madman
Super Moderator
Post-Finasteride Syndrome: Current Views and Where do We Stand? (2022)
Ghadah I Alhetheli, Fahad Hamoud Alrashidi, and Saleh H Alhammad
Abstract
Introduction: Androgenetic alopecia is the most frequent cause of hair loss worldwide, affecting around 70% of males and 40% of females. Since the approval of finasteride for androgenetic alopecia, several studies have reported various psychological and sexual side effects. In 2012, the food and drug organization made changes to the drug insert stating the possibility of persistent side effects, or what is known as post-finasteride syndrome. There is still not much known about the rate of these side effects and the causal relationship.
Methods: A literature search was performed using the Pubmed and Google Scholar databases that included studies conducted from 1995 to 2020.
Results: There were 47 identified articles in Pubmed, while 152 articles were identified using Google Scholar. Duplicates were removed, leaving a total of 185 articles. Following a second, thorough screening of the titles and abstracts, only 62 full-text articles were reviewed. Of those, 35 articles were chosen to be included.
Conclusion: Based on the existing literature, the medical community believes that these patterns of symptoms constitute the basis for PFS in individuals predisposed to epigenetic susceptibility. The medical community must define and characterize the pathophysiological mechanisms underlying PFS, and more attention should be devoted to patient education and counseling as well as to developing novel management modalities. Further high-quality clinical studies are needed to evaluate the potential neuropsychiatric side effects of finasteride in humans and to establish whether finasteride has any exact causal relationship with suicidal ideation and other reported side effects.
Introduction
Andro Genetic Alopecia (AGA) is the most frequent cause of hair loss worldwide, affecting around 70% of males as Male Pattern Hair Loss (MPHL) and 40% of females as Female Pattern Hair Loss (FPHL) at some point in their lives. [1,2] It is characterized by progressive non-cicatricial baldness of the scalp vertex and recession of temporal hairlines due to 5α-Dihydrotestosterone (5α-DHT) dependent miniaturization of hair follicles. [3] The enzyme 5α-Reductase (5α-R) plays a crucial role in the activation of neuroactive steroids like Testosterone (T) and Progesterone (PROG). Subsequently, T and PROG are metabolized by (5αR) into Dihydrotestosterone (DHT) and Dihydroprogesterone (DHP), respectively. All neuroactive steroids (i.e. steroids synthesized by the peripheral nervous system and also those synthesized directly by the central nervous system) are then further transformed by either 3α-Hydroxysteroid Oxidoreductase (3α-HSOR) or 3β-Hydroxysteroid Oxidoreductase (3β-HSOR) into more metabolites, such as 5α-androstane-3α, 17β-diol (3α-diol) or 5α-androstane-3β, 17β-diol (3β-diol) in case of DHT, and Tetrahydroprogesterone (THP, also known as allopregnanolone) or isopregnanolone in case of DHP. All these neuroactive steroids together with their precursors (i.e. Pregnenolone: PREG and Dehydroepiandrosterone: DHEA), which interact with classical steroid receptors (e.g. Progesterone: PR, Androgen: AR, and Estrogen Receptors: ER) and non-classical (e.g. neurotransmitter and membrane steroid receptors) steroid receptors, act as vital modulators of nervous system function. [4,5]
Finasteride, an inhibitor (5α-R), was approved for the treatment of AGA in 1997. [6] Over the years, finasteride has been well-tolerated and has a relatively good safety profile with rare and reversible side effects, such as decreased sexual libido and ejaculatory volume, specifically when prescribed in a dose of 5 mg for cases of Benign Prostatic Hyperplasia (BPH). [7] However, there are several reports describing a constellation of persistent sexual, neuropsychiatric and physical side effects that appear or continue after drug discontinuation, inducing what is called Post-Finasteride Syndrome (PFS). Consequently, related authorities in several countries raised warnings related to this drug. In 2012, the Food and Drug Administration (FDA) made changes to the package insert in the United States, stating the possibilities of persistent side effects. [8] In 2015, the National Institute of Health (NIH) categorized PFS under rare and genetic diseases. [9,10]
There is still not much known about the rate of these side effects and the causal relationship, and the results of current studies are insufficient and non-conclusive. This review article aimed to shed light on the genesis of PFS, how common it is, and the magnitude of its impact on patients taking it for AGA. It also offers general recommendations on how to avoid and manage the condition.
