Genes and Male Infertility: What Can Go Wrong?


  • Maria Rosa Maduro,

    1. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
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    • These authors contributed equally to the paper.

  • Kirk C. Lo,

    1. Scott Department of Urology, Baylor College of Medicine, Houston, Texas.
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    • These authors contributed equally to the paper.

  • Weber W. Chuang,

    1. Scott Department of Urology, Baylor College of Medicine, Houston, Texas.
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    • These authors contributed equally to the paper.

  • Dolores J. Lamb

    Corresponding author
    1. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
    2. Scott Department of Urology, Baylor College of Medicine, Houston, Texas.
      Scott Department of Urology, Baylor College of Medicine, One Baylor Plaza, N730, Houston, TX 77030 (e-mail:
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Scott Department of Urology, Baylor College of Medicine, One Baylor Plaza, N730, Houston, TX 77030 (e-mail:

Normal sperm production (spermatogenesis), maturation (spermiogenesis), delivery to and passage through the female genital tract (ejaculation and sperm transport), and function (capacitation, egg penetration, and decondensation of the head) are essential to achieve fertilization and early embryonic development. These are long and complex processes, which not only require an appropriate hormonal environment, but also well-balanced autocrine, paracrine, and juxtacrine signaling events between the various components of the male reproductive system. Accordingly, when the molecules involved in these signaling cascades fail, male infertility occurs (Figure 1). Unfortunately, there is a paucity of information available concerning the molecular events regulating these complex processes, hence an inability to properly diagnose the cause of infertility for many patients. In fact, nearly one-quarter of all male infertility patients are diagnosed as “idiopathic,” meaning we do not understand the etiology. Today, it is thought that much of what we currently diagnose as idiopathic may have a genetic basis. This review focuses on our current understanding of the molecular control of male fertility and the few genetic tests available for its diagnosis.

Figure 1.

. Genetic etiologies of human male infertility. Developmental disorders causing human male infertility result from a failure of gonadal development or testis determination, endocrinopathies, well-known genetic syndromes, and numerical and structural chromosomal abnormalities (translocations, deletions and inversions). CBAVD, congenital bilateral absence of the vas deferens; PMDS, persistent Müllerian duct syndrome. (Reprint from Matzuk MM, Lamb DJ. Genetic dissection of mammalian fertility pathways Nature Cell Biology 2002:4(S1)33-S40).

Chromosomal Defects

Chromosomal abnormalities are common in infertile men, with an incidence of 5.8% as compared to an incidence of 0.5% in the fertile population (Johnson, 1998). Chromosomal abnormalities can occur on several genetic levels: 4.2% of abnormalities occur on the sex chromosomes, whereas 1.5% occur on the autosomes. The gain or loss of an entire single chromosome results in aneuploidy, whereas a polyploid state occurs when the entire chromosomal content is multiplied (polyploid cells are most commonly associated with malignancies). Structural abnormalities include the rearrangement or translocation of fragments of chromosomes, as in Robertsonian translocations, or deletions of single genes or portions of a chromosome.

Numerical Chromosomal Defects

The incidence of abnormalities in chromosomal number, such as Klinefelter syndrome (XXY male), is greater in infertile men. This is a defect that is present in the majority of the cells of the individual. Defects in chromosome number are also present with an increased incidence in the sperm of infertile men as compared to fertile men (Finkelstein et al, 1998). These infertile men demonstrate normal somatic karyotype by blood exam, indicating the presence of a mosaicism between somatic and nonsomatic tissues or the presence of a mitotic or meiotic defect during spermatogenesis. Multicolor fluorescence in situ hybridization (FISH) on morphologically normal sperm from infertile patients demonstrates an increased rate of nondisjunction and aneuploidy (Huang et al, 1999), suggesting that normal sperm morphology cannot be used to identify sperm with a normal chromosomal complement. Additionally, pregnancies after intracytoplasmic sperm injection (ICSI) with sperm from these patients result in an increased rate of autosomal trisomies and sex chromosomal aneuploidies in the offspring (Martin, 1996).

