Infertility is defined as a failure to conceive after 12 months of unprotected intercourse ^1–3 and it affects 10% to 15% of American couples. Infertility is a devastating disorder that affects equally men and women, and both male and female evaluations are necessary to optimize a couple’s success for conception. Infertility can be syndromic, ie, expressed as part of a major genetic syndrome, or idiopathic, where the cause is unknown and usually confined to the gonads with no obvious extra-gonadal manifestation. A three-generation family pedigree is very helpful in detecting clues to heritable disorders. For example, a family history of infertility and anemia or cancer may indicate Fanconi syndrome, while a family history with infertility in the females and mental retardation among males may indicate the Fragile X syndrome. A detailed physical examination is important to rule out dysmorphic features, which may be an indication of syndromic cause of infertility.

The causes of male infertility include environmental exposures, anatomic obstruction, and genetic, infectious, and autoimmune disorders and other diverse etiologies.¹ Male infertility has many psychological, economic, and social sequelae, including decreased quality of life, and can be associated with serious medical disorders.^1,12

Among infertile men, almost 20% have azoospermia (no sperm in the ejaculate) or oligozoospermia/oligospermia (low-sperm concentration, less than 15 million sperm per milliliter of ejaculate), while another 20% have asthenospermia (sperm with low motility). Other sperm abnormalities include teratozoospermia (abnormal sperm morphology). Genetic factors are known to play an important role in male infertility, and at least 2300 testes genes may be involved in male fertility.

Studies in infertile men demonstrated that up to 20% carry constitutional chromosome aberrations.^4,5 Genomic aberrations found in these patients include numerical abnormalities, such as Klinefelter syndrome and its variants; XYY karyotype; testicular disorders of sex development, such as XX males; structural chromosome rearrangements, including Robertsonian translocations, balanced reciprocal translocations and inversions; as well as submicroscopic DNA copy number alterations (microdeletions and microduplications) encompassing genes associated with spermatogenesis or gonadal development.

Klinefelter Syndrome

Klinefelter men can present with variable phenotypes and the only reliable diagnosis is based on the karyotype. These men usually present due to infertility and nonobstructive azoospermia. Physical examination is significant for small testes. Other findings that have been associated with Klinefelter men, but are not always present, include gynecomastia, long legs/arms, developmental delay, speech and language deficits, learning disabilities and inferior performance in school. Serum testosterone levels may be low with elevated follicle stimulating hormone and luteinizing hormone levels. Klinefelter syndrome occurs in approximately 0.1% of live male births and is the most common chromosomal aberration among infertile men, accounting for 14% of azoospermia patients.⁶ Klinefelter syndrome is characterized by the presence of one or more extra X chromosomes in association with a normal Y chromosome. The most common variant, the 47,XXY karyotype, is seen in approximately 90% of Klinefelter men.

Due to the variability of the phenotype, Klinefelter syndrome is underdiagnosed, with only 10% of Klinefelter patients recognized prepubertally and an additional 15% identified after puberty.^4,5,7 Infertility and small testes are the most prevalent characteristics in adult Klinefelter syndrome patients. The testes in adult Klinefelter syndrome males are characterized by extensive fibrosis and hyalinization of the seminiferous tubules and impaired spermatogenesis, with azoospermia or severe oligozoospermia. Although most Klinefelter syndrome patients are infertile, testicular spermatozoa can be identified and recovered from at least 50% of men with the nonmosaic 47,XXY karyotype.^4,8 Testicular sperm extraction (TESE) combined with intracytoplasmic sperm injection (ICSI) allows some patients with Klinefelter syndrome to father their own biological children.^6,9

Sperm from Klinefelter syndrome men usually have a normal 23,X or 23,Y haploid chromosome complement. Despite this, an increased frequency for both autosomal and sex chromosome aneuploidy has been reported in fetuses of such men.^4,10

Y Chromosome Microdeletions

The human Y chromosome contains many genes that are essential for male sex determination and spermatogenesis.^1,11 Microdeletions (deletions that cannot be visualized via standard microscopy) on the long arm of chromosome Y (Yq) are one of the most significant pathogenic defects in infertile males, found in about 10% of men with oligozoospermia, and in up to 15% of azoospermic patients.^5,6,8 The most common deletions involve the AZF region that is made up of three genetic domains (AZFa, AZFb, and AZFc) located on the long arm of the Y chromosome. Microdeletions encompassing genes other than those located in the AZFa, AZFb, and AZFc regions on the Y chromosome have been proposed to influence spermatogenesis, although their role remains to be elucidated. In addition, gross structural abnormalities of the Yq chromosome, such as whole long arm deletions (del(Y)(q11.2)), isochromosome Yp (i(Yp)) and dicentric Yp (dic(Yp)), can result in complete absence of germ cells.^4,9 These abnormalities are much less common than the microdeletions.

