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Post-finasteride syndrome: a surmountable challenge for clinicians
Abdulmaged M. Traish, Ph.D. Department of Urology, Boston University School of Medicine, Boston, Massachusetts
Post-finasteride syndrome (PFS) is a constellation of serious adverse side effects manifested in clinical symptoms that develop and persist in patients during and/or after discontinuing finasteride treatment in men with pattern hair loss (androgenetic alopecia) or benign prostatic hyperplasia. These serious adverse side effects include persistent or irreversible sexual, neurological, physical and mental side effects. To date, there are no evidence-based effective treatments for PFS. Although increasing number of men report persistent side effects, the medical community has yet to recognize this syndrome nor are there any specific measures to address this serious and debilitating symptoms. Here we evaluate the scientific and clinical evidence in the contemporary medical literature to address the very fundamental question: Is PFS a real clinical condition caused by finasteride use or are the reported symptoms only incidentally associated with but not caused by finasteride use? One key indisputable clinical evidence noted in all reported studies with finasteride and dutasteride was that use of these drugs is associated with development of sexual dysfunction, which may persist in a subset of men, irrespective of age, drug dose or duration of study. Also, increased depression, anxiety and suicidal ideation in a subset of men treated with these drugs were commonly reported in a number of studies. It is important to note that many clinical studies suffer from incomplete or inadequate assessment of adverse events and often limited or inaccurate data reporting regarding harm. Based on the existing body of evidence in the contemporary clinical literature, the author believes that finasteride and dutasteride induce a constellation of persistent sexual, neurological and physical adverse side effects, in a subset of men. These constellations of symptoms constitute the basis for PFS in individuals predisposed to epigenetic susceptibility. Indeed, delineating the pathophysiological mechanisms underlying PFS will be of paramount importance to the understanding of this syndrome and to development of potential novel therapeutic modalities.
5 a-reductases (5a-Rs) are a family of isozymes expressed in a wide host of organs and tissues including central nervous system (CNS). 5a-Rs play key physiological roles in regulation and development of male sexual differentiation and metabolism (1–7). 5a-Rs catalyze the transformation of multiple gonadal, adrenal and CNS steroid precursors into active functional hormones and neuroactive steroids (8–15).
Finasteride and dutasteride are synthetic 5a-reductase inhibitors (5aRIs) which bind to 5a-Rs active sites with high affinity. The pharmacokinetics of finasteride and dutasteride are as such that they are nearly irreversible inhibitor of 5a-Rs, with slow rate of dissociation, leading to a long lasting effect of the drug, regardless of dose administered. The irreversible nature of the inhibition by this class of drugs may lead to epigenetic changes, such as DNA methylation of the androgen receptor gene or the 5a-reductases genes. In addition, this class of drugs may act as endocrine disruptors, contributing to several potential mechanisms by which these drugs elicit serious and undesirable sexual and psychological adverse effects.
Since 5a-dihydrotestosterone (5aDHT) plays a key role in erectile physiology (16–22), including activation of nitric oxide synthase (NOS) and increasing blood flow in penile tissue, inhibition of 5a-Rs by finasteride or dutasteride contributes to erectile dysfunction (ED).
Several pre-clinical studies emphasized the importance of neuro-steroids in maintaining central nervous system (CNS) function (23–48). Since neuro-steroid biosynthesis is limited by 5a-Rs activities, inhibition of these enzymes in the CNS by finasteride or dutasteride reduces the bioavailability of these critical physiological modulators.
DISCUSSION
It is time to acknowledge and recognize that patients who are suffering from PFS are not psychotic or delusional, as some in the clinical community wish to label them (65, 66). It is time for action, and this necessitates development of more effective approaches to understanding the pathophysiological mechanism of PFS and development of novel therapeutic options. The medical community has an obligation not to turn a blind eye on this rare yet debilitating condition in young men. Patients with this condition should not be stereotyped or stigmatized by untrained and unprepared clinicians, due to lack of awareness and knowledge pertaining to this new and rare syndrome. Greater awareness and education are needed among the medical and scientific communities in order to develop better approaches for managing men with PFS. It is paramount that steps are taken to develop better understanding of the underlying mechanisms contributing to the onset and progression of PFS and to promote educational and training programs to increase awareness and improve management of this condition.
