Male infertility refers to a male's inability to cause pregnancy in a fertile female. In humans it accounts for 40–50% of infertility. It affects approximately 7% of all men. Male infertility is commonly due to deficiencies in the semen, and semen quality is used as a surrogate measure of male fecundity.
Antisperm antibodies (ASA) have been considered as infertility cause 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.
One of the most commonly known causes of infertility is Klinefelter Syndrome, affecting 1 out of 500–1000 newborn males Klinefelter Syndrome is a chromosomal defect that occurs during gamete formation due to a non-disjunction error during cell division. Resulting 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 (links to learning disabilities and speech development have also been shown to be affected). There are varieties in Klinefelter Syndrome, where some cases may have the extra X chromosome in some cells but not others, referred to as Mosaic Klinefelter Syndrome, or where individuals have the extra X chromosome in all cells. The reduction of testosterone in the male body normally results in an overall decrease in the production of viable sperm for these individuals thereby forcing them to turn to fertility treatments to father children.
Y chromosome deletions
Y chromosomal infertility is a direct cause of male infertility due to its effects on sperm production, occurring in 1 out of every 2000 males. Usually affected men show no sign of symptoms other than at times can exhibit smaller teste size. Men with this condition can exhibit azoospermia (no sperm production), oligozoospermia (small number of sperm production), or they will produce abnormally shaped sperm (teratozoospermia). This case of infertility occurs during the development of gametes in the male, where a normal healthy male will produce both 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”, although daughters are not affected due to the lack of the Y chromosome.
- Age (see also: Paternal age effect)
- Abnormal set of chromosomes
- Neoplasm, e.g. seminoma
- Idiopathic failure
- 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 factors refer to conditions that impede adequate support of the testes and include situations of poor hormonal support and poor general health including:
Varicocele, is a condition of swollen testicle veins.
It is present in 15% of normal men and in about 40% of infertile men.
- Hypogonadotropic hypogonadism due to various causes
- 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, 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
There is increasing evidence that the harmful products of tobacco smoking may damage the testicles and kill sperm, but their effect on male fertility is not clear. 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.
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.
An increasing amount of recent evidence has been recorded documenting abnormal sperm DNA methylation in association with abnormal semen parameters and male infertility. Until recently, scientists have thought that epigenetic markers only affect the individual and are not passed down due to not changing the DNA. New studies suggest that environmental factors that changed an individual's epigenetic markers can be seen in their grandchildren, one such study demonstrating this through rats and fertility disruptors. Another study bred rats exposed to an endocrine disruptor, observing effects up to generation F5 including decreased sperm motility and decreased sperm count. These studies suggest that environmental factors that influence fertility can be felt for generations even without changing the DNA.
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:
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.
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.
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.
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. 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.
Semen sample obtaining
Semen sample obtaining is the first step in spermiogram. The optimal sexual abstinence for semen sample obtaining is of 2–7 days. The first way to obtain the semen sample is through masturbation, and the best place to obtain it is in the same clinic, as this way temperature changes during transport can be avoided, which can be lethal for some spermatozoa.
A single semen sample is not determining for disease diagnosis, so two different samples have to be analyzed with an interval between them of seven days to three months, as sperm production is a cyclic process. It is prudent to ask about possible sample loss, as that could mask true results of spermiogram.
To obtain the sample, a sterile plastic recipient is put directly inside, always no more than one hour before being studied. Conventional preservatives shouldn't be used, as they have chemical substances as lubricants or spermicides that could damage the sample. If preservatives have to be used, for cases of religious ethics in which masturbation is forbidden, a preservative with holes is used. In case of paraplegia it is possible to use mechanic tools or electroejaculation.
The sample should never be obtained through coitus interruptus for several reasons:
- Some part of ejaculation could be lost.
- Bacterial contamination could happen.
- The acid vaginal pH could be deleterious for sperm motility.
Also is very important to label the sample correctly the recipient with patient identification, date, hour, abstinence days, among other data required to be known.
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. 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
- Necrozoospermia – all sperm in the ejaculate are dead
- Leucospermia – a high level of white blood cells in semen
- Normozoospermia or normospermia – It is a result of semen analysis that shows normal values of all ejaculate parameters by WHO but still there are chances of being infertile. This is also called as unexplained Infertility
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.
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.
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. 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. 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.
Dilation of the head or tail of the epididymis is suggestive of obstruction or inflammation of the male reproductive tract. Such abnormalities are associated with abnormalities in sperm parameters, as are abnormalities in the texture of the epididymis. 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. 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.
Some strategies suggested or proposed for avoiding male infertility include the following:
- Avoiding smoking as it damages sperm DNA
- Avoiding heavy marijuana and alcohol use.
- Avoiding excessive heat to the testes.
