder. There have also been some instances of their implanting in dogs [2] Other testicular issues: • •

Cryptorchidism or "undescended testicles", when the testicle does not descend into the scrotum of the infant boy. Retractile testicle, when the testicle occasionally moves up into the lower abdomen as the cremaster muscle contracts.

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Chapter 12 - EPIDEMIOLOGY OF MALE REPRODUCTIVE DISORDERS Aleksander Giwercman, MD, PhD Professor, Consultant in Andrology, Malmo University Hospital, Reproductive Medicine Centre and Molecular Reproductive Medicine Research Group, Malmo University, SE 205 02 Malmo, Sweden

Yvonne Lundberg Giwercman, PhD - Associate Professor, Consultant in Andrology, Malmo University Hospital, Reproductive Medicine Centre and

Index Contributors Search

Molecular Reproductive Medicine Research Group, Malmo University, SE 205 02 Malmo, Sweden

Revised 20 May 2008 TO OBTAIN A DOWNLOAD OF THIS CHAPTER IN WORD OR PDF FORMAT, CLICK HERE

INTRODUCTION Disorders of reproductive organs are common through the whole life span of a man. Maldescended testes (cryptorchidism) and hypospadias, abnormally located urethral orifices along the ventral side of the penis, , represent the two most common congenital malformations of newborn boys, affecting 2-4%, and 0.3-0.7%, respectively, at birth. In young men, testicular germ cell tumours are the most common neoplasm, whereas prostate cancer is the over all leading cancer form in older men. In the western societies as many as 15% of all couples experience infertility problems and rough estimates indicate a 'male factor' in at least 50% of these cases. Thus, failure of the reproductive system comprises a significant proportion of men and is of concern, not only on an individual basis, but also for the society, where t he financial burden of management is substantial. Unfortunately, our understanding of the underlying mechanisms is still very limited. Recent reports of a possible deterioration of semen quality over the past 50 years, and an increasing incidence of testicular cancer noted in many countries are a source of worry (1). A hypothesis of a common cause underlying these abnormalities has been put forward but is still subject of controversy (2). This debate has stimulated to a great deal of research, which has generated new knowledge on the impact of genetic, environmental, life-style related, geographic and social factors on male reproductive parameters. In the current review we summarise current information on epidemiological trends in male reproductive function, with focus on fertility and semen quality, and discuss to which extent such trends might be related to exposure of endocrine disruptors.

SECULAR TRENDS IN MALE REPRODUCTIVE FUNCTION Traditionally, semen quality is considered as the most significant marker of male fertility. However, several other characteristics can be used for monitoring the function of male reproductive organs including the incidences of cancer or of congenital malformations of genital organs, testicular size and fecundability (a couple’s chance of conceiving). Interestingly, to some degree concordant, secular trends have been reported for most of these characteristics.

Semen quality

During the past decades several reports have suggested a time related decline in semen quality (3-5) A meta-analysis of 63 studies by Carlsen et al published in 1992, mainly from USA and from Western Europe, indicated almost 50% reduction – from 113 x 10 6 /mL to 65 x 10 6 /mL – in mean sperm concentration, during the period 1940 to 1990 (6). This publication evoked an intensive debate (7;8). The main points of criticism were the question of comparability of the methodology for sperm counting with and between laboratories over the period of five decades, and the criteria of subject selection. Such uncertainties could heavily bear on the validity of the statistical model applied for estimation of the time-related changes. However, Swan et al (9) performed a careful re-analysis of the data and included additional reports in their calculations, ending up with a total of 101 studies. They concluded, that even taking possible confounding factors into consideration, there was a significant time-related negative trend in sperm concentration both in North America (0.8% per year) and in the western Europe (2.4% per year) during this period. However, other reports emerging as a part of the ongoing debate on secular trend in sperm concentration have suggested that the picture is by no means clear. Thus, no secular trend was found in Finland (10), whereas in France similarly selected material of sperm donor candidates from Paris (11) and Toulouse (11) showed quite opposite pictures with a significant decline in Paris (from 89 x 10 6 /mL in 1973 to 60 x 10 6 /mL in 1992), but no such change in Toulouse (12). The study on sperm donor candidates from Paris did not only show a decline in sperm concentration, but also in the percentage of motile and morphologically normal sperm (11). Furthermore, it was demonstrated that the levels of sperm parameters were more closely related to the year of the birth than the year of sample collection, which indicated an impact of events occurring in foetal life on semen quality. Other studies indicating secular trend in sperm concentration came from Scotland (13) and Belgium (14) whereas two American (15) (16), one Danish (17) and an Australian study (18) did not show such a trend. All these publications were, however, based on retrospective materials. It has been shown that there is a close correlation between the sperm concentration and the fertility potential of a male (19). Unfortunately, there is a scarcity of data to show whether the fertility has changed over recent decades although some studies have suggested it has not changed (20;21). However, fertility is dependent on several factors (e.g. social, female factors), the male reproductive capability being just a part of the equation.

