Is there a role for phosphodiesterase inhibitors in the treatment of male subfertility?

Intracytoplasmic sperm injection (ICSI) is frequently used to overcome severe deficits in semen quality. Concerns, however, are arising over its increasing use for non-male factor infertility. Moreover, increased risk of cardiovascular disease, congenital abnormalities, aneuploidies and childhood cancers have all been reported in the literature in relation to ICSI and it is possible that the quality of sperm chosen for injection may be an important factor in these unwanted outcomes. Given the wider adoption of ICSI to treat beyond the requirements of male infertility alone, research focussed on alternative methods to diagnose and treat the infertile couple is gaining increasing attention. This review focuses on the information available to date on the use of non-selective phosphodiesterase inhibitors (PDEI), specifically pentoxifylline (PF), caffeine (CF) and theophylline (TP) to stimulate sperm motility, thereby potentially reducing the need for ICSI in certain patient groups who may benefit from either expectant management or from a less stressful, minimally invasive and inexpensive treatment such as intrauterine insemination (IUI). The review focuses firstly on the mechanism of action of PDEI followed by treatment effects on sperm parameters such as motility and hyperactivated motility and sperm DNA integrity. Specific clinical implications are discussed that outline the potential role of PDEI in clinical practice and highlights areas in need of further research.