Klinefelter syndrome is the most common numerical sex chromosomal abnormality, occurring at a rate of 1/500 live male births (Rao and Rao, 1977), while accounting for 14% of all cases of azoospermia. The etiology is related to paternal or maternal sex chromosomal nondisjunction during meiosis, resulting in 90% of patients with the 47XXY karyotype and about 10% with the mosaic 46XY/47XXY. Phenotypically, patients present with increased height, decreased intelligence, obesity, diabetes mellitus, small firm testes, decreased Leydig cell function, variable sperm production, and an increased risk of leukemia, extragonadal germ cell tumors, and breast cancer (Therman, 1993). Although rare pregnancies have been achieved through natural conception, most patients will require the assistance of reproductive techniques to conceive, with the potential of passing the defect to their offspring (Harari et al, 1995); however, all offspring to date have had a normal chromosomal complement (Poulakis et al, 2001).

Other sex chromosome defects occur less commonly. An XYY male occurs in 1/1000 live births and presents with increased height, decreased intelligence, antisocial behavior, increased risk of leukemia, and Sertoli-cell-only syndrome (SCOS) or maturation arrest, although many of these men are fertile (Griffin and Wilson, 1992). Mixed gonadal dysgenesis patients may present phenotypically as male, female, or with ambiguous genitalia. The most common karyotype observed in these patients is the 45X/46XY mosaic and may result from the loss of a Y chromosome early in embryonic development. However, 33% of patients have a normal karyotype, suggesting that factors other than sex chromosomal aneuploidy may be involved. The testes lack germ cells and, when intra-abdominal, have an increased risk of malignancy (Wegner et al, 1994).

Structural Abnormalities

Structural chromosomal abnormalities occur in azoospermia and severely oligospermic patients more frequently than in fertile men (Jaffe and Oates, 1996). A Robertsonian translocation occurs 8.5-fold more often in infertile patients and consists of the exchange of entire chromosomal arms between 2 chromosomes (Antonelli et al, 2000). A reciprocal translocation occurs with the same frequency as a Robertsonian translocation and is defined as the mutual exchange of fragments between 2 chromosomes (Antonelli et al, 2000). These patients may present with sperm densities ranging from normal to azoospermia.

The XX male syndrome occurs in 1 of 20 000 live births. Theories of how this happens range from the translocation of the SRY on the Y chromosome to the homologous region on the × chromosome to the mutation or deletion of an × gene that inhibits an autosomal testis determining gene (Page et al, 1987; Andersson et al, 1988). As described below in greater detail, molecular analysis demonstrates that most of these men have a translocation of a small piece of the Y chromosome containing the SRY or “sex determining gene” to the × chromosome. These patients are azoospermic, with 10% of them presenting with ambiguous genitalia or hypospadias (Schweikert et al, 1982).

Because abnormal karyotypes are present in approximately 7–13% of patients with idiopathic infertility, testing for chromosomal abnormalities using routine karyotyping with high-resolution banding cytogenetics is recommended for men suspected of having more severe defects such as sperm densities of less than 5 million per milliliter. FISH may be used to detect aneuploidy in the sperm of patients contemplating assisted reproduction, given that higher rate of sex chromosome aneuploidy has been found in the sperm of patients with severe spermatogenic defects. Finally, prenatal genetic diagnosis is recommended for those with known genetic abnormalities (Van Assche et al, 1996; Pauer et al, 1997; Huang et al, 1999).

Deletions of the Y Chromosome

The Y chromosome is the smallest chromosome, with 60 million base pairs, and is divided into a long arm (Yq) and a short arm (Yp) (Morton, 1991). Although most of the chromosome does not undergo meiotic recombination, the pseudoautosomal regions located at both ends of the Y chromosome pair with the corresponding regions on the × chromosome during meiosis (Figure 2). The genetic information on the Y chromosome is important for male sex determination and for normal spermatogenesis.

Figure 2.

