In 30%–80% of cases, sperm damage is the result of oxidative stress caused by reactive oxidative species (ROS), which damages the DNA of sperms. This leads to a decrease in sperm motility, damage to the membrane of the acrosome, and a decrease in the ability of the sperm to fertilise the oocyte.⁴ 

Conditions associated with male infertility 

Major biological factors that can result in male infertility include oligozoospermia, asthenozoospermia, azoospermia, or a combination of these conditions.²  

Lifestyle and behavioral factors impacting sperm count and quality include the use of certain medications, infections, illicit drug use (eg marijuana, cocaine, anabolic–androgenic steroids, opiates, and methamphetamines), psychological stress, caffeine, an unhealthy diet, and coital frequency.² 

Environmental factors that have been implicated include exposure to toxic metals, such as lead, zinc deficiency, pesticides, industrial chemicals, mycotoxins, chemotherapeutic agents, radiation exposure, and pharmaceutical agents that act either as direct spermatotoxins or through a steroidal pathway. In men living with obesity, hypotestosteronaemia is the main cause of infertility because it lowers fecundity.² 

Sperm count and quality 

Oligozoospermia 

Oligozoospermia is a defect in sperm production (low sperm count). It is defined as decreased numbers of sperm in the ejaculate (< 15 million sperm/mL), which is further subdivided depending on the number of sperm into mild (10–15 million sperm/mL), moderate (5–10 million sperm/mL), and severe (< 5 million sperm/mL). See Table 1.^5,6  

Causes of oligozoospermia include hypothalamic (e.g. Kallmann syndrome, and a normosmic form, which is inherited through different genetic mutations), pituitary (e.g. pituitary adenomas, craniopharyngiomas, and Rathke’s cleft cysts), adrenal (e.g. congenital adrenal hyperplasia) dysfunctions, thyroid disease (e.g. hyperthyroidism and hypothyroidism), genetic syndromes (eg Klinefelter syndrome), and anatomic disorders (e.g. varicoceles affect 35%-40% of men with oligozoospermia). Lifestyle, behavioral, and environmental factors mentioned above also play a role.⁶ 

Despite comprehensive testing, 60%-75% of men will not receive a clear diagnosis to explain their condition.⁶ 

Asthenozoospermia 

Asthenozoospermia is characterised by reduced sperm motility (the ability of sperm to move efficiently, <40% or <32% with progressive motility). The molecular mechanism behind this impairment is not fully understood in the majority of cases.^7,8 

One of the major causes is the production of ROS, which directly affects sperm motility by the production of high concentrations of malondialdehyde in semen.⁷ 

Men with primary ciliary dyskinesia, characterised by congenital impairment of mucociliary clearance or immotile ciliary syndrome. Another cause of asthenozoospermia is dysplasia of the fibrous sheath, leading to impaired sperm motility.⁹  

The fibrous sheath regulates the degree of flagellar flexibility, but also acts as a scaffold for several signalling and/or metabolic pathways. In addition to structural defects found in the axoneme and fibrous sheath, functional defects in flagella may also cause asthenozoospermia.⁹ 

Azoospermia 

Azoospermia, defined as the complete absence of spermatozoa in the ejaculate, invariably results in infertility but does not necessarily imply sterility.¹⁰ 

Azoospermia is classified as obstructive azoospermia (OA) or non-obstructive azoospermia (NOA), each having quite different aetiologies and treatments. Differentiation between these two aetiologies is of paramount importance.¹¹ 

OA is the consequence of physical blockage to the male excurrent ductal system and may occur in any region between the rete testis and the ejaculatory ducts.¹¹  

NOA, the aetiology affecting about 60% of azoospermic men, includes non-obstructive causes of azoospermia, including toxic exposures or abnormal testicular development.¹¹  

NOA results from either primary testicular failure (elevated luteinizing hormone [LH], follicle-stimulating hormone [FSH], small testes affecting up to 10% of men presenting with infertility), secondary testicular failure (congenital hypogonadotropic hypogonadism with decreased LH and FSH, small testes), or incomplete or ambiguous testicular failure (either increased FSH and normal volume testes, normal FSH and small testes, or normal FSH and normal testis volume).¹¹ 

How is infertility treated? 

The American Urological Association and American Society for Reproductive Medicine recently published their first guidelines on the diagnosis and treatment of infertility in men.³  

Semen analysis should guide management, and clinicians should obtain hormonal evaluation including FSH and testosterone for men with impaired libido, erectile dysfunction, oligozoospermia (<15 million sperm/mL) or azoospermia, atrophic testes, or evidence of hormonal abnormality on physical evaluation  

• Infertile men and men with abnormal semen parameters should be advised of the relevant, associated health risks and conditions eg cancer. This risk is highest in azoospermic men (5%-8% of men with testicular cancer have this condition)¹² 
• Surgical correction of palpable varicocele(s) should be considered for infertile men with sperm in the ejaculate and abnormal semen parameters  
• For men with NOA who are undergoing sperm retrieval, microdissection testicular sperm extraction should be performed  
• Men should be informed about the adverse effects of cancer treatments (chemotherapy, radiation therapy, surgery) on fertility and offered sperm cryopreservation before initiation of these therapies  
• Testosterone monotherapy should not be prescribed for men interested in current or future fertility, but other therapies (aromatase inhibitors, human chorionic gonadotropin, selective oestrogen receptor modulators) can be used in these men to treat low testosterone. 

