Pharmacological treatments, including finasteride and oral contraceptives, that inhibit 5α-RI, which results in a blood and brain allopregnanolone decrease also affect subunit expression of GABAA receptor and are associated with mood symptoms and suicide and are part of post-finasteride syndrome. Post-finasteride syndrome, in addition to depression, anxiety and cognitive deficits also induces sexually-related side effects, such as loss of libido, erectile dysfunction, decreased arousal and difficulty in achieving an orgasm that persist despite drug withdrawal. Evidence suggests during pregnancy and across the estrous cycle a switch of extrasynaptic δ with synaptic γ2 subunits may be operative. Rapid and dynamic changes among synaptic and extrasynaptic GABAA receptor conformation in areas that regulate cognitive functions and emotions, including the hippocampus have been reported.
Pinna G (2020) Allopregnanolone, the Neuromodulator Turned Therapeutic Agent: Thank You, Next? Front. Endocrinol. 11:236. doi: 10.3389/fendo.2020.00236 [Frontiers in Endocrinology]
Among 31 male patients with foveal cavitation, 5-ARI was used for 10 of 14 patients (71.4%) with macular abnormalities of unknown origin and for 2 of 17 patients (11.8%) with macular abnormalities of well-known specific origin… Optical coherence tomography imaging showed a disease spectrum ranging from tiny foveal cavitation to an impending macular hole. Of the total male patients, 80.0% (8 of 10) had no symptoms… The findings suggest that macular abnormalities associated with 5-ARI are characterized by cystoid abnormalities and foveal cavitation in male patients, which may progress to outer foveal defect and macular hole.
Yong KS, Geun WL, Se WK, et al. JAMA Ophthalmol. 2020;138(7):732-739. doi:10.1001/jamaophthalmol.2020.1279 [JAMA Ophthalmology]
Post-finasteride syndrome (PFS) has been described as physical, neurological, or psychiatric side effects which persist for three or more months after discontinuing the medication, affecting approximately 900,000–1.5 million men. In 2015, the National Institute of Health (NIH) added PFS to their list of genetic and rare disease... Analysis of FAERS data suggests [adverse events] of 5ARIs are dose-independent with greater likelihood of occurrence in younger patients, particularly in sexual and mental domains.
Harrell, M.B., Ho, K., Te, A.E. et al. World J Urol (2020). https://doi.org/10.1007/s00345-020-03314-9 [World Journal of Urology]
While the sexual side effects of 5ARIs are well known, there may be persistent genitourinary, physical, psycho-cognitive, anti-androgenic and penile vascular changes after 5ARI discontinuation. Use of 5ARIs for treatment of AGA may lead to persistent sexual, genitourinary, physical, psycho-cognitive, and anti-androgenic sequelae even after cessation of 5ARI therapy... Two subjects (8%) committed suicide during or after the study.
Khera, M: Transl Androl Urol 2020 | http://dx.doi.org/10.21037/tau.2020.03.21 [Translational Andrology and Urology]
Here we advance the concept that blockade of the 5α-R enzymatic activities by such irreversible inhibitors results in a state of new form of androgen deficiency, independent of circulating T levels. This new form of androgen deficiency has not been recognized before, simply, it is thought that as long as T levels are in the physiological range, androgen sufficiency is considered normal. Because finasteride and dutasteride are often prescribed to treat LUTS in men with BPH and male pattern hair loss in men with AGA for prolonged periods of time, it is postulated that men treated with these drugs are in a state of androgen deficiency and are at high risk of developing NAFLD IR, T2DM, dry eye disease, potential kidney dysfunction, among other metabolic dysfunctions
Triash, AM: World J Mens Health. 2020 Mar 20. doi: 10.5534/wjmh.200012 [The World Journal of Men's Health]
[F]inasteride is associated with common adverse health effects in women with long-term treatment for androgenetic alopecia such as; irregular menstrual cycle, aromatase disorder, high cholesterol, heavy menstrual bleeding and induced DNA damage…Finally, the study recommended that finasteride should not be administrated as treatment for androgenetic alopecia in women.
Albasher G, Bin-Jumah M, Alfarraj S, et al. Biosci Rep (2020) 40 (2): BSR20191434: [Bioscience Reports]
In this postmarketing case series of 6 former finasteride users who committed suicide, all reported insomnia and persistent sexual dysfunction after medication discontinuation. The most prominent psychiatric symptoms were depression, anxiety, panic attacks, feelings of isolation and “brain fog.” Some of the most debilitating symptoms were insomnia and fatigue. Apart from 1 case who had hyperlipidemia, there is no documentation of concomitant medication use with finasteride or any baseline medical or psychiatric diagnoses prior to starting finasteride... In summary, among the men who committed suicide in the setting of finasteride treatment for alopecia, the most debilitating symptoms were insomnia, fatigue, depression, anxiety and isolation. Clinicians should be aware that men under the age of 40 who use finasteride for alopecia are at risk for suicide if they develop persistent sexual adverse effects and insomnia.
Irwig, MS: 2020 Jan 14:1-6. doi: 10.1159/000505151: [Dermatology]
It is not surprising that almost all studies published to date do report increased sexual adverse effects. However, even when such sexual adverse events were reported, many argued that the numbers of subjects afflicted are small and propagated the falsehood that the adverse effects do resolve with continued treatment. This is unfortunately a willful blindness and a deceptive method to continue to prescribe these drugs to unsuspecting young men. The number of subjects experiencing adverse events is neither small nor irrelevant, given the persistent nature of adverse events in susceptible individuals. For those individuals afflicted, this constitutes a life sentence of sexual dysfunction, depression and/or anxiety. To put this in perspective, approximately 30 million young men, worldwide, would be prescribed finasteride or dutasteride to treat male pattern hair loss. Even if the incidence of persistent sexual adverse events is 3% to 5%, which may be viewed as a small number, approximately 900,000 to 1.5 million men would suffer persistent sexual and psychiatric adverse events. By no means this would be considered a small number and should not be dismissed or ignored. By no means this can be considered a small number and should not be dismissed or ignored.
