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Male infertility
SpecialtyUrology, reproductive medicine Edit this on Wikidata

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] It affects approximately 7% of all men.[4] Male infertility is commonly due to deficiencies in the semen, and semen quality is used as a surrogate measure of male fecundity.[5]

Causes

Factors relating to male infertility include:[6]

Immune infertility

Antisperm antibodies (ASA) have been considered as infertility cause in around 10–30% of infertile couples.[7] 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.[7][8]

Testicular factors

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

Varicocele

Varicocele, is a condition of swollen testicle veins.

It is present in 15% of normal men and in about 40% of infertile men.

It is present in up to 35% of cases of primary infertility and 69-81% of secondary infertility.[9]

Other

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:

Tobacco smoking

See also: Smoking and pregnancy

There is increasing evidence that the harmful products of tobacco smoking may damage the testicles[19] and kill sperm,[20][21] but their effect on male fertility is not clear.[22] 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.[23]

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.[24] As men age there is a consistent decline in semen quality, and this decline appears to be due to DNA damage.[25] 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.[26] These findings suggest that DNA damage is an important factor in male infertility.

Epigenetic

See also: DNA methylation

An increasing amount of recent evidence has been recorded documenting abnormal sperm DNA methylation in association with abnormal semen parameters and male infertility.[27][28]

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:

Diagnosis

The diagnosis of infertility begins with a medical history and physical exam by a physician, physician assistant, 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 or retroperitoneal 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, physician assistant, or nurse practitioner will perform a thorough examination of the penis, scrotum, testicles, I vas deferens, spermatic cords, ejaculatory ducts, urethra, urinary bladder, anus and rectum. An orchidometer can measure testicular volume, which in turn is tightly associated with both sperm and hormonal parameters.[4] A physical exam of the scrotum can reveal a varicocele, but the impact of detecting and surgically correct a varicocele on sperm parameters or overall male fertility is debated.[4]

Sperm sample

Main article: Semen analysis
Further information: Semen quality

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.[29][30] Semen deficiencies are often labeled as follows:

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.

Ultrasonography

Scrotal ultrasonography is useful when there is a suspicion of some particular diseases. It may detect signs of testicular dysgenesis, which is often related to an impaired spermatogenesis and to a higher risk of testicular cancer.[4] Scrotum ultrasonography may also detect testicular lesions suggestive of malignancy. A decreased testicular vascularization is characteristic of testicular torsion, whereas hyperemia is often observed in epididymo-orchitis or in some malignant conditions such as lymphoma and leukemia.[4] Doppler ultrasonography useful in assessing venous reflux in case of a varicocele, when palpation is unreliable or in detecting recurrence or persistence after surgery, although the impact of its detection and surgical correction on sperm parameters and overall fertility is debated.[4]

Dilation of the head or tail of the epididymis is suggestive of obstruction or inflammation of the male reproductive tract.[4] Such abnormalities are associated with abnormalities in sperm parameters, as are abnormalities in the texture of the epididymis.[4] Scrotal and transrectal ultrasonography (TRUS) are useful in detecting uni- or bilateral congenital absence of the vas deferens (CBAVD), which may be associated with abnormalities or agenesis of the epididymis, seminal vesicles or kidneys, and indicate the need for testicular sperm extraction.[4] TRUS plays a key role in assessing azoospermia caused by obstruction, and detecting distal CBAVD or anomalies related to obstruction of the ejaculatory duct, such as abnormalities within the duct itself, a median cyst of the prostate (indicating a need for cyst aspiration), or an impairment of the seminal vesicles to become enlarged or emptied.[4]

