From bench to babies – drug development for male subfertility

Abstract

Infertility is estimated to affect more than 50 million couples around the world, with the 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, diminishing 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. Lay summary Globally, millions of men suffer from infertility, but with very few exceptions, there is no effective treatment or cure other than complex fertility treatments such as in vitro fertilisation. This review article considers various approaches to treat men, or sperm, which have been largely unsuccessful to date. A significant issue is that we lack a detailed understanding of how sperm work and why treatments do not work. Another issue is that drug discovery is slow and costly because many potential treatments fail early on. However, we discuss recent technical and technological advancements that offer hope, such as high-throughput and phenotypic screening, which allow for the rapid testing of thousands of chemicals to observe their effects on sperm, and combinatorial chemistry, which involves generating large numbers of compounds to find those with beneficial properties. Finding relevant new uses for prescription drugs could also significantly speed up the drug discovery process and result in much-needed new treatments for male infertility.

Keywords

• male infertility
• sperm
• drug development
• drug discovery
• high throughput phenotypic screening