Traish, AM: Fertil Steril. 2020 Jan;113(1):21-50. doi: 10.1016/j.fertnstert.2019.11.030. [Fertility and Sterility]
[T]hese data indicate the urgent need for high quality clinical trials, with long-term follow up, specifically addressing sexual function and mood disorders. In addition, it is imperative to study in detail the molecular mechanisms that cause this condition, trying to identify a possible genetic predisposition, in order to limit the burden of PFS. Finally, therapeutic strategies, like...neuroactive steroid treatment, able to relieve or to cure this condition are also urgently needed.
Diviccaro S, Melcangi RC, Giatti S: [Neurobiology of Stress]
[W]e tested the effects of [finasteride (FIN)] in a battery of tests aimed at capturing complementary aspects of mood regulation and stress reactivity in rats. FIN reduced exploratory, incentive, prosocial, and risk-taking behavior; furthermore, it decreased stress coping, as revealed by increased immobility in the forced-swim test (FST). This last effect was also observed in female and orchiectomized male rats, suggesting that the mechanism of action of FIN does not primarily reflect changes in gonadal steroids. The effects of FIN on FST responses were associated with a dramatic decrease in corticotropin release hormone (CRH) mRNA and adrenocorticotropic hormone (ACTH) levels. These results suggest that FIN impairs stress reactivity and reduces behavioral activation and impulsive behavior by altering the function of the hypothalamus–pituitary–adrenal (HPA) axis.
Godar SC, Cadeddu R, Floris G, Mosher LJ, Mi Z, Jarmolowicz DP, Scheggi S, Walf AA, Koonce CJ, Frye CA, Muma NA, Bortolato M 2019 Nov 19;9(11). pii: E749. doi: [Biomolecules]
Recent findings in rat models confirmed that altered epigenetic processes, consisting in abnormal DNA methyltransferase protein levels and increased global DNA methylation levels, are linked to anxiety- and depression-like behaviour. Our finding of high levels of methylated SRD5A2 in CNS cells of a normotensive hydrocephalus individual, displaying an epigenetic status at odds with all other control subjects, further supports the link between DNA methylation pattern and disorders of the nervous system. If abnormal SRD5A2 promoter methylation is established prenatally, these subjects could be predisposed to develop the PFS and alteration of neuroactive steroid levels in the brain. In this case, treatment by finasteride might precipitate a dormant depressive phenotype linked to such specific epigenetic pattern... In conclusion, our results demonstrate methylation of SRD5A2 promoter in a tissue-specific manner in PFS patients. Whether this epigenetic pattern is established prenatally or induced by finasteride treatment cannot be concluded but this study pinpoints the relevance of this specific methylation pattern and its correlation with levels of neuroactive steroids and their effects.
Melcangi RC, Casarini L, Marino M, Santi D, Sperduti S, Giatti S, Diviccaro S, et al. Endocr Connect. 2019 Jul 1. pii: EC-19-0199.R1. doi: 10.1530/EC-19-0199. [Endocrine Connections]
Although there is some evidence against sexual dysfunction occurring in patients taking 5 mg and 10 mg of finasteride, most studies describe relatively common adverse effects of decreased libido, impotence, and ejaculation disorders... We identified 5 studies that did not support the increased rates of sexual dysfunction in men taking 1 mg finasteride for androgenic alopecia. However, we feel that the evidence describing increased rates of sexual dysfunction is more compelling. We identified 10 studies demonstrating sexual adverse effects, including ED and decreased libido... Three studies identified in this review describe complete reversibility of sexual dysfunction in all patients, but 11 studies describe patients experiencing irreversible adverse effects. These findings were most convincing in a retrospective review of 11,909 patients that identified 167 with persistent ED.
Zakhem, George A. et al. [Journal of the American Academy of Dermatology]
1. The finasteride treatment of adult male rats led to a decrease in androgen receptor expression and its cellular translocation within the kidney cortex.
2. The pathomorphological changes (glomerulosclerosis, tubulosclerosis, dysplastic glomeruli, and tubules with lumen dilatation) in rats’ kidneys with disturbed steroid hormone imbalance were associated with the diminished expression of intracellular junctional proteins.
3. The changed apoptotic/proliferating ratio of nephron cells and the increase in the numberof lymphocytes in the area of pathologically altered convoluted tubules were accompanied by impaired androgen/estrogen homeostasis.
Although studies of exogenous DHT supplementation in animals previously receiving finasteride have not been performed, it can be suggested that these described evidences from the animal model of experiment could indicate that the patients with renal dysfunction or following renal transplantation with androgen supplementation or with pharmacologically (i.e., by finasteride) induced DHT deficiency should be under special control and covered by extended diagnostics, due to the potential adverse effect of DHT deficiency on the progression of kidney disease.
Baig MS, Kolasa-Wołosiuk A, Pilutin A, Safranow K, Baranowska-Bosiacka I, Kabat-Koperska J, Wiszniewska B. Int. J. Environ. Res. Public Health 2019, 16(10), 1726 [International Journal of Environmental Research and Public Health]
Conclusions: The risk of developing new onset type 2 diabetes appears to be higher in men with benign prostatic hyperplasia exposed to 5α-reductase inhibitors than in men receiving tamsulosin, but did not differ between men receiving dutasteride and those receiving finasteride. Additional monitoring might be required for men starting these drugs, particularly in those with other risk factors for type 2 diabetes.