Discussion
Finasteride is an orally active specific inhibitor of 5-alpha reductase, which is an enzyme that blocks the conversion of testosterone to Dihydrotestosterone (DHT). It is widely used to treat Benign Prostatic Hypertrophy (BPH) and Male Pattern Hair Loss (MPHL), which are associated with elevated levels of DHT and 5-a-reductase activity in the prostate and hair follicles, respectively. [38,39] A study conducted by Irwig et al. showed that a significant proportion of men reported intolerable Adverse Effects (AEs) after initiating finasteride therapy and continued to experience these effects after stopping the medication. [23] The most frequent AEs are classified into physical, sexual, cognitive, and psychological effects. Physical AEs include chronic fatigue, gynecomastia, muscle atrophy, skin thinning, and penile and scrotal shrinkage. Decreased libido, intermittent erectile dysfunction, and impotence are reported as sexual AEs. Cognitive AEs include brain fog and difficulty with concentrating and maintaining focus. Emotional sensitivity, depression, and excessive anxiety are reported as psychological AEs. [22,38]
*Many clinicians are unaware of the scope of the persistent physical and psychological adverse effects of finasteride while it is in usage and despite its discontinuation. The treating clinician should have knowledge and awareness about the higher prevalence of depression and sexual dysfunction in the subset of men seeking treatment for AGA in comparison to the general population. Hence, it is mandatory to ask about patients’ histories of preexisting depression or sexual dysfunction before starting finasteride treatment. Studies agree that 5-alpha reductase inhibitors are well-tolerated, but not without risk. Accordingly, patient education prior to treatment is of the utmost importance, and alternative therapies for treating alopecia may be considered during patient counseling.
Conclusion
Post-Finasteride Syndrome (PFS) is considered a serious group of adverse effects that range between persistent, irreversible sexual, neurological, physical, and psychological symptoms that develop and persist in patients during and/or after discontinuing finasteride treatment in men. Based on the existing literature and clinical research, the medical community believes that these patterns of symptoms constitute the basis for PFS in individuals predisposed to epigenetic susceptibility. The medical community must define and characterize the pathophysiological mechanisms underlying PFS, and more attention should be devoted to patient education and counseling as well as to developing novel management modalities. In addition, further high-quality clinical studies are needed to evaluate potential neuropsychiatric side effects of finasteride in humans and to establish whether finasteride has any exact causal relationship with suicide ideation and other reported side effects.
Ghadah I Alhetheli, Fahad Hamoud Alrashidi, and Saleh H Alhammad
Abstract
Introduction: Androgenetic alopecia is the most frequent cause of hair loss worldwide, affecting around 70% of males and 40% of females. Since the approval of finasteride for androgenetic alopecia, several studies have reported various psychological and sexual side effects. In 2012, the food and drug organization made changes to the drug insert stating the possibility of persistent side effects, or what is known as post-finasteride syndrome. There is still not much known about the rate of these side effects and the causal relationship.
Methods: A literature search was performed using the Pubmed and Google Scholar databases that included studies conducted from 1995 to 2020.
Results: There were 47 identified articles in Pubmed, while 152 articles were identified using Google Scholar. Duplicates were removed, leaving a total of 185 articles. Following a second, thorough screening of the titles and abstracts, only 62 full-text articles were reviewed. Of those, 35 articles were chosen to be included.
Conclusion: Based on the existing literature, the medical community believes that these patterns of symptoms constitute the basis for PFS in individuals predisposed to epigenetic susceptibility. The medical community must define and characterize the pathophysiological mechanisms underlying PFS, and more attention should be devoted to patient education and counseling as well as to developing novel management modalities. Further high-quality clinical studies are needed to evaluate the potential neuropsychiatric side effects of finasteride in humans and to establish whether finasteride has any exact causal relationship with suicidal ideation and other reported side effects.