Testicular cancer Whereas there is a lot of dispute regarding the possible secular trend in sperm counts, there is a general agreement that – at least among Caucasians – there has been a significant increase in the incidence of testicular cancer, with present figures being 2-3 times higher than 30-40 years ago (22). This trend relates to testicular germ cell cancer (TGCC), the most common form of testicular malignancy, mainly appearing among males aged 25 to 40 years. The risk of TGCC was shown to be strongly correlated to the year of the birth of an individual, pointing to prenatal factors as being of significance in the aetiology and pathogenesis of this malignancy (23). The hypothesis of such association has been additionally strengthened by finding of decreased risk of testicular malignancy among boys born during the Second World War as compared to pre- and post-war birth cohorts (24).

Genital malformations A time-related increase in the incidence of congenital malformations of the male genital organs – maldescended testes (25) and hypospadias (26-28) has also been suggested. However, for both conditions comparisons of studies from different countries may be problematic due to variations in criteria, diagnosis and registration, but in general data on cryptorchidism is registered as less reliably than that on hypospadias. Cryptorchidism affects 2–9% of all newborn boys and 1–3% of boys at 3 months of age. Hence,the age of the baby at the time of examination and the proportion of prematurely born children, who have a higher prevalence of cryptorchidism, may play a role in determining the incidence of this defect. Cryptorchidism can also be obtained by postnatal ascent of the testes. In addition, the criteria for offering treatment may vary depending on the region and over time. In a report from the UK on cryptorchidism, attempts were made to apply identical diagnostic and selection criteria with a thirty years interval. These studies have shown a significant increase in the incidence of cryptorchidism over a period lasting from the late 1950's to the 1980's (29). The magnitude of this increase depends partly on the age at the time of investigation and whether premature babies with “physiological” testicular non-descent are included. However, when the analysis was restricted to those babies having a birth weight above 2,500 g, the increase at the age of 3 months was from 0.8% in the 1950’s to 1.4% in the late 1980’s.

In regard to hypospadias the data are quite uncertain, but at least in some parts of the world there are trends indicating a time-related increase in the frequency of this abnormality by 100200% over a period of 20 years (26-28;30) although this trend seems not to be global (31). This discrepancy may be due to differences in the diagnostic criteria, quality of registers and /or geographical trends in the state of male reproductive function (see below).

GEOGRAPHIC TRENDS Whereas there are hard data and general agreement that a secular trend exists in the incidence of testicular cancer, the question of time-related deterioration of male reproductive function in general, is still a matter of debate. The issue of geographical trends in male reproductive function has attracted increased attention. Exploring regional differences may add to our understanding of the impact of genetic, environmental and life-style related factors on reproductive parameters. Furthermore, a coupling between the risk of TGCC and sperm concentration in a given area, as suggested in some studies, may provide an additional piece of evidence in support of time-related decline in sperm concentration.

Remarkable regional and ethnic differences have been found in the risk of TGCC. Caucasian men have a significantly higher risk of this cancer than Black men living in the same area (32).

However, in addition, in Caucasian men there are significant differences in the incidence of TGCC between geographically and socially closely related areas. Danish and Norwegian men seem to have one of the highest risks whereas in the neighbouring country Sweden this risk is reduced by 50%. Finnish men have a risk, which is only 20% of their Danish counterparts (22). Interestingly, despite the geographical differences in the actual incidence rates, where reliable cancer registries are available, an equal rise in TGCC risk has been observed all over the world, the only exception being African Americans in whom the incidence of TGCC has not changed over time (32).