Wei L, Chia-Cheng Lai E, Kao-Yang Y, Walker BR, MacDonald TM, Andrew R. BMJ 2019;365:l1204. [The British Medical Journal]
Our findings indicate that finasteride treatment causes several alterations in the hippocampus that are detected at the end of the treatment... coincide with the apparition of depressive-like behavior, suggesting that long term effects of finasteride treatment on neurogenesis and neuroinflammation may participate in the enduring effects of the drug on depressive-like behavior, which are detected even one month after stopping the administration of the drug... Since neuroactive steroids regulate neurogenesis, gliosis and neuroinflammation and since PFS patients also show changes in neuroactive steroid levels, the effect of finasteride on depression, neuroactive steroid levels, neurogenesis and neuroinflammation may be interrelated events. In addition, the changes here observed at the end of treatment and at withdrawal on gut microbiota may depict further possible signals involved in the so call gut microbiota-brain axis.
Diviccaro S, Giatti S, Borgo F, Barcella M, Borghi E, Trejo JL, Garcia-Segura LM, Melcangi RC. 2018 Sep 18;99:206-215. doi: 10.1016/j.psyneuen.2018.09.021. [Psychoneuroendocrinology]
Finasteride treatment impairs biosynthesis and function of neurosteroids, which are critical regulators of central (CNS) as well as peripheral nervous system functions and modulate a host of neurotransmitter receptors, such as gamma amino butyric acid receptors. Thus, finasteride-induced neuroendocrine disruption of biosynthesis of critical signaling molecules results in pathophysiological states, which contribute to inhibition of biochemical pathways responsible for a host of physiological functions, ranging from sexual activity, mood, and cognition. In addition, finasteride-induced epigenetic changes in gene expression, including upregulation of androgen receptors (AR), increased histone acetylation, and methylation results in undesirable biological outcomes such as impairment of dopaminergic signaling and modulation of other neurotransmitter receptors, may be the underlying mechanism causing persistent or permanent adverse effects, manifested in anxiety, depression, and suicidal ideation.... The medical community has an obligation not to turn a blind eye on this rare yet debilitating condition in young men.
Traish, A.M. Curr Sex Health Rep (2018) 10: 88. https://doi.org/10.1007/s11930-018-0161-6 [Curr Sex Health Rep]
The persistent symptoms reported by men after treatment of BPH or AGA with 5α-reductase inhibitors have been increasingly studied over the past decade. However, many of the studies investigated PFS using surveys of patients seeking treatment for PFS or from PFS-specific online forums, exposing the results to potential selection and recall bias. Further, there is a paucity of randomized clinical trials to more definitively outline the relationship between 5α-reductase inhibitors and persistent adverse effects. Additionally, much of the research centers on the adverse effects after finasteride use leaving the occurrence of PFS after dutasteride use inadequately explored. Treatment options for the symptoms of PFS have also yet to be clearly outlined or investigated.
Than, J. K., Rodriguez, K., & Khera, M. (2018). Post-finasteride Syndrome: A Review of Current Literature. Current Sexual Health Reports, 10(3), 152–157. doi:10.1007/s11930-018-0163-4 [Curr Sex Health Rep]
Finasteride, which crosses the blood-brain barrier, therefore lowers overall androgen activity. A decrease in androgen levels has been associated with [obstructive sleep apnea] and lower sleep efficiency in some studies. The odds of OSA with finasteride for any indication versus OSA with all other medication in FAERS used for any indication revealed…1,490 all other AE with finasteride versus 11,390 all other AE with all other medications in FAERS. Conclusion: Finasteride was associated with a significantly higher odds of OSA, a finding that has not been previously reported.
Gupta MA, Vujcic B, Sheridan AD, Gupta AK. Finasteride is Associated with a Higher Odds of Obstructive Sleep Apnea (OSA): Results from the US FDA Adverse Events Reporting System (FAERS) [Sleep]
Users of finasteride…report serious physical and emotional adverse effects, collectively known as post-finasteride syndrome… Limited research exists exploring the psychological corollaries of post-finasteride syndrome and preexisting Axis I and Axis II mental health conditions… An important finding in this study was that almost 57% (n = 97) of men reported a psychiatric diagnosis and 28% (n = 27) had a first-degree relative with a mental health disorder, of this group 17 only had a family history. Nearly 50% of the men surveyed reported clinically significant depression as evidenced by Beck Depression Inventory score and 34% experienced anxiety on the Beck Anxiety Inventory.
Ganzer CA, Jacobs AR, et al. Emotional Consequences of Finasteride: Fool’s Gold. Am J Mens Health. 2018 Jan; 12(1): 90–95. Published online 2016 Feb 11. doi: 10.1177/1557988316631624. PMCID: PMC5734544. PMID: 26868914. [PubMed]
The levels of some neuroactive steroids analyzed in CSF of PFS patients were significantly different versus those in healthy controls. In particular, the levels of PREG, as well as of its further metabolites, PROG and DHP, were significantly decreased in CSF of PFS patients. PFS patients show altered levels of important physiological regulators of brain function, such as neuroactive steroids. This could explain the andrological and psychiatric features observed in PFS patients.
Melcangi RC, Santi D, Spezzano R, Grimoldi M, Tabacchi T, Fusco ML, Diviccaro S, Giatti S, Carrà G, Caruso D, Simoni M, Cavaletti G. Neuroactive steroid levels and psychiatric and andrological features in post-finasteride patients. J Steroid Biochem Mol Biol. 2017 Jul;171:229-235. doi: 10.1016/j.jsbmb.2017.04.003. Epub 2017 Apr 10. [PubMed]
Our chief objective was to assess whether longer duration of 5α-RI exposure increases risk of [persistent erectile dysfunction], independent of age and other known risk factors… Among men with 5α-RI exposure, 167 of 11,909 (1.4%) developed PED… Of 530 men with new ED, 167 (31.5%) had new PED. Men without prostate disease who combined NSAID use with >208.5 days of 5α-RI exposure had 4.8-fold higher risk of PED than men with shorter exposure… Of 103 young men with new ED, 34 (33%) had new PED. Young men with >205 days of finasteride exposure had 4.9-fold higher risk of PED (NNH 108.2, p < 0.004) than men with shorter exposure. Conclusion and relevance: Risk of PED was higher in men with longer exposure to 5α-RIs. Among young men, longer exposure to finasteride posed a greater risk of PED than all other assessed risk factors.