. Schematic representation of the Y chromosome. Yp = short arm; Yq = long arm. (Reprinted from Maduro MR, Lamb DJ. Understanding the new genetics of male Infertility. Journal of Urology 2002;168: 2199, Lippincott Williams & Williams

The Y chromosome is crucial for testis formation in early development, with the testis-determining factor (SRY) located on the proximal portion of Yp (Koopman et al, 1991). A deficient or absent SRY results in a 46XY female (Jager et al, 1990). Alternatively, a different sex reversed locus (SRVX) on the × chromosome may explain why SRY is impaired in only a small portion of 46XY females (Ogata and Matsuo, 1994). In addition to SRY, other autosomal and X-linked genes, such as those for androgen synthesis and metabolism, are also required for normal male sexual differentiation. Although not critical for survival, the Y chromosome does contain genes that are not involved in male reproduction, such as those for stature, crown tooth size, and depression.

The azoospermic factor region (AZF) located at Yq11 was hypothesized by Tiepolo and Zuffardi (1976) to contain genes that control spermatogenesis. Three distinct intervals comprise this region and are associated with variable degrees of spermatogenic impairment: AZFa, AZFb, and AZFc; an AZFd is debated to reside between AZFb and AZFc (Kent-First et al, 1999; Oates, 2003).

The proximal portion of the AZFa region contains pseudogene sequences homologous to genes at Xp22. Other genes in the region include DFFRY (human homologue of the Drosophila development fat facets gene), dead box on the Y (DBY), ubiquitously transcribed tetretricopeptide repeat gene on the Y (UTY), and AZFaT1 (Sargent et al, 1999). DDFRY, recently renamed USP9Y, is widely expressed in various tissues, whereas the murine homologue is testis specific. A homologous copy of USP9Y also exists on the × chromosome. Deletions or point mutation of USP9Y results in hypospermatogenesis; with the thought that the gene may regulate protein turnover (Lahn and Page, 1997). Y chromosome analysis of infertile men shows that DBY is deleted more frequently than USP9Y, resulting in hypospermatogenesis or SCOS. Deletion of both USP9Y and DBY results in SCOS (Foresta et al, 2000).

Located mainly in the AZFb region, RNA binding motif protein on the Y (RBMY) consists of 30 genes and pseudogenes and may be divided into 6 subclasses (RBMY1-RBMY6) (Chai et al, 1997). As its name suggests, RBM may function in RNA metabolism. Deletion of the murine homologue of RBM results in male sterility, suggesting a similar role for the gene when it is absent in a small percentage of infertile men (Delbridge et al, 1997). Chromodomain protein on the Y (CDY) is another multicopy gene that is expressed during spermatogenesis and is thought to be involved in chromatin modifications during meiosis (Lahn and Page, 1999).

DAZ (deleted in azoospermia) was the first candidate spermatogenesis gene identified in the AZFc region (Reijo et al, 1995). DAZ represents a multigene family with considerable variation in number and sequence of repeats. The DAZ protein is expressed mainly in postmeiotic germ cells, suggesting a role in posttranscriptional control during the later stages of differentiation (Habermann et al, 1998). Deletion of the Drosophila equivalent, boule, results in azoospermia, suggesting a critical role in spermatogenesis (Eberhart et al, 1996). The murine homologue of DAZ, dazla, exists only on chromosome 17, not on the Y, with the thought that the DAZ gene migrated to the Y after the divergence of the New World monkeys (Gromoll et al, 1999). The human autosomal homologue of daz, DAZLA, is mapped to chromosome 3p24 and is expressed specifically in the testis and at lower levels in the ovary. The murine dazla is expressed in both male and female germ cells and when deleted results in absence of gamete production. Other genes in the AZFc region include testis transcript Y2 (TTY2) and basic protein Y2 (BPY2); although their exact function remains unknown, they share characteristics with DAZ in that they are Y-specific genes in multiple copies and exhibit testis-specific expression (Lahn and Page, 1997).