In the last few years, several studies have shown that the difference between Denmark and Finland in regard to the risk of testicular cancer is accompanied by higher sperm counts and other indications of superior reproductive function in Finnish men as compared to a corresponding group of Danes (33). In a study of the partners of pregnant women, Finnish men were not only found to have higher sperm concentrations than those from Copenhagen, Denmark, but also in comparison to men recruited in Edinburgh and Paris (34). This difference was also found when sperm counts from Danish and Finnish military conscripts, cohorts more or less corresponding to general populations of adolescent males, were compared (35). Furthermore, Danish newborns were found to have a higher risk of cryptorchidism and hypospadias than Finish boys (36-38). The question remains whether the Danish-Finnish difference is due to genetic or environmental factors. Recent studies, showing that the risk of TGCC in second generation Finish immigrants in Sweden corresponds to the level of native Swedes, which is much higher than that in Finland, would point to a strong effect of environment and/or life style. In Southern Sweden, where the population is genetically very similar to that in Denmark, the total sperm counts were found to be 30% higher than among Danish conscripts, whereas the frequency of self-reported history of cryptorchidism was significantly lower (39). Thus, comparing Denmark and Sweden also points to a significant impact of environment and/or life style on the reproductive parameters (Fig 1).

Fig 1: Comparison between relative levels of total sperm counts among military conscripts and the incidence of testicular cancer in three countries in the Nordic-Baltic area, Denmark, Finland and Sweden (22;35;39). The figures are given as percentages of the reference level (Finland for sperm counts and Denmark for testicular cancer).

Geographical variations in sperm concentration have not only been found between countries, but also when comparing different regions of France (12;40) and USA (15;41) . In the latter study, based on samples from fertile males, the mean sperm concentration was significantly lower in Columbia, Missouri, than in New York; Minneapolis, Minnesota and Los Angeles, California, ranging from 59 x 10 6 /mL to 103 x 10 6 /mL. Even the total number of motile sperm was lower in Missouri than in the other centres, the calculations being made in multivariate models that controlled for abstinence time, semen analysis time, age, race, smoking, history of sexually transmitted diseases, and recent fever. The authors suggested that sperm concentration may be reduced in semi-rural and agricultural areas relative to more urban and less agriculturally exposed areas. Recent studies have demonstrated a significant correlation between the levels of sperm concentration and male fertility potential (42). It would therefore be expected that these interregional discrepancies in sperm concentrations should be reflected in corresponding differences in the fertility, as measured as waiting time to pregnancy (TTP). Joffe reported a significantly higher fertility rate in Finland as compared to Britain (43). However, in the above-mentioned European four-city study, decreased probability of conception was found among French couples as compared to those from Denmark, Finland and Scotland (33). No difference in TTP was found for the three latter countries. Thus, the TTP data did not correspond to sperm concentrations making the picture somewhat blurred . Furthermore, men selected because of being the partners of pregnant women represented a highly selected group and may, therefore, not represent the most ideal population for studying geographical trends in fertility parameters. Such studies will not reveal changes in the proportion of males with semen quality so poor as to preclude conception. There are ongoing European Union sponsored studies on semen parameters among military conscripts (44). Such data may provide more unbiased evidence regarding semen quality in the

general male population. New markers of sperm quality e.g. sperm chromatin structure, were found to be of significance for sperm function but only partly correlated with traditional semen parameters (45;46).