- Maintaining optimal frequency of coital activity: sperm counts can be depressed by daily coital activity and sperm motility may be depressed by coital activity that takes place too infrequently (abstinence 10–14 days or more).
- 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.
Treatments vary according to the underlying disease and the degree of the impairment of the male's 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, which is associated with sperm DNA damage and reduced sperm motility. A hormone-antioxidant combination may improve sperm count and motility. Giving oral antioxidants to men in couples undergoing in vitro fertilisation for male factor or unexplained subfertility may lead to an increase in the live birth rate but overall the risk of adverse effects is unclear.
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. Although controversial, off-label clomiphene citrate, an antiestrogen, may also be effective by elevating gonadotropin levels.
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. 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) 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). 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). This is because suppression of gonadotropin levels results in decreased testicular androgen production (causing diminished local concentrations in the testes) and because FSH is independently critical for spermatogenesis. In contrast to FSH, LH has little role in male fertility outside of inducing gonadal testosterone production.
Estrogen, at some concentration, has been found to be essential for male fertility/spermatogenesis. However, estrogen levels that are too high can impair male fertility by suppressing gonadotropin secretion and thereby diminishing intratesticular androgen levels. As such, clomiphene citrate (an antiestrogen) and aromatase inhibitors such as testolactone or anastrozole have shown effectiveness in benefiting spermatogenesis.
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. If reproduced in humans, this could potentially enable infertile men to father children with their own sperm.
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."
Currently, there are no solid numbers on how many couples worldwide experience infertility, but the World Health Organization estimates between 60 and 80 million couples are affected. The population in different regions suffer from varying amounts of infertility.
Starting in the late 20th century, scientists have expressed concerns about the declining semen quality in men. A study was done in 1992 with men who had never suffered from infertility showed that the amount of sperm in semen had declined by 1% per year since 1938. Further research a few years later also confirmed the decline in sperm count and also seminal volume. Various studies in Finland, Southern Tunisia, and Argentina also showed a decline in sperm count, motility, morphology, and seminal volume.
Males from India suffered a 30.3% decline in sperm count, 22.9% decline in sperm motility, and a 51% decrease in morphology over a span of a decade. Doctors in India disclosed that the sperm count of a fertile Indian male had decreased by a third over a span of three decades. Some factors may include exposure to high temperatures at places such as factories. A 1 degree increase in temperature will reduce 14% of spermatogenesis.
Society and culture
There are a variety of social stigmas that surround male infertility throughout the world. A lot of research has pointed to the relationship between infertility and emasculation. In places like Egypt, Zimbabwe, and Mexico, erectile dysfunction also known as impotence, is considered a determinant of infertility. When stereotypical ideals of manhood are virility and strength, men sharing problems of infertility can face feelings of inadequacy, unworthiness, and have thoughts of suicide. In many cases, a variety of socio-economic interventions come in play to determine penile activity. For the Shona people, since impotence is linked to infertility, an examination to check on the penile function spans from infancy to post marriage. At infancy, there are daily check-ups by the mothers on the son's erection and urine quality. When the son reaches puberty, they are asked to ejaculate in river banks and for their male elders to examine sperm quality. The traditions last until post-marriage, when the family of the bride take part to check on consummation and the groom's sperm quality.
- "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.
- 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.
- Hirsh A (2003). "Male subfertility". BMJ. 327 (7416): 669–72. doi:10.1136/bmj.327.7416.669. PMC 196399. PMID 14500443.
- Lotti, F.; Maggi, M. (2014). "Ultrasound of the male genital tract in relation to male reproductive health" (PDF). Human Reproduction Update. 21 (1): 56–83. doi:10.1093/humupd/dmu042. ISSN 1355-4786. PMID 25038770.
- 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.
- 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 978-0-521-77474-1.
- Restrepo, B.; Cardona-Maya, W. (October 2013). "Antisperm antibodies and fertility association". Actas Urologicas Espanolas. 37 (9): 571–578. doi:10.1016/j.acuro.2012.11.003. ISSN 1699-7980. PMID 23428233.
- Rao, Kamini (2013-09-30). Principles & Practice of Assisted Reproductive Technology (3 Vols). JP Medical Ltd. ISBN 9789350907368.
- Ferlin, Alberto; Arredi, Barbara; Foresta, Carlo (2006-08-01). "Genetic causes of male infertility". Reproductive Toxicology. 22 (2): 133–141. doi:10.1016/j.reprotox.2006.04.016. ISSN 0890-6238. PMID 16806807.
- Reference, Genetics Home. "Klinefelter syndrome". Genetics Home Reference. Retrieved 2018-11-23.
