Male infertility

Male infertility
Classification and external resources
Specialty urology
ICD-10 N46
ICD-9-CM 606
DiseasesDB 7772
MedlinePlus 001191
eMedicine med/3535 med/1167
Patient UK Male infertility
MeSH D007248

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]

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

There is increasing evidence that the harmful products of tobacco smoking may damage the testicles[12] and kill sperm,[13][14] but their effect on male fertility is not clear.[15] 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.[16]

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.[17] As men age there is a consistent decline in semen quality, and this decline appears to be due to DNA damage.[18] (Silva et al., 2012). 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.[19][20]

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:

Radiation therapy to a testis decreases its function, but infertility can efficiently be avoided by avoiding radiation to both testes.[25]

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 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, 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.[26][27] 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

Ultrasonography of the scrotum 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:

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,[30] which is associated with sperm DNA damage and reduced sperm motility.[31] A hormone-antioxidant combination may improve sperm count and motility.[32] Oral antioxidants given to males in couples undergoing in vitro fertilisation for male factor or unexplained subfertility result in significantly higher live birth rate.[33]

Hormonal therapy

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.[34] Although controversial,[35] off-label clomiphene citrate, an antiestrogen, may also be effective by elevating gonadotropin levels.[34]

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.[36] 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)[37] 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).[36] 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).[34][36] This is because suppression of gonadotropin levels results in decreased testicular androgen production (causing diminished local concentrations in the testes)[34][36] and because FSH is independently critical for spermatogenesis.[38][39] In contrast to FSH, LH has little role in male fertility outside of inducing gonadal testosterone production.[40]

Estrogen, at some concentration, has been found to be essential for male fertility/spermatogenesis.[41][42] However, estrogen levels that are too high can impair male fertility by suppressing gonadotropin secretion and thereby diminishing intratesticular androgen levels.[36] As such, clomiphene citrate (an antiestrogen) and aromatase inhibitors such as testolactone or anastrozole have shown effectiveness in benefiting spermatogenesis.[36]

Low-dose estrogen and testosterone combination therapy may improve sperm count and motility in some men,[43] including in men with severe oligospermia.[44][45]

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.[46] If reproduced in humans, this could potentially enable infertile men to father children with their own sperm.[47][48]
Researchers from Montana State University developed precursor of sperm from skin of infertile men. It is a ray of hope in real mean for future treatment of infertility in men.[49]