Balanced Chromosome Rearrangements

Structural chromosomal abnormalities are frequent in infertile men, with an overall incidence of about 5%, tenfold higher than the 0.5% prevalence for structural chromosomal abnormalities in the general population.^6,12 Chromosome rearrangements are found in approximately 14% of azoospermic and 4.5% of oligozoospermic patients. Autosome aberrations (3%) are more commonly associated with oligozoospermia, whereas sex chromosome defects (12.6%) predominate among azoospermic men.^12,13 Structural chromosome rearrangements may cause impaired spermatogenesis by adversely affecting chromosome synapsis during meiosis.^5,13 Alternatively, chromosome breaks that cause rearrangements may result in disruption/inactivation of a single dosage-sensitive gene(s) involved in spermatogenesis, thus resulting in the arrest of normal male germ cell development.^{12, 13}

Carriers of balanced chromosome rearrangements usually have a normal phenotype and are often diagnosed during evaluation of their infertility problem, or following the birth of a child with an unbalanced chromosome complement. Chromosome segregation analyses demonstrate a high proportion (up to 80%) of unbalanced spermatozoa among carriers of reciprocal translocations. Fertility problems in male carriers can be attributed to disturbance of the meiotic process, and various degrees of sperm defects. However, the presence of a balanced chromosome rearrangement is not necessarily associated with spermatogenic failure. Infertility and the finding of a balanced rearrangement should not preclude doing a full infertility evaluation on the couple. Fertilization by an unbalanced gamete does occur, and many resulting embryos do not survive. Therefore, individuals carrying balanced rearrangements can benefit from preimplantation genetic diagnosis (PGD) to identify and implant embryos with a normal or balanced chromosome complement.

Individuals who carry chromosome inversions are usually healthy; however, infertility, recurrent pregnancy losses, and chromosomally abnormal offspring have been reported.^5,12,13 In carriers of paracentric inversions (see Chapter 2), unbalanced chromosomal complements have been reported in about 1% of spermatozoa, but this finding is based on a limited number of individuals.¹³ In contrast, carriers of pericentric inversions may have a high proportion (up to 54%) of spermatozoa with unbalanced recombinant chromosomes.^5,9 In general, large pericentric inversions (encompassing more than half of the chromosome length) are more likely to produce unbalanced chromosomes, and are therefore more frequently observed among infertile men.

Complex chromosome rearrangements (CCRs) involve at least three breakpoints and exchange of genetic material between two or more chromosomes, and occur in around 0.5% of newborns.¹⁴ Unbalanced CCRs are often associated with intellectual disability and congenital abnormalities. Balanced CCRs are seen in phenotypically normal individuals with a history of recurrent abortions and infertility. Each CCR is unique and reproductive risks will depend upon multiple factors such as chromosome origin, location of breakpoints, number of chromosomes involved, genome content, and rearrangement type and complexity. There are 64 possible combinations of chromosomes in spermatozoa of a carrier for CCR with three breaks involving three chromosomes. The number of combinations increases with the involvement of additional chromosomes and/or breakpoints. Because of the low proportion of balanced sperm available (∼10%-20%), intracytoplasmic sperm injection is not recommended in male CCR carriers.

Robertsonian translocations are the most common structural chromosomal rearrangement in humans, resulting in a derivative chromosome composed of the long arms of two acrocentric chromosomes (13, 14, 15, 21, and 22). The most frequent Robertsonian translocations are der(13;14) and der(14;21) with incidences of about 1:1000 and 1:5000, respectively.^15,16 Carriers of Robertsonian translocations have an increased risk for infertility, chromosomally unbalanced offspring, and spontaneous abortions, but are otherwise healthy. Studies involving male carriers of der(13;14) showed that in about 80% of cases the partners had spontaneous pregnancies, while in 20% of cases the male carriers were infertile.^15,16 Among infertile male patients, 1.6% are Robertsonian translocation carriers. The infertility in these individuals likely involves abnormal meiosis with subsequent meiotic arrest that causes oligozoospermia or azoospermia.