Introduction
Andro Genetic Alopecia (AGA) is the most frequent cause of hair loss worldwide, affecting around 70% of males as Male Pattern Hair Loss (MPHL) and 40% of females as Female Pattern Hair Loss (FPHL) at some point in their lives. [1,2] It is characterized by progressive non-cicatricial baldness of the scalp vertex and recession of temporal hairlines due to 5α-Dihydrotestosterone (5α-DHT) dependent miniaturization of hair follicles. [3] The enzyme 5α-Reductase (5α-R) plays a crucial role in the activation of neuroactive steroids like Testosterone (T) and Progesterone (PROG). Subsequently, T and PROG are metabolized by (5αR) into Dihydrotestosterone (DHT) and Dihydroprogesterone (DHP), respectively. All neuroactive steroids (i.e. steroids synthesized by the peripheral nervous system and also those synthesized directly by the central nervous system) are then further transformed by either 3α-Hydroxysteroid Oxidoreductase (3α-HSOR) or 3β-Hydroxysteroid Oxidoreductase (3β-HSOR) into more metabolites, such as 5α-androstane-3α, 17β-diol (3α-diol) or 5α-androstane-3β, 17β-diol (3β-diol) in case of DHT, and Tetrahydroprogesterone (THP, also known as allopregnanolone) or isopregnanolone in case of DHP. All these neuroactive steroids together with their precursors (i.e. Pregnenolone: PREG and Dehydroepiandrosterone: DHEA), which interact with classical steroid receptors (e.g. Progesterone: PR, Androgen: AR, and Estrogen Receptors: ER) and non-classical (e.g. neurotransmitter and membrane steroid receptors) steroid receptors, act as vital modulators of nervous system function. [4,5]
Finasteride, an inhibitor (5α-R), was approved for the treatment of AGA in 1997. [6] Over the years, finasteride has been well-tolerated and has a relatively good safety profile with rare and reversible side effects, such as decreased sexual libido and ejaculatory volume, specifically when prescribed in a dose of 5 mg for cases of Benign Prostatic Hyperplasia (BPH). [7] However, there are several reports describing a constellation of persistent sexual, neuropsychiatric and physical side effects that appear or continue after drug discontinuation, inducing what is called Post-Finasteride Syndrome (PFS). Consequently, related authorities in several countries raised warnings related to this drug. In 2012, the Food and Drug Administration (FDA) made changes to the package insert in the United States, stating the possibilities of persistent side effects. [8] In 2015, the National Institute of Health (NIH) categorized PFS under rare and genetic diseases. [9,10]
There is still not much known about the rate of these side effects and the causal relationship, and the results of current studies are insufficient and non-conclusive. This review article aimed to shed light on the genesis of PFS, how common it is, and the magnitude of its impact on patients taking it for AGA. It also offers general recommendations on how to avoid and manage the condition.
Discussion
Finasteride is an orally active specific inhibitor of 5-alpha reductase, which is an enzyme that blocks the conversion of testosterone to Dihydrotestosterone (DHT). It is widely used to treat Benign Prostatic Hypertrophy (BPH) and Male Pattern Hair Loss (MPHL), which are associated with elevated levels of DHT and 5-a-reductase activity in the prostate and hair follicles, respectively. [38,39] A study conducted by Irwig et al. showed that a significant proportion of men reported intolerable Adverse Effects (AEs) after initiating finasteride therapy and continued to experience these effects after stopping the medication. [23] The most frequent AEs are classified into physical, sexual, cognitive, and psychological effects. Physical AEs include chronic fatigue, gynecomastia, muscle atrophy, skin thinning, and penile and scrotal shrinkage. Decreased libido, intermittent erectile dysfunction, and impotence are reported as sexual AEs. Cognitive AEs include brain fog and difficulty with concentrating and maintaining focus. Emotional sensitivity, depression, and excessive anxiety are reported as psychological AEs. [22,38]
*Many clinicians are unaware of the scope of the persistent physical and psychological adverse effects of finasteride while it is in usage and despite its discontinuation. The treating clinician should have knowledge and awareness about the higher prevalence of depression and sexual dysfunction in the subset of men seeking treatment for AGA in comparison to the general population. Hence, it is mandatory to ask about patients’ histories of preexisting depression or sexual dysfunction before starting finasteride treatment. Studies agree that 5-alpha reductase inhibitors are well-tolerated, but not without risk. Accordingly, patient education prior to treatment is of the utmost importance, and alternative therapies for treating alopecia may be considered during patient counseling.
Conclusion
Post-Finasteride Syndrome (PFS) is considered a serious group of adverse effects that range between persistent, irreversible sexual, neurological, physical, and psychological symptoms that develop and persist in patients during and/or after discontinuing finasteride treatment in men. Based on the existing literature and clinical research, the medical community believes that these patterns of symptoms constitute the basis for PFS in individuals predisposed to epigenetic susceptibility. The medical community must define and characterize the pathophysiological mechanisms underlying PFS, and more attention should be devoted to patient education and counseling as well as to developing novel management modalities. In addition, further high-quality clinical studies are needed to evaluate potential neuropsychiatric side effects of finasteride in humans and to establish whether finasteride has any exact causal relationship with suicide ideation and other reported side effects.