Interventions such as subinguinal microsurgical varicocelectomy can improve spontaneous pregnancy rates from 13.9% to 32.9%. However, this procedure has potential risks including injury to the testicle that could jeopardise spermatogenesis and testosterone production.³ 

The guideline recommends that men with clinically palpable varicoceles, infertility, and semen parameter abnormalities (except azoospermia) are most likely to benefit from correction.³ 

By contrast, the guidelines recommend against surgical correction of varicoceles detected only on imaging studies (nonpalpable subclinical varicoceles), given the lack of demonstrable clinical benefit in semen parameters or pregnancy rates.³  

Sperm extraction in the setting of nonobstructive azoospermia can potentially lead to haematoma, infection, testicular fibrosis and atrophy, or long-term hypogonadism.³  

To attain the best retrieval rates and minimise the risk of these sequelae, the guideline recommends microsurgical testicular sperm extraction (microTESE) for men with NOA instead of conventional testicular sperm extraction (cTESE) or percutaneous approaches, with a study suggesting only 3% of men develop chronic fibrosis with microTESE vs 30% of men with cTESE.³ 

The guideline also notes that male factor infertility may be managed using artificial reproductive techniques (ART) such as in vitro fertilisation). The authors caution, however, that while this may be an effective and expeditious therapeutic approach for some couples, this treatment strategy may result in greater morbidity (eg ovarian hyperstimulation) in the female partner– vs male partner–directed therapies that may be similarly efficacious.³ 

Moreover, ART for male factor infertility is often associated with significantly greater costs vs treatment involving lifestyle modification or simpler medical and surgical approaches.³ 

Lifestyle modifications 

Healthy lifestyle changes should be recommended or at least discussed with all male patients living with infertility. These changes include:¹² 

• Smoking cessation  
• Limiting or eliminating alcohol intake 
• Adopting a more nutritious diet 
• Weight loss measures if overweight or living with obesity  
• Increasing physical activity  
• Avoiding potentially toxic artificial lubricants during sexual activity 
• Reducing stress 
• Eliminating illegal and recreational drug use (such as marijuana) 
• Minimising the use of prescription drugs 
• Avoiding exposure to pesticides and heavy metals (such as lead, mercury, boron, and cadmium) 
• Eliminating any unnecessary chemical exposures 
• Wearing boxers rather than briefs  
• Avoiding hot baths, saunas. 

Can complementary and alternative medicine improve sperm quality and counts? 

Many couples opt for CAM due to their availability, affordability, and accessibility. However, the use of CAM is controversial. While the European Association of Urology supports the use of complementary herbal medicines to treat male infertility, the World Health Organization cautions that scientific evidence is lacking.⁴ 

According to Roozbeh et al, differences in the daily dose of the medical plants and the duration of the interventions may be at the root of these controversies.¹³ 

Numerous studies have shown that some medicinal plants have properties that prevent free radicals, lipid peroxidation, and sperm damage by improving antioxidant activity. They have also been shown to increase the number of testicular veins, the number and lifespan of spermatozoa, protect germ cells, and enhance the activity of the hypothalamic-pituitary-gonadal axis.⁴ 

Shahid et al conducted a comprehensive review of the effectiveness, safety, and mechanism of herbal treatments in the improvement of male fertility. Their review included 20 studies. This is what they found:⁴ 