See also

References

  1. ↑ "Men's Health - Male Factor Infertility". University of Utah Health Sciences Center. 2003-04-01. Archived from the original on 2007-07-04. Retrieved 2007-11-21.
  2. ↑ Brugh VM, Lipshultz LI (2004). "Male factor infertility". Medical Clinics of North America. 88 (2): 367–85. doi:10.1016/S0025-7125(03)00150-0. PMID 15049583.
  3. ↑ Hirsh A (2003). "Male subfertility". BMJ. 327 (7416): 669–72. doi:10.1136/bmj.327.7416.669. PMC 196399Freely accessible. PMID 14500443.
  4. 1 2 3 4 5 6 7 8 9 10 Lotti, F.; Maggi, M. (2014). "Ultrasound of the male genital tract in relation to male reproductive health". Human Reproduction Update. 21 (1): 56–83. doi:10.1093/humupd/dmu042. ISSN 1355-4786.
  5. ↑ Cooper TG, Noonan E, Von Eckardstein S, Auger J, Baker HW, Behre HM, Haugen TB, Kruger T, Wang C (2009). "World Health Organization reference values for human semen characteristics". Human Reproduction Update. 16 (3): 231–45. doi:10.1093/humupd/dmp048. PMID 19934213.
  6. ↑ Rowe PJ, Comhaire FH, Hargreave TB, Mahmoud AM (2000). "Chapter 2: History taking". WHO manual for the standardized investigation, diagnosis and management of the infertile male. Cambridge [England]: Published on behalf of the World Health Organization by Cambridge University Press. pp. 5–16. ISBN 0-521-77474-8.
  7. 1 2 Teerds KJ, de Rooij DG, Keijer J (2011). "Functional relationship between obesity and male reproduction: from humans to animal models". Hum. Reprod. Update. 17 (5): 667–83. doi:10.1093/humupd/dmr017. PMID 21546379.
  8. 1 2 Hozyasz, K (Mar 2001). "Coeliac disease and problems associated with reproduction". Ginekol Pol. 72 (3): 173–9. PMID 11398587.
  9. 1 2 Sher, KS; Jayanthi, V; Probert, CS; Stewart, CR; Mayberry, JF (1994). "Infertility, obstetric and gynaecological problems in coeliac sprue". Dig Dis. 12 (3): 186–90. doi:10.1159/000171452. PMID 7988065.
  10. ↑ Freeman, HJ (Dec 2010). "Reproductive changes associated with celiac disease". World J Gastroenterol. 16 (46): 5810–4. doi:10.3748/wjg.v16.i46.5810. PMC 3001971Freely accessible. PMID 21155001.
  11. ↑ Leibovitch I, Mor Y (2005). "The Vicious Cycling: Bicycling Related Urogenital Disorders". European Urology. 47 (3): 277–86; discussion 286–7. doi:10.1016/j.eururo.2004.10.024. PMID 15716187.
  12. ↑ Thompson J, Bannigan J (Apr 2008). "Cadmium: toxic effects on the reproductive system and the embryo". Reprod Toxicol (Review). 25 (3): 304–15. doi:10.1016/j.reprotox.2008.02.001. PMID 18367374.
  13. ↑ Agarwal A, Prabakaran SA, Said TM (2005). "Prevention of Oxidative Stress Injury to Sperm". Journal of Andrology. 26 (6): 654–60. doi:10.2164/jandrol.05016. PMID 16291955.
  14. ↑ Robbins WA, Elashoff DA, Xun L, Jia J, Li N, Wu G, Wei F (2005). "Effect of lifestyle exposures on sperm aneuploidy". Cytogenetic and Genome Research. 111 (3–4): 371–7. doi:10.1159/000086914. PMID 16192719.
  15. ↑ Harlev A, Agarwal A, Gunes SO, Shetty A, du Plessis SS (Dec 2015). "Smoking and Male Infertility: An Evidence-Based Review". World J Mens Health (Review). 33 (3): 143–60. doi:10.5534/wjmh.2015.33.3.143. PMC 4709430Freely accessible. PMID 26770934.
  16. ↑ Emsley J (2001). Nature's building blocks: an A-Z guide to the elements. Oxford [Oxfordshire]: Oxford University Press. p. 76. ISBN 0-19-850340-7.