Prevention

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

  • Avoiding smoking[32] as it damages sperm DNA
  • Avoiding heavy marijuana and alcohol use.[33]
  • Avoiding excessive heat to the testes.[33]
  • Maintaining optimal frequency of coital activity: sperm counts can be depressed by daily coital activity[33] and sperm motility may be depressed by coital activity that takes place too infrequently (abstinence 10–14 days or more).[33]
  • Wearing a protective cup and jockstrap to protect the testicles, in any sport 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.
  • Diet: Healthy diets (i.e. the Mediterranean diet) rich in such nutrients as omega-3 fatty acids, some antioxidants and vitamins, and low in saturated fatty acids (SFAs) and trans-fatty acids (TFAs) are inversely associated with low semen quality parameters. In terms of food groups, fish, shellfish and seafood, poultry, cereals, vegetables and fruits, and low-fat dairy products have been positively related to sperm quality. However, diets rich in processed meat, soy foods, potatoes, full-fat dairy products, coffee, alcohol and sugar-sweetened beverages and sweets have been inversely associated with the quality of semen in some studies. The few studies relating male nutrient or food intake and fecundability also suggest that diets rich in red meat, processed meat, tea and caffeine are associated with a lower rate of fecundability. This association is only controversial in the case of alcohol. The potential biological mechanisms linking diet with sperm function and fertility are largely unknown and require further study.[34]

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.

Vitamin E helps counter oxidative stress,[35] which is associated with sperm DNA damage and reduced sperm motility.[36] A hormone-antioxidant combination may improve sperm count and motility.[37] However there is only some low quality evidence from few small studies that oral antioxidants given to males in couples undergoing in vitro fertilisation for male factor or unexplained subfertility result in higher live birth rate.[38] It is unclear if there are any adverse effects.[38]

Hormonal therapy

See also: Spermatogenesis § Hormonal control

Administration of luteinizing hormone (LH) (or human chorionic gonadotropin) and follicle-stimulating hormone (FSH) is very effective in the treatment of male infertility due to hypogonadotropic hypogonadism.[39] Although controversial,[40] off-label clomiphene citrate, an antiestrogen, may also be effective by elevating gonadotropin levels.[39]

Though androgens are absolutely essential for spermatogenesis and therefore male fertility, exogenous testosterone therapy has been found to be ineffective in benefiting men with low sperm count.[41] This is thought to be because very high local levels of testosterone in the testes (concentrations in the seminiferous tubules are 20- to 100-fold greater than circulating levels)[42] are required to mediate spermatogenesis, and exogenous testosterone therapy (which is administered systemically) cannot achieve these required high local concentrations (at least not without extremely supraphysiological dosages).[41] Moreover, exogenous androgen therapy can actually impair or abolish male fertility by suppressing gonadotropin secretion from the pituitary gland, as seen in users of androgens/anabolic steroids (who often have partially or completely suppressed sperm production).[39][41] This is because suppression of gonadotropin levels results in decreased testicular androgen production (causing diminished local concentrations in the testes)[39][41] and because FSH is independently critical for spermatogenesis.[43][44] In contrast to FSH, LH has little role in male fertility outside of inducing gonadal testosterone production.[45]

Estrogen, at some concentration, has been found to be essential for male fertility/spermatogenesis.[46][47] However, estrogen levels that are too high can impair male fertility by suppressing gonadotropin secretion and thereby diminishing intratesticular androgen levels.[41] As such, clomiphene citrate (an antiestrogen) and aromatase inhibitors such as testolactone or anastrozole have shown effectiveness in benefiting spermatogenesis.[41]

Low-dose estrogen and testosterone combination therapy may improve sperm count and motility in some men,[48] including in men with severe oligospermia.[49]

Future potential treatments

Researchers at Münster University developed in vitro culture conditions using a three-dimensional agar culture system which induces mouse testicular germ cells to reach the final stages of spermatogenesis, including spermatozoa generation.[50] If reproduced in humans, this could potentially enable infertile men to father children with their own sperm.[51][52]

Researchers from Montana State University developed precursors of sperm from skin cells of infertile men.[53][54][55]

Sharpe et al comment on the success of intracytoplasmic sperm injection (ICSI) in women saying, "[t]hus, the woman carries the treatment burden for male infertility, a fairly unique scenario in medical practice. Ironically, ICSI’s success has effectively diverted attention from identifying what causes male infertility and focused research onto the female, to optimize the provision of eggs and a receptive endometrium, on which ICSI’s success depends."[56][57]

See also

References

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