Abdulmaged M. Traish, Ph.D. Department of Urology, Boston University School of Medicine, Boston, Massachusetts
Post-finasteride syndrome (PFS) is a constellation of serious adverse side effects manifested in clinical symptoms that develop and persist in patients during and/or after discontinuing finasteride treatment in men with pattern hair loss (androgenetic alopecia) or benign prostatic hyperplasia. These serious adverse side effects include persistent or irreversible sexual, neurological, physical and mental side effects. To date, there are no evidence-based effective treatments for PFS. Although increasing number of men report persistent side effects, the medical community has yet to recognize this syndrome nor are there any specific measures to address this serious and debilitating symptoms. Here we evaluate the scientific and clinical evidence in the contemporary medical literature to address the very fundamental question: Is PFS a real clinical condition caused by finasteride use or are the reported symptoms only incidentally associated with but not caused by finasteride use? One key indisputable clinical evidence noted in all reported studies with finasteride and dutasteride was that use of these drugs is associated with development of sexual dysfunction, which may persist in a subset of men, irrespective of age, drug dose or duration of study. Also, increased depression, anxiety and suicidal ideation in a subset of men treated with these drugs were commonly reported in a number of studies. It is important to note that many clinical studies suffer from incomplete or inadequate assessment of adverse events and often limited or inaccurate data reporting regarding harm. Based on the existing body of evidence in the contemporary clinical literature, the author believes that finasteride and dutasteride induce a constellation of persistent sexual, neurological and physical adverse side effects, in a subset of men. These constellations of symptoms constitute the basis for PFS in individuals predisposed to epigenetic susceptibility. Indeed, delineating the pathophysiological mechanisms underlying PFS will be of paramount importance to the understanding of this syndrome and to development of potential novel therapeutic modalities.
5 a-reductases (5a-Rs) are a family of isozymes expressed in a wide host of organs and tissues including central nervous system (CNS). 5a-Rs play key physiological roles in regulation and development of male sexual differentiation and metabolism (1–7). 5a-Rs catalyze the transformation of multiple gonadal, adrenal and CNS steroid precursors into active functional hormones and neuroactive steroids (8–15).
Finasteride and dutasteride are synthetic 5a-reductase inhibitors (5aRIs) which bind to 5a-Rs active sites with high affinity. The pharmacokinetics of finasteride and dutasteride are as such that they are nearly irreversible inhibitor of 5a-Rs, with slow rate of dissociation, leading to a long lasting effect of the drug, regardless of dose administered. The irreversible nature of the inhibition by this class of drugs may lead to epigenetic changes, such as DNA methylation of the androgen receptor gene or the 5a-reductases genes. In addition, this class of drugs may act as endocrine disruptors, contributing to several potential mechanisms by which these drugs elicit serious and undesirable sexual and psychological adverse effects.
Since 5a-dihydrotestosterone (5aDHT) plays a key role in erectile physiology (16–22), including activation of nitric oxide synthase (NOS) and increasing blood flow in penile tissue, inhibition of 5a-Rs by finasteride or dutasteride contributes to erectile dysfunction (ED).
Several pre-clinical studies emphasized the importance of neuro-steroids in maintaining central nervous system (CNS) function (23–48). Since neuro-steroid biosynthesis is limited by 5a-Rs activities, inhibition of these enzymes in the CNS by finasteride or dutasteride reduces the bioavailability of these critical physiological modulators.
DISCUSSION
It is time to acknowledge and recognize that patients who are suffering from PFS are not psychotic or delusional, as some in the clinical community wish to label them (65, 66). It is time for action, and this necessitates development of more effective approaches to understanding the pathophysiological mechanism of PFS and development of novel therapeutic options. The medical community has an obligation not to turn a blind eye on this rare yet debilitating condition in young men. Patients with this condition should not be stereotyped or stigmatized by untrained and unprepared clinicians, due to lack of awareness and knowledge pertaining to this new and rare syndrome. Greater awareness and education are needed among the medical and scientific communities in order to develop better approaches for managing men with PFS. It is paramount that steps are taken to develop better understanding of the underlying mechanisms contributing to the onset and progression of PFS and to promote educational and training programs to increase awareness and improve management of this condition.
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