  17. ↑ Ji G, Long Y, Zhou Y, Huang C, Gu A, Wang X (2012). "Common variants in mismatch repair genes associated with increased risk of sperm DNA damage and male infertility". BMC Med. 10: 49. doi:10.1186/1741-7015-10-49. PMC 3378460Freely accessible. PMID 22594646.
  18. ↑ Silva LF, Oliveira JB, Petersen CG, Mauri AL, Massaro FC, Cavagna M, Baruffi RL, Franco JG (2012). "Jr (2012). The effects of male age on sperm analysis by motile sperm organelle morphology examination (MSOME)". Reprod Biol Endocrinol. 10: 19. doi:10.1186/1477-7827-10-19. PMID 22429861.
  19. ↑ Kenneth I. Aston; Philip J. Uren; Timothy G. Jenkins; Alan Horsager; Bradley R. Cairns; Andrew D. Smith; Douglas T. Carrell (December 2015). "Aberrant sperm DNA methylation predicts male fertility status and embryo quality". Fertility and Sterility. 104 (6): 1388–1397. doi:10.1016/j.fertnstert.2015.08.019. PMID 26361204.
  20. ↑ Dada R, Kumar M, Jesudasan R, Fernández JL, Gosálvez J, Agarwal A (2012). "Epigenetics and its role in male infertility". J. Assist. Reprod. Genet. 29: 213–23. doi:10.1007/s10815-012-9715-0. PMID 22290605.
  21. ↑ Kupis Ł, Dobroński PA, Radziszewski P (2015). "Varicocele as a source of male infertility - current treatment techniques". Cent European J Urol (Review). 68 (3): 365–70. doi:10.5173/ceju.2015.642. PMC 4643713Freely accessible. PMID 26568883.
  22. ↑ Masarani M, Wazait H, Dinneen M (2006). "Mumps orchitis". Journal of the Royal Society of Medicine. 99 (11): 573–5. doi:10.1258/jrsm.99.11.573. PMC 1633545Freely accessible. PMID 17082302.
  23. ↑ Zhang J, Qiu SD, Li SB, Zhou DX, Tian H, Huo YW, Ge L, Zhang QY (2007). "Novel mutations in ubiquitin-specific protease 26 gene might cause spermatogenesis impairment and male infertility". Asian Journal of Andrology. 9 (6): 809–14. doi:10.1111/j.1745-7262.2007.00305.x. PMID 17968467.
  24. ↑ Cavallini G (2006). "Male idiopathic oligoasthenoteratozoospermia". Asian Journal of Andrology. 8 (2): 143–57. doi:10.1111/j.1745-7262.2006.00123.x. PMID 16491265.
  25. ↑ Gutfeld O, Wygoda M, Shavit L, Grenader T (2007). "Fertility After Adjuvant External Beam Radiotherapy for Stage I Seminoma". The Internet Journal of Oncology. 4 (2). doi:10.5580/2188.
  26. ↑ Hargreave TB, McGowan B, Harvey J, McParland M, Elton RA (April 1986). "Is a male infertility clinic of any use?". Br. J. Urol. 58 (2): 188–93. doi:10.1111/j.1464-410x.1986.tb09024.x. PMID 3697634.
  27. ↑ Hwang K, Walters RC, Lipshultz LI (February 2011). "Contemporary concepts in the evaluation and management of male infertility". Nature Reviews Urology. 8 (2): 86–94. doi:10.1038/nrurol.2010.230. PMID 21243017.
  28. ↑ Gaur DS, Talekar M, Pathak VP (2007). "Effect of cigarette smoking on semen quality of infertile men" (PDF). Singapore Medical Journal. 48 (2): 119–23. PMID 17304390.
  29. 1 2 3 4 Speroff L, Glass RH, Kase NG (1999). Clinical Endocrinology and Infertility (6th ed.). Lippincott Williams and Wilkins. p. 1085. ISBN 0-683-30379-1.
  30. ↑ Traber MG, Stevens JF (2011). "Vitamins C and E: Beneficial effects from a mechanistic perspective". Free Radical Biology and Medicine. 51 (5): 1000–13. doi:10.1016/j.freeradbiomed.2011.05.017. PMC 3156342Freely accessible. PMID 21664268.
  31. ↑ Lombardo F, Sansone A, Romanelli F, Paoli D, Gandini L, Lenzi A (2011). "The role of antioxidant therapy in the treatment of male infertility: An overview". Asian Journal of Andrology. 13 (5): 690–7. doi:10.1038/aja.2010.183. PMID 21685925.