Kiguradze T, Temps WH, Yarnold PR, Cashy J, Brannigan RE, Nardone B, Micali G, West DP, Belknap SM. Persistent erectile dysfunction in men exposed to the 5α-reductase inhibitors, finasteride, or dutasteride. PeerJ. 2017 Mar 9;5:e3020. doi: 10.7717/peerj.3020. eCollection 2017. [PubMed]
This study showed that short and/or long (CAG)n and (GGN)n repeats had different frequencies according to symptoms reported by patients with PFS, likely reflecting the vast array of genes modulated by the AR. This study showed a U-curvilinear profile of (CAG)n repeats for skin dryness symptoms, where the two extremes exhibited a worse condition than medium repeats. Further studies are necessary to investigate the PFS pathophysiology using a precision medicine approach.
Cauci S, Chiriacò G, Cecchin E, et al. Sex Med. 2017 Mar;5(1):e61-e71. doi: 10.1016/j.esxm.2016.11.001. [Journal of Sexual Medicine]
Recent evidence has shown that [finasteride], albeit generally well tolerated, can induce untoward psychological effects in a subset of patients; furthermore, this drug may have therapeutic efficacy for a number of different neuropsychiatric conditions, ranging from Tourette syndrome to schizophrenia. In rat models of these conditions, FIN has been shown to block the effects of dopamine receptors in the nucleusaccumbens (NAcc), a key terminal of the dopamine mesolimbic system. The biological underpinnings of these effects, however, remain mostly elusive… [O]ur results showed that FIN treatment affected the expression of a number of accumbal proteins involved in key functional processes, such as regulation of GABAergic neurotransmission, as well as steroid and pyrimidine metabolism. These findings may prove crucial to understanding the neurochemical mechanisms of FIN’s neuropsychiatric side effects, as well as its potential therapeutic properties for neurological and mental disorders.
Soggiu A, Piras C, Greco V, Devoto P, Urbani A, Calzetta L, Bortolato M, Roncada P, et al. Exploring the neural mechanisms of finasteride: a proteomic analysis in the nucleus accumbens. Psychoneuroendocrinology. 2016 Dec;74:387-396. doi: 10.1016/j.psyneuen.2016.10.001. Epub 2016 Oct 6. [PubMed]
Symptomatic finasteride users had “significantly lower International Index of Erectile Function composite score” and “significantly lower scores for each of its domains of erectile function, sexual desire, orgasmic function, intercourse satisfaction, and overall satisfaction”… There exists “a significant positive correlation between a subset of Beck Depression Inventory scores related to negative attitude and blood oxygen level-dependent activity in the right nucleus accumbens, left pregenual anterior cingulate cortex, right insula, right lateral orbitofrontal cortex, and left posterior cingulate, as well as a negative correlation between BDI subscores and BOLD activity in the right parahippocampal/ fusiform gyrus. This neural circuitry overlaps with functional abnormalities that have been identified in major depression.”
Basaria S, Jasuja R, Huang G, Wharton W, Pan H, Pencina K, Li Z, Travison TG, Bhawan J, Gonthier R, Labrie F, Dury AY, Serra C, Papazian A, O'Leary M, Amr S, Storer TW, Stern E, Bhasin S, et al. Characteristics of Men Who Report Persistent Sexual Symptoms After Finasteride Use for Hair Loss. J Clin Endocrinol Metab. 2016 Dec;101(12):4669-4680. Epub 2016 Sep 23. [PubMed]
Concern regarding adverse effects of finasteride is increasing. We aimed to determine the type and frequency of symptoms in men having long-term sexual and non-sexual side effects after finasteride treatment (a condition recently called post-finasteride syndrome, PFS).… Out of 79 participants…the most frequent sexual symptoms referred were a loss of penis sensitivity (87.3%), decreased ejaculatory force (82.3%), and low penile temperature (78.5%). The most frequent non-sexual symptoms have reduced the feeling of life pleasure or emotions (anhedonia) (75.9%), lack of mental concentration (72.2%), and loss of muscle tone/mass (51.9%).…Further studies are necessary to investigate the pathophysiological and biochemical pathways leading to the post-finasteride syndrome.
Chiriacò G, Cauci S, Mazzon G, Trombetta C, et al. An observational retrospective evaluation of 79 young men with long-term adverse effects after use of finasteride against androgenetic alopecia. Andrology. 2016 Mar;4(2):245-50. doi: 10.1111/andr.12147. Epub 2016 Jan 13. [PubMed]
The effects in the brain of finasteride…have been poorly explored. Therefore, the effects of a subchronic treatment of finasteride…and the consequences of its withdrawal on neuroactive steroid levels in plasma, cerebrospinal fluid and some brain regions…have been evaluated in male rats. After subchronic treatment…the following effects were detected: (i) depending on the compartment considered, alteration in the levels of neuroactive steroids, not only in 5alpha-reduced metabolites but also in its precursors and in neuroactive steroids from other steroidogenic pathways and (ii) upregulation of androgen receptor in the cerebral cortex and beta3 subunit of GABA-A receptor in the cerebellum. One month after the last treatment (i.e., withdrawal period), some of these effects persisted…Moreover, other changes in neuroactive steroid levels, steroid receptors…and GABA-A receptor subunits…were detected. These findings suggest that finasteride treatment may have broad consequences for brain function.
