Male infertility refers to a sexually mature male's inability to impregnate a fertile female. Male infertility can wholly or partially account for 40% of infertility among couples who are trying to have children. "A problem with the male is the sole cause, or a contributing cause, of infertility in about 40 percent of infertile couples. It affects approximately 7% of all men. Male infertility is commonly due to deficiencies in the semen. Semen quality is used as a surrogate measure of male fecundity. More recently, advanced sperm analyses that examine intracellular sperm components are being developed.
Age considerations Sperm motility increases from puberty through one's mid-thirties. Research shows that, from the age of 36 onwards, sperm motility decreases from 40% Grade A & B to 31% in one's 50s. The effects of aging on semen quality is summarized below based on a study of 1,219 subjects: Age group (years) Number of subjects (n) Motility (% Grade A+B) [Min-Max] 21–28 57 47.5 ± 25.4 [0-88] 29–35 450 48.1 ± 30.4 [0-95] 36–42 532 40.0 ± 27.1 [0-83] 43–49 165 33.1 ± 25.1 [0-84] 50–60 15 31.3 ± 23.9 [0-59] 90% of seminiferous tubules in men in their 20s and 30s contain spermatids, whereas men in their 40s and 50s have spermatids in 50% of their seminiferous tubules, and only 10% of seminiferous tubules from men aged over 80 contain spermatids. In a random international sample of 11,548 men confirmed to be biological fathers by DNA paternity testing, the oldest father was found to be 66 years old at the birth of his child. The ratio of DNA-confirmed versus DNA-rejected paternity tests around that age is in agreement with the notion of general male infertility above age 65–66.
Causes Factors relating to male infertility include:
Immune infertility Antisperm antibodies (ASA) have been considered as the cause of infertility in around 10–30% of infertile couples. ASA production are directed against surface antigens on sperm, which can interfere with sperm motility and transport through the female reproductive tract, inhibiting capacitation and acrosome reaction, impaired fertilization, influence on the implantation process, and impaired growth and development of the embryo. Risk factors for the formation of antisperm antibodies in men include the breakdown of the blood‑testis barrier, trauma and surgery, orchitis, varicocele, infections, prostatitis, testicular cancer, failure of immunosuppression and unprotected receptive anal or oral sex with men.
Genetics
Chromosomal anomalies and genetic mutations account for nearly 10–15% of all male infertility cases.
Mitochondrial DNA Mature human sperm contains almost no mitochondrial DNA at all. An increased amount of mitochondrial DNA in the sperm cells has shown to have a negative impact on fertility.
Klinefelter syndrome One of the most commonly known causes of infertility is Klinefelter syndrome, which affects one in 500–1000 newborn males. Klinefelter syndrome is a chromosomal defect that occurs during gamete formation due to a non-disjunction error during cell division. This results in males having smaller testes, reducing the amount of testosterone and sperm production. Males with this syndrome carry an extra X chromosome (XXY), meaning they have 47 chromosomes compared to the normal 46 in each cell. This extra chromosome directly affects sexual development before birth and during puberty. A variation of Klinefelter syndrome is when some cells in an individual have the extra X chromosome but others do not, referred to as mosaic Klinefelter syndrome. The reduction of testosterone in the male body normally results in an overall decrease in the production of viable sperm for these individuals, thereby making it hard for them to father children without fertility treatment.
Y chromosome deletions Y chromosomal infertility is a direct cause of male infertility due to its effects on sperm production, occurring in approximately one in 2000 males. Usually, affected men show no symptoms, although they may have smaller testes. Men with this condition may exhibit azoospermia (no sperm production), oligozoospermia (small number of sperm production), or they may produce abnormally shaped sperm (teratozoospermia). This case of infertility occurs during the development of gametes in the male. Where a normal healthy male will have both an X and a Y chromosome, affected males have genetic deletions in the Y chromosome. These deletions affect protein production that is vital for spermatogenesis. Studies have shown that this is an inherited trait; if a male is fathered by a man who also exhibited Y chromosome deletions then this trait will be passed down. These individuals are thereby "Y-linked". Daughters are not affected and cannot be carriers due to their lack of a Y chromosome.
Other Age group 12–49 (Paternal age effect) Aneuploidy, an abnormal number of chromosomes Centriole Neoplasm, e.g. seminoma Idiopathic failure Cryptorchidism Trauma Hydrocele, particularly hydrocele testis Hypopituitarism in adults, and hypopituitarism untreated in children (resulting in growth hormone deficiency and proportionate dwarfism.) Mumps Malaria Testicular cancer Defects in USP26 in some cases Acrosomal defects affecting egg penetration Idiopathic oligospermia – unexplained sperm deficiencies account for 30% of male infertility.
