Male infertility

Male infertility

Male infertility refers to a male's inability to cause pregnancy in a fertile female. In humans it accounts for 40-50% of infertility.^[1][2][3]Male infertility is commonly due to deficiencies in the semen, and semen quality is used as a surrogate measure of male fecundity.^[4]

Causes

Factors relating to male infertility include:^[5]

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:

• Hypogonadotropic hypogonadism due to various causes
  • Obesity increases the risk of hypogonadotropic hypogonadism.^[6] Animal models indicate that obesity causes leptin insensitivity in the hypothalamus, leading to decreasedKiss1 expression, which, in turn, alters the release of gonadotropin-releasing hormone (GnRH).^[6]
• Drugs, alcohol
• Strenuous riding (bicycle riding,^[7] horseback riding)
• Medications, including those that affect spermatogenesis such as chemotherapy, anabolic steroids, cimetidine, spironolactone; those that decrease FSH levels such asphenytoin; those that decrease sperm motility such as sulfasalazine and nitrofurantoin
• Genetic abnormalities such as a Robertsonian translocation

Tobacco smoking

Male smokers also have approximately 30% higher odds of infertility.^[8] There is increasing evidence that the harmful products of tobacco smoking kill sperm cells.^[9][10] Therefore, some governments require manufacturers to put warnings on packets. Smoking tobacco increases intake of cadmium, because the tobacco plant absorbs the metal. Cadmium, being chemically similar to zinc, may replace zinc in the DNA polymerase, which plays a critical role in sperm production. Zinc replaced by cadmium in DNA polymerase can be particularly damaging to the testes.^[11]

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.^[12] As men age there is a consistent decline in semen quality, and this decline appears to be due to DNA damage.^[13] (Silva et al., 2012). These findings suggest that DNA damage is an important factor in male infertility.

Testicular factors

Testicular factors refer to conditions where the testes produce semen of low quantity and/or poor quality despite adequate hormonal support and include:

• Age
• Genetic defects on the Y chromosome
  • Y chromosome microdeletions
• Abnormal set of chromosomes
  • Klinefelter syndrome
• Neoplasm, e.g. seminoma
• Idiopathic failure
• Cryptorchidism
• Varicocele (14% in one study)^[14][15]
• Trauma
• Hydrocele
• Mumps^[16]
• Malaria
• Testicular cancer
• Defects in USP26 in some cases^[17]
• Acrosomal defects affecting egg penetration
• Idiopathic oligospermia - unexplained sperm deficiencies account for 30% of male infertility.^[18]

Radiation therapy to a testis decreases its function, but infertility can efficiently be avoided by avoiding radiation to both testes.^[19]

Post-testicular causes

Post-testicular factors decrease male fertility due to conditions that affect the male genital system after testicular sperm production and include defects of the genital tract as well as problems in ejaculation:

• Vas deferens obstruction
• Lack of Vas deferens, often related to genetic markers for Cystic Fibrosis
• Infection, e.g. prostatitis
• Retrograde ejaculation
• Ejaculatory duct obstruction
• Hypospadias
• Impotence

Diagnosis

The diagnosis of infertility begins with a medical history and physical exam by a physician or nurse practitioner. Typically two separate semen analyses will be required. The provider may order blood tests to look for hormone imbalances, medical conditions, or genetic issues.

Medical history

The history should include prior testicular or penile insults (torsion, cryptorchidism, trauma), infections (mumps orchitis, epididymitis), environmental factors, excessive heat,radiation, medications, and drug use (anabolic steroids, alcohol, smoking).

Sexual habits, frequency and timing of intercourse, use of lubricants, and each partner's previous fertility experiences are important.

Loss of libido and headaches or visual disturbances may indicate a pituitary tumor.

The past medical or surgical history may reveal thyroid or liver disease (abnormalities of spermatogenesis), diabetic neuropathy (retrograde ejaculation), radical pelvic orretroperitoneal surgery (absent seminal emission secondary to sympathetic nerve injury), or hernia repair (damage to the vas deferens or testicular blood supply).

A family history may reveal genetic problems.

Physical examination

Usually, the patient disrobes completely and puts on a gown. The physician or NP will perform a thorough examination of the penis, scrotum, testicles, anus and rectum.

Sperm sample

The volume of the semen sample, approximate number of total sperm cells, sperm motility/forward progression, and % of sperm with normal morphology are measured. This is the most common type of fertility testing.^[20][21] Semen deficiencies are often labeled as follows:

• Oligospermia or Oligozoospermia - decreased number of spermatozoa in semen
• Aspermia - complete lack of semen
• Hypospermia - reduced seminal volume
• Azoospermia - absence of sperm cells in semen
• Teratospermia - increase in sperm with abnormal morphology
• Asthenozoospermia - reduced sperm motility

There are various combinations of these as well, e.g. Teratoasthenozoospermia, which is reduced sperm morphology and motility. Low sperm counts are often associated with decreased sperm motility and increased abnormal morphology, thus the terms "oligoasthenoteratozoospermia" or "oligospermia" can be used as a catch-all.

Blood sample

Common hormonal test include determination of FSH and testosterone levels. A blood sample can reveal genetic causes of infertility, e.g. Klinefelter syndrome, a Y chromosome microdeletion, or cystic fibrosis.

Prevention

Some strategies suggested or proposed for avoiding male infertility include the following:

• Avoiding smoking^[22] as it damages sperm DNA
• Avoiding heavy marijuana and alcohol use.^[23]
• Avoiding excessive heat to the testes.^[23]
• Sperm counts can be depressed by daily coital activity^[23] and sperm motility may be depressed by coital activity that takes place too infrequently (abstinence 10–14 days or more).^[23]
• When participating in contact sports, wear a Protective Cup and Jockstrap to protect the testicles. Sports such as Baseball, Football, Cricket, Lacrosse, Hockey, Softball,Paintball, Rodeo, Motorcross, Wrestling, Soccer, Karate or other Martial Arts or any sport where a ball, foot, arm, knee or bat can come into contact with the groin.

Treatment

Treatments vary according to the underlying disease and the degree of the impairment of the male fertility. Further, in an infertility situation, the fertility of the female needs to be considered.

Pre-testicular conditions can often be addressed by medical means or interventions.

Testicular-based male infertility tends to be resistant to medication. Usual approaches include using the sperm for intrauterine insemination (IUI), in vitro fertilization (IVF), or IVF with intracytoplasmatic sperm injection (ICSI). With IVF-ICSI even with a few sperm pregnancies can be achieved.

Obstructive causes of post-testicular infertility can be overcome with either surgery or IVF-ICSI. Ejaculatory factors may be treatable by medication, or by IUI therapy or IVF.

The off-label use of Clomiphene citrate, an anti-estrogen drug designed as a fertility medicine for women, is controversial.^[24] Vitamin E helps counter oxidative stress,^[25] which is associated with sperm DNA damage and reduced sperm motility.^[26] A hormone-antioxidant combination may improve sperm count and motility.^[27] The Low dose Estrogen Testosterone Combination Therapy may improve sperm count and motility in some men.^[28] including severe oligospermia.^[29][30]

Oral antioxidants e.g. brand name Maxoza-L given to males in couples undergoing in vitro fertilisation for male factor or unexplained subfertility result in significantly higher live birth rate.^[31]