- Arai, T.; Kitahara, S.; Horiuchi, S.; Sumi, S.; Yoshida, K. (January 1998). "Relationship of testicular volume to semen profiles and serum hormone concentrations in infertile Japanese males". International Journal of Fertility and Women's Medicine. 43 (1): 40–47. ISSN 1534-892X. PMID 9532468.
- Reference, Genetics Home. "Y chromosome infertility". Genetics Home Reference. Retrieved 2018-11-23.
- Avidor-Reiss T, Khire A, Fishman EL, Jo KH (2015). "Atypical centrioles during sexual reproduction". Frontiers in Cell and Developmental Biology. 3: 21. doi:10.3389/fcell.2015.00021. PMC 4381714. PMID 25883936.
- 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 1633545. PMID 17082302.
- 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.
- 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.
- 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 4643713. PMID 26568883.
- 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.
- Hozyasz, K (Mar 2001). "Coeliac disease and problems associated with reproduction". Ginekol Pol. 72 (3): 173–9. PMID 11398587.
- 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.
- 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 3001971. PMID 21155001.
- 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.
- 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.
- 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.
- 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.
- 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 4709430. PMID 26770934.
- Emsley J (2001). Nature's building blocks: an A-Z guide to the elements. Oxford [Oxfordshire]: Oxford University Press. p. 76. ISBN 978-0-19-850340-8.
- 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 3378460. PMID 22594646.
- 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. PMC 3317862. PMID 22429861.
- Gorczyca W, Traganos F, Jesionowska H, Darzynkiewicz Z (July 1993). "Presence of DNA strand breaks and increased sensitivity of DNA in situ to denaturation in abnormal human sperm cells: analogy to apoptosis of somatic cells". Experimental Cell Research. 207 (1): 202–5. doi:10.1006/excr.1993.1182. PMID 8391465.
- 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.
- 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 (3): 213–23. doi:10.1007/s10815-012-9715-0. PMC 3288140. PMID 22290605.
- Saey, Tina Hesman (2013). "FROM Great Grandma TO You: Epigenetic changes reach down through the generations". Science News. 183 (7): 18–21. doi:10.1002/scin.5591830718. JSTOR 23599013.
- Anway, Matthew D.; Cupp, Andrea S.; Uzumcu, Mehmet; Skinner, Michael K. (2005). "Epigenetic Transgenerational Actions of Endocrine Disruptors and Male Fertility". Science. 308 (5727): 1466–1469. doi:10.1126/science.1108190. JSTOR 3841510. PMID 15933200.
- 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.
- 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. PMC 3654691. PMID 21243017.
- Hajder M, Hajder E, Husic A (February 2016). "The Effects of Total Motile Sperm Count on Spontaneous Pregnancy Rate and Pregnancy After IUI Treatment in Couples with Male Factor and Unexplained Infertility". Medical Archives. 70 (1): 39–43. doi:10.5455/medarh.2016.70.39-43. PMC 4779344. PMID 26980930.
- 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.
- Speroff L, Glass RH, Kase NG (1999). Clinical Endocrinology and Infertility (6th ed.). Lippincott Williams and Wilkins. p. 1085. ISBN 978-0-683-30379-7.
- Salas-Huetos A, Babio N, Carrell DT, Bulló M & Salas-Salvadó J. Adherence to the Mediterranean diet is positively associated with sperm motility: A cross-sectional analysis. Scientific Reports, 2019; In Press. DOI: 10.1038/s41598-019-39826-7 https://www.nature.com/articles/s41598-019-39826-7
- Salas-Huetos A, Bulló M, Salas-Salvadó J (July 2017). "Dietary patterns, foods and nutrients in male fertility parameters and fecundability: a systematic review of observational studies". Human Reproduction Update. 23 (4): 371–389. doi:10.1093/humupd/dmx006. PMID 28333357.
- 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 3156342. PMID 21664268.
- 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. PMC 3739574. PMID 21685925.
- 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.
- Smits, RM; Mackenzie-Proctor, R; Yazdani, A; Stankiewicz, MT; Jordan, V; Showell, MG (14 March 2019). "Antioxidants for male subfertility". Cochrane Database of Systematic Reviews. 3: CD007411. doi:10.1002/14651858.CD007411.pub4. PMC 6416049. PMID 30866036.
- 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.
- 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.
- Rodney Rhoades; David R. Bell (2009). Medical Physiology: Principles for Clinical Medicine. Lippincott Williams & Wilkins. p. 685. ISBN 978-0-7817-6852-8.
- 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.
- 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.
- 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 3516447. PMID 19682538.
- 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.
- 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.
- Carreau S, Bouraima-Lelong H, Delalande C (2012). "Role of estrogens in spermatogenesis". Front Biosci. 4: 1–11. doi:10.2741/e356. PMID 22201851.
- 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.
- 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.
- 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. PMC 3735096. PMID 22057383.