ENVIRONMENT AND LIFE-STYLE We tend to forget that environmental toxicants have been used and misused for thousands of years for different purposes. For example lead compounds were used to induce illegal abortions and that these compounds could cause unwanted adverse pregnancy outcome and higher mortality of children was also known by women working in lead industries in the 19 th century. Male fertility was also known to be lower and the risk of impotence higher among lead workers (47). This was, however, not new knowledge. The Romans produced significant amounts of lead for centuries, which was used for glazing pottery, piping and cooking utensils. They also used lead pots for boiling and condensing of grape juice for preserving and sweetening of wine. Lead poisoning was pandemic, with the severity of poisoning proportional to the power, which has led to the hypothesis that lead poisoning, selectively affecting those who drank much wine and had access to plumbing i.e. patricians, contributed to the fall of the Roman Empire (48). Use from the late 1940s to early 1970s of the estrogenic compound – diethylstilbestrol (DES) - to prevent abortions and pregnancy complications, gave a possibility to evaluate the impact of oestrogen exposure in foetal life in relation to the risk of reproductive disorders. Follow-up studies of DES-treated mothers’ sons indicated that they might have an increased risk of several male reproductive disorders, such as cryptorchidism, urethral abnormalities, epididymal cysts and testicular hypoplasia (49;50). In addition, the semen quality seemed to be negatively affected (51). However, at interpretation of these data the relatively small sample size must be taken into account and the fact that the DES treatment may have been initiated at various times during pregnancy and therefore the presumed critical period during which adverse effects of estrogens appear might have been missed. The detrimental effects of estrogens on male reproductive organs have been confirmed in animal experiments. Thus, the outcome of in utero DES exposure of experimental animals revealed an increased incidence of cryptorchidism, urethral abnormalities, testicular hypoplasia, poor semen quality and infertility as well as abnormalities of accessory sex glands. These data are consistent with the potential range of adverse effects suggested in humans, except for the TGCC, which as far not yet has been described in any animal species (32). The focus on potential adverse effect of estrogenic compounds in relation to male reproductive function has been reinforced by the fact that several groups of compounds that are used daily in industry, agriculture or in the home act as xenoestrogens yielding their effect through oestrogen receptors or interfering with the metabolism of this hormone and thereby increasing levels of the endogenously produced ligand. Another possible mechanism of disturbing the oestrogen-androgen balance is by an anti-androgenic effect. The list of compounds supposed to have such ‘endocrine disrupting’ effect is impressively long (32). However, it is still a matter of discussion whether the exposure to a relatively small amount of such compounds may explain the dramatic increase in reproductive abnormalities, for example in testicular cancer (32). A number of recent reports have indicated associations between levels of exposure to environmental toxicants and markers of reproductive function in humans. In a small study of teenagers exposed to substantial amounts of

biopersistent organochlorines in utero due to intake of contaminated cooking oil by their mothers, an increase in the percentage of morphologically abnormal spermatozoa was seen, as well as reduced sperm motility and ability to penetrate hamster oocytes as compared to spermatozoa from control subjects (52). Swan et al reported that in an agricultural area of Missouri, where sperm concentration and motility were reported to be lower than in the rural parts of the USA, levels of pesticide metabolites were higher among those having abnormal sperm parameters as compared to men with normal semen quality (53) . Among Swedish young men undergoing a conscript evaluation for military service, despite low level of exposure, a negative correlation was found between serum concentrations of CB-153, which is a biomarker of exposure to POP, and the proportion of motile sperm (54). In 2002-2006 an EU-financed project under the acronym INUENDO (www.inuendo.dk), with the objective to identify and characterize the impact of dietary pollutants on human fertility and to provide epidemiologic evidence on possible health impacts of environmental exposure to xenobiotics with hormone like actions, was conducted . The study had the specific objective to study fertility in European populations with high or low POP exposure, such as the Greenland Inuit, with the highest body burdens of POP in the world, Swedish fishermen from the polluted east coast as well as from the west coast, Ukrainians, who are mostly exposed by use of pesticides, and a Polish population, as a low exposure group. The POP exposure was negatively correlated to sperm motility and sperm DNA integrity. However, no association between the POP exposure level and fecundity or sperm counts was found, despite the fact that some of the subjects included in the study presented with extremely high POP levels in serum (55). However, an indication of gene-environment interaction in relation to reproductive parameters was seen for the association between levels of POP exposure and sperm counts. Thus, despite the lack of association between POP exposure and sperm numbers, in men with short androgen receptor CAG repeat lengths (see below) high exposure to POP was associated with sperm counts which were 40% lower than in those with low POP levels (56).