Giatti S, Foglio B, Romano S, Pesaresi M, Panzica G, Garcia-Segura LM, Caruso D, Melcangi RC, et al. Effects of Subchronic Finasteride Treatment and Withdrawal on Neuroactive Steroid Levels and Their Receptors in the Male Rat Brain. Neuroendocrinology. 2016;103(6):746-57. doi: 10.1159/000442982. Epub 2015 Dec 9. [PubMed]
Conclusions: Persistent adverse effects of finasteride in younger men include erectile dysfunction, low libido, lack of orgasms, depression, and decreased alcohol consumption. One study has found lower levels of several neurosteroids in this population. Out of the various persistent side effects, erectile dysfunction and decreased alcohol consumption have been the most studied in animal models. Further research is needed on who is susceptible to the persistent adverse side effects of finasteride and on the underlying mechanisms of the medication.
Irwig, MS. Persistent Sexual and Nonsexual Adverse Effects of Finasteride in Younger Men. Sex Med Rev. 2014 Jan;2(1):24-35. doi: 10.1002/smrj.19. Epub 2015 Oct 19. [PubMed]
Conclusions: This study showed that long-term 5α-RIs therapy but not tamsulosin in men with BPH is associated with continued worsening of ED, which does not resolve with continuing treatment, contrary to previous claims. Most importantly, it appears that 5α-RIs therapy but not tamsulosin results in a reduction of T levels and increased AMS score as well as AST and ALT in the liver. These findings raise a safety concern regarding 5α-RI therapy for the long-term. Clinicians are urged to discuss the impact of 5α-RIs therapy with their patients before commencing this therapy.
Traish AM, Haider KS, Doros G, Haider A, et al. Finasteride, not tamsulosin, increases the severity of erectile dysfunction and decreases testosterone levels in men with benign prostatic hyperplasia. Horm Mol Biol Clin Investig. 2015 Sep;23(3):85-96. doi: 10.1515/hmbci-2015-0015. [PubMed]
Recent preclinical and clinical findings indicate that 5α-R inhibitors evoke not only beneficial but also adverse effects. Future studies should investigate the biochemical and physiological mechanisms that underlie the persistence of the adverse sexual side effects to determine why a subset of patients is afflicted with such persistence or irreversible adverse effects. Also, a better focus of clinical research is urgently needed to better define those subjects who are likely to be adversely affected by such agents.
Traish AM, Melcangi RC, Bortolato M, Garcia-Segura LM, Zitzmann M, et al. Adverse effects of 5α-reductase inhibitors: What do we know, don't know, and need to know? Rev Endocr Metab Disord. 2015 Sep;16(3):177-98. doi: 10.1007/s11154-015-9319-y. [PubMed]
5α-Reductase inhibitors (5α-RIs) such as finasteride and dutasteride have proven useful in the clinical management of lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH) and also in the treatment of androgenetic alopecia (AGA). However, these drugs have serious and, in some patients, persistent or irreversible sexual side effects. These agents interfere with the biosynthesis and metabolism of neurosteroids and may adversely affect mood, stress, and anxiety and potentiate the onset of depression. Data from preclinical and clinical studies have provided substantial evidence that these agents cause loss or reduction of libido, increase the risk of erectile dysfunction and ejaculatory dysfunction, and may contribute to the onset of depression. It is imperative that clinicians give serious considerations to these adverse effects and their impact on patients’ health and engage their patients in an open and honest discussion regarding the potential harm of these agents prior to prescribing them.
Traish AM, et al. The Impact of the 5α-Reductase Inhibitors (5α-RIs) on Male Sexual Function and Psychological Well-Being. Curr Sex Health Rep (2015) 7: 210. https://doi.org/10.1007/s11930-015-0061-y. [Springer Link]
Overview of Sexual Dysfunction (SD) and Suicidal Ideation (SI) Reports: A total of 15,518 adverse event reports were submitted [to the FDA] for low-dose finasteride between 1998 and 2013, corresponding to 4910 reports submitted for men aged 18–45 years. Persistent SD and SI adverse events accounted for 11.8% (577 reports) and 7.9% (39 reports), respectively, of the reports submitted for young men using low-dose finasteride. Approximately 87% (34/39 men) who had experienced SI had also reported SD. Conclusion: Our study suggests that young men receiving low-dose finasteride as a treatment for androgenic alopecia are at risk of persistent SD, and this risk might contribute to SI.
Ali AK, Heran BS, Etminan M. Persistent Sexual Dysfunction and Suicidal Ideation in Young Men Treated with Low-Dose Finasteride: A Pharmacovigilance Study. Pharmacotherapy. 2015 Jul;35(7):687-95. doi: 10.1002/phar.1612. Epub 2015 Jul 1. [PubMed]
Results: Of 34 clinical trials, none had adequate safety reporting, 19 were partially adequate, 12 were inadequate, and 3 reported no adverse events. Funnel plots were asymmetric with a bias toward lower odds ratio for sexual adverse effects, suggesting systematic underdetection. No reports assessed the adequacy of blinding, 18 (53%) disclosed conflicts of interest, and 19 (56%) received funding from the manufacturer. Duration of drug safety evaluation was 1 year or less for 26 of 34 trials (76%). Of 5704 men in the clinical data repository who were treated for AGA with finasteride, 1.25 mg/d or less, for [androgenetic alopecia], only 31% met inclusion criteria for the pivotal trials referenced in the manufacturer’s full prescribing information and 33% took finasteride for more than 1 year. Conclusions and Relevance: Available toxicity information from clinical trials of finasteride in men with AGA is very limited, is of poor quality and seems to be systematically biased. In a cohort of men prescribed finasteride for routine treatment of AGA, most would have been excluded from the pivotal studies that supported US Food and Drug Administration approval for AGA. Published reports of clinical trials provide insufficient information to establish the safety profile for finasteride in the treatment of AGA.
