Abstract

Post-Finasteride Syndrome as an Epigenetic Post-Androgen Deprivation Syndrome: A potential pathological link between Drug-Induced Androgen Receptor Overexpression and Polyglutamine Toxicity

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Post-Finasteride Syndrome (PFS) is a rare and devastating disease encompassing persistent physiological, sexual, and neurological health problems following exposure to a 5alpha reductase inhibitor. The condition comprises a broad and variable clinical spectrum and is responsible for relationship breakdown, disability preventing work, isolation and suicide. Herein, the administrators of the patient support website propeciahelp.com summarise the current published research into PFS, add to the understanding of the condition, and present a mechanistic hypothesis to support further scientific investigation. We argue that PFS cannot be understood with exclusive consideration as to Finasteride and is of unappreciated significance to health and disease. More appropriately considered a Post-Androgen Deprivation Syndrome, patients are increasingly seeking support following exposure to diverse substances capable of anti-androgenic endocrine disruption including 5alpha reductase inhibitors, isotretinoin, serotonergic antidepressants, saw palmetto extract and concentrated phenolic compounds marketed as health supplements. A symptomatic and potentially mechanistic overlap between PFS and the polyglutamine disease Spinal and Bulbar Muscular Atrophy is discussed. Transgenic models illustrate that polyQ toxicity can be recapitulated through overexpression of the wild-type AR. Persistent AR overexpression has been established in symptomatic tissue of PFS patients and is a mechanistic consequence of androgen deprivation. We suggest that site-specific epigenetic changes induced by androgen deprivation may result in a pathological AR deregulation. The role of the androgen receptor as a ubiquitous and critical regulator in the physiological and neurological domains relevant to PFS symptomatology is reviewed. We urge clinical education to end psychosomatic misdiagnosis, aid patient management and ensure a genuinely informed consent before prescription of these substances to young men. We urge molecular-level investigation of PFS patients to achieve pathomechanistic understanding, discover safe therapeutic options and ultimately disease-modifying treatment. Discovery of predisposing genetic and epigenetic factors will aid in assessing the suitability of young patients for therapies with antiandrogenic modality, while promising significant translational insight to a range of disease states.