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Infertility is estimated to affect more than 50 million couples around the world, with male factor accounting for half of these cases, yet there is a notable absence of effective treatment options for men, other than in-vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI). This review considers unlicensed and empirical treatments used for male subfertility, including hormonal therapy, phosphodiesterase inhibitors, and antioxidants. Compounds generally demonstrate variable improvements in sperm function but benefits for fertility are less clear.
There is a pressing need for effective treatment options for subfertile men, however, our knowledge of sperm function is limited, restricting the identification of precise treatment targets. The traditional drug discovery pathway is also notorious for its extensive resource and time requirements, often extending over decades and demanding significant financial investment. Unfortunately, a substantial number of potential therapies fail before reaching the marketplace. Furthermore, reliance on mammalian models is not possible in the drug development process for male subfertility, due to significant variability between animals and man.
We review recent breakthroughs and highlight novel methods aimed at improving the effectiveness and efficiency of drug discovery for male subfertility. High-throughput screening, combinatorial chemistry, and the repurposing of established medications have great potential. These strategies offer the promise of accelerating the pace of drug development, curbing the extensive demand for resources, and, in the case of drug repurposing, diminish the demand for comprehensive pharmacokinetic and pharmacodynamic studies. As these innovative approaches are adopted, the feasibility of addressing male subfertility through scientific advancements appears to be increasingly attainable.
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Infertility is a time-consuming and exhaustive process, which disproportionally affects women. Although concerns have been raised about deficiencies in the clinical evaluation of infertile men, there are currently little published data documenting this. A SurveyMonkey questionnaire was therefore created to capture the current clinical practice of fertility specialists working in in vitro fertilisation clinics. Responses were collected from May to July 2021. A total of 112 clinicians completed the pilot survey with respondents from Europe (n = 49; 43.8%), Africa (n = 39, 34.8%), North America (n = 6; 5.4%), Asia (n = 16; 14.3%), South America (n = 1; 0.9%) and Australasia (n = 1; 0.9%). Forty-one percent of fertility specialists (45/110) reported taking only a brief medical history and 24% reported that they never routinely examined infertile male patients. Fifty-four percent of fertility specialists also reported issues getting men to undertake diagnostic semen analysis. Treatment for male infertility spanned assisted reproductive technology (ART), with themes of individualised medicine influencing treatment recommendations. Of the clinicians, 48.2% clinicians reported using empirical medical therapy for unexplained male infertility. Notably, 3.6% respondents recommended testosterone treatment, despite the likely negative impact on spermatogenesis. However, high levels of opportunistic general health advice were reported, including discussion of life exposures thought to be important for male reproductive health. This study adds novel evidence and highlights current deficiencies in clinical practice relating to male infertility. Evaluation of the infertile male using simple medical tools (detailed history taking and clinical examination) has the potential to identify treatable or reversible conditions and should be an immediate focus for education and improvement in reproductive medicine. Investment in research and development is much needed in the field of andrology to develop effective non-ART treatment options for male infertility.
Lay summary
Poor sperm quality (male infertility) significantly reduces the chance of natural conception and accounts for half of all cases of infertility, yet affected men are frequently overlooked when couples seek fertility investigations and treatment. Despite a growing awareness of men’s issues and a need to improve patient experience, there is very little documented about how fertility specialists (clinicians) routinely assess and treat male infertility. This study used a SurveyMonkey® questionnaire to capture current clinical practice, with 112 respondents from around the world. Forty-one percent of clinicians did not routinely consider male medical history in detail and 24% never routinely examined infertile men. This should be a focus for improvement in clinical care. As expected, fertility treatment recommended for male infertility was mostly in vitro fertilisation and intracytoplasmic sperm injection, where a single sperm is injected into each mature egg. However, 48.2% of clinicians also reported prescribing unproven medical therapy for unexplained male infertility. Of concern, a few clinicians routinely recommended testosterone treatment, which is likely to harm sperm production. However, advice regarding general health was universally delivered.
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Fifteen percent of couples are globally estimated to be infertile, with up to half of these cases attributed to male infertility. Reactive oxidative species (ROS) are known to damage sperm leading to impaired quantity and quality. Although not routinely assessed, oxidative stress is a common underlying pathology in infertile men. Antioxidants have been shown to improve semen analysis parameters by reducing ROS and facilitating repair of damage caused by oxidative stress, but it remains unclear whether they improve fertility. Carnitines are naturally occurring antioxidants in mammals and are normally abundant in the epididymal luminal fluid of men. We conducted a systematic review and meta-analysis to evaluate the safety and efficacy of carnitine supplementation for idiopathic male infertility. We searched ClinicalKey, ClinicalTrials.gov, Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE, MEDLINE, PubMed and ScienceDirect for relevant studies published from 1 January 2000 to 30 April 2020. Of the articles retrieved, only eight randomised controlled trials were identified and included. Analysis showed that carnitines significantly improve total sperm motility, progressive sperm motility and sperm morphology, but without effect on sperm concentration. There was no demonstrable effect on clinical pregnancy rate in the five studies that included that outcome, although patient numbers were limited. Therefore, the use of carnitines in male infertility appears to improve some sperm parameters but without evidence of an increase in the chance of natural conception.
Lay summary
Although male infertility affects 1:15 men, there is no obvious reason in the vast majority of cases. Reactive oxidative species (ROS) are highly active molecules containing oxygen and are natural byproducts of normal metabolism. However, high concentrations of ROS have been shown to damage sperm, which negatively impacts a couple’s ability to conceive. Carnitines are natural antioxidants found in the body that counterbalance the damaging effects of ROS. We conducted a comprehensive review of published studies to assess whether carnitine supplements are safe and effective in improving sperm quality and pregnancy rates. Our analysis shows that carnitines improve sperm swimming and production of normal-shaped sperm cells but do not affect sperm count or pregnancy rates, although there are only a few studies and scientific evidence is limited. Whilst it is possible that carnitines may benefit male infertility, more evidence is required regarding chances of pregnancy after carnitine therapy.
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Lay summary
In IVF, eggs and sperm are added together for fertilisation to occur whereas ICSI involves injecting a single sperm into each egg. ICSI is very effective where sperm count or swimming is poor (male infertility) but is slightly riskier than IVF in terms of health problems in children, although these risks are small. However, the risk of no eggs fertilising is higher for IVF compared to ICSI and couples undertaking fertility preservation, for example, before cancer treatment, usually only have time for one attempt. Using fertility preservation treatment cycle data reported to Human Fertilisation and Embryology Authority (HFEA), this study shows that ICSI results in higher number of fertilised eggs and embryos for storage or treatment compared to IVF. However, 19% of eggs are not used in ICSI treatment, so IVF appears to be better overall. Clinics should choose IVF or ICSI for fertility preservation depending on sperm characteristics rather than using ICSI for all.