Belknap SM, Aslam I, Kiguradze T, Temps WH, Yarnold PR, Cashy J, Brannigan RE, Micali G, Nardone B, West DP, et al. Adverse Event Reporting in Clinical Trials of Finasteride for Androgenic Alopecia: A Meta-analysis. JAMA Dermatol. 2015 Jun;151(6):600-6. doi: 10.1001/jamadermatol.2015.36. [PubMed]
Recent postmarketing reports and a US Food and Drug Administration analysis have documented uncommon persistent sexual and nonsexual side-effects in a subset of younger men who have taken finasteride 1 mg for androgenic alopecia. While the mechanisms of the sexual side-effects in humans is incompletely understood, one study found lower cerebrospinal fluid concentrations of dihydrotestosterone, progesterone, dihydroprogesterone and allopregnanolone, and higher levels of testosterone, 5α-androstane-3α,17β-diol, and pregnenolone. Another study found up-regulation of the androgen receptor in the human foreskin with a mean of 5 years after finasteride discontinuation.
Irwig MS. Safety concerns regarding 5α reductase inhibitors for the treatment of androgenetic alopecia. Curr Opin Endocrinol Diabetes Obes. 2015 Jun;22(3):248-53. doi: 10.1097/MED.0000000000000158. [PubMed]
Finasteride is a synthetic 5-α reductase inhibitor, which prevents the conversion of testosterone to dihydrotestosterone and has been used for more than 20 years in the treatment of male pattern hair loss. Randomized, controlled trials have associated finasteride with both reversible and persistent adverse effects. In this pilot study, we sought to characterize sexual and nonsexual adverse effects that men reported experiencing at least 3 months after stopping the medication. Based on previous research on persistent side effects of finasteride, we constructed an Internet survey targeting six domains: physical symptoms, sexual libido, ejaculatory disorders, disorders of the penis and testes, cognitive symptoms, and psychological symptoms and was e-mailed to patients who reported experiencing symptoms of side effects of finasteride. Responses from 131 generally healthy men (mean age, 24 years) who had taken finasteride for male pattern hair loss was included in the analysis. The most notable finding was that adverse effects persisted in each of the domains, indicating the possible presence of a “post-finasteride syndrome.”
Ganzer CA, Jacobs AR, Iqbal F, et al. Persistent sexual, emotional, and cognitive impairment post-finasteride: a survey of men reporting symptoms. Am J Mens Health. 2015 May;9(3):222-8. doi: 10.1177/1557988314538445. Epub 2014 Jun 13. [PubMed]
Recent postmarketing studies and the [FDA] have found that finasteride, 1 mg, for androgenic alopecia has been associated with persistent sexual and nonsexual adverse effects. The present study was designed to assess whether otherwise healthy former users of finasteride with persistent sexual adverse effects have a higher prevalence of low serum androgens and spermatogenic deficits.… 3 of 19 participants (16%) [had] severe oligospermia (<5 million/mL). The mean and median motilities were 50% (23%) and 50%, respectively, with 4 of 9 participants (44%) having 2 confirmed low motility.
Irwig MS. Androgen levels and semen parameters among former users of finasteride with persistent sexual adverse effects. JAMA Dermatol. 2014 Dec;150(12):1361-3. doi: 10.1001/jamadermatol.2014.1830. [PubMed]
Finasteride is still one of the most common therapeutic drugs prescribed for AGA, a distinctive alopecia pattern involving hairline recession and vertex balding, a condition more frequent with increasing age… However, treatment of young subjects is of increasing concern due to accumulating evidence that daily use of oral finasteride has several severe adverse effects. Our main finding was the assessment of a significant increase of AR nuclear levels in some types of cells, specifically, stromal and epithelial cells, in dermis samples of foreskin from patients with major sexual adverse side-effects long after use of finasteride (on average almost 5 years later). As our patients are suffering from symptoms suggestive of local androgens deficiency, it was important to assess if this phenomenon was due to intrinsic inability to express and/or translocate the AR into the cell nuclei, specifically in the genital tissues. Since finasteride inhibits T conversion into DHT, which is responsible for most androgen activity, it is plausible that prolonged finasteride use in predisposed individuals could simulate the effects of aging in young men. Since some of the effects of androgen inhibition cannot be reversed once local androgen levels are re-established, it is temping to speculate that patients could still suffer from adverse sexual effects several months or even permanently after finasteride discontinuation because of aging effects caused prematurely by androgens deprivation, namely by artificially reduced DHT concentrations.
Di Loreto C, La Marra F, Mazzon G, Belgrano E, Trombetta C, Cauci S, et al. Immunohistochemical evaluation of androgen receptor and nerve structure density in human prepuce from patients with persistent sexual side effects after finasteride use for androgenetic alopecia. PLoS One. 2014 Jun 24;9(6):e100237. doi: 10.1371/journal.pone.0100237. eCollection 2014. [PubMed]
A substantial body of evidence exists which points to serious and potentially ill-health effects of [finasteride and dutasteride] therapy. These include loss or reduced libido, erectile dysfunction, orgasmic and ejaculatory dysfunction, development of high-grade PCa tumors, potential negative cardiovascular events, and depression. The side effects are potentially harmful in some individuals and in young men may be persistent or irreversible. The argument that the benefits of these drugs outweigh the risks is slowly eroding in the face of new emerging scientific evidence from preclinical and clinical studies. The available data demonstrate that such drugs do pose serious adverse effects, especially in a subset of men who may have the predisposition to be affected severely. This is also corroborated by the overwhelming FDA disapproval of these drugs for the chemoprevention of PCa. The FDA mandated relabeling issued in 2011 equally points to the dark side of these drugs on human health. Physicians need to be aware of the adverse side effects of these drugs and are encouraged to share this information with their patients prior to commencing therapy with finasteride or dutasteride.