Large deletions of the Y chromosome can be detected by high-resolution cytogenetics as reported by Tiepolo and Zufferdi (1976) 25 years ago. Used more commonly today, polymerase chain reaction (PCR) is a technique that amplifies a portion of DNA as defined by sequence tagged sites (STSs). The STSs flank a portion of DNA that is amplified by PCR and then identified by molecular size on an agarose gel. The number of STSs used by a clinical laboratory may vary but should at least span interval 6 and AZFa, b, c, d regions believed to be involved in spermatogenesis. Small microdeletions on the Y chromosome may not be detected by PCR; thus, a normal analysis indicates only that no large deletions of the Y chromosome are present.

Autosomal Gene Defects and Male Infertility

Defects of the Hypothalamic—Pituitary—Gonadal Axis

Human sexual maturation and spermatogenesis is intricately controlled by the hypothalamic—pituitary—gonadal (HPG) axis; hence, disorders affecting this delicate balance can severely impair male sexual development and fertility. These rare disorders are usually the result of mutations, small deletions, or polymorphic expansions within the regulatory genes involved in the biosynthesis of hormones, growth factors, the androgen receptors, and their associated signal transduction pathways. Therefore, a good understanding of the genetic defects leading to the disturbance of the HPG axis is essential in the evaluation and treatment of male infertility.

Gonadotropin-releasing hormone (GnRH) from the hypothalamus regulates the production of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) by the pituitary gonadotropes. FSH and LH are dimeric molecules that share a common α subunit with human chorionic gonadotropin and thyroid-stimulating hormone, but each has specific β-subunits. Hypogonadotropic hypogonadism (HH) is characterized by a decreased output of GnRH and low circulating levels of FSH and LH, resulting in the deficient androgen secretion and spermatogenesis in the testis (Seminara et al, 2000). Kallmann syndrome is the most common X-linked HH disorder in male infertility. A mutation in KAL-1 gene, which encodes a neural cell adhesion molecule, is the basis for this disease and occurs in approximately 1 in 10 000–60 000 live births. Patients with Kallmann syndrome usually seek medical attention in their late teens for delayed puberty with small, nonfunctioning testes and a short penis. Clinical features include anosmia, congenital deafness, asymmetry of the cranium and face, cleft palate, cerebellar dysfunction, cryptorchidism, and renal abnormalities. On the other hand, infertility may be the sole phenotypic abnormality that leads to the diagnosis. Hormone replacement is the treatment of choice, and spermatogenesis and subsequent fertility has been reported with coordinated gonadotropin stimulation (Sigman, 1992).

The Dax1 gene found on the × chromosome encodes an orphan nuclear hormone receptor that plays a critical role in the development of the hypothalamus, pituitary, adrenal, and gonads (Burris et al, 1996). It appears to function in the maintenance of the integrity of the testicular epithelium and spermatogenesis. Mutations in Dax1 can also lead to HH in association with congenital adrenal hyperplasia, a devastating condition that can lead to early infant death due to electrolyte imbalance.

Mutation in PC1, or convertase-1 gene, has also been linked with HH in conjunction with obesity and diabetes. This gene is believed to play a role in GnRH secretion and release of the precursor molecule in the hypothalamus (Jackson et al, 1997).

Prader-Willi syndrome (PWS) patients, whose predominant features are obesity, mild to moderate mental retardation, and infantile hypotonia, can also present with HH. The culprit for this disease is thought to be mutations or deletions of a specific locus within paternal chromosome 15 (Smeets et al, 1992). This syndrome also follows a phenomenon called genomic imprinting, where differential expression of the 2 alleles at an autosomal locus is based on their parent of origin; usually 1 allele is expressed and the other silenced. Thus, while mutation of paternal 15q11q13 is required for PWS to occur, maternal loss of 15q11q13 results in Angelman syndrome (Jiang et al, 1998).

Mutations leading to direct abnormal synthesis and function of the gonadotropins FSH and LH can also result in male infertility. Though variable phenotypes ranging from complete virilization failure to less severe forms of hypogonadism have been observed, lack of optimal Leydig cell stimulation and absence of spermatogenesis are characteristic features of LH mutation (Park et al, 1976; Weiss et al, 1992). Rarely, deficiencies in FSH are reported in subfertile males. Although FSH β-subunit mutations have been suggested, the exact genetic causes of these abnormalities are yet to be identified (Matthews et al, 1993).

