Phosphodiesterases (PDEs) are a family of enzymes that regulate intracellular levels of cyclic nucleotides, such as cyclic adenosine monophosphate and cyclic guanosine monophosphate. PDEs are considered key modulators of cellular signaling processes, including those governing male reproductive health. Owing to the pivotal role played by PDEs in male reproductive health, pharmacologic inhibition of PDEs has gained substantial attention in improving male reproductive health. However, despite the potential therapeutic application of PDE inhibitors (PDEis) in this field, a comprehensive understanding remains limited of the PDE subtype-specific actions in male reproductive tissues, the potential off-target effects, and the long-term safety of PDE inhibition, emphasizing a critical gap in current knowledge. A systematic evaluation of existing evidence on the role of PDEs, as well as the therapeutic application of PDEis and their safety, is necessary for a better understating in the context of male reproductive and sexual health.
This narrative review aims to critically synthesize and highlight the current evidence on the function of PDEs in male reproductive organs and evaluate the clinical applications of PDEis as therapeutic agents in male reproductive health and sexual medicine.
A comprehensive literature search was conducted in PubMed and Scopus to identify the expression and function of PDEs in male reproductive organs and the use of PDEis for the treatment of erectile dysfunction and reproductive cancer and for the improvement of male fertility.
PDEs of different families are expressed in a tissue-specific manner in the testis, epididymis, prostate gland, seminal vesicle, and penis, indicating their significant role in male reproductive health. Inhibitors of PDEs, even though popularly known for their therapeutic role in treating erectile dysfunction, have exhibited a promising role in the treatment of prostate cancer, testicular cancer, testicular function enhancement, and sperm motility improvement.
PDEis have a promising role in improving male reproductive and sexual health. However, the lack of studies addressing their long-term health effects and safety limits their routine therapeutic applications for improving male reproductive health. Future systematic clinical trials and mechanistic studies can certainly illuminate the possible role of PDEis in improving male reproductive health.
Sexual medicine reviews. 2026 Apr 01 [Epub]
Yashas Kiran Ninjoor, Vanishree Vasave Madhvacharya, Sandhya Kumari, M R Nagaraja, Jagadish P C, Dagur Singh Hanuman, Eerappa Rajakumara, Suranga P Kodithuwakku, Satish Kumar Adiga, Kshitish K Acharya, Guruprasad Kalthur
Divison of Reproductive Biology, Department of Reproductive Science, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, 576104, India., Department of Biochemistry, Akash Institute of Medical Sciences and Research Centre, Bengaluru, 562110, India., Department of Pharmaceutical Chemistry, Manipal College of Pharmaceutical Sciences, Manipal, Manipal Academy of Higher Education, Manipal, 576104, India., Macromolecular Structural Biology Lab, Department of Biotechnology, Indian Institute of Technology, Â Sangareddy, 502285, India., Department of Animal Science, Faculty of Agriculture, University of Peradeniya, Peradeniya, 20400, Sri Lanka., Centre of Excellence in Clinical Embryology, Department of Reproductive Science, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, 576104, India., Institute of Bioinformatics and Applied Biotechnology, Bengaluru, 560100, India.