Traish MT, Mulgaonkar A, Giordano N, et al. The Dark Side of 5α-Reductase Inhibitors' Therapy: Sexual Dysfunction, High Gleason Grade Prostate Cancer and Depression. Korean J Urol. 2014 Jun; 55(6): 367–379. Published online 2014 Jun 16. doi: 10.4111/kju.2014.55.6.367. [PubMed]
Observations performed in a subset of patients treated for male pattern hair loss indicate that persistent sexual side effects as well as anxious/depressive symptomatology have been reported even after discontinuation of finasteride treatment. Due to the capability of finasteride to block the metabolism of progesterone (PROG) and/or testosterone (T) we have evaluated, by liquid chromatography–tandemmass spectrometry, the levels of several neuroactive steroids in paired plasma and cerebrospinal fluid (CSF) samples obtained from post-finasteride patients and in healthy controls. At the examination, post-finasteride patients reported muscular stiffness, cramps, tremors and chronic fatigue in the absence of clinical evidence of any muscular disorder or strength reduction. Although the severity of the anxious/depressive symptoms was quite variable in their frequency, overall all the subjects had a fairly complex and constant neuropsychiatric pattern. The present observations show that altered levels of neuroactive steroids, associated with depression symptoms, are present in androgenic alopecia patients even after discontinuation of the finasteride treatment.
Caruso D, Abbiati F, Giatti S, Romano S, Fusco L, Cavaletti G, Melcangi RC, et al. Patients treated for male pattern hair with finasteride show, after discontinuation of the drug, altered levels of neuroactive steroids in cerebrospinal fluid and plasma. J Steroid Biochem Mol Biol. 2015 Feb;146:74-9. doi: 10.1016/j.jsbmb.2014.03.012. Epub 2014 Apr 6. [PubMed]
This study significantly extends understanding of the effects of long-term treatment with these drugs on sexual function in men with lower urinary tract symptoms associated with benign prostatic hyperplasia. Treatment with finasteride or combined therapy was associated with worsening sexual function while treatment with doxazosin alone was associated with minimal negative impact if any. Physicians should discuss with their patients the possible long-term effects of these drugs for lower urinary tract symptoms associated with benign prostatic hyperplasia on sexual function.
Fwu CW, Eggers PW, Kirkali Z, McVary KT, Burrows PK, Kusek JW, et al. Change in sexual function in men with lower urinary tract symptoms/benign prostatic hyperplasia associated with long-term treatment with doxazosin, finasteride, and combined therapy. J Urol. 2014 Jun;191(6):1828-34. doi: 10.1016/j.juro.2013.12.014. Epub 2013 Dec 14. [PubMed]
Introduction: Observations performed in a subset of subjects treated with finasteride (an inhibitor of the enzyme 5α-reductase) for male pattern hair loss seem to indicate that sexual dysfunction, as well as anxious/depressive symptomatology, may occur at the end of the treatment and continue after discontinuation.
Aim: A possible hypothesis to explain depression symptoms after finasteride treatment might be impairment in the levels of neuroactive steroids. Therefore, neuroactive steroid levels were evaluated in paired plasma and cerebrospinal fluid samples obtained from male patients who received finasteride for the treatment of androgenic alopecia and who, after drug discontinuation, still show long-term sexual side effects as well as anxious/depressive symptomatology.
Conclusion: The present observations confirm that an impairment of neuroactive steroid levels, associated with depression symptoms, is still present in androgenic alopecia patients treated with finasteride despite the discontinuation of the treatment.
Melcangi RC, Caruso D, Abbiati F, Giatti S, Calabrese D, Piazza F, Cavaletti G, et al. Neuroactive steroid levels are modified in cerebrospinal fluid and plasma of post-finasteride patients showing persistent sexual side effects and anxious/depressive symptomatology. Expert Opin Drug Saf. 2013 Jan;12(1):81-90. doi: 10.1517/14740338.2013.742885. Epub 2012 Nov 22. [PubMed]
Background: There is a robust literature in rodents, but not in humans, on the interaction between finasteride and alcohol, particularly as it relates to neurosteroids. Finasteride has been shown to reduce alcohol intake and suppress alcohol preference in male mice. This study examines the role of finasteride in alcohol consumption in humans with male pattern hair loss.
Results: Of the 63 men who consumed at least 1 alcoholic beverage/wk prior to starting finasteride, 41 (65%) noted a decrease in their alcohol consumption after stopping finasteride. This reduction typically began before discontinuing finasteride. Twenty men (32%) reported no change in their alcohol consumption, and 2 men (3%) reported an increase in their alcohol consumption. For the 63 consumers of alcohol, the mean number (±SE) of alcoholic beverages/wk declined from 5.2 ± 0.7 before finasteride to 2.0 ± 0.3 after finasteride (p < 0.0001). A major study limitation is the lack of a comparison group.
Conclusions: In former male users of finasteride who developed persistent sexual side effects, 65% noticed a decline in their alcohol consumption as compared to baseline. This finding is consistent with finasteride’s ability to modulate alcohol intake in rodents. Further research is needed on the central nervous system effects of finasteride in humans.
Irwig, MS. Decreased alcohol consumption among former male users of finasteride with persistent sexual side effects: a preliminary report. Alcohol Clin Exp Res. 2013 Nov;37(11):1823-6. doi: 10.1111/acer.12177. Epub 2013 Jun 13. [PubMed]
Clinical trials with 5ARI report prevalence rates of de novo erectile dysfunction of 5 - 9%. Decreased circulating dihydrotestosterone (DHT) resulting from 5ARI use is associated with diminished sexual desire and/or orgasm. The presence of adverse sexual effects is associated with decreased self-esteem, quality of life and ability to maintain an intimate relationship. Inhibition of 5ARI additionally influences progesterone and deoxycorticosterone levels and may alter psychological functions, including increased depression, melancholy, and loss of general well being. Ejaculatory dysfunction has not been well studied in patients using 5ARI. Patients receiving therapy with 5ARI should be counseled as to potential sexual and psychological adverse effects. Future clinical studies are needed to further investigate the sexual side effects associated with this class of drugs.