- James G (2012-01-03). "Sperm Grown In Laboratory In Fertility Breakthrough". Huffingtonpost.co.uk. Retrieved 2012-08-26.
- "Scientists grow sperm in laboratory dish". Health News. London: The Daily Telegraph. 2012-01-02.
- "Researchers made Sperm Cells from Skin of infertile men". Retrieved 2014-05-08.
- Press Association (17 August 2017). "New sperm creation method could overcome genetic male infertility – study". The Guardian. Retrieved 13 September 2017.
- Dr. Sherman J. Silber. "A Modern Approach to Male Infertility". The Infertility Center of St. Louis. Retrieved 13 September 2017.
- Barratt, Christopher L.R.; De Jonge, Christopher J.; Sharpe, Richard M. (7 February 2018). "'Man Up': the importance and strategy for placing male reproductive health centre stage in the political and research agenda". Human Reproduction. Oxford University Press. 33 (4): 541–545. doi:10.1093/humrep/dey020. PMC 5989613. PMID 29425298.
- Knapton, Sarah (6 March 2018). "IVF to fix male infertility 'infringes human rights of women' argue scientists". The Telegraph. Retrieved 7 March 2018.
- Menkveld, R.; Van Zyl, J. A.; Kotze, T. J.; Joubert, G. (1986). "Possible changes in male fertility over a 15-year period". Archives of Andrology. 17 (2): 143–144. doi:10.3109/01485018608990186. ISSN 0148-5016. PMID 3827388.
- Murature, D. A.; Tang, S. Y.; Steinhardt, G.; Dougherty, R. C. (August 1987). "Phthalate esters and semen quality parameters". Biomedical & Environmental Mass Spectrometry. 14 (8): 473–477. doi:10.1002/bms.1200140815. ISSN 0887-6134. PMID 2957007.
- Carlsen, E.; Giwercman, A.; Keiding, N.; Skakkebaek, N. E. (1992-09-12). "Evidence for decreasing quality of semen during past 50 years". BMJ (Clinical Research Ed.). 305 (6854): 609–613. doi:10.1136/bmj.305.6854.609. ISSN 0959-8138. PMC 1883354. PMID 1393072.
- Sengupta, Pallav (July 2012). "Challenge of infertility: How protective the yoga therapy is?". Ancient Science of Life. 32 (1): 61–62. doi:10.4103/0257-7941.113796. ISSN 0257-7941. PMC 3733210. PMID 23929997.
- "Male and Female Infertility Just Keeps on 'Rising'". The New Indian Express. Retrieved 2018-11-21.
- Mukhopadhyay, Dyutiman; Varghese, Alex C.; Pal, Manisha; Banerjee, Sudip K.; Bhattacharyya, Asok K.; Sharma, Rakesh K.; Agarwal, Ashok (2010-05-01). "Semen quality and age-specific changes: a study between two decades on 3,729 male partners of couples with normal sperm count and attending an andrology laboratory for infertility-related problems in an Indian city". Fertility and Sterility. 93 (7): 2247–2254. doi:10.1016/j.fertnstert.2009.01.135. ISSN 1556-5653. PMID 19328484.
- Moyo, Stanzia (June 2013). "Indigenous knowledge systems and attitudes towards male infertility in Mhondoro-Ngezi, Zimbabwe". Culture, Health & Sexuality. 15 (6): 667–679. doi:10.1080/13691058.2013.779029. ISSN 1369-1058. PMID 23550631.
- Inhorn, Marcia (2004). "Middle Eastern Masculinities in the Age of New Reproductive Technologies: Male Infertility and Stigma in Egypt and Lebanon". Medical Anthropology Quarterly. 18 (2): 162–182. doi:10.1525/maq.2004.18.2.162. PMID 15272802.
- Serour, G.I. (2008-07-01). "Medical and socio-cultural aspects of infertility in the Middle East". ESHRE Monographs. 2008 (1): 34–41. doi:10.1093/humrep/den143. ISSN 1477-741X.
- Inhorn, Marcia C.; Wentzell, Emily A. (November 2011). "Embodying emergent masculinities: Men engaging with reproductive and sexual health technologies in the Middle East and Mexico". American Ethnologist. 38 (4): 801–815. doi:10.1111/j.1548-1425.2011.01338.x. ISSN 0094-0496.
- Smith, James F.; Walsh, Thomas J.; Shindel, Alan W.; Turek, Paul J.; Wing, Holly; Pasch, Lauri; Katz, Patricia P. (September 2009). "Sexual, Marital, and Social Impact of a Man's Perceived Infertility Diagnosis". The Journal of Sexual Medicine. 6 (9): 2505–2515. doi:10.1111/j.1743-6109.2009.01383.x. ISSN 1743-6095. PMC 2888139. PMID 19619144.