The integrity of the LH and FSH receptors also plays a critical role in maintaining the HPG axis function. Constitutive activation of the LH receptor leads to male precocious pseudopuberty, whereas pseudohermaphroditism and Leydig cell agenesis are the clinical phenotypes of LH resistance (Wu et al, 2000). Though it is rare in humans, LH receptor deficiency has been reported in a “knock out” animal model that renders the genetically modified mice infertile with the anatomical features of hypogonadism (Lei et al, 2001). On the other hand, less is known about the FSH receptors; only 1 mutation has been reported in a hypophysectomized man who is fertile (Gromoll et al, 1996).

Disruption in any genes involved in androgen biosynthesis, metabolism, and action can negatively affect male sexual development and spermatogenesis. Testosterone is the product of a complex biosynthetic pathway that starts with cholesterol biodegradation. Members of the steroid receptor superfamily and their transcriptional coactivators are pivotal in the regulation of reproductive functions. In the male, conversion of testosterone to dihydrotestosterone by 5α-reductase is crucial for external genitalia and prostate growth. Therefore, deficiencies in 5α-reductase are associated with male infertility as a result of underdeveloped external genitalia and the inability to effectively deliver sperm (Griffin and Wilson, 1992).

Androgen insensitivity syndromes are X-linked disorders that present with a range of internal and external virilization defects. These diseases include Reifenstein syndrome, testicular feminization (male pseudohermaphroditism), Lub syndrome, and Rosewater syndrome (Quigley et al, 1995; Jaffe and Oates, 1996). Ambiguous genitalia, micropenis, and hypospadias are common features. Most androgen receptor (AR) abnormalities causing clinical syndromes result from point mutations or small deletions in the AR gene. Identification of the same mutation in different individuals does not necessarily result in the same clinical phenotype, suggesting that other modulating genes may be involved (McPhaul et al, 1992).

Kennedy disease (X-linked spinal and bulbar muscular atrophy) belongs to a family of polyglutamine neurodegenerative diseases characterized by the abnormal increase in CAG tandem repeats (La Spada et al, 1991). It is a rare (<1:50 000) motor neuron disease caused by a unique mutation in exon 1 of the AR gene. In addition to their neuromuscular dysfunction, patients with Kennedy disease present with androgen insensitivity, gynecomastia, testicular atrophy, and male infertility. The symptoms range in severity from mild muscular weakness and tremor to severe disabling weakness and death by aspiration. Of note, these neurodegenerative diseases follow an inheritance pattern called “genetic anticipation.” This inheritance pattern is characterized by the increasing severity of the genetic disease in succeeding generations associated with the increasing number of CAG tandem repeats. The onset of the disease occurs earlier in the affected offspring. This transmission pattern raises a serious issue in genetic counseling of couples who wish to conceive via assisted reproductive technology.

Although the estrogen receptor is known to be required for male fertility in a mouse model (Eddy et al, 1996), less is known in humans. A mutation in the estrogen receptor gene exon 2 that is functionally similar to that developed in the mouse model has been described in a male patient (Smith et al, 1994). However, this patient's fertility status is unknown.

Endocrine Evaluation of the Infertile Male

Laboratory analysis of serum FSH, LH, total and free testosterone, estradiol, and prolactin levels are commonly available to reproductive technologists and represent the first-line evaluation in patients suspected of HPG axis abnormality. Tests are also available to monitor specific cytokines and growth factors in special circumstances, but these are rarely, if ever, ordered for an infertility evaluation. Although other specialized genetic testing for defects in the hormonal control of male reproduction are not normally performed, knowledge of these disorders may eventually prove helpful in the treatment of male infertility in the era of gene therapy.