Gur S, Kadowitz PJ, Hellstrom WJ, et al. Effects of 5-alpha reductase inhibitors on erectile function, sexual desire and ejaculation. Expert Opin Drug Saf. 2013 Jan;12(1):81-90. doi: 10.1517/14740338.2013.742885. Epub 2012 Nov 22. [PubMed]
In a group of 54 otherwise healthy former users of finasteride who developed persistent sexual side effects that lasted for at least 3 months, 96% continued to experience these effects when reassessed 9–16 months (mean 14 months) later, raising the possibility of permanent effects. To explain the long-term neurological effects of finasteride, it is possible that reduced concentrations of neuroactive steroids are affecting the plasticity of neuronal architecture in regions of the brain responsible for sexual function. The most volunteered changes related to the urogenital system in terms of semen quality and decreased ejaculate volume, reduction in penis size, penile curvature or reduced sensation, fewer spontaneous erections, decreased the testicular size, testicular pain, and prostatitis. Many subjects also noted changes to their mental abilities, sleeping patterns, and/or depressive symptoms. Many subjects reported a “disconnection” between the mental and physical aspects of sexual function. Further valuable research could determine who would be susceptible to finasteride through genetic studies of polymorphisms of 5a reductase and the androgen receptor. Further research with validated instruments is needed to study the nonsexual persistent side effects associated with finasteride.
Irwig, MS. Persistent sexual side effects of finasteride: could they be permanent? J Sex Med. 2012 Nov;9(11):2927-32. doi: 10.1111/j.1743-6109.2012.02846.x. Epub 2012 Jul 12. [PubMed]
5α-reductases are a family of isozymes that play a critical role in transformation not only of testosterone but also of progesterone, DOC, aldosterone, and cortisol into a host of neuro-active steroids that regulate a multitude of functions in human physiology… the neuro-active steroid hormones modulate a multitude of functions in human physiology encompassing regulation of sexual differentiation, neuroprotection, memory enhancement, anxiety, sleep, and stress, among others. Until recently, the adverse effects of 5α-reductase inhibitor therapy were thought to be very minor and well tolerated. However, new information suggests that these drugs may impair sexual function including sexual desire, erectile and orgasmic function. Recent studies in animal models suggested that these agents alter penile tissue histo-architecture and nitric oxide synthase function in penile tissue and thus can contribute to erectile dysfunction. It is particularly important to note that in a subset of patients, the effects of these drugs are long-lasting and may be irreversible. An association between the use of these inhibitors and depression is also noted, suggesting a potential adverse effect on the brain.
Traish, AM. 5α-reductases in human physiology: an unfolding story. Endocr Pract. 2012 Nov-Dec;18(6):965-75. doi: 10.4158/12108.RA. [PubMed]
In a group of 61 otherwise healthy former users of finasteride who developed persistent sexual side effects, depressive symptoms were present and categorized as mild in 11% of users, moderate in 28% of users, and severe in 36% of users. Suicidal thoughts were present in 39% of former finasteride users, and an additional 5% chose the statement “I would like to kill myself.” The corresponding rates of depressive symptoms and suicidal thoughts were significantly lower in a control group of young men with male pattern hair loss who had not used finasteride and who did not have any current or past psychiatric conditions or use of psychiatric medications. It turns out that finasteride crosses the blood-brain barrier and blocks the enzyme 5α-reductase, which reduces the concentrations of multiple neuroactive steroids derived not only from testosterone but also from progesterone and deoxycorticosterone... reduced concentrations of neuroactive steroids are associated with depression in several human studies. Although the effects of finasteride in the human brain are poorly understood, clinicians, as well as potential finasteride users, should be aware of the serious potential risks of this medication, especially as it is being used cosmetically to alter a normal age-related process. This is the first study to document suicidal thoughts in (former) users of finasteride.
Irwig MS. Depressive symptoms and suicidal thoughts among former users of finasteride with persistent sexual side effects. J Clin Psychiatry. 2012 Sep;73(9):1220-3. doi: 10.4088/JCP.12m07887. Epub 2012 Aug 7. [PubMed]
A subset of otherwise healthy men taking finasteride for MPHL developed persistent sexual side effects in temporal association with the medication. Most men developed sexual dysfunction in multiple domains with 94% experiencing low libido, 92% experiencing erectile dysfunction, 92% experiencing decreased arousal, and 69% experiencing problems with orgasm.... The mean duration of the persistent sexual side effects was at least 40 months, with 20% of subjects reporting durations of over 6 years. The mean number of sexual episodes per month dropped from 25.8 before finasteride to 8.8 after finasteride (P < 0.0001). The total sexual dysfunction score increased from 7.4 to 21.6 for before and after finasteride use (P < 0.0001).... Physicians treating MPHL should discuss the potential risk of persistent sexual side effects associated with finasteride.
Irwig MS, Kolukula S, et al.Persistent sexual side effects of finasteride for male pattern hair loss. J Sex Med. 2011 Jun;8(6):1747-53. doi: 10.1111/j.1743-6109.2011.02255.x. Epub 2011 Mar 18. [PubMed]
5a-RIs therapy, while improving urinary symptoms in patients with BPH and may prevent hair loss, produce significant adverse effects in some individuals including loss of libido, ED, ejaculatory dysfunction, and potential depression. They are serious enough to preclude them from pursuing such therapy.... The effects of these agents on vascular health should also be noted in light of recent findings that patients treated with 5a-RIs therapy had significant adverse cardiovascular events.... These observations suggest that extreme caution should be exercised prior to prescribing 5a-RIs therapy to patients for hair growth or for BPH symptoms.
Traish AM, Hassani J, Guay AT, Zitzmann M, Hansen ML, et al. Adverse side effects of 5α-reductase inhibitors therapy: persistent diminished libido and erectile dysfunction and depression in a subset of patients. J Sex Med. 2011 Mar;8(3):872-84. doi: 10.1111/j.1743-6109.2010.02157.x. Epub 2010 Dec 22. [PubMed]