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Future perspectives for PDE5 inhibitors bridging the gap between cardiovascular health and psychological status.

Basic Clin Androl

January 2025

Chair of Endocrinology and Medical Sexology (ENDOSEX), Dept. of Systems Medicine, University of Rome Tor Vergata, via Montpellier 1, Rome, 00133, Italy.

The serendipitous discovery that inhibiting type 5 phosphodiesterase (PDE5) using sildenafil, a potent PDE5 inhibitor (PDE5i) initially developed for cardioprotection, introduced the possibility of orally managing erectile dysfunction (ED) led to an increase in research data, which are currently considered groundbreaking for the new discipline of sexual medicine. Findings from a number of laboratories and clinics around the world unanimously demonstrated the following: (i) the major cause of ED is directly or indirectly related to cardiovascular disease (CVD); (ii) ED and CVDs share the same risk factors, which are related mainly to lifestyle choices; (iii) the first therapeutic approach to both ED and CVDs is to transform harmful lifestyles into virtuous lifestyles; and (iv) PDE5is in general, particularly sildenafil, are very safe, if not protective, for use in CVD patients. However, the use of PDE5is has faced several challenges.

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Background: The prevalence of obesity has risen dramatically worldwide. Beyond its metabolic implications, obesity profoundly impacts sexual health, particularly in males, with erectile dysfunction (ED) emerging as a prevalent and distressing co-morbidity. Studies show that bariatric surgery alleviates ED.

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Introduction: Dolutegravir is now extensively used in sub-Saharan Africa as a preferred component of antiretroviral therapy (ART). There is a paucity of large studies using routinely collected data from African people living with HIV on dolutegravir-based regimens to inform HIV programmes. We reviewed data in a large programme clinic of people living with HIV on dolutegravir to determine the real-world safety and tolerability of dolutegravir and to describe drivers of treatment discontinuation.

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Phosphodiesterases, particularly the type 5 isoform (PDE5), have gained recognition as pivotal regulators of male reproductive physiology, exerting significant influence on testicular function, sperm maturation, and overall fertility potential. Over the past several decades, investigations have expanded beyond the original therapeutic intent of PDE5 inhibitors for erectile dysfunction, exploring their broader reproductive implications. This narrative review integrates current evidence from in vitro studies, animal models, and clinical research to clarify the roles of PDEs in effecting the male reproductive tract, with an emphasis on the mechanistic pathways underlying cyclic nucleotide signaling, the cellular specificity of PDE isoform expression, and the effects of PDE5 inhibitors on Leydig and Sertoli cell functions.

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