  32. ↑ Ghanem H, Shaeer O, El-Segini A (2010). "Combination clomiphene citrate and antioxidant therapy for idiopathic male infertility: A randomized controlled trial". Fertility and Sterility. 93 (7): 2232–5. doi:10.1016/j.fertnstert.2009.01.117. PMID 19268928.
  33. ↑ Farquhar, C.; Rishworth, J. R.; Brown, J.; Nelen, W. L. M.; Marjoribanks, J. (2013). Brown, Julie, ed. "Assisted reproductive technology: an overview of Cochrane Reviews". The Cochrane Library. 8: CD010537. doi:10.1002/14651858.CD010537.pub2. PMID 23970457.
  34. 1 2 3 4 Edmund S. Sabanegh, Jr. (20 October 2010). Male Infertility: Problems and Solutions. Springer Science & Business Media. pp. 82–83. ISBN 978-1-60761-193-6.
  35. ↑ Pasqualotto FF, Fonseca GP, Pasqualotto EB (2008). "Azoospermia after treatment with clomiphene citrate in patients with oligospermia". Fertility and Sterility. 90 (5): 2014.e11–2. doi:10.1016/j.fertnstert.2008.03.036. PMID 18555230.
  36. 1 2 3 4 5 6 Rodney Rhoades; David R. Bell (2009). Medical Physiology: Principles for Clinical Medicine. Lippincott Williams & Wilkins. p. 685. ISBN 978-0-7817-6852-8.
  37. ↑ Wolf-Bernhard Schill; Frank H. Comhaire; Timothy B. Hargreave (26 August 2006). Andrology for the Clinician. Springer Science & Business Media. pp. 76–. ISBN 978-3-540-33713-3.
  38. ↑ Liu YX (2005). "Control of spermatogenesis in primate and prospect of male contraception". Arch. Androl. 51 (2): 77–92. doi:10.1080/01485010490485768. PMID 15804862.
  39. ↑ Cheng CY, Wong EW, Yan HH, Mruk DD (2010). "Regulation of spermatogenesis in the microenvironment of the seminiferous epithelium: new insights and advances". Mol. Cell. Endocrinol. 315 (1-2): 49–56. doi:10.1016/j.mce.2009.08.004. PMC 3516447Freely accessible. PMID 19682538.
  40. ↑ Fody EP, Walker EM (1985). "Effects of drugs on the male and female reproductive systems". Ann. Clin. Lab. Sci. 15 (6): 451–8. PMID 4062226.
  41. ↑ O'Donnell L, Robertson KM, Jones ME, Simpson ER (2001). "Estrogen and spermatogenesis". Endocr. Rev. 22 (3): 289–318. doi:10.1210/edrv.22.3.0431. PMID 11399746.
  42. ↑ Carreau S, Bouraima-Lelong H, Delalande C (2012). "Role of estrogens in spermatogenesis". Front Biosci (Elite Ed). 4: 1–11. PMID 22201851.
  43. ↑ Sah P (1998). "Role of low-dose estrogen–testosterone combination therapy in men with oligospermia". Fertility and Sterility. 70 (4): 780–1. doi:10.1016/S0015-0282(98)00273-8. PMID 9797116.
  44. ↑ Sah P (2002). "Oligospermia due to partial maturation arrest responds to low dose estrogen-testosterone combination therapy resulting in live-birth: A case report". Asian Journal of Andrology. 4 (4): 307–8. PMID 12508135.
  45. ↑ "Oligospermia in a Man with Small Testes and Elevated Serum FSH Responds to Low Dose Estrogen-Testosterone Combination Therapy, Resulting in His Wife's Pregnancy and Live Birth". The Internet Journal of Endocrinology. 2. 2005. doi:10.5580/1f84.
  46. ↑ Abu Elhija M, Lunenfeld E, Schlatt S, Huleihel M (2011). "Differentiation of murine male germ cells to spermatozoa in a soft agar culture system". Asian Journal of Andrology. 14 (2): 285–93. doi:10.1038/aja.2011.112. PMID 22057383.
  47. ↑ James G (2012-01-03). "Sperm Grown In Laboratory In Fertility Breakthrough". Huffingtonpost.co.uk. Retrieved 2012-08-26.
  48. ↑ "Scientists grow sperm in laboratory dish". Health News. London: The Daily Telegraph. 2012-01-02.
  49. ↑ "Researchers made Sperm Cells from Skin of infertile men". Retrieved 2014-05-08.
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