47,XYY Karyotype

An extra copy of the Y chromosome is present in 47,XYY males. This chromosomal aneuploidy occurs in 1 of 1000 live male births in the general population, and is seen more frequently in the infertile population. The vast majority of men with the 47,XYY karyotype have normal phenotype and normal fertility. Semen analyses in a minority of some men may show oligozoospermia or azoospermia, while the majority of 47,XYY males are fertile with normal semen parameters, and produce normal haploid spermatozoa.⁹

Cystic Fibrosis and Congenital Absence of Vas Deferens

Obstructive azoospermia is due to a physical obstruction between the testes and the urethra and can be caused by vasectomy, agenesis of the vas deferens, or ejaculatory duct obstruction among other things. Obstructive azoospermia can be differentiated from nonobstructive azoospermia by testicular biopsy. In obstructive azoospermia, testicular biopsy will show normal spermatogenesis, and such individuals are candidates for intracytoplasmic sperm injection (ICSI), while few if any sperm will be identified in nonobstructive azoospermia. Congenital absence of vas deferens is a form of obstructive azoospermia, and accounts for approximately 2% of all cases of male infertility, and up to 25% of cases of obstructive azoospermia. More than 95% of males with cystic fibrosis have congenital absence of vas deference (CAVD) bilaterally with resulting azoospermia. This has led to investigations whether men with isolated CAVD, but without overt symptoms of cystic fibrosis (pulmonary, pancreatic and intestinal manifestations), also carry mutations in the cystic fibrosis gene. Multiple studies have shown that the majority of men with CAVD do carry mutations in the cystic fibrosis gene. Approximately 80% of men with CAVD carry at least one mutation and approximately 50% carry two mutations. Mutations in the CFTR gene in the idiopathic form of CAVD are usually compound heterozygous and involve one allele that is highly damaging such as F508del, and mild alleles such as 5T (c.1210–12T[5]) and R117H (c.350G >A).

Men with CAVD should be offered genetic screening for CFTR mutations, and such couples should undergo genetic counseling. Men with CAVD are candidates for intracytoplasmic sperm injection, and at high risk for carrying a CFTR mutation. Hence, they are at risk to have a child with cystic fibrosis. If testing of the male with CAVD shows mutations in the CFTR gene, their partner should be tested for CFTR mutations prior to ICSI to establish her carrier status and provide appropriate risk assessment. Preimplantation genetic diagnosis can be offered to couples when both are carriers for CFTR mutations in order to identify which embryos are affected.

In Case 1, John had chromosome studies done, and the karyotype showed 47,XXY, consistent with the diagnosis of Klinefelter syndrome. Hormonal studies indicated low testosterone and elevated FSH levels, consistent with hypergonadotropic hypogonadism due to absence of germ cells and gonadal dysfunction. John and his wife are interested in further understanding the Klinefelter syndrome, and how it will affect their ability to conceive. Laura is currently 35 years of age and does not have children. This is a first marriage for both of them. John was counseled that his lifespan will be normal, and that the extra X chromosome results in decreased fertility due to unknown mechanisms. Because of germ cell and spermatogonia depletion in the Klinefelter syndrome, testosterone production is lowered with resultant decreased libido and sexual performance. John was initiated on testosterone replacement and noticed improvement with libido, erection, and memory after 2 months of treatment. He was referred to an urologist, who performed testicular biopsy to determine the presence of viable sperm. Testicular biopsy revealed complete absence of sperm and John and Laura were not candidates for intracytoplasmic sperm injection (ICSI). The couple was counseled to consider sperm from a donor, or adoption as options to have a child.

Female infertility is often due to impairment of ovarian function that can result from several different genetic mechanisms—numerical X chromosome abnormalities, including Turner syndrome and the triple X karyotype; balanced structural chromosomal rearrangements, genomic imbalances involving the X chromosome and autosomes, XY gonadal dysgenesis, and single gene alterations leading to ovarian dysgenesis, premature ovarian failure, and reproductive dysfunction. X chromosome-linked aberrations play a major role among currently known genetic defects.¹⁷

Premature ovarian insufficiency (POI), also called premature ovarian failure (POF), not caused by surgery, chemotherapy, radiation or other exposures such as chronic smoking, affects approximately 1% to 4% of women, and is clinically defined as a cessation of menses prior to age 40 (normal being 50–52), with elevated FSH levels and low serum estradiol levels.¹⁸ The incidence of POI prior to age 30 is 0.1%. Women with POI present with amenorrhea, either primary or secondary, hot flashes, and vaginal dryness. Women with POI have 50% higher overall mortality, with an 80% increase in mortality due to ischemic heart disease, and an increased risk of cognitive impairment and dementia, as well as premature osteoporosis.^19–22 The association of POI with accelerated overall aging, signifies that ovarian aging may be a window into women’s aging in general.