Regarding female exposure, a human exposure study found elevated levels of polychlorinated bisphenyls (PCBs) and dioxin among mothers living in Greenland, relating to their high intake of marine food, mostly marine mammals and fish (57). A variety of studies have demonstrated the estrogenic, anti-estrogenic, and androgen competing properties of these compounds. Thus, it was reasonable to believe that these chemicals also could disrupt normal male sex differentiation. Consequently, a high incidence of hypospadias among the Inuit population could be expected if POP exposure was of significant importance for the aetiology. By utilizing the birth register of Greenland, 11,076 live male births during the period 1982-2002 were identified. Through the local register on congenital malformations, all reported cases of hypospadias were traced. The incidence of hypospadias in Greenland was compared to that in Scandinavia, based on information obtained from International Clearinghouse for Birth Defects Monitoring Systems ( www.icbd.org ). Only two cases of hypospadias were identified in Greenland among the boys born during the actual period, corresponding to an incidence of 0.02%. This was approximately 10 times lower than among Scandinavian boys, who have an incidence of 0.2%. Since Greenland is a part of the Kingdom of Denmark and the neonatal health care system in Greenland is similar to that in Denmark, the risk of incomplete ascertainment of hypospadias could hence be assumed to be at the same level as in the Nordic countries. Interestingly, 85% of the population in Greenland carried a specific androgen receptor variant GGN=23, encoding 23 units of the aminoacid glycine. This variant was in vitro proven to result in

a more active androgen receptor than other lengths tested (58). Another possibility is that GGN=23 acts as an effect modifier on the anti-androgenic effects of endocrine disrupters as e.g. p,p’-DDE, which is a metabolite of DDT in subjects with this gene variant. These two mechanisms might also be interacting with each other (Figure 2).

Figure 2. The relative risk of developing a disease is enhanced in individuals who are carrying a genetic variant in a particular gene and exposed to the environmental contaminant.

Exposure to phthalates, another type of compounds belonging to the family of "endocrine disrupters", was also reported to be associated with deterioration of classical sperm parameters as well as sperm DNA integrity (69;70). Ano-genital distance among newborn boys, considered as marker of prenatal androgen exposure, was reported to be negatively correlated to the levels of phthalates in the serum of the mothers (59). Although the above mentioned reports might indicate an association between environmental exposure and male reproductive dysfunction, the evidence is still limited. One of the problems is that the majority of available data relate to postnatal exposure whether some evidence points to early foetal life or puberty as the critical time window for the deleterious effects of environmental pollutants on male reproductive function (60). For example in Seveso Italy in 1976, when a dioxin manufacturing plant exploded, only boys younger than 19 years of age exposed before puberty were as adults found to have lower chance to father male offspring (61), which was a permanent outcome related to the developmental time of exposure. Furthermore, a still unresolved problem

is the issue of assessing mixed exposures to several compounds, each of them being present in rather modest concentration, but the total effect being additive or even multiplicative. Finally, the effect of the environmental toxicants might be modified by genetically determined susceptibility, which complicates the interpretation of studies focusing on the impact of environment on male reproductive function. The proposition that male reproductive function can be impaired by environmental exposures has been reinforced by reports indicating that such a trend is not only found in humans, but has also been observed in wildlife. The list of changes in male reproduction in wildlife involve such issues as feminisation, demasculinisation, reduced fertility, reduced hatchability, reduced viability of offspring, impaired hormone secretion or activity and altered sexual behaviour (62). Many of these reproductive disorders have been ascribed to xenoestrogenic effects on the foetus, often caused by a mixture of compounds, some of which are known to have a hormone like activity and act cumulatively.

The chemical spill of dicofol, DDT (and its metabolites) and sulfuric acid followed by agricultural sewage dumping was followed in the subsequent 3 years by a significant decline in the number of juvenile alligators and reproductive abnormalities among the males, including presence of abnormal germ cells in the testes and microphalli (63;64). In fish species, bio-assayed levels of vitellogenin in rainbow trout have been used to assess the degree of exogenous estrogenic exposure. Vitellogenin is synthesised in liver under oestrogen control and in males only after exogenous oestrogen treatment (65). Sewage treatment water exposure of caged rainbow trout induced a 500- to 100,000-fold increase in plasma vitellogenin levels, which in males almost reached the levels seen in female animals (66). This observation was coupled to the demonstration estrogenic activity of degradation products of several alkylphenol-polyethoxylates, a major group of surfactants present in sewage. In vitro , their effect on trout hepatocytes could be blocked by tamoxifen, an anti-oestrogen, acting at the oestrogen receptor level (67).