Sex Determination/Developmental Abnormalities

Numerous conditions associated with abnormal sex determination and development have long been recognized as the cause for extratesticular ductal, ejaculatory, and sperm production/function abnormalities, which may ultimately lead to male infertility. Whereas for some of these diseases the genetic and molecular bases are still poorly understood, for others the genes involved have already been identified, allowing an easier and faster diagnosis and treatment/management of the disease. Here are some examples of diseases for which sex determination/development genes either have already been shown to be altered or that are likely to be altererd.

Congenital Bilateral Absence of the Vas Deferens and Other Types of Ductal Obstruction

Congenital bilateral absence of the vas deferens (CBAVD) is the most frequent abnormality of the extratesticular ductal and ejaculatory systems (Quinzii and Castellani, 2000). This condition is part of the phenotypic spectrum of cystic fibrosis (CF), an autosomal recessive disorder caused by more than 500 different mutations and 2 intron polymorphisms in the CF transmembrane conductance regulator (CFTR) gene, which quantitatively and qualitatively influence the production of the CFTR protein (Rommens et al, 1989). CBAVD male patients often present with nonfunctional seminal vesicles and ejaculatory ducts, leading to male infertility. However, most patients with CBAVD do not have the severe respiratory and gastrointestinal defects seen in the typical cystic fibrosis patient (Daudin et al, 2000). Since spermatogenesis is usually not impaired, sperm retrieved from the testis or epididymis can be used to perform ICSI; however, there is a concern of transmitting the CFTR gene mutation to the offspring.

Laboratory genetic screening for CFTR gene mutations in both the CBAVD patient and the female partner are extremely important to determine the risk of cystic fibrosis inheritance by the potential offspring. Because of the large gene size, only about 30 mutations are regularly screened in the clinical diagnostic laboratory. Thus, although an abnormal CFTR test result is able to successfully confirm a previously supposed cystic fibrosis diagnosis, a normal test result does not ensure a total absence of CFTR mutations (Mak et al, 1999). Alternatively, a noninvasive sweat test can also be performed to diagnose cystic fibrosis. This test, which determines the amount of chloride in the sweat, can, however, often lead to inconclusive results when they fall into “borderline” range. False positive results are also possible if conditions such as adrenal insufficiency, hypothyroidism, diabetes insipidus, or renal failure are present. Usually, 2 positive sweat test results done on different dates are required to diagnose cystic fibrosis. Finally, several mutations in the CFTR gene do not lead to detectable chloride changes, which may guide to false negative test results (Rosenstein and Cutting, 1998). This illustrates both the power and the limitations of the present clinical laboratory screening tests in this genomic era.

In summary, all patients with CBAVD are now thought to have a genital form of cystic fibrosis (Daudin et al, 2000). Patients presenting with unilateral absence of the vas deferens are also considered at risk and should undergo testing, although the absence of a kidney on the same side might indicate a different etiology (McCallum et al, 2001). Renal agenesis on the same side probably means a Wolffian (mesonephric) duct defect. If vasal agenesis is part of the phenotype, a polymorphic region of thymidines in intron 9 of the CFTR gene should also be tested (5T allele), as it might be responsible for a less efficient processing of CFTR mRNA that results in a lower amount of protein (Daudin et al, 2000).

Persistent Müllerian duct syndrome is a type of male pseudohermaphroditism that results from a quantitative, qualitative, or temporal deficiency of the male anti-Müllerian hormone or its receptor during prenatal development (Thompson et al, 1994). The lack of Müllerian duct regression in an otherwise phenotypically normal man often results in cryptorchidism and ductal obstruction, thus impairing fertility (Jaffe and Oates, 1996).

Disorders of Erection and Ejaculation

Ejaculatory and erectile dysfunction are two conditions linked to male infertility, which can also be associated with bladder exstrophy/epispadias (Woodhouse, 1994). An abnormal closure of the lower anterior abdominal wall during fetal development is responsible for the phenotype. Since spermatogenesis is not compromised, patients may still conceive through sperm retrieval from the testis or epididymis, followed by assisted reproductive technology.