Pre-testicular causes Pre-testicular factors refer to conditions that impede adequate support of the testes and include situations of poor hormonal support and poor general health including:
Varicocele, a condition of swollen testicle veins with an incidence of 15% in fertile men and about 40% in infertile men. It is present in up to 35% of cases of primary infertility and 69–81% of secondary infertility. Hypogonadotropic hypogonadism due to various causes Obesity increases the risk of hypogonadotropic hypogonadism. Animal models indicate that obesity causes leptin insensitivity in the hypothalamus, leading to decreased Kiss1 expression, which, in turn, alters the release of gonadotropin-releasing hormone (GnRH). Undiagnosed and untreated coeliac disease (CD). Coeliac men may have reversible infertility. Nevertheless, CD can present with several non-gastrointestinal symptoms that can involve nearly any organ system, even in the absence of gastrointestinal symptoms. Thus, the diagnosis may be missed, leading to a risk of long-term complications. In men, CD can reduce semen quality and cause immature secondary sex characteristics, hypogonadism and hyperprolactinaemia, which causes impotence and loss of libido. The giving of gluten free diet and correction of deficient dietary elements can lead to a return of fertility. It is likely that an effective evaluation for infertility would best include assessment for underlying celiac disease, both in men and women. Drugs, alcohol Strenuous riding (bicycle riding, horseback riding) Medications, including those that affect spermatogenesis such as chemotherapy, fluoxetine, anabolic steroids, cimetidine, spironolactone; those that decrease FSH levels such as phenytoin; those that decrease sperm motility such as sulfasalazine and nitrofurantoin Genetic abnormalities such as a Robertsonian translocation
Tobacco smoking
Both first- and second-hand exposure to tobacco and marijuana smoke can damage the testicles and interfere with sperm production. Tobacco contains more than 7000 compounds, of which at least 70 are carcinogenic. Some governments require manufacturers to put warnings on packets.
Cigarette smoke contains both particulate matter such as nicotine and tar and gases such as carbon monoxide (CO). Particulate matter and carbon monoxide are major criteria pollutants, known to have negative effects on male fertility. Nicotine and other components of smoke can cross the blood-testis barrier and harm germ cells and spermatozoa, resulting in decreased measures of sperm health and increases in DNA fragmentation, sperm mutagenesis and genetic abnormalities.
Smoking tobacco increases intake of the heavy metal cadmium, which naturally accumulates in the tobacco plant. When cadmium particles are inhaled, they diffuse from the lungs into the blood stream and circulate throughout the body to various tissues. Cadmium tends to accumulate in the testicles, where it can cause severe structural damage and sperm loss.
Pollutants
Exposure to environmental pollutants in indoor and outdoor air can affect fertility, fetal development, health of offspring in later life, and the genetics of future generations. Common sources of pollutants include tobacco and marijuana smoke and e-cigarettes.; burning of fossil fuels through vehicle use, heating and cooking; cleaning and personal care products; and microplastics. Steps can be taken to minimize exposures such as avoiding smoking, minimizing dust, using glass instead of plastics, carefully selecting cleaning products and personal care products, and avoiding vehicle exhaust fumes and heavy traffic areas.
The criteria air pollutants sulfur dioxide, nitrogen dioxide, particulate matter (PM2.5, PM10), carbon monoxide, O3 and lead have been identified as harmful to human health by the World Health Organization and the U.S. Environmental Protection Agency (EPA) and are known to interfere with reproduction.
A study of counties in China reported a decrease in fertility of 2% for each 10 μg/m3 increase in PM2.5 exposure. PM10, PM2.5 and SO2 have been related to decreased total sperm motility. PM2.5, CO, and O3 exposure were related to decreases in total sperm number. Studies in Turkey, Poland, and California, among others, have linked exposure to particulate matter with decreases in sperm count and motility and increases in abnormal cell development.
Nitric oxide (NO) is essential to the synthesis and secretion of reproductive hormones. In males, highly specific levels of NO are needed to regulate key functions related to sperm motility, hyperactivation, capacitation, and maturation. As pollutants, nitric oxide (NO) and nitrogen dioxide (NO2) can disrupt these chemically-sensitive activities.
A study in Hefei, China found that sulfur dioxide (SO2) exposure negatively affected progressive motility and total motility of sperm during 0–90 lag days and 70–90 lag days. SO2 exposure also had negative effects on sperm concentration and total sperm number during 10–14 lag days.
Endocrine disruptors include both polycyclic aromatic hydrocarbons (PAHs) such as benzo(a)pyrene (BaP) and heavy metals such as lead (Pb), cadmium (Cd), copper (Cu), zinc (Zn) and mercury (Hg). BaP has been reported to reduce sperm motility and increase sperm abnormalities. This effect increases with exposure. Research has demonstrated that more BaPs were found in men with reported fertility issues compared to men without.
Heavy metals such as lead (Pb) and cadmium (Cd) have been found in semen samples. Exposures to heavy metals are linked to lower sperm density, motility, and sperm counts. Heavy metals are also linked to damage to the physical shape and structure of sperm (sperm morphology) and to sperm DNA fragmentation, making sperm less viable.
DNA damage Common inherited variants in genes that encode enzymes employed in DNA mismatch repair are associated with increased risk of sperm DNA damage and male infertility. As men age there is a consistent decline in semen quality, and this decline appears to be due to DNA damage. The damage manifests by DNA fragmentation and by the increased susceptibility to denaturation upon exposure to heat or acid, the features characteristic of apoptosis of somatic cells. These findings suggest that DNA damage is an important factor in male infertility.
Epigenetic