Adverse reproductive effects have also been observed in mammals, e.g. panthers in Florida, which exhibited low ejaculate volume and sperm concentration, poor semen quality and an increased proportion of sperm with abnormal morphology. In addition, male sterility and a high incidence of cryptorchidism have been observed among these animals and were suggested to be due to contamination of mothers by endocrine-disrupting environmental xenobiotics, rather than problems associated with inbreeding (68). For more examples of deterioration of reproductive function among wildlife, see review (62).

Thus, there are examples from wildlife indicating occurrence of reproductive defects similar to these observed in humans. In some cases a direct coupling to exposure to chemicals acting as endocrine disrupters, has been shown. A State-of –the-Science document regarding the effects of the ‘endocrine disrupters’ can be found on: http://ehp.niehs.nih.gov/who/ However, not only environmental but also life-style related factors may have a significant impact on male reproductive parameters. It is well known that the length of the period of abstinence affects sperm concentration and total sperm counts (39). Little is known about possible changes

and geographical discrepancies in sexual habits, which, at least partly, might explain some of above described secular and geographical trends in the quality of semen.

Other factors like cigarette smoking (69), alcohol consumption (70) and dietary habits (71) should also be taken into consideration. The life-style related habits are known to be subject of geographical as well as time-related variation, and if associated with male reproductive function, might at least partly explain some of the observed epidemiological trends. Whereas low to moderate alcohol intake does not seem to affect the fertility potential of a male (72), most recent data show that cigarette smoking has a negative impact on sperm number as well as seminal volume indicating an anti-androgenic effect of smoking (73). Recently, decreased sperm counts were reported among sons of mothers who smoked more than 10 cigarettes per day during pregnancy (73), a finding which has been confirmed by several other studies. In the Nordic countries, the pattern of increased smoking among females mirrors the rise in the incidence of testicular cancer, but so far no association between maternal smoking during pregnancy and the risk of TGCC among their sons has been disclosed.

IMPACT OF GENETIC FACTORS About one in six or seven couples of reproductive age experiences involuntary childlessness, roughly half of the cases being attributable, at least in part, to a male factor. The underlying cause is unknown in a significant proportion of men suffering from infertility, but in many of those men, it is believed that a genetic cause undetectable by conventional cytogenetic analysis is responsible for poor spermatogenesis. Microdeletions of the Y chromosome were the first (74) and so far only group of such subtle genetic lesions to be discovered that are associated with a significant proportion of male infertility. In recent years, much attention has been directed towards the possible modulating effect of androgen receptor (AR) function on male fertility potential. Androgens, acting via the AR, initiate and maintain spermatogenesis, and mutations in the AR gene associated with poor sperm counts as the main symptom of androgen insensitivity have occasionally been reported (75;76). Androgens, mainly testosterone and 5α - dihydrotestosterone (DHT) and a functional androgen receptor (AR) are crucial for male sexual differentiation, secondary sex characteristics at puberty and sperm maturation (77). The AR is present as a single copy gene on chromosome Xq11-12 (78). Absent or dysfunctional AR in otherwise healthy 46,XY individuals causes the androgen insensitivity syndrome (AIS) and various degrees of under masculinization (79), ranging from complete sex reversal to men with gynecomastia and/or hampered spermatogenesis at the other end of the spectrum (76;80)(See also Endotext Chapter by Brinkman). Presently over 300 different AR gene mutations are documented in a mutational database (AR mutation database: http://www.mcgill.ca/androgendb/). The majority of alterations within the AR gene are point mutations disrupting the receptor function and thereby diminishing androgen response. A few of these mutations have been identified in men with poor sperm production (81;82,76), but do not seem to be a frequent cause of idiopathic male infertility. There is no evidence, that these mutations are geographically clustered or affecting any ethnic group in particular.

There is only one AR gene, but there are multiple allelic variants in the general population; i. e., the AR is highly polymorphic (83). The gene polymorphism affects the protein coding sequence of exon 1 of the AR, such that it contains a glutamine repeat, encoded by (CAG)n CAA and a glycine repeat, encoded by (GGT)3(GGG)GGT)2(GGC)n, commonly referred to as the CAG- and the GGN repeat, respectively (84-86). Both repeats are varying in length among individuals in the general population as well as between different ethnic groups (87), paralleling epidemiological observations, reporting that the incidence of clinical prostate cancer differs substantially both geographically and between different ethnic groups, with highest incidence and death rates in African Americans and Scandinavians and the lowest in Asians (88;89). A number of patientbased studies have found that a shorter CAG and/or GGN repeat confers a higher risk of prostate cancer whereas others have been unable to confirm that association (90). In men from general Caucasian population, the CAG region spans over approximately 10-30 CAG (91), but an abnormal elongation of the number to more than 40 repeats occurs in spinal and bulbar muscular atrophy (SBMA), also known as Kennedy’s disease (92). Kennedy’s disease is characterized by adult onset of slowly progressing proximal muscle weakness and atrophy. The length of the CAG segment has been found to correlate with the severity of the disease (93). In vitro an inverse relation between CAG repeat length and the AR transactivating capability has been found (94), which is in accordance with the idea of the segments interaction with the transcription machinery. In addition to the classical symptoms, affected men sometimes also present with gynecomastia and reduced or absent reproductive capacity, which is why much attention recently has been paid to this region in relation to idiopathic male infertility. Some reports claim that longer CAG tracts, although still within the normal range, increase the risk of impaired spermatogenesis (Fig. 3) (94;95;96), whereas others do not find any association between these parameters (97) (98;99;100). In contrast, there is also one study claiming, that a short number of CAG repeats is associated with infertility (101). It is unknown whether differences between these studies, including ethnicity of study participants, inconsistencies in case and control inclusion criteria or methods for analysing the repeat, are responsible for conflicting findings, but in a recent meta-analyse that included statistical measures of heterogeneity, support for the hypothesis that longer AR CAG repeat lengths are associated with reduced male fertility was provided (102).

There are also ethnical differences in the GGN diversity, with populations of African descent presenting with larger spectrum of alleles than all other populations studied (87). One predominant allele of 23 (GGN23) has evolved among Caucasians and is carried by 53% of the Swedish subjects. GGN24, which is the second most common allele, was reported in approximately 32%. However, among patients with hypospadias or cryptorchidism the opposite pattern was found, GGN24 or longer being the most frequent genotype, followed by GGN23 (103). I n a recent publication on early-onset androgenetic alopecia – male pattern baldness, which is characterized by an androgen dependent defined pattern of hair loss from the scalp, the authors found that GGN23 was associated with the disorder (104). GGN24 on the other hand, seemed to have a protective effect. These in vivo results indicated that GGN lengths above 23 were associated with lower androgenicity as compared to the most common genotype, GGN23. With respect to GGN lengths shorter than 23, it was recently shown that GGN<23 was associated with lower semen volume, as compared to GGN=23 and GGN>23 (105). When different GGN lengths were tested in vitro in a reporter gene system, ARs with other glutamine numbers than 23 had lower transactivating capacity in response to both testosterone and DHT, paralleling the frequency of this repeat in most, if not all, Caucasian populations studied to date (106).

CONCLUSION Perhaps provoked by reports since the early 90’s that were indicating a time-related decline in sperm concentration, more focus has been directed against factors related to male reproductive function. A growing body of toxicology data based on aquatic and wildlife species as well as on laboratory animal studies, suggests that exposure to endocrine disrupting agents are associated with disorders of the male reproductive system. We should also keep in mind that humans are exposed to numerous mixtures of compounds, of which several have the potential to disrupt the hormonal balance. The rapid increase in the incidence of testicular cancer and possibly also of some other reproductive failures can hardly be explained by genetic changes. Instead, genetic factors may have an important modulating effect making certain individuals and population groups more or less susceptible to the effects of life-style and environment. Many men with fertility problems will eventually take advantage of powerful tools such as intracytoplasmic sperm injection at assisted reproduction technology clinics. The genetic disorder may then be passed on to the next generation. Unfortunately, this fact has been underestimated and even neglected for a long time.