• Oligosaccharides (e.g. raffinose, stachyose, and verbascose): protect sperm DNA against damage. 
• Mucuna pruriens or velvet bean (a tropical legume native to Africa): significantly increases testosterone, LH, dopamine, adrenaline, and noradrenaline levels but decreased FSH and prolactin levels. Moreover, treatment restores sperm count and motility to their normal ranges.  
• Micro-elements isolated from palm pollen (e.g. oestrogen and sterols): enhance male fertility and improving sperm motility and viability, acrosome reaction, and lipid peroxidation.  
• Saffron: reduces oxidative stresses, increases the lifespan of spermatozoa and the number of viable spermatozoa. The compounds in saffron stimulate FSH, LH, and testosterone hormones and thus promote epithelial cell proliferation in seminiferous tubules, enhance the activity of Leydig cells, increase the number of spermatocytes, and ultimately promote spermatogenesis. 
• Withania somnifera or winter cherry (an evergreen shrub that grows in parts of Africa): restores LH, FSH, and prolactin levels, which are directly correlated with semen quality. Owing to the alkaloids, ergostane steroids, amino acids (including tryptophan), central nervous system inhibitors, centrally acting hypotensive agents, and gamma-aminobutyric acid and serotonin agonists available in its roots, W. somnifera can treat stress-induced infertility. 
• Ginseng: enhances spermatogenesis by promoting the expression of glial cell-derived neurotrophic factor (GDNF). GDNF is a growth factor involved in the communication between sertoli cells and spermatogonia. Ginseng can also upregulate C21-steroid hormone metabolism via Cyp11a1 and thus cause anti-aging effects in senescent rat testes.  
• Nigella sativa: improves sperm and reproductive parameters have also been documented in various studies.  
• Tomato juice: A randomised controlled trial evaluated the effect of tomato juice on male infertility. A total of 54 patients were randomised into two treatment groups and one control group. Treatment group 1 was given 30mg lycopene (from tomato), and treatment group 2 was given an antioxidant capsule, once daily for 12 weeks. Significant improvement in sperm concentration and motility was detected in treatment group 1 by the sixth week, but no improvement was observed in group 2. 

The following supplements may improve sperm count and male fertility issues.¹⁴ 

• D-aspartic acid:  can increase testosterone levels.  
• Vitamin C: protects the body's cells from oxidative stress, which leads to deterioration of cells. Taking 2000mg milligrams of vitamin C per day for two months increased sperm motility by over 90% and doubled sperm count. It also decreased the amount of damaged sperm by more than half. 
• Vitamin D:  taking vitamin D for a year increased testosterone levels significantly. 
• Fenugreek: improves testosterone levels, sexual function, and sexual frequency.  
• Zinc: increases both sperm count and testosterone levels, but only in those already deficient in it. However, too much zinc in semen may damage sperm. More studies are therefore needed. 
• Maca root (also called Peruvian ginseng): taking the powder daily for four months improved both motility and sperm count.  
• Coenzyme Q10: increases sperm counts by about 17% and motility by over 50%. 

REFERENCES 

1. Assidi M. Infertility in Men: Advances towards a Comprehensive and Integrative Strategy for Precision Theranostics. Cells, 2022. 
2. Okonofua FE, Ntoimo LFC, Omonkhua A, et al. Causes and Risk Factors for Male Infertility: A Scoping Review of Published Studies. Int J Gen Med, 2022. 
3. Halpern JA, Davis AM, Brannigan RE. Diagnosis and Treatment of Infertility in Men. JAMA, 2022. 
4. Shahid MN, Afzal HS, Farooq B, et al. A systematic review on the effectiveness of herbal interventions for the treatment of male infertility. Frontiers Physiol, 2022. 
5. Hussein A. Overview Treatment and Male Reproductive Medicine. Encyclopedia of Reproduction (Second Edition). Volume 4, 2018, Pages 307-313. https://www.sciencedirect.com/science/article/pii/B9780128012383647827 
6. Choy JT, Amory JK. Nonsurgical Management of Oligozoospermia. J Clin Endocrinol Metab. 2020;105(12):e4194-e4207. doi:10.1210/clinem/dgaa390 
7. Soumya JN, Jena RS, Chapter 4.3 - Oxidative Stress and Sperm Dysfunction: An Insight Into Dynamics of Semen Proteome. Oxidants, Antioxidants, and Impact of the Oxidative Status in Male Reproduction, 2019, Pages 261-275. 
8. Barak S, Baker HWG. Endocrinology: Adult and Pediatric (Seventh Edition), 2016. https://www.ncbi.nlm.nih.gov/books/NBK279160/ 
9. Castañeda JM et al, in Encyclopedia of Reproduction (Second Edition), 2018. https://www.elsevier.com/books/encyclopedia-of-reproduction/skinner/978-0-12-811899-3 
10. Esteves SC, Agarwai A. The azoospermic male: current knowledge and future perspectives. Clinics (Sao Paulo), 2013. 
11. Sharma M, Leslie SW. Azoospermia. [Updated 2022 Sep 24]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. https://www.ncbi.nlm.nih.gov/books/NBK578191/ 
12. Leslie SW, Siref LE, Soon-Sutton TL, et al. Male Infertility. [Updated 2022 Jul 19]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. https://www.ncbi.nlm.nih.gov/books/NBK562258/#:~:text=%5B2%5D%20Male%20infertility%20is%20defined,40%25%20of%20all%20infertility%20cases. 
13. Roozbeh N, Amirian A, Abdi F, Haghdoost S. A Systematic Review on Use of Medicinal Plants for Male Infertility Treatment. J Family Reprod Health. 2021. 
14. WebMD editorial contributors. Remedies for Low Sperm Count and Motility. https://www.webmd.com/infertility-and-reproduction/remedies-low-sperm-count-motility