Myelodysplasia, a condition commonly known as spina bifida, is believed to be due to a currently unidentified multifactorial genetic mechanism, which causes a characteristic spinal dysraphism. This is frequently associated with emission or antegrade ejaculation failure or both, with a consequent negative impact on fertility. Spermatogenesis deficiencies have also been reported in some patients, but their direct association with myelodysplasia remains to be proven (Reilly, 1992; Jaffe and Oates, 1996).

Prune-belly syndrome affects predominantly men and is most likely caused by a mutation in a gene involved in the canalization of the anterior/posterior urethral junction. A lax abdominal wall musculature, genitourinary tract malformations, and cryptorchidism are characteristic features. Male infertility is compromised through ejaculatory dysfunction and spermatogenic deterioration (Terada et al, 1994).

Other Genetic Defects Associated With Defective Spermatogenesis or Sperm Function

Well-characterized expansions of an unstable CTG trinucleotide repeat within a gene encoding a serine—threonine kinase protein are associated with myotonic dystrophy, the most common cause of adult-onset muscular dystrophy. This condition, which causes muscular atrophy, endocrinopathy, and cataracts, is also characterized by seminiferous tubules atrophy, with a consequent negative impact on spermatogenesis (Harley et al, 1993).

The main features of Noonan syndrome include facial dysmorphism, webbed neck, short stature, and pulmonary and cardiac problems. In men, fertility is compromised because of cryptorchidism and elevated FSH levels, which negatively affect spermatogenesis (Elsawi et al, 1994). Although several deletions have already been shown to be associated with the disease, no candidate gene is available yet.

Sickle-cell anemia and β-thalassemia are conditions that result from deficiencies in hemoglobin synthesis. Hypothalamic—pituitary defects or gonadal failure due to iron deposition after multiple transfusions may impair testicular function and deteriorate fertility in these patients (Osegbe and Akinyanju, 1987).

Primary ciliary dyskinesia phenotypes include chronic sinusitis, bronchiectasis, situs inversus, retinitis pigmentosa, deafness, and infertility. All these features are due to a defect in the motor apparatus, or axoneme, of ciliated cells resulting from gene defects in the gene encoding dynein. Kartagener and Usher syndromes are 2 good examples of diseases with this phenotype (Hunter et al, 1986; Yokota et al, 1993). In these patients, fertility is impaired through sperm motility. However, since spermatogenesis is not affected, ICSI or in vitro fertilization can still be used to achieve a pregnancy (Bongso et al, 1989), with unknown consequences for the generated offspring.

Young syndrome is most likely caused by a ciliary function deficiency, which causes structural abnormalities of the axoneme, resulting in sperm dysfunction due to motion deficiencies. In addition, Young patients, who also suffer from chronic sinusitis and bronchiectasis, may present epididymal obstruction, further impairing their fertility. This situation can, however, be reversed through microsurgical reconstitution (Wilton et al, 1991; Jaffe and Oates, 1996).

Technological advances in research, like embryonic stem cell targeting, which disrupts specific genomic loci in animal models, have resulted in the identification of hundreds of genes previously unknown to be related to infertility. Genes involved in sex determination and development have not been an exception, most notably the genes involved in cryptorchidism. For example, mutations in Insl3, Great, and Hoxa10 have all been shown to be related to deficient testicular descent in mice (Satokata et al, 1995; Nef and Parada, 1999; Zimmermann et al, 1999; Overbeek et al, 2001; Hsu et al, 2002). All of these genes are also related to cryptorchidism in humans, but in a relatively small percentage of patients. Certainly, these provide an example of advances first described in animal models that will enable an improved understanding of the molecular basis of male infertility.


The widespread use of assisted reproductive technologies has permitted many couples previously considered hopelessly infertile to experience parenthood. Nevertheless, these technologies also bypass natural barriers to fertilization by defective sperm. Given the current limitation of genetic analysis of men with idiopathic male infertility, it is likely that many of these men have a genetic cause of their infertility. Thus, while the current data on the safety of ICSI are re-assuring, our increasing knowledge of the genetic causes of male infertility should encourage